Antihypertensive Agents Zhu Yi Zhun, Dept. of Pharmacology, SPFDU Email: zhuyz@fwww.book118.com Hypertension e.g. 5 millions Americans have 	hypertension. 		 Hypertension is usually asymptomatic Complications of untreated hypertension Hypertensive cardiovascular disease Hypertensive cerebrovascular disease and dementia Hypertensive renal disease Aortic dissection Atherosclerotic complication Classification of Hypertension Classification of Blood Pressure Regulation of Blood Pressure Regulation of Blood Pressure Diagnosis of Hypertension is based on repeated, reproducible measurements of elevated blood pressure. BP 140/90 mm Hg Management of Hypertension Antihypertensive Therapy RENIN-ANGIOTENSIN SYSTEM (RAS) ACE INHIBITOR Originally found in snake venom The synthesized inhibitors are competitive 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 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 inactivation of vasodilatory bradykinins is reduced Inhibit local formation of angiotensin-II in vascular tissue and in myocardium. Improve insulin resistance ACE INHIBITORS Indications * Hypertension 		(e.g. usual daily dose of Captopril 25-50 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 		Angioedema-- rare 		Renal failure–rare 		Hyperkalemia-- rare 		Skin reactions-- rare 		 		 Captopril (Captone) Enalapril (Vasotec) Losartan (Cozaar) Management of Hypertension Antihypertensive Therapy Water excretion Diurectics Continue to be used as first-line therapy for hypertension Class of the diuretics * Carbonic anhydrase inhibitors (e.g. acetazolamide) Pharmacokinetics : absorbed rapidly; Diuretic response extremely rapid following intravenous injection (3min); 30-90 min if by orally; t1/2 depends on renal function Contraindication : *Renal edema with poor renal function *Hypokalemia *Ventricular arrhythmias *Cotherapy with proarrhythmia drugs Management of Hypertension Antihypertensive Therapy Calcium channel blocking drugs * Effects of all types of calcium blockers is the inhibition of the L-calcium current in arterial smooth muscle 	 Calcium channel blocking drugs Pharmacokinetics: 	orally active agents, high first-pass effect, high plasma protein binding, and extensive metabolism	 Indications: 	Hypertension 	Chronic stable angina, unstable angina 	Superaventricular Arrhythmias 	Others: hypertrophic cardiomyopathy, migraine and atherosclerosis. Management of Hypertension Antihypertensive Therapy * Metoprolol, atenolol, and betaxolol are members of 1-selective group 	 Pharmacokinetics: 	well absorbed after oral administration; peak concentrations after 1-3 h ingestion; high hepatic metabolism; low bioavailablity; rapid distribution Indications: 	Hypertension 	Ischemic heart disease 	Cardiac arrhythmias 	Others cardiovascular disorders: increasing stroke volume (in patients with obstructive cardiomyopathy), congestive heart failure (in certain carefully selected patients) 	Glaucoma, Hyperthroidism, Neurologic diseases Other antihypertensive agentsSodium nitroprusside Is a powerful parenterally administered vasodilator Is used to treat hypertensive emergencies and severe cardiac failure Dilates both arterial and venous vessels Rapid onset of effect (i.v.) and very short duration of action (effect disappear within 1-10 min after discontinuation) * Verapamil, the first clinical useful drug of calcium channel blockers 	 * Nifidipine, the most extensively studied of this group 	 * Diltiazem, very popular and available worldwide 	 Pharmacodynamics: 	mechanism of action: blocking L-type calcium channel 	organ system effect: relaxing smooth muscle (VSM most sensitive); reducing cardiac contractility or decreasing cardiac output; BP= CO x PVR Calcium channel blocking drugs Side-effects 	Headache, facial flushing, dizziness, and constipation (but Nifedipine not ) -blocker Ca-Blocker BP Diuretics Alternative Medicine ACEI: angiotensin-converting Enzyme inhibitor A II ant: angiotensin II receptor antagonist ACEI AII ant. -adrenoceptor blocking drugs * Propranolol, prototype -blocking drug 	 * Useful in the management of angina pectoris (decrease myocardial oxygen demand) 	 * Timolol, Nadolol, and Carteolol are nonselective agents 	 * Pindolol, acebutolol, carteolol have partial -agonist activity 	 * Celiprolol, 1-selective antagonist with a modest capacity to activate 2-receptors 	 -adrenoceptor blocking drugs Pharmacodynamics: 	Effects on cardiovascular system: lowering BP (effects on heart, blood vessels, RAS, CNS) 	Effects on Respiratory tract: increasing resistance in airway by blocking 2-receptors in bronchial smooth muscle. 1-selective antagonists have some advantage over nonselective -antagonists. All -blockers should be avoided in patients with asthma!!! Effects on the eye; Metabolic and endocrine effects; Local anesthetic effect (membrane stabilizing) -adrenoceptor blocking drugs Side-effects Worsening of preexisting asthma and other forms of airway obstruction (nonselective agents due to 2 blockade); Rash, fever, sedation, sleep disturbance, and even depression End ! * 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. 		 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. -- Primary (Essential) Hypertension (PH): 	About 90%-95%. Onset 25-55 years. 	No cause can be established for 95% cases 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. 	 BP= CO x PVR 	 CO: Cardiac Output; 			 PVR: Peripheral Vascular Resistance. 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 Adrenoceptors Brain 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 -blocker Ca-Blocker BP Diuretics Alternative Medicine ACEI: angiotensin-converting Enzyme inhibitor A II ant: angiotensin II receptor antagonist ACEI AII ant. 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 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, only active once converted to the diacid. E.g. Enalapril Enalaprilat; Ramipril Ramiprilat * Acute myocardial infarction 		(e.g. initial dose of Captopril 6.25 mg) * Postinfarct congestive heart failure 		(e.g. maintenance dose of Captopril up to 50 mg) * Left ventricle dysfunction 		 (e.g. maintenance dose of Captopril up to 50 mg) 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 daily 37.5 to 150 mg. 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