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Losartan, the first ARB

Angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. Their main use is in hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure.

Contents

Discovery and development

Structure

Losartan, irbesartan, olmesartan, candesartan and valsartan include the tetrazole group (a ring with four nitrogen and one carbon).
Losartan, irbesartan, olmesartan, candesartan, and telmisartan include one or two imidazole groups.

Mechanism of action

These substances are AT1-receptor antagonists – that is, they block the activation of angiotensin II AT1 receptors. Blockade of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, reduces production and secretion of aldosterone, amongst other actions – the combined effect of which is reduction of blood pressure.

The specific efficacy of each ARB within this class is made up of a combination of three pharmacodynamic and pharmacokinetic parameters. For these three key PD/ PK areas that indicate efficacy, it is important to see that one needs a combination of all three at an effective level; the parameters of the three characteristics will need to compiled into a table similar too one below, eliminating duplications and arriving at consensus values; the latter are at variance now.

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Pressor inhibition

Pressor inhibition at trough level - this clinically important measurement relates to the amount of blockade or inhibition of the BP raising effect of angiotensin II. Pressor inhibition is not a measure of blood pressure efficacy, though. The rates as listed in the US FDA Package Inserts for inhibition of this effect at the 24th hour for the ARBs are as follows: (all doses listed in PI are included)

AT1 affinity

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

Biological half life

The third area that completes the overall efficacy picture of an ARB is its biological half life. The half-lives from the US FDA Package Inserts are as follows:

Drug comparison and pharmacokinetics

Table 1: Comparison of ARB pharmacokinetics
Drug Trade Name Biological half-life [h] Protein binding [%] Bioavailability [%] Renal/hepatic clearance [%] Food effect Daily dosage [mg]
Losartan Cozaar 2 h 98.7% 33% 10%/90% Minimal 50–100 mg
EXP 3174 6–9 h 99.8% 50%/50%
Candesartan Atacand 9h >99% 15% 60%/40% No 4–32 mg
Valsartan Diovan 6 h 95% 25% 30%/70% No 80–320 mg
Irbesartan Avapro 11–15 h 90–95% 70% 1%/99% No 150–300 mg
Telmisartan Micardis 24 h >99% 42–58% 1%/99% No 40–80 mg
Eprosartan Teveten 5 h 98% 13% 30%/70% No 400–800 mg
Olmesartan Benicar 14–16 h >99% 29% 40%/60% No 10–40 mg

Uses

Angiotensin II receptor antagonists are primarily used for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy. They do not inhibit the breakdown of bradykinin or other kinins, and are thus only rarely associated with the persistent dry cough and/or angioedema that limit ACE inhibitor therapy. More recently, they have been used for the treatment of heart failure in patients intolerant of ACE inhibitor therapy, particularly candesartan. Irbesartan and losartan have trial data showing benefit in hypertensive patients with type II diabetes, and may delay the progression of diabetic nephropathy. Candesartan is used experimentally in preventive treatment of migraine.[1]

The angiotensin II receptor blockers have differing potencies in relation to blood pressure control, with statistically differing blood pressure effects at the maximal doses.[2] When used in clinical practice, the particular agent used may vary based on the degree of blood pressure response required.

Some of these drugs have a uricosuric effect.[3][4]

In 2008 they were reported to have a remarkable negative association with Alzheimer's Disease. A retrospective analysis of five million patient records with the US Department of Veterans Affairs system found that different types of commonly used anti-hypertensive medications had very different AD outcomes. Those patients taking angiotensin receptor blockers (ARBs) were 35—40% less likely to develop AD than those using other anti-hypertensives. (Preliminary unpublished data)[5][6]

Adverse effects

This class of drugs is usually well-tolerated, with common adverse drug reactions (ADRs) including: dizziness, headache, and/or hyperkalemia. Infrequent ADRs associated with therapy include: first dose orthostatic hypotension, rash, diarrhea, dyspepsia, abnormal liver function, muscle cramp, myalgia, back pain, insomnia, decreased haemoglobin levels, renal impairment, pharyngitis, and/or nasal congestion.[7]

While one of the main rationales for the use of this class is the avoidance of dry cough and/or angioedema associated with ACE inhibitor therapy, they may still rarely occur. Additionally, there is also a small risk of cross-reactivity in patients who have experienced angioedema with ACE inhibitor therapy.[7]

Myocardial Infarction: the controversy

The question of whether or not Angiotensin II receptor antagonists slightly increase the risk of heart attack (myocardial infarction) is currently being investigated. Some studies have demonstrated that ARBs can increase the risk of myocardial infarction[8]. However, other studies have found that ARBs do not increase the risk of myocardial infarction.[9] To date, there is no consensus on whether ARBs have a tendency to increase the risk of myocardial infarction, and further investigations are underway.

Indeed, as a consequence of AT1 blockade, ARBs increase Angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating Angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition upregulated. Unfortunately, recent data suggest that AT2 receptor stimulation may be less beneficial than previously proposed and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy , as well as proatherogenic and proinflammatory effects.[10][11][12]

References

  1. ^ Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. (2003). "Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial". JAMA 1 (289 Pt 1): 65–9. doi:10.1001/jama.289.1.65. PMID 12503978.  
  2. ^ Kassler-Taub K, Littlejohn T, Elliott W, Ruddy T, Adler E. (1998). "Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators". Am J Hypertens 11 (4 Pt 1): 445–53. doi:10.1016/S0895-7061(97)00491-3. PMID 9607383.  
  3. ^ Dang A, Zhang Y, Liu G, Chen G, Song W, Wang B (January 2006). "Effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia in Chinese population". J Hum Hypertens 20 (1): 45–50. doi:10.1038/sj.jhh.1001941. PMID 16281062.  
  4. ^ Daskalopoulou SS, Tzovaras V, Mikhailidis DP, Elisaf M (2005). "Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia". Curr. Pharm. Des. 11 (32): 4161–75. PMID 16375738. http://www.bentham-direct.org/pages/content.php?CPD/2005/00000011/00000032/0008B.SGM.  
  5. ^ "Angiotensin receptor blockers are lower incidence, progression of Alzheimer's disease" 28 July 2008
  6. ^ "Potential of antihypertensive drugs for the prevention and treatment of Alzheimer's disease". Expert Review of Neurotherapeutics 8 (9): 1286. September 2008. doi:10.1586/14737175.8.9.1285.  
  7. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  8. ^ Strauss MH, Hall AS (2006). "Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox". Circulation 114 (8): 838–54. doi:10.1161/CIRCULATIONAHA.105.594986. PMID 16923768.  
  9. ^ Tsuyuki RT, McDonald MA (2006). "Angiotensin receptor blockers do not increase risk of myocardial infarction". Circulation 114 (8): 855–60. doi:10.1161/CIRCULATIONAHA.105.594978. PMID 16923769.  
  10. ^ Levy BI (2005). "How to explain the differences between renin angiotensin system modulators". Am. J. Hypertens. 18 (9 Pt 2): 134S–141S. doi:10.1016/j.amjhyper.2005.05.005. PMID 16125050.  
  11. ^ Lévy BI (2004). "Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system". Circulation 109 (1): 8–13. doi:10.1161/01.CIR.0000096609.73772.C5. PMID 14707017.  
  12. ^ Reudelhuber TL (2005). "The continuing saga of the AT2 receptor: a case of the good, the bad, and the innocuous". Hypertension 46 (6): 1261–2. doi:10.1161/01.HYP.0000193498.07087.83. PMID 16286568.  

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