Srikanth htn role of ar bs 2
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TREATMENT OF HYPERTENSION ROLE OF ANGIOTENSIN RECEPTOR BLOCKERS
Dr.SRIKANTH POST GRADUATE
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INTRODUCTION • The angiotensin receptor blockers (ARB),
also called angiotensin 1(AT1) receptors antagonists or sartans modulate the renin–angiotensin system.
• Their main uses are in the treatment of hypertension , diabetic nephropathy and congestive heart failure. They act by blocking the effects of the hormone angiotensin( AT11) in the body .
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• Angiotensin receptors are mainly found in the heart ,adrenal glands,brain ,liver and kidneys.
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ANGIOTENSIN RECEPTORS• Specific angiotensin receptors have been discovered,grouped and abbreviated as - AT1 AT2
• They are present on the surface of target cells.
• Most of the physiological actions of angiotensin are mediated via AT1 receptors.
• Losartan is the specific AT1receptors.
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Difference between AT1&AT2 receptors • All the adverse effects of angiotensin 11 by AT1 receptors.
1. Vasoconstriction
2. Sodium retention
3. Cell growth promotion & connective tissue deposition
4. LDL-C transport increased.
5. Increased afferent arteriolar constriction & thus increasing intra glomerular pressure.This increase proteinuria.
• On the other hand when the same angiotensin 11 stimulates AT2 receptors the exactly opposite and beneficial effects occur.
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Potential Pathogenic Properties of Angiotensin 11• HEART
1. Myocardial Hypertrophy
2. Interstitial fibrosis
• CORONARY ARTERIES
A. Endothelial dysfunction
B. Coronary constriction via release of norepinephrine.
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• Increased oxidative stress.
• Promotion of inflammatory response & Atheroma.
• Promotion of LDL cholesterol uptake.
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1. Kidneys
• Increased intraglomerular pressure.
• Increased protein leak.
• Glomeruler growth & fibrosis.
• Increased sodium reabsorbtion.
2. Adrenals
• Increased formation of aldosterone.
3. Coagulation system:Increased fibrinogen level
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DEVELOPMENT OF ARB• 1970 saralasin is the first Ang 11
antagonist.
• 1986 Losartan
• 1991 Telmisartan
• 1995 Olmessartan medoxomil
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• LOSARTAN:It is a competitive antagonist and inverse agonist, 10,000 times more selective for AT1 than for AT2 receptor.
• Losartan causes fall in BP in hypertensive patients which lasts for 24 hours, while HR remains unchanged and cardiovascular reflexes are not interfered.
• The plasma t½ of losartan is 2 hr.
• Side effects: Hypotension ,Hyperkalemia,Angioedema.
• 50 mg OD
• Liver disease or volume depleted 25 mg OD
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• Candesartan: It has the highest affinity for the AT1 receptor .
• Elimination occurs by both hepatic metabolism and renal excretion
• t½ of 8-12 hours: action lasts 24 hours.
• Dose: 8 mg OD (max 8 mg BD), liver/kidney impairment 4 mg OD.
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• Telmisartan :The AT1 receptor blocking action of telmisartan is similar to losartan, but it does not produce any active metabolite. After an oral dose, peak action occurs in 3 hours and action lasts > 24 hours.
• Dose: 20–80 mg OD.
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• IRBESARTAN : t½ is ~12 hours.
• Dose: 150–300 mg OD.
• VALSARTAN: The AT1 receptor affinity of valsartan is similar to that of losartan.
• t½ of 6–9 hours; action lasts 24 hours.
• Dose: 80–160 mg OD 1 hour before meal (initial dose in liver disease 40 mg).
• OLMESARTAN: Another potent ARB with high affinity for AT1 receptor. It is available as an ester prodrug which is completely hydrolysed during absorption from the gut.
• t½ of ~12 hours.
• Dose: 20–40 mg OD.
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INDICATIONS Hypertension
CHF
Diabetic nephropathy
Myocardial infarction
Stroke
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• Patients with HFrEF (left ventricular EF [LVEF] ≤40 percent) with current or prior symptoms of HF who are ACE inhibitor intolerant due to cough, ARB is recommended as an alternative.
• Reduced sympathetic activity
• Effect on remodeling
• Effect on cytokine levels
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COMBINATION THERAPY [ACE+ARB]• To slow the progression of proteinuric
diabetic and nondiabetic chronic renal failure.
• To improve hemodynamics and survival in patients with heart failure with reduced ejection fraction (HFrEF).
• To lower the blood pressure in patients with hypertension and also allow more rapid regression of left ventricular hypertrophy.
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DIRECT CARDIAC EFFECTS OF ANGIOTENSIN II
• Inotropy
• Chronotropy
• Hypertrophy
• Ventricular remodeling
• Electrical remodeling
• Pathogenesis of atherosclerosis
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SIDE EFFECTS
• Hypotension
• Hyperkalemia
• Angioedema
• Impairment of renal function.
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RECENT ARB
• Azilsartan medoxomil:
• Approved on February 25, 2011
• 80 mg once daily
• Fimasartan
• Higher potency and longer duration than losartan.
• Dosage range of 60-120 mg once daily.
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ARBs under development
Several new nonpepetide ARBs are undergoing clinical s trials
1. Embusartan
2. Fonsartan
3. Pratosartan
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