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Renin-Angiotensin System Drugs

Renin-Angiotensin System Drugs. Igor Spigelman, Ph.D. Division of Oral Biology & Medicine, UCLA School of Dentistry, CA. Rm. 63-078 CHS. Email: igor@ucla.edu. RENIN-ANGIOTENSIN SYSTEM.

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Renin-Angiotensin System Drugs

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  1. Renin-Angiotensin System Drugs Igor Spigelman, Ph.D. Division of Oral Biology & Medicine, UCLA School of Dentistry, CA Rm. 63-078 CHS Email: igor@ucla.edu

  2. RENIN-ANGIOTENSIN SYSTEM - plays a major role in the regulation of hemodynamics and water and electrolyte balance via its circulating hormone, angiotensin II. Control of renin secretion: • Mechanical • Ionic • NE release Renin: rate-limiting enzyme in angiotensin II production

  3. Blood Pressure Rises Blood Pressure Falls Blood Volume Falls Blood Volume Rises Renin Release - + Na+ Retention Na+ Depletion Vasoconstriction Aldosterone Secretion Angiotensin Formation A schematic portrayal of the homeostatic roles of the renin-angiotensin system

  4. ANGIOTENSIN II Altered Altered Altered Peripheral Cardiovascular Renal Resistance Structure Function + I. Direct vasoconstriction I. Increased Na I. Stimulation of cell growth reabsorption II. Enhancement of by proximal tubule II. Hemodynamic changes peripheral noradrenergic neurotransmission II. Increased aldosterone A. Increased cardiac release afterload + preload III. Increased sympathetic discharge (CNS) III. Altered renal B. Increased vascular hemodynamics wall tension IV. Catecholamine release (vasoconstriction) from adrenal medulla Vascular + Cardiac Rapid Pressor Response Slow Pressor Response Hypertrophy + Remodeling

  5. ACE Inhibitors Active molecules: Captopril, Lisinopril, Enalaprilat Prodrugs: Enalapril, Benazepril, Fosinopril, Quinapril, Ramipril, Moexipril, Spirapril Beneficial effects in: Hypertension CHF

  6. Adverse effects of ACE Inhibitors • Hypotension • Renal insufficiency • Cough • Hyperkalemia • Hyperreninemia • Ageusia • Skin rash • Proteinuria • Neutropenia

  7. 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

  8. HYPERTENSION • elevation of systolic/diastolic pressure above 140/90 mm Hg • - most common cardiovascular disease in USA Essential Secondary Unknown etiology Known etiology 80-90% of all cases Treat to eliminate Treatment mainly symptomatic cause of the disease

  9. Mortality Is Related to Blood Pressure

  10. Congestive heart failure Cerebral hemorrhage Renal failure Retinopathy Dissecting aneurysm Hypertensive crisis Coronary artery disease Angina pectoris Myocardial infarction 2° renovascular hypertension Peripheral vascular insufficiency Cerebral thrombosis - stroke Clinical disorders resulting fromhypertension and atherosclerosis Hypertension Atherosclerosis

  11. Risk factors for cardiovascular complications in hypertensive subjects Obesity Salt intake Previous cardiovascular disease Family history of cardiovascular disease Age Sex Race Hyperlipoproteinemia Diabetes mellitus Cigarette smoking

  12. TREATMENT OF HYPERTENSION Non-pharmacological Pharmacotherapy • Restriction of salt intake • Reduction of body weight •  cardiac output (ß-blockers, Ca2+ channel blockers) •  plasma volume (diuretics) •  peripheral vascular resistance (vasodilators) MAP = CO X TPR

  13. "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

  14. PHARMACOTHERAPY OF HYPERTENSION Drugs used only in combination MONOTHERAPY • ACE inhibitors • ATII antagonists • Diuretics • -adrenoceptor blockers • a1-adrenoceptor blockers • Ca2+ channel blockers • Centrally acting antihypertensives • Guanethidine • Minoxidil • Hydralazine

  15. Sites of action of drugs that relax vascular smooth muscle Activators of the NO/guanylate cyclase pathway a -Adrenoceptor Hydralazine antagonists Nitroglycerin Prazosin Nitroprusside Ca2+-channel blockers NO Terazosin Dihydropyridines Verapamil Ca2+ Diltiazem K+ K+-channel activators Angiotensin II receptor Minoxidil antagonists Diazoxide Losartan Valsartan

  16. HYPERTENSIVE EMERGENCIES e.g. cerebral hemorrhage, myocardial infarction Sodium nitroprusside Glyceryl trinitrate Trimethaphan Hydralazine Parenteral administration

  17. 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)

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