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Renin-Angiotensin System Drugs Igor Spigelman, Ph.D. Division of Oral Biology & Medicine, UCLA School of Dentistry, CA Rm. 63-078 CHS Email: [email protected] RENIN-ANGIOTENSIN SYSTEM - plays a major role in the regulation of hemodynamics and water and electrolyte balance via its circulating hormone, angiotensin II. Renin: rate-limiting enzyme in angiotensin II production Control of renin secretion: • Mechanical • Ionic • NE release Blood Pressure Rises Blood Volume Rises Blood Pressure Falls - Renin Release + Na+ Retention Vasoconstriction Aldosterone Secretion Blood Volume Falls Na+ Depletion Angiotensin Formation A schematic portrayal of the homeostatic roles of the renin-angiotensin system ANGIOTENSIN II Altered Peripheral Resistance I. Direct vasoconstriction II. Enhancement of peripheral noradrenergic neurotransmission III. Increased sympathetic discharge (CNS) IV. Catecholamine release from adrenal medulla Rapid Pressor Response Altered Renal Function I. Increased Na + reabsorption by proximal tubule Altered Cardiovascular Structure I. Stimulation of cell growth II. Hemodynamic changes II. Increased aldosterone release A. Increased cardiac afterload + preload III. Altered renal hemodynamics (vasoconstriction) B. Increased vascular wall tension Slow Pressor Response Vascular + Cardiac Hypertrophy + Remodeling ACE Inhibitors Active molecules: Captopril, Lisinopril, Enalaprilat Prodrugs: Enalapril, Benazepril, Fosinopril, Quinapril, Ramipril, Moexipril, Spirapril Beneficial effects in: Hypertension CHF Adverse effects of ACE Inhibitors • Hypotension • Renal insufficiency • Cough • Hyperkalemia • Hyperreninemia • • • • Ageusia Skin rash Proteinuria Neutropenia AT-Receptor Antagonists Losartan,Valsartan, Candesartan, *sartan Non-peptide competitive inhibitors of AT1 receptors. Block ability of angiotensins II and III to stimulate pressor and cell proliferative effects. Antihypertensive effects Cell growth effects Lack of “bradykinin” effects Renin Inhibitors - angiotensinogen analogs show promise HYPERTENSION - elevation of systolic/diastolic pressure above 140/90 mm Hg - most common cardiovascular disease in USA Essential Unknown etiology 80-90% of all cases Treatment mainly symptomatic Secondary Known etiology Treat to eliminate cause of the disease Mortality Is Related to Blood Pressure Clinical disorders resulting from hypertension and atherosclerosis Hypertension • • • • • • Congestive heart failure Cerebral hemorrhage Renal failure Retinopathy Dissecting aneurysm Hypertensive crisis Atherosclerosis • • • • • Coronary artery disease Angina pectoris Myocardial infarction 2° renovascular hypertension Peripheral vascular insufficiency • Cerebral thrombosis - stroke Risk factors for cardiovascular complications in hypertensive subjects Age Sex Race Hyperlipoproteinemia Diabetes mellitus Cigarette smoking Obesity Salt intake Previous cardiovascular disease Family history of cardiovascular disease TREATMENT OF HYPERTENSION Non-pharmacological Pharmacotherapy • Restriction of salt intake • cardiac output (ß-blockers, Ca2+ channel blockers) • Reduction of body weight • plasma volume (diuretics) • peripheral vascular resistance (vasodilators) MAP = CO X TPR "Individualized Care" • Risk factors considered • Non-pharmacological therapy tried first • Monotherapy is instituted • Considerations for choice of initial monotherapy: Renin status Coexisting cardiovascular conditions Other conditions PHARMACOTHERAPY OF HYPERTENSION MONOTHERAPY Drugs used only in combination • • • • • • • ACE inhibitors ATII antagonists Diuretics -adrenoceptor blockers a1-adrenoceptor blockers Ca2+ channel blockers • • • Centrally acting antihypertensives Guanethidine Minoxidil Hydralazine Sites of action of drugs that relax vascular smooth muscle a-Adrenoceptor antagonists Prazosin Terazosin Activators of the NO/guanylate cyclase pathway Hydralazine Nitroglycerin Nitroprusside Ca2+-channel blockers NO Dihydropyridines Verapamil Ca2+ Diltiazem K+ Angiotensin II receptor antagonists Losartan Valsartan K+-channel activators Minoxidil Diazoxide HYPERTENSIVE EMERGENCIES e.g. cerebral hemorrhage, myocardial infarction Sodium nitroprusside Glyceryl trinitrate Trimethaphan Hydralazine Parenteral administration Implications for Dentistry • Care in use of vasoconstrictors (e.g. supersensitivity to catecholamines with guanethidine) • Orthostatic hypotention (common to all antihypertensive drugs) • Judicious use of CNS depressants (esp. with centrally-acting antihypertensive drugs) • Salivary inhibition (xerostomia common with centrally-acting antihypertensive drugs) • NSAIDs (decrease action of captopril, spironolactone, furosemide) • Gingival hyperplasia (with long-term use of Ca2+channel blockers)