Renin-Angiotensin System Drugs Igor Spigelman, Ph.D. Division of Oral Biology & Medicine, UCLA School of Dentistry, CA Rm CHS

RENIN-ANGIOTENSIN SYSTEM Control of renin secretion: Mechanical Ionic NE release - 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

RENIN-ANGIOTENSIN SYSTEM Angiotensins I, II & III: Angiotensin I is rapidly converted to angiotensin II. Angiotensin III retains most of aldosterone secretory ability of angiotensin II, but it’s much less potent in stimulating the adrenal medulla and in elevating blood pressure. Angiotensin converting enzyme (ACE): Converts angiotensin I to angiotensin II. Nonspecific, cleaves dipeptides from many substrates (e.g. bradykinin). Aminopeptidases: Nonspecific, involved in degradation of angiotensin II & III.

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

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

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 AT 1 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

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

Mortality Is Related to Blood Pressure

Clinical disorders resulting from hypertension and atherosclerosis 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 HypertensionAtherosclerosis

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

 cardiac output (ß-blockers, Ca 2+ channel blockers)  plasma volume (diuretics)  peripheral vascular resistance (vasodilators) MAP = CO X TPR PharmacotherapyNon-pharmacological TREATMENT OF HYPERTENSION Restriction of salt intake Reduction of body weight

"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

ACE inhibitors ATII antagonists Diuretics  -adrenoceptor blockers  1 -adrenoceptor blockers Ca 2+ channel blockers MONOTHERAPY Centrally acting antihypertensives Guanethidine Minoxidil Hydralazine Drugs used only in combination PHARMACOTHERAPY OF HYPERTENSION

Sites of action of drugs that relax vascular smooth muscle Angiotensin II receptor antagonists Losartan Valsartan Ca 2+ -channel blockers Dihydropyridines Verapamil Diltiazem K + -channel activators Minoxidil Diazoxide Activators of the NO/guanylate cyclase pathway Hydralazine Nitroglycerin Nitroprusside  -Adrenoceptor antagonists Prazosin Terazosin K+K+ Ca 2+ NO

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

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 Ca 2+ channel blockers)