Angiotensin II receptor blockers (ARBs); Types, Uses, Effects

Angiotensin II receptor blockers (ARBs), also known as angiotensin II receptor antagonists, AT₁ receptor antagonists or sartans, are a group of pharmaceuticals that modulate the renin-angiotensin system. Their main uses are in the treatment of hypertension (high blood pressure), diabetic nephropathy(kidney damage due to diabetes) and congestive heart failure. They block the activation of AT₁ receptors, preventing the binding of angiotensin II.

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Angiotensin II is a hormone that may act on the central nervous system to regulate renal sympathetic nerve activity, renal function, and, therefore, blood pressure. Angiotensin II is produced locally within the kidney and mediates tissue injury through a series of nonhemodynamic effects. angiotensin II is not only involved in the regulation of blood pressure, water, and sodium homeostasis, and control of other neurohumoral systems, but also leads to excessive production of reactive oxygen species and to hypertrophy, proliferation, migration, and apoptosis of vascular cells. Angiotensin II is one of the main factors involved in hypertension-induced tissue damage. This peptide regulates the inflammatory process. Angiotensin II activates circulating cells and participates in their adhesion to the activated endothelium and subsequent transmigration through the synthesis of adhesion molecules, chemokines, and cytokines. Among the intracellular signals involved in angiotensin II-induced inflammation, the production of reactive oxygen species and the activation of nuclear factor-kappaB are the best known. Classical, well-defined actions of Angiotensin II in the brain include the regulation of hormone formation and release, the control of the central and peripheral sympathoadrenal systems, and the regulation of water and sodium intake. As a consequence of changes in the hormone, sympathetic and electrolyte systems, feedback mechanisms, in turn, modulate the activity of the brain Angiotensin II systems. There are two Angiotensin II systems in the brain. The discovery of brain Angiotensin II receptors located in neurons inside the blood-brain barrier confirmed the existence of an endogenous brain Angiotensin II system, responding to Angiotensin II generated in and/or transported into the brain. In addition, Angiotensin II receptors in circumventricular organs and in cerebrovascular endothelial cells respond to circulating Angiotensin II of peripheral origin. Thus, the brain responds to both circulating and tissue Angiotensin II, and the two systems are integrated. [1](PMID: 17147923, 16672146, 16601568, 16481883, 16075377).

Types of Angiotensin II receptor blockers

Pressor inhibition

Pressor inhibition at trough level – this relates to the degree of blockade or inhibition of the blood pressure-raising (“pressor”) effect of angiotensin II. However, pressor inhibition is not a measure of blood pressure-lowering (BP) efficacy per se. The rates as listed in the US FDA Package Inserts (PIs) for inhibition of this effect at the 24th hour for the ARBs are as follows: (all doses listed in PI are included)

• Valsartan 80 mg 30%
• Telmisartan 80 mg 40%
• Losartan 100 mg 25–40%
• Irbesartan 150 mg 40%
• Irbesartan 300 mg 60%
• Azilsartan 32 mg 60%
• Olmesartan 20 mg 61%
• Olmesartan 40 mg 74%

AT₁ affinity

AT₁ affinity vs AT₂ is not a meaningful efficacy measurement of BP response. The specific AT₁ affinity relates to how specifically attracted the medicine is for the correct receptor, the US FDA PI rates for AT₁affinity are as follows:

• Losartan 1000-fold
• Telmisartan 3000-fold
• Irbesartan 8500-fold
• Candesartan greater than 10000-fold
• Olmesartan 12500-fold
• Valsartan 30000-fold
• Saprisartan

Biological half-life

The third area needed to complete the overall efficacy picture of an ARB is its biological half-life. The half-lives from the US FDA PIs are as follows:

• Valsartan 6 hours
• Losartan 6–9 hours
• Azilsartan 11 hours
• Irbesartan 11–15 hours
• Olmesartan 13 hours
• Telmisartan 24 hours
• Fimasartan 7–11 hours

Overall classification

Mechanism of action of Angiotensin II receptor blockers

These substances are AT₁-receptor antagonists; that is, they block the activation of angiotensin II AT₁ receptors. Blockage of AT₁ receptors directly causes vasodilation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone, among other actions. The combined effect reduces blood pressure.The specific efficacy of each ARB within this class depends upon a combination of three pharmacodynamic and pharmacokinetic parameters. Efficacy requires three key PD/PK areas at an effective level; the parameters of the three characteristics will need to be compiled into a table similar to one below, eliminating duplications and arriving at consensus values; the latter is at variance now.

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Indications  of Angiotensin II receptor blockers

• Chronic stable angina pectoris
• High blood pressure (hypertension)
• Raynaud’s syndrome
• Heart failure
• Angina pectoris prophylaxis
• Hypertensive emergency
• Hypertrophic cardiomyopathy
• Migraine prevention
• Premature labor
• Pulmonary edemas
• Pulmonary hypertension 
• Ureteral ualculus
• Vasospastic Angina
• Heart attack
• Congestive heart failure,
• Systolic dysfunction,
• Myocardial infarction
• Diabetic nephropathies

Contra-Indications of Angiotensin II receptor blockers

• Porphyria
• An acute syndrome of the heart
• Severe narrowing of the aortic heart valve
• Severe heart failure
• Abnormally low blood pressure
• Kidney disease with a reduction in kidney function
• Fluid Retention in the Legs, arms or hands
• Blood circulation failure due to the serious heart condition
• Chronic idiopathic constipation
• Stomach or intestine blockage
• Narrowing of the intestines
• Decreased motility function of stomach or itestines
• Heart attack
• Allergies to calcium channel blockers
• Calcium channel blocking agents-dihydropyridines
• Symptomatic left ventricular ejection fraction ≤ 35% Chronic heart failure
• Treatment of uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy.
• Coronary artery disease in those intolerant of ACE inhibitors.
• Pediatric hypertension 6 to 16 years of age.
• Post-myocardial infarction.

Side Effects

The most common 

• severe headache, rapid heartbeat, stiffness in your neck,  
• chest pain, fast or slow heart rate;
• swelling, rapid weight gain;
• Xerostomia (dry mouth)
• Headache 
• Fatigue
• Skin reactions 
• Hypotension
• Anxiety
• Constipation
• Nausea/vomiting
• Weight gain/loss
• Erectile dysfunction

More common

• Abdominal or stomach pain, discomfort, or tenderness
• chills or fever
• difficulty with moving
• headache, severe and throbbing
• joint or back pain
• muscle aching or cramping
• muscle pains or stiffness
• chest pressure or squeezing pain in chest
• discomfort in arms, shoulders, neck or upper back
• excessive sweating
• feeling of heaviness, pain, warmth and/or swelling in a leg or in the pelvis
• sudden tingling or coldness in an arm or leg
• sudden slow or difficult speech
• sudden drowsiness or need to sleep
• fast breathing
• sharp pain when taking a deep breath
• fast or slow heartbeat
• coughing up blood
• rust colored urine
• decreased amount of urine

Rare

• Anxiety
• change in vision
• chest pain or tightness
• confusion
• cough
• Agitation
• arm, back, or jaw pain
• blurred vision
• chest pain or discomfort
• convulsions
• extra heartbeats
• fainting
• hallucinations
• headache
• irritability
• lightheadedness
• mood or mental changes
• muscle pain or cramps
• muscle spasm or jerking of all extremities
• nervousness

Drug Interactions of Angiotensin II receptor blockers

Angiotensin II receptor blockers may interact with the following drug, supplements, & may change the efficacy of the drug

• allopurinol
• alpha blockers (e.g., alfuzosin, doxazosin, tamsulosin)
• alpha agonists (e.g., clonidine, methyldopa)
• angiotensin II receptor blockers (ARBs; e.g., candesartan, losartan)
• antidiabetes medications (e.g., insulin, metformin, glyburide)
• atypical anti-psychotics (e.g., clozapine, olanzapine, quetiapine, risperidone)
• azathioprine
• barbiturates (e.g., butalbital, pentobarbital phenobarbital)
• beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
• “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
• calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
• canagliflozin
• ciprofloxacin
• calcium supplements (e.g., calcium carbonate, calcium citrate)
• carbamazepine
• clopidogrel
• cyclosporine
• diuretics (water pills; e.g., furosemide, hydrochlorothiazide, triamterene)
• duloxetine
• “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
• guanfacine
• heparin
• levodopa
• medications that increase potassium levels (e.g., potassium supplements, spironolactone, amiloride, and salt substitutes containing potassium)
• metformin
• nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen, indomethacin, naproxen)
• other angiotensin-converting-enzyme inhibitors (ACEIs; e.g., captopril,  ramipril)
• pentoxifylline
• macrolide antibiotics (e.g., clarithromycin, erythromycin)
• methylphenidate
• monoamine oxidase inhibitors (MAOIs; e.g., moclobemide, phenelzine, rasagiline,selegiline, tranylcypromine)
• phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)
• pregabalin
• sodium phosphates
• tizanidine
• trimethoprim
• valproic acid
• warfarin

References

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