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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: igorucla.edu,RENIN-ANGIOTENSIN SYSTEM,Control of renin secretion: Mechanical Ionic NE release,- plays a major role in the regulation of hemodynamics and water a
2、nd 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 angio
3、tensin II, but its 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 deg
4、radation 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,
5、ANGIOTENSIN II,Altered,Peripheral,Resistance,Altered,Renal,Function,Altered,Cardiovascular,Structure,Rapid Pressor Response,Slow Pressor Response,Vascular + Cardiac,Hypertrophy + Remodeling,I. Direct vasoconstriction,II. Enhancement of,peripheral noradrenergic,neurotransmission,III. Increased sympat
6、hetic,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
7、. Increased vascular,wall tension,ACE Inhibitors,Active molecules: Captopril, Lisinopril, EnalaprilatProdrugs: Enalapril, Benazepril, Fosinopril, Quinapril, Ramipril, Moexipril, Spirapril,Beneficial effects in: Hypertension CHF,Adverse effects of ACE Inhibitors,Hypotension Renal insufficiency Cough
8、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 e
9、ffectsCell growth effectsLack 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
10、 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
11、 disease Angina pectoris Myocardial infarction 2 renovascular hypertension Peripheral vascular insufficiency Cerebral thrombosis - stroke,Hypertension,Atherosclerosis,Age Sex Race Hyperlipoproteinemia Diabetes mellitus Cigarette smoking,Obesity Salt intake Previous cardiovascular disease Family hist
12、ory of cardiovascular disease,Risk factors for cardiovascular complications in hypertensive subjects, cardiac output (-blockers, Ca2+ channel blockers) plasma volume (diuretics) peripheral vascular resistance (vasodilators),MAP = CO X TPR,Pharmacotherapy,Non-pharmacological,TREATMENT OF HYPERTENSION
13、,Restriction of salt intakeReduction of body weight,“Individualized Care“,Risk factors considered Non-pharmacological therapy tried first Monotherapy is instituted Considerations for choice of initial monotherapy:Renin statusCoexisting cardiovascular conditionsOther conditions,ACE inhibitors ATII an
14、tagonists Diuretics -adrenoceptor blockersa1-adrenoceptor blockers Ca2+ 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,Angiote
15、nsin II receptor,antagonists,Losartan,Valsartan,Ca2+-channel blockers,Dihydropyridines,Verapamil,Diltiazem,K+-channel activators,Minoxidil,Diazoxide,Activators of the,NO/guanylate cyclase pathway,Hydralazine,Nitroglycerin,Nitroprusside,a,-Adrenoceptor,antagonists,Prazosin,Terazosin,K+,Ca2+,NO,HYPERT
16、ENSIVE 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 hypotentio
17、n (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),
