Fatigue can be described as a lack of energy and motivation (both physical and mental). It is a subjective feeling of tiredness which is distinct from weakness and has a gradual onset. Fatigue is a feeling of tiredness, exhaustion, or lack of energy. You may feel mildly fatigued because of overwork, poor sleep, worry, boredom, or lack of exercise. Fatigue can have physical or mental causes. Physical fatigue is the transient inability of a muscle to maintain optimal physical performance and is made more severe by intense physical exercise. Mental fatigue is a transient decrease in maximal cognitive performance resulting from prolonged periods of cognitive activity.
Fatigue is a subjective feeling of tiredness that has a gradual onset. Unlike weakness, fatigue can be alleviated by periods of rest. Fatigue can have physical or mental causes. Physical fatigue is the transient inability of a muscle to maintain optimal physical performance, and is made more severe by intense physical exercise. Mental fatigue is a transient decrease in maximal cognitive performance resulting from prolonged periods of cognitive activity. It can manifest as somnolence, lethargy, or directed attention fatigue.
Types of Fatigue
There are different types of fatigue.
Physical fatigue: A person finds it physically hard to do the things they normally do or used to do, for example, climbing stairs. It includes muscle weakness. Diagnosis may involve a strength test.
Mental fatigue It is harder to concentrate on things. The person may feel sleepy, have a decreased level of consciousness, and in some cases show signs similar to that of an intoxicated state.
According to the severity, there are two types
Causes of Fatigue
Mental health issues
It can result from stress, bereavement and grief, eating disorders, alcohol abuse, drug abuse, anxiety, moving home, boredom, and divorce. It can occur with clinical depression, either due to the depression itself, or because of associated problems, such as insomnia.
Endocrine and metabolic reasons
Conditions such as Cushing’s disease, kidney disease, electrolyte problems, diabetes, hypothyroidism, anemia, kidney disease, and liver disease can all lead to fatigue.
Drugs and medications
Some antidepressants, antihypertensives, statins, steroids, antihistamines, medication withdrawal, sedatives, and anti-anxiety drugs can cause drowsiness.
Heart and lung conditions
Pneumonia, arrhythmias, asthma, chronic obstructive pulmonary disease (COPD), valvular heart disease, coronary heart disease, and congestive heart failure, among other heart and lung diseases, can cause fatigue.
Working late, shift work, jet lag, sleep apnea, narcolepsy, insomnia, and reflux esophagitis can lead to a lack of sleep and fatigue.
Chemicals and substances
Vitamin deficiencies, mineral deficiencies, poisoning, and consuming too many caffeinated or alcoholic beverages may make it harder to get to sleep, or stay asleep, especially if these are consumed too close to bedtime.
Various diseases, conditions, states, and treatments
Cancer, chemotherapy, radiation therapy, chronic fatigue syndrome (CFS), fibromyalgia, systemic lupus, rheumatoid arthritis, obesity, massive blood loss, and weakened immune systems can all cause fatigue.Fatigue can also be a sign of infection. Some infections that cause tiredness include malaria, tuberculosis (TB), infectious mononucleosis, also known as glandular fever, cytomegalovirus, HIV infection, flu, and hepatitis, among others.
Patients with chronic pain often wake up tired, even after sleeping for a long time, especially if pain disrupts their sleep.The combination of pain and lack of sleep can cause persistent tiredness.
Being overweight or underweight
Being overweight increases the risk of fatigue, for various reasons.These include having to carry more weight, and being more likely to have a condition where fatigue is a common symptom, such as diabetes and sleep apnea.
Too much or too little activity
A person who feels tired may not exercise, and lack of exercise can cause further fatigue. Lack of exercise may eventually make it harder and more tiring to perform a physical chore.
A low thyroid level (hypothyroidism) can cause fatigue, weakness, lethargy, weight gain, depression, memory problems, constipation, dry skin, intolerance to cold, coarse and thinning hair, brittle nails, or a yellowish tint to the skin.A high thyroid level (hyperthyroidism) can cause fatigue, weight loss, increased heart rate, intolerance to heat, sweating, irritability, anxiety, muscle weakness, and thyroid enlargement.
antidepressants; anti-anxiety medications; sedative medications; medication and drug withdrawal; antihistamines; steroids; some blood pressure medications; some antidepressants
Psychiatric (Mental Health)
depression; anxiety; drug abuse; alcohol abuse; Eating disorders (for example; bulimia; anorexia); grief and bereavement
sleep apnea; reflux esophagitis; insomnia; narcolepsy; shift work or work shift changes; pregnancy; Extra night hours at “work”
vitamin B12 deficiency, vitamin D deficiency, folic acid deficiency, iron deficiency
cancer; rheumatology illnesses such as rheumatoid arthritis and systemic lupus; fibromyalgia; chronic fatigue syndrome; normal muscle exertion; obesity; chemotherapyand radiation therapy
Chronic fatigue is a self-reported fatigue lasting at least six consecutive months. Chronic fatigue may be either persistent or relapsing.Chronic fatigue is a symptom of many diseases and conditions. Some major categories of diseases that feature fatigue include:
Chem-7 looks at 7 common substances circulating in the blood. It consists of electrolytes (sodium, potassium, chloride, and bicarbonate), waste products of metabolism cleared by normally functioning kidneys (BUN and creatinine) and the source of energy for the body’s cells (glucose).
Appropriate treatment for the condition can help alleviate fatigue.
Yoga, CBT, and mindfulness for fatigue
Researchers have found, for example, that cognitive behavioral therapy (CBT) combined with graded exercise therapy (GET) can be an effective treatment for myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS).
Another study found that symptoms of fatigue and depression fell in patients with multiple sclerosis(MS) who underwent mindfulness meditation training.
Yoga has been found to improve symptoms of fatigue and sleep quality in cancer survivors. The 4-week program included postures, meditation, breathing, and some other techniques.
It is important not to drive while sleepy. A survey carried out by the CDC found that around 1 in 25 drivers aged 18 years and above had fallen asleep while driving in the previous 30 days.
Lifestyle-related causes of fatigue
Common lifestyle factors that can cause fatigue include
Lack of sleep – typically adults need about eight hours of sleep each night. Some people try to get by on fewer hours of sleep.
Too much sleep – adults sleeping more than 11 hours per night can lead to excessive daytime sleepiness.
Alcohol and drugs – alcohol is a depressant drug that slows the nervous system and disturbs normal sleep patterns. Other drugs, such as cigarettes and caffeine, stimulate the nervous system and can cause insomnia.
Sleep disturbances – disturbed sleep may occur for a number of reasons, for example, noisy neighbors, young children who wake in the night, a snoring partner, or an uncomfortable sleeping environment such as a stuffy bedroom.
Lack of regular exercise and sedentary behavior – physical activity is known to improve fitness, health, and wellbeing, reduce stress, and boost energy levels. It also helps you sleep.
Poor diet – low kilojoule diets, low carbohydrate diets or high energy foods that are nutritionally poor don’t provide the body with enough fuel or nutrients to function at its best. Quick fix foods, such as chocolate bars or caffeinated drinks, only offer a temporary energy boost that quickly wears off and worsens fatigue.
Individual factors – personal illness or injury, illnesses or injuries in the family, too many commitments (for example, working two jobs) or financial problems can cause fatigue.
Shift work – the human body is designed to sleep during the night. This pattern is set by a small part of the brain known as the circadian clock. A shift worker confuses their circadian clock by working when their body is programmed to be asleep.
Poor workplace practices – can add to a person’s level of fatigue. These may include long work hours, hard physical labour, irregular working hours (such as rotating shifts), a stressful work environment (such as excessive noise or temperature extremes), boredom, working alone with little or no interaction with others, or fixed concentration on a repetitive task.
Workplace stress – can be caused by a wide range of factors including job dissatisfaction, heavy workload, conflicts with bosses or colleagues, bullying, constant change, or threats to job security.
Burnout – can be described as striving too hard in one area of life while neglecting everything else. ‘Workaholics’, for example, put all their energies into their career, which puts their family life, social life and personal interests out of balance.
Unemployment – financial pressures, feelings of failure or guilt, and the emotional exhaustion of prolonged job hunting can lead to stress, anxiety, depression, and fatigue.
Ultrasound (also known as diagnostic sonography or ultrasonography) is a diagnostic imaging technique based on the application of ultrasound. It is used to see internal body structures such as tendons, muscles, joints, blood vessels, and internal organs. Its aim is often to find a source of a disease or to exclude any pathology. The practice of examining pregnant women using ultrasound is called obstetric ultrasound and is widely used. Ultrasound is sound waves with frequencies which are higher than those audible to humans (>20,000 Hz). Ultrasonic images, also known as sonograms, are made by sending pulses of ultrasound into tissue using a probe. The sound echoes off the tissue; with different tissues reflecting varying degrees of sound. These echoes are recorded and displayed as an image to the operator.
Types of Ultrasound
Most ultrasounds are done using a transducer on the surface of the skin. Sometimes, however, doctors and technicians can get a better diagnostic image by inserting a special transducer into one of the body’s natural openings:
In a transvaginal ultrasound, a transducer wand is placed in a woman’s vagina to get better images of her uterus and ovaries.
A transrectal ultrasound is sometimes used in the diagnosis of prostate conditions.
A transesophageal echocardiogram uses the transducer probe in the esophagus so that the sonographer can obtain clearer images of the heart.
Additionally, ultrasound technology has advanced to allow for different types of imaging:
Doppler is a special type of ultrasound that creates images of blood flow through vessels.
Bone sonography helps doctors diagnose osteoporosis.
Echocardiograms are used to view the heart.
3D imaging adds another dimension to the ultrasound image, creating three-dimensional interpretations rather than the flat two-dimensional images that are made with traditional ultrasound.
4D ultrasounds show 3D images in motion.
According to the imaging types of Ultrasound
The twelve major types of ultrasound procedures described in other articles, make use of four kinds of the available ultrasound image. The choice of which type of image to use depends on the goals for a particular test, the phenomena being investigated and what equipment is available.
The most common and type of ultrasound picture is a series of flat, two-dimensional cross-section images of the scanned tissue. Referred to simply as 2d ultrasound, this mode of scanning is still standard for many diagnostic and obstetric situations after a half-century of use.
In recent years, 2d ultrasound images have also been projected into three-dimensional representations. This is achieved by scanning tissue cross sections at many different angles and reconstructing the data received into a three-dimensional image. A common use for 3d ultrasound pictures is to provide a more complete and realistic image of a developing fetus.
4D Ultrasound Imaging
By updating 3d ultrasound images in rapid succession, sonographers can also create 4d ultrasound pictures. In the 4d ultrasound, the fourth dimension, time, adds movement and creates the most realistic representation of all.
Evaluating blood flow as it moves through blood vessels is a common component of many of the types of ultrasound. While traditional 2d ultrasound and its three-dimensional offshoot show internal tissues and structures, a different kind of ultrasound is required to evaluate blood flow and pressure within a blood vessel.
Doppler ultrasonography employs the Doppler effect to assess whether structures (usually blood) are moving towards or away from the probe, and its relative velocity. By calculating the frequency shift of a particular sample volume, for example, flow in an artery or a jet of blood flow over a heart valve, its speed and direction can be determined and visualized.
Color Doppler is the measurement of velocity by a color scale. Color Doppler images are generally combined with grayscale (B-mode) images to display duplex ultrasonography images. Uses include
Doppler echocardiography– the use of Doppler ultrasonography to examine the heart. An echocardiogram can, within certain limits, produce an accurate assessment of the direction of blood flow and the velocity of blood and cardiac tissue at any arbitrary point using the Doppler effect. Velocity measurements allow assessment of cardiac valve areas and function, any abnormal communications between the left and right side of the heart, any leaking of blood through the valves (valvular regurgitation), calculation of the cardiac output and calculation of E/A ratio (a measure of diastolic dysfunction). Contrast-enhanced ultrasound using gas-filled microbubble contrast media can be used to improve velocity or other flow-related medical measurements.
Transcranial Doppler (TCD) and transcranial color Doppler (TCCD)– which measure the velocity of blood flow through the brain’s blood vessels transcranially (through the cranium). They are used as tests to help diagnose emboli, stenosis, vasospasm from a subarachnoid hemorrhage (bleeding from a ruptured aneurysm), and other problems.
Doppler fetal monitors– although usually not technically -graph but rather sound-generating, use the Doppler effect to detect the fetal heartbeat for prenatal care. These are hand-held, and some models also display the heart rate in beats per minute (BPM). Use of this monitor is sometimes known as Doppler auscultation. The Doppler fetal monitor is commonly referred to simply as a Doppler or fetal Doppler. Doppler fetal monitors provide information about the fetus similar to that provided by a fetal stethoscope.
According to the Body Position of Ultrasound
Abdominal Ultrasound Imaging
An abdominal ultrasound is a useful way of examining internal organs, including the liver, gallbladder, spleen, pancreas, kidneys, and bladder. Because US images are captured in real time, they can show the movement of internal tissues and organs and enable physicians to see blood flow. This can help to diagnose a variety of conditions and to assess the damage caused by illness.
Carotid and Abdominal Aorta Ultrasound Imaging
Ultrasound of the carotid arterial system provides a fast, noninvasive means of identifying blockages of blood flow in the neck arteries to the brain that might produce a stroke or mini-stroke. Ultrasound of the abdominal aorta is primarily used to evaluate for an aneurysm which is an abnormal enlargement of the aorta usually from atherosclerotic disease.
Obstetric Ultrasound Imaging
Obstetric ultrasound refers to the specialized use of sound waves to visualize and thus determine the condition of a pregnant woman and her embryo or fetus.
Obstetric ultrasound should be performed only when clinically indicated.
The prostate gland is located directly in front of the rectum, so the ultrasound exam is performed transrectally. A protective cover is placed over the transducer, lubricated, and then placed into the rectum so the sound need only travel a short distance. The images are obtained from different orientations to get the best view of the prostate gland. Ultrasound of the prostate is most often performed with the patient lying with his left side down on the table and with his knees bent up slightly toward the chest.
For the transabdominal approach, the patient has a full urinary bladder and is positioned on an examination table. A clear gel is applied to the lower abdomen to help the transducer make secure contact with the skin. The sound waves produced by the transducer cannot penetrate air, so the gel helps to eliminate air pockets between the transducer and the skin. With transabdominal ultrasound, you will lie on your back on an examining table. The sonographer will spread some gel on your skin and then presses the transducer firmly against the skin and sweeps it back and forth to image the pelvic organs. Doppler sonography can be performed through the same transducer. There may be varying degrees of discomfort from pressure as the transducer is moved over your abdomen, especially if you are required to have a full bladder.
Transvaginal ultrasound involves the insertion of the transducer into the vagina after the patient empties her bladder and is performed very much like a gynecologic exam. The tip of the transducer is smaller than the standard speculum used when performing a Pap test. A protective cover is placed over the transducer, lubricated with a small amount of gel, and then inserted into the vagina. Only two to three inches of the transducer end is inserted into the vagina.
Pelvic Ultrasound Imaging
Pelvic ultrasound is most often used to examine the uterus and ovaries and, during pregnancy, to monitor the health and development of the embryo or fetus. In men, a pelvic ultrasound usually focuses on the bladder and the prostate gland.
Millions of expectant parents have seen the first “picture” of their unborn child thanks to pelvic ultrasound examinations of the uterus and fetus (see the Ultrasound-Obstetric page).
What are some common uses of the procedure?
Ultrasound examinations can help to diagnose a variety of conditions and to assess organ damage following an illness.
Ultrasound is used to help physicians evaluate symptoms such as
Ultrasound is a useful way of examining many of the body’s internal organs, including but not limited to the
Heart and blood vessels, including the abdominal aorta and its major branches
Uterus, ovaries, and unborn child (fetus) in pregnant patients
Thyroid and parathyroid glands
Brain in infants
Hips in infants
Spine in infants
Ultrasound is also used to
Guide procedures such as needle biopsies, in which needles are used to sample cells from an abnormal area for laboratory testing.
Image the breasts and guide biopsy of breast cancer (see the Ultrasound-Guided Breast Biopsy page.
Diagnose a variety of heart conditions, including valve problems and congestive heart failure, and to assess damage after a heart attack. Ultrasound of the heart is commonly called an “echocardiogram” or “echo” for short.
Doppler ultrasound images can help the physician to see and evaluate
Blockages to blood flow (such as clots
Narrowing of vessels
Tumors and congenital vascular malformations
Reduced or absent blood flow to various organs
Greater than normal blood flow to different areas, which is sometimes seen in infections
With knowledge about the speed and volume of blood flow gained from a Doppler ultrasound image, the physician can often determine whether a patient is a good candidate for a procedure like angioplasty..
An ultrasound exam may be performed throughout pregnancy for the following medically-necessary reasons
Confirm viable pregnancy
Measure the crown-rump length or gestational age
Confirm molar or ectopic pregnancies
Assess abnormal gestation
Diagnose fetal malformation
Weeks 13-14 for characteristics of potential Down syndrome
Weeks 18-20 for congenital malformations
Confirm multiples pregnancy
Verify dates and growth
Confirm intrauterine death
Identify hydramnios or oligohydramnios – excessive or reduced levels of amniotic fluid
Evaluation of fetal well-being
Identify placental location
Confirm intrauterine death
Observe fetal presentation
Observe fetal movements
Identify uterine and pelvic abnormalities of the mother
Modes of Ultrasound
Several modes of ultrasound are used in medical imaging These are
A-mode – A-mode (amplitude mode) is the simplest type of ultrasound. A single transducer scans a line through the body with the echoes plotted on screen as a function of depth. Therapeutic ultrasound aimed at a specific tumor or calculus is also A-mode, to allow for the pinpoint accurate focus of the destructive wave energy.
B-mode or 2D mode – In B-mode (brightness mode) ultrasound, a linear array of transducers simultaneously scans a plane through the body that can be viewed as a two-dimensional image on the screen. More commonly known as 2D mode now.
B-flow image of venous reflux. Video is available
B-flow – is a mode that digitally highlights weak flow reflectors (mainly red blood cells) while suppressing the signals from the surrounding stationary tissue. It can visualize flowing blood and surrounding stationary tissues simultaneously.
C-mode – A C-mode image is formed in a plane normal to a B-mode image. A gate that selects data from a specific depth from an A-mode line is used; then the transducer is moved in the 2D plane to sample the entire region at this fixed depth. When the transducer traverses the area in a spiral, an area of 100 cm2 can be scanned in around 10 seconds.
M-mode – In M-mode (motion mode) ultrasound, pulses are emitted in quick succession – each time, either an A-mode or B-mode image is taken. Over time, this is analogous to recording a video in ultrasound. As the organ boundaries that produce reflections move relative to the probe, this can be used to determine the velocity of specific organ structures.
Doppler mode – This mode makes use of the Doppler effect in measuring and visualizing blood flow
Color Doppler – Velocity information is presented as a color-coded overlay on top of a B-mode image
Continuous wave (CW) Doppler – Doppler information is sampled along a line through the body, and all velocities detected at each time point are presented (on a timeline)
Pulsed wave (PW) Doppler – Doppler information is sampled from only a small sample volume (defined in the 2D image), and presented on a timeline
Duplex – a common name for the simultaneous presentation of 2D and (usually) PW Doppler information. (Using modern ultrasound machines, color Doppler is almost always also used; hence the alternative name
Pulse inversion mode – In this mode, two successive pulses with opposite sign are emitted and then subtracted from each other. This implies that any linearly responding constituent will disappear while gases with non-linear compressibility stand out. Pulse inversion may also be used in a similar manner as in
Harmonic mode – In this mode, a deep penetrating fundamental frequency is emitted into the body and a harmonic overtone is detected. This way noise and artifacts due to reverberation and aberration are greatly reduced. Some also believe that penetration depth can be gained with improved lateral resolution; however, this is not well documented.
A contrast medium for medical ultrasonography is a formulation of encapsulated gaseous microbubbles to increase echogenicity of blood, discovered by Dr. Raymond Gramiak in 1968 and named contrast-enhanced ultrasound. This contrast medical imaging modality is clinically used throughout the world, in particular for echocardiography in the United States.
Microbubbles-based contrast media is administrated intravenously inpatient bloodstream during the medical ultrasonography examination. The microbubbles being too large in diameter, they stay confined in blood vessels and cannot extravasate towards the interstitial fluid. An ultrasound contrast media is therefore purely intravascular, making it an ideal agent to image organ microvascularization for diagnostic purposes. A typical clinical use of contrast ultrasonography is the detection of a hypervascular metastatic tumor, which exhibits a contrast uptake (kinetics of microbubbles concentration in blood circulation) faster than healthy biological tissue surrounding the tumor. Other clinical applications using contrast exist, such as in echocardiography to improve delineation of left ventricle for visually checking contractibility of heart after a myocardial infarction. Finally, applications in quantitative perfusion .(relative measurement of blood flow ) emerge for identifying early patient response to an anti-cancerous drug treatment (methodology and clinical study by Dr Nathalie Lassau in 2011), enabling to determine the best oncological therapeutic options.
In the oncological practice of medical contrast ultrasonography, clinicians use the method of parametric imaging of vascular signatures invented by Dr Nicolas Rognin in 2010. This method is conceived as cancer aided diagnostic tool, facilitating characterization of a suspicious tumor (malignant versus benign) in an organ. This method is based on medical computational science to analyze a time sequence of ultrasound contrast images, a digital video recorded in real-time during a patient examination. Two consecutive signal processing steps are applied to each pixel of the tumor
calculation of a vascular signature (contrast uptake difference with respect to healthy tissue surrounding the tumor);
Automatic classification of the vascular signature into a unique parameter, this last coded in one of the four following colors:
green for continuous hyper-enhancement (contrast uptake higher than healthy tissue one),
blue for continuous hypo-enhancement (contrast uptake lower than healthy tissue one),
red for fast hyper-enhancement (contrast uptake before healthy tissue one) or
yellow for fast hypo-enhancement (contrast uptake after healthy tissue one).
Once signal processing in each pixel completed, a color spatial map of the parameter is displayed on a computer monitor, summarizing all vascular information of the tumor in a single image called parametric image (see the last figure of press article as clinical examples). This parametric image is interpreted by clinicians based on predominant colorization of the tumor: red indicates a suspicion of malignancy (risk of cancer), green or yellow – a high probability of benignity. In the first case (suspicion of a malignant tumor), the clinician typically prescribes a biopsy to confirm the diagnostic or a CT scan examination as a second opinion. In the second case (quasi-certain of benign tumor), only a follow-up is needed with a contrast ultrasonography examination a few months later. The main clinical benefits are to avoid a systematic biopsy (a risky invasive procedure) of benign tumors or a CT scan examination exposing the patient to X-ray radiation. The parametric imaging of vascular signatures method proved to be effective in humans for characterization of tumors in the liver. In a cancer screening context, this method might be potentially applicable to other organs such as breast or prostate.
The future of contrast ultrasonography is in molecular imaging with potential clinical applications expected in cancer screening to detect malignant tumors at their earliest stage of appearance. Molecular ultrasonography (or ultrasound molecular imaging) uses targeted microbubbles originally designed by Dr. Alexander Klibanov in 1997; such targeted microbubbles specifically bind or adhere to tumoral microvessels by targeting biomolecular cancer expression (overexpression of certain biomolecules occurs during neo-angiogenesis or inflammation processes in malignant tumors). As a result, a few minutes after their injection in blood circulation, the targeted microbubbles accumulate in the malignant tumor; facilitating its localization in a unique ultrasound contrast image. In 2013, the very first exploratory clinical trial in humans for prostate cancer was completed at Amsterdam in the Netherlands by Dr Hessel Wijkstra.
In molecular ultrasonography, the technique of acoustic radiation force (also used for shear wave elastography) is applied in order to literally push the targeted microbubbles towards microvessels wall; firstly demonstrated by Dr Paul Dayton in 1999. This allows maximization of binding to the malignant tumor; the targeted microbubbles being in more direct contact with cancerous biomolecules expressed at the inner surface of tumoral microvessels. At the stage of scientific preclinical research, the technique of acoustic radiation force was implemented as a prototype in clinical ultrasound systems and validated in vivo in 2D and 3D imaging modes.
Elastography (Ultrasound Elasticity Imaging)
Ultrasound is also used for elastography, which is a relatively new imaging modality that maps the elastic properties of soft tissue. This modality emerged in the last two decades. Elastography is useful in medical diagnoses as it can discern healthy from unhealthy tissue for specific organs/growths. For example, cancerous tumors will often be harder than the surrounding tissue, and diseased livers are stiffer than healthy ones. There are many ultrasound elastography techniques.
Interventional ultrasonography involves a biopsy, emptying fluids, intrauterine Blood transfusion (Hemolytic disease of the newborn).
Thyroid cysts – The high-frequency thyroid ultrasound (HFUS) can be used to treat several gland conditions. The recurrent thyroid cyst that was usually treated in the past with surgery, can be treated effectively by a new procedure called percutaneous ethanol injection, or PEI. With the ultrasound-guided placement of a 25 gauge needle within the cyst, and after the evacuation of the cyst fluid, about 50% of the cyst volume is injected back into the cavity, under strict operator visualization of the needle tip. The procedure is 80% successful in reducing the cyst to minute size.
Metastatic thyroid cancer neck lymph nodes – The other thyroid therapy use for HFUS is to treat metastatic thyroid cancer neck lymph nodes that occur in patients who either refuse surgery or are no longer a candidate for surgery. Small amounts of ethanol are injected under ultrasound guided needle placement. A blood flow study is done prior to the injection, by power Doppler. The blood flow can be destroyed and the node becomes inactive, although it may still be there. Power Doppler visualized blood flow can be eradicated, and there may be a drop in the cancer blood marker test, thyroglobulin, TG, as the node become non-functional. Another interventional use for HFUS is to mark a cancer node one hour prior to surgery to help locate the node cluster at the surgery. A minute amount of methylene dye is injected, under careful ultrasound-guided placement of the needle on the anterior surface, but not in the node. The dye will be evident to the thyroid surgeon when he opens the neck. A similar localization procedure with methylene blue can be done to locate parathyroid adenomas at surgery.
Medical Uses of Ultrasound
Relatively high power ultrasound can break up stony deposits or tissue, accelerate the effect of drugs in a targeted area, assist in the measurement of the elastic properties of tissue, and can be used to sort cells or small particles for research.
Focused high-energy ultrasound pulses can be used to break calculi such as kidney stones and gallstones into fragments small enough to be passed from the body without undue difficulty, a process known as lithotripsy.
Cleaning teeth in dental hygiene.
Focused ultrasound sources may be used for cataract treatment by phacoemulsification.
Ultrasound can ablate tumors or other tissue non-invasively. This is accomplished using a technique known as High-Intensity Focused Ultrasound (HIFU), also called focused ultrasound surgery (FUS surgery). This procedure uses generally lower frequencies than medical diagnostic ultrasound (250–2000 kHz), but significantly higher time-averaged intensities. The treatment is often guided by Magnetic Resonance Imaging (MRI); the combination is then referred to as Magnetic resonance-guided focused ultrasound (MRgFUS).
Enhanced drug uptake using acoustic targeted drug delivery(ATDD).
Delivering chemotherapy to brain cancer cells and various drugs to other tissues is called acoustic targeted drug delivery (ATDD). These procedures generally use high-frequency ultrasound (1–10 MHz) and a range of intensities (0–20 W/cm2). The acoustic energy is focused on the tissue of interest to agitate its matrix and make it more permeable for therapeutic drugs.
Ultrasound has been used to trigger the release of anti-cancer drugs from delivery vectors including liposomes, polymeric microspheres and self-assembled polymeric.
Ultrasound is essential to the procedures of ultrasound-guided sclerotherapy and endovenous laser treatment for the non-surgical treatment of varicose veins.
Ultrasound-assisted lipectomy is Liposuction assisted by ultrasound.
There are three potential effects of ultrasound. The first is the increase in blood flow in the treated area. The second is the decrease in pain from the reduction of swelling and edema. The third is the gentle massage of muscle tendons and/ or ligaments in the treated area because no strain is added and any scar tissue is softened. These three benefits are achieved by two main effects of therapeutic ultrasound. The two types of effects are – thermal and nonthermal effects. Thermal effects are due to the absorption of the sound waves. Nonthermal effects are from cavitation, microstreaming and acoustic streaming.
Cavitational effects result from the vibration of the tissue causing microscopic bubbles to form, which transmit the vibrations in a way that directly stimulates cell membranes. This physical stimulation appears to enhance the cell-repair effects of the inflammatory response.
The effectiveness of therapeutic ultrasound for pain, musculoskeletal injuries, and soft tissue lesions remains questionable. A 2017 meta-analysis of randomized controlled trials concluded that there is no benefit of low-intensity pulsed ultrasound on bone healing. An associated guideline published in the British Medical Journal recommends against the use of ultrasound for bone healing.
Risks and side-effects
Ultrasonography is generally considered safe imaging, with the World Health Organizations saying”Diagnostic ultrasound is recognized as a safe, effective, and highly flexible imaging modality capable of providing clinically relevant information about most parts of the body in a rapid and cost-effective fashion”.
Diagnostic ultrasound studies of the fetus are generally considered to be safe during pregnancy. This diagnostic procedure should be performed only when there is a valid medical indication, and the lowest possible ultrasonic exposure setting should be used to gain the necessary diagnostic information under the “as low as reasonably practicable” or ALARP principle.
However, medical ultrasonography should not be performed without a medical indication to perform it. To do otherwise would be to perform unnecessary health care to patients, which bring unwarranted costs and may lead to another testing. Overuse of ultrasonography is sometimes as routine as screening for deep vein thrombosis after orthopedic surgeries in patients who are not at heightened risk for having that condition.
Similarly, although there is no evidence ultrasound could be harmful to the fetus, medical authorities typically strongly discourage the promotion, selling, or leasing of ultrasound equipment for making “keepsake fetal videos”.
Studies on the safety of ultrasound
A meta-analysis of several ultrasonography studies published in 2000 found no statistically significant harmful effects from ultrasonography but mentioned that there was a lack of data on long-term substantive outcomes such as neurodevelopment.
A study at the Yale School of Medicine published in 2006 found a small but significant correlation between prolonged and frequent use of ultrasound and abnormal neuronal migration in mice.
A study performed in Sweden in 2001 has shown that subtle effects of neurological damage linked to ultrasound were implicated by an increased incidence in left-handedness in boys (a marker for brain problems when not hereditary) and speech delays.
The above findings, however, were not confirmed in a later follow-up study.
A later study, however, performed on a larger sample of 8865 children, has established a statistically significant, albeit weak association of ultrasonography exposure and being non-right handed later in life.
Sciatica Pain Pregabalin is ineffective. The nerve pain drug pregabalin is not an effective treatment for sciatica and is associated with a significant number of side effects, researchers have concluded.
The Australian research team carrying out the study says that while it is difficult to know how many patients with sciatica are prescribed the drug, its use is growing year on year.
Previous research looking at pregabalin in sciatica had been inconclusive, so the team carried out an eight-week, double-blind, randomised controlled trial in just over 200 patients.
After the two-month study, there was no difference in leg pain as measured on a ten-point scale in patients who had taken the drug or placebo, the researchers report in The New England Journal of Medicine(online, 23 March 2017).
Over one year of follow-up, the researchers also assessed extent of disability, back-pain intensity and quality-of-life measures and found no difference between the two groups.
But 227 adverse events were reported by patients taking pregabalin compared with 124 in the placebo group, with dizziness being the most common complaint.
Those taking part had been suffering from at least moderate pain from sciatica from between one week and one year before starting the trial.
Study leader Christine Lin, senior research fellow in medicine at The George Institute for Global Health, University of Sydney, says sciatica is commonly caused by the irritation of nerve routes in the lower back.
She adds that while pregabalin had shown to be effective in other nerve pain conditions, she wasn’t completely surprised that it was ineffective in sciatica because other evidence to date had been unconvincing.
“Taking pregabalin is no better than taking placebo in patients with sciatica, but will likely give patients more side effects, for example dizziness. Based on that, we do not recommend the use of pregabalin in people with sciatica,” she says.
Lin adds: “Unfortunately, it is not exactly clear what helps people with sciatica. We have no clear evidence that medicines such as anti-inflammatories, oral steroids and opioids are effective for sciatica. Corticosteroid injections have a small and short-term treatment effect.”
But she says most patients with sciatica do improve even though the pain can initially be quite severe.
“It is important that the patients are reassured of the fact that sciatica will get better with time.
“Patients should also be advised to stay as active as possible and to avoid prolonged bed rest.”
Lin also says that anyone taking pregabalin for sciatica should not stop taking it but see their doctor for advice because they may need to come off gradually.
Roger Knaggs, associate professor in clinical pharmacy practice at the University of Nottingham and an expert in pain management, says the results are disappointing for patients with acute sciatica but not surprising.
He echoes Lin’s advice that many symptoms will resolve, usually over 8–12 weeks, and that patients should keep active.
“All medicines should be used to promote activity and it is clear that side effects for patients taking pregabalin in this study were a major barrier to this.”
Gastrointestinal Disorders refer to diseases involving the gastrointestinal tract, namely the esophagus, stomach, small intestine, large intestine and rectum, and the accessory organs of digestion, the liver, gallbladder, and pancreas.
Gastrointestinal disorders such as chronic or acute diarrhea, malabsorption, abdominal pain, and inflammatory bowel diseases can indicate immune deficiency. The gastrointestinal tract is the largest lymphoid organ in the body, so it is not surprising that intestinal diseases are common among immunodeficient patients. Gastroenterologists, therefore, must be able to diagnose and treat patients with primary immunodeficiency. Immune-related gastrointestinal diseases can be classified as those that develop primarily via autoimmunity, infection, an inflammatory response, or malignancy. Immunodeficient and immunocompetent patients with gastrointestinal diseases present with similar symptoms. However, intestinal biopsy specimens from immunodeficient patients often have distinct histologic features, and these patients often fail to respond to conventional therapies. Therefore, early recognition of symptoms and referral to an immunologist for a basic immune evaluation is required to select appropriate treatments. Therapies for primary immunodeficiency comprise immunoglobulin replacement, antibiotics, and, in severe cases, bone marrow transplantation. Treatment of immunodeficient patients with concomitant gastrointestinal disease can be challenging, and therapy with immunomodulators often is required for severe disease. This review aims to guide gastroenterologists in the diagnosis and treatment of patients with primary immunodeficiency.
Clinical utility of agonists and antagonists associated with 5-HT metabolism in gastrointestinal disorders
Potential and documented clinical utility
FD; IBS; GERD
IBS-D (women only)
GERD; constipation-predominant IBS
IBS-D; FD; nocturnal GERD; chemotherapy-induced nausea and vomiting; radiation induced nausea and vomiting; post-operative vomiting
Table adapted from references 58,79,80,81,82,83,84,85,86 as well as company websites and FDA.gov.
Types of Gastrointestinal Disorders
Even though anatomically part of the GI tract, diseases of the mouth are often not considered alongside other gastrointestinal diseases. By far the most common oral conditions are plaque-induced diseases (e.g. gingivitis, periodontitis, dental caries). Some diseases which involve other parts of the GI tract can manifest in the mouth, alone or in combination, including:
Gastroesophageal reflux disease can cause acid erosion of the teeth and halitosis.
Gardner’s syndrome can be associated with failure of tooth eruption, supernumerary teeth, and dentigerous cysts.
Peutz–Jeghers syndrome can cause dark spots on the oral mucosa or on the lips or the skin around the mouth.
Several GI diseases, especially those associated with malabsorption, can cause recurrent mouth ulcers, atrophic glossitis, and angular cheilitis (e.g. Crohn’s disease is sometimes termed orofacial granulomatosis when it involves the mouth alone).
Sideropenic dysphagia can cause glossitis, angular cheilitis.
Oesophageal diseases include a spectrum of disorders affecting the oesophagus. The most common condition of the oesophagus in Western countries is gastroesophageal reflux disease,which in chronic forms is thought to result in changes to the epithelium of the oesophagus, known as Barrett’s oesophagus.
Acute disease might include infections such as oesophagitis, trauma caused ingestion of corrosive substances, or rupture of veins such as oesophageal varices, Boerhaave syndrome or Mallory-Weiss tears. Chronic diseases might include congenital diseases such as Zenker’s diverticulum and esophageal webbing, and oesophageal motility disorders including the nutcracker oesophagus, achalasia, diffuse oesophageal spasm, and oesophageal stricture.
Oesophageal disease may result in a sore throat, throwing up blood, difficulty swallowing or vomiting. Chronic or congenital diseases might be investigated using barium swallows, endoscopy and biopsy, whereas acute diseases such as reflux may be investigated and diagnosed based on symptoms and a medical history alone.
Gastric diseases refer to diseases affecting the stomach. Inflammation of the stomach by infection from any cause is called gastritis, and when including other parts of the gastrointestinal tract called gastroenteritis. When gastritis persists in a chronic state, it is associated with several diseases, including atrophic gastritis, pyloric stenosis, and gastric cancer. Another common condition is gastric ulceration, peptic ulcers. Ulceration erodes the gastric mucosa, which protects the tissue of the stomach from the stomach acids. Peptic ulcers are most commonly caused by a bacterial
As well as peptic ulcers, vomiting blood may result from abnormal arteries or veins that have ruptured, including Dieulafoy’s lesion and Gastric antral vascular ectasia. Congenital disorders of the stomach include pernicious anaemia, in which a targeted immune response against parietal cells results in an inability to absorb vitamin B12. Other common symptoms that stomach disease might cause include indigestion or dyspepsia, vomiting, and in chronic disease, digestive problems leading to forms of malnutrition. In addition to routine tests, an endoscopy might be used to examine or take a biopsy from the stomach.
The small and large intestines may be affected by infectious, autoimmune, and physiological states. Inflammation of the intestines is called enterocolitis, which may lead to diarrhoea.
Acute conditions affecting the bowels include infectious diarrhoea and mesenteric ischaemia. Causes of constipation may include faecal impaction and bowel obstruction, which may in turn be caused by ileus, intussusception, volvulus. Inflammatory bowel disease is a condition of unknown aetiology, classified as either Crohn’s disease or ulcerative colitis, that can affect the intestines and other parts of the gastrointestinal tract. Other causes of illness include intestinal pseudoobstruction, and necrotizing enterocolitis.
Diseases of the intestine may cause vomiting, diarrhoea or constipation, and altered stool, such as with blood in stool. Colonoscopy may be used to examine the large intestine, and a person’s stool may be sent for culture and microscopy. Infectious disease may be treated with targeted antibiotics, and inflammatory bowel disease with immunosuppression. Surgery may also be used to treat some causes of bowel obstruction,
The small intestine consists of the duodenum, jejunum and ileum. Inflammation of the small intestine is called enteritis, which if localised to just part is called duodenitis, jejunitis and ileitis, respectively. Peptic ulcers are also common in the duodenum.
Chronic diseases of malabsorption may affect the small intestine, including the autoimmune coeliac disease, infective Tropical sprue, and congenital or surgical short bowel syndrome. Other rarer diseases affecting the small intestine include Curling’s ulcer, blind loop syndrome, Milroy disease and Whipple’s disease. Tumours of the small intestine include gastrointestinal stromal tumours, lipomas, hamartomas and carcinoid syndromes.
Diseases of the small intestine may present with symptoms such as diarrhoea, malnutrition, fatigue and weight loss. Investigations pursued may include blood tests to monitor nutrition, such as iron levels, folate and calcium, endoscopy and biopsy of the duodenum, and barium swallow. Treatments may include renutrition, and antibiotics for infections.
Diseases that affect the large intestine may affect it in whole or in part. Appendicitis is one such disease, caused by inflammation of the appendix. Generalised inflammation of the large intestine is referred to as colitis, which when caused be the bacteria Clostridium difficile is referred to as pseudomembranous colitis. Diverticulitis is a common cause of abdominal pain resulting from outpouchings that particularly affects the colon. Functional colonic diseases refer to disorders without a known cause, and include irritable bowel syndrome and intestinal pseudoobstruction. Constipation may result from lifestyle factors, impaction of a rigid stool in the rectum, or in neonates, Hirschprung’s disease.
Diseases affecting the large intestine may cause blood to be passed with stool, may cause constipation, or may result in abdominal pain or a fever. Tests that specifically examine the function of the large intestine include barium swallows, abdominal x-rays, and colonoscopy.
Rectum and anus
Diseases affecting the rectum and anus are extremely common, especially in older adults. Hemorrhoids, vascular outpouchings of skin, are very common, as is pruritus ani, referring to anal itchiness. Other conditions, such as anal cancer may be associated with ulcerative colitis or with sexually transmitted infections such as HIV. Inflammation of the rectum is known as proctitis, one cause of which is radiation damage associated with radiotherapy to other sites such as the prostate. Faecal incontinence can result from mechanical and neurological problems, and when associated with a lack of voluntary voiding ability is described as encopresis. Pain on passing stool may result from anal abscesses, small inflamed nodules, anal fissures, and anal fistulas.
Rectal and anal disease may be asymptomatic, or may present with pain when passing stools, fresh blood in stool, a feeling of incomplete emptying, or pencil-thin stools. In addition to regular tests, medical tests used to investigate the anus and rectum include the digital rectal exam and proctoscopy.
Functional Gastrointestinal Disorders
In 2013, a CDC study reported that gastrointestinal (GI)- related dysfunction was responsible for 13,011 annual outpatient office visits. These disorders can be classified as functional, structural, or biochemical, and they differ in presentation, symptoms, location, and severity of disease/ symptoms. Functional GI disorders (FGIDs) are the most common, affecting 40% of patients. This review does not cover all possible GI disorders; the goal is to present an overview of FGIDs commonly seen in an ambulatory/hospital setting.
GI tract disorders are treated, but also exacerbated, by several different classes of medications. The goal for health care providers is to treat the causative factor(s), not just the symptoms. The clinician’s evaluation and involvement in medication management are vital components of the treatment of GI disorders.
What is an FGID?
FGIDs encompass dysfunctions in motility, mucosal membranes, the central nervous system, normal gut flora, and the immune system, as well as organ hypersensitivity. In addition, the normal motility of the GI tract may be shallower or prolonged and spasms may or may not be present, which can create pain ranging from mild to extremely intense. The three most important features of FGIDs are brain-gut dysfunction, sensation, and peristalsis.
There are multiple exogenous factors that may hinder normal peristalsis, including the following:
• Diet lacking in fiber or including excessive amounts of dairy products
• Inadequate intake of water
• Lack of exercise
• Change in lifestyle or daily routine
• Refusal to execute a bowel movement
• Use/overuse of certain medications
The average adult in the Western hemisphere produces 2 to 3 bowel movements per day, 2 to 3 times per week. Therefore, when motility is affected, so are bowel habits. These sensorial changes occur because the nerves within the GI tract are highly sensitive, which cause an individual to experience pain while the body performs normal activities such as digestion. Braingut irregularities are caused by a malfunction in communication between these organ systems. Diagnostic tools, such as x-rays, may not detect obstructions and other structural abnormalities because these abnormalities are not a manifestation of functional disorders.
The Rome Foundation is an independent nonprofit dedicated to the treatment and awareness of FGIDs. The newest edition of its diagnostic criteria, Rome IV, outlines common symptoms, physiological abnormalities, typical pain experience, disease severity, and any other biological markers that are synonymous with the suspected disorder. The goal is refinement in the clinician’s treatment, accurate diagnosis of GI disorders, and improved quality of life for patients.
Functional Disorders of the GI System
The GI system is an expansive system in the body. Disorders tend to be managed with OTC treatments for too long by patients rather than seeking proper attention from a health care professional. The diseases discussed in this section are the most common condition resulting from FGIDs for which patients seek treatment.
Infections top the list, with 135 million (33%) patients affected. These typically are related to other common conditions that disrupt the homeostasis of normal gut flora, such as gastroesophageal reflux disease (GERD), nausea, and vomiting, all of which may put the GI tract, especially the stomach and esophagus, at risk due to erosion of the epithelium lining from the stomach acid. The causative agents that are customarily responsible for GI infections are Escherichia coli, Shigella, Campylobacter, Clostridium difficile, rotavirus, and parasites such as giardia.
GERD (more commonly known as acid reflux) is characterized by the backflow of stomach acid, secondary to inadequate closure of the lower esophageal sphincter muscles that separate the esophagus and the stomach. As a chronic disorder, GERD causes many patients to seek OTC interventions for relief, which makes clinician involvement imperative for the proper diagnosis and treatment of this disease.
Constipation and hemorrhoids are similar in that they have the greatest relation to a patient’s external habits and exposures. The most common origin of these disorders is insufficient fiber intake, although opioid use is a major risk factor. These simple disorders have the potential to escalate into more serious problems such as anal fissures, fistulas, or abscesses.
Diverticulitis, another result of inadequate fiber intake, is the occurrence of protrusions of the muscular wall of the intestines that can weaken the structure to the point of creating severe complications, including infection, obstruction, inflammation, and bleeding.
Peptic ulcer disease (PUD) encompasses ulcerations that jut deep into the muscularis mucosae of the GI tract. Helicobacter pylori, overuse of nonsteroidal anti-inflammatory drugs, and stress are the 3 main causes agents of PUD. Diet, tobacco use, and excessive amounts of stress must be reduced substantially to properly treat PUD. It is critical to balance pharmacologic and nonpharmacologic interventions to appropriately treat this disorder.
Irritable bowel syndrome (IBS), irritable bowel disease (IBD), and celiac disease make up the remaining common FGIDs. IBS is the byproduct of a spastic colon, which causes sporadic and uncontrollable bowel habits, gas, and bloating. IBDs, such as ulcerative colitis (UC) and Crohn’s disease (CD) occur because of lesions within the GI tract. This immunological disease can be more difficult to treat because it originates from hypersensitive immunoresponses. CD affects a patient’s ability to properly absorb key nutrients. Therefore, patients who consume gluten expose their digestive tracts to a heightened immune response, which results in problematic bowel habits, bloating, vomiting, weight loss, anemia, or seizures.
Pharmacological Therapy for FGIDS
In general, antibiotic drug therapy consists of various therapy categories, and may include beta-lactams, vancomycin, and fluoroquinolones.
Anaerobic coverage may be maximized with the addition of metronidazole and piperacillin-tazobactam. Vancomycin is frequently used in patients who are allergic to beta-lactams or cephalosporins. Prebiotics and probiotics help to replenish normal flora after antibiotic use. Overall, the selection of antibiotic coverage is determined by the suspected infecting organism and microbiology cultures and requires a thoughtful review of patient history, microbiology cultures, and previous antibiotic treatment. Table enumerates the drug therapies used in infectious gastroenteritis.
When selecting an appropriate drug therapy, it is important to ensure that both the disorder’s underlying cause and the patient’s symptoms are being treated. The appropriate dosage also is critical, as the best therapeutic option may require a plan that encompasses pharmacologic and nonpharmacologic selections. Further, with the increased frequency of administration and use of multiple drugs, clinicians must be vigilant about the risk of patients’ nonadherence to treatment plans/medications and of drug–drug interactions.
Proton pump inhibitors (PPIs) and histamine2 (H2)-receptor antagonists are staples of many GI disorders. Because these are OTC medications, it is important to monitor their use and counsel patients on possible adverse effects (AEs). H2-receptor antagonists block the H2 receptor within the stomach, which prevents the secretion of acid. Similarly, PPIs block the secretion of hydrogen ions. Clostridium difficile overgrowth is common with overuse of these medications. Ultimately, thesemedications increase the pH of the stomach. Calcium analogs also may be used to increase the pH of the stomach; however, they usually do not have enough potency to provide relief.
Antiemetics are the most common medications used in GI disorders; examples include serotonin antagonists (5-HT3), dopamine antagonists (DAs), and neurokinin-1 receptor antagonists. These classes collectively inhibit the chemoreceptor trigger zone of the brain, which ameliorates nausea and vomiting in some patients. Utilization of a 5-HT3 or a DA may generate a drug–drug interaction and result in QT prolongation. When macrolides are used as prokinetic agents and combined with antiemetics, patients should be monitored carefully and their comorbid conditions evaluated. In some patient groups, a diagnostic electrocardiogram and the possibility of cardiac arrhythmia should be considered. Many of these agents may have interactions with cytochrome P450 (table 2). The nontraditional antiemetics that may be used in some instances are steroids, benzodiazepines, and cannabinoids.
Biologics and nonbiologics are classes exclusive to CD because of their immunosuppressant activity. Patients receiving these medications should have their liver, kidney, and cardiac functions monitored, as well as their differential white blood cell count, depending on the medication. They should avoid live vaccines and individuals with infectious disease(s) or those at risk of contracting them. Steroids used for UC and CD also can be grouped into this immunosuppressant pharmacotherapy class. Aminosalicylates provide local immunosuppression and are reserved for lesions of the GI tract.
Medication that worsen GI function
When evaluating patient choices, it is important to assess the risk–benefit ratio being presented. GI-protective medications, such as PPIs or misoprostol, reduce the risk of complications. Some cases, however, necessitate a GI-toxic medication.online table 3 reviews common medications and their AEs on the GI system.
Treatment for GI disorders should include pharmacologic and nonpharmacologic methodologies,with modifications to patients’ diets and lifestyles and the institution of an exercise regimen serving as the foundation. Clinicians should stress the importance of adequate nutrition, fiber intake, hydration, and exercise; avoiding tobacco smoking/chewing, overuse of alcohol, and abuse of prescription/illicit drugs; and specific, measurable, attainable, realistic, and time-based goals. In counseling patients, clinicians must educate patients on why they need to adhere to all aspects of the treatment plan.
GERD: When Medication Management Fails
More than 60 million Americans experience heartburn at least once a month and 15 million suffer daily. Heartburn and acid regurgitation are hallmark gastroesophageal reflux disease (GERD) symptoms.
Lifestyle interventions and anti-secretory medications like proton pump inhibitors (PPIs) are commonly used for GERD management. Seventeen to 32% of patients experience persistent symptoms despite medical therapy and are considered to have refractory GERD.
Physicians can manage refractory GERD surgically, but must consider its phenotype. Reflux hypersensitivity may only partially respond to surgery and functional heartburn should not be managed surgically.
A June 2017 article published in Journal of Gastrointestinal Surgery explores surgical advancements in management of GERD.
Laparoscopic Nissen fundoplication and concurrent hiatal hernia repair, if necessary, is the backbone in surgical GERD treatment. GERD and obesity are closely related and symptoms improve with weight loss. Laparoscopic Roux-en-Y gastric bypass surgery is recommended in obese patients who meet American Society for Metabolic and Bariatric Surgery.
Researchers are currently studying other GERD treatment technologies.
The Linx Reflux Management System uses a circular ring of magnetic beads to augment the lower esophageal sphincter (LES) and demonstrates symptomatic improvement in patients with small hiatal hernias.
Lower Esophageal Sphincter Stimulation for GERD (LESS-GERD) is a randomized, controlled, trial studying EndoStim LES stimulation system in patients who respond partially to PPIs. Here, electrodes are placed anteriorly along the esophagus at the gastroesophageal junction. LESS-GERD results seems to result in esophageal acid exposure and less PPI use.
Other novel technologies and minimally invasive endoscopic methods exist, but they lack long-term evidence and are not consistently used.
Surgical and endoscopic GERD management methods have similar risks including infection, postoperative dysphagia, and recurrent symptoms. Studies show surgical management is effective for refractory patients and outcomes to depend on appropriate procedure selection.
Keloid Scar is also known as keloid disorder and keloidal scar, is the formation of a type of scar which, depending on its maturity, is composed mainly of either type III (early) or type I (late) collagen. It is a result of an overgrowth of granulation tissue (collagen type 3) at the site of a healed skin injury which is then slowly replaced by collagen type 1. Keloids are firm, rubbery lesions or shiny, fibrous nodules, and can vary from pink to the color of the person’s skin or red to dark brown in color.
Keloid scar dermal benign fibro-proliferative growth that extends outside the original wound and invades adjacent dermal tissue due to extensive production of extracellular matrix, especially collagen, which caused by overexpression of cytokines and growth factors. Although many attempts were made to understand the exact pathophysiology and the molecular abnormalities, the pathogenesis of keloid scar is yet to be determined. Even though there are several treatment options for keloid scars include a combination of medical and surgical therapies like a combination of surgical removal followed by cryotherapy or intralesional steroid therapy, the reoccurrence rate is still high despite the present treatment. This paper reviews literature about keloid scar formation mechanism, the most recent therapeutic options including the ones under research.
A keloid scar is benign and not contagious, but sometimes accompanied by severe itchiness, pain, and changes in texture. In severe cases, it can affect movement of skin. Keloid scars are seen 15 times more frequently in people of African descent than in people of European descent.
Pathology of Hypertrophic Scars
Although there is a defined clinical distinction between hypertrophic scars and keloid scars these two disorders may lie within a spectrum of the same pathophysiologic process. Wound healing is divided up into three phases (inflammatory, proliferative, remodeling). The scar is formed in the last phase (remodeling phase).
There are increased numbers of myofibroblasts in hypertrophic scars. Transforming growth factor beta stimulates differentiation of both local and bone fibroblasts into myofibroblasts, which then creates tension on the wound. Certain pro-inflammatory mediators are unregulated in keloid scars. These include tumor necrosis factor-alpha, interleukin-1 alpha, interleukin-1 beta, and interleukin-6. Some experts believe that these mediators are more sensitive to being released in response to trauma in patients predisposed to hypertrophic and keloid scarring.
Burn wounds can be divided into superficial (partial thickness) and deep (full thickness). The majority of partial thickness burn wounds heal without hypertrophic scarring. Deep wounds stimulate dermal fibroblasts to produce collagen and inflammatory mediators like transforming growth factor-beta 1 (TGF-beta1). TGF-beta1 further stimulates fibroblasts to deposit elastin and collagen.
Causes of Keloid Scar
Most skin injury types can contribute to keloid scarring. These include:
According to the American Osteopathic College of Dermatology (AOCD), an estimated 10 percent of people experience keloid scarring. Men and women are equally likely to have keloid scars. Those with darkly pigmented skin, such as African-Americans, are more prone to keloids.
Symptoms of Keloid Scar
Keloids occur from the overgrowth of scar tissue. Symptoms occur at a site of previous skin injury.
The symptoms of keloids can include:
a localized area that is flesh-colored, pink, or red in color
a lumpy or ridged area of skin that’s usually raised
an area that continues to grow larger with scar tissue over time
an itchy patch of skin
Keloid scars usually have the following characteristics
Raised above the skin.
Hairless and has a shiny appearance.
Continues to grow even after the wound heals.
Has a hard and rubbery texture.
Can be itchy.
Maybe painful to the touch.
Lumps may appear on it.
Red or purple in color when new, but then turns pale over time.
Constant exposure may darken them.
Could affect movement if the scar is tight and occurs near a joint.
Keloid scars tend to be larger than the original wound itself. They may take weeks or months to develop fully.
While keloid scars may be itchy, they’re usually not harmful to your health. You may experience discomfort, tenderness, or possible irritation from your clothing or other forms of friction. In rare instances, you may experience keloid scarring on a significant amount of your body. When this occurs, the hardened, tight scar tissue may restrict your movements.
Keloids are often more of a cosmetic concern than a healthy one. You may feel self-conscious if the keloid is very large or in a highly visible location, such as an earlobe or on the face. Sun exposure or tanning may discolor the scar tissue, making it slightly darker than your surrounding skin. This can make the keloid stand out even more than it already does. Keep the scar covered when you’re in the sun to prevent discoloration.
Diagnosis of a Keloid Scar
There is no particular test for a keloid scar. It is diagnosed from the clinical story (a slow-growing overgrowth of a scar, usually in a dark-skinned person), with the scar growing beyond the location of the original skin damage.
Occasionally a keloid scar can mimic other skin tumors.
Very rarely, a skin tumor like a dermatofibroma or a soft tissue sarcoma can be mistaken for a keloid scar or vice versa.
The biopsy will be looked at under a microscope and a specialist (histopathologist) will be able to see the typical microscopic features of a keloid scar: a swirling nodular pattern of collagen fibers.
Note: a biopsy is hardly ever necessary because the history – ie the patient’s story – and the appearance of the skin growth are very typical of a keloid scar.
Treatment of Keloid Scar
Treatment can be difficult and isn’t always successful.
Scars can never be completely removed but can be made less visible.
Steroid injections directly into the scar – this may help to flatten small early ones
Apply silicone gel – sheeting on healing skin (not open wounds) for 12 hours a day, for at least 3 months. Silicone gels or sheets are available from some pharmacies.
Use pressure bandages – to provide long-term compression.
Other medicines may improve keloids – These include verapamil, fluorouracil, bleomycin, and interferon alfa-2b shots. They are not as well studied as corticosteroid shots, but your doctor may recommend trying one. They are most likely to work when used with another treatment.
Imiquimod – Imiquimod (1-[2-methylpropyl]-1H-imidazo[4,5-c]quinolin-4-amin) belongs to the family of imidazoquinolines. Imiquimod induces TNF-alpha, IFN-alpha and IFN-gamma, IL-1, IL-4, IL-5, IL-6, IL-8, and IL-12 and alters the expression of markers for apoptosis.
Tacrolimus – Tacrolimus is an immunomodulator that inhibits TNF-alpha. Gli -1, an oncogene, has been found to be overexpressed in fibroblasts of keloids. Inhibition of this oncogene may restore the natural apoptosis process and decrease proliferation of the ECM protein.Rapamycin, a close analog of tacrolimus, was used in an in vitro study and was found to inhibit the gli -1 oncogene, thus giving a rationale to initiate clinical trials of topical tacrolimus and rapamycin.
Sirolimus – Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a serine/threonine kinase that regulates collagen expression. By inhibiting mTOR, sirolimus blocks the response to IL-2 and decreases ECM deposition. Similar to rapamycin, sirolimus inhibits Gli -1 signal transduction. mTOR kinases form 2 distinct multiprotein complexes, mTORC1 and mTORC2. In an in vitro and ex vivo study, 2 compounds, KU-0063794 and KU-0068650, were demonstrated to be potent and highly selective competitive inhibitors of mTORC1 and mTORC2 compared with rapamycin, which inhibits mTORC1 alone. The compounds have shown promising antifibrotic activity, with apparent no toxicity in vivo.
Others Treatment of Keloid Scar
Corticosteroid injections, ointments, and tapes/plasters effectively treat keloids and hypertrophic scars. In addition to their direct anti-inflammatory effect, we believe that the steroids also act by inducing vasoconstriction. This is supported by the fact that corticosteroid administration causes keloids to whiten: this suggests that the blood flow in the scar has been decreased by vasoconstriction.
The vasoconstrictor effects of topical steroids seem to be mediated by their binding to classical glucocorticoid receptors, rather than by nonspecific pharmacological mechanisms. Moreover, corticosteroid administration rapidly reduces the itching and pain associated with keloids, possibly because the vasoconstriction prevents the perivascular delivery of the inflammatory factors that elicit these symptoms
Adhesive tape support/silicone gel sheeting
Hydration and occlusion have been suggested in the literature to be the main mechanisms of action of topical adhesive tape (plastic or paper) and silicone materials (sheets, strips, gels, creams, sprays, and foams; available over the counter or custom-made). Accordingly, it seems that silicone, in particular, is not always required.
In fact, silicone and non-silicone gel dressings may be equally effective in the treatment of hypertrophic scars [rx]; however, studies have shown that silicone gel and silicone gel sheeting (SGS) appear to provide an appropriate occlusion level to treat abnormal scars, in contrast to other materials, such as vaseline [rx].
Among the different available silicone formats, although silicone gel and SGS have equivalent efficacy in the management of excessive scarring after an operation, silicone gel currently appears to be the preferred silicone therapy, due mainly to ease of use, as Mustoe and colleagues advocate [rx].
Compression therapy reduces both the objective and subjective symptoms of keloids and hypertrophic scars. We speculate that it acts by occluding the blood vessels in the scar, thereby inhibiting the inflammatory signals coming from the blood vessels. An additional mechanism may be that it stabilizes the wound, thereby decreasing inflammation.
Pressure therapy has gained popularity for the management of hypertrophic scars and keloids since the 1970s. To date, pressure garments are frequently being used for the prevention of excessive scar formation post-burn. However, their underlying mechanism of action remains poorly understood.
Decreased collagen synthesis by limiting capillary perfusion and thus decreased oxygen supply to the scar tissue[rx]–[rx], as well as increased apoptosis rates of fibroblasts35, are being discussed. Pressure therapy is usually performed with pressure suits or bandages, sometimes with transparent plastic masks or pressure buttons in special locations.
Recommendations for the amount of pressure and the duration of the therapy are merely based on empirical observations and support continuous pressure of 15–40 mmHg for at least 23 hours per day for more than 6 months while the scar is still active[rx]
Since stretching wounds can evoke inflammation of the reticular dermis, wounds should be stabilized. Thus, prolonged external mechanical support using tapes, sheets, and/or garments is recommended for scar prevention. This is supported by our study, which showed that silicone gel sheets reduce the tension on the wound site.
Silicone tape is better than paper tape as it prevents the epidermal injury caused by repeated taping. Moreover, silicone tape keeps the scar surface moist. These tapes can be kept in place until they detach naturally. The patient does not need to change the tape after taking a bath/shower.
In our experience, patients generally keep silicone tape in place for about 1–2 weeks. The exception is in summer: perspiration can reduce tape adherence. However, if a patient has a clear history of pathological scars, then stabilization tapes should be exchanged for steroid plaster/tape.
Superficial X-rays, electron beam and low- or high-dose-rate brachytherapy have been employed primarily as an adjunct to surgical removal of keloids, with overall good results in terms of reduced recurrence,[rx]–[rx]with the exception of one report.[rx] Radiation mediates its effects through inhibition of neovascular buds and proliferating fibroblasts, resulting in decreased collagen production.[rx]
Electron beam irradiation should be started early (24–48 hours) after keloid excision. A total dose of usually 12 Gy divided into six to ten fractions applied daily or every second day is currently recommended by dermatologists.16 Side effects include hypo- and hyper-pigmentation, erythema, telangiectasia, and atrophy.[rx] Since radiation represents some risk in terms of carcinogenesis, particularly in areas such as the breast or thyroid, its use should be handled with caution.[rx]
Various lasers have been evaluated in the past decades for the improvement of hypertrophic scars and keloids.[rx] However, current data is difficult to compare due to the different laser settings utilized. The most encouraging results have been demonstrated with the 585-nm pulsed dye laser (PDL), which was first described as promising for the treatment of younger hypertrophic scars and keloids in a milestone study by Alster et al published in the Lancet in 1995.[rx]
It is thought that the PDL improves keloids or hypertrophic scars by inducing capillary destruction, which generates hypoxemia and in turn alters local collagen production.[rx]–[rx] Also, increased production of MMPs (eg, collagenase) has been described upon PDL treatment.[rx] Non-overlapping laser pulses at fluences ranging from 6.0 to 7.5 J/cm2 (7-mm spot) or from 4.5 to 5.5 J/cm2 (10-mm spot) are currently recommended for the treatment of hypertrophic scars and keloids.[rx] According to Alster and colleagues, two to six treatment sessions are necessary to successfully improve scar color, height, pliability, and texture.[rx]
Laser and Light-Based Therapy
Many different lasers have been studied and utilized in the treatment of hypertrophic scars and keloids including CO2, Er: Y AG and PDL, among others [rx]. The vascular PDL (pulsed dye laser) 585–595 nm is a nonablative non-fractional laser that has been recognized as an excellent first-line treatment and especially preventive strategy for hypertrophic scars [rx].
Indeed, the primary indication for PDL is to reduce erythema [rx]. The conventional short-pulsed dye laser (585 nm PDL) has been described as the most appropriate and effective system for the treatment of scars, with improvement in scar texture, color, and pliability, as well as minimal side effects [rx].
Indeed, this type of laser improves the appearance of hypertrophic scars, keloids, erythematous scars and striae, and diminishes pruritus [rx,rx,rx].
5-FU is a chemotherapy drug, a pyrimidine analog with antimetabolite activity [rx], effective in the treatment of keloid scars [rx], especially during the first 5 years of appearance. Wound ulceration, hyperpigmentation and pain are potential complications of the treatment [rx,rx]. Weekly intralesional 5-FU injections (50 mg/ml) for 12 weeks resulted in reduction in scar size of at least 50% with no recurrence in 24 months [rx].
The triple combination of 5-FU, corticosteroids and PDL is a successful multifaceted approach for the treatment of hypertrophic scars and keloids [rx] and it currently appears to be the most promising therapy for keloids [rx].
Cryotherapy in combination with intralesional steroid (triamcinolone) has been the most popular classic treatment for both keloid and hypertrophic scars. It is also a very good way to heal small scars like acne scars. Moreover, the common side effect of cryotherapy is permanent hypopigmentation.
Although it is used as multiple sessions every month, the least number of sessions the better chance for post-operative healing. Further, the success rates after 2 sessions are ranged from 30 to 75% either by using spray or contact cryosurgery with liquid nitrogen, and it is lower in keloid than in hypertrophic scars.[rx]
Intralesional cryo-needle is the most effective method in treating keloid scar compared with contact and spray probes.[rx] Cryotherapy has been used to treat keloids either as a monotherapy or in combination with intralesional triamcinolone injection [rx]. Cryotherapy delivery methods include contact, sprays, or intralesional needles.
In recent years, fat grafting/lipofilling [rx], stem cell therapy [rx], and electrochemotherapy [rx] have been used to treat burn scars, hypertrophic scars, and scar contractures. The effectiveness of these techniques remains unclear. Large-scale clinical trials on these techniques are expected.
Moreover, it is likely that, in the next few years, a number of drugs that target specific molecules and thereby improve or prevent pathological scarring will be tested in clinical trials. These drugs may target molecules that participate in inflammation and angiogenesis in the reticular dermis.
In particular, drugs that target mechanosensors may be highly effective given that pathological scars are sensitive to mechanical forces [rx].
Interferon (IFN) subdermal injections are reported to be more efficient than triamcinolone acetonide injections in preventing postsurgical recurrence of keloids. However, these painful injections may require regional anesthesia [rx,rx,rx] and flu-like adverse effects are also common [rx].
Interferon-α, β, and γ have been shown to increase collagen breakdown . Furthermore, IFN-α2b has been suggested to have antiproliferative properties [rx]. IFN-γ inhibits TGF-β and therefore fibrosis, via initial activation of Jak1, which in turn stimulates the negative regulator of collagen YB-1 (Y-box protein-1), which activates Smad7, eventually leading to TGF-β1 suppression [rx]. However, there is a study where IFN-γ failed to antagonize TGF-β-mediated fibrotic response in keloid-derived dermal fibroblasts [rx].
In vivo, intralesional IFN-γ has been shown to be effective in improving the appearance of keloids and hypertrophic scars, and in reducing keloid recurrence after excision [rx], with variable treatment regimens. For instance, 0.01–0.1 mg, 3 times a week for 3 weeks [rx], or a unique weekly maximal dose of 0.05 mg for 10 weeks [rx]. IFN-α2b intralesional injection is usually used at 1.5 million IU twice daily over 4 days in keloids or three times weekly for hypertrophic scars [rx,rx]. Although IFN is an expensive form of therapy, it remains a promising therapeutic approach for excessive scarring [rx].
Bleomycin induces apoptosis, inhibits collagen synthesis via decreased stimulation by TGF-β1 [rx], and is frequently used as an antitumor agent. It has also antibacterial and antiviral activity [rx]. Intralesional multiple jet injections of bleomycin 0.1 ml (1.5 IU/ml) at a maximum dose of 6 ml to avoid toxicity (cutaneous and less frequent pulmonary), 2–6 sessions within a month, may currently be indicated as a therapy for keloids and hypertrophic scars unresponsive to intralesional steroid injection [rx,rx], such as patients with old scars [rx]; however, its use is still uncommon.
Bleomycin can be used as intralesional injections. The recommended dosage starts at 0.1 ml (1.5 IU/ml) and can go up to a maximum dose of 6 ml in order to prevent adverse effects which are usually cutaneous and less common pulmonary.[rx], [rx] For patients with old scars that do not respond to the intralesional steroid, the recommended treatment is between 2 and 6 sessions per month. Bleomycin usage is still uncommon in clinical practice.[rx]
Imiquimod 5% cream
Imiquimod is an immune-response modifier and Toll-like receptor (TLR) agonist [rx], approved for the treatment of genital warts, basal cell carcinoma and actinic keratoses [rx].
Imiquimod stimulates interferon and TNF-α, which increases collagen breakdown and reduces fibroblast-mediated collagen production, respectively [rx]. The cream is applied on alternate nights for 8 weeks after surgery. Adverse effects include irritation and hyperpigmentation [rx]. Although many clinical studies suggest the beneficial effect of imiquimod in the prevention of postsurgical keloid recurrence [rx–rx], it still remains questionable [rx].
Tranilast (N-(3,4-dimethoxy cinnamoyl) anthranilic acid) is an anti-allergic drug that inhibits the release of histamine and prostaglandins from mast cells, a H1 receptor antagonist [rx]. It also suppresses collagen synthesis of keloids and hypertrophic scar-derived-fibroblasts by downregulating TGF-β1 [rx]. This drug is approved in Japan and Korea for the treatment of hypertrophic scarring [rx].
Mitomycin C (MMC), a derivative of Streptomyces caespitosus that was isolated in 1958 by Wakaki, is an antibiotic agent with antineoplastic and antiproliferative activities, which has been used as a therapeutic agent to treat pterygium since1963.[rx]
MMC inhibits DNA, RNA and protein synthesis by alkylating and crosslinking DNA at guanine adenosine nucleotides. MMC has been shown to decrease the DNA synthesis and density cultured keloid fibroblasts in vitro. It has been also shown to suppress fibroblast proliferation and thereby reduce the formation of scars in vitro and in vivo.[rx]
Botulinum toxin A (BTA)
BTA immobilizes local muscles, reduces skin tension caused by a muscle pull, and thus, decreases microtrauma and subsequent inflammation.[rx] Reduction of the tensile force during the course of cicatrization and effective regulation of the balance between fibroblast proliferation and cellular apoptosis[rx] may represent a novel therapeutic option for the aesthetic improvement of post-surgical scars.
Indeed, Gassner and colleagues could demonstrate that botulinum toxin injections into the musculature adjacent to the wound (15 U of BTA (Botox, Allergan, Irvine, CA, USA) per 2 cm intraoperative length) within 24 hours after wound closure resulted in enhanced wound healing and less noticeable scars compared with placebo.[rx] By injecting BTA 4–7 days prior to surgery, we have seen similar results using a slightly reduced dose regime, depending on the respective anatomic location (risk of severe asymmetry if injecting only one side of the musculus frontalis, brow ptosis).
Photodynamic Therapy (PDT)
Topical PDT has been used extensively in treating superficial basal cell carcinoma, actinic keratosis, and Bowen’s disease. Very recently, PDT has been suggested as a novel therapeutic approach for the treatment of keloids. The potential underlying mechanism is currently unknown. However, the photodynamic reaction generates reactive oxygen species, which in turn leads to cell apoptosis, membrane and mitochondrial damage, and activates various signaling molecules such as tumor necrosis factor-α.
PDT has been demonstrated to reduce type I collagen synthesis and fibroblast proliferation in vitro, which may be responsible for the improvement seen clinically.[rx],[rx] Ud-Din et al recently demonstrated in 20 patients that three treatments of PDT (37 J/cm[rx]) at weekly intervals were effective in reducing pruritus and pain, and in increasing pliability of symptomatic keloids.
Also, when applied postoperatively after excision of keloids, no recurrence rates were seen at 9-month follow-up, with the exception of one patient.[rx] Based on this small amount of data available, PDT represents a promising, noninvasive treatment which produces a good cosmetic outcome with minimal side effects. However, more studies are needed to further evaluate the optimal PDT treatment regime for this indication.
Recombinant TGF-β3, Justiva (avotermin)
In 2009, Ferguson and colleagues summarized the results of three double-blind, placebo-controlled trials in a milestone study published in the Lancet:[rx] Intradermal avotermin (recombinant, active, human TGF-β3, Justiva) was administered in healthy subjects to both margins of 1 cm, full-thickness skin incisions, before wounding and 24 hours later and was judged to be effective by lay observers and clinicians.
Even though the investigators acknowledged their commercial interests in TGF-β3, adherence to established standards in this translational investigation and the rigorous nature of the statistical analysis in a well-powered series of studies provided strong evidence for the benefits of Justiva in this setting. However, in spring 2011, Justiva failed to hit its primary and secondary endpoints in a pivotal Phase III trial.
In light of these findings, the company regrettably concluded that the efficacy of Justice may be insufficient to demonstrate significant benefit when tested in a broad population of scar revision patients.[rx] To date, the clinical future of recombinant TGF-β3 remains uncertain.
UV-A1 (340–400 nm) Light Therapy
It is a potential noninvasive option to treat keloid scars. The mechanism of action of ultraviolet light therapy appears to be related to an increase in the collagenase activity. A higher dosage is better than a lower one, and the best response appeared at average 25 dosages.[rx]
The control of collagen production and wound healing has been shown to be affected by the renin-angiotensin system locally. According to Ardekani et al, local application of captopril on New Zeland white rabbits successfully stopped hypertrophic scarring. This group recently reported the first treated human case.[rx]
Calcium channel blockers
Like verapamil enhance scar tissue degradation through stimulating collagenase production. They cause changes in the gene expression of the fibroblasts, thereby resulting in decreased collagen production with increased collagenase synthesis. Verapamil cream applied on the keloid scar appears to prevent rebound scarring from intralesional injections.[rx]
Other agents that may enhance scar degradation are calmodulin inhibitors (e.g. trifluoperazine) and protein C kinase inhibitors (tamoxifen). These agents are promising to treat noninflamed older scar with no active remodeling.[rx]
It is an immune response modulator through increasing expression of tissue necrotic factor alpha, gamma and alpha interferons (IFN-α, g), and interleukin 1, 6, 8, 12.[rx] In addition, imiquimod also acts as a Toll-like receptor (TLR) agonist,33 and shows promising results in a few reported cases.[rx] Imiquimod (Aldara) cream 5% concentration is used topically to treat different dermatological diseases like warts.[rx], [rx]
Other miscellaneous current practices against scarring
Usually intralesional 2.5 mg/ml [rx], but also topical 7% cream [rx].
It is a calcium antagonist that decreases collagen production in the ECM and stimulates
collagenase synthesis, reducing fibrotic tissue production [rx].
Topical retinoic acid
Clinical studies suggest that it lightly diminishes the size and symptoms of keloids, but it should not be
considered first-line therapy [rx]
Controversial results: While some argue it may prevent excessive scarring [rx], others [rx] defend the
Although collagen fibril changes have been reported, significant clinical improvement is still lacking
Microsurgical needle tattooing provides camouflage pigmentation and induces scar atrophy via the
cutting action of the needles.
Dyspigmentation and textural abnormalities of large scars can be reduced with dermatography [rx].
This anti-fibrinolytic drug, popularly used to manage the peripheral vascular disease, inhibits burn scar
fibroblasts in vitro [rx]
Putrescine 50 mmol/l
Alters cytoskeleton and the mitotic phase of the cell cycle. Inhibits inflammation and may prevent
keloid recurrence [rx]
Appears to prevent scar tissue formation, but not keloid recurrence [rx]
=Moist Exposed Burn Ointment.
Contains multiple herbs with beta-sitosterol [rx].
Mederma skin gel
Onion extract gel with scarce scientific evidence yet, although onion extracts are gaining popularity in
the literature [rx,rx]
Contains onion extract with heparin and allantoin [rx]
May actually worsen scars or cause contact dermatitis [rx]
Promising preclinical studies [rx], but more research warranted
Tamoxifen, a synthetic nonsteroidal antiestrogen used to treat breast cancer, has been shown to inhibit proliferation of keloid fibroblasts and their collagen synthesis in monolayer cultures. Hu et al demonstrated that tamoxifen exhibits a dose-dependent and reversible inhibition of contraction of adult human dermal fibroblast in vitro.
Tacrolimus is an immunomodulator that inhibits TNF-alpha. Gli -1, an oncogene, has been found to be overexpressed in fibroblasts of keloids. Inhibition of this oncogene may restore the natural apoptosis process and decrease proliferation of the ECM protein.Rapamycin, a close analogue of tacrolimus, was used in an in vitro study and was found to inhibit the gli -1 oncogene, thus giving a rationale to initiate clinical trials of topical tacrolimus and rapamycin.
Epidermal growth factor
Epidermal growth factor (EGF) is a growth factor produced by platelets, macrophages, and monocytes and is activated by binding with the EGF receptor present on keratinocytes and fibroblasts.It acts by stimulating keratinocyte proliferation and altering fibroblast activity, resulting in reduced healing time and improved tensile strength of scars.It has been found to be involved in wound healing. It is up-regulated early in the fetal period and is thought to be an important cytokine in scarless fetal healing.
Hydrogel scaffold is approved for used in Europe for improvement of wound healing and scarring and is available as an injectable porcine gelatin-dextran hydrogel scaffold.Its approval is for injection of incisional sites immediately prior to closure. It is thought to function as a lattice for fibroblast adherence, leading to more regulated and organized distribution, with improved wound healing outcome.
Freeze it. This is called cryotherapy. It is best used for small keloids, such as from acne. Cryotherapy can lighten the skin.Freezing early keloids with liquid nitrogen to stop them growing
Laser treatment to reduce redness – but this won’t make the scar smaller
Surgery to remove the keloid, sometimes followed by radiotherapy for the most severe cases. It is effective about 70% of the time
Surgery followed immediately afterwards with steroid injections at the site of the removed scar
Interferon injections – recent studies of interferon injections have shown promise in reducing the size of keloids, although it’s not certain how long the effects will last
Fluorouracil injections – this chemotherapy agent, injected alone or together with steroids, has been used as a treatment for keloids
Dermal fillers can be used to ‘plump’ any scars that are pitted. However, results are usually temporary
Skin needling – rolling a small device covered in hundreds of tiny needles across the skin is reported to be helpful but results vary and repeat treatments are often needed.
Topical treatment –Some doctors like to use sheeting made out of silicone to apply on the keloid or even hypertrophic scars. “The dressing provides pressure on the wound and helps keep more moisture within the skin, which both help to get rid of them,” Khosh says
Surgery of Keloid Scar
Surgery – If the keloid is larger than normal, your best bet is to minimize the scar through surgery, thus creating a new scar, says Umar. From there, the doctor injects steroids into your new scar to prevent it from growing again.
Laser Some doctors use lasers to diminish the look, but both doctors say that they find this method to be the least effective way of getting rid of keloids, especially ones formed from a surgical procedure.
Drug interaction is a situation in which a substance (usually another drug) affects the activity of a drug when both are administered together. This action can be synergistic (when the drug’s effect is increased) or antagonistic (when the drug’s effect is decreased) or a new effect can be produced that neither produces on its own. Typically, interactions between drugs come to mind (drug-drug interaction). However, interactions may also exist between drugs and foods (drug-food interactions), as well as drugs and medicinal plants or herbs (drug-plant interactions). People taking antidepressant drugs such as monoamine oxidase inhibitors should not take food containing tyramine as hypertensive crisis may occur (an example of a drug-food interaction). These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances.
Types of Drug Interactions
The change in an organism’s response to the administration of a drug is an important factor in pharmacodynamic interactions. These changes are extraordinarily difficult to classify given the wide variety of modes of action that exist and the fact that many drugs can cause their effect through a number of different mechanisms. This wide diversity also means that, in all but the most obvious cases, it is important to investigate and understand these mechanisms. The well-founded suspicion exists that there are more unknown interactions than known ones.
Effects of the competitive inhibition of an agonist by increases in the concentration of an antagonist. A drugs potency can be affected (the response curve shifted to the right) by the presence of an antagonistic interaction. pA2 known as the Schild representation, a mathematical model of the agonist-antagonist relationship or vice versa.
Pharmacodynamic interactions can occur on
Pharmacological receptors – Receptor interactions are the most easily defined, but they are also the most common. From a pharmacodynamic perspective, two drugs can be considered to be:
Homodynamic if they act on the same receptor. They, in turn, can be
Pure agonists – if they bind to the main focus of the receptor, causing a similar effect to that of the main drug.
Partial agonists – if, on binding to one of the receptor’s secondary loci, they have the same effect as the main drag, but with a lower intensity.
Antagonists – if they bind directly to the receptor’s main locus but their effect is opposite to that of the main drug. These include:
Competitive antagonists – if they compete with the main drug to bind with the receptor. The amount of antagonist or main drug that binds with the receptor will depend on the concentrations of each one in the plasma.
Uncompetitive antagonists – when the antagonist binds to the receptor irreversibly and is not released until the receptor is saturated. In principle, the quantity of antagonist and agonist that binds to the receptor will depend on their concentrations. However, the presence of the antagonist will cause the main drug to be released from the receptor regardless of the main drug’s concentration, therefore all the receptors will eventually become occupied by the antagonist.
Heterodynamic competitors – if they act on distinct receptors.
Signal transduction mechanisms – these are molecular processes that commence after the interaction of the drug with the receptor. For example, it is known that hypoglycemia (low blood glucose) in an organism produces a release of catecholamines, which trigger compensation mechanisms thereby increasing blood glucose levels. The release of catecholamines also triggers a series of symptoms, which allows the organism to recognize what is happening and which act as a stimulant for preventative action (eating sugars). Should a patient be taking a drug such as insulin, which reduces glycemia, and also is taking another drug such as certain beta-blockers for heart disease, then the beta-blockers will act to block the adrenaline receptors. This will block the reaction triggered by the catecholamines should a hypoglycemic episode occur. Therefore, the body will not adopt corrective mechanisms and there will be an increased risk of a serious reaction resulting from the ingestion of both drugs at the same time.
Antagonist physiological systems –Imagine a drug A that acts on a certain organ. This effect will increase with increasing concentrations of physiological substance S in the organism. Now imagine a drug B that acts on another organ, which increases the amount of substance S. If both drugs are taken simultaneously it is possible that drug A could cause an adverse reaction in the organism as its effect will be indirectly increased by the action of drug B. An actual example of this interaction is found in the concomitant use of digoxin and furosemide. The former acts on cardiac fibers and its effect is increased if there are low levels of potassium (K) in blood plasma. Furosemide is a diuretic that lowers arterial tension but favors the loss of K+. This could lead to hypokalemia (low levels of potassium in the blood), which could increase the toxicity of digoxin.
Modifications in the effect of a drug are caused by differences in the absorption, transport, distribution, metabolization or excretion of one or both of the drugs compared with the expected behavior of each drug when taken individually. These changes are basically modifications in the concentration of the drugs. In this respect, two drugs can be homergic if they have the same effect in the organism and heterergic if their effects are different.
Changes in motility
Some drugs, such as the prokinetic agents increase the speed with which a substance passes through the intestines. If a drug is present in the digestive tract’s absorption zone for less time its blood concentration will decrease. The opposite will occur with drugs that decrease intestinal motility.
pH – Drugs can be present in either ionized or non-ionised form, depending on their pKa (pH at which the drug reaches equilibrium between its ionized and non-ionised form). The non-ionized forms of drugs are usually easier to absorb, because they will not be repelled by the lipidic bilayer of the cell, most of them can be absorbed by passive diffusion, unless they are too big or too polarized (like glucose or vancomycin), in which case they may have or not specific and non specific transporters distributed on the entire intestine internal surface, that carry drugs inside the body. Obviously increasing the absorption of a drug will increase its bioavailability, so, changing the drug’s state between ionized or not, can be useful or not for certain drugs.
Drug solubility – The absorption of some drugs can be drastically reduced if they are administered together with food with high fat content. This is the case for oral anticoagulants and avocado.
Formation of non-absorbable complexes
Chelation – The presence of di- or trivalent cations can cause the chelation of certain drugs, making them harder to absorb. This interaction frequently occurs between drugs such as tetracycline or the fluoroquinolones and dairy products (due to the presence of Ca++).
Binding with proteins – Some drugs such as sucralfate binds to proteins, especially if they have a high bioavailability. For this reason, its administration is contraindicated in enteral feeding.
Another possibility – is that the drug is retained in the intestinal lumen forming large complexes that impede its absorption. This can occur with cholestyramine if it is associated with sulfamethoxazole, thyroxine, warfarin or digoxin.
Acting on the P-glycoprotein of the enterocytes – This appears to be one of the mechanisms promoted by the consumption of grapefruit juice in increasing the bioavailability of various drugs, regardless of its demonstrated inhibitory activity on first pass metabolism.
A drug interaction can be defined as an interaction between a drug and another substance that prevents the drug from performing as expected. This definition applies to interactions of drugs with other drugs (drug-drug interactions), as well as drugs with food (drug-food interactions) and other substances.
How do drug interactions occur?
There are several mechanisms by which drugs interact with other drugs, food, and other substances. An interaction can result when there is an increase or decrease in:
the absorption of a drug into the body
distribution of the drug within the body
alterations made to the drug by the body (metabolism) and
elimination of the drug from the body.
Most of the important drug interactions result from a change in the absorption, metabolism, or elimination of a drug. Drug interactions also may occur when two drugs that have similar (additive) effects or opposite (canceling) effects on the body are administered together. For example, there may be major sedation when two drugs that have sedation as side effects are given, for example, narcotics and antihistamines. Another source of drug interactions occurs when one drug alters the concentration of a substance that is normally present in the body. The alteration of this substance reduces or enhances the effect of another drug that is being taken. The drug interaction between warfarin (Coumadin) and vitamin K-containing products is a good example of this type of interaction. Warfarin acts by reducing the concentration of the active form of vitamin K in the body. Therefore, when vitamin K is taken, it reduces the effect of warfarin.
Change in absorption
Most drugs are absorbed into the blood and then travel to their site of action. Most drug interactions that are due to altered absorption occur in the intestine. There are various potential mechanisms through which the absorption of drugs can be reduced. These mechanisms include:
alteration in blood flow to the intestine;
change in drug metabolism (breakdown) by the intestine;
increased or decreased intestinal motility (movement);
alterations in stomach acidity, and
a change in the bacteria that reside in the intestine.
Drug absorption also can be affected if the drug’s ability to dissolve (solubility) is changed by another drug or if a substance (for example, food) binds to the drug and prevents its absorption.
Change in drug metabolism and elimination
Most drugs are eliminated through the kidney in either an unchanged form or as a by-product that results from the alteration (metabolism) of the drug by the liver. Therefore, the kidney and the liver are very important sites of potential drug interactions. Some drugs are able to reduce or increase the metabolism of other drugs by the liver or their elimination by the kidney.
Metabolism of drugs is the process through which the body converts (alters or modifies) drugs into forms that are more or less active (for example, by converting drugs that are given in inactive forms into their active forms that actually produce the desired effect) or that are easier for the body to eliminate through the kidneys. Most drug metabolism takes place in the liver, but other organs also may play a role (for example, the kidneys, intestine, etc.). The cytochrome P450 enzymes are a group of enzymes in the liver that is responsible for the metabolism of most drugs. They are, therefore, often involved in drug interactions. Drugs and certain types of food may increase or decrease the activity of these enzymes and therefore affect the concentration of drugs that are metabolized by these enzymes. An increase in the activity of these enzymes leads to a decrease in the concentration and effect of an administered drug. Conversely, a decrease in enzyme activity leads to an increase in drug concentration and effect.
Consequences of drug interactions
Drug interactions may lead to an increase or decrease in the beneficial or the adverse effects of the given drugs. When a drug interaction increases the benefit of the administered drugs without increasing side effects, both drugs may be combined to increase the control of the condition that is being treated. For example, drugs that reduce blood pressure by different mechanisms may be combined because the blood pressure lowering effect achieved by both drugs may be better than with either drug alone.
The absorption of some drugs is increased by food. Therefore, these drugs are taken with food in order to increase their concentration in the body and, ultimately, their effect. Conversely, when a drug’s absorption is reduced by food, the drug is taken on an empty stomach.
Drug interactions that are of greatest concern are those that reduce the desired effects or increase the adverse effects of the drugs. Drugs that reduce the absorption or increase the metabolism or elimination of other drugs tend to reduce the effects of other drugs. This may lead to failure of therapy or warrant an increase in the dose of the affected drug. Conversely, drugs that increase absorption or reduce the elimination or metabolism of other drugs – increase the concentration of the other drugs in the body – and lead to increased amounts of the drug in the body and more side effects. Sometimes, drugs interact because they produce similar side effects. Thus, when two drugs that produce similar side effects are combined, the frequency and severity of the side effect are increased.
How often do drug interactions occur?
The prescribing information for most drugs contains a list of potential drug interactions. Many of the listed interactions may be rare, minor, or only occur under specific conditions and may not be important. Drug interactions that cause important changes in the action of a drug are of greatest concern.
Drug interactions are complex and chiefly unpredictable. A known interaction may not occur in every individual. This can be explained because there are several factors that affect the likelihood that a known interaction will occur. These factors include differences among individuals in their:
lifestyle (diet, exercise),
the duration of combined therapy, and
the relative time of administration of the two substances. (Sometimes, interactions can be avoided if two drugs are taken at different times.)
Examples of interactions at the intestinal absorption level: selection of relevant substrates, inducers, and inhibitors of P-glycoprotein (ABCB1)
Interactions at the cytochrome P450 enzyme level: selection of relevant substrates for which, when used in combination with inhibitors or inducers of the same enzyme, either increased effects and increased occurrence of unwanted effects, or reduced effects or loss of effect must be anticipated (modified from [rx])
HIV protease inhibitors
Overview of selected serious drug interactions[Rx]
Time to effect
Recommendations and comments
Warfarin (Coumadin) plus ciprofloxacin (Cipro), clarithromycin (Biaxin), erythromycin, metronidazole (Flagyl) or trimethoprim-sulfamethoxazole (Bactrim, Septra)
Increased effect of warfarin
Generally within 1 week
Select alternative antibiotic
Warfarin plus acetaminophen
Increased bleeding, increased INR
Use lowest possible acetaminophen dosage and monitor INR
Warfarin plus acetylsalicylic acid (aspirin)
Increased bleeding, increased INR
Limit aspirin dosage to 100 mg per day and monitor INR
Warfarin plus NSAID
Increased bleeding, increased INR
Avoid concomitant use if possible; if coadministration is necessary, use a cyclooxygenase-2 inhibitor and monitor INR
Fluoroquinolone plus divalent/trivalent cations or sucralfate (Carafate)
Decreased absorption of fluoroquinolone
Space administration by 2–4 h
Carbamazepine (Tegretol) plus cimetidine (Tagamet), erythromycin, clarithromycin or fluconazole (Diflucan)
Increased carbamazepine levels
Generally within 1 week
Monitor carbamazepine levels
Phenytoin (Dilantin) plus cimetidine, erythromycin, clarithromycin or fluconazole
Increased phenytoin levels
Generally within 1 week
Monitor phenytoin levels
Phenobarbital plus cimetidine, erythromycin, clarithromycin or fluconazole
Increased phenobarbital levels
Generally within 1 week
Clinical significance has not been established.
Monitor phenobarbital levels
Phenytoin plus rifampin (Rifadin)
Decreased phenytoin levels
Generally within 1 week
Clinical significance has not been established.
Monitor phenytoin levels
Phenobarbital plus rifampin
Decreased phenobarbital levels
Generally within 1 week
Monitor phenobarbital levels
Carbamazepine plus rifampin
Decreased carbamazepine levels
Generally within 1 week
Clinical significance has not been established. Monitor carbamazepine levels
Lithium plus NSAID or diuretic
Increased lithium levels
Decrease lithium dosage by 50% and monitor lithium levels
Oral contraceptive pills plus rifampin
Decreased effectiveness of oral contraception
Avoid if possible. If combination therapy is necessary, have the patient take an oral contraceptive pill with a higher estrogen content (>35 µg of ethinyl estradiol) or recommend alternative method of contraception
Oral contraceptive pills plus antibiotics
Decreased effectiveness of oral contraception
Avoid if possible. If combination therapy is necessary, recommend use of alternative contraceptive method during cycle
Oral contraceptive pills plus troglitazone (Rezulin)
Decreased effectiveness of oral contraception
Have the patient take an oral contraceptive pill with a higher estrogen content or recommend an alternative method of contraception
Cisapride (Propulsid) plus erythromycin, clarithromycin, fluconazole, itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), indinavir (Crixivan) or ritonavir (Norvir)
Prolongation of QT interval along with arrhythmias secondary to inhibited cisapride metabolism
Generally within 1 week
Avoid. Consider whether metoclopramide (Reglan) therapy is appropriate for the patient
Cisapride plus class IA or class III antiarrhythmic agents, tricyclic antidepressants or phenothiazine
Prolongation of QT interval along with arrhythmias
Avoid. Consider whether metoclopramide therapy is appropriate for the patient
INR, International Normalized Ratio; NSAID, nonsteroidal anti-inflammatory drug; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; SSRI, selective serotonin reuptake inhibitor
Ways to Prevent a Deadly Drug Interaction
You should not be afraid to take your medications because of the possibility of drug interactions. Drug interactions can be intimidating for anyone who regularly takes prescription medications, but you can learn how to manage and prevent them.
Nevertheless, important drug interactions occur frequently and they add millions of dollars to the cost of health care. Moreover, many drugs have been withdrawn from the market because of their potential to interact with other drugs and cause serious health care problems.
Drugs with a narrow therapeutic index (that is, having little difference between toxic and therapeutic doses), and certain disease states like epilepsy or depression are especially prone to serious drug interactions. In addition, multiple interactions may occur when someone is taking several drugs, as is often the case with older patients.
While most interactions are usually not life-threatening, some mixtures of medications can lead to serious — and even fatal — consequences. Pharmacists and doctors are well-trained to review and predict drug interactions. You can also use online drug interactions tools to help gauge the risk prior to discussing with your doctor or pharmacist.
Education and communication are key. You should consult with your health care providers, research reliable drug information, and empower yourself to lower the risk of interactions and maximize your medical treatments. Here are nine tips to achieve that goal.
Management of Drug Interaction
The role of pharmacogenetics and pharmacogenomics[rx]
An individual’s genetic makeup can alter their response to a drug. Genetics affect pharmacokinetics and pharmacodynamics. Unrecognized mutations can be associated with ADRs or can affect the magnitude of a drug interaction. A common example is the metabolism of ethanol. There are ethnic differences in the metabolism of ethanol by alcohol dehydrogenase. People of Chinese descent have a higher incidence of atypical alcohol dehydrogenase and therefore become flushed and dizzy when they consume alcohol. Their capacity for consuming alcohol is lower than that for other populations.
To apply pharmacogenetics and pharmacogenomics to the management of drug interactions, it is important to know the difference between the two terms. Pharmacogenetics applies to inherited traits and genetic polymorphisms. Polymorphism refers to stable allelic variations found in the population (occurring at a frequency >1%) that result in altered protein activity. Pharmacogenomics applies to the entire spectrum of genes. With pharmacogenetics, the focus is on metabolizing enzymes and transporters, whereas with pharmacogenomics, the focus is on individualized drug and dosage for a specific disease.
The role of the pharmacist in the management of drug interaction
The pharmacist, along with the prescriber has a duty to ensure that patients are aware of the risk of side effects and a suitable course of action should they occur. With their detailed knowledge of medicine, pharmacists have the ability to relate unexpected symptoms experienced by patients to possible adverse effects of their drug therapy. The practice in clinical pharmacy also ensures that ADRs are minimized by avoiding drugs with potential side effects in susceptible patients. Thus, the pharmacist has a major role to play in relation to prevention, detection, and reporting ADRs.[rx]
Management options of drug interaction include
Avoiding the combination entirely – For some drug interactions, the risk always outweighs the risk, and the combination should be avoided. Because drug classes are usually heterogeneous with regard to drug interactions (as described above), one can often select a no interacting alternative for either the object drug or the precipitant drug.[rx]
Adjusting the dose of the object drug – Sometimes, it is possible to give the two interacting drugs safely as long as the dose of the object drug is adjusted.
Spacing dosing times to avoid the interaction – For some drug interactions involving binding in the gastrointestinal tract, to avoid the interaction one can give the object drug at least 2 h before or 4 h after the precipitant drug. In this way, the object drug can be absorbed into the circulation before the precipitant drug appears.
Monitoring for early detection – In some cases, when it is necessary to administer interacting drug combinations, the interaction can be managed through close laboratory or clinical monitoring for the evidence of the interaction. In this way, the appropriate dosage changes can be made, or the drugs discontinued if necessary.
Provide information on patient risk factors that increase the chance of an adverse outcome – It is clear from the clinical experience of physicians and pharmacists as well as published studies that most patients who take interacting drug combinations do not manifest adverse consequences.[rx] Substantial evidence from both the clinical experience of physicians and pharmacists as well as published studies suggest that the risk of statin-induced myopathy increases with increasing serum concentrations of the statin. Accordingly, it has been recommended that simvastatin should not exceed 20 mg daily in patients receiving verapamil concurrently.[rx]
Improve computerized screening systems – It is clear that computerized drug interaction screening systems have not been as successful as one hoped.[rx,rx]
The excessive number of drug interactions on the systems – Many pharmacists find that computerized drug interaction screening systems detect a large number of DDIs of questionable clinical significance.
Drug class differences not handled correctly – Almost all drug classes interact heterogeneously because individual members of a drug class are often not metabolized by the same cytochrome P450 isozymes or ABC (ATP-binding cassette) transporters as other members of the class. The statins are a good example, because simvastatin and lovastatin are extensively metabolized by CYP3A4, atorvastatin is moderately metabolized by CYP3A4, fluvastatin is metabolized by CYP2C9, and pravastatin and rosuvastatin are not metabolized by cytochrome P450 isozymes.[rx] Thus, combining all members of this drug class together is rarely justified when considering drug interactions. Nonetheless, it is common for reviews and computer systems to include all statins together as interacting with CYP3A4 inhibitors, even though the risk is primarily limited to lovastatin, simvastatin, and to a lesser extent, atorvastatin.[rx]
Before starting any new prescription drug or over-the-counter drug, talk to your primary health care provider or pharmacist. Make sure that they are aware of any vitamins or supplements that you take.
Make sure to read the patient information handout given to you at the pharmacy. If you are not given an information sheet, ask your pharmacist for one.
Check the labels of your medications for any warnings and look for the “Drug Interaction Precaution.” Read these warnings carefully.
Make a list of all your prescription medications and over-the-counter products, including drugs, vitamins, and supplements. Review this list with all health care providers and your pharmacist.
If possible, use one pharmacy for all your prescription medications and over-the-counter products. This way your pharmacist has a record of all your prescription drugs and can advise you about drug interactions and side effects.
This brief overview of drug interactions does not cover every possible scenario. Individuals should not be afraid to use their drugs because of the potential for drug interactions. Rather, they should use the information that is available to them to minimize the risk of such interactions and to improve the success of their therapy.[rx,rx]
Some Community Guideline for Pharmacist
Performing or obtaining necessary assessments of the patient’s health status is as follows
Formulating a medication treatment plan: selecting, initiating, modifying, or administering medication therapy.
Monitoring and evaluating the patient’s response to therapy, including safety and effectiveness.
Performing a comprehensive medication review to identify, resolve, and prevent medication-related problems, including adverse drug events.
Documenting the care delivered and communicating essential information to the patient’s other primary care providers.
Providing verbal education and training designed to enhance patient understanding and appropriate use of his or her medications.
Providing information, support services, and resources designed to enhance patient adherence with his or her therapy.
Coordinating and integrating medication therapy management services within the broader health care management services being provided to the patient.
Give health care practitioners a complete list of all of the drugs that you are using or have used within the last few weeks. This should include over-the-counter medications, vitamins, food supplements, and herbal remedies.
Inform health care practitioners when medications are added or discontinued.
Inform health care practitioners about changes in lifestyle (for example, exercise, diet, alcohol intake).
Ask your health care practitioners about the most serious or frequent drug interactions with the medications that you are taking.
Since the frequency of drug interactions increases with the number of medications, work with your health care practitioners to eliminate unnecessary medications.
Tell your pharmacist each time you start or stop a medication, including any over-the-counter (OTC) drug, herbal supplement, or vitamin. Keep an updated list of meds, including nonprescription drugs — and share with your health care providers, including your dentist, anytime you start or stop a medication.
Prescription drugs are not the only medicines that can interact. Non-prescription drugs can have serious consequences, too. For example, the herbal St. John’s Wort is commonly used as an OTC supplement for depression. If combined with other antidepressants such as the SSRIs like fluoxetine (Prozac) or sertraline (Zoloft), the risk of a rare but serious and potentially fatal condition called serotonin syndrome can occur, with symptoms such as confusion, hallucination, seizure, extreme changes in blood pressure, and even death.
Read your Medication Guide each time you get a new prescription or refill. The FDA updates prescription drug labels frequently, and there could be changes in your Medication Guide. Review your possible interactions and ask questions if you are concerned or don’t quite understand the medical jargon.
If you discover that you are at risk for an interaction, call your doctor. It may be that the interaction is minor, and no action is needed. On the other hand, you may need to avoid the drug or have an alternative medicine prescribed. NEVER stop a medication without first speaking to your doctor.
Research Your Meds Yourself
Use a reliable online drug interaction tool like the Drugs.com Interaction Checker to become engaged in your health and learn about your medications. If you need help understanding the information, be sure to call your pharmacist. Always check for drug interactions even when you purchase OTC medications, herbal supplements or vitamins.
The Drug Interaction Checker explains the mechanism of each drug interaction, the level of significance of the interaction (major, moderate or minor), and in certain cases, can provide the recommended course of action to manage the interaction. The Drug Interaction Checker will also display any interactions between your chosen drug(s), food or beverages, and even other diseases.
To see all possible drug interactions, just enter one drug name and select “check for interactions.” Information is provided for all interactions at both the consumer and professional level.
Keep All of Your Prescriptions at One Pharmacy
By keeping all of your prescriptions at one pharmacy, a regular drug review and drug interaction screen can be done electronically that incorporates all of your medicines. Talk with your pharmacist and doctor and communicate new and discontinued medications with all of your health care providers. Communication is key to preventing drug interactions.
When you buy OTCs or herbal supplements, ask your pharmacist to double check for interactions and ask if they can add the agent to your regular drug profile for future drug interaction checks. If your pharmacist does not know that you are taking OTC products, they can’t check for drug interactions with prescription medication. Be sure to read the Drug Facts Label on each OTC product you use, too.
Take Any Food and Beverage Drug Interactions Seriously
Your pharmacist or doctor may ask about specific foods or drinks you consume depending upon which drugs you take. Common food items involved in drug interactions include foods rich in vitamin K, which can interact with certain blood thinners like warfarin and make them less effective, possibly leading to a clot. Certain citrus juices like grapefruit juice are notorious for changing blood levels of some drugs, too. Calcium can bind with some drugs and prevent absorption.
For example, if you take the blood thinner warfarin, increasing vitamin K levels in the body can increase clotting and reduce the effectiveness of warfarin, which could result in a stroke. Foods rich in vitamin K include beef liver, broccoli, brussels sprouts, cabbage, collard greens, endive, kale, lettuce, mustard greens, parsley, soy beans, spinach, Swiss chard, turnip greens, watercress, and several other foods. While there is no need to avoid products that contain vitamin K, you should maintain a consistent level of consumption of these products.
Grapefruit or grapefruit juice consumption can also result in drug interactions that may increase the level of the medicine in your blood, possibly causing drug toxicity. For example, blood levels of some cholesterol drugs known as statins — atorvastatin, lovastatin, or simvastatin — can be affected by drinking grapefruit juice, and lead to severe muscle injury known as rhabdomyolysis. Not all medicines contained in a class of drugs like the statins may lead to the interaction, so your doctor will be able to prescribe another drug. Cranberry juice, orange juice, pomegranate juice, and even garlic can lead to interactions with drugs, too.
Tell Your Doc About Caffeine Use, Alcohol Use, and Illegal Drug Use
Socially-used drugs can have an especially harsh effect with other drugs. For example, some asthma drugs like the beta-2 agonist albuterol (Proventil HFA, Ventolin HFA) can have a stimulant effect, and if combined with caffeine, can interfere with sleep or lead to a rapid heart rate, which can be dangerous in people woth heart disease. The stimulant effect from caffeine can be additive to stimulation from decongestants, too.
Alcohol can worsen drowsiness, especially when mixed with other drugs that cause sedation, which may put you at a higher risk for a fall or a car accident. Alcohol should never be combined with opioid painkillers or anxiety medications like benzodiazepines. Life-threatening respiratory depression can occur.
A particularly concerning, yet often unknown interaction between alcohol and cocaine has been reported. The National Institute on Drug Abuse (NIDA) has found that the human liver combines cocaine and alcohol and manufactures a third substance, cocaethylene, that intensifies cocaine’s euphoric effects but may increase the risk of sudden death. According to the NIDA, this drug-drug interaction, between cocaine and alcohol, is the most common two-drug combination that results in drug-related deaths.
Illicit drugs combined with other illicit drugs can be particularly dangerous. Combining heroin and cocaine into one syringe, often called a “speedball”, is a mixture that is used by some injecting drug users, often with fatal results.
Don’t Take a Medication Prescribed for Someone Else
Medications are prescribed specifically for an individual person, often based on their age, weight, and specific type of medical condition. In addition, when you take medications that are not prescribed for you, there is no health care provider involved to review for potential interactions or safety based on your medical conditions.
For example, taking someone else’s antibiotic for a sore throat might not only lead to a possible drug interaction, it might worsen your infection. The antibiotic might not be the appropriate drug to treat the bacterial strain, and you probably won’t have a full course of antibiotic which can result in antibiotic resistance and failed treatment. Plus, if your sore throat is viral, instead of bacterial, you may not need an antibiotic at all. Your doctor can test you for this.
Follow All Dosing Recommendations on Your Prescription Bottle
Your prescription bottle will have specific directions for taking your medicine. For example, you may need to space the timing of when you take your medications. Some drug interactions involve binding of one drug to the other in the stomach. Antacids are commonly linked to this type of interaction. Your pharmacist will put a sticker on the your bottle to warn you of this interaction. To avoid the interaction you may space the timing of your doses, taking each drug 2 hours before or 4 hours after the other drug.
Antacids can also raise the pH in your stomach, and may result in an early dissolution of enteric coatings — for example, enteric-coated aspirin or ibuprofen — which should normally dissolve in the intestine. This could lead to severe stomach bleeding or lowered absorption of the drug. Your pharmacist will provide specific instructions.
DO NOT change the dose of your medication unless approved by your doctor. If your warning sticker suggests that you avoid a drug, or a certain class of drugs altogether, be sure to follow these instructions. Many patients that take blood thinners like warfarin need to avoid over-the-counter and prescription drugs that may increase the risk of bleeding; for example, NSAIDs (ibuprofen, naproxen) or aspirin.
Tell Your Health Care Provider About Your Medical Conditions
In people who have high blood pressure, OTC oral decongestants like pseudoephedrine (Sudafed) or phenylephrine (Sudafed PE) may increase blood pressure, even if their blood pressure is controlled with a medication. People with uncontrolled or severe high blood pressure need to avoid these medications.
Another common example of a disease-drug interaction is the use of the antihistamine diphenhydramine (Benadryl) in patients with certain types of glaucoma known as acute angle-closure (narrow-angle) glaucoma. For example, diphenhydramine can exhibit anticholinergic effects which can dilate the pupil and provoke angle closure in people with narrow angles. Antihistamines should be avoided in people with angle-closure glaucoma or only used under the supervision of a physician.
Do NOT Buy Drugs From Risky Online Pharmacies
While it may be a tempting way to save money on medications, buying medications — prescription or OTC — from foreign countries or from unreliable websites on the Internet can be costly to your health. According to the U.S. Food and Drug Administration “the safety and effectiveness of imported drugs have not been reviewed by the FDA, and their identity and potency can’t be assured.” You could receive the wrong drug, the wrong strength, or even outdated, expired medications. If you are not sure what’s in your medication, you can’t run a reliable drug interaction check to look for any serious problems.
How can drug interactions be avoided
Give health care practitioners a complete list of all of the drugs that you are using or have used within the last few weeks. This should include over-the-counter medications, vitamins, food supplements, and herbal remedies.
Inform health care practitioners when medications are added or discontinued.
Inform health care practitioners about changes in lifestyle (for example, exercise, diet, alcohol
Ask your health care practitioners about the most serious or frequent drug interactions with the medications that you are taking.
Since the frequency of drug interactions increases with the number of medications, work with your health care practitioners to eliminate unnecessary medications.
Hypertension is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high blood pressure, however, is a major risk factor for coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral vascular disease, vision loss, chronic kidney disease, and dementia. High blood pressure is classified as either primary (essential) high blood pressure or secondary high blood pressure. About 90–95% of cases are primary, defined as high blood pressure due to nonspecific lifestyle and genetic factors.
Blood pressure is expressed by two measurements, the systolic and diastolic pressures, which are the maximum and minimum pressures, respectively. For most adults, normal blood pressure at rest is within the range of 100–130 millimeters mercury (mmHg) systolic and 60–80 mmHg diastolic. For most adults, high blood pressure is present if the resting blood pressure is persistently at or above 130/90 or 140/90 mmHg. Different numbers apply to children. Ambulatory blood pressure monitoring over a 24-hour period appears more accurate than office-based blood pressure measurement.
Hypertension is a chronic elevation of blood pressure that, in the long-term, causes end-organ damage and results in increased morbidity and mortality. Blood pressure is the product of cardiac output and systemic vascular resistance. It follows that patients with arterial hypertension may have an increase in cardiac output, an increase in systemic vascular resistance, or both. In the younger age group, the cardiac output is often elevated, while in older patients increased systemic vascular resistance and increased the stiffness of the vasculature play a dominant role. The vascular tone may be elevated because of increased α-adrenoceptor stimulation or increased release of peptides such as angiotensin or endothelins. The final pathway is an increase in cytosolic calcium in vascular smooth muscle causing vasoconstriction. Several growth factors, including angiotensin and endothelins, cause an increase in vascular smooth muscle mass termed vascular remodeling. Both an increase in systemic vascular resistance and an increase in vascular stiffness augment the load imposed on the left ventricle; this induces left ventricular hypertrophy and left ventricular diastolic dysfunction.
Causes: Common Secondary Hypertension by age
Age under 18 years
Renal parenchymal disease (most common in underage <12 years)
Vesicoureteral Reflux Nephropathy
3. Age 19 to 39 years
Renal Artery Stenosis due to fibromuscular dysplasia
4. Age 40 to 64 years
Obstructive Sleep Apnea
5. Age over 65 years
Renal Artery Stenosis due to atherosclerotic disease
Chronic Kidney Disease
Causes: Secondary Hypertension in AdultsEndocrine Causes
Most common treatable secondary cause of Hypertension
Evaluate as cause in Refractory Hypertension where Hypokalemia or borderline low Potassium
Hyperthyroidism causes systolic Hypertension
Hypothyroidism causes diastolic Hypertension
Renal Artery Stenosis
Medications or substances
Cocaine or another stimulant
Obstructive Sleep Apnea
Renal parenchymal disease
Causes: Secondary Hypertension in age <18 years old
Renal parenchymal disease (Most common cause in children under age 12 years – up to 70%)
Vesicoureteral Reflux Nephropathy
Renal Artery Stenosis (due to fibromuscular dysplasia)
Rare in age <10 years
Most common cause in adolescents and adults
Medication Causes of Hypertension
Causes:Sodium retaining agents
Oral Contraceptives (occurs in 5% of users)
Estrogen Replacement Therapy
High Sodium Antacids
Glucocorticoids or Corticosteroids
Causes: Miscellaneous agents
Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors such as Celebrex)
Hypertension Combination Therapy if >20/10 over goal
Symptoms of Hypertension
Blood in the Urine
Decreased Urine Output
Pounding Sensation in the Neck, Chest, or Ears
Shortness of Breath
Other inconclusively related symptoms – A variety of symptoms may be indirectly related to but are not always caused by, high blood pressure, such as:
Blood spots in the eyes – blood spots in the eyes (subconjunctival hemorrhage) are more common in people with diabetes or high blood pressure, but neither condition causes the blood spots. Floaters in the eyes are also not related to high blood pressure. However, an eye doctor (ophthalmologist) may be able to detect damage to the optic nerve caused by untreated high blood pressure.
Facial flushing – Facial flushing occurs when blood vessels in the face dilate. It can occur unpredictably or in response to certain triggers such as sun exposure, cold weather, spicy foods, wind, hot drinks, and skin-care products. Facial flushing can also occur with emotional stress, exposure to heat or hot water, alcohol consumption and exercise — all of which can raise blood pressure temporarily. While facial flushing may occur while your blood pressure is higher than usual, high blood pressure is not the cause of facial flushing.
Dizziness – While dizziness can be a side effect of some blood pressure medications, it is not caused by high blood pressure. However, dizziness should not be ignored, especially if the onset is sudden. Sudden dizziness, loss of balance or coordination and trouble walking are all warning signs of a stroke. High blood pressure is a leading risk factor for stroke.
People often do not seek medical care until they have symptoms arising from the organ damage caused by chronic (ongoing, long-term) high blood pressure. The following types of organ damage are commonly seen in chronic high blood pressure:
Stroke or transient ischemic attack(TIA)
Eye damage with progressive vision loss
Peripheral arterial disease causing leg pain with walking (claudication)
Outpouchings of the aorta called aneurysms
About 1% of people with high blood pressure do not seek medical care until high blood pressure is very severe, a condition known as malignant hypertension.
In malignant hypertension, the diastolic blood pressure (the lower number) often exceeds 140 mm Hg.
Malignant hypertension may be associated with headache, lightheadedness, nausea, vomiting, and stroke-like symptoms
Malignant hypertension requires emergency intervention and lowering of blood pressure to prevent brain hemorrhage or stroke
Criteria: Hypertension in Adults
JNC-8 Blood Pressures goals (modified as of 2014)
Renal Insufficiency: <140/90 mmHg
Diabetes Mellitus: <140/90 mmHg > ADA recommends <140/80 mmHg, Age >80 years: <150/90 mmHg
No Diabetes Mellitus or renal disease
Age <60 years: <140/90 mmHg
Age >60 years: <150/90 mmHg
Goal Blood Pressures for Hypertensive Patients (JNC-7 Guidelines)
Hypertension without Co-morbidity: <140/90
Diabetes Mellitus: <130/80
Congestive Heart Failure: <130/80
Renal Insufficiency: <130/80
Renal Failure and >1g Proteinuria/24 hours: <125/75
JNC-7 Blood Pressure definitions
Optimal Blood Pressure: <115/80
Normal Blood Pressure: <120/80
Stage 1 Hypertension: 140-159/90-99
Stage 2 Hypertension: >160/100
Stages eliminated in JNC-7
Stage 3 Hypertension: 180-209/110-119
Stage 4 Hypertension: >210/120
Isolated Systolic Hypertension
Systolic Blood Pressure: >140 mmHg
Diastolic Blood Pressure: <90 mmHg
Criteria: Hypertension in Children and Adolescents (based on age, height, gender over at least 3 values)
Normal Blood Pressur
Blood Pressure <90% for age, height, gender
Blood Pressure 90% to 95% for age, height, gender or
Blood Pressure >120/80
Stage I Hypertension
Blood Pressure 95 to 99% plus 5 mm Hg for age, height, gender
Stage II Hypertension
Blood Pressure >99% plus 5 mm Hg for age, height, gender
Criteria: Hypertension in Adolescents
Age 16-18 years
Significant Hypertension: BP> 142/92
Severe Hypertension: BP> 150/98
Age: 13-15 years
Significant Hypertension: BP> 136/86
Severe Hypertension: BP> 144/92
Criteria: Hypertension in Children
Age 10-12 years
Significant Hypertension: BP> 126/82
Severe Hypertension: BP> 134/90
Age 6-9 years
Significant Hypertension: BP> 122/78
Severe Hypertension: BP> 130/86
Age 3-5 years
Significant Hypertension: BP> 116/76
Severe Hypertension: BP> 124/84
Age 1 month to 2 years
Significant Hypertension: BP> 112/74
Severe Hypertension: BP> 118/82
Age 8-30 days
Significant Hypertension: SBP> 104
Severe Hypertension: SBP> 110
Age <7 day old
Significant Hypertension: SBP> 96
Severe Hypertension: SBP> 106
BP Examination >Consider arm to leg systolic BP measurements (difference >20 mmHg suggests Aortic Coarctation)
Assess for Obesity
Weight and Height
Ideal Body Weight or BMI
Waist Circumference (assess for Metabolic Syndrome)
Mouth Exam > Mallampati Score increased in Sleep Apnea
Neck vein exam
Congestive Heart Failure signs
Palpable intercostal pulses
S4 Gallop rhythm (decreased LV compliance)
Accentuated S2 Heart Sound
Aortic Insufficiency murmur
Abnormal EKG or Echocardiogram
Prior Angiography results
Renal artery bruit > May be present in Renal Artery Stenosis
Abdominal Aortic Aneurysm
Enlarged or tender Kidneys (CVA pain)
Abnormal Sexual Development
Exam: Peripheral Vascular Disease
Femoral pulses > Delayed or absent in Aortic Coarctation
Lower extremity shin Hair Loss
Stigmata of Cirrhosis
Signs of Cushing’s Disease
A typical physical examination to evaluatehypertensionincludes:
ophthalmoscopy:Examination of thebloodvessels in theeye
Themedicalandfamilyhistoryhelpthephysiciandetermine if thepatienthasanyconditions or disordersthat might contribute to or causehypertension. A familyhistory of hypertensionmightsuggest a geneticpredisposition for hypertension.
Thephysicalexammayincludeseveralbloodpressurereadings at differenttimesand in differentpositions. The physician uses a stethoscope to listen to soundsmade by theheartandbloodflowingthroughthearteries.Thepulse, reflexes,andheightandweightarecheckedandrecorded.
Lifestyle changes are important for both treatment and prevention of high blood pressure, and they can be as effective as a drug treatment. These lifestyle changes can also have wider benefits for heart health and overall health. So the first choice is diuretics. It helps the kidneys eliminate excess salt and water from the body’s tissues and blood.
hydrochlorothiazide and chlorothiazide
Calcium channel blockers
Calcium channel blockers block the entry of calcium into muscle cells in artery walls.
JNC8 recommends calcium channel blockers to be a first-line treatment either as monotherapy or in combination with thiazide-type diuretics, ACE inhibitors, or angiotensin II receptor antagonists for all patients regardless of age or race.
Captopril, the prototypical ACE inhibitor
ACE inhibitors inhibit the activity of the angiotensin-converting enzyme (ACE), an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor.
A systematic review of 63 trials with over 35,000 participants indicated ACE inhibitors significantly reduced doubling of serum creatinine levels compared to other drugs (ARBs, α blockers, β blockers, etc.), and the authors suggested this as the first line of defense. The AASK trial showed that ACE inhibitors are more effective at slowing down the decline of kidney function compared to calcium channel blockers and beta-blockers. As such, ACE inhibitors should be the drug treatment of choice for patients with chronic kidney disease regardless of race or diabetic status.
ACE inhibitors (and angiotensin II receptor antagonists) – should not be a first-line treatment for black hypertensives without chronic kidney disease. Results from the ALLHAT trial showed that thiazide-type diuretics and calcium channel blockers were both more effective as monotherapy in improving cardiovascular outcomes compared to ACE inhibitors for this subgroup. Furthermore, ACE inhibitors were less effective in reducing blood pressure and had a 51% higher risk of stroke in black hypertensives when used as initial therapy compared to a calcium channel blocker. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations.
Notable side effects of ACE inhibitors include dry cough, hyperkalemia, fatigue, dizziness, headaches, loss of taste and a risk for angioedema.
Angiotensin II receptor antagonists
Valsartan, an angiotensin II receptor antagonist
Angiotensin II receptor antagonists work by antagonizing the activation of angiotensin receptors.
Whether angiotensin receptor blockers may or may not increase the risk of myocardial infarction (heart attack) was announced in BMJ and was debated in 2006 in the medical journal of the American Heart Association. To date, there is no consensus on whether ARBs have a tendency to increase MI, but there is also no substantive evidence to indicate that ARBs are able to reduce MI.
In the VALUE trial, the angiotensin II receptor blocker valsartan produced a statistically significant 19% (p=0.02) relative increase in the prespecified secondary endpoint of myocardial infarction (fatal and non-fatal) compared with amlodipine.
The CHARM-alternative trial showed a significant +52% (p=0.025) increase in myocardial infarction with candesartan (versus placebo) despite a reduction in blood pressure.
Indeed, as a consequence of AT1 blockade, ARBs increase Angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating Angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition, upregulated. Unfortunately, recent data suggest that AT2 receptor stimulation may be less beneficial than previously proposed and may even be harmful under certain circumstances through the mediation of growth promotion, fibrosis, and hypertrophy, as well as proatherogenic and proinflammatory effects.
Adrenergic receptor antagonists
Propranolol, the first beta-blocker to be successfully developed
Mixed Alpha + Beta-blockers
Despite lowering blood pressure, alpha-blockers have significantly poorer endpoint outcomes than other antihypertensives and are no longer recommended as a first-line choice in the treatment of hypertension. However, they may be useful for some men with symptoms of prostate disease.
Vasodilators act directly on the smooth muscle of arteries to relax their walls so blood can move more easily through them; they are only used in hypertensive emergencies or when other drugs have failed, and even so are rarely given alone.
Sodium nitroprusside, a very potent, short-acting vasodilator, is most commonly used for the quick, temporary reduction of blood pressure in emergencies (such as malignant hypertension or aortic dissection). Hydralazine and its derivatives are also used in the treatment of severe hypertension, although they should be avoided in emergencies. They are no longer indicated as first-line therapy for high blood pressure due to side effects and safety concerns, but hydralazine remains a drug of choice in gestational hypertension.
Although controversial over this off-label purpose, benzodiazepines may play a role in lowering blood pressure. They work as an agonist of the GABA-a receptors in the brain, thus slowing down neurotransmission and dilating blood vessels. GABA is an abbreviation for gamma-aminobutyric acid. It is an inhibitory neurotransmitter among others (glycine, adenosine, etc.) GABA-a receptors are ion channels that are the primary target for benzodiazepines. When an agonist binds to this receptor site, the protein channel opens, allowing negative chloride ions entering the channel and penetrating the voltage-gated ion site. Thus, giving negative feedback in neurotransmission and easing stress, anxiety and tension in patients that can be associated with elevated blood pressure. In addition to GABA, benzodiazepines inhibit the re-uptake of a nucleoside chemical called Adenosine, which serves as an inhibitory chemical mentioned above. It also serves as a coronary vasodilator, allowing the cardiac muscle to relax and dilating cardiac arteries. However, long-term use of benzodiazepines are associated with dependence and tolerance, which is likely the result of GABA-a receptor downregulation. Therefore, withdrawal symptoms include hypertension, even in healthy individuals
Renin comes one level higher than angiotensin-converting enzyme (ACE) in the renin-angiotensin system. Inhibitors of renin can therefore effectively reduce hypertension. Aliskiren (developed by Novartis) is a renin inhibitor which has been approved by the U.S. FDA for the treatment of hypertension.
Aldosterone receptor antagonists
Aldosterone receptor antagonists
Aldosterone receptor antagonists are not recommended as first-line agents for blood pressure, but spironolactone and eplerenone are both used in the treatment of heart failure and resistant hypertension.
Alpha-2 adrenergic receptor agonists
Central alpha agonists lower blood pressure by stimulating alpha-receptors in the brain which open peripheral arteries easing blood flow. These alpha 2 receptors are known as autoreceptors which provide negative feedback in neurotransmission (in this case, the vasoconstriction effects of adrenaline). Central alpha agonists, such as clonidine, are usually prescribed when all other anti-hypertensive medications have failed. For treating hypertension, these drugs are usually administered in combination with a diuretic.
Adverse effects of this class of drugs include sedation, drying of the nasal mucosa and rebound hypertension.
Some indirect anti-adrenergic are rarely used in treatment-resistant hypertension
guanethidine – replaces norepinephrine in vesicles, decreasing its tonic release
mecamylamine – antinicotinic and ganglion blocker
reserpine – indirect via irreversible VMAT inhibition
For the most resistant and severe disease, oral minoxidil (Loniten) in combination with diuretic and β-blocker or another sympathetic nervous system suppressant may be used.
Endothelin receptor blockers
Bosentan belongs to a new class of drug and works by blocking the receptors of the hormone endothelin. It is specifically indicated only for the treatment of pulmonary artery hypertension in patients with moderate to severe heart failure.
Future Treatment Options
Blood pressure vaccines
Blood pressure vaccinations are being trialed and may become a treatment option for high blood pressure in the future. CYT006-AngQb was only moderately successful in studies, but similar vaccines are being investigated.
Peripheral adrenergic inhibitors
This group of drugs works to block certain chemical messengers inside the brain, which keeps the smooth muscles from getting the message to constrict. These medications are generally used only if other medications aren’t effective. They include:
guanethidine monosulfate (Ismelin)
Vasodilators relax the muscles in the walls of blood vessels, especially small arteries (arterioles). This widens the blood vessels and allows blood to flow through them more easily. Blood pressure falls as a result. Hydralazine hydrochloride (Apresoline) and minoxidil (Loniten) are examples of these.
Starting hypertension treatment
Consider treating immediately if BP in the clinic is ≥180/110 mm Hg; otherwise, consider after results of ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM), blood tests and cardiovascular risk assessment are available.
Diagnose hypertension if the average of ABPM or HBPM readings is ≥135/85 mm Hg, (ignore first-day readings and average the rest – see separate Hypertension article).
Stage 1 hypertension – clinic readings ≥140/90 mm Hg and ABPM/HBPM ≥135/85 mm Hg.
Stage 2 hypertension – clinic readings ≥160/100 mm Hg and ABPM/HBPM ≥150/95 mm Hg.
Hypertension treatment should be commenced in people aged under 80 years with stage 1 hypertension plus signs of end-organ damage (known cardiovascular or renal disease), or with diabetes mellitus or a 10-year cardiovascular disease (CVD) risk ≥20%. Treatment in mild hypertension without target-organ damage or cardiovascular risk remains contentious.
The recommendation criteria for long time Treatment
Treatment should be started in all patients (any age) with stage 2 hypertension. Treat isolated systolic hypertension in the same way.
Initial antihypertensive choices
If the patient is young (≤55 years) and non-black, start with:
(A) angiotensin-converting enzyme (ACE) inhibitor or low-cost angiotensin-II receptor antagonist (AIIRA) – also called an angiotensin receptor blocker (ARB).
A beta-blocker may be appropriate in younger adults if an ACE inhibitor is not tolerated, in women who may become pregnant or if there is evidence of increased sympathetic drive. Beta-blockers were the B in the previous ABCD hypertension advice but are no longer preferred treatment, as evidence suggests they are inferior to other agents in terms of outcome.
If the patient has aged>55 years or a black person of African or Caribbean family origin, use:
(C) calcium-channel blocker (CCB).
(D) thiazide-like diuretic if CCB not suitable. Chlortalidone (12.5-25.0 mg once daily) or indapamide (1.5 mg modified-release once daily or 2.5 mg once daily) are specifically recommended choices.
Step 2 choices
(A+C) ACE inhibitor or AIIRA with CCB.
Use an ACE inhibitor/AIIRA and a thiazide-like diuretic (D) if CCB is not tolerated (or if there is any evidence of heart failure).
If initially started on a beta-blocker, add a CCB rather than a thiazide-like diuretic second-line (reduce diabetic risk).
Consider an AIIRA rather than an ACE inhibitor with a CCB in black people of African or Caribbean origin.
Step 3 choices
(A+C+D) ACE inhibitor or AIIRA and a CCB and a thiazide-like diuretic (chlorthalidone or indapamide).
Step 4 choices
Consider a fourth agent or referral for specialist advice.
(A+C+D) ACE inhibitor or AIIRA and a CCB and a thiazide-like diuretic plus a further diuretic (higher-dose thiazide-like diuretic or spironolactone, depending on potassium). Monitor renal function and electrolytes.
If the higher-dose diuretic is not tolerated, consider an alpha-blocker or a beta-blocker, or seek expert advice.
The combination of an ACE inhibitor with an AIIRA is not recommended for the treatment of hypertension.
The PATHWAY-2 trial, published in 2015, suggested that spironolactone is the most effective fourth-line agent for resistant hypertension. A drug safety update from the Medicines and Healthcare products Regulatory Agency (MHRA) in 2016 warns of the risk of hyperkalemia when an ACE inhibitor or AIIRA is combined with spironolactone. Routine use of this combination is not recommended but where it is, the lowest possible dose should be used and electrolytes monitored closely.
Natural/Ayurvedic & Unani Remedies High Blood Pressure
Garlic is gaining more and more popularity for its use in lowering high blood pressure. This herb also has blood-thinning properties which makes it great for improving overall cardiac health.
Garlic is also a natural diuretic — meaning it forces out excess sodium and water from the body, and into your urine. This effect takes the pressure off of an overworked heart and decreases blood pressure.
Method: If the taste of garlic is too strong for you, popular odorless garlic supplements are also available.
If you cannot handle eating the entire clove raw, hold a slice of garlic in your mouth and try sucking on the juices for 15 minutes.
You can also finely mince 1-2 cloves of garlic, mix it into a glass of water, and drink it.
Another method is to take the finely minced pieces, put it on a piece of fruit, and cover it with honey.
Tip — try adding a few cloves to your smoothies.
Carrots contain high levels of antioxidants beta-carotene, Vitamin A, and Vitamin C. Antioxidants reduce the amount of cancer-causing free radicals in the body. They also protect against damage to blood vessels and cellular death.
Carrots are also high in the electrolyte, potassium. Potassium is great at keeping the fluid within the body balanced and normalizing blood pressure. Potassium positively counteracts the effects of sodium. Consumed in large amounts, sodium can negatively affect blood pressure.
Method: Drink 1-3 glasses of carrot juice a day. Make sure to buy organic and do not add any sugar.
Tomatoes contain beta-carotene, vitamin E, potassium, and antioxidants — which are all great at lowering high blood pressure.
Tomatoes also contain lycopene, a chemical that gives it its rich red color. Lycopene has antioxidant effects that lowers bad cholesterol (LDL) and prevents the build-up of fatty deposits in arteries (atherosclerosis). These buildups can lead to cardiovascular disease.
Eat a cup of fresh tomatoes, tomato sauce, or blended tomato juice, everyday. If you do not like the taste of tomatoes, try taking lycopene supplements. Avoid commercial tomato sauce, which contain high levels of sodium.
Celery seeds are widely used in the Chinese culture for lowering blood pressure. Specifically, the Chinese use celery seeds to lower high blood pressure of the liver.
Celery is a fibrous vegetable that also acts as a diuretic. Diuretics flush out excess water from the heart and the body. This causes a decrease in blood pressure.
Pomegranates not only are dense in nutrients but are also high in antioxidants — specifically in tannins and anthocyanins. Pomegranates are fruits that have a hard shell and edible juicy red seeds.
Pomegranates contain phytochemicals, flavonoids, polyphenols, and punicalagin. Phytochemicals naturally occur in plant foods that act as antioxidants and prevent damage to our cells. Antioxidants such as flavonoids and polyphenols fight against heart disease and cancers.
Punicalagin is a compound that is mostly responsible for the health benefits in pomegranates. It improves the functions of the heart and blood vessels, lowers bad (LDL) cholesterol, raises good (HDL) cholesterol, lowers high blood pressure, and reverses the effects of arterial blockage (atherosclerosis).
Pomegranates contain more antioxidants than red wine, berries, or even green tea.
Method: Add pomegranate seeds to your salad, or juice the seeds into a tasty drink.
Method: Mix celery seeds into your tea, your cooking, or drink fresh celery juice — 3 times a day.
Beets & Radishes
Beets & radishes are under-appreciated and overcooked vegetables. Both beets and radishes are high in nitrates, which are great at lowering high blood pressure, by improving vasodilation.
Nitrates change into vasodilator nitric oxide after being ingested. Nitric acid dilates blood vessels, regulates blood pressure, decreases endothelial inflammation, and platelet aggregation.
Both the leaves and the roots of the radish lowers elevated blood pressures.
Juice made out of beets or radishes is the best form of the vegetables, in lowering blood pressure. Drink a glass of blended beets or radishes juice, daily. Also, add fresh beets and radishes to any dish!
Sesame oil contains omega-6s, polyunsaturated fatty acids (PUFA), Vitamin E, and sesamin, which are great for lowering blood pressure, cardiovascular disease, and diabetes.
Sesamin is a lignan compound in sesame oil that has been shown to reduce blood pressure levels. Sesame lignans reduce the absorption of cholesterol in the body.
PUFA and sesamin work together to relax the arterial wall and reduce blood pressure.
Method: Incorporate 1 ounce of sesame seeds or oil into your daily cooking, for at least 2 months.
Ginger has been used for centuries in Asian and Indian cultures, especially for its numerous health benefits. Ginger is great for preventing heart conditions, such as lowering blood pressure, decreasing cholesterol, and preventing blood clots.
Ginger decreases bad cholesterol (Low-Density Lipoproteins), by preventing plaque build-up on arterial walls, that can lead to increased blood pressure.
Method: Add fresh ginger to your smoothies and juices, and try to incorporate ginger into your daily cooking.
Coconut water is filled with potassium and magnesium electrolytes, which are good for the heart muscle.
Coconut water lowers blood pressure by acting as a potassium-sparing diuretic. This removes the excess water from the body while retaining vital potassium. Coconut water is best when it is organic and bottled in its raw form.
Drink 8 ounces of organic coconut water, 1-3 times a day. The effects are weight-based, so if you are on the heavier side, drink more coconut water (3 times a day).
Cayenne Pepper (Capsaicin)
Cayenne pepper is a known vasodilator. It quickly expands blood vessels, which improves the flow of blood. Faster and more efficient flow takes the pressure off of the arteries, thus decreasing your blood pressure. Capsaicin is one of the major ingredients in red peppers. The spicier the pepper, the more capsaicin it contains.
Cayenne pepper helps to create new red blood cells, improves blood structure, and aids in detoxing the blood. During detoxification, cayenne pepper is thought to also remove some plaque build-up off of the arterial walls. Cayenne pepper is also known to stop bleeding fast. If you have a cut, try sprinkling some cayenne pepper over it.
The recommended dosage is 1 teaspoon of organic cayenne pepper a day, and slowly work your way up to one teaspoon, 3 times a day. If the taste is too spicy for you, try taking capsaicin supplements.
Dark Chocolate (Caca0)
Dark chocolate is made from the seeds of the cocoa tree (Theobroma cacao) and is loaded with antioxidants (cancer-fighting) — including polyphenols, flavonoids, catechins.
The cocoa tree seeds contain flavonoids, but more importantly, it is exceptionally high in its levels of flavanols.
Flavanols (Flavan-3-ol) are phytonutrients, which is known as plant-based nutrients. Not many other foods come close to the number of flavanols that are found in cocoa seeds.
Activated nitric oxide dilates blood vessels, making it easier for the blood to circulate throughout the body. NO is absolutely necessary for maintaining a healthy body.
By keeping the blood vessels open, it allows the blood to efficiently carry vital oxygen and nutrients to all parts of the body. Dilated blood vessels decrease stress in the body. This in turn, lowers blood pressure and reduces the risk of stroke or a heart attack.
Make sure your dark chocolates or cocoa powders contain at least 50-80% of cocoa to reap the benefits of the flavanols. Just remember that the more cocoa content your chocolate contains, the more nutritious it is.
Cardamom is a spice that has been used for thousands of years in Ayurveda medicine. It is widely used for cardiac disorders, gastrointestinal disorders, renal problems, heartburn, and respiratory disorders.
Cardamom is also known for its antioxidant, gastroprotective, anti-spasmodic, antibacterial, anti-platelet aggregation, and anti-cancer properties.
Cardamom causes vasodilation (dilation of blood vessels) and allows blood to flow more easily, thus lowering blood pressure.
Mix 1 teaspoon of cardamom powder with raw organic honey in a cup of warm filtered water. Drink twice a day.
Hibiscus is widely used around the world to manage blood pressure.
Hibiscus acts as a diuretic and flushes out all the excess fluid that is in your heart and in your tissues. This decreases the pressure on the arterial walls. Vessel walls are relaxed and blood volume is decreased, thus lowering your blood pressure.
A study performed in 2008 shows that 3 cups of hibiscus tea daily lowers systolic blood pressure (SBP) by 7 mm Hg, after only 6 weeks.
Seep dried hibiscus leaves into a cup of hot filtered water. Add raw organic honey and lemon for taste
For centuries, hawthorn has been used for cardiac, circulatory, and respiratory disorders. The berries of the plant has been specifically used to treat high blood pressure, irregular heartbeats, chest pain, atherosclerosis, and heart failure.
Hawthorn also contains flavonoids, which are antioxidants that destroy free radicals. Flavonoids help dilate blood vessels, improve the flow of blood, and protect against blood vessel damage.
Drink hawthorn tea 1-3 times a day.
Cat’s claw (uncaria tomentosa) is a popular herb in China, South America, and Central America. It is widely used in China for the treatment of high blood pressure. Cat’s claw lowers blood pressure by inducing vasodilation. Dilated blood vessels allow the blood to flow more easily. It also acts as a mild diuretic and rids the body of harmful excess
Activated NO dilates blood vessels, making it easier for the blood to circulate throughout the body.
By keeping the blood vessels open, blood is able to efficiently carry vital oxygen and nutrients all over the body. Dilated blood vessels decrease stress in the body, ultimately lowering blood pressure and reduces the risk of stroke and heart attacks.
A typical daily dose of cat’s claw is 350 milligrams. Cat’s claw tea is also a good alternative.
Mistletoe is not the first thing that may come to one’s mind when thinking about lowering elevated blood pressures. There is a lot more to this plant than just being a beautiful holiday decoration.
Mistletoe boosts the immune system, lowers blood pressure, and helps treat cancer and hepatitis. Mistletoe extracts contain an active compound called alkaloids. Alkaloids lower blood pressure by controlling nerve impulses along the heart and arterial walls. The actions of mistletoe are gradual but have a long-lasting effect on blood pressure.
Mistletoe can be harmful and poisonous if consumed raw and unprocessed. Always consult with a doctor before taking mistletoe extracts, to avoid hypotension (below normal blood pressure).
Curcumin is the main component of turmeric. Turmeric is one of the most studied spices in the world. It is known to significantly decrease inflammation throughout the body. By reducing inflammation, turmeric improves blood flow and improves cardiovascular function.
Turmeric can help remove some of the plaque build-ups off arterial walls. Turmeric is also a natural blood thinner, which improves blood flow and thus, lowers blood pressure.
Add turmeric powder to your favorite tea, and flavor it with ginger and raw organic honey. Turmeric capsules or tinctures are also available.
Omega-3 (Fatty Acids)
Omega-3 is great at lowering blood pressure and cholesterol.
Fish oil contains Essential Fatty Acids (EFA). EFAs are polyunsaturated fats derived from linolenic (Omega-3), linoleic (Omega-6), and oleic acids. These are essential fats, meaning that our bodies cannot produce them on its own. It is crucial that EFAs are obtained from our diet.
The balanced ratio that is needed by our bodies of Omega-6 and Omega-3 is between 2:1-4:1. Due to the American diet, our ratios have become 10:1-30:1. Unfortunately, a large chunk of the population is lacking in Omega-3.
Omega-3 is important for decreasing inflammation throughout the body. Decreasing inflammation helps prevent heart disease, autoimmune diseases, stroke, and mental illnesses (inflammation of the brain). It is also well-known that Omega-3s are effective at fighting depression and anger.
Fatty fish such as salmon, herring, trout, krill, canned tuna, and sardines contain a good amount of Omega-3. The daily recommended dose of Omega-3 is 1,000 milligrams.
Vitamin D is a “sun vitamin” that regulates over 200 genes. It is also responsible for proper cell growth and development. Usually, 50-90% of vitamin D is absorbed by our bodies, directly from the sun. The remainder comes from our diet. Natural sources of Vitamin D can be found in eggs, fatty fish, fortified dairy and meats.
Since people are spending less and less time outdoors, vitamin D deficiency is on the rise and is affecting people worldwide.
A study published in 2014 shows that Vitamin D supplementation helps to lower high blood pressure. Vitamin D suppresses the hormone renin, which is similar to the effect of angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors are popularly prescribed antihypertensives.
If you are going to take supplements, make sure to get D3 (cholecalciferol), and not D2 (ergocalciferol). Vitamin D3 is the active form that our bodies can use. The recommended daily dose of Vitamin D3 is 2,000 IU.
CoQ10 is a naturally occurring enzyme. It contains antioxidants that are good for maintaining cardiac health.
CoQ10 has been shown to decrease blood pressure and reduces the thickening of the heart muscle (hypertrophy).
There are no known side effects of CoQ10 since it naturally occurs in the body.
According to Mayo Clinic, for the treatment of hypertension, take 60-360 milligrams daily for 8-12 weeks.
Lavender is a popular fragrance that is widely used as a relaxer of the mind, body and soul. This herb is also known to help decrease your blood pressure and heart rate.
One study shows that aromatherapy with certain essential oils can lower blood pressure. Effective oils include blends of lavender, ylanglang, and bergamot. The recommended usage is once daily, for 4-weeks.
Use lavender essential oils, or incorporate lavender into your baked foods and daily cooking.
Relax & Listen to (Classical) Music
Surprisingly, stress plays a huge role in cardiovascular disease.
Music has a calming effect and can be used as stress-relieving therapy. Music subconsciously affects our mood. The right type of music can have a positively calming effect and has been proven to lower blood pressure.
Listening to music for at least 30-minutes a day can lower blood pressure, slow down heart rate, and decrease anxiety.
Set aside sometime every day to just relax and listen to some Giuseppe Verdi or Beethoven’s Ninth Symphony.
Exercise – Get Walking
Being overweight puts extra pressure on your arterial walls and forces your heart to work harder 24/7. It also puts you at risk for developing other diseases, such as atherosclerosis, which can lead to hypertension, cardiovascular disease, heart attacks, and stroke. A sedentary lifestyle can increase your risk of having high blood pressure by 30 percent. Walking is the best exercise you can do for your entire body.
One study shows that light exercising (brisk walking or light jogging) aids in decreasing elevated blood pressure. Walking daily can also help you to go to sleep more easily, and stay asleep.
Homeopathic Remedies to Lower Blood Pressure
Belladonna – While good for throbbing and violent conditions that start suddenly, it can be useful for high blood pressure as well. It’s one of the main remedies in a hypertensive crisis, with flushes of heat, pounding headache, an impending stroke.
Glonoinum – This one is helpful for high blood pressure that may be accompanied by a pulsating, congestive headache that worsens in the sun. A headache is worse from the sun. Your face is flushed. Along with hypertension, you may have angina that causes a hot sensation in the chest.
Nux Vomica – The candidates for Nux are easily angered or upset, and compulsive workaholics. They are chilly in body temperature and tend to complain of gastrointestinal upset (diarrhea, constipation, stomach pain, nausea, etc.). They crave stimulants, such as drugs, caffeine or alcohol. This character profile paves the way toward high blood pressure.
Natrum Mur – This is a salty remedy that helps symptoms caused by grief. High blood pressure can return following an emotional event, like the death of a spouse. These people tend not to like sympathy and are emotionally closed off.
Baryta Carbonica – Used for hypertension in people who are very shy and have difficulty concentrating. Symptoms are worse when lying on the left side. They can include strong stomach pain that recedes when lying on the stomach.
Aurum – A common recommendation for people with hypertension triggered by stress endured over the long term. It’s like it’s burning inside them; this feeling is often linked to their job.
Lachesis – This remedy is good for high blood pressure where one’s face is flushed and whose behavior is overactive, and who overall appears primed to explode one day.
Healthy diet to Prevent Hypertension
Advice from NICE includes
Weight reduction should be suggested if necessary, to maintain an ideal body mass index (BMI) of 18.5-24.9 kg/m. Offer a diet sheet and/or dietetic appointment. Dietary self-help (eg, dieting clubs, for which there may be local referral options) may be appropriate. Encourage physical activity alongside dietary changes. NICE guidelines for obesity make further recommendations about pharmaceutical and surgical options where appropriate.
Use of wholegrain varieties of starchy food (eg, rice, pasta, bread) where possible.
Reduction of saturated fats, and increasing monounsaturated fats, using olive or rapeseed oils and spreads.
Reduction in sugar intake and that of foods containing refined sugars.
Eating at least five portions of fruit and vegetables per day.
Eating at least two portions of fish per week, including a portion of oily fish.
Eating at least 4-5 portions of unsalted nuts, seeds, and legumes per week
Reducing any excessive caffeine consumption.
Low dietary salt
Keeping alcohol within current national recommended levels. (Currently, no more than 14 units per week for men and women, spread through the week, with at least two days alcohol-free.)
Calcium, magnesium or potassium supplements are not recommended.
Chronic disease are on the rise in the United States, leaving healthcare payers with the challenge of covering care for patients with these expensive, long-term conditions. Chronic diseases are such a costly healthcare endeavor that experts such as the AMA have asked private and public payers to fund chronic disease management programs, and other stakeholders have established chronic disease management funds that provides Medicare beneficiaries financial support to pay for the high costs of chronic care and treatment.
Selected Definitions for Chronic Disease and Other Chronic Conditions by Source and Year
We defined a person as having a chronic condition if that person’s condition had lasted or was expected to last 12 or more months and resulted in functional limitations and/or the need for ongoing medical care.
Duration: ≥12 months
Functional limitation: yes
Need for ongoing medical care: yes
Authors noted that they defined “chronic condition” broadly for several reasons, including the following: 1) a high proportion of individuals who have a chronic condition have more than 1 chronic condition; 2) functional limitations and other consequences of health problems often are independent of specific diseases; and 3) whereas diagnoses are important for medical management, a diagnosis alone may provide incomplete information on morbidity because of variations in condition-specific severity.
A chronic disease or condition has 1 or more of the following characteristics: is permanent; leaves residual disability; is caused by nonreversible pathological alteration; requires special training of the patient for rehabilitation; or may be expected to require a long period of supervision, observation, or care.
Functional limitation: yes (residual disability)
Need for ongoing medical care: yes
Includes a broad spectrum of factors affecting health and functional status.
The chronic condition is defined as a condition that lasts 12 months or longer and meets 1 or both of the following tests: 1) it places limitations on self-care, independent living, and social interactions; and 2) it results in the need for ongoing intervention with medical products, services, and special equipment.
Duration: ≥12 months
Functional limitation: yes
Need for ongoing medical care: yes
Definition combines minimum duration with function and needs for treatment.
The chronic condition is a general term that includes chronic illnesses and impairments. It includes conditions that are expected to last a year or longer, limit what one can do, and/or may require ongoing medical care. Serious chronic conditions are a subset of chronic conditions that require ongoing medical care and limit what a person can do.
Duration: ≥1 year
Functional limitation: yes
Need for ongoing medical care: yes
The definition further differentiates the level of severity of the condition.
A health condition is a departure from a state of physical or mental well-being. In the National Health Interview Survey, each condition reported as a cause of an individual’s activity limitation has been classified as chronic, not chronic, or unknown if chronic, based on the nature and duration of the condition. Conditions that are not cured once acquired (such as heart disease, diabetes, and birth defects in the original response categories, and amputee and old age in the ad hoc categories) are considered chronic, whereas conditions related to pregnancy are not considered chronic. Other conditions must have been present for 3 months or longer to be considered chronic. An exception is made for children aged less than 1 year who have had a condition since birth: such conditions are always considered chronic.
Duration: not cured once acquired or lasts ≥ 3 months
Functional limitation: no
Need for ongoing medical care: no
Combines multiple factors, including duration, nonamenability of condition to cure, and others.
US Department of Health and Human Services (HHS), 2010 (rx)
Chronic illnesses are “conditions that last a year or more and require ongoing medical attention and/or limit activities of daily living.”
Duration: ≥1 year
Functional limitation: yes
Need for ongoing medical care: yes
This definition, adapted from other sources (rx,rx), incorporates elements of duration, medical requirements, and functional status. It also has the advantage of being compact. The HHS Strategic Framework (rx) also adopts the definition of “multiple” used in another source (rx) as 2 or more concurrent chronic conditions.
They are generally characterized by uncertain etiology, multiple risk factors, a long latency period, a prolonged course of illness, noncontagious origin, functional impairment or disability, and incurability.
Duration: the prolonged course of illness or “incurability”
Functional limitation: yes (“functional impairment or disability”)
Need for ongoing medical care: no
The most recent definition in this well known, practice-oriented guide evolved from the definition in the guide’s first edition in 1993: “those that have a prolonged course, that do not resolve spontaneously, and for which a complete cure is rarely achieved.”
Chronic diseases have a long course of illness. They rarely resolve spontaneously, and they are generally not cured by medication or prevented by a vaccine.
Duration: “long course”
Functional limitation: no
Need for ongoing medical care: no
The definition of chronic disease includes an element of treatment.
1. Hepatitis C Virus: Advances Are Significant
Hepatitis C virus (HCV) is not only costly, it’s frequently a hot news item. With health officials urging baby-boomers to get tested for HCV, and new all-oral regimens offering a cure in a matter of a few months, HCV has undergone major treatment advances.
As with any big breakthrough, treatment of HCV does not come cheap. Uproar started over high-priced antiviral treatments like Sovaldi (sofosbuvir) and Harvoni (ledipasvir and sofosbuvir). For these agents, total treatment costs hover in the $45,000 to $50,000 range for 12 weeks of treatment (IMS 2016).
However, cost effectiveness of a cure may offset a continued lifetime of difficult-to-control disease, as reported in 2016 by JAMA Internal Medicine. Costs for HCV are expected to peak in 2024 at over $9.1 billion. Whether insurance will cover early HCV disease with the newer oral agents (in early vs. late liver fibrosis) has some questioning the timeline to eradicate HCV, suggesting it could be a decade or longer.
2. Low Back Pain and Neck Pain
Almost everyone experiences some form of musculoskeletal pain during their lifetime, and necks and backs are certainly at the top of the list. Personal healthcare spending for this group comes in at a whooping $88 billion annually (2013) in the US, according to a Journal of American Medical Association (JAMA) report published in 2016. Back pain usually originates in the spine and the muscles that support it. Neck pain can originate from poor posture and osteoarthritis, too.
3. High Blood Pressure: Often Undetected
With 1 in every 3 American adults diagnosed with high blood pressure it’s no wonder the cost for treating patients with this condition totals over $83 billion yearly, according to the Journal of American Medical Association (JAMA) as reported in 2016.
Blood pressure is the force of blood against your artery walls as it circulates through your body. It can greatly increase your risk of certain health problems like heart disease and stroke if it remains untreated. High blood pressure often goes undetected because it has no warning signs or symptoms so it is important to get your blood pressure checked regularly. Adults ages 30 and older without high blood pressure should have their blood pressure checked yearly, but with heart risk factors, older age, borderline readings, or history of high blood pressure more frequent readings may be needed.
4. Diabetes: The Top Cost
Diabetes affects just over 9% of Americans with medical expenses totaling over $100 billion per year; the top healthcare-related expense in the nation as reported in JAMA in 2016. Plus, it is estimated 86 million Americans age 20 and older have prediabetes, a precursor to full-blown diabetes. In all forms of diabetes there is too much sugar in the blood which can lead to serious health complications including heart and kidney disease, eye problems, nerve damage and even limb amputations.
Hospital care, anti-diabetic medications and supplies, prescription medicines to treat complications and regular doctor visits all contribute to the burden of cost. Healthy lifestyle choices such as eating a well-balanced diet, exercising regularly and managing your weight may lower your chance of getting diabetes.
5. Costs of Osteoarthritis & Joint Problems
It is estimated that 1 in 2 people will get some form of osteoarthritis (OA) in their lifetime. The back, neck, knees, hips, and hands are common targets of OA. It is no surprise then that annual cost for osteoarthritis exceeds $47 billion annually according to a 2016 JAMA report.
OA is caused from the gradual wear and tear of the cartilage between the bone causing pain, stiffness and inflammation. This chronic condition is more common as we age and often results in a knee or hip replacement. Medications, physical therapy, and hospitalization for surgery all contribute to the cost. Maintaining a healthy body weight and non-weight bearing exercise like swimming or cycling may help to keep the joints mobile without pain.
6. Falls, Injuries, and Broken Bones
Falls are costly and serious events. In fact, 1 out of every 5 falls causes a serious injury such as a broken bone or a head injury, according to the CDC. Each year, trauma accounts for 37 million emergency department visits and 2.6 million hospital admissions so it’s no surprise that annual costs due to injuries from falls comes in $76 billion.
Falls in the elderly are a top concern due to morbidity and mortality linked with hip fractures. Each year at least 300,000 older people are hospitalized for hip fractures. Research shows that women have a 5-fold increase of death within one year after sustaining a hip fracture, and men an 8-fold increase.
7. Heart Disease: The no 1 Killer
Heart disease is the number one cause of death in the United States, killing over 370,000 people a year. As reported in 2016 by the American Heart Association, costs of cardiovascular diseaseand stroke total more than $316.6 billion, including health expenditures and lost productivity. After diabetes, ischemic heart disease (coronary artery disease) ranks as the nation’s 2nd most costly medical condition with a grand expenditure of just over $88 billion per year.
Hospitalization, surgery, diagnostic tests, monitoring, specialist doctor visits and medicines all contribute to the price. To reduce your risk of heart disease, adjust your lifestyle by maintaining a normal weight, eating a healthy diet, not smoking, and getting regular exercise. Preventing and controlling high blood pressureand high cholesterol also play a significant role in heart health.
8. Chronic Obstructive Pulmonary Disease (COPD) and Asthma
Can’t catch your breath? Here’s why. Long term breathing problems including asthma, bronchitis and emphysema/COPDmake up this group with costs of care totaling almost $86 billion per year.
Roughly 11 million American adults are living with some form of COPD, and 25 million have asthma. Smoking tobacco is the main cause of COPD but air pollutants and genetics are also culprits. There is no cure for COPD and costs incurred are from medications, frequent doctor visits, and in severe cases, hospitalization. For current smokers, smoking cessation is essential for preventing and managing COPD. To control asthma attacks, avoid triggers, like tobacco smoke, dust mites, and pollution. Take anti-inflammatory inhalers or other medications as instructed and exercise regularly.
9. Mental & Behavioral Health Disorders
Mental health disorders encompass many different conditions. Annual U.S. medical cost for depression is roughly $71 billion, according to the JAMA report from 2016. About 15 million live with major depressive disease. Anxiety disodrers results in a cost of over $29 billion, and attention-deficit hyperactivity disorder (ADHD) tallies $23 billion per year.
Medicines are expensive and doctors’ visits frequent. But noncompliance and lack of follow up with doctors can be high in this group of patients, too, adding to the total healthcare dollar.
Cancer: Advances Lead to Increased Survival
Every year, cancer ends the lives of more than 500,000 Americans. In fact, 1 in every 4 deaths in the US is due to a cancer-related illness. According to a JAMA report published in 2016, the top 4 cancer costs include colorectal cancers, breast cancer, other neoplasms, and non-melanoma skin cancers.
Costs exceed $50 billion just for these top 4 cancers. Based on the continued aging and growth of the U.S. population, costs of new immunotherapy agents, and new diagnostic tools, these costs are predicted to increase. It’s not all bad news though – the cancer death rate has significantly decreased over the last decade. Factors driving this drop include less tobacco use, sun protection, eating well, regular exercise, earlier detection and better
Chronic Disease Prevention
In this section, we briefly review dietary and lifestyle changes that reduce the incidence of chronic disease. The potential magnitude of benefit is also discussed.
Recommended Lifestyle Changes
Specific changes in diet and lifestyle and likely benefits are summarized. These relationships and supporting evidence are summarized here.
Convincing and Probable Relationships between Dietary and Lifestyle Factors and Chronic Diseases.
Avoid Tobacco Use
Avoidance of smoking by preventing initiation or by cessation for those who already smoke is the single most important way to prevent CVD and cancer (rx). Avoiding the use of smokeless tobacco will also prevent a good deal of oral cancer.
Maintain a Healthy Weight
Obesity is increasing rapidly worldwide (rx). Even though obesity—a body mass index (BMI) of 30 or greater—has received more attention than overweight, overweight (BMI of 25 to 30) is typically even more prevalent and also confers elevated risks of many diseases. For example, overweight people experience a two- to threefold elevation in the risks of CAD and hypertension and a more than tenfold increase in the risk of type 2 diabetes compared with lean individuals (BMI less than 23) (Willett, Dietz, and Colditz 1999). Both overweight and obese people also experience elevated mortality from cancers of the colon, breast (postmenopausal), kidney, endometrium, and other sites (Calle and others 2003).
Many people with a BMI of less than 25 have gained substantial weight since they were young adults and are also at increased risk of these diseases, even though they are not technically overweight (Willett, Dietz, and Colditz 1999). For example, in rural China, where the average BMI was less than 21 for both men and women, F. B. Hu and others (2000) found that the prevalence of hypertension was nearly five times greater for those with a BMI of approximately 25 than for the leanest people. Because many Asians are experiencing adverse consequences of excess body fat with a BMI of less than 25, the definition of overweight for Asia has recently been expanded to include a BMI of 23 to 25 (WHO 2000). For most people, unless obviously malnourished as an adolescent or young adult, bodyweight should ideally not increase by more than 2 or 3 kilograms after age 20 to maintain optimal health (Willett, Dietz, and Colditz 1999). Thus, a desirable weight for most people should be within the BMI range of 18.5 to 25.0, and preferably less than 23.
Additional valuable information can be obtained by measuring waist circumference, which reflects abdominal fat accumulation. In many studies, waist circumference is a strong predictor of CAD, stroke, and type 2 diabetes, even after controlling for BMI (Willett, Dietz, and Colditz 1999). A waist circumference of approximately 100 centimeters for men and 88 centimeters for women has been used as the criterion for the upper limit of the healthy range in the United States, but for many people this extent of abdominal fat would be far above optimal. Because abdominal circumference is easily assessed, even where scales may not be available, further work to develop locally appropriate criteria could be worthwhile. In the meantime, increases of more than 5 centimeters can be used as a basis for recommending changes in activity patterns and diet.
Views about the causes of obesity and ways to prevent or reduce it have been controversial. Diets low in fat and high in carbohydrates were believed to limit caloric intake spontaneously and thus to control adiposity, but such diets have not reduced bodyweight in trials that have lasted for a year or more (Willett and Leibel 2002). Some researchers have suggested that diets with a high energy density, referring to the amount of energy per volume, offer an alternative explanation for the observed increases in obesity (Swinburn and others 2004), but long-term studies have not examined this theory. Sugar-sweetened beverages contribute significantly to the overconsumption of calories, in part because calories in fluid form appear to be poorly regulated by the body (E. A. Bell, Roe, and Rolls 2003). In children, an increase in soda consumption of one serving per day was associated with an odds ratio of 1.6 for incidence of obesity (Ludwig, Peterson, and Gortmaker 2001), and in a randomized trial, replacement of a standard soda with a zero-calorie diet soda was associated with significant weight loss (Raben and others 2002). Reductions in dietary fiber and increases in the dietary glycemic load (large amounts of rapidly absorbed carbohydrates from refined starches and sugar) may also contribute to obesity (Ebbeling and others 2003; Swinburn and others 2004).
Aspects of the food supply unrelated to its macronutrient composition are also likely to be contributing to the global rise in obesity. Inexpensive food energy from refined grains, sugar, and vegetable oils has become extremely plentiful in most countries. Food manufacturers and suppliers use carefully researched methods to make products based on these cheap ingredients maximally convenient and attractive.
Maintain Daily Physical Activity and Limit Television Watching
Contemporary life in developed nations has markedly reduced people’s opportunities to expend energy, whether in moving from place to place, in the work environment or at home (Koplan and Dietz 1999). Dramatic reductions in physical activity are also occurring in developing countries because of urbanization, increased availability of motorized transportation to replace walking and bicycle riding, and mechanization of labor. However, regular physical activity is a key element in weight control and prevention of obesity (IARC 2002; Swinburn and others 2004). For example, among middle-aged West African women, more walking was associated with a three-unit lower BMI (Sobngwi, Gautier, and Mbanya 2003), and in China, car owners are 80 percent more likely to be obese (Hu 2002).
In addition to its key role in maintaining a healthy weight, regular physical activity reduces the risk of CAD, stroke, type 2 diabetes, colon and breast cancer, osteoporotic fractures, osteoarthritis, depression, and erectile dysfunction (table 44.1). Important health benefits have even been associated with walking for half an hour per day, but greater reductions in risk are seen with longer durations of physical activity and more intense activity.
The number of hours of television watched per day is associated with increased obesity rates among both children and adults (Hernandez and others 1999; Ruangdaraganon and others 2002) and with a higher risk of type 2 diabetes and gallstones (F. B. Hu, Leitzmann, and others 2001; Leitzmann and others 1999). This association is likely attributable both to reduced physical activity and to increased consumption of foods and beverages high in calories, which are typically those promoted on television. Decreases in television watching reduce weight (Robinson 1999), and the American Academy of Pediatrics recommends a maximum of two hours of television watching per day.
Eat a Healthy Diet
Medical experts have long recognized the effects of diet on the risk of CVD, but the relationship between diet and many other conditions, including specific cancers, diabetes, cataracts, macular degeneration, cholelithiasis, renal stones, dental disease, and birth defects, have been documented more recently. The following list discusses six aspects of diet for which strong evidence indicates important health implications. These goals are consistent with a detailed 2003 World Health Organization (WHO) report (WHO and FAO 2003).
Replace saturated and trans fats with unsaturated fats, including sources of omega-3 fatty acids – Replacing saturated fats with unsaturated fats will reduce the risk of CAD (F. B. Hu and Willett 2002; Institute of Medicine 2002; WHO and FAO 2003) by reducing serum low-density lipoprotein (LDL) cholesterol. Also, polyunsaturated fats (including the long-chain omega-3 fish oils and probably alpha-linoleic acid, the primary plant omega-3 fatty acid) can prevent ventricular arrhythmias and thereby reduce fatal CAD. In a case-control study in Costa Rica, where fish intake was extremely low, the risk of myocardial infarction was 80 percent lower in those with the highest alpha-linoleic acid intake (Baylin and others 2003). Intakes of omega-3 fatty acids are suboptimal in many populations, particularly if fish intake is low and the primary oils consumed are low in omega-3 fatty acids (for example, partially hydrogenated soybean, corn, sunflower, or palm oil). These findings have major implications because changes in the type of oil used for food preparation are often quite feasible and not expensive.
Trans fatty acids produced by the partial hydrogenation of vegetable oils have uniquely adverse effects on blood lipids (F. B. Hu and Willett 2002; Institute of Medicine 2002) and increase risks of CAD (F. B. Hu and Willett 2002); on a gram-for-gram basis, both the effects on blood lipids and the relationship with CAD risk are considerably more adverse than for saturated fat. In many developing countries, trans fat consumption is high because partially hydrogenated soybean oil is among the cheapest fats available. In South Asia, vegetable ghee, which has largely replaced traditional ghee, contains approximately 50 percent trans fatty acids (Ascherio and others 1996). Independent of other risk factors, higher intakes of trans fat and lower intakes of polyunsaturated fat increase risk of type 2 diabetes (F. B. Hu, van Dam, and Liu 2001).
Ensure generous consumption of fruits and vegetables and adequate folic acid intake –Strong evidence indicates that high intakes of fruits and vegetables will reduce the risk of CAD and stroke (Conlin 1999). Some of this benefit is mediated by higher intakes of potassium, but folic acid probably also plays a role (F. B. Hu and Willett 2002). Supplementation with folic acid reduces the risk of neural tube defect pregnancies. Substantial evidence also suggests that low folic acid intake is associated with greater risk of colon—and possibly breast—cancer and that use of multiple vitamins containing folic acid reduces the risk of these cancers (Giovannucci 2002). Findings relating folic acid intake to CVD and some cancers have major implications for many parts of the developing world. In many areas, consumption of fruits and vegetables is low. For example, in northern China, approximately half the adult population is deficient in folic acid (Hao and others 2003).
Consume cereal products in their whole-grain, high-fiber form –Consuming grains in a whole-grain, high-fiber form has double benefits. First, consumption of fiber from cereal products has consistently been associated with lower risks of CAD and type 2 diabetes (F. B. Hu, van Dam, and Liu 2001; F. B. Hu and Willett 2002), which may be because of both the fiber itself and the vitamins and minerals naturally present in whole grains. High consumption of refined starches exacerbates the metabolic syndrome and is associated with higher risks of CAD (F. B. Hu and Willett 2002) and type 2 diabetes (F. B. Hu, van Dam, and Liu 2001). Second, higher consumption of dietary fiber also appears to facilitate weight control (Swinburn and others 2004) and helps prevent constipation.
Limit consumption of sugar and sugar-based beverages – Sugar (free sugars refined from sugarcane or sugar beets and high-fructose corn sweeteners) has no nutritional value except for calories and, thus, has negative health implications for those at risk of overweight. Furthermore, sugar contributes to the dietary glycemic load, which exacerbates the metabolic syndrome and is related to the risk of diabetes and CAD (F. B. Hu, van Dam, and Liu 2001; F. B. Hu and Willett 2002; Schulze and others 2004). WHO has suggested an upper limit of 10 percent of energy from sugar, but lower intakes are usually desirable because of the adverse metabolic effects and empty calories.
Limit excessive caloric intake from any source – Given the importance of obesity and overweight in the causation of many chronic diseases, avoiding excessive consumption of energy from any source is fundamentally important. Because calories consumed as beverages are less well-regulated than calories from solid food, limiting the consumption of sugar-sweetened beverages is particularly important.
Limit sodium intake –The principal justification for limiting sodium is its effect on blood pressure, a major risk factor for stroke and coronary disease. WHO has suggested an upper limit of 1.7 grams of sodium per day (5 grams of salt per day) (WHO and FAO 2003).
Potential of Dietary and Lifestyle Factors to Prevent Chronic Diseases
Several lines of evidence indicate that realistic modifications of diet and lifestyle can prevent most CAD, stroke, diabetes, colon cancer, and smoking-related cancers. Less progress has been made in identifying practically modifiable causes of breast and prostate cancers.
One line of evidence is based on declines in CAD in countries that have implemented preventive programs. Rates of CAD mortality have been cut in half in several high-income countries, including Australia, the United Kingdom, and the United States.
Success in Finland. Finland provides one of the best-documented examples of community intervention. In 1972, Finland had the world’s highest CVD mortality rate. Planners examined the policy and environmental factors contributing to CVD and sought appropriate (more…)
Other evidence derives from randomized intervention studies. These often have serious limitations for estimating the potential magnitude of benefits, because typically only one or a few factors are modified, durations are usually only a few years, and noncompliance with lifestyle change is often substantial. Nevertheless, some examples are illustrative of the potential benefit. In two randomized studies among adults at high risk of type 2 diabetes, those assigned to a program emphasizing dietary changes, weight loss, and physical activity experienced only half the risk of incident diabetes (Knowler and others 2002; Tuomilehto and others 2001). The Lyon Heart Study, conducted among those with existing heart disease, found a Mediterranean-type diet high in omega-3 fatty acids reduced recurrent infarction by 70 percent compared with an American Heart Association diet (de Lorgeril and others 1994).
A third approach is to estimate the percentage of disease that is potentially preventable by reducing multiple behavioral risk factors using prospective cohort studies. Among U.S. adults, more than 90 percent of type 2 diabetes, 80 percent of CAD, 70 percent of stroke, and 70 percent of colon cancer are potentially preventable by a combination of nonsmoking, avoidance of overweight, moderate physical activity, healthy diet, and moderate alcohol consumption (Willett 2002).
Collectively, these findings indicate that the low rates of these diseases suggested by international comparisons and time trends are attainable by realistic, moderate changes that are compatible with 21st-century lifestyles.
Interventions aimed at changing diet and lifestyle factors include educating individuals, changing the environment, modifying the food supply, undertaking community interventions, and implementing economic policies. In most cases, quantifying the effects of the intervention is difficult, because behavioral changes may take many years and synergies are potentially important but hard to estimate in formal studies. Substantial nihilism often exists regarding the ability to change populations’ diets or behaviors, but major changes are possible over extended periods of time. For example, per capita, egg consumption in the United States decreased from approximately 420 to 270 per year between 1940 and 1990 following recommendations for preventing CAD (though in reality, the evidence for benefits was meager). Similarly, the prevalence of smoking, despite its being a physically addictive behavior, halved among men in the United States between 1965 and 2000. Because changing behaviors related to diet and lifestyle requires sustained efforts, long-term persistence is needed. However, opportunities exist that do not require individual behavior changes, and these can lead to more rapid benefits.
Efforts to change diets, physical activity patterns and other aspects of lifestyle have traditionally attempted to educate individuals through schools, health care providers, worksites, and general media. These efforts will continue to play an important role, but they can be strongly reinforced by policy and environmental changes.
School-based programs include the roles of nutrition and physical activity in maintaining physical and mental health. School food services should provide healthy meals, both because they directly affect health and because they provide a special opportunity to teach by example. In many countries, school-based physical education remains a significant source of physical activity for young people. In China, 72 percent of children age 6 to 18 engage in moderate to vigorous physical activity for a median of 90 to 100 minutes per week (Tudor-Locke and others 2003). Maintaining these programs should be a high priority because they have likely contributed to the historically low rates of obesity in such countries.
The Planet Health Program. Planet Health, developed for middle school students, in the United States, has an immediate goal of reducing television viewing time with the long-range goal of preventing unhealthy weight gain (Gortmaker and others 1999). Teachers (more…)
Worksite interventions can efficiently include a wide variety of health promotion activities because workers spend a large portion of their waking hours and eat a large percentage of their food there. Interventions can include educating employees; screening them for behavioral risk factors; offering incentive programs to walk, ride a bicycle, or take public transportation to work; offering exercise programs during breaks or after work; improving the physical environment to promote activity; and providing healthier foods in cafeterias. Worksite health promotion can result in a positive return on investment through lower health costs and fewer sick days.
Interventions by Health Care Providers
Controlled intervention trials for smoking cessation and physical activity have shown that physician counseling, especially when accompanied by supporting written material, can be efficacious in modifying behavior. Studies of dietary counseling by physicians indicate that even brief messages about nutrition can influence behavior and that the magnitude of the effect is related to the intensity of the intervention (Pignone and others 2003). Identifying patients who are overweight or obese, or who are gaining weight but are not yet overweight, is an initial step in preventing and treating overweight. However, many physicians are not well trained to measure and calculate BMI and identify weight problems.
Transportation Policy and Environmental Design
Transportation policies and the design of urban environments are fundamental determinants of physical activity and therefore influence the risks of obesity and other chronic diseases. Countries can take a number of steps to make positive changes.
Limit the Role of Automobiles
In wealthy countries, the automobile has strongly influenced the trend toward low-density, automobile-based suburban developments, many built without sidewalks. These sprawling settlements tend to have few services within walking distance and are usually not linked to public transportation. Dependence on automobiles affects physical activity, because those who use public transportation tend to walk more. In a prospective study in eight provinces in China, 14 percent of households acquired a car between 1889 and 1997, and the likelihood of men becoming obese during the same period was twice as great in households that acquired a car than in those that did not (A. C. Bell, Ge, and Popkin 2002).
National policies strongly influence automobile use and dependency. In the United States, low taxes on gasoline, free parking, and wide streets encourage car ownership: almost 92 percent of U.S. households own at least one car, and 59 percent own two or more cars (Pucher and Dijkstra 2003). In contrast, in most of Western Europe, narrow streets, limited parking, and high gasoline prices make the costs of automobile use almost double those in the United States (Pucher and Dijkstra 2003). As a result, Europeans walk or bike more and use their cars approximately 50 percent less than their American counterparts. Investment in roads rather than in public transportation creates a vicious cycle: poor public transportation systems lead to more dependency on the automobile.
Reducing Automobile Use in Brazil. Curitiba, Brazil, provides an example of the benefits of a strategy that reduces automobile use and increases the use of public transportation. In 1965, city planners adopted a master plan that promoted development along (more…)
Promote Walking and Bicycle Riding
Walking or cycling for transportation and leisure are effective and practical means of engaging in physical activity and are still the most common ways to travel in many developing countries. In Bangkok and Manila, only 25 percent of travel is by car, motorcycle, or taxi, compared with 75 percent by public transportation or walking (Pendakur 2000). In Madras, India, only 8 percent of the population travels by private, motorized transportation; 22 percent of people walk; 20 percent bike; and the rest use public transportation (Pendakur 2000). In China, approximately 90 percent of the urban population walks or rides a bicycle to work, shopping, or school each day (G. Hu and others 2002). Walking or biking is more likely to be prevalent in smaller cities—that is, those with 1 million to 5 million people—than in larger ones.
Bicycle riding and walking are also important for children’s health. Most American children do not walk or bike to school, even when distances are short. In contrast, almost 90 percent of Chinese children under 12 walk or ride a bicycle to school (Hu 2002).
Walking and Cycling to School. One of the most effective ways to promote walking and cycling is through local schools. The Safe Routes to School program (http://www.saferoutestoschools.org/), established in Marin County, California, is a private-public (more…)
In many areas, the shift toward private car use has not yet begun and can perhaps be forestalled by policies that benefit walkers and cyclists rather than drivers. Such policies include implementing road designs that promote a safe and well-lit environment for walking and cycling, including traffic-calming measures to reduce automobile speeds.
Many Western European countries have taken steps to increase safety for cyclists and walkers. In Germany and the Netherlands, bike paths serve as travel routes, not just weekend recreational destinations as they do in the United States. The former countries have invested heavily in bike paths and have also created extensive car-free areas in cities, with well-lit sidewalks, clearly marked crosswalks, and pedestrian islands that have improved safety. Both countries have increased the number of bicycle-friendly streets (on which cars are permitted but bicycles have the right of way) and have created systems to separate streams of traffic, including cars, pedestrians, and bicycles. A meta-analysis of selected traffic-calming studies in many countries reported reductions in traffic speed, accidents, injuries, and fatalities and an increase in bicycle use and walking (Bunn and others 2003).
Design Cities and Towns to Promote Health
Handy and others’ (2002) comprehensive assessment of recent research on urban planning concludes that a combination of urban design, land-use patterns, and transportation systems that promotes walking and bicycling will help create active, healthier, and more livable communities. In densely developed cities that have been built around public transportation rather than away from it, individuals are much more likely to take public transit, walk, or bicycle than in other areas and to weigh less and be less likely to suffer from hypertension (Ewing, Schieber, and Zegeer 2003; Lopez 2004; Saelens, Sallis, and Frank 2003).
Those living in walker-friendly neighborhoods also appear to be more mentally healthy and are more likely to know their neighbors, to be socially active, and to participate in the political process (Leyden 2003). In contrast, urban sprawl has been linked to decreases in mental health and social capital (Frumkin 2002) as well as anger and frustration over long commutes (Surface Transportation Policy Project 1999). Sprawl adversely affects the elderly in particular because they are unable to walk to places of interest and many cannot drive. Such isolation does not promote good physical or mental health.
The so-called smart growth movement has resulted from concerns about urban sprawl and unsustainable development and is encouraging governments worldwide to rethink how they develop new areas and redevelop older suburbs and cities. Smart growth principles include mixing land uses, using compact building designs, including a range of transportation and housing choices, building walker-friendly neighborhoods in attractive communities with a distinctive sense of place, and implementing a philosophy of directing development toward existing communities and the preservation of open space (Office of the Administrator 2001) (box 44.7).
Enhancing Urban Life in the Republic of Korea. In Seoul, the government is managing growth by creating six satellite communities with high-rise residential buildings outside the city center. These communities are intended to become new job-creation centers (more…)
The involvement of public health practitioners in transportation planning and building design is becoming more common. In Edinburgh, a health impact assessment conducted on proposed options for transportation policy showed the effects of specific choices on both affluent members of the community and the poor. Its recommendations, now adopted, included new spending on pedestrian safety, a citywide bicycle network, more greenways and park-and-ride programs, and more rail transportation or bus services. Priorities are to benefit pedestrians first, cyclists second, public transportation users third, freight and delivery people fourth, and car users last. Establishing criteria for building design can also lead to increases in physical activity. For example, increasing signage promoting stair use, as well as the attractiveness of the facilities themselves, encourages people to use the stairs (Boutelle and others 2001).
Improved Food Supply
People’s diets can be enhanced by improving the food supply. The usual position of the food industry is that it simply provides whatever consumers demand, but this argument is misleading because the industry spends more than US$12 billion annually to influence consumer choices just within the United States and many times this amount globally. Much of this sum goes to promote foods with adverse health effects, and children are primary targets.
Improving Processing and Manufacturing
Altering the manufacturing process can rapidly and effectively improve diets because such action does not require the slow process of behavioral change. One example is eliminating the partial hydrogenation of vegetable oils, which destroys essential omega-3 fatty acids and creates trans fatty acids. European manufacturers have largely eliminated trans fatty acids from their food supply by altering production methods.
Regulations can facilitate changes in manufacturing directly or indirectly by providing an incentive for manufacturers to change their processes. For example, in 2003, the U.S. Food and Drug Administration announced that food manufacturers had to include trans fatty acid content on the standard food label. Following the imposition of this requirement, several large food companies said that they would reduce or eliminate trans fats, and many more are planning to do so (U.S. Food and Drug Administration 2003). In Mauritius, the government required a change in the commonly used cooking oil from mostly palm oil to soybean oil, which changed people’s fatty acid intake and reduced their serum cholesterol levels (Uusitalo and others 1996). Changes in types of fat can often be almost invisible and inexpensive. Omega-3 fatty acid intakes can be increased by incorporating oils from rapeseed, mustard, or soybean into manufactured foods, cooking oils sold for use at home, or both. Selective breeding and genetic engineering provide alternative ways to improve the healthfulness of oils by modifying their fatty acid composition.
When the consumption of processed food is high, a reduction in salt consumption will usually require changes at the manufacturing level, because processed food is a major salt source. If the salt content of foods is reduced gradually, the change is imperceptible to consumers. Coordination among manufacturers or government regulation is needed; otherwise, producers whose foods are lower in salt may be placed at a disadvantage. Unfortunately, good examples are not available. Another example of improved processing would be to reduce the refining of grain products, which can be done in small, almost invisible decrements.
Food fortification has eliminated iodine deficiency, pellagra, and beriberi in much of the world. In regions where iodine deficiency remains a serious problem, fortification should be a high priority. Folic acid intake is suboptimal in many regions of both developing and developed countries. Fortifying foods with folic acid is extremely inexpensive and could substantially reduce the rates of several chronic diseases. Grain products—such as flour, rice, and pasta—are usually the best foods to fortify, and in many countries, they are already being fortified with other B vitamins. Since 1998, grain products in the United States have been fortified with folic acid, which has almost eliminated folate deficiency, and rates of neural tube defect pregnancies have declined by about 19 percent (Honein and others 2001). Where intakes of vitamins B12 and B6 are also low and contribute to elevations of homocysteine, as among vegetarian populations in India, simultaneous fortification of food with these vitamins should be considered. The effects of fortification on reducing CVD are not considered proven, but the potential benefits are huge; therefore, intervention trials to evaluate the effects of fortification should be a high priority.
Increasing the Availability and Reducing the Cost of Healthy Foods
Policies regarding the production, importation, distribution, and sale of specific foods can influence their cost and availability. Policies may be directed at the focus of agricultural research and the types of production promoted by extension services. Policies often promote grains, dairy products, sugar, and beef, whereas those that encourage the production and consumption of fruits, vegetables, nuts, legumes, whole grains, and healthy oils would tend to enhance rather than reduce health.
Promoting Healthy Food Choices and Limiting Aggressive Marketing to Children
Almost every national effort to improve nutrition incorporates the promotion of healthy food choices, such as fruits, vegetables, and legumes. Ideally, such efforts are coordinated among government groups, retailers, professional groups, and nonprofit organizations, and investment in such efforts should include careful testing and refining of social marketing strategies.
Another strategy is to protect consumers from aggressive marketing of unhealthy foods. Producers spend billions of dollars a year encouraging children to consume foods that are detrimental to their health. Manufacturers and fast-food chains personify food products with cartoon characters; display food brands on toys; and issue “educational” card games that subvert children’s natural gift for play, storytelling, and make-believe. The willingness to limit advertising depends on a country’s political culture, but the public clearly distinguishes between advertising aimed at adults and that targeted at children. For example, in the United States, 46 percent of adults surveyed supported restrictions on advertising to children (Blendon 2002). Restrictions can range from banning advertising to children to limiting the types of products that advertisers may promote to this audience.
Modeling Likely Interventions
Primary targets for reducing lifestyle diseases include changing the fat composition of the diet, limiting sodium intake, and engaging in regular physical activity.
Using available data, we calculated a range of estimates under given assumptions for the cost-effectiveness of replacing dietary saturated fat with monounsaturated fat, replacing trans fat with polyunsaturated fat, and reducing salt intake. An increase in moderate physical activity by three to five hours per week is considered likely to lower the risk of many diseases, but data to model the cost-effectiveness of this intervention are not currently available. For further details of methods and assumptions underlying the analyses presented here, see the Web site version of this book.
Reducing Saturated Fat Content
In the base case, assuming a 3 percent drop in cholesterol and a US$6 per person cost of the intervention, averting one disability-adjusted life year (DALY) would cost as little as US$1,865 in South Asia and as much as US$4,012 in the Middle East and North Africa. The intervention’s effectiveness could be increased by replacing part of the saturated fat with polyunsaturated fat, which has additional beneficial effects mediated by mechanisms other than LDL cholesterol
Replacing Dietary Trans Fat from Partial Hydrogenation with Polyunsaturated Fat
We could not use the model for saturated fat to estimate the effects of replacing trans fat with polyunsaturated fat because only a small part of the benefit is attributable to reducing LDL cholesterol (F. B. Hu and Willett 2002). Trans fats also adversely affect high-density lipoprotein (HDL) cholesterol, triglycerides, endothelial function, and inflammatory markers. In addition, increases in polyunsaturated fat (assuming a mix of N-6 and omega-3 fatty acids) will reduce LDL cholesterol, insulin resistance, and probably fatal cardiac arrhythmias.
In calculations that are based only on the adverse effects on LDL and HDL, replacing 2 percent of the energy from trans fat with polyunsaturated fat was estimated to reduce CAD by 7 to 8 percent (Grundy 1992; Willett and Ascherio 1994). Epidemiological studies, which include the contributions of the additional causal pathways, suggest a much greater reduction, from about 25 to 40 percent (F. B. Hu and others 1997; Oomen and others 2001). Another likely benefit is a reduction in the incidence of type 2 diabetes: estimates indicate that the same 2 percent reduction would reduce incidence by 40 percent (Salmeron and others 2001).
Because voluntary action by industry (as has nearly been achieved in the Netherlands) or by regulation (as occurred in Denmark) can eliminate partially hydrogenated fat from the diet, this initiative does not require consumer education, and the costs can be extremely low. In an analysis required before implementing food labeling, the U.S. Food and Drug Administration (2003) estimated that trans fat labeling would be highly cost-effective. Even though the effect of labeling itself was estimated to have only a modest effect on consumer behavior, as noted earlier, it is having a major effect on manufacturers’ behavior.
The potential for reducing CVD rates by replacing trans fats with polyunsaturated fats will depend on the diets of specific populations. Whereas the intake of trans fat is low in China, it is likely to be high in parts of India, Pakistan, and other Asian countries because of the extraordinarily high content in commonly used cooking fats.
Reducing the Salt Content of Manufactured Foods through Legislation and an Accompanying Education Campaign
The actual blood pressure reduction from lower salt consumption could vary from the base-case assumption, as could the costs of the education campaign. Shows the results of lower costs of the education campaign and higher or lower effects of the intervention on blood pressure. These results may argue for initial efforts to focus on reductions in the use of salt during the manufacturing process with no public education campaign. The cost-effectiveness of such a change is high and could be augmented with a public education campaign only if needed to support the legislated change. At lower implementation costs, the intervention is highly cost-effective, even with half the assumed effect on blood pressure.
Adopting Physical Activity Interventions
Even though health experts believe that physical activity interventions are effective in reducing the risk of lifestyle diseases, no studies of their cost-effectiveness are available from developing countries. If people walk voluntarily (the model assumes no opportunity cost), a net economic benefit would accrue to all segments of the U.S. population. If we project the economic benefits to the entire U.S. population and assume 25 percent compliance by the sedentary population, the voluntary program would generate US$6.8 billion in savings (in 2001 U.S. dollars).
Aggregate Costs of Obesity and Unhealthy Lifestyles
A series of U.S. studies appear to confirm that the avoidable costs of chronic diseases are substantial, although many developing countries have not yet experienced the full demands on their health sectors resulting from these conditions. Colditz (1999) estimates that obesity is responsible for 7 percent of all U.S. direct health care costs and that inactivity is responsible for an additional 2.4 percent of all health care costs. Indirect costs associated with obesity and inactivity account for another 5 percent of health care costs. Pronk and others (1999) assess the difference in health care costs between adult patients with and without risk factors for noncommunicable diseases (physical activity, BMI, and smoking status) and find that a healthier lifestyle of physical activity three times per week, a moderate BMI, and nonsmoking status reduce health care costs by 49 percent compared with an unhealthy lifestyle.