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1、Antihypertensive Agents,Zhu Yi Zhun, Dept. of Pharmacology, SPFDU Email: ,Hypertension,e.g. 5 millions Americans have hypertension.,Incidence: 10-20% in adults,68% are aware of their diagnosis. 53% are receiving treatment.,Only 27% are under control of the 140/90 mm Hg threshold.,Hypertension,is usu
2、ally asymptomatic,Therefore, it is important to treat hypertension and reduce mortality and morbidity of these conditions,End organ damage,is associated with increased risk from ischemic heart disease, cerebrovascular accidents, heart and renal failure.,Complications of untreated hypertension,Hypert
3、ensive cardiovascular disease Hypertensive cerebrovascular disease and dementia Hypertensive renal disease Aortic dissection Atherosclerotic complication,Classification of Hypertension,- Primary (Essential) Hypertension (PH): About 90%-95%. Onset 25-55 years. No cause can be established for 95% case
4、s of PH.,- Secondary Hypertension (SH): About 5%-10%. Cause: Renal disease Hormonal (e.g. Estrogen) therapy Renal vascular hypertension Hypertension associated with pregnancy Hypercalcemia, hyper- or hypothyroidism etc.,Classification of Blood Pressure,BP= CO x PVR CO: Cardiac Output; PVR: Periphera
5、l Vascular Resistance.,Regulation of Blood Pressure,Adrenoceptors,Brain Stem,Sympathetic Stimulation,Peripheral Resistance ,BP ,Cardiac Output ,Renin,Renal blood flow ,Angiotensinogen,Angiotensin I,Aldosterone,Sodium Retension,Angiotensin II,BP= CO x PVR,Regulation of Blood Pressure,Adrenoceptors,Br
6、ain Stem,Sympathetic Stimulation,Peripheral Resistance ,BP ,Cardiac Output ,Renin,Renal blood flow ,Angiotensinogen,Angiotensin I,Aldosterone,Sodium Retension,Vasodilator,Sympatholytic drugs,Angiotensin II,ACE inhibitors,Diuretics,ANG II blocker,-blocker,BP,Diagnosis of Hypertension,is based on repe
7、ated, reproducible measurements of elevated blood pressure. BP 140/90 mm Hg,Management of Hypertension,Antihypertensive Therapy,-blocker,Ca-Blocker,BP,Diuretics,Alternative Medicine,ACEI: angiotensin-converting Enzyme inhibitor A II ant: angiotensin II receptor antagonist,ACEI AII ant.,RENIN-ANGIOTE
8、NSIN SYSTEM (RAS),ANGIOTENSINOGEN,ANGIOTENSIN I,ANGIOTENSIN II,AT 1 RECEPTOR,AT 2 RECEPTOR,ACE,RENIN,KININOGENS,BRADYKININ,INACTIVE METABOLITES,KALLIKREINS,ACE: Angiotensin Converting Enzyme,ACE inhibitor,ANG II blocker,ACE INHIBITOR,Originally found in snake venom The synthesized inhibitors are com
9、petitive inhibitor tightly bound to the Zn2+ ions of the ACE preventing the access of the ACE substrates to the active site of ACE Inhibit Angiotensin II synthesis Inhibit Bradykinin degradation Captopril was the 1st ACE inhibitor introduced to the market. Ramipril, Enalapril, Moexipril, Lisinopril
10、etc. have been synthesized thereafter.,Mechanisms of ACE inhibitors on blood pressure reduction,Inhibit the normal conversion of circulating angiotensin-I to angiotensin-II Reduce the secretion of aldosterone to induce a natriuresis Specific renal vasodilation may enhance natriuresis The inactivatio
11、n of vasodilatory bradykinins is reduced Inhibit local formation of angiotensin-II in vascular tissue and in myocardium. Improve insulin resistance,ACE INHIBITORS,Class I,Class II,Class II,Class II,Class II,Class II,Class III: Lisinopril, water-soluble,Class I: 1st ACE inhibitor,Class II: pro-drug,
12、only active once converted to the diacid. E.g. EnalaprilEnalaprilat; Ramipril Ramiprilat,Indications,* Hypertension (e.g. usual daily dose of Captopril 25-50 mg),* Acute myocardial infarction (e.g. initial dose of Captopril 6.25 mg),* Postinfarct congestive heart failure (e.g. maintenance dose of Ca
13、ptopril up to 50 mg),* Left ventricle dysfunction (e.g. maintenance dose of Captopril up to 50 mg),Contraindications and side-effects of ACE inhibitors,Contraindications: Renal-bilateral renal artery stenosis or equivalent lesions Hypotension Pregnancy Side-effects: Cough-common Hypotension-variable
14、 Angioedema- rare Renal failure rare Hyperkalemia- rare Skin reactions- rare,Captopril (Captone),Pharmacokinetics: metabolized by the liver and kidney Half-life 4-6 hours Dose: for hypertension, 25-50 mg orally (average daily ). for CHF, an initial test dose of 6.25 mg is required. maintenance dose
15、daily 37.5 to 150 mg.,Enalapril (Vasotec),Pharmacokinetics: About 60% of oral dose is absorbed. De-esterified in the liver and kidney to the active form Half-life 4-5 hours in hypertension patients and 7-8 in CHF. Dose: for hypertension, 2.5- 20 mg orally as 1 or 2 daily. for CHF, an initial test do
16、se of 2.5 mg twice daily is required. maintenance dose daily up to 10 mg twice.,Losartan (Cozaar),* A new class of nonpeptide angiotensin II blocker * A specific competitive antagonist of Angiotensin II AT1 receptor * Orally active and does not exhibit agonist activity Indication: Hypertension Congestive heart failure Side-effect: Headache,Management of Hypertension,Antihypertensive Therapy,-blocker,Ca-Blocker,BP,Diuretic
