Category Archive Drugs A-Z

Top 65 Pharmacology Tips Every Student Should know

Pharmacology is the study of how medicinal substances interact with living systems. Pharmacology is The study of drugs, their nature, their sources, and their properties, absorption, distribution, biotransformation, elimination, interactions, toxicology and their therapeutic applications. Pharmacology is the study of the body’s reaction to drugs. or Pharmacology is a study of Pharmacokinetics and Pharmacodynamics of a drug.

It is Very Difficult To Summarize the whole Pharmacology but We have collected some very important Points from Various Pharmacology Books and other resources Which will Help Students Pass their exams.

Important Pharmacology Points 1-10

1. Amphotericin is active against most fungi and yeasts. It can be used for intestinal candidiasis.

2. Atenolol is a beta-adrenoceptor blocker that, when administered during pregnancy, may cause intrauterine growth restriction, neonatal hypoglycaemia and bradycardia.

3. Trigger factors for migraine include intake of specific food such as caffeine, chocolate, cheese and alcoholic drinks, exposure to light, hunger and missed meals, and air travel.

4. Nalidixic acid is a quinolone that is indicated only for urinary tract infections.

5. Both levofloxacin and ciprofloxacin are quinolones. Levofloxacin has greater activity against pneumococci than ciprofloxacin.

6. Levofloxacin, which is a quinolone that has activity against Gram-positive and Gram-negative organisms including pneumococci.Quinolones are bactericidal.

7. Terazosin is a selective alpha-blocker that relaxes smooth muscle and is indicated in benign prostatic hyperplasia because it increases urinary flow rate and improves obstructive symptoms. Terazosin is also indicated in the manage-ment of mild-to-moderate hypertension. After the first dose a rapid reduction in blood pressure may occur.

8. Norfloxacin is a quinolone antibacterial agent. Quinolones should be used with caution in patients with a history of epilepsy because they may cause confusion, hallucinations and convulsions as side-effects. They may precipitate convulsions in patients with epilepsy and in those with no previous history of
convulsions.

9. Tinnitus is an adverse effect of furosemide, especially when it is administered in large parenteral doses, as a rapid administration and in renal impairment.Not all diuretics are associated with tinnitus.

10. Propranolol is a beta-adrenoceptor blocking agent. The antagonist effect is associated with up-regulation of receptors. Once the drug is withdrawn abruptly, adverse reactions may occur due to the up-regulation of the receptors.

Important Pharmacology Points 11-20

11. Pseudoephedrine and ephedrine are sympathomimetic agents that stimulate alpha- and beta-adrenergic receptors in the sympathetic nervous system, causing constriction of smooth muscles and blood vessels and producing bronchodilatation. They have central nervous system stimulant activity.

12. Miconazole is an imidazole antifungal that is available as an oral gel. The gel is to some extent absorbed from the oral mucosa and, because animal studies have shown that miconazole is fetotoxic, miconazole oral gel should be avoided during pregnancy.

13. Imipramine is a tricyclic antidepressant that, when administered during the third trimester, may cause tachycardia, irritability and muscle spasms in the neonate.

14. Hyoscine is an antimuscarinic agent that can be used for prophylaxis of motion sickness. Because it has a rapid onset of action it is administered 30 minutes before travelling. Cinnarizine is an antihistamine that is used for the prophylaxis of motion sickness but it has to be administered 2 h before travelling.Cetirizine is a non-sedating antihistamine that is used for symptomatic relief of allergies.

15. Chlorpromazine is an antipsychotic drug, specifically a phenothiazine derivative, that is characterised by pronounced sedative effects. Cautionary labels recommended are to avoid exposure of skin to direct sunlight or sun lamps and a warning that it may cause drowsiness and, if affected, not to drive or operate machinery and to avoid alcoholic drinks.

16. Ceftazidime is a ‘third-generation’ cephalosporin antibacterial agent. It has greater activity than cefuroxime against certain Gram-negative bacteria and less activity against Gram-positive bacteria. Ceftazidime is administered by deep intramuscular injection or intravenous injection or infusion. It is not available as tablets.

17. Salmeterol is a long-acting beta2 agonist that can be used regularly in patients with mild or moderate asthma. It can be used in combination with corticosteroid therapy. However, it should not be used in acute asthma attacks.

18. Remifentanil is a short-acting and potent opioid drug, which is preferred for use by injection for intra-operative analgesia compared with pethidine and morphine because it acts within 1–2 minutes. Its short duration of action allows prolonged administration at high dosage without accumulation and with little
risk of residual respiratory depression.

19. Griseofulvin and rifampicin are enzyme inducers. They can increase the rate of synthesis of cytochrome P450 enzymes, resulting in enhanced clearance of other drugs. When enzyme inducers are administered to patients receiving warfarin, a decreased effect of warfarin results. However, warfarin itself is not known to be an enzyme inducer.

20. Finasteride is an inhibitor of the enzyme 5-reductase, which is responsible for the metabolism of testosterone into the androgen dihydrotestosterone.Finasteride is used in benign prostatic hyperplasia and at a lower dose in male-pattern baldness.

Important Pharmacology Points 21-30

21. Imipramine is a tricylic antidepressant and, as with all types of antidepressants, hyponatraemia may occur in older people. This is possibly due to inappropriate secretion of antidiuretic hormone.

22. Lidocaine is indicated for ventricular arrhythmias, especially after myocardial infarction, because it suppresses ventricular tachycardia and reduces the risk of ventricular fibrillation.

23. Trifluoperazine, a phenothiazine. It may cause pancytopenia, which includes agranulocytosis. Agranulocytosis is a condition resulting in a marked decrease in the number of granulocytes.

24. Piroxicam, which is a non-steroidal anti-inflammatory drug that does not exhibit selectivity for cyclo-oxygenase-2 inhibition.Celecoxib, etoricoxib, meloxicam and Lumiracoxib are all selective inhibitors of cyclo-oxygenase-2.

25. Ibuprofen is a non-steroidal anti-inflammatory drug which brings about a reduction in the formation of prostaglandins that occur in an inflammatory reaction. Ibuprofen achieves this action by reversibly inhibiting cyclooxygenase enzymes. It is a propionic acid derivative.

26. Zanamivir is an antiviral agent used in influenza because it reduces replication of influenza A and B viruses by inhibiting the viral enzyme neuraminidase.It normally reduces the duration of symptoms by around 1–1.5 days.Zanamivir is not licensed for prophylaxis of influenza. It is indicated for the treatment of influenza and should be started within 48 h of the first symptoms.It is available as a dry powder for inhalation.

27. Metolazone is a diuretic with actions and uses similar to thiazide diuretics. It interferes with electrolyte reabsorption and is associated with profound diuresis. The maximum daily dose is 80 mg. Natrilix is indapamide.

28. Tramadol has fewer of the typical opioid side-effects, particularly less respiratory depression, less constipation and a lower potential for addiction.Tramadol, in addition to its opioid effect, also enhances serotonergic and adrenergic pathways.

29. Alfuzosin is an alpha-blocker that may cause drowsiness as a side-effect.

30. Ranitidine, an H2-receptor antagonist that can be administered as 150 mg twice daily or 300 mg at night.

Important Pharmacology Points 31-40

31. Rifampicin causes colouring of body secretions. Because of this side-effect,rifampicin causes discolouration of soft contact lenses and therefore patients should be advised not to wear soft contact lenses during treatment.

32. In adults the maximum daily dose of paracetamol should not exceed 4 g.Intake of paracetamol in excess of this dose may cause severe hepatocellular necrosis. Early features of paracetamol overdose are nausea and vomiting that tend to settle within 24 h. Liver damage is maximal 3–4 days after ingestion and this may lead to encephalopathy, haemorrhage and progress to death.

33. Pyridoxine (vitamin B6) is used in premenstrual syndrome. Deficiency of pyridoxine is rare but it may occur during treatment with the antituberculous drug,isoniazid.

34. Citalopram is a selective serotonin re-uptake inhibitor (SSRI). SSRIs are associated with suicidal behaviour and this risk is higher in young adults. For this reason SSRIs should not be used in patients under 18 years.

35. Alfacalcidol is the hydroxylated derivative of Vitamin D. Alfacalcidol has a short duration of action and therefore problems associated with hypercalcaemia due to excessive dosage are short lasting and easy to treat.

36. Benzydamine is an analgesic that is indicated for the management of painful inflammatory conditions of the oropharynx such as mouth ulcers. It is available as an oral rinse and an oral spray.

37. Lactulose is a disaccharide that retains water in the bowel, leading to osmotic diarrhoea of low faecal pH. It discourages the proliferation of ammonia producing microorganisms and this characteristic is an advantage in hepatic encephalopathy.

38. Lactulose and is an osmotic laxative that is useful in constipation, producing an effect within 48 h. It is also useful in hepatic encephalopathy, which is a neurological syndrome occurring as a result of liver disease. The condition occurs as a result of toxic substances such as ammonia that accumulate because they are normally metabolised by the liver.

39. Diclofenac and is used during and after cataract surgery. Being a non-steroidal anti-inflammatory drug (NSAID), its anti-inflammatory properties are useful in the post-operative stage. It is also used in other conditions such as accidental trauma and radial keratotomy for its analgesic and anti-inflammatory properties.

40. Diclofenac is an NSAID and its use is associated with gastrointestinal side-effects including nausea, diarrhoea, bleeding and ulceration. Diclofenac is contraindicated in patients with a history of active peptic ulceration.

Important Pharmacology Points 41-50

41. Chlorpromazine, a phenothiazine that may be used at a maximum daily dose of 300 mg for adults in the management of psychomotor agitation. Twelve tablets daily of Largactil 25 mg would be necessary to achieve this dose.

42. Fluconazole,  is a triazole antifungal agent that is used as a single dose of 150 mg for the management of vaginal candidiasis and candidal balanitis.

43. It is recommended to avoid using chloramphenicol during breastfeeding. Chloramphenicol is an antibacterial agent. It may cause bone-marrow toxicity in the infant.

44. Chlorpromazine, may be used in childhood schizophrenia and in autism.

45. Metabolism of phenytoin (anti-epileptic drug) is inhibited by clarithromycin (macrolide antibacterial agent) resulting in an increased plasma concentration of phenytoin. Phenytoin accelerates the metabolism of doxycycline (tetracycline antibacterial drug) resulting in a reduced plasma concentration of doxycycline.

46. Terbinafine is an allylamine derivative used as an antifungal agent. When used topically, terbinafine clears infection up to four times more quickly than imidazole antifungal agents. Terbinafine is the drug of choice for fungal nail infections.

48. Zolpidem, a non-benzodiazepine hypnotic agent. Dependence has been reported. Side-effects include amnesia, diarrhoea, nausea, vomiting, vertigo, dizziness, headache, drowsiness, asthenia and disturbances of hearing, smell, speech and vision.

49. Zolmitriptan, which is a 5HT1-agonist used as an anti-migraine drug. It produces vasoconstriction of cranial arteries. Zolmitriptan is metabolised in the liver.

50. Valsartan is an angiotensin-II receptor antagonist that blocks the actions of angiotensin resulting in the lowering of blood pressure.

Important Pharmacology Points 51-60

51. Celecoxib is selective of cyclo-oxygenase-2 inhibitor that confers gastrointestinal tolerance.

52. Metronidazole is an anti-infective agent with high activity against anaerobic bacteria and protozoa.

53. Codeine, an opioid drug, suppresses the cough reflex by depressing the cough centres in the brain. Cough suppressants may cause sputum retention.

54. Fluticasone is a corticosteroid that can be used as an intranasal preparation in nasal allergy.

55. Mixture of levodopa and carbidopa (dopa-decarboxylase inhibitor) is used in parkinsonism to replenish the depleted striatal dopamine.

56. Diltiazem is a calcium-channel blocker, specifically a benzodiazepine derivative. All calcium-channel blockers have peripheral and coronary vasodilator properties. Diltiazem has a negative inotropic effect as a cardiac effect, although less than verapamil.

57. Enalapril is an angiotensin-converting enzyme (ACE) inhibitor. ACE inhibitors are associated with a persistent cough as a side-effect. Sometimes this side effect impacts negatively on the patient’s lifestyle and warrants withdrawal of treatment. ACE inhibitors, through their inhibition of angiotensin II formation, result in a reduction of aldosterone release.

58. Nitrazepam is a benzodiazepine that is used as a hypnotic in the short-term management of insomnia. Nitrazepam has a long half-life and therefore it is associated with more hangover effects than shorter-acting products such as lorazepam.

59. Isosorbide is a nitrate used in the management of angina and left ventricular failure. It is a potent vasodilator and side-effects associated with its use include dizziness, throbbing headache, flushing and postural hypotension.

60. Clarithromycin is an erythromycin derivative. Gastrointestinal side-effects include nausea, vomiting, dyspepsia and diarrhoea.

Important Pharmacology Points 61-65

61. Amiloride is a weak diuretic but its characteristic is that it causes potassium retention. When used in combination with thiazide diuretics, amiloride counteracts the potassium loss attributed to thiazide diuretics.

62. Metoclopramide is an anti-emetic agent that is usually recommended for the management of vomiting during pregnancy as a second-line treatment after an antihistamine drug such as promethazine has been used unsuccessfully.

63. Promethazine is a sedating antihistamine that may be used in the management of insomnia and may be used as a prophylactic agent in motion sickness.

64. Levocetirizine is an isomer of cetirizine. It is an antihistamine that may be recommended together with topical or systemic administration of sympathomimetic agents in the management of nasal allergy. The dosage regimen for adults and children over 6 years is one 5 mg tablet daily.

65. Antacid preparations provide effective and immediate relief from a gastric ulcer. Liquid formulations have a faster onset of action. However, antacids do not provide any healing of the condition. They are most effective when taken 1 h after food.

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Salicylic Acid – Indications, Contraindications

Salicylic acid is a monohydroxybenzoic acid that is benzoic acid with a hydroxy group at the ortho position. It is obtained from the bark of the white willow and wintergreen leaves. It has a role as an anti-infective agent, an antifungal agent, a keratolytic drug, an EC 1.11.1.11 (L-ascorbate peroxidase) inhibitor, a plant metabolite, an algal metabolite, and a plant hormone. It is the conjugate acid of salicylate.

Salicylates have been available since the early 1900s. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, and monitoring, of salicylic acid, so providers can direct patient therapy in treating indicated conditions as part of the interprofessional team.

Salicylates have been derived from the willow tree bark. The Sumerians were noted to have used remedies derived from the willow tree for pain management as far back as 4000 years ago. Hippocrates used it for managing pain and fever. He even utilized tea brewed from it for pain management during childbirth.

In a 1763 clinical trial, the first of its kind, Reverend Edward Stone studied the effects of willow bark powder for treating fever. About a 100 years later the effects of the willow bark powder were studied for acute rheumatism.

In 1828, Professor Johann Buchner used salicin, the Latin word for willow. Henri Leroux used it to treat rheumatism after isolating it in a crystalline form in 1829. In the 1800s, the Heyden Chemical Company was the first to mass-produce salicylic acid commercially. It was not until 1899 when a modified version by the name of acetylsalicylic acid was registered and marketed by Bayer under the trade name aspirin.

Even though it has been available since the early 1900s, its real mode of action was not known until the late 1970s.

Mechanism of Action

Salicylic acid directly irreversibly inhibits COX-1 and COX-2 to decrease the conversion of arachidonic acid to precursors of prostaglandins and thromboxanes. Salicylate’s use in rheumatic diseases is due to its analgesic and anti-inflammatory activity. Salicylic acid is a key ingredient in many skin-care products for the treatment of acne, psoriasis, calluses, corns, keratosis pilaris, and warts. Salicylic acid allows cells of the epidermis to more readily slough off. Because of its effect on skin cells, salicylic acid is used in several shampoos used to treat dandruff. Salicylic acid is also used as an active ingredient in gels that remove verrucas (plantar warts). Salicylic acid competitively inhibits oxidation of uridine-5-phosphoglucose (UDPG) with nicotinamide adenosine dinucleotide (NAD) and noncompetitively with UDPG. It also competitively inhibits the transferring of the glucuronyl group of uridine-5-phosphoglucuronic acid (UDPGA) to a phenolic acceptor. Inhibition of mucopolysaccharide synthesis is likely responsible for the slowing of wound healing with salicylates.

Indications

Some of the indications for aspirin use are as follows

  • Key additive in many skin-care products for the treatment of acne, psoriasis, calluses, corns, keratosis pilaris, and warts.
  • Angina pectoris
  • Angina pectoris prophylaxis
  • Ankylosing spondylitis
  • Cardiovascular risk reduction
  • Colorectal cancer
  • Fever
  • Ischemic stroke
  • Ischemic stroke: Prophylaxis
  • Myocardial infarction
  • Myocardial infarction: Prophylaxis
  • Osteoarthritis
  • Pain
  • Revascularization procedures: Prophylaxis
  • Rheumatoid arthritis
  • Systemic lupus erythematosus

Contraindications

  • People who are allergic to ibuprofen should not take aspirin as there is cross-reactivity. Patients who have asthma should be cautious if they have asthma or known bronchospasm associated with NSAIDs.
  • Aspirin increases the risk of GI bleeding in patients who already suffer from peptic ulcer disease or gastritis. The risk of bleeding is still present even without these conditions if there is concomitant consumption of alcohol or if the patient is on warfarin. Patients who have inborn coagulopathies such as hemophilia should avoid all salicylates. Acquired diathesis as in the setting of dengue or yellow hemorrhagic fever should avoid the use of aspirin.
  • Patients who have glucose-6-phosphate dehydrogenase deficiency are at risk of acute intravascular hemolytic anemia. Many factors can precipitate these hemolytic episodes. Aspirin is one such know cause.
  • Avoid using aspirin in children who are suffering from a viral infection to avoid Reye syndrome.

Dosage

Therapeutic Index and Toxic Doses 

  • Therapeutic drug levels for aspirin are 150 to 300 mcg/mL (salicylate).
  • Toxic Levels: Greater than 300 mcg/mL
  • Timing: 1 to 3 hours after the dose
  • Time to Steady State: 5 to 7 days
  • Plasma levels of aspirin can range from 3 to 10 mg/dL for therapeutic doses to as high as 70 to 140 mg/dL for acute toxicity. Due to delayed absorption of certain preparations, levels should be checked 4 hours after consumption and every 2 hours after that until maximum levels are reached.

Treatment needs to be individualized based on symptomatology as well as levels. Aspirin levels do not need to be monitored in most cases. For certain diseases, serum creatinine at baseline, along with serum drug levels if patients have adult or juvenile rheumatoid arthritis, Kawasaki disease, or arthritis/pleurisy.

Aspirin can be administered via the oral, rectal, and intravenous (IV) route.

It is available in different doses, the lowest being 81 mg also called a baby aspirin.

  • Tablet: 325 mg, 500 mg
  • Delayed-release tablet: 81 mg, 325 mg, 500 mg, 650 mg
  • Chewable: 81 mg
  • Suppository: 60 mg, 120 mg, 200 mg, 300 mg, 600 mg
  • Intravenous: 250 mg, 500 mg

Pharmacokinetics

Aspirin absorption from the gastrointestinal (GI) tract depends on the formulation state. When consumed as a liquid preparation, it is rapidly absorbed as opposed to tablets. Its hydrolysis yields salicylic acid. Salicylic acid has a narrow therapeutic window. If maintained within that narrow range, it provides the appropriate anti-inflammatory effect.

Aspirins absorption is pH sensitive at the level of the small intestine. Absorption is higher through the small intestine than the stomach for the same pH range. At pH 3.5 or 6.5, aspirin’s intestinal absorption is greater than the gastric absorption of the compound. The stomach does not absorb aspirin at pH 6.5.

Salicylate elimination occurs through two pathways via the creation of salicylic acid and salicyl phenolic glucuronide. Salicylic acid is really cleared which can be increased by raising the urinary pH. Medications like antacids can increase renal clearance as they raise urinary pH. It can cross the blood-placental barrier. It is also expressed in breast milk.

Pharmacodynamics

Almost 90% of COX inhibition can be achieved with the administration of 160 to 325 mg of aspirin. These effects last for about 7 to 10 days which usually correspond with the lifespan of a platelet. Prostacyclin inhibition can be achieved with the use of higher doses. This inhibition occurs in the endothelial cells of blood vessels.

Side Effects

Aspirin has had multiple metanalyses which suggest that aspirin reduces the risk of major adverse cardiovascular events in patients who have diabetes without cardiovascular disease, while also causing a trend toward higher rates of bleeding and gastrointestinal complications.

The most common side effect of aspirin is gastrointestinal upset ranging from gastritis to gastrointestinal bleed.

  • Hypersensitivity  – Hypersensitivity to NSAIDs is common among the general population. The rate is about 1% to 2%. Symptoms could be as mild as a simple rash to angioedema and anaphylaxis. In patients with asthma or chronic rhinosinusitis, the prevalence of these allergic symptoms could be as high as 26%. If this is accompanied by nasal polyps and inflammation of the respiratory tract with eosinophils, it is called the aspirin triad. NSAID-exacerbated respiratory disease (NERD) is a new term associated with this syndrome due to upper and lower respiratory mucosal inflammation.
  • Reye Syndrome  – Reye syndrome, named after the Australian pathologist, Dr. R.D. Reye was first described in 1963. It is a rare but fatal condition with an estimated mortality rate of between 30% to 45%. It is a form of encephalopathy secondary to fatty changes in an otherwise healthy liver. The clinical vignette of Reye syndrome constitutes a viral upper respiratory tract infection in children and concomitant administration of aspirin for the treatment of fever. It is thought that mitochondrial injury secondary to the preceding viral illness is the first hit to both the liver and the brain. Aspirin or similar compounds provide the second hit completing the syndrome. The incidence has dramatically decreased due to better awareness and use of acetaminophen for the management of fever in children instead of aspirin.
  • Intracerebral Hemorrhage – Aspirin increases the risk of intracranial bleeding (RR = 1.65; 95% CI, 1.06 to 5.99) versus placebo.

Pregnancy and lactation

  • No information is available on the clinical use of salicylic acid on the skin during breastfeeding. Because it is unlikely to be appreciably absorbed or appear in breastmilk, it is considered safe to use during breastfeeding. Avoid application to areas of the body that might come in direct contact with the infant’s skin or where the drug might be ingested by the infant via licking.

Toxicity

Patients who have aspirin toxicity can have a myriad of symptoms. Symptoms of mild toxicity can be but are not limited to tinnitus, dizziness, lethargy, nausea, and vomiting. For more severe toxicity the signs and symptoms include hyperthermia, tachypnea leading to respiratory alkalosis, high anion gap metabolic acidosis, hypokalemia, hypoglycemia, seizures, coma, and cerebral edema. Death commonly occurs due to cardiopulmonary edema secondary to pulmonary edema.

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Ezetimibe – Uses, Dosage, Side Effects, Interactions

Ezetimibe is an azetidine derivative and a cholesterol absorption inhibitor with lipid-lowering activity. Ezetimibe appears to interact physically with cholesterol transporters at the brush border of the small intestine and inhibits the intestinal absorption of cholesterol and related phytosterols. As a result, ezetimibe causes a decrease in the level of blood cholesterol or an increase in the clearance of cholesterol from the bloodstream. Overall, the following effects observed are a reduction of hepatic cholesterol stores and a reduction of total cholesterol, LDL cholesterol, and other triglycerides in the blood.

Ezetimibe is a medication used in the management and treatment of hypercholesterolemia. It is among a novel class of selective cholesterol-absorption inhibitors. This activity describes the indications, actions, and contraindications for ezetimibe as a valuable agent in the treatment of hypercholesterolemia. This activity highlights the administration and monitoring principles that the interprofessional team should employ in the management of patients with hypercholesterolemia.

Mechanism of Action

Ezetimibe mediates its blood cholesterol-lowering effect via selectively inhibiting the absorption of cholesterol and phytosterol by the small intestine without altering the absorption of fat-soluble vitamins and nutrients. The primary target of ezetimibe is the cholesterol transport protein Niemann-Pick C1-Like 1 (NPC1L1) protein. NPC1L1 is expressed on enterocytes/gut lumen (apical) as well as the hepatobiliary (canalicular) interface and plays a role in facilitating internalization of free cholesterol into the enterocyte in conjunction with the adaptor protein 2 (AP2) complex and clathrin. Once cholesterol in the gut lumen or bile is incorporated into the cell membrane of enterocytes, it binds to the sterol-sensing domain of NPC1L1 and forms an NPC1L1/cholesterol complex. The complex is then internalized or endocytosed by joining AP2 clathrin, forming a vesicle complex that is translocated for storage in the endocytic recycling compartment. Ezetimibe does not require exocrine pancreatic function for its pharmacological activity; rather, it localizes and appears to act at the brush border of the small intestine. Ezetimibe selectively blocks the NPC1L1 protein in the jejunal brush border, reducing the uptake of intestinal lumen micelles into the enterocyte. Overall, ezetimibe causes a decrease in the delivery of intestinal cholesterol to the liver and reduction of hepatic cholesterol stores, and an increase in clearance of cholesterol from the blood. While the full mechanism of action of ezetimibe in reducing the entry of cholesterol into both enterocytes and hepatocytes is not fully understood, one study proposed that ezetimibe prevents the NPC1L1/sterol complex from interacting with AP2 in clathrin-coated vesicles and induces a conformational change in NPC1L1, rendering it incapable of binding to sterols. Another study suggested that ezetimibe disrupts the function of other protein complexes involved in regulating cholesterol uptake, including the CAV1–annexin 2 heterocomplex.

Indications

Ezetimibe is indicated to reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor (statin). It is also indicated to reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate, and to reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin. Ezetimibe may also be used to reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia).

Ezetimibe is a dyslipidemic agent used to treat people with hyperlipidemia. It was FDA-approved in 2002. Ezetimibe is an inhibitor of intestinal cholesterol absorption and is indicated in reducing total cholesterol, low-density lipoprotein (LDL), apolipoprotein B (apo B), and non-high-density lipoprotein (HDL) in patients with primary hyperlipidemia, mixed hyperlipidemia, familial hypercholesterolemia (HoFH), and homozygous sitosterolemia (phytosterolemia). Clinicians can use ezetimibe as monotherapy, in combination with fenofibrate, or with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. There is a commercially marketed combination agent made up of ezetimibe and simvastatin that has been available since 2002. There is also another combination agent made up of atorvastatin and ezetimibe that has been on the market since 2012. This combination is indicated in patients with primary or mixed lipidemia as well as patients with homozygous familial hypercholesteremia. Secondary causes of hyperlipidemia should undergo evaluation before initiating ezetimibe therapy.

Atherosclerosis is one of the major causes of coronary heart disease. Therapeutic lifestyle changes, including weight reduction, increased physical activity, and dietary changes, are first-line management for elevated cholesterol levels. Patients at an increased risk for coronary heart disease need to have a more targeted LDL level. Drugs that help lower cholesterol include HMG-CoA reductase inhibitors (statins), bile acid sequestrants, nicotinic acid, and fibric acids. Ezetimibe is different from these agents because it selectively inhibits the intestinal absorption of cholesterol. The IMPROVE-IT trial showed that lipid-lowering with ezetimibe when used in addition to statins in post-acute coronary syndrome patients, resulted in a significant improvement in cardiovascular outcomes. The American College of Cardiology recommends consideration of ezetimibe therapy in addition to maximally tolerated statin therapy for both primary and secondary prevention in patients who have not achieved target reduction in their LDL levels by maximally tolerated statin therapy alone. Another study found that lipid-lowering therapy in those over the age of 75 was as effective in decreasing cardiovascular events as in those less than 75 years of age.

Mechanism of Action

Cholesterol is synthesized in the liver or absorbed from the gastrointestinal tract. Ezetimibe is a synthetic 2-azetidine agent. Ezetimibe is different from other cholesterol-lowering agents because it does not increase bile acid excretion or inhibit cholesterol synthesis in the liver. Ezetimibe inhibits the absorption of cholesterol at the brush border of the small intestine mediated by the sterol transporter, Niemann-Pick C1-Like-1 (NPC1L1).

The decrease in cholesterol absorption leads to a reduction in the delivery of cholesterol to the liver, an increase in cholesterol clearance from the blood, and a reduction in hepatic cholesterol stores. The reduction in cholesterol absorption results in a decrease in total cholesterol, triglycerides, LDL cholesterol, and an increase in HDL cholesterol. Ezetimibe has no significant effect on fat-soluble vitamins, including vitamin A, vitamin D, and vitamin E. Ezetimibe causes an LDL reduction of approximately 20%.

Administration

Ezetimibe has a long half-life of about 22 hours, which is why it can be administered orally once daily with or without meals with a cholesterol-lowering diet. The dose is 10 mg daily. It may be taken at the same time as fenofibrate or HMG-CoA reductase inhibitors, but the recommendation is to dose it at least 2 hours before or 4 hours after taking bile acid sequestrants. Ezetimibe is neither a cytochrome P450 inhibitor nor a cytochrome p450 inducer, which is why metabolism with other drugs and agents is not affected. Due to once-daily dosing and limited adverse effects, compliance should not be of concern.

Contraindications

Contraindications for the use of ezetimibe include hypersensitivity to any component of the formulation, concomitant use with an HMG-CoA reductase inhibitor in patients with active hepatic disease, or unexplained persistent elevations in serum transaminases. It is also contraindicated in pregnancy and breastfeeding when used in combination with an HMG-CoA reductase inhibitor. When used as monotherapy, it is not necessary to adjust the dosage for patients with renal impairment. Ezetimibe is not recommended in patients with moderate to severe hepatic impairment.

Adverse Effects

The most common adverse effects of ezetimibe include headache, runny nose, and sore throat. Less common reactions include body aches, back pain, chest pain, diarrhea, joint pain, fatigue, and weakness. There have been reports of rhabdomyolysis in combination with statin therapy and, rarely, with monotherapy.

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Anticoagulants Drugs – Uses, Dosage, Side Effects, Interaction

Anticoagulants Drugs/Anticoagulants are medicines that help prevent blood clots. They’re given to people at a high risk of getting clots, to reduce their chances of developing serious conditions such as strokes and heart attacks. A blood clot is a seal created by the blood to stop bleeding from wounds.

Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood.[rx][rx] As a class of medications, anticoagulants are used in therapy for thrombotic disorders.[rx] Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals.[rx][rx] Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart-lung machines, and dialysis equipment.[rx][rx] One of the first anticoagulants, warfarin, was initially approved as a rodenticide.[rx]

Stages

  • The first stage – involves the creation of a platelet plug consequent from disruption of the vascular endothelium from injuries due to diabetes, hypertension, smoking as well as vascular wall tear. Following damage to the vascular wall, the Von Willibrand factor (VWF) is released by the endothelial cells and megakaryocytes, which mediates platelet adhesion to the damaged vascular surface, and aggregation of platelets.
  • The second stage – involves the propagation of clots by activation of various proenzymes to their active form. This clotting cascade is a regulatory process of the clotting system initiated by the extrinsic pathway and propagated via the intrinsic pathway. The extrinsic pathway is initiated by factor III (tissue factor), a membrane-bound glycoprotein that is present in the subendothelial tissues and fibroblast. Tissue factor is activated by exposure from vascular disruption or damage. Exposed tissue factor binds to factor VII and calcium, which then converts factor X to activated factor X.The intrinsic pathway results from activation of factor XI by factor XII, HMW Kininogen, and prekallikrein. Activated XI then activates factor IX. Activated factor IX in conjunction with its cofactor (factor VIII), leads to the activation of factor X.The coagulation cascade has a common pathway that bridges the intrinsic and extrinsic pathways. Activated factor X with its cofactor (factor V) in conjunction with calcium, tissue, and platelet phospholipids, converts prothrombin to thrombin. Thrombin breaks circulating fibrinogen to fibrin and activates factor XIII, which crosslinks fibrin leading to a stable clot.
  • The third stage – in the clotting process is the termination of clot formation and the antithrombin control mechanism which are designed to prevent and mediate the extent of clot formation, thereby preventing processes that can lead to thrombosis, vascular inflammation, and tissue damage. This phase in the clotting pathway ensures the fluidity of blood.Removal of the clot by fibrinolysis is the last stage in clot formation. This stage ensures the removal of organized clots by plasmin as well as wound healing and tissue remodeling. Anticoagulation or clot prevention can be directed at different sites of the coagulation pathway, with overlaps at multiple points. Direct thrombin inhibitors and direct factor Xa inhibitors can inhibit the formation of a fibrin clot. Other mechanisms through which anticoagulation can be achieved include inhibition of vitamin K-dependent factors by preventing their synthesis in the liver or modification of their calcium-binding properties. The use of anticoagulation in pregnancy is an important consideration; pregnancy is associated with a five-fold increase in the risk of venous thromboembolism, with the risk rising to twenty-fold or more during puerperium. The risk further increases if underlying thrombophilia is present. The risk of venous thromboembolism persists until nearly 12 weeks postpartum.

Anatomy and Physiology

Anticoagulants derive their effect by acting at different sites of the coagulation cascade. Some act directly by enzyme inhibition, while others indirectly, by binding to antithrombin or by preventing their synthesis from the liver (vitamin K dependent factors).

Available Anticoagulants

  • Unfractionated Heparin (UFH): These include heparin, make complexes with antithrombin III, and inactivates various clotting factors. Its onset of action is rapid, a short half-life and can be monitored using activated partial thromboplastin (aPTT), activated clotting time, and anti-factor Xa activity. The recommended target ratio of aPTT is 1.5 to 2.2 times the patients’ aPTT.
  • Low Molecular Weight Heparin (LMWH): These are enoxaparin, dalteparin, tinzaparin, nadroparin, have a longer length of action, long half-life, and can be monitored using anti-factor Xa activity. However, monitoring is not indicated except in certain conditions like pregnancy and renal failure.
  • Vitamin K Dependent Antagonists (VKA): Warfarin, one of the most common anticoagulants available. It acts by inhibiting vitamin K epoxide reductase (VKOR), which is needed for the gamma-carboxylation of vitamin K-dependent factors (factors II, VII, IX, X, protein C and S). It has a narrow therapeutic window of dosing, and its effect is profoundly altered by certain factors including diet (leafy green vegetables, fruits like avocado, kiwi), medications, and genetic mutations in the VKOR complex which leads to resistance. It requires frequent monitoring with an international normalized ratio (INR).
  • Direct Thrombin Inhibitors: Bivalirudin, argatroban, and dabigatran are direct thrombin inhibitors; these inhibit the cleavage of fibrinogen to fibrin by thrombin. All products are really metabolized.
  • Direct Factor Xa Inhibitors: These include rivaroxaban, apixaban, edoxaban, and betrixaban. Mechanism of action involves inhibition of the cleavage of prothrombin to thrombin by binding directly to factor Xa. These products are only orally administered.

The terms direct oral anticoagulants (DOACs), new oral anticoagulants (NOACs), or target-specific oral anticoagulants (TSOACs) refer to those oral anticoagulants which specifically inhibit factors IIa (thrombin) or Xa. According to the International Society of Thrombosis and Haemostasis, DOACs is the preferred term. DOACs have been found to have similar effects when compared to other anticoagulants. Some studies have also shown possible decreased bleeding incidence with DOACs. DOACs have increased ease of dosing with less susceptibility to dietary and drug interaction.

Indications

Indications for Anticoagulation

The choice of anticoagulation should be a shared decision and tailored to the patient’s preference, risk stratification, and medical condition. Anticoagulants are indicated in several conditions listed below. The main indications for anticoagulation include atrial fibrillation, venous thromboembolism, and post-heart valve replacement. Venous thromboembolism is important because they sometimes are the first sign in multiple medical conditions.

  • Acute Myocardial Infarction (AMI) – Early anticoagulation (AC) with heparin is indicated for all patients with a documented diagnosis of acute myocardial infarction or acute coronary syndrome. The choice of AC (heparin, unfractionated heparin (UFH), low-molecular-weight heparin, fondaparinux, or bivalirudin) depends on the therapy instituted. AC has been found to lower the risk of thrombus formation when it started early and continued for more than 48 hours. Heparin (UFH) is indicated for patients undergoing percutaneous coronary intervention (PCI). For those patients receiving fibrinolytic therapy, heparin is also indicated and continued for at least two days. Patients not undergoing PCI should be treated with low molecular weight heparin such as enoxaparin or parenteral heparin (UFH).
  • Left Ventricular (LV) Thrombus – Studies have suggested the benefits of early initiation of anticoagulation in patients with documented LV thrombus to prevent embolization of thrombus. Anticoagulation therapy should be continued for three to four months as the risk of embolization was found to be highest within the first 3-4 months. Although no extensive randomized studies have been conducted with the NOACs in this disease state, as compared to warfarin, it is recommended that NOACs be used due to the convenience of dosing. Vitamin K-dependent anticoagulants like warfarin with a therapeutic target INR of 2-3, continue to be used most commonly.
  • Atrial Fibrillation – Anticoagulation reduces the embolic risk in patients with atrial fibrillation. The risk for embolization is the same for patients with paroxysmal, persistent, or chronic atrial fibrillation. Atrial fibrillation is an independent risk factor for stroke. It is present in approximately 20% of patients with a first-time stroke and contributes to increased mortality and disability. The embolic risk for patients with atrial fibrillation can be assessed using scoring systems like the CHA2DS2-Vasc score.
  • Left Ventricular Aneurysm – A left ventricular aneurysm can be a complication of acute myocardial infarction. Patients with a left ventricular aneurysm are at high risk for a thromboembolic event. Among other medical therapies, anticoagulation reduces thromboembolic events, especially in those with arrhythmia.
  • Prosthetic Heart Valve – Anticoagulation therapy is indicated in patients with a prosthetic heart valve. Vitamin K-dependent anticoagulants are recommended for patients with prosthetic heart valves in addition to the use of unfractionated heparin or low-molecular-weight heparin at any point when vitamin K antagonist therapy is interrupted. Direct oral anticoagulants are not indicated in patients with a prosthetic heart valve. The ideal level of vitamin K-dependent anticoagulants varies depending on the diseased valve and the presence of additional thromboembolic risk factors.
  • Venous Thromboembolism Treatment – Anticoagulation is used in the treatment of venous thromboembolism (deep vein thrombosis and pulmonary emboli). The duration for anticoagulation in these clinical states depends on the precipitating circumstances, and additional thromboembolic risk and comorbidities.
  • Venous Thromboembolism Prophylaxis – Anticoagulants are indicated for the prevention of venous thromboembolism in selected patient populations (hospitalized patients, post-operative state, cancer patients). Adverse events like thromboembolism are reduced in patients receiving prophylactic anticoagulation.
  • Treatment of Venous Thromboembolism in Patients with Cancer – Thromboembolism is a frequent complication in cancer patients due to the release of procoagulants from neoplastic cells. Several studies have demonstrated that LMWH is superior to VKAs in the treatment of VTE in cancer patients.
  • Heparin-Induced Thrombocytopenia – Although thrombocytopenia increases bleeding risk, it has been shown to predispose patients to venous thromboembolism. Heparin-induced thrombocytopenia is antibody-mediated with complications that include pulmonary embolism, acute myocardial infarction, and ischemic limb necrosis. Therefore, estimation of the bleeding risk before initiation of anticoagulation is essential. The use of argatroban, lepirudin, or danaparoid is recommended over other non-heparin anticoagulants.
  • Pregnancy – Anticoagulants are indicated in pregnancy for the treatment of acute venous thromboembolism, valvular heart disease, and pregnancy-related complications in women with antiphospholipid antibody syndrome, antithrombin deficiency, or other thrombophilias who had a prior VTE. Warfarin is more efficacious than unfractionated heparin for the prevention of thromboembolism in pregnant ladies with mechanical valves. But, warfarin therapy in the first trimester of pregnancy is associated with a significant increase in fetal anomalies.

Contraindications

Anticoagulation should be avoided in patients with absolute contraindications, such as in the following conditions:

  • Active bleeding
  • Coagulopathy
  • Recent major surgeries
  • Acute intracranial hemorrhage
  • Major trauma

Anticoagulation may be considered in those with relative contraindications such as the following conditions:

  • Gastrointestinal bleed
  • Low-risk surgeries
  • Aortic dissection or aneurysm

Anticoagulation should be used cautiously in these patients:

  • Geriatrics
  • Pregnant patients

Equipment

Laboratory Monitoring and Testing for Anticoagulation

Measurement and monitoring of anticoagulation levels and concentrations may be indicated in certain situations like:

  • Bleeding
  • Thrombosis
  • Urgent or elective invasive procedures
  • Thrombolysis
  • Overdose
  • Therapeutic levels for multiple conditions
  • Preoperative testing
  • Liver disease

Routine monitoring of direct oral anticoagulants (DOAC) levels is not generally indicated unless in certain conditions with high bleeding risk, such as neural procedures that require no anticoagulant effect. Assays for anti-Xa or anti-IIa activity are recommended methods in these conditions for quantitative information.

The initial testing in any individual with suspected bleeding history is listed below. Several point-of-care tests (POCT) for anticoagulation are used in operating rooms. POCT can measure bleedings assays like prothrombin time (PT) and activated partial thromboplastin time (aPTT), fibrinogen assay, and whole blood platelet function test.

  • CBC – with platelet count and morphology
  • Bleeding Time: An insensitive test that is not commonly in use. This test shows how quickly bleeding can stop. The test provides information on platelet disorder, vascular contractility, Von Willibrand disorder (VWD), and thrombocytopenia.
  • Clotting Time: This is the time it takes for plasma to clot after the addition of different substrates in vitro under standard conditions using the capillary method. The average clotting time is between 8 to 15 minutes. Some studies have disputed the use of clotting time as a screening test.
  • Prothrombin Time (PT)/INR: This is the initial test used to identify defects in secondary hemostasis. It is the time taken for blood to clot and generates thrombin. A delay in the PT or aPTT indicates the presence of either a deficiency or inhibitor of the clotting factor, except for the antiphospholipid antibody, which can result in delayed aPTT. The normal range for PT levels is approximately 11 to 13 seconds, although levels may vary depending on the laboratory.
  • Activated Partial Thromboplastin Time (aPTT): Used to assess the intrinsic and common pathways of coagulation. The typical values range from 25 to 35 seconds, though this may vary between laboratories.
  • Thrombin Time: This measures the final step in the clotting cascade. Abnormal thrombin time can be caused by thrombin inhibitor anticoagulants like heparin, dabigatran, argatroban, and any abnormalities in fibrinogen.
  • Specific Clotting Factor Assays: This test is specific for individual factor deficiencies. It is done with the mixing study.
  • Clot Solubility: This test is used to assess for deficiency of factor XIII. Factor XIII crosslinks the fibrin clot after its formation.
  • Fibrin D-dimer: Released from the cleavage of fibrin cross-linked by plasmin.

Interactions

Foods and food supplements with blood-thinning effects include nattokinase, lumbrokinase, beer, bilberry, celery, cranberries, fish oil, garlic, ginger, ginkgo, ginseng, green tea, horse chestnut, licorice, niacin, onion, papaya, pomegranate, red clover, soybean, St. John’s wort, turmeric, wheatgrass, and willow bark. Many herbal supplements have blood-thinning properties, such as danshen and feverfew.[rx] Multivitamins that do not interact with clotting are available for patients on anticoagulants.[rx]

However, some foods and supplements encourage clotting.[rx] These include alfalfa, avocado, cat’s claw, coenzyme Q10, and dark leafy greens such as spinach.[rx][rx] Excessive intake of aforementioned food should be avoided whilst taking anticoagulants or, if coagulability is being monitored, their intake should be kept approximately constant so that anticoagulant dosage can be maintained at a level high enough to counteract this effect without fluctuations in coagulability.[rx][rx]

Grapefruit interferes with some anticoagulant drugs, increasing the amount of time it takes for them to be metabolized out of the body, and so should be eaten with caution when on anticoagulant drugs.[rx]

Anticoagulants are often used to treat acute deep vein thrombosis.[rx][rx] People using anticoagulants to treat this condition should avoid using bed rest as a complementary treatment because there are clinical benefits to continuing to walk and remaining mobile while using anticoagulants in this way.[rx] Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary.[rx]

When anticoagulants are used

If a blood clot blocks the flow of blood through a blood vessel, the affected part of the body will become starved of oxygen and will stop working properly.

Depending on where the clot forms, this can lead to serious problems such as:

  • strokes or transient ischaemic attacks (“mini-strokes”)
  • heart attacks
  • deep vein thrombosis (DVT)
  • pulmonary embolism

Treatment with anticoagulants may be recommended if your doctor feels you’re at an increased risk of developing one of these problems. This may be because you’ve had blood clots in the past or you’ve been diagnosed with a condition such as atrial fibrillation that can cause blood clots to form.

You may also be prescribed an anticoagulant if you’ve recently had surgery, as the period of rest and inactivity you need during your recovery can increase your risk of developing a blood clot.

How to take anticoagulants

Your doctor or nurse should tell you how much of your anticoagulant medicine to take and when to take it.

Most people need to take their tablets or capsules once or twice a day with water or food.

The length of time you need to keep taking your medicine for depends on why it’s been prescribed. In many cases, treatment will be lifelong.

If you’re unsure how to take your medicine or are worried that you missed a dose or have taken too much, check the patient information leaflet that comes with it or ask your GP, anticoagulant clinic or pharmacist what to do. You can also call NHS 111 for advice.

Things to consider when taking anticoagulants

There are several things you need to be aware of when taking anticoagulant medicines.

If you’re going to have surgery or a test such as an endoscopy, make sure your doctor or surgeon is aware that you’re taking anticoagulants, as you may have to stop taking them for a short time.

Speak to your GP, anticoagulant clinic or pharmacist before taking any other medications, including prescription and over-the-counter medicines, as some medications can affect how your anticoagulant works.

If you’re taking warfarin, you’ll also need to avoid making significant changes to what you normally eat and drink, as this can affect your medication.

Most anticoagulant medicines aren’t suitable for pregnant women. Speak to your GP or anticoagulant clinic if you become pregnant or are planning to try for a baby while taking anticoagulants.

About your anticoagulant dose

For most people, anticoagulant tablets or capsules should be taken at the same time once or twice a day. It’s important to take your medicine as scheduled because the effect of some anticoagulants can start to wear off within a day.

Warfarin, apixaban (Eliquis), and dabigatran (Pradaxa) should be taken with water. Rivaroxaban (Xarelto) is normally taken with food.

Depending on your dose, you may need to take more than one tablet or capsule at a time.

Warfarin tablets come in different colors (white, brown, blue and pink) to indicate their strength. You may need to take a combination of different colored tablets to reach your total dose. Other anticoagulants come in different strengths and colors.

Your doctor or nurse will explain how many tablets you need to take when to take them, and what the different colors mean.

Missed or extra doses

Warfarin

If you’re taking warfarin and you miss one of your doses, you should skip the dose you missed and wait to take your next scheduled dose as normal. Don’t take a double dose to make up for the one you missed.

If you accidentally take a dose that was much higher than recommended, contact your anticoagulant clinic or GP for advice.

Newer anticoagulants

If you’re taking apixaban or dabigatran twice a day and you miss one of your doses, you should take it as soon as you remember if it’s still more than 6 hours until your next scheduled dose. If it’s less than 6 hours until your next dose, skip the dose you missed and take the next scheduled dose as normal.

If you accidentally take a double dose, skip your next scheduled dose and take the following dose the next day as scheduled.

If you’re taking rivaroxaban once a day and you miss one of your doses, you should take it as soon as you remember if it’s still more than 12 hours until your next scheduled dose. If it’s less than 12 hours until your next dose, skip the dose you missed and take the next scheduled dose as normal.

If you accidentally take a double dose, take your next dose the next day as scheduled.

Side effects of Anticoagulants Drugs

Like all medicines, there’s a risk of experiencing side effects while taking anticoagulants.

The main side effect is that you can bleed too easily, which can cause problems such as:

  • passing blood in your urine
  • passing blood when you poo or having black poo
  • severe bruising
  • prolonged nosebleeds
  • bleeding gums
  • vomiting blood or coughing up blood
  • heavy periods in women

For most people, the benefits of taking anticoagulants will outweigh the risk of excessive bleeding.

Complications of Anticoagulants Drugs

Bleeding Risk on Anticoagulation

Several factors can increase the risk of bleeding in patients receiving anticoagulation therapy. The risks can be anticoagulant-related or patient-related. Providers need to consider other factors or errors that can increase the risk of bleeding in patients.

Anticoagulant-Related Risks
  • Studies have shown that the risk of significant bleed is higher with warfarin than with direct oral anticoagulants.
  • Dose of anticoagulant
  • Concomitant use of other medications (e.g., antiplatelet agents) that independently increase the risk of bleeding
Patient-Related Risks
  • Age
  • Race (risk increased in Black/Brown population)
  • Underlying medical conditions
  • Recent surgery
  • Coagulopathy

Anticoagulation Reversal

The initial step for any condition requiring urgent reversal of anticoagulation is always to discontinue the anticoagulant. Other standard measures that can be applied to most anticoagulants in certain significant and life-threatening bleeding situations include:

  • Use of activated charcoal with 2 hours of the last dose of anticoagulant
  • Hemodialysis
  • Red blood cell transfusion for anemia
  • Platelet transfusion if thrombocytopenic
  • Some cases may warrant surgical or endoscopic intervention

Different anticoagulants have specific reversal agents that act to counteract their effects.

  • Unfractionated Heparin – Protamine sulfate counteracts the anti-Xa activity of unfractionated heparin. Protamine sulfate has a short half-life and is usually administered intravenously. The ideal dose to achieve full resolution of anti-Xa action can be calculated by 1mg /100units of heparin remaining in the blood. The amount of heparin remaining in the blood can be estimated based on the previous dose of heparin, the interval since the last treatment, considering its half-life of one to two hours (doses of 50mg or 25mg via slow intravenous infusion).
  • Low Molecular Weight (LMW) Heparin – Protamine sulfate is indicated for bleeding in patients on LMW heparin, although not as effective as with bleeding associated with unfractionated heparin. It is known to neutralize the larger molecules of the LMW heparin, which are the culprits in bleeding.
  • Direct Oral Anticoagulants (Dabigatran) – Idarucizumab is an anti-dabigatran monoclonal antibody fragment used in patients treated with dabigatran presenting with life-threatening bleeding. Its dose is 5 grams intravenously.
  • Direct Oral Anticoagulants (Apixaban, Betrixaban, Edoxaban, Rivaroxaban) – Andexanet alfa can be given as 800 mg bolus at 30 mg/minute followed by 960 mg infusion at 8 mg/minute or half of this dose depending on the dose of anticoagulation and last dose of direct oral anticoagulant received above 8 hours.
  • Other Agents – Other nonspecific reversal agents that can be used if andexanet is not available are; 4-factor activated prothrombin complex concentrate (4-factor PCC), factor eight inhibitor bypassing activity (FEIBA), antifibrinolytic agents (tranexamic acid, epsilon-aminocaproic acid), or desmopressin (DDAVP).

References

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Anticoagulants – Indications, Contraindications

Anticoagulants are medicines that help prevent blood clots. They’re given to people at a high risk of getting clots, to reduce their chances of developing serious conditions such as strokes and heart attacks. A blood clot is a seal created by the blood to stop bleeding from wounds.

Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood.[rx][rx] As a class of medications, anticoagulants are used in therapy for thrombotic disorders.[rx] Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals.[rx][rx] Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart-lung machines, and dialysis equipment.[rx][rx] One of the first anticoagulants, warfarin, was initially approved as a rodenticide.[rx]

Stages

The first stage – involves the creation of a platelet plug consequent from disruption of the vascular endothelium from injuries due to diabetes, hypertension, smoking as well as vascular wall tear. Following damage to the vascular wall, the Von Willibrand factor (VWF) is released by the endothelial cells and megakaryocytes, which mediates platelet adhesion to the damaged vascular surface, and aggregation of platelets.

The second stage – involves the propagation of clots by activation of various proenzymes to their active form. This clotting cascade is a regulatory process of the clotting system initiated by the extrinsic pathway and propagated via the intrinsic pathway. The extrinsic pathway is initiated by factor III (tissue factor), a membrane-bound glycoprotein that is present in the subendothelial tissues and fibroblast. Tissue factor is activated by exposure from vascular disruption or damage. Exposed tissue factor binds to factor VII and calcium, which then converts factor X to activated factor X.

The intrinsic pathway results from activation of factor XI by factor XII, HMW Kininogen, and prekallikrein. Activated XI then activates factor IX. Activated factor IX in conjunction with its cofactor (factor VIII), leads to the activation of factor X.

The coagulation cascade has a common pathway that bridges the intrinsic and extrinsic pathways. Activated factor X with its cofactor (factor V) in conjunction with calcium, tissue, and platelet phospholipids, converts prothrombin to thrombin. Thrombin breaks circulating fibrinogen to fibrin and activates factor XIII, which crosslinks fibrin leading to a stable clot.

The third stage – in the clotting process is the termination of clot formation and the antithrombin control mechanism which are designed to prevent and mediate the extent of clot formation, thereby preventing processes that can lead to thrombosis, vascular inflammation, and tissue damage. This phase in the clotting pathway ensures the fluidity of blood.

Removal of the clot by fibrinolysis is the last stage in clot formation. This stage ensures the removal of organized clots by plasmin as well as wound healing and tissue remodeling.

Anticoagulation or clot prevention can be directed at different sites of the coagulation pathway, with overlaps at multiple points. Direct thrombin inhibitors and direct factor Xa inhibitors can inhibit the formation of a fibrin clot. Other mechanisms through which anticoagulation can be achieved include inhibition of vitamin K-dependent factors by preventing their synthesis in the liver or modification of their calcium-binding properties.

The use of anticoagulation in pregnancy is an important consideration; pregnancy is associated with a five-fold increase in the risk of venous thromboembolism, with the risk rising to twenty-fold or more during puerperium. The risk further increases if underlying thrombophilia is present. The risk of venous thromboembolism persists until nearly 12 weeks postpartum.

Anatomy and Physiology

Anticoagulants derive their effect by acting at different sites of the coagulation cascade. Some act directly by enzyme inhibition, while others indirectly, by binding to antithrombin or by preventing their synthesis from the liver (vitamin K dependent factors).

Available Anticoagulants

  • Unfractionated Heparin (UFH): These include heparin, make complexes with antithrombin III, and inactivates various clotting factors. Its onset of action is rapid, a short half-life and can be monitored using activated partial thromboplastin (aPTT), activated clotting time, and anti-factor Xa activity. The recommended target ratio of aPTT is 1.5 to 2.2 times the patients’ aPTT.
  • Low Molecular Weight Heparin (LMWH): These are enoxaparin, dalteparin, tinzaparin, nadroparin, have a longer length of action, long half-life, and can be monitored using anti-factor Xa activity. However, monitoring is not indicated except in certain conditions like pregnancy and renal failure.
  • Vitamin K Dependent Antagonists (VKA): Warfarin, one of the most common anticoagulants available. It acts by inhibiting vitamin K epoxide reductase (VKOR), which is needed for the gamma-carboxylation of vitamin K-dependent factors (factors II, VII, IX, X, protein C and S). It has a narrow therapeutic window of dosing, and its effect is profoundly altered by certain factors including diet (leafy green vegetables, fruits like avocado, kiwi), medications, and genetic mutations in the VKOR complex which leads to resistance. It requires frequent monitoring with an international normalized ratio (INR).
  • Direct Thrombin Inhibitors: Bivalirudin, argatroban, and dabigatran are direct thrombin inhibitors; these inhibit the cleavage of fibrinogen to fibrin by thrombin. All products are really metabolized.
  • Direct Factor Xa Inhibitors: These include rivaroxaban, apixaban, edoxaban, and betrixaban. Mechanism of action involves inhibition of the cleavage of prothrombin to thrombin by binding directly to factor Xa. These products are only orally administered.

The terms direct oral anticoagulants (DOACs), new oral anticoagulants (NOACs), or target-specific oral anticoagulants (TSOACs) refer to those oral anticoagulants which specifically inhibit factors IIa (thrombin) or Xa. According to the International Society of Thrombosis and Haemostasis, DOACs is the preferred term. DOACs have been found to have similar effects when compared to other anticoagulants. Some studies have also shown possible decreased bleeding incidence with DOACs. DOACs have increased ease of dosing with less susceptibility to dietary and drug interaction.

Indications

Indications for Anticoagulation

The choice of anticoagulation should be a shared decision and tailored to the patient’s preference, risk stratification, and medical condition. Anticoagulants are indicated in several conditions listed below. The main indications for anticoagulation include atrial fibrillation, venous thromboembolism, and post-heart valve replacement. Venous thromboembolism is important because they sometimes are the first sign in multiple medical conditions.

  • Acute Myocardial Infarction (AMI) – Early anticoagulation (AC) with heparin is indicated for all patients with a documented diagnosis of acute myocardial infarction or acute coronary syndrome. The choice of AC (heparin, unfractionated heparin (UFH), low-molecular-weight heparin, fondaparinux, or bivalirudin) depends on the therapy instituted. AC has been found to lower the risk of thrombus formation when it started early and continued for more than 48 hours. Heparin (UFH) is indicated for patients undergoing percutaneous coronary intervention (PCI). For those patients receiving fibrinolytic therapy, heparin is also indicated and continued for at least two days. Patients not undergoing PCI should be treated with low molecular weight heparin such as enoxaparin or parenteral heparin (UFH).
  • Left Ventricular (LV) Thrombus – Studies have suggested the benefits of early initiation of anticoagulation in patients with documented LV thrombus to prevent embolization of thrombus. Anticoagulation therapy should be continued for three to four months as the risk of embolization was found to be highest within the first 3-4 months. Although no extensive randomized studies have been conducted with the NOACs in this disease state, as compared to warfarin, it is recommended that NOACs be used due to the convenience of dosing. Vitamin K-dependent anticoagulants like warfarin with a therapeutic target INR of 2-3, continue to be used most commonly.
  • Atrial Fibrillation – Anticoagulation reduces the embolic risk in patients with atrial fibrillation. The risk for embolization is the same for patients with paroxysmal, persistent, or chronic atrial fibrillation. Atrial fibrillation is an independent risk factor for stroke. It is present in approximately 20% of patients with a first-time stroke and contributes to increased mortality and disability. The embolic risk for patients with atrial fibrillation can be assessed using scoring systems like the CHA2DS2-Vasc score.
  • Left Ventricular Aneurysm – A left ventricular aneurysm can be a complication of acute myocardial infarction. Patients with a left ventricular aneurysm are at high risk for a thromboembolic event. Among other medical therapies, anticoagulation reduces thromboembolic events, especially in those with arrhythmia.
  • Prosthetic Heart Valve – Anticoagulation therapy is indicated in patients with a prosthetic heart valve. Vitamin K-dependent anticoagulants are recommended for patients with prosthetic heart valves in addition to the use of unfractionated heparin or low-molecular-weight heparin at any point when vitamin K antagonist therapy is interrupted. Direct oral anticoagulants are not indicated in patients with a prosthetic heart valve. The ideal level of vitamin K-dependent anticoagulants varies depending on the diseased valve and the presence of additional thromboembolic risk factors.
  • Venous Thromboembolism Treatment – Anticoagulation is used in the treatment of venous thromboembolism (deep vein thrombosis and pulmonary emboli). The duration for anticoagulation in these clinical states depends on the precipitating circumstances, and additional thromboembolic risk and comorbidities.
  • Venous Thromboembolism Prophylaxis – Anticoagulants are indicated for the prevention of venous thromboembolism in selected patient populations (hospitalized patients, post-operative state, cancer patients). Adverse events like thromboembolism are reduced in patients receiving prophylactic anticoagulation.
  • Treatment of Venous Thromboembolism in Patients with Cancer – Thromboembolism is a frequent complication in cancer patients due to the release of procoagulants from neoplastic cells. Several studies have demonstrated that LMWH is superior to VKAs in the treatment of VTE in cancer patients.
  • Heparin-Induced Thrombocytopenia – Although thrombocytopenia increases bleeding risk, it has been shown to predispose patients to venous thromboembolism. Heparin-induced thrombocytopenia is antibody-mediated with complications that include pulmonary embolism, acute myocardial infarction, and ischemic limb necrosis. Therefore, estimation of the bleeding risk before initiation of anticoagulation is essential. The use of argatroban, lepirudin, or danaparoid is recommended over other non-heparin anticoagulants.
  • Pregnancy – Anticoagulants are indicated in pregnancy for the treatment of acute venous thromboembolism, valvular heart disease, and pregnancy-related complications in women with antiphospholipid antibody syndrome, antithrombin deficiency, or other thrombophilias who had a prior VTE. Warfarin is more efficacious than unfractionated heparin for the prevention of thromboembolism in pregnant ladies with mechanical valves. But, warfarin therapy in the first trimester of pregnancy is associated with a significant increase in fetal anomalies.

Contraindications

Anticoagulation should be avoided in patients with absolute contraindications, such as in the following conditions:

  • Active bleeding
  • Coagulopathy
  • Recent major surgeries
  • Acute intracranial hemorrhage
  • Major trauma

Anticoagulation may be considered in those with relative contraindications such as the following conditions:

  • Gastrointestinal bleed
  • Low-risk surgeries
  • Aortic dissection or aneurysm

Anticoagulation should be used cautiously in these patients:

  • Geriatrics
  • Pregnant patients

Equipment

Laboratory Monitoring and Testing for Anticoagulation

Measurement and monitoring of anticoagulation levels and concentrations may be indicated in certain situations like:

  • Bleeding
  • Thrombosis
  • Urgent or elective invasive procedures
  • Thrombolysis
  • Overdose
  • Therapeutic levels for multiple conditions
  • Preoperative testing
  • Liver disease

Routine monitoring of direct oral anticoagulants (DOAC) levels is not generally indicated unless in certain conditions with high bleeding risk, such as neural procedures that require no anticoagulant effect. Assays for anti-Xa or anti-IIa activity are recommended methods in these conditions for quantitative information.

The initial testing in any individual with suspected bleeding history is listed below. Several point-of-care tests (POCT) for anticoagulation are used in operating rooms. POCT can measure bleedings assays like prothrombin time (PT) and activated partial thromboplastin time (aPTT), fibrinogen assay, and whole blood platelet function test.

  • CBC – with platelet count and morphology
  • Bleeding Time: An insensitive test that is not commonly in use. This test shows how quickly bleeding can stop. The test provides information on platelet disorder, vascular contractility, Von Willibrand disorder (VWD), and thrombocytopenia.
  • Clotting Time: This is the time it takes for plasma to clot after the addition of different substrates in vitro under standard conditions using the capillary method. The average clotting time is between 8 to 15 minutes. Some studies have disputed the use of clotting time as a screening test.
  • Prothrombin Time (PT)/INR: This is the initial test used to identify defects in secondary hemostasis. It is the time taken for blood to clot and generates thrombin. A delay in the PT or aPTT indicates the presence of either a deficiency or inhibitor of the clotting factor, except for the antiphospholipid antibody, which can result in delayed aPTT. The normal range for PT levels is approximately 11 to 13 seconds, although levels may vary depending on the laboratory.
  • Activated Partial Thromboplastin Time (aPTT): Used to assess the intrinsic and common pathways of coagulation. The typical values range from 25 to 35 seconds, though this may vary between laboratories.
  • Thrombin Time: This measures the final step in the clotting cascade. Abnormal thrombin time can be caused by thrombin inhibitor anticoagulants like heparin, dabigatran, argatroban, and any abnormalities in fibrinogen.
  • Specific Clotting Factor Assays: This test is specific for individual factor deficiencies. It is done with the mixing study.
  • Clot Solubility: This test is used to assess for deficiency of factor XIII. Factor XIII crosslinks the fibrin clot after its formation.
  • Fibrin D-dimer: Released from the cleavage of fibrin cross-linked by plasmin.

Interactions

Foods and food supplements with blood-thinning effects include nattokinase, lumbrokinase, beer, bilberry, celery, cranberries, fish oil, garlic, ginger, ginkgo, ginseng, green tea, horse chestnut, licorice, niacin, onion, papaya, pomegranate, red clover, soybean, St. John’s wort, turmeric, wheatgrass, and willow bark. Many herbal supplements have blood-thinning properties, such as danshen and feverfew.[rx] Multivitamins that do not interact with clotting are available for patients on anticoagulants.[rx]

However, some foods and supplements encourage clotting.[rx] These include alfalfa, avocado, cat’s claw, coenzyme Q10, and dark leafy greens such as spinach.[rx][rx] Excessive intake of aforementioned food should be avoided whilst taking anticoagulants or, if coagulability is being monitored, their intake should be kept approximately constant so that anticoagulant dosage can be maintained at a level high enough to counteract this effect without fluctuations in coagulability.[rx][rx]

Grapefruit interferes with some anticoagulant drugs, increasing the amount of time it takes for them to be metabolized out of the body, and so should be eaten with caution when on anticoagulant drugs.[rx]

Anticoagulants are often used to treat acute deep vein thrombosis.[rx][rx] People using anticoagulants to treat this condition should avoid using bed rest as a complementary treatment because there are clinical benefits to continuing to walk and remaining mobile while using anticoagulants in this way.[rx] Bed rest while using anticoagulants can harm patients in circumstances in which it is not medically necessary.[rx]

When anticoagulants are used

If a blood clot blocks the flow of blood through a blood vessel, the affected part of the body will become starved of oxygen and will stop working properly.

Depending on where the clot forms, this can lead to serious problems such as:

  • strokes or transient ischaemic attacks (“mini-strokes”)
  • heart attacks
  • deep vein thrombosis (DVT)
  • pulmonary embolism

Treatment with anticoagulants may be recommended if your doctor feels you’re at an increased risk of developing one of these problems. This may be because you’ve had blood clots in the past or you’ve been diagnosed with a condition such as atrial fibrillation that can cause blood clots to form.

You may also be prescribed an anticoagulant if you’ve recently had surgery, as the period of rest and inactivity you need during your recovery can increase your risk of developing a blood clot.

How to take anticoagulants

Your doctor or nurse should tell you how much of your anticoagulant medicine to take and when to take it.

Most people need to take their tablets or capsules once or twice a day with water or food.

The length of time you need to keep taking your medicine for depends on why it’s been prescribed. In many cases, treatment will be lifelong.

If you’re unsure how to take your medicine or are worried that you missed a dose or have taken too much, check the patient information leaflet that comes with it or ask your GP, anticoagulant clinic or pharmacist what to do. You can also call NHS 111 for advice.

Things to consider when taking anticoagulants

There are several things you need to be aware of when taking anticoagulant medicines.

If you’re going to have surgery or a test such as an endoscopy, make sure your doctor or surgeon is aware that you’re taking anticoagulants, as you may have to stop taking them for a short time.

Speak to your GP, anticoagulant clinic or pharmacist before taking any other medications, including prescription and over-the-counter medicines, as some medications can affect how your anticoagulant works.

If you’re taking warfarin, you’ll also need to avoid making significant changes to what you normally eat and drink, as this can affect your medication.

Most anticoagulant medicines aren’t suitable for pregnant women. Speak to your GP or anticoagulant clinic if you become pregnant or are planning to try for a baby while taking anticoagulants.

About your anticoagulant dose

For most people, anticoagulant tablets or capsules should be taken at the same time once or twice a day. It’s important to take your medicine as scheduled because the effect of some anticoagulants can start to wear off within a day.

Warfarin, apixaban (Eliquis), and dabigatran (Pradaxa) should be taken with water. Rivaroxaban (Xarelto) is normally taken with food.

Depending on your dose, you may need to take more than one tablet or capsule at a time.

Warfarin tablets come in different colors (white, brown, blue and pink) to indicate their strength. You may need to take a combination of different colored tablets to reach your total dose. Other anticoagulants come in different strengths and colors.

Your doctor or nurse will explain how many tablets you need to take when to take them, and what the different colors mean.

Missed or extra doses

Warfarin

If you’re taking warfarin and you miss one of your doses, you should skip the dose you missed and wait to take your next scheduled dose as normal. Don’t take a double dose to make up for the one you missed.

If you accidentally take a dose that was much higher than recommended, contact your anticoagulant clinic or GP for advice.

Newer anticoagulants

If you’re taking apixaban or dabigatran twice a day and you miss one of your doses, you should take it as soon as you remember if it’s still more than 6 hours until your next scheduled dose. If it’s less than 6 hours until your next dose, skip the dose you missed and take the next scheduled dose as normal.

If you accidentally take a double dose, skip your next scheduled dose and take the following dose the next day as scheduled.

If you’re taking rivaroxaban once a day and you miss one of your doses, you should take it as soon as you remember if it’s still more than 12 hours until your next scheduled dose. If it’s less than 12 hours until your next dose, skip the dose you missed and take the next scheduled dose as normal.

If you accidentally take a double dose, take your next dose the next day as scheduled.

Side effects of anticoagulants

Like all medicines, there’s a risk of experiencing side effects while taking anticoagulants.

The main side effect is that you can bleed too easily, which can cause problems such as:

  • passing blood in your urine
  • passing blood when you poo or having black poo
  • severe bruising
  • prolonged nosebleeds
  • bleeding gums
  • vomiting blood or coughing up blood
  • heavy periods in women

For most people, the benefits of taking anticoagulants will outweigh the risk of excessive bleeding.

Complications

Bleeding Risk on Anticoagulation

Several factors can increase the risk of bleeding in patients receiving anticoagulation therapy. The risks can be anticoagulant-related or patient-related. Providers need to consider other factors or errors that can increase the risk of bleeding in patients.

Anticoagulant-Related Risks
  • Studies have shown that the risk of significant bleed is higher with warfarin than with direct oral anticoagulants.
  • Dose of anticoagulant
  • Concomitant use of other medications (e.g., antiplatelet agents) that independently increase the risk of bleeding
Patient-Related Risks
  • Age
  • Race (risk increased in Black/Brown population)
  • Underlying medical conditions
  • Recent surgery
  • Coagulopathy

Anticoagulation Reversal

The initial step for any condition requiring urgent reversal of anticoagulation is always to discontinue the anticoagulant. Other standard measures that can be applied to most anticoagulants in certain significant and life-threatening bleeding situations include:

  • Use of activated charcoal with 2 hours of the last dose of anticoagulant
  • Hemodialysis
  • Red blood cell transfusion for anemia
  • Platelet transfusion if thrombocytopenic
  • Some cases may warrant surgical or endoscopic intervention

Different anticoagulants have specific reversal agents that act to counteract their effects.

  • Unfractionated Heparin – Protamine sulfate counteracts the anti-Xa activity of unfractionated heparin. Protamine sulfate has a short half-life and is usually administered intravenously. The ideal dose to achieve full resolution of anti-Xa action can be calculated by 1mg /100units of heparin remaining in the blood. The amount of heparin remaining in the blood can be estimated based on the previous dose of heparin, the interval since the last treatment, considering its half-life of one to two hours (doses of 50mg or 25mg via slow intravenous infusion).
  • Low Molecular Weight (LMW) Heparin – Protamine sulfate is indicated for bleeding in patients on LMW heparin, although not as effective as with bleeding associated with unfractionated heparin. It is known to neutralize the larger molecules of the LMW heparin, which are the culprits in bleeding.
  • Direct Oral Anticoagulants (Dabigatran) – Idarucizumab is an anti-dabigatran monoclonal antibody fragment used in patients treated with dabigatran presenting with life-threatening bleeding. Its dose is 5 grams intravenously.
  • Direct Oral Anticoagulants (Apixaban, Betrixaban, Edoxaban, Rivaroxaban) – Andexanet alfa can be given as 800 mg bolus at 30 mg/minute followed by 960 mg infusion at 8 mg/minute or half of this dose depending on the dose of anticoagulation and last dose of direct oral anticoagulant received above 8 hours.
  • Other Agents – Other nonspecific reversal agents that can be used if andexanet is not available are; 4-factor activated prothrombin complex concentrate (4-factor PCC), factor eight inhibitor bypassing activity (FEIBA), antifibrinolytic agents (tranexamic acid, epsilon-aminocaproic acid) or desmopressin (DDAVP).

References

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Pituitary Hormones – Anatomy, Types, Functions

The pituitary hormones are special chemical messengers that are produced by the pituitary gland, also known as “the master gland of the body.” The hormones are peptides or glycoproteins in nature and play a vital role in regulating the functions of other endocrine glands. The anterior pituitary hormones are produced by five different endocrine cell types (somatotropes, gonadotropes, lactotrophs, corticotropes, and thyrotropes) and include growth hormone (GH), prolactin, adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), adrenocorticotropic hormone (ACTH), and thyroid-stimulating hormone (TSH). The release of these hormones is under the regulation of inhibitory or stimulatory signals from the hypothalamus. The posterior pituitary hormones are the nano peptide and oligo-peptide vasopressin and oxytocin, respectively, which regulate water retention and uterine contraction.

Cellular

The hormones of the pituitary gland are protein or polypeptide in nature and vary in complexity.

Anterior Pituitary Hormones

Human Growth Hormone

Human growth hormone (HGH), also known as somatotropin, is a protein of 191 amino acid single chain polypeptides secreted by the acidophilic somatotropic cells of the anterior pituitary gland. Its levels in the body are under tight regulation by the hypothalamus mediators, growth hormone-releasing hormone (GHRH), and growth hormone-inhibiting hormone (GHIH or somatostatin).

Prolactin

Prolactin is a protein hormone secreted by the acidophilic lactotroph cells of the anterior pituitary gland. Chemically, prolactin is similar to a growth hormone composing of 199 amino acids, and forms after a 28-amino acid signal peptide are proteolytically cleaved from the prolactin prohormone (pre-prolactin). The secretion of prolactin by the anterior pituitary is tonically inhibited by dopamine from the tuberoinfundibular pathway of the hypothalamus and stimulated by thyrotropin-releasing hormone (TRH), estrogen, dopamine antagonist (antipsychotics), and multiple factors including suckling, stress, and sleep.

Follicle-stimulating Hormone (FSH) and Luteinizing Hormone (LH)

FSH and LH, also known as gonadotropins, are glycoprotein hormones secreted by the gonadotropin cells of the adenohypophysis. They are both glycoproteins made up of an alpha and beta subunit. The alpha subunits are identical between the two hormones, but the beta subunit of each is different and gives each hormone its biological specificity. Particularly, the alpha subunit of LH is made up of 92 amino acids, and the beta subunit contains 120 amino acids. The gonadotropic cells do not react well with acid or basic stains and thus appear either basophilic or chromophobic under the microscope. The secretion of these hormones is regulated by the release of gonadotropin-releasing hormone secreted by the hypothalamus.

Adrenocorticotrophic Hormone (ACTH)

The adrenocorticotrophic hormone is a polypeptide tropic hormone produced and secreted by the basophilic corticotropic cells of the anterior pituitary gland. ACTH is synthesized from Pro-opiomelanocortin (POMC) and consists of 39 amino acids. The hypothalamus-pituitary axis and secretion tightly regulate its production is in response to the corticotropin-releasing hormone.

Thyroid-stimulating Hormone (TSH)

Thyroid-stimulating hormone is a peptide hormone secreted by the basophilic thyrotropes of the anterior pituitary gland. It is composed of 1 alpha chain and one beta chain. The hypothalamus-pituitary axis regulates its release. The hypothalamus releases thyroid-releasing hormone (TRH), which stimulates thyrotrophs of the anterior pituitary to secrete TSH.

Posterior Pituitary Hormones

Vasopressin & Oxytocin

Vasopressin, also known as antidiuretic hormone (ADH), is synthesized in the supraoptic nuclei of the hypothalamus while oxytocin synthesis occurs in the paraventricular nuclei of the hypothalamus. Both the posterior pituitary hormones are packaged in secretory granules and move down the axon where they are stored in the Herring bodies. These bodies are neurosecretory granules that represent the terminal ends of the axons coming from the hypothalamus.

Development

The developmental origin of the pituitary gland is unique with a dual origin and begins in the fourth week of fetal development. The anterior pituitary, also called the adenohypophysis, is derived from embryonic ectoderm and is epithelial in origin, whereas the posterior pituitary, also known as neurohypophysis derives from neuroectoderm. The development of the pituitary gland can broadly classify into the following stages:

  • Formation of Rathke’s pouch
  • Evagination of Rathke’s pouch and cell proliferation
  • Cellular differentiation 

Function

Growth Hormone

The effects of HGH on the tissues of the body can generally be described as anabolic. Their primary function is to induce growth in almost all tissues and organs of the body, especially during adolescence. It increases the uptake of amino acids from the blood, enhances cellular proliferation, and reduces apoptosis. HGH also impacts metabolism, primarily by up-regulating the production of insulin-like growth factor-1 and its subsequent effect on peripheral cells. It stimulates a diabetogenic effect by stimulating the liver to break down glycogen to glucose and releasing it into the blood. Furthermore, HGH stimulates lipolysis, breaking down stored fat and releasing it into the bloodstream. Subsequently, many tissues switch from glucose to fatty acid as their main energy source, resulting in increased levels of glucose in the bloodstream.

Prolactin

Prolactin is best known for its multiple actions on the mammary gland with its two main functions; stimulation of milk production and development of breast tissues. During pregnancy, it contributes to the development and growth of the breast tissue with estrogen and progesterone and stimulates the enlargement of the alveoli in preparation for lactation. Prolactin stimulates milk production by inducing the enzyme that synthesizes the constituents of milk, such as lactose (the carbohydrate of milk), casein (the protein of milk), and lipids.

Follicle-stimulating Hormone and Luteinizing Hormone

The gonadotropins primarily regulate reproductive function and sexual development in both males and females. In the case of females, the onset and cessation of reproductive capacity are also dependent on these hormones.

FSH stimulates the production and maturation of sex cells, sperm in males, and ova in females. It also promotes follicular maturation in females during the ovarian cycle; these follicles then release estrogen in the female ovaries. LH triggers ovulation in women and causes the release of progesterone from the corpus luteum after ovulation. Furthermore, it causes the release of estrogen and progesterone from the ovaries. In males, LH stimulates the release of testosterone from the Leydig cells of the testes.

Adrenocorticotrophic Hormone

ACTH primarily functions to regulate cortisol and androgen production. The ACTH released from the anterior pituitary acts on its target organ, the Adrenal gland, and stimulates the production of Glucocorticoids from the Zona Fasiculata and androgens from the Zona Reticularis.

Thyroid-stimulating Hormone

TSH triggers the secretion of thyroid hormones thyroxine, or T4, and triiodothyronine, or T3 by stimulating receptors found in the follicular cells of the thyroid gland. Subsequently, the thyroid hormones promote bone and central nervous system maturation, increase basal metabolic rate, and heat production. TSH is also necessary to maintain the size of the thyroid follicles and their continued ability to produce thyroid hormones.

Vasopressin

Vasopressin acts as a water-saving hormone and is released into the bloodstream to vasoconstrict and reabsorb water from the kidney’s collecting duct; this ensures the equilibrium of intracellular and extracellular contents.

Oxytocin

The polypeptide hormone oxytocin is commonly released in females during the process of childbirth. It allows the uterus to contract, which advances the fetus into the vagina for delivery. During lactation, oxytocin also releases milk from the breast tissue into the baby’s oral cavity. Finally, oxytocin is also present in males during ejaculation and stimulates contraction of the vas deferens to push the semen and sperm forward.

Mechanism

Growth Hormone

Growth Hormone has a direct and indirect mechanism of action. The direct effect of growth hormone involves growth hormone directly binding to its receptors on target cells to stimulate a response. The indirect effect is mediated by the action of insulin-like growth factor-1(IGF-1), which is secreted by the liver hepatocytes in response to growth hormone. Insulin-like growth factor-1 binds to its receptor, IGF-1R, on the cellular surface and activates a tyrosine kinase-mediated intracellular signaling pathway that phosphorylates various proteins intracellularly leading to increased anabolism, cellular replication and division, and metabolism.

Prolactin

Prolactin initiates its effect by binding to the prolactin receptor found on various tissues across the body, including but not limited to mammillary glands, ovaries, skeletal muscle, uterus, and thymus. Upon the binding of prolactin to its receptor, Jannu kinase 2, a tyrosine kinase is activated that furthermore initiates the JAK-STAT pathway.

FSH & LH

Both LH & FSH bind to G protein-coupled receptors. Upon binding to the receptor, adenylyl cyclase, an enzyme is activated, which goes on to produce cyclic-AMP. The intracellular concentrations of cyclic-AMP rise, which further activates a kinase molecule called protein kinase A. Protein kinase A primarily functions to phosphorylate specific intracellular proteins that then subsequently complete the physiological actions of FSH and LH.

Adrenocorticotropic Hormone

ACTH interacts with G protein-coupled receptors found on the extracellular membranes of the zona fasciculata and zona reticularis of the adrenal cortex. cAMP is the secondary messenger system. Activation of the g-couple receptor activates adenylyl cyclase, thus increase cAMP production and subsequent activation of Protein Kinase A.

Thyroid Stimulating Hormone (TSH)

TSH binds and activates the TSH receptor (TSHR) found on the basolateral surface of thyroid follicle cells. This binding site is a G-protein coupled receptor (GPCR), which couples to both Gs and Gq G-proteins, and hence activating both the cAMP pathway (via Gsa) and the phosphoinositol/calcium (IP/Ca2+; via Gq) second messenger signaling cascades. The Gs pathway activates iodide uptake,  increases thyroid hormone production, and enhances gland growth and differentiation. The Gq pathway is rate-limiting for hormone production by stimulating iodide organification.

Vasopressin

Two regulating receptors, the subfornical organ and the organum vasculum in the hypothalamus, since water deprivation and signal for ADH secretion. A small concentration of vasopressin is sufficient to generate water conservation in the renal tubules. The renal tubules are divided into the proximal, descending, ascending, distal regions, and the collecting duct. The most ADH-dependent segment of the renal tubule is the collecting duct, which has ADH receptors on its basolateral side for ADH to bind and stimulate the Gs protein. The Gs protein stimulates adenylyl cyclase, which further converts ATP into cAMP. High levels of cAMP cause the phosphorylation of protein kinase A, subsequently opening water channels known as aquaporins to allow passage of water from the luminal side to the basolateral side.

Oxytocin

Oxytocin binds to its extracellular receptor present in the myometrium of the uterus, which then activates the Gq protein further leading to activation of phospholipase C. The phospholipase C functions to break down the phosphoinositol diphosphate into two components, Inositol triphosphate (IP3) which will release calcium from the sarcoplasmic reticulum and diacylglycerol (DAG) which will activate protein kinase C. The protein kinase C phosphorylates proteins specifically on the cell membrane to allow calcium entry from the extracellular space. The increased intracellular calcium generates enough energy to cause the contraction of the uterus.

During lactation, when the newborn suckles, it transmits signals to the central nervous system to release oxytocin, a process known as the “milk letdown reflex.” The oxytocin binds to the breast myoepithelial cell receptors and initiates the same Gq cascade similar to uterine contraction, and ejects milk into the baby’s oral cavity.

Pathophysiology

Growth Hormone

Dysfunction of the endocrine system control and release of growth hormone can result in several disorders. Hypersecretion of GH can cause acromegaly and gigantism, both of which are most commonly caused by a GH secreting adenoma of the pituitary gland.

Acromegaly

Acromegaly typically is caused by a GH secreting pituitary adenoma that occurs after the closure of the epiphyseal growth plate. It leads to characteristic facies, large extremities, frontal bossing, diaphoresis, and impaired glucose tolerance. An increased insulin-like growth factor-1 (IGF-1) level establishes the diagnosis. Surgical excision is the first line of treatment for acromegaly. However, further medical treatment with somatostatin analogs or radiation is necessary as complete recovery is rare.

Gigantism

Gigantism occurs when due to hypersecretion of growth hormone before the fusion of long bone epiphysis. It is characterized by tall stature and should be suspected when the patient’s height is three standard deviations above normal mean height.

Growth Hormone Deficiency

The effect of GH deficiency depends on the age at which the deficiency occurs. Onset in childhood is associated with decreased growth of all skeletal structures, subsequently leading to dwarfism. Adult-onset deficiency is more difficult to diagnose as it does not have a single identifying pathognomic factor. It usually presents with increased fat mass in visceral tissues and decreased skeletal muscle, as well as decreased bone density and remodeling, leading to osteoporosis.

Prolactin

The pathology related to prolactin can be due to either prolactin excess or a deficiency of prolactin.

Prolactin deficiency, most commonly due to pituitary destruction, presents with failure to lactate.

Increased levels of prolactin can be physiological, pathological, or drug-induced. Physiological causes include pregnancy, exercise, sleep, stress, neonatal period, nipple stimulation and lactation, and sexual intercourse. Physiological hyperprolactinemia is transient and adaptive, and most patients may remain asymptomatic. Pharmacological and pathological hyperprolactinemia are symptomatic conditions (hypogonadism and galactorrhea) that have unwanted long-term consequences. Regardless of etiology, treatment options for prolactin excess include dopamine agonist medications such as bromocriptine and cabergoline.

Follicle-stimulating hormone and Luteinizing Hormone

Hyperfunctioning pituitary adenomas or unresponsive gonads can lead to increased FSH & LH. Decreased levels of FSH & LH can stem from pathology within either the hypothalamus or anterior pituitary.

Adrenocorticotropic Hormone

Pathophysiology of ACTH can stem from either dysfunction of the pituitary, the adrenal glands, or ectopic secretions from a pathogenic source.

Hypofunctioning or hyperfunctioning of the pituitary gland can lead to a decrease or increase of ACTH levels in the body, respectively. Common causes of decreased ACTH include pituitary insufficiency due to an adenoma compressing the pituitary gland, pituitary apoplexy, the sudden hemorrhage into the pituitary gland causing loss of ACTH, or Sheehan syndrome, a condition of pituitary infarction after blood loss during childhood.

Thyroid-stimulating Hormone

A TSH assay is the recommended screening test for thyroid disease. It is the test of choice in patients suspected of having a deficiency (hypothyroidism) or excess (hyperthyroidism) of thyroid hormones. Abnormal levels indicate the pathological functioning of the thyroid gland.

When TSH levels are below normal levels, the primary diagnosis is hyperthyroidism. Low levels of TSH present in patients on steroids, dopamine, and somatostatin analogs. Patients with thyroid cancer who receive treatment with thyroxine can also have decreased levels of TSH. Graves disease is another common pathology that presents with low TSH levels and is due to an autoimmune disorder, which stimulates the thyroid gland to make excess thyroid hormones. The increased thyroid hormones cause feedback inhibition of TSH secretion by the anterior pituitary gland.

Vasopressin

Central Diabetes Insipidus

Decreased levels of vasopressin can cause different pathological states. The most common form of pathology secondary to decreased ADH secretion from the pituitary gland is central diabetes insipidus. Low levels of ADH result in excess free water in the urine. There are no identifiable causes for the majority of the cases, and therefore, those cases are labeled as idiopathic central diabetes insipidus. Acquired forms of central diabetes insipidus include vascular and autoimmune diseases, craniopharyngioma, sarcoidosis, hypoxic brain injury, surgery, trauma, structural malformations, metastasis, Langerhans cell histiocytosis, or ischemia. Common presenting symptoms of patients include polyuria, polydipsia, and nocturia but may also include less common findings of weakness, lethargy, fatigue, and myalgias.

Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Excess ADH from an ectopic source or the posterior pituitary leads to the syndrome of inappropriate antidiuretic hormone (SIADH). The excess ADH causes increased water retention and hypervolemic hyponatremia. Common etiologies behind SIADH include malignancies, trauma, stroke, infection, medications, and/or anesthesia.

Oxytocin

Oxytocin insufficiency is not a common pathology but can occur rarely. Decreased levels of oxytocin slow down uterine contractions and reduce milk ejection during the birthing process. Panyypopituarism, a pathology in which both anterior and posterior hormone levels are below normal, can be the cause of oxytocin hyposecretion.

Excess oxytocin is also rarely seen and causes an overactive uterus causing hypertrophy, which further leads to difficulty in maintaining pregnancy due to insufficient space for holding the fetus.

References

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Autonomic Pharmacology – Drugs Work on Autonomic Nervous System

Autonomic Pharmacology/The basis of autonomic pharmacology reflects the physiology of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS) to regulate involuntary reactions to stresses on multiorgan systems within the body. When a pathologic process is present that affects the homeostasis achieved between the SNS and PSNS in this process, either of these branches can become overactive while the other is excessively inhibited. This activity outlines the indications, mechanism of action, safe administration, adverse effects, contraindications, toxicology, and monitoring of the broad array of physiological possibilities when using autonomic pharmacology.

The basis of autonomic pharmacology reflects the physiology of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS) to regulate involuntary reactions to stresses on multiorgan systems within the body. When a pathologic process is present that affects the homeostasis achieved between the SNS and PSNS in this process, either of these branches can become overactive while the other is excessively inhibited. This break in homeostasis results in various clinical manifestations that can range in severity from simply presenting rhinorrhea symptomology to fatal presentations like cardiovascular collapse. For a wide range of presentations and severity of pathologies, the agents classified in autonomic pharmacology are indicated to re-establish the homeostasis that the human body attempts to produce via the autonomic nervous system (ANS).

Within autonomic pharmacology, there are four specific categories of drugs based on how they affect the ANS:

  1. Cholinomimetics/cholinesterase antagonists
  2. Anticholinergics
  3. Adrenoreceptor agonists/sympathomimetics
  4. Adrenoreceptor antagonists

The clinical indications of medications from each of the four categories are listed below. Important to note is that this is not a complete list due to the vastness of this topic; the drugs included are representative of each category.

 FDA-labeled indications

Cholinomimetics/Cholinesterase antagonists:

  • Bethanechol – postoperative and neurogenic ileus and urinary retention
  • Pilocarpine – glaucoma and alleviating the symptoms of Sjogren’s syndrome
  • Nicotine – found in smoking cessation regimens
  • Cholinesterase inhibitors (neostigmine, edrophonium, pyridostigmine, physostigmine) – the diagnosis and treatment of myasthenia gravis, maintenance treatment of Alzheimer disease, and specifically neostigmine used commonly with glycopyrrolate to reverse neuromuscular blockade in postoperative anesthesia practice

Anticholinergics:

  • Atropine – used in ACLS guidelines to correct bradyarrhythmias and in ophthalmic surgery as a retinal dilator
  • Ipratropium and tiotropium – correct acute exacerbations of bronchospasm (asthma, COPD), as well as exacerbation prophylaxis for those conditions
  • Scopolamine – prevents motion sickness and postoperative nausea/vomiting
  • Oxybutynin – urge incontinence and postoperative bladder spasm
  • Dicyclomine, glycopyrrolate – can be used for reducing diarrhea output in irritable bowel syndrome; glycopyrrolate can also be added to cholinesterase reversal of neuromuscular blockades in postoperative anesthesia care to prevent bronchospasm and is currently undergoing investigation as an adjunct treatment in COPD

Adrenoreceptor agonists/Sympathomimetics:

  • Clonidine – used as an antihypertensive
  • Dobutamine, phenylephrine, epinephrine – used to correct severe hypotension in cardiogenic shock and acute heart failure exacerbation; epinephrine specifically also used in ACLS guidelines for non-shockable heart rhythms in cardiac arrest and rapid reversal of fatal anaphylactic reactions
  • Albuterol – fast-acting bronchodilator used in acute asthma exacerbations
  • Fenoldopam – corrects hypertension
  • Bromocriptine – involved in the maintenance of Parkinson disease and conditions involving prolactinoma

Adrenoreceptor antagonists:

  • Phenoxybenzamine, phentolamine – used to correct high catecholamine states
  • Prazosin, doxazosin, terazosin, tamsulosin – indicated to correct urinary retention in benign prostatic hyperplasia
  • Beta-blockers (propranolol, metoprolol, labetalol, etc.) – indicated for many cardiovascular conditions since they are in the classification of class II antiarrhythmics; these agents are used to manage tachyarrhythmias, hypertension, angina, heart failure, and migraine prophylaxis

Mechanism of Action

As with the homeostasis established via processes performed by the SNS and PSNS, drugs from each of the four categories listed above also work inversely to each other. The primary mechanism of action for most of these agents are to serve as either agonists or antagonists of specific receptors within these systems. The receptors with their locations and physiologic actions are listed below.

For adrenoreceptors stimulated by norepinephrine (synapses) and epinephrine (endocrine), involved in SNS processes:

  • Alpha-1 (A1) – located mostly in postsynaptic effector cells found in smooth muscle; effects mediated by IP3/DAG path, include mydriasis due to contraction of radial muscles, constriction of arteries and veins, urinary retention due to internal/external urethral sphincter contraction, and a decrease in renin release from renal juxtaglomerular cells
  • Alpha-2 (A2) – located in presynaptic adrenergic terminals found in lipocytes and smooth muscle; effects mediated by decreasing cAMP, including a decrease in norepinephrine release, stimulates platelet aggregation and decreases insulin secretion
  • Beta-1 (B1) – located in postsynaptic effector cells in the SA node of the heart, lipocytes, brain, juxtaglomerular apparatus of renal tubules, and the ciliary body epithelium; effects mediated by increasing cAMP, including increased heart rate and the conduction velocity through the cardiac nodes, also increases renin release from renal juxtaglomerular cells
  • Beta-2 (B2) – located in postsynaptic effector cells in smooth muscle and cardiac myocytes; effects mediated by increasing cAMP, include vasodilation, bronchiole dilation, increased insulin secretion, and uterine relaxation
  • Beta-3 (B3) – located in postsynaptic effector cells in lipocytes and myocardium; similar effects to beta-1 receptors mediated by increasing cAMP

For choline receptors stimulated by acetylcholine, most involved in PSNS processes:

  • Muscarinic-1 (M1) – important to note is the only choline receptor involved in an SNS process, located in sweat glands of the skin; effects mediated by IP3/DAG path, include glandular contraction and increased secretion
  • Muscarinic-2 (M2) – located in SA and AV nodes and myocardium; effects mediated by decreasing cAMP, include decreasing heart rate and myocardial conduction velocity
  • Muscarinic-3 (M3) – located in the smooth muscle of various organ systems; effects mediated by IP3/DAG path, include contraction of the ciliary muscle causing miosis, contraction of bronchioles, increased bronchiole secretions, increased GI motility, detrusor muscle contraction, and internal/external urethral sphincter relaxation
  • Muscarinic-4 (M4) and Muscarinic (M5) – located primarily in the CNS, e.g., forebrain and substantial nigra, respectively
  • Nicotinic-N (NN) – located in postsynaptic dendrites of both sympathetic and parasympathetic postganglionic neurons; effects mediated by Na+/K+ depolarization, include increased neurotransmission
  • Nicotinic-M (NM) – located in neuromuscular endplates of skeletal muscle; effects mediated by Na+/K+ depolarization, include skeletal muscle contraction

For dopamine receptors, most involved in both SNS and PSNS processes:

  • Dopamine 1-5 (D1-5) – located in the CNS, except for Dopamine-1 receptors, which also appear in renal vasculature; effects mediated by cAMP path, include renal artery vasodilation, increased renal blood flow, and modulation of neuroendocrine signaling

In terms of the four categories mentioned, each is an agonist and/or antagonist of the receptors listed. Cholinomimetics have agonist activity at muscarinic receptors augmenting PSNS activity to achieve the desired effects of increasing GI motility and decreasing intraocular pressure. Whereas the other agents mentioned work directly on receptors as agonists/antagonists, the subcategory of drugs that also achieve similar effects to cholinomimetics is the cholinesterase antagonists. These agents inhibit acetylcholinesterase enzymes within the synaptic cleft to increase the concentration of acetylcholine, resulting in increased PSNS neurotransmission and facilitating skeletal muscle contraction. Inversely, the anticholinergic agents work to inhibit PSNS activity, the main mechanism of action involving antagonism of muscarinic receptors resulting in increased heart rate and conduction velocity and stimulate bronchodilation.

Within the SNS system, adrenoreceptor agonists/sympathomimetics work at alpha and beta receptors to potentiate SNS activity to achieve higher cardiac output and fast bronchodilation. Inversely, adrenoreceptor antagonists are also active at alpha and beta receptors in decreasing SNS neurotransmission to reduce heart rate, dampen high catecholamine states, and increase urinary smooth muscle relaxation.

Administration

Most agents are available as IV, IM, SC, PO formulations. Some agents can also be given topically as eye drops, specific to ophthalmologic surgery requiring extended pupillary dilation and the medical treatment of open-angle and closed-angle glaucoma.

Adverse Effects

Due to the various effects of the ANS on cardiovascular, pulmonary, gastrointestinal, and genitourinary systems, the general theme of reactions to these medications involves effects on these organ systems. The various reactions to each of the categories of agents include:

  • Cholinomimetics/cholinesterase inhibitors – nausea, vomiting, diarrhea, urinary urgency, excessive salivation, sweating, cutaneous vasodilation, bronchial constriction
  • Anticholinergics – tachycardia, urinary retention, xerostomia (dry mouth), constipation, increased intraocular pressure
  • Adrenoreceptor agonists/sympathomimetics – tremor, tachycardia, hypertension, urinary retention, piloerection
  • Adrenoreceptor antagonists – bradycardia, bronchospasm, hypotension

Contraindications of Autonomic Pharmacology

Based on the adverse reaction profiles of each category, several significant contraindications can be elucidated:

  • Cholinomimetics/Cholinesterase inhibitors – relative contraindications in asthma/COPD, bradycardia, volume-depleted/hypotension, cardiogenic shock, sepsis, reduced ejection fraction heart failure
  • Anticholinergics – relative contraindications in glaucoma especially angle-closure, older men with benign prostatic hyperplasia, and peptic ulcer disease; atropine specifically not recommended for children, especially infants who are sensitive to its hyperthermic effects
  • Adrenoreceptor agonists/Sympathomimetics – relative contraindications in patients with a previous/current history of tachycardia or hypokalemia, hypertension, urinary retention, gastroparesis; for clonidine specifically in elderly who are more prone to fall from orthostatic hypotension, and epinephrine in those with angle-closure glaucoma
  • Adrenoreceptor antagonists – relative contraindications for alpha-blockers in orthostatic hypotension, tachycardia, myocardial ischemia; for beta-blockers asthma/COPD for the nonselective agents, bradycardia, hypotension

Toxicity for Autonomic Pharmacology

Toxic profiles of the four categories described are mostly involved in overdose, exhibiting the same effects that are augmented so that the benefits no longer outweigh the risks. The primary reversal strategy for these situations typically is to discontinue the offending agent and treat the resultant symptoms. Several agents of each category have toxic effects which require more specific reversal methods as listed:

  • Cholinesterase inhibitors (neostigmine, pyridostigmine, physostigmine) – formerly, high doses of these agents were used in chemical warfare would present as miosis, bronchial constriction, vomiting and diarrhea, and progress to convulsions, coma, and finally death; this toxicity profile remains the same and can be reversed with pralidoxime with adjunctive parenteral atropine and benzodiazepines for possible seizure activity
  • Atropine – can cause vision disturbances when in excess resulting in prolonged mydriasis and cycloplegia, can also exacerbate closed-angle glaucoma by increasing intraocular pressure; reversal generally is to discontinue; however, physostigmine has utility in extreme cases such as severe elevation of body temperature and rapid supraventricular tachycardia
  • Clonidine – can cause xerostomia and sedation; though currently there is no approved reversal, studies are currently investigating the use of naloxone as a reversal agent
  • Beta-blockers – besides severe hypotension and bradycardia, tremors and bronchospasm are worrisome in the event of overdose; glucagon serves as the reversal agent

Enhancing Healthcare Team Outcomes for Autonomic Pharmacology

Healthcare professionals who prescribe medications that work on the autonomic system must be fully aware of the side effects of these agents. Requisite close monitoring of vital signs, including blood pressure, heart rate, respiratory rate, oxygen saturation, and the temperature is strongly recommended when attempting to reestablish autonomic homeostasis with ANS agents. Several common conditions which require autonomic pharmacological correction need specific monitoring:

  • Glaucoma – ocular telemetry sensors can help to continuously monitor intraocular pressure.
  • Shock – requires several monitoring functions as listed:

    • Maintaining a MAP of 65 and above
    • MAP measurements via an arterial line
    • Pulse pressure variation to guide fluid therapy
    • Bedside echocardiography to assess chambers of the heart and looking for cardiogenic shock vs. obstructive shock (massive PE) and calculate cardiac output/ejection fraction
    • Pulse index continuous cardiac output (PiCCO) device which can serve to continuously monitor continuous cardiac output and assess fluid response
  • Asthma/COPD – pulmonary function testing is the standard to diagnose and monitor the severity of pulmonary obstruction; can also evaluate the effectiveness of inhaled autonomic agents in reversing obstructive processes
  • Arrhythmias – for acute monitoring 4-lead ECG and 12-lead EKG are standard for monitoring tachycardias or bradycardias; if extended monitoring is required extended continuous ambulatory rhythm monitors (ECAM) is the monitoring modality of choice

Physicians, nurses, and pharmacists need to work collaboratively when using medications that interact with the autonomic nervous system to make sure that the pharmacotherapy is safe and effective for each patient. [Level V]

References

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Levetiracetam – Uses, Dosage, Side Effects, Interactions

Levetiracetam is a pyrrolidine with antiepileptic activity. The exact mechanism through which levetiracetam exerts its effects is unknown but does not involve inhibitory and excitatory neurotransmitter activity. Stereoselective binding of levetiracetam was confined to synaptic plasma membranes in the central nervous system with no binding occurring in peripheral tissue. Levetiracetam inhibits burst firing without affecting normal neuronal excitability, which suggests that it may selectively prevent hyper-synchronization of epileptiform burst firing and propagation of seizure activity.

Levetiracetam is a relatively unique anticonvulsant that is typically used in combination with other antiepileptic medications for partial-onset seizures. Levetiracetam has been linked to rare instances of serum aminotransferase and alkaline phosphatase elevations during treatment and too rare cases of clinically apparent drug-induced liver disease.

Levetiracetam is a pyrrolidinone and carboxamide that is N-methyl pyrrolidine-2-one in which one of the methyl hydrogens is replaced by an aminocarbonyl group, while another is replaced by an ethyl group (the S enantiomer). An anticonvulsant, it is used for the treatment of epilepsy in both human and veterinary medicine. It has a role as an anticonvulsant, an environmental contaminant and a xenobiotic.

Levetiracetam is a novel, antiepileptic drug used in the treatment of partial seizures, myoclonic seizures, and tonic-clonic seizures. In 2000, the FDA approved the use of the oral formulation as adjunctive therapy for the treatment of focal seizures, myoclonic seizures, and primary generalized seizures. The FDA approved intravenous levetiracetam in 2006 for use in patients older than 15 years, as adjunctive anticonvulsant therapy when the oral formulation is not tolerated. This activity covers levetiracetam, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, monitoring, and highlights the role of the interprofessional team in the management of conditions where levetiracetam therapy is helpful.

Mechanism of Action of Levetiracetam

The mechanisms by which LEV exerts its antiepileptic effects are not clearly defined. The most relevant mechanism of action is believed to be through binding to a unique protein known as synaptic vesicle protein 2A (SV2A). SV2A protein is a part of secretory vesicle membranes that mediates calcium-dependent vesicular neurotransmitter release. The binding of LEV to SV2A appears to decrease the rate of vesicle release.

The exact mechanism through which levetiracetam exerts its antiepileptic effects is unclear but is thought to be unique amongst other anti-epileptic medications. Current knowledge suggests that levetiracetam’s binding to synaptic vesicle protein 2A (SV2A) is a key driver of its action. SV2A is a membrane-bound protein that is found on synaptic vesicles and is ubiquitous throughout the CNS[A12546] – it appears to play a role in vesicle exocytosis[L8606, L8615] and in the modulation of synaptic transmission by increasing the available amount of secretory vesicles available for neurotransmission.[A12552] Stimulation of pre-synaptic SV2A by levetiracetam may inhibit neurotransmitter release,[A12551] but this action does not appear to affect normal neurotransmission. This has led to the suggestion that levetiracetam exclusively modulates the function of SV2A only under pathophysiological conditions.[A12546] Levetiracetam and related analogs showed a correlation between affinity for SV2A and anti-epileptic potency, further suggesting that action at this site contributes to the anti-epileptic activity of the drug.[L8606, L8615] Levetiracetam has also been shown to indirectly affect GABAergic neurotransmission (despite having no direct effect on GABAergic or glutamatergic receptors) and modulate ionic currents.[A12552] Similarly, levetiracetam has been shown in vitro to inhibit N-type calcium channels.[A16562] How, or even if, these actions are implicated in its anti-epileptic action have yet to be elucidated.

Indications of Levetiracetam

Levetiracetam is a novel, antiepileptic drug used in the treatment of partial seizures, myoclonic seizures, and tonic-clonic seizures. In 2000, the FDA approved the use of the oral formulation as adjunctive therapy for the treatment of focal seizures, myoclonic seizures, and primary generalized seizures. The FDA approved intravenous levetiracetam (LEV) in 2006 for use in patients older than 15 years, as adjunctive anticonvulsant therapy when the oral formulation is not tolerated. In Europe, it is approved for the treatment of partial seizures as a single agent and as an add-on treatment for partial seizures, tonic-clonic seizures, and myoclonic seizures.

It is chemically unrelated to other antiepileptic drugs. Its favorable safety profile, distinct mechanism of action, and fewer drug interactions make it an attractive therapeutic choice for the treatment of seizures.

Uses

  • Myoclonic seizures It is approved for use as adjunctive therapy in the treatment of myoclonic seizures in adults and juvenile myoclonic epilepsy in adolescents 12 years and older.
  • Partial seizures  It can be used as adjunctive therapy for treating partial seizures in adults and children one month or older with epilepsy.
  • Primary generalized tonic-clonic seizure  Used for adjunctive therapy for the treatment of primary generalized tonic conic seizure in adults and children more than 5 years old with idiopathic generalized epilepsy.
  • Levetiracetam is indicated as adjunctive therapy in the treatment of partial-onset seizures in adults and children 4 years of age and older with epilepsy.
  • It is sometimes used off-label (non-FDA-approved) for status epilepticus and seizure prophylaxis in subarachnoid hemorrhage.
  • Levetiracetam is indicated as adjunctive therapy in the treatment of partial-onset seizures in epileptic patients who are one month of age and older. Additionally, it is indicated as an adjunct in the treatment of myoclonic seizures in patients with juvenile myoclonic epilepsy who are 12 years of age and older, and in primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy who are 6 years of age and older.[L8606] Levetiracetam is also available as an orally dissolvable tablet that is indicated as an adjunct in the treatment of partial-onset seizures in patients with epilepsy who are 4 years of age and older and weigh more than 20kg.[L8609]
  • Levetiracetam Actavis is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Levetiracetam Actavis is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children, and infants from one month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
  • Levetiracetam Actavis Group is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Levetiracetam Actavis Group is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children, and infants from 1 month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
  • Levetiracetam Hospira is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with newly diagnosed epilepsy. Levetiracetam Hospira is indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in adults, adolescents, and children from 4 years of age with epilepsy. in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy. in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy. Levetiracetam Hospira concentrate is an alternative for patients when oral administration is temporarily not feasible.
  • Levetiracetam Ratiopharm is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Levetiracetam Ratiopharm is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children, and infants from 1 month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
  • Levetiracetam is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Levetiracetam is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children and infants from one month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
  • Levetiracetam Teva is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with newly diagnosed epilepsy. Levetiracetam Teva is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, adolescents, children, and infants from 1 month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
  • Keppra is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Keppra is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children, and infants from one month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
  • Mater is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Mater is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults, children, and infants from one month of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.
  • Levetiracetam Sun is indicated as monotherapy in the treatment of partial-onset seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy. Levetiracetam Sun is indicated as adjunctive therapy: in the treatment of partial-onset seizures with or without secondary generalization in adults and children from four years of age with epilepsy; in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy. Levetiracetam Sun concentrate is an alternative for patients when oral administration is temporarily not feasible.

Contraindications

  • Hypersensitivity reaction to LEV or any component of the formulation.
  • anemia
  • decreased blood platelets
  • low levels of white blood cells
  • low levels of a type of white blood cell called neutrophils
  • psychotic disorder
  • suicidal thoughts
  • depression
  • hallucinations
  • abnormal manner of walking
  • loss of muscle coordination
  • chronic kidney disease stage 2 (mild)
  • chronic kidney disease stage 3A (moderate)
  • chronic kidney disease stage 3B (moderate)
  • chronic kidney disease stage 4 (severe)
  • kidney disease with likely reduction in kidney function

Dosage of Levetiracetam

Strengths: 100 mg/mL; 250 mg; 500 mg; 750 mg; 1000 mg; 500 mg/100

 Epilepsy

Immediate-Release

  • Initial dose: 500 mg orally or IV twice a day
  • Increase in increments of 500 mg twice a day every 2 weeks based on efficacy and tolerability
  • Maintenance dose: 500 to 1500 mg orally or IV twice a day
  • Maximum dose: 3000 mg/day

Extended-Release (Partial Onset Seizures Only)

  • Initial dose: 1000 mg orally once a day
  • Increase in increments of 1000 mg every 2 weeks based on efficacy and tolerability
  • Maintenance dose: 1000 to 3000 mg orally once a day
  • Maximum dose: 3000 mg/day

Seizures

Immediate-Release

  • Initial dose: 500 mg orally or IV twice a day
  • Increase in increments of 500 mg twice a day every 2 weeks based on efficacy and tolerability
  • Maintenance dose: 500 to 1500 mg orally or IV twice a day
  • Maximum dose: 3000 mg/day

Extended-Release (Partial Onset Seizures Only)

  • Initial dose: 1000 mg orally once a day
  • Increase in increments of 1000 mg every 2 weeks based on efficacy and tolerability
  • Maintenance dose: 1000 to 3000 mg orally once a day
  • Maximum dose: 3000 mg/day

Pediatric Dose for Epilepsy

PARTIAL ONSET SEIZURES:

Immediate-Release

1 month to less than 6 months

  • Initial dose: 7 mg/kg oral/IV twice a day; increase in increments of 7 mg/kg twice a day in 2-week intervals
  • Maximum dose: 21 mg/kg twice a day (clinical trials mean daily dose=35 mg/kg/day).

6 months to less than 4 years

  • Initial dose: 10 mg/kg oral/IV twice a day; increase in increments of 10 mg/kg twice a day in 2-week intervals
    Maximum dose: 25 mg/kg twice a day; (clinical trials mean daily dose=47 mg/kg/day)

4 years to less than 16 years

  • Initial dose: 10 mg/kg twice a day; increase in increments of 10 mg/kg twice a day in 2-week intervals
  • Maximum dose: 30 mg/kg twice a day (clinical trials mean daily dose=44 mg/kg/day)

Alternatively, 4 years to less than 16 years:

  • weight 20 to 40 kg: 250 mg oral/IV twice a day, increase in increments of 250 mg twice a day in 2-week intervals; Maximum dose: 750 mg twice a day
  • 4 years to less than 16 years: weight greater than 40 kg: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals; Maximum dose: 1500 mg twice a day\
  • 16 years and older: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals; Maximum dose: 1500 mg twice a day

Extended-Release

12 years or older

  • Initial dose: 1000 mg orally once a day
  • Increase in increments of 1000 mg every 2 weeks to the maximum daily dose
  • Maintenance dose: 1000 to 3000 mg orally once a day
  • Maximum dose: 3000 mg/day

MYOCLONIC SEIZURES

12 years and older

  • Initial dose: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals
  • Maintenance dose: 500 to 1500 mg twice a day
  • Maximum dose of 3000 mg/day

PRIMARY GENERALIZED TONIC-CLONIC SEIZURES

6 years to less than 16 years

  • Initial dose: 10 mg/kg oral/IV twice a day, increase in increments of 10 mg/kg twice a day in 2-week intervals
  • Maximum dose: 30 mg/kg twice a day

16 years and older

  • Initial dose: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals
  • Maximum dose: 1500 mg twice a day.

Seizures

PARTIAL ONSET SEIZURES

Immediate-Release

  • 1 month to less than 6 months:
  • Initial dose: 7 mg/kg oral/IV twice a day; increase in increments of 7 mg/kg twice a day in 2-week intervals
  • Maximum dose: 21 mg/kg twice a day (clinical trials mean daily dose=35 mg/kg/day)
  • 6 months to less than 4 years:
  • Initial dose: 10 mg/kg oral/IV twice a day; increase in increments of 10 mg/kg twice a day in 2-week intervals
  • Maximum dose: 25 mg/kg twice a day; (clinical trials mean daily dose=47 mg/kg/day)

4 years to less than 16 years

  • Initial dose: 10 mg/kg twice a day; increase in increments of 10 mg/kg twice a day in 2-week intervals
  • Maximum dose: 30 mg/kg twice a day (clinical trials mean daily dose=44 mg/kg/day)

Alternatively,

  • 4 years to less than 16 years: weight 20 to 40 kg: 250 mg oral/IV twice a day, increase in increments of 250 mg twice a day in 2-week intervals; Maximum dose: 750 mg twice a day
  • 4 years to less than 16 years: weight greater than 40 kg: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals; Maximum dose: 1500 mg twice a day
  • 16 years and older: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals; Maximum dose: 1500 mg twice a day.

Extended-Release 12 years or older

  • Initial dose: 1000 mg orally once a day
  • Increase in increments of 1000 mg every 2 weeks to the maximum daily dose
  • Maintenance dose: 1000 to 3000 mg orally once a day
  • Maximum dose: 3000 mg/day.

MYOCLONIC SEIZURES

12 years and older:

  • Initial dose: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week interval
  • Maintenance dose: 500 to 1500 mg twice a day
  • Maximum dose of 3000 mg/day

PRIMARY GENERALIZED TONIC-CLONIC SEIZURES

6 years to less than 16 years

  • Initial dose: 10 mg/kg oral/IV twice a day, increase in increments of 10 mg/kg twice a day in 2-week intervals
  • Maximum dose: 30 mg/kg twice a day

16 years and older

  • Initial dose: 500 mg oral/IV twice a day, increase in increments of 500 mg twice a day in 2-week intervals
  • Maximum dose: 1500 mg twice a day
  • LEV is available in oral and intravenous (IV) formulations. Oral forms are available in immediate-release and extended-release forms.

Afterall

  • The Minimum recommended dose is 500 mg twice daily. Some older adults may respond to doses as low as 500 mg per day. It should be started at a low dose and titrated up for a clinical response. Increase the dose at 250 or 500 mg at 1 to 2-week intervals until the clinical response is achieved. The maximum recommended dose is 3000 mg per day. Rapid dose escalation can lead to adverse effects. An immediate-release form is dosed twice daily and extended-release forms once daily. A therapeutic serum concentration is not established for LEV and dosage is guided by clinical response.
  • Efficacy of more than 3000 mg/day dose is not fully established. Some suggest that dose can be increased up to 4000 mg /day in patients who have shown clear response but have occasional breakthrough seizures. There are some reports of seizure exacerbation with higher doses, and the physician should keep that in mind while using higher doses.
  • The total daily dosage of IV LEV is equivalent to oral. It is administered as a 15-minute infusion. There is no evidence to use a loading dose.
  • It is also used off-label sometimes for status epilepticus. The dose used is 1000 to 3000 mg IV infusion at a rate of 2 mg/kg per minute or a single dose of 60 mg/kg.
  • LEV may be used safely (with caution) in children older than 4 years of age. The recommended starting dose is 20 mg/kg per day in 2 divided doses. It can be titrated up to 20 mg/kg every 2 weeks up to the maximum dose of 60 mg/kg per day.

Side Effects of Levetiracetam

The Most Common 

  • Central nervous system (CNS) – Most common side effects are neurobehavioral like somnolence, fatigue, mood swings, headache, agitation, irritability, aggression, depression, memory loss, confusion, paresthesia, the decline in cognition and increased suicide risk. Most of the time side effects are mild. About 1% of patients experience serious side effects like psychosis, hallucinations and suicidal thoughts. These side effects are more common in the first month of treatment but can develop any time during treatment and improve once the drug is discontinued. Dose reduction is associated with improvement in behavioral problems.
  • Cardiovascular (CVS) – Increased diastolic blood pressure in infants and children
  • Gastrointestinal (GI) – Vomiting, abdominal pain, nausea, anorexia
  • Infections – Pharyngitis, rhinitis has been reported in 7% to 15% of patients.
  • Hypersensitivity reactions – Rarely, serious, life-threatening reactions have been reported with the use of LEV. These include angioedema, anaphylaxis, Steven-Johnson syndrome, toxic epidermal necrolysis, hives, respiratory distress.
  • Hematologic – Leukopenia, eosinophilia, and rarely pancytopenia have been reported with the use of LEV.

Common

  • unusual changes in mood or behavior (unusual risk-taking behavior, being irritable or talkative);
  • confusion, hallucinations, loss of balance or coordination;
  • extreme drowsiness, feeling very weak or tired;
  • problems with walking or movement;
  • a skin rash, no matter how mild;
  • easy bruising, unusual bleeding; or
  • fever, chills, weakness, or other signs of infection.
  • dizziness, drowsiness, tiredness;
  • weakness;
  • feeling aggressive or irritable
  • loss of appetite;
  • stuffy nose; or
  • infection.

Less common

  • Bloody nose
  • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
  • clumsiness or unsteadiness
  • discouragement
  • dizziness or lightheadedness
  • double vision
  • earache
  • feeling of constant movement of self or surroundings
  • feeling sad or empty
  • increase in body movements
  • loss of bladder control
  • loss of memory
  • mood or mental changes
  • outburst of anger
  • pain or tenderness around the eyes and cheekbones
  • problems with memory
  • redness or swelling in the ear
  • seizures
  • sensation of spinning
  • shakiness and unsteady walk
  • shakiness in the legs, arms, hands, or feet
  • tightness of the chest
  • trembling or shaking of the hands or feet
  • trouble concentrating
  • unsteadiness, trembling, or other problems with muscle control or coordination

Drug Interactions of Levetiracetam

No significant drug interactions of LEV are observed with other anti-epileptics like phenytoin, valproic acid, carbamazepine, phenobarbital, primidone. No significant interactions with drugs like digoxin or warfarin.

LEV metabolism rate and its clearance may be increased in patients taking enzyme-inducing anti-epileptics like phenytoin, carbamazepine, and phenobarbital.

  • Aspirin Low Strength (aspirin)
  • Aspirin Low Strength (aspirin)
  • Fish Oil (omega-3 polyunsaturated fatty acids)
  • Fish Oil (omega-3 polyunsaturated fatty acids)
  • Lyrica (pregabalin)
  • Lyrica (pregabalin)
  • Metoprolol Succinate ER (metoprolol)
  • Metoprolol Succinate ER (metoprolol)
  • Metoprolol Tartrate (metoprolol)
  • Metoprolol Tartrate (metoprolol)
  • MiraLAX (polyethylene glycol 3350)
  • MiraLAX (polyethylene glycol 3350)
  • Tylenol (acetaminophen)
  • Tylenol (acetaminophen)
  • Vitamin B12 (cyanocobalamin)
  • Vitamin B12 (cyanocobalamin)
  • Vitamin C (ascorbic acid)
  • Vitamin C (ascorbic acid)
  • Vitamin D3 (cholecalciferol)
  • Vitamin D3 (cholecalciferol)

Since LEV can cause somnolence and CNS depression, it may enhance the CNS-depressant effect of alcohol, cannabis, and other drugs like azelastine, carbamazepine, opioids, among others.

Pregnancy Category of Levetiracetam

Pregnancy

LEV is a pregnancy category C drug. Maternal serum levels can fall significantly during the third trimester, and monitoring of serum concentration should be used to guide dosing. No significant congenital abnormalities have been reported following maternal use of LEV. It is excreted in breast milk, but serum drug levels in infants have been shown to below. 

Monitoring

Baseline creatinine should be checked before initiating LEV therapy. Signs and symptoms of depression, suicidality, and psychosis should be closely monitored. Blood pressure should be monitored closely in children less than 4 years old.

Generally, no blood monitoring is required during therapy. Serum concentrations may help assess compliance and may be used as a dosing guide in pregnant and elderly patients.

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    1-Pyrrolidineacetamide, α-ethyl-2-oxo-, (αS)
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  17. Levetiracetam metabolite (184)
    Levetiracetam metabolite (184)
    Levetiracetam metabolite (184)
    (2S)-2-(2-ketopyrrolidino)butyramide
    (2S)-2-(2-ketopyrrolidino)butyramide
    (2S)-2-(2-ketopyrrolidino)butyramide
    (2S)-2-(2-ketopyrrolidino)butyramide
    (2S)-2-(2-ketopyrrolidino)butyramide
    (2S)-2-(2-ketopyrrolidino)butyramide
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  19. Therapeutic category of drugs in Japan
    Anatomical Therapeutic Chemical (ATC) classification
    Target-based classification of drugs
  20. Target Classification
  21. NCBI

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Lamotrigine – Uses, Dosage, Side Effects, Interactions

Lamotrigine is a synthetic phenyltriazine with antiepileptic and analgesic properties. Lamotrigine enhances the action of gamma-aminobutyric acid, an inhibitory neurotransmitter, which may result in a reduction of pain-related transmission of signals along nerve fibers. This agent may also inhibit voltage-gated sodium channels, suppress glutamate release, and inhibit serotonin reuptake. (NCI04)

Lamotrigine can be used to treat the following partial seizures, primary generalized tonic-clonic seizures, bipolar I disorder maintenance, and Lennox-Gastaut syndrome. Off-label uses include treatment of acute bipolar depression, fibromyalgia, schizophrenia, and unipolar depression. This activity covers lamotrigine, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, contraindications, monitoring, and highlights the interprofessional team’s role in the management of lamotrigine therapy.

Mechanism of Action

The exact mechanism of action of lamotrigine is not fully elucidated, as it may exert cellular activities that contribute to its efficacy in a range of conditions. Although chemically unrelated, lamotrigine actions resemble those of phenytoin and carbamazepine, inhibiting voltage-sensitive sodium channels, stabilizing neuronal membranes, thereby modulating the release of presynaptic excitatory neurotransmitters. Lamotrigine likely acts by inhibiting sodium currents by selective binding to the inactive sodium channel, suppressing the release of the excitatory amino acid, glutamate. The mechanism of action of lamotrigine in reducing anticonvulsant activity is likely the same in managing bipolar disorder. Studies on lamotrigine have identified its binding to sodium channels in a fashion similar to local anesthetics, which could explain the demonstrated clinical benefit of lamotrigine in some neuropathic pain states. Lamotrigine displays binding properties to several different receptors. In laboratory binding assays, it demonstrates weak inhibitory effect on the serotonin 5-HT3 receptor. Lamotrigine also weakly binds to Adenosine A1/A2 receptors, α1/α2/β adrenergic receptors, dopamine D1/D2 receptors, GABA A/B receptors, histamine H1 receptors, κ-opioid receptor (KOR), mACh receptors and serotonin 5-HT2 receptors with an IC50>100 µM. Weak inhibitory effects were observed at sigma opioid receptors.[L9404] An in vivo study revealed evidence that lamotrigine inhibits Cav2.3 (R-type) calcium currents, which may also contribute to its anticonvulsant effects.[A31737]

or

The mechanism of action for lamotrigine is not entirely understood. It is a triazine, and research has shown that lamotrigine selectively binds sodium channels, stabilizing presynaptic neuronal membranes and inhibiting glutamate release. Researchers have not demonstrated that lamotrigine to have significant effects on other neurotransmitters such as serotonin, norepinephrine, or dopamine. There is a theory that lamotrigine may interact with voltage-activated calcium-gated channels, contributing to its broad range of activity. In vitro studies have also shown that lamotrigine inhibited dihydrofolate reductase, potentially contributing to concerns for its teratogenicity. Lamotrigine follows first-order kinetics with a half-life of 29 hours.

Indications of Lamotrigine

  • Lamotrigine can be used to treat the following: partial seizures, primary generalized tonic-clonic seizures, bipolar depression, bipolar disorder type I maintenance), and Lennox-Gastaut syndrome.
  • Off-Label uses include treatment of rapid-cycling bipolar depression, basilar migraine, panic disorder, and binge eating disorder.
  • Anticonvulsants; Calcium Channel Blockers; Excitatory Amino Acid Antagonists; Voltage-Gated Sodium Channel Blockers
  • Bipolar 1 Disorder
  • Grand mal Generalized tonic-clonic seizure
  • Partial-Onset Seizures
  • Generalized seizure
  • Borderline Personality Disorder
  • Bipolar Disorder
  • Anxiety
  • Cyclothymic Disorder
  • Depression
  • Epilepsy
  • Migraine Prevention
  • Post Traumatic Stress Disorder
  • Restless Legs Syndrome
  • Schizoaffective Disorder

Lamotrigine is indicated as adjunctive therapy for the following seizure types in patients ≥2 years of age: partial seizures, primary generalized tonic-clonic seizures, and generalized seizures due to Lennox-Gastaut syndrome. It is also indicated for the process of conversion to drug monotherapy for those at least 16 years of age or older with partial seizures and currently are receiving treatment with carbamazepinephenytoinphenobarbitalprimidone, or valproate as the single antiepileptic drug (AED).[L9404] In addition to the above, lamotrigine is also indicated for the maintenance treatment of bipolar I disorder, delaying the time to mood episodes (which may include mania, hypomania, depression, mixed episodes) in adults at least 18 years or older, who have been treated for acute mood symptoms with standard therapy.[L9404] Limitations of use It is important to note that lamotrigine should not be used in the treatment of acute mood episodes, as efficacy has not been established in this context.

Contraindications of Lamotrigine

  • Hypersensitivity to lamotrigine or its ingredients is the primary contraindication for the administration of lamotrigine.
  • Evaluating gender, age, and contraceptive use are essential for the consideration of starting lamotrigine. While some studies in humans have not shown an increased risk for congenital malformations during lamotrigine therapy during pregnancy, animal studies have demonstrated that an increased risk exists. The drug is pregnancy risk factor C; animal studies have shown the risk for congenital malformations.
  • Lamotrigine is present in breast milk and is detectable in the blood of breast-fed infants. Symptoms of lamotrigine in infants include poor feeding, drowsiness, rash, and apnea. These symptoms can improve with the discontinuation of lamotrigine.
  • Consideration for other drugs’ effects on glucuronidation merit consideration, as glucuronic acid conjugation primarily metabolizes lamotrigine.
  • Drugs that induce lamotrigine glucuronidation include carbamazepine, phenytoin, phenobarbital, rifampin, lopinavir/ritonavir, atazanavir/ritonavir, and primidone.
  • Valproic acid inhibits lamotrigine glucouronidation.
  • Concurrent use with central nervous system (CNS) depressants may increase the potency of CNS depression.
  • Lamotrigine reportedly interferes with urine drug screening and can cause false-positive readings of phencyclidine

Dosage of Lamotrigine

  • Lamotrigine is available as tablets, chewable tablets, and orally disintegrating tablets. It is available in formulations of 25 mg, 100 mg, 150 mg, and 200 mg tablets in a tablet form. A chewable, dispersible tablet form is available in formulations of 2 mg, 5 mg, and 25 mg dispersible tablets. The orally disintegrating tablets are available in formulations of 25 mg, 50 mg, 100 mg, and 200 mg. All formulations should be stored at room temperature and needs protection from light.
  • Lamotrigine dosing requires alteration if given concurrently with carbamazepine, phenytoin, phenobarbital, primidone, rifampin, lopinavir/ritonavir, and atazanavir, ritonavir, and valproic acid.
  • If it is necessary to discontinue lamotrigine, it should be done in a step-wise fashion over two weeks, if possible. There is a possibility of withdrawal seizures when discontinuing lamotrigine, which lessens if the drug is tapered rather than stopped quickly.

For Seizures

  • If not used concurrently with carbamazepine, phenytoin, phenobarbital, primidone, rifampin, lopinavir/ritonavir, atazanavir, ritonavir, and valproic acid, dosing instructions are as follows. Initially, dosing is 25 mg given daily. At week three, the dose should increase to 50 mg daily. At week five, increase by an additional 50 mg each week or every other week. The typical maintenance ranges from 225 mg to 375 mg in two divided doses.
  • If being used concurrently with valproic acid, dosing instructions are as follows. Initially, dosing is 25 mg given every other day. At week three, the dose should increase to 25 mg daily. At week 5, increase the dose by an additional 25 mg to 50 mg every week or every other week. Typical maintenance varies from 100 mg to 200 mg daily in one or two divided doses if given with valproic acid alone or 100 mg to 400 mg in one or two divided doses if given with other medications that induce glucuronidation.
  • If used concurrently with carbamazepine, phenytoin, phenobarbital, primidone, rifampin, lopinavir/ritonavir, and atazanavir or ritonavir, dosing instructions are as follows. Initially, the dose is 50 mg given daily. At week three, the dose should increase to 100 mg daily in 2 divided doses. At week five, increase by an additional 100 mg every week or every other week. Typical maintenance ranges from 300 mg to 500 mg to two divided doses.

For Bipolar I

  • Maintenance is from 200 mg to 400 mg, with additional consideration given to medication given concurrently with lamotrigine.

Side Effects of Lamotrigine

Other adverse effects include multi-organ sensitivity, blood dyscrasias, suicidal behavior/ideations, aseptic meningitis, status epilepticus, and sudden unexplained death in epilepsy.

The Most Common

  • Nausea, vomiting
  • Chest pain, back pain
  • Xerostomia
  • Edema
  • Dysmenorrhea
  • Weight changes
  • Constipation
  • Abdominal pain
  • Pain, weakness
  • Insomnia, drowsiness
  • Dizziness, ataxia, diplopia.
  • Headache.

Common

  • fast, slow, or pounding heartbeats or fluttering in your chest;
  • chest pain, shortness of breath;
  • fever, swollen glands, weakness, severe muscle pain;
  • any skin rash, especially with blistering or peeling;
  • painful sores in your mouth or around your eyes;
  • headache, neck stiffness, increased sensitivity to light, nausea, vomiting, confusion, drowsiness;
  • jaundice (yellowing of the skin or eyes); or
  • pale skin, cold hand and feet, easy bruising, unusual bleeding.

Rare

  • headache, dizziness;
  • blurred vision,
  • double vision;
  • tremor,
  • loss of coordination;
  • dry mouth, nausea, vomiting,
  • stomach pain,
  • diarrhea;
  • fever, sore throat,
  • runny nose;
  • drowsiness,
  • tired feeling;
  • back pain; or
  • sleep problems (insomnia).

Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of this medication. Rash severity varies but includes a risk for Stevens-Johnson syndrome. The incidence of Stevens-Johnson syndrome in the pediatric population is 0.3% to 0.8% and 0.03% to 0.08% in adult populations. The number of cases associated with toxic epidermal necrolysis is too low to report an estimated incidence. Nearly all cases of a rash occur 2 to 8 weeks after the initiation of lamotrigine. It should also bear mentioning that the discontinuation of lamotrigine may not prevent a rash from becoming life-threatening. Patient education should include continuous monitoring of the rash for improvement after the discontinuation of the medication.United States Boxed Warning

Drug interactions of Lamotrigine

View interaction reports for lamotrigine and the medicines listed below.

  • Abilify (aripiprazole)
  • Adderall (amphetamine / dextroamphetamine)
  • Adderall XR (amphetamine / dextroamphetamine)
  • Cymbalta (duloxetine)
  • Fish Oil (omega-3 polyunsaturated fatty acids)
  • Klonopin (clonazepam)
  • Latuda (lurasidone)
  • Lexapro (escitalopram)
  • Lithium Carbonate ER (lithium)
  • Lyrica (pregabalin)
  • Prozac (fluoxetine)
  • Seroquel (quetiapine)
  • Synthroid (levothyroxine)
  • Vitamin B12 (cyanocobalamin)
  • Vitamin C (ascorbic acid)
  • Vitamin D3 (cholecalciferol)
  • Vyvanse (lisdexamfetamine)
  • Wellbutrin XL (bupropion)
  • Xanax (alprazolam)
  • Zoloft (sertraline)

The concomitant use of valproic acid and/or hepatic enzyme-inducing anticonvulsant drugs (e.g., phenobarbital, primidone, carbamazepine, phenytoin) can increase or decrease the metabolism and elimination of lamotrigine, requiring dosage adjustments to maintain efficacy and/or avoid toxicity. The addition of valproic acid to lamotrigine therapy reduces lamotrigine clearance and increases steady-state plasma lamotrigine concentrations by slightly more than 50% whether or not hepatic enzyme-inducing anticonvulsant drugs are given concomitantly. Conversely, steady-state plasma concentrations of lamotrigine are decreased by about 40% when phenobarbital, primidone, or carbamazepine is added to lamotrigine therapy and by about 45-54% when phenytoin is added to lamotrigine therapy; the magnitude of the effect with phenytoin is dependent on the total daily dosage of phenytoin (from 100-400 mg daily). Discontinuance of an enzyme-inducing anticonvulsant drug can be expected to increase, and discontinuance of valproic acid can be expected to decrease, the elimination half-life and plasma concentrations of lamotrigine. Although the manufacturers state that a therapeutic plasma concentration range has not been established for lamotrigine and that dosage should be based on the therapeutic response, the change in plasma lamotrigine concentrations resulting from the addition or discontinuance of enzyme-inducing anticonvulsant drugs or valproic acid should be considered when these drugs are added to or withdrawn from an existing anticonvulsant drug regimen that includes lamotrigine.

Pregnancy Category

  • AU TGA pregnancy category D
  • US FDA pregnancy category Not Assigned:
Pregnancy

The benefit should outweigh the risk. The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Several prospective pregnancy exposure registries and epidemiological studies have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population; animal studies have shown developmental toxicities at doses administered clinically.

Monitoring

The value of monitoring lamotrigine concentrations remains unestablished to date. Due to pharmacokinetics between lamotrigine and other drugs and their effect on lamotrigine concentration, clinical judgment must be exercised during concomitant use if there are concerns regarding lamotrigine levels. Dofetilide can have a severe interaction with lamotrigine, and the combination is strongly discouraged. Other drugs with potential serious interactions include valproic acid, rifampin, estrogen-containing contraceptives and estrogen replacement therapy medications, as well as certain barbiturates.

Labs should include pertinent serum levels of concurrent anticonvulsants and liver function testing, and renal function assessments. Clinical team staff should spend ample time educating patients on monitoring themselves for hypersensitivity, particularly rashes or other skin changes occurring near or on the mucosa. Patient education should also include discussing how to monitor for changes in seizures and their frequency and duration. Patients should also monitor for changes in suicidality, including suicidal thoughts and increased desire to commit suicide. Finally, patients should learn how to watch for signs/symptoms of aseptic meningitis.

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    6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine
    6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine
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Dorzolamide – Uses, Dosage, Side Effects, Interactions

Dorzolamide is an inhibitor of carbonic anhydrase, a zinc-containing enzyme that catalyzes the rapid conversion of carbon dioxide and water into carbonic acid, protons, and bicarbonate ions. Distributed throughout many cells and tissues, various carbonic anhydrases play important roles in mineral and metabolic homeostasis. (NCI04)

Dorzolamide is 5,6-Dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide in which hydrogens at the 4 and 6 positions are substituted by ethylamino and methyl groups, respectively (4S, trans-configuration). A carbonic anhydrase inhibitor, it is used as the hydrochloride in ophthalmic solutions to lower increased intraocular pressure in the treatment of open-angle glaucoma and ocular hypertension. It has a role as an EC 4.2.1.1 (carbonic anhydrase) inhibitor, an antihypertensive agent, and an antiglaucoma drug. It is a sulfonamide and a member of thiophenes.

Dorzolamide is a non-bacteriostatic sulfonamide derivative and topical carbonic anhydrase (CA) inhibitor that treats elevated intraocular pressure (IOP) associated with open-angle glaucoma and ocular hypertension. It works by blocking an enzyme in the ciliary process that regulates ion balance and fluid pressure in the eyes. Unlike oral CA inhibitors, dorzolamide has negligible effects of acid-base or electrolyte disturbances and other systemic adverse effects. First marketed in 1995, dorzolamide is available in ophthalmic solutions as monotherapy marketed as Trusopt or in combination with [timolol] as Cosopt PF.

Mechanism of Action

Elevated intraocular pressure is a characteristic manifestation of ocular hypertension or open-angle glaucoma. The level of intraocular pressure (IOP) is governed by the balance between the production of aqueous humor (by ocular ciliary processes) and its outflow from the anterior segment of the eye via trabecular (conventional) or uveoscleral (unconventional) pathways. When there is an increase in the resistance to the trabecular outflow of aqueous humor, the intraocular pressure is elevated. Subsequently, optic nerve damage can occur from blood flow restrictions and mechanical distortion of ocular structures. Optic nerve damage can further result in optic disc cupping and progressive visual field loss (and blindness in some cases).[A1304] Carbonic anhydrase (CA) is a ubiquitous enzyme that catalyzes the reversible hydration of carbon dioxide to bicarbonate ions and dehydration of carbonic acid.[A1304, L11377] In the ocular ciliary processes, the local production of bicarbonate by CAs promotes sodium and fluid transport. CA-II is a key isoenzyme found primarily in red blood cells (RBCs) that regulates aqueous humor production.[A1304] Dorzolamide is a highly specific CA-II inhibitor, where it displays a 4000-fold higher affinity for carbonic anhydrase II than carbonic anhydrase I.[A1304] The inhibition of CA-II in the ciliary process disrupts the formation of bicarbonate ions and reduces sodium and fluid transport, which leads to decreased aqueous humor secretion and reduced intraocular pressure.[A1304, L11377]

Indications of Dorzolamide 

  • Dorzolamide is indicated for the management of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.[L11377] It can also be used in combination with [timolol] for the same indication in patients who are insufficiently responsive to ophthalmic beta-blockers.[L11380] Its pre-operative use was also investigated to prevent elevated intraocular pressure after neodymium yttrium aluminum garnet laser posterior capsulotomy.
  • Intraocular Hypertension
  • Glaucoma, Open-Angle
  • Treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma

Contraindications Of Dorzolamide

  • Hyperchloremic acidosis
  • Hypokalemia (low blood potassium)
  • Hyponatremia (low blood sodium)
  • Adrenal insufficiency
  • Impaired kidney function
  • Hypersensitivity to acetazolamide or other sulfonamides.
  • Marked liver disease or impairment of liver function, including cirrhosis because of the risk of development of hepatic encephalopathy. Acetazolamide decreases ammonia clearance
  • type 1 diabetes mellitus
  • a condition where the adrenal glands produce less hormones called Addison’s disease
  • a type of joint disorder due to excess uric acid in the blood called gout
  • respiratory acidosis, an acid-base disorder
  • a blood disorder
  • decreased lung function
  • liver problems
  • severe liver disease
  • renal tubular acidosis
  • recurrent calcium-containing kidney stones
  • decreased kidney function
  • hyperchloremic acidosis

Dosage of Dorzolamide

  • Strengths: 2%; 2% preservative-free

Intraocular Hypertension

  • One drop in the affected eye(s) three times a day

Glaucoma (Open Angle)

  • One drop in the affected eye(s) three times a day

Pediatric Dose for Intraocular Hypertension

  • Safety and effectiveness have been demonstrated in pediatric patients in a 3-month, multicenter, double-masked, active-treatment-controlled trial:
  • One drop in the affected eye(s) three times a day.

Side Effects of Dorzolamide

The Most Common

  • Burning, stinging, or discomfort when the medicine is applied
  • itching, redness, swelling, or other sign of eye or eyelid irritation
  • Burning, dry, or itching eyes
  • discharge from the eye
  • excessive tearing
  • redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
  • Blood in the urine
  • blurred vision
  • nausea or vomiting
  • pain in the side, back, or abdomen
  • skin rash
  • tearing

Common

  • Blistering, burning, crusting, dryness, or flaking of the skin
  • change in vision
  • chills
  • cough
  • diarrhea
  • difficult or labored breathing
  • flashes of light
  • floaters in vision
  • hives or welts
  • itching skin
  • joint or muscle pain
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • noisy breathing
  • redness of the skin
  • sore throat
  • sores, ulcers, or white spots in the mouth or on the lips
  • tightness in the chest
  • unusual tiredness or weakness

Rare

  • Confusion
  • irregular heartbeat
  • muscle cramps or pain
  • numbness, tingling, pain, or weakness in the hands or feet
  • seizures
  • trembling
  • weakness and heaviness of the legs

Drug Interactions of Dorzolamide

  • acetazolamide
  • aspirin
  • bismuth subsalicylate
  • choline salicylate
  • dichlorphenamide
  • diflunisal
  • magnesium salicylate
  • methazolamide
  • salsalate
  • sodium salicylate
  • sodium thiosalicylate
  • topiramate
  • zonisamide

Pregnancy Category

US FDA Pregnancy Category  – C

Pregnancy

There are no adequate and well-controlled studies in pregnant women with Dorzolamide hydrochloride ophthalmic solution. Dorzolamide caused fetal vertebral malformations when administered orally to rabbits at 2.5 mg/kg/day (37 times the clinical exposure). Dorzolamide administered during the period of organogenesis was not teratogenic in rabbits dosed up to 1 mg/kg/day (15 times the clinical exposure). Dorzolamide hydrochloride administered orally to rats during late gestation and lactation caused growth delays in offspring at 7.5 mg/kg/day (52 times the clinical exposure). Growth was not delayed at 1 mg/kg/day (8.0 times the clinical exposure).

Lactation

There are no data on the presence of Dorzolamide hydrochloride ophthalmic solution in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Dorzolamide hydrochloride ophthalmic solution and any potential adverse effects on the breast-fed child from Dorzolamide hydrochloride ophthalmic solution. Dorzolamide is present in the milk of lactating rats (see Data).

References

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Diclofenamide – Uses, Dosage, Side Effects, Interaction

Diclofenamide is a sulfonamide that is benzene-1,3-sulfonamide in which the hydrogens at positions 4 and 5 are substituted by chlorine. An oral carbonic anhydrase inhibitor partially suppresses the secretion (inflow) of aqueous humor in the eye and so reduces intraocular pressure. It is used for the treatment of glaucoma. It has a role as an EC 4.2.1.1 (carbonic anhydrase) inhibitor, an antiglaucoma drug, and an ophthalmology drug. It is a sulfonamide and a dichlorobenzene.

Mechanism of Action

Carbonic anhydrase inhibitors reduce intraocular pressure by partially suppressing the secretion of aqueous humor (inflow), although the mechanism by which they do this is not fully understood. Evidence suggests that HCO3- ions are produced in the ciliary body by hydration of carbon dioxide under the influence of carbonic anhydrase and diffuse into the posterior chamber which contains more Na+ and HCO3- ions than does plasma and consequently is hypertonic. Water is then attracted to the posterior chamber by osmosis, resulting in a drop in pressure.

Indications of Diclofenamide

  • For adjunctive treatment of chronic simple (open-angle) glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where delay of surgery is desired in order to lower intraocular pressure.
  • Hyperkalemic Periodic Paralysis
  • Hypokalemic Periodic Paralysis
  • Primary Periodic Paralysis

Contraindications of Diclofenamide

  • Hyperchloremic acidosis
  • Hypokalemia (low blood potassium)
  • Hyponatremia (low blood sodium)
  • Adrenal insufficiency
  • Impaired kidney function
  • Hypersensitivity to acetazolamide or other sulfonamides.
  • Marked liver disease or impairment of liver function, including cirrhosis because of the risk of development of hepatic encephalopathy. Acetazolamide decreases ammonia clearance
  • type 1 diabetes mellitus
  • a condition where the adrenal glands produce less hormones called Addison’s disease
  • a type of joint disorder due to excess uric acid in the blood called gout
  • respiratory acidosis, an acid-base disorder
  • a blood disorder
  • decreased lung function
  • liver problems
  • severe liver disease
  • renal tubular acidosis
  • recurrent calcium-containing kidney stones
  • decreased kidney function
  • hyperchloremic acidosis

Dosage of Diclofenamide

  • Strengths: 50 mg

Primary Periodic Paralysis

  • Initial dose: 50 mg orally 2 times a day; the initial dose may be increased or decreased based on individual response, at weekly intervals (or sooner in case of adverse reaction)
  • Maximum dose: 200 mg orally per day

Side Effects of Diclofenamide

The Most Common

  • Abdominal or stomach pain
  • black, tarry stools
  • blistering, peeling, or loosening of the skin
  • chest pain or discomfort
  • chills
  • confusion
  • convulsions
  • cough or hoarseness
  • dark urine
  • decreased urine
  • diarrhea
  • dilated neck veins
  • dizziness
  • drowsiness
  • dry mouth
  • extreme fatigue
  • fever with or without chills
  • the general feeling of tiredness or weakness
  • headache
  • increased thirst
  • irregular breathing
  • irregular heartbeat
  • itching or rash
  • joint or muscle pain
  • light-colored stools
  • loss of appetite
  • lower back or side pain
  • mood changes
  • muscle pain or cramps
  • nausea or vomiting
  • numbness or tingling in the hands, feet, or lips
  • painful or difficult urination
  • rapid, deep breathing
  • red skin lesions, often with a purple center
  • red, irritated eyes
  • restlessness
  • sore throat
  • sores, ulcers, or white spots in the mouth or on the lips
  • stomach cramps
  • swelling of the face, fingers, feet, or lower legs
  • swollen or painful glands
  • tightness in the chest
  • unpleasant breath odor
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • vomiting of blood
  • weight gain
  • yellow eyes or skin

Common

  • Bloody or cloudy urine
  • bloody, black, or tarry stools
  • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
  • continuing ringing or buzzing or other unexplained noise in the ears
  • difficult or painful urination
  • fainting
  • hearing loss
  • high fever
  • pale skin
  • shakiness and unsteady walk
  • shakiness in the legs, arms, hands, or feet
  • a sudden decrease in the amount of urine
  • unsteadiness, trembling, or other problems with muscle control or coordination

Rare

  • Burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
  • change in taste
  • difficulty with moving
  • a general feeling of discomfort or illness
  • loss of taste
  • muscle pain or stiffness
  • muscle spasms
  • muscle twitching
  • pain in the joints
  • trouble performing routine tasks
  • unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness

Drug Interactions of Diclofenamide

Increase consumption of potassium-rich foods. Diclofenamide may cause hypokalemia, therefore consuming more potassium-rich foods may help prevent hypokalemia.

  • acarbose
  • acetazolamide
  • acetohexamide
  • albiglutide
  • albuterol
  • aldesleukin
  • alogliptin
  • alprazolam
  • amiodarone
  • amphotericin b
  • amphotericin b cholesteryl sulfate
  • amphotericin b lipid complex
  • amphotericin b liposomal
  • apomorphine
  • arformoterol
  • arsenic trioxide
  • aspirin
  • atracurium
  • avanafil
  • beclomethasone
  • benazepril
  • betamethasone
  • bisacodyl
  • bismuth subsalicylate
  • bitolterol
  • brinzolamide ophthalmic
  • canagliflozin
  • captopril
  • carbamazepine
  • casanthranol
  • cascara sagrada
  • castor oil
  • chlordiazepoxide
  • chlorpropamide
  • chlorthalidone
  • choline salicylate
    cisapride
  • cisatracurium
  • citalopram
    clobazam
  • clonazepam
  • clorazepate
  • clozapine
  • corticorelin
  • corticotropin
  • cortisone
  • cosyntropi
  • dapagliflozin
  • deflazacort
  • demeclocycline
  • desvenlafaxine
  • dexamethasondiatrizoate
  • diazepam
  • diflunisal
  • digitoxin
  • digoxin
  • dofetilide
  • dorzolamide ophthalmic
  • doxacurium
  • doxycycline
  • dronedarone
  • droperidol
  • dulaglutide
  • duloxetine
  • empagliflozin
  • enalapril
  • enalaprilat
  • epoprostenol
  • ertugliflozin
  • escitalopram
  • eslicarbazepine
  • estazolam
  • exenatide
  • fenoldopam
  • fludrocortisone
  • fluoxetine
  • flurazepam
  • fluvoxamine
  • formoterol
  • fosinopril
  • hydrocortisone
  • indacaterol
  • iodamid
  • iodipamide
  • iopromide
  • iothalamate
  • ioversol
  • ioxaglate
  • lactitol
  • magnesium citrate
  • magnesium hydroxide
  • magnesium salicylate
  • memantine
  • metaproterenol
  • metformin
  • methazolamide
  • methenamine
  • methylprednisolone
  • metocurine
  • metrizamide
  • midazolam
  • miglitol
  • milnacipran
  • mineral oil
  • minocycline
  • mivacurium
  • moexipril
  • oxazepam
  • oxytetracycline
  • pancuronium
  • paroxetine
  • perindopril
  • phenolphthalein
  • pimozide
  • pioglitazone
  • pipecuronium
  • pirbuterol
  • polyethylene glycol 3350
  • polyethylene glycol 3350 with electrolytes
  • pramlintide
  • prednisolone
  • prednisone
  • primidone
  • ramipril
  • rapacuronium
  • remimazolam
  • repaglinide
  • rocuronium
  • rosiglitazone
  • terbutaline
  • tetracycline
  • tizanidine
  • tolazamide
  • tolbutamide
  • topiramate
  • trandolapril
  • treprostinil
  • triamcinolone
  • triazolam
  • troglitazone
  • tubocurarine
  • vardenafil
  • vecuronium
  • venlafaxine
  • vilazodone
  • vortioxetine
  • ziprasidone
  • zonisamide

Pregnancy Category

  • FDA Pregnancy Category  – C.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Teratogenic effects (fetal limb reduction defects) were reported following oral administration of dichlorphenamide to pregnant rats during organogenesis at 350 mg/kg, or 17 times the maximum recommended human dose (200 mg/day) on a body surface area (mg/m²) basis. A no-effect dose has not been established. Diclofenamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

It is not known whether dichlorphenamide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dichlorphenamide is administered to a nursing woman.

There are no adequate and well-controlled studies on pregnant women. Dichlorphenamide should not be used in women of childbearing age or in pregnancy, especially during the first trimester, unless the potential benefits outweigh the potential risks.

References

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Ethoxzolamide – Uses, Dosage, Side Effects, Interactions

Ethoxzolamide is a sulfonamide and carbonic anhydrase (CA) inhibitor with diuretic and anti-glaucoma activity. In the eye, ethoxzolamide inhibits CA, thereby decreasing the secretion of aqueous humor. This may relieve intraocular pressure. Also, this agent prevents reabsorption of bicarbonate and sodium in the proximal convoluted tubule thereby producing a mild diuresis.

Ethoxzolamide is a sulfonamide that is 1,3-benzothiazole-2-sulfonamide which is substituted by an ethoxy group at position 6. A carbonic anhydrase inhibitor, it has been used in the treatment of glaucoma, and as a diuretic. It has a role as an EC 4.2.1.1 (carbonic anhydrase) inhibitor, a diuretic, and an antiglaucoma drug. It is a member of benzothiazoles and a sulfonamide.

Ethoxzolamide is a sulfonamide used as a diuretic and in glaucoma. It inhibits carbonic anhydrase activity in proximal renal tubules to decrease the reabsorption of water, sodium, potassium, bicarbonate. Its pharmacological activity thus confers the risk for hypokalemia.

Mechanism of Action

Ethoxzolamide binds to and inhibits carbonic anhydrase I, which plays an essential role in facilitating the transport of CO2 and H+ in the intracellular space, across biological membranes, and in the layers of the extracellular space. Through inhibition of the enzyme, the balance of applicable membrane equilibrium systems are affected.

Ethoxzolamide is an inhibitor of the carbonic anhydrase enzyme in proximal renal tubules that works by decreasing the reabsorption of water, sodium, potassium, bicarbonate. It also decreases the activity of carbonic anhydrase expressed in the CNS, which leads to an increased seizure threshold. Inhibition of carbonic anhydrase in the eye contributes to its effect of reducing intraocular pressure and decreasing aqueous humor.

Indications of Ethoxzolamide

  • For use in the treatment of duodenal ulcers, as a diuretic, and in the treatment of glaucoma, and may also be useful in the treatment of seizures associated with epilepsy.
  • Carbonic Anhydrase Inhibitors; Diuretics
  • For use in the treatment of duodenal ulcers, as a diuretic, and in the treatment of glaucoma, and may also be useful in the treatment of seizures associated with epilepsy.
  • Carbonic anhydrase inhibitors enhance sodium excretion by reducing sodium bicarbonate reabsorption in the early proximal convoluted tubule. Passive sodium chloride reabsorption in the late proximal convoluted tubule is consequently decreased, potassium excretion is increased during initial therapy. Clinically significant hypokalemia is seldom a problem because excess hydrogen ions in the extracellular fluid tend to diffuse into the cells and displace potassium ions. After several days of continuous administration, a mild hyperchloremic acidosis develops, which decreases the diuretic effect.

Contraindications of Ethoxzolamide

  • Information not available

Dosage

  • Information not available

Side Effects of Ethoxzolamide

The most Common

  • paresthesias, “tingling” feeling in the extremities,
  • some loss of appetite,
  • polyuria,
  • occasional drowsiness,
  • confusion and photosensitivity
  • papular or erythematous skin eruptions,
  • nausea,
  • acidosis and blood dyscrasias.
  • myopia, malaise syndrome,
  • fatigue,
  • anorexia,
  • loss of weight,
  • depression and loss of libido;
  • gastrointestinal distress,
  • elevated blood urate,
  • acute gouty arthritis skin rashes and hair loss or excess growth of hair.

Common 

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of too much acid in the blood (acidosis) like confusion; fast breathing; fast heartbeat; a heartbeat that does not feel normal; very bad stomach pain, upset stomach, or throwing up; feeling very sleepy; shortness of breath; or feeling very tired or weak.
  • Signs of electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up.
  • Change in eyesight.
  • Change in hearing.
  • Ringing in ears.

Rare

  • Paresthesias, hearing dysfunction or tinnitus, anorexia, altered taste, nausea, vomiting, diarrhea, polyuria, drowsiness, confusion.
  • A burning, numbness, or tingling feeling that is not normal.
  • Pain when passing urine or blood in the urine.
  • Not able to pass urine or change in how much urine is passed.
  • Muscle weakness.
  • Change in balance.
  • Trouble moving around.
  • Upset stomach or throwing up.
  • Change in taste.
  • Diarrhea.
  • Not hungry.
  • Blurred eyesight.
  • Feeling dizzy, sleepy, tired, or weak.
  • Headache.
  • Flushing.
  • Feeling nervous and excitable.

Drug Interactions of Ethoxzolamide

View interaction reports for ethoxzolamide and the medicines listed below.

  • diphenhydramine
  • CoQ10 ubiquinone
  • duloxetine
  • Fish Oil (omega-3 polyunsaturated fatty acids)
  • furosemide
  • pregabalin
  • esomeprazole
  • acetaminophen / hydrocodone
  • acetaminophen
  • albuterol
  • magnesium salicylate
  • metformin
  • methazolamide
  • dichlorphenamide
  • dofetilide
  • dronedarone
  • droperidol
  • citalopram
  • clobazam
  • clonazepam
  • clorazepate
  • clozapine
  • corticorelin
  • corticotropin
  • cortisone
  • montelukast
  • levothyroxine
  • topiramate
  • acetaminophen
  • Vitamin B12 (cyanocobalamin)
  • Vitamin C (ascorbic acid)
  • Vitamin D2 (ergocalciferol)
  • Vitamin D3 (cholecalciferol)
  • ondansetron
  • cetirizine

Pregnancy Category

Pregnancy

Ethoxzolamide is pregnancy category B3 in Australia, which means that studies in rats, mice, and rabbits in which ethoxzolamide was given intravenously or orally caused an increased risk of fetal malformations, including defects of the limbs.[rx] Despite this, there is insufficient evidence from studies in humans to either support or discount this evidence.[rx]

Lactation

Limited data are available on the effects of nursing mothers taking ethoxzolamide. Therapeutic doses create low levels of breast milk and are not expected to cause problems in infants.[rx]

Before taking acetazolamide,

  • tell your doctor and pharmacist if you are allergic toethoxzolamide sulfa drugs, diuretics (‘water pills’), or any other drugs.
  • tell your doctor and pharmacist what prescription and nonprescription medications you are taking, especially amphetamines, aspirin, cyclosporine (Neoral, Sandimmune), medications for depression or irregular heartbeat, diflunisal (Dolobid), digoxin (Lanoxin), diuretics (‘water pills’), lithium (Eskalith, Lithobid), phenobarbital, primidone (Mysoline), and vitamins.
  • tell your doctor if you have or have ever had heart, liver, or kidney disease; or diabetes.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking ethoxzolamide, call your doctor immediately.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking ethoxzolamide.
  • you should know that this drug may make you drowsy. Do not drive a car or operate machinery until you know how this drug affects you.
  • remember that alcohol can add to the drowsiness caused by this drug.
  • plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Ethoxzolamide may make your skin sensitive to sunlight.

References

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