Antihypertensive Drugs PDF

Antihypertensive Drugs Kenza E. Benzeroual, B.S, M.S., Ph.D. [email protected] 1  Antihypertensive Agents § Drugs interfering with storage vesicles § Reserpine § Drugs Altering Sympathetic Activity § a2 agonists: clonidine and...

Antihypertensive Drugs Kenza E. Benzeroual, B.S, M.S., Ph.D. [email protected] 1  Antihypertensive Agents § Drugs interfering with storage vesicles § Reserpine § Drugs Altering Sympathetic Activity § a2 agonists: clonidine and methyldopa § ᾳ-antagonist: prazosin, doxazosin, terazosin, tamsulosin § b-blockers: metoprolol, acebutolol, atenolol § Direct-Acting Vasodilators § Hydralazine, Minoxidil and Nitroprusside 2  Antihypertensive Agents § Calcium Channel Blockers § Dihydropyridine (DPH): Nifedipine and amlodipine § Non-DPH: Verapamil and Diltiazem § Diuretics § Thiazides, loop diuretics, potassium-sparring diuretics § Angiotensin converting enzyme inhibitors (ACEIs) § captopril, enalapril, lisinopril § Angiotensin receptor blockers (ARBs) § Losartan, valsartan, telmisartan 3 Drug Strategy for Treating Hypertension § BP= CO x TPR § ¯ Sympathetic tone: § ¯ TPR (α-blockers, vasodilators); ¯ CO (β-blockers) § ¯ body fluid volume (diuretics) § ¯ Angiotensin effects § Compensatory responses to some drugs: Reflex tachycardia and Reflexive Edema § Why? And How can you work around this problem? 4  mecamylamine Modified from Katzung, Masters and Trevor Basic and Clinical Pharmacology, 11th Edition. McGraw Hill, 5 Drugs Altering Sympathetic Activity: a2 agonists a2 agonists: Reduce sympathetic outflow from vasopressor centers in the brainstem. Clonidine methyldopa a2 receptor activation in the CNS ¯ CO and ¯ TPR by inhibiting sympathetic outflow (shut off the sympathetic nervous system). 6  a2-agonists By activating α2-adrenoceptors in the brain, clonidine and α-methyl- dopa shut down sympathetic activity in the periphery. 7  a2-agonists Uses: Mild-to-moderate hypertension Opiate withdrawal (clonidine patch) Hypertensive management in pregnancy (methyldopa) Side effects of a2 receptor agonists: Risk for hemolytic anemia detected by positive Coombs test (methyldopa) CNS depression Edema Rebound HTN upon abrupt withdrawal (treat with phentolamine and propranolol) 8 Drugs Altering Sympathetic Activity: a1 blockers § a1- blockers: Prazosin; Doxazosin (Cardura); Terazosin, Tamsulosin § Relax both arterial and venous smooth muscle. § ¯ arteriolar and venous resistance § Reflex tachycardia § Uses: Hypertension, benign prostatic hyperplasia (BPH) (Tamsulosin) § Side effects: § ‘First-dose syncope, Orthostatic hypotension § Advantage: favorable effect on lipid profile (↓ LDL while ↑ HDL levels). 9  Drugs Altering Sympathetic Activity: b blockers b-blockers: block β-adrenoceptors; ↓ CO and ↓ renin Side effects- unfavorable lipid profile § Caution in use – use non-selective β-blockers with caution in patients with diabetes, peripheral vasculature disease (Raynaud’s) and asthma/COPD. § Use ISA (pindolol or acebutolol) or cardioselective agents (acebutolol, atenolol or metoprolol) in these patients - they produce fewer respiratory and vascular effects. 10  BP = CO x TPR R. Harvey & P. Champe, Pharmacology, 4th edition 11  b-Blockers Drugs b1-Selective ISA Propranolol Acebutolol Yes Yes Atenolol Yes Esmolol Yes Labetalol **spelling) Metoprolol Yes Nadolol Pindolol Yes Timolol 12  b-Blockers β-Blockers with Unique Properties Labetalol – HTN Carvedilol – (notice spelling) – for HF antagonize α1, ß1 and ß2 adrenoceptors Clinical Uses: angina, hypertension 13  Vasodilators § Direct-acting vasodilators: § Oral vasodilators: § Hydralazine (Apresoline) and Minoxidil (Loniten) are used for long term outpatient therapy of HTN. § The parenteral vasodilators: § Nitroprusside, Diazoxide, and Fenoldopam, are used to treat hypertensive emergencies § Calcium channel blockers (CCBs) are used in both. § All vasodilators produce relaxation of vascular smooth muscle which decreases resistance and PB 14  Vasodilators Direct-Acting Vasodilators Modified from Table 11-3 in Masters and Trevor Basic and Clinical Pharmacology, 11th Edition. McGraw Hill, a Lange Medical Book. 15  Hydralazine Hydralazine releases nitric NO from endothelial cells ↓ TPR via arteriolar dilation Use: moderate-to-severe hypertension Side effects: Drug-induced lupus erythematosus (DILE) in slow acetylators Edema Reflex tachycardia Administer b-blockers and diuretics as concomitant therapy to counter the reflex tachycardia and edema, respectively. 16 17 Compensatory Responses to reduced BP Katzung, Masters and Trevor Basic and Clinical Pharmacology, 11th Edition. McGraw Hill, a Lange Medical Book. 18  Direct-Acting Vasodilators Minoxidil Uses: § Hypertensive emergencies (diazoxide, parenteral) § Severe hypertension (minoxidil) § Baldness (topical minoxidil) Side effects: § Hypertrichosis (minoxidil) § Hyperglycemia (¯ insulin release - diazoxide) § Tachycardia, edema 19  Direct-Acting Vasodilators Nitroprusside Nitroprusside - available parenterally No is released from the drug ¯ TPR via dilation of both arterioles and venules Uses: hypertensive emergencies, heart failure (HF) Side effects: cyanide toxicity - treat with sodium nitrite/sodium thiosulfate 20  Calcium Channel Blockers Calcium Channel Blockers (CCB) Calcium Channel Blockers: Block L-type Ca2+ channels in heart and blood vessels Result in ¯ intracellular Ca++ Cause ¯ CO (verapamil and diltiazem), ¯ TPR (all CCBs) Drugs: Verapamil Diltiazem Nifedipine and Amlodipine - dihydropyridines (-“dipines”, nifedipine is the prototype:)- more effective at blocking Ca++ channels in vasculature 21  Calcium Channel Blockers Calcium Channel Blockers continued. Hypertension - nifedipine Angina and Antiarrhythmics (verapamil, diltiazem) Side effects: Constipation (verapamil) Reflect tachycardia (-“dipine”s), edema Gingival hyperplasia (-“dipine”s; nifedipine, amlodipine) 22 Diuretics effects are on the kidneys and are commonly used in the management of hypertension. Diuretic Class Site of Action Mechanism Loop Diuretics Thick ascending limb of the Inhibition of active salt Furosemide loop of Henle (LH) transport Ethacrynic acid Block Na/K/2Cl transporter Bumetanide Thiazides Early distal tubule: Inhibition of NaCl Hydrochlorothiazide Block Na/Cl transporter reabsorption Chlorthalidone Increases excretion of Indapamide Na, Cl, water, and K (hypokalemia) Potassium-sparing Late distal tubule and cortical Inhibition of Na+ diuretics collecting duct. reabsorption and K+ Spironolactone competitive antagonism of secretion Amiloride aldosterone (spironolactone) (hyperkalemia) Triamterene or by direct action 23 (triamterene or amiloride)  Diuretics Katzung, Masters and Trevor Basic and Clinical Pharmacology, 11th Edition. 24 McGraw Hill, a Lange Medical Book. R. Harvey & P. Champe, Pharmacology, 4th edition 25 Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) B.Katzung, Basic & Clinical Pharmacology, 10th Edition, Chapter 11, figure 11-5 26 Angiotensin Converting Enzyme Inhibitors (ACEIs) Angiotensin Converting Enzyme Inhibitors (ACEIs) Captopril Enalapril Lisinopril § ACEIs block the formation of angiotensin II, preventing vasoconstriction. § ¯ aldosterone release (preventing fluid retention) § Bradykinin is a potent vasodilator. ACEIs prevent bradykinin degradation, potentiating the vasodilatory properties of the compound 27  ACEI’s and ARB’s Angiotensin Receptor Blockers (ARBs) Angiotensin Receptor Blockers (ARBs) Losartan Valsartan Telmisartan § Block AT1 receptors § ARBs do not interfere with bradykinin degradation (and do not induce dry cough) 28 Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) Clinical Uses: Mild-to-moderate hypertension CHF, and after MI Protective of diabetic nephropathy Side effects: Dry cough (ACEIs) Hyperkalemia C/I in bilateral renal artery stenosis Contraindication: pregnancy – renal damage to the fetus 29 Angiotensin II maintains GFR in patients with bilateral renal artery stenosis by constricting the efferent arteriole. ACEIs prevent the synthesis of angiotensin II and can lead to renal failure 30