AntihypertensiveDrugs-HomeUniversityof.pptVIP

* itogen-activated protein (MAP) kinases(EC?2.7.11.24) are?serine/threonine-specific protein kinases?that respond to extracellular stimuli (mitogens,?osmotic stress,?heat shockand?proinflammatory cytokines) and regulate various cellular activities, such as?gene expression,?mitosis,?differentiation, proliferation, and cell survival/apoptosis.[1 Angiotensin Receptor Blockers (ARBs) - Angiotensin Receptors: Specific angiotensin receptors have been discovered, grouped and abbreviated as – AT1 and AT2 They are present on the surface of the target cells Most of the physiological actions of angiotensin are mediated via AT1 receptor Transducer mechanisms of AT1 inhibitors: In different tissues show different mechanisms. For example - PhospholipaseC-IP3/DAG-intracellular Ca++ release mechanism – vascular and visceral smooth muscle contraction In myocardium and vascular smooth muscles AT1 receptor mediates long term effects by MAP kinase and others Losartan is the specific AT1 blocker Angiotensin Receptor Blockers (ARBs) - Losartan Competitive antagonist and inverse agonist of AT1 receptor Does not interfere with other receptors except TXA2 Blocks all the actions of A-II - vasoconstriction, sympathetic stimulation, aldosterone release and renal actions of salt and water reabsorption No inhibition of ACE Losartan Theoretical superiority over ACEIs: Cough is rare – no interference with bradykinin and other ACE substrates Complete inhibition of AT1 – alternative remains with ACEs Result in indirect activation of AT2 – vasodilatation (additional benefit) Clinical benefit of ARBs over ACEIs – not known However, losartan decreases BP in hypertensive which is for long period (24 Hrs) heart rate remains unchanged and cvs reflxes are not interfered no significant effect in plasma lipid profile, insulin sensitivity and carbohydrate tolerance etc Mild uricosuric effect Losartan Pharmacokinetic: Absorption not affected by food but unlike ACEIs its bioavailability is low High first