Transcript
TREATMENT OF HYPERTENSION ROLE OF ANGIOTENSIN RECEPTOR BLOCKERS
Dr.SRIKANTH POST GRADUATE
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 .
• Angiotensin receptors are mainly found in the heart ,adrenal glands,brain ,liver and kidneys.
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.
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.
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.
• Increased oxidative stress.
• Promotion of inflammatory response & Atheroma.
• Promotion of LDL cholesterol uptake.
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
DEVELOPMENT OF ARB• 1970 saralasin is the first Ang 11
antagonist.
• 1986 Losartan
• 1991 Telmisartan
• 1995 Olmessartan medoxomil
• 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
• 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.
• 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.
• 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.
INDICATIONS Hypertension
CHF
Diabetic nephropathy
Myocardial infarction
Stroke
• 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
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.
DIRECT CARDIAC EFFECTS OF ANGIOTENSIN II
• Inotropy
• Chronotropy
• Hypertrophy
• Ventricular remodeling
• Electrical remodeling
• Pathogenesis of atherosclerosis
SIDE EFFECTS
• Hypotension
• Hyperkalemia
• Angioedema
• Impairment of renal function.
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.
ARBs under development
Several new nonpepetide ARBs are undergoing clinical s trials
1. Embusartan
2. Fonsartan
3. Pratosartan
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