Antihypertensive Agents PDF

Antihypertensive Agents HUSSEIN HALLAK, PH.D. AL-QUDS UNIVERSITY  Hypertension DEFINITION: RAISED ARTERIAL BLOOD PRESSURE ABOVE "NORMAL" Current Criteria for Adults Systolic - > 140 mm Hg and/or Diastolic - > 90 mm Hg Prevalence: about 25% of US population I...

Antihypertensive Agents HUSSEIN HALLAK, PH.D. AL-QUDS UNIVERSITY  Hypertension DEFINITION: RAISED ARTERIAL BLOOD PRESSURE ABOVE "NORMAL" Current Criteria for Adults Systolic - > 140 mm Hg and/or Diastolic - > 90 mm Hg Prevalence: about 25% of US population Incidence increases with age Types of Hypertension Primary or “essential” ◦ Unknown cause ◦ 90 percent of all patients ◦ Drugs main therapy Secondary ◦ 10 percent of all patients ◦ Identifiable cause  Secondary Hypertension ▪Renal vascular disease ▪Primary and secondary aldosteronism ▪Pheochromocytoma ▪Drugs - e.g., oral contraceptives, sympathomimetics and drugs of abuse Why reduce high blood pressure? Slow or interrupt progressive tissue and organ damage ◦ Brain ◦ Eyes ◦ Kidney ◦ Heart Prolongs life – no question!  Treatment Rationale Long-term goal of antihypertensive therapy: Reduce mortality due to hypertension-induced disease ◦ Stroke ◦ Congestive heart failure ◦ Coronary artery disease ◦ Nephropathy ◦ Peripheral artery disease ◦ Retinopathy Major Risk Factors That Increase Mortality in Hypertension Smoking Dyslipidemias Diabetes Mellitus Age >60 Gender: men, postmenopausal women Family history Current problems Awareness - no symptoms Treatment problems ◦ Inappropriate prescribing ◦ Patient noncompliance - 10 percent of hypertension patients stop taking their medication Control - Complex drug treatment Awareness, treatment and control have not changed significantly in past several years  Non-pharmacological Interventions Diet. Stress reduction. Regular aerobic exercise. Weight reduction (if required). Control of other risk factors (blood lipids, smoking).  Non-pharmacological Interventions Diet involves several aspects that may include: ◦Reduction of sodium intake. ◦Caloric restriction for obese patients. ◦Restriction of cholesterol and saturated fat intake. Blood Pressure = Cardiac Output (x) Total Peripheral Resistance Cardiac Output = Heart Rate (x) Stroke Volume Reduce cardiac output (ß- blockers, Ca2+ channel blockers) Reduce plasma volume (diuretics) Reduce peripheral vascular resistance (vasodilators) MAP = CO X TPR  Reflex control Baroreceptor mechanism ◦Pressure sensing areas throughout the CV system ◦Alters autonomic outflow ◦Acts minute by minute Renin-angiotensin ◦Acts long-term (weeks/months)  Renin-Angiotensin System Liver Angiotensinogen Kidney Renin Increased Angiotensin I Increase BP Vas. Res. ACE Increased Cardiac Output Angiotensin II Increased Salt & Water Blood Volume Aldosterone Retention Medications Used to Treat Hypertension Adrenergic agents Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers Calcium channel blockers Diuretics Vasodilators Adrenoceptor Antagonists Alpha blockers ◦ Non-selective – block both Alpha-1 and Alpha-2 receptors ◦ Selective – selectively block alpha-1 receptors Beta Blockers ◦ non-selective ◦ selective ◦ Intrinsic sympathomimetic activity (ISA) Alpha Blockers: Nonselective Nonselective alpha blockers – e.g. Phenoxybenzamine: irreversible inhibitor Phentolamine: reversible Major side-effect: postural hypotension Uses ◦ Excessive sympathetic tone ◦ High circulating levels of adrenergic agonists  Alpha-1 Blockers: Selective agents Examples - ◦ Prazosin ◦ Terazosin ◦ Doxazosin Selective blockade of postsynaptic alpha-1 receptors Reduce arterial resistance and expands venous capacitance  BPH Tamsulosin (extended-release tablets): ◦ a selective α1 receptor antagonist that has preferential selectivity for the α1A receptor in the prostate versus the α1B receptor in the blood vessels Selective Alpha Blockers Side- effects "First dose effect" i.e. syncope 1 to 3 hrs after first dose or when the dosage is adjusted upward during therapy Beta Blockers ▪Nonselective – both beta receptors ▪Cardioselective - 1 > 2 ▪Intrinsic sympathomimetic activity (ISA) Beta Blockers: Nonselective Block ◦ Beta-1 – mainly in the heart ◦ Beta-2 - in bronchi and skeletal muscle vasculature Examples: ◦ Propranolol (mainly eliminated by metabolism) ◦ Nadolol (mainly eliminated by kidney) ◦ Timolol (eye drops for Glaucoma) ◦ Labetolol (hypertension during pregnancy)  Propranolol Uses ◦ in mild/moderate Hypertension ◦ to block tachycardia caused by direct vasodilators Does not usually produce postural hypotension Variable response: Blood levels do not follow antihypertensive effects Wide dosing differences between patients Given once or twice daily  Beta Blocker Potential Mechanisms 1. Decreased cardiac output (usually compensated by reflexes) 2. Reduced renin release (more effective in patients with high renin HTN) 3. Changes in transmitter release or storage Side Effects of Propranolol ◦ CNS – nightmares, sexual dysfunction, sedation ◦ May increase plasma Triglycerides and decrease HDL ◦ Nausea, diarrhea, vomiting ◦ Withdrawal syndrome possible – nervousness, tachycardia, HTN, MI Beta Blockers: Selective Provide relatively selective beta-1 blockade in lower doses Block both 1 and 2 at higher therapeutic doses Example: ◦ Atenolol ◦ Bisoprolol ◦ Metoprolol ◦ Others: Esmolol, Betaxolol Beta Blockers with Sympathetic Activity Blocks Beta receptor Possesses intrinsic activity (they are partial agonists) Examples ◦Nonselective - Pindolol ◦Selective – Acebutolol  Beta Blocker Contraindications Unstable diabetes mellitus ◦ Prolong hypoglycemia – blocks physiological response to hypoglycemia ◦ Mask symptoms of tachycardia Bronchospastic disease – never use beta blockers, not even selectives AV block Central Nervous System: Sympathoplegics Clonidine Methyldopa Guanabenz Guanfacine  Clonidine Full agonist at Alpha-2 receptors and partial agonist at Alpha-1 receptors Alpha-2 agonist in the CNS which lowers sympathetic nervous outflow Reflexes are maintained - minimal postural hypotension Lowers CO more than TPVR Clonidine Relatively short half-life (2 to 4 hours) and may be given BID Available as a transdermal patch ◦ lasts for 7 days ◦ increases compliance ◦ said to provide smoother BP control ◦ fewer side effects Clonidine: Major side-effects Sedation Dry mouth Withdrawal syndrome – after missing one or two doses ◦ headache, apprehension, tremors ◦ sweating, tachycardia ◦ hypertensive crisis Methyldopa Chemically similar to precursors of NE Converted in adrenergic nerve terminals to alpha- methyl-norepinephrine (-MNE) -MNE handled like NE by the adrenergic neuron ie., stored and released -MNE is a better agonist at alpha-2 than alpha-1 receptors  tyrosine hydroxylase tyrosine DOPA methyldopa DOPA decarboxylase dopamine OR  - methyldopamine dopamine beta hydroxylase norepinephrine OR  - methylnorepinephrine  Methyldopa ® (Aldomet ) Acts in the brain to lower BP Also appears to lower TPVR more than CO CV reflexes remain intact Postural hypotension usually only occurs in volume- depleted patients Advantage: reduces renal vascular resistance  Methyldopa (Aldomet®) A favorite during pregnancy (other options during pregnancy include labetalol or nifedipine) Side Effects: Dry mouth Sedation Altered AST/ALT — monitor (potentially hepatotoxic). Fever that mimics sepsis  Calcium Channel Blockers They antagonize Ca++ movement across cell membranes Smooth muscle cells require extracellular Ca++ for contraction Other names: ◦ Slow Ca++ channel blockers ◦ Ca++ channel antagonists ◦ Ca++ entry blockers  Two Groups Dihydropyridines - primary action on arterioles ◦ Nifedipine ◦ Nimodipine ◦ Amlodipine (Norvac®) ◦ Felodipine ◦ Isradipine ◦ Non-dihydropyridines Diliazem, Verapamil - primary action on heart  Vascular effects Dihydropyridines ◦ relax arteries and arterioles > veins ◦ fall in BP due to reduced TPVR ◦ reflex tachycardia Non-Dihydropyridines Verapamil and Diltiazem - lesser effect on arterioles and more depression of heart  Cardiac effects Verapamil and Diltiazem reduce Ca++ entry in the heart ◦ slow pacemaker - HR decreases ◦ slow AV conduction ◦ lessen strength of contraction - decreased stroke volume Dihydropyridines have minimal effects on Ca++ entry in heart muscle Summary ◦ Verapamil and Diltiazem affect heart more than arterioles ◦ Dihydropyridines (e.g. nifedipine, amlodipine) affect arterioles more than heart  Use of Ca++Channel Blockers Used alone or in combination Magnitude of effect determined by pretreatment BP BP effects seen in 3 to 4 weeks Especially effective for black patients ◦ Nifedipine available as sustained release formulation, rapid release associated with higher MI events  Ca++ Channel Blocker Adverse Effects constipation headache dizziness hypotension peripheral edema (swelling of ankles) induction of heart failure possible Inhibitors of Angiotensin About 20% of hypertension patients have HIGH renin activity ◦ respond well to beta blockers ◦ respond well to angiotensin blockers About 20% of hypertension patients have LOW renin activity ◦ respond poorly to beta blockers ◦ respond poorly to angiotensin blockers  Renin-Angiotensin System Liver Angiotensinogen Kidney Renin Increased Angiotensin I Increase BP Vas. Res. ACE Increased Cardiac Output Angiotensin II Increased Salt & Water Blood Volume Aldosterone Retention  The Renin-Angiotensin System ◦ Renin release from the juxtaglomerular cell ◦ Renin acts upon angiotensinogen to form angiotensin I ◦ Angiotensin I is converted to angiotensin II by a converting enzyme called ACE Angiotensin II releases aldosterone Aldosterone enhances Na+ and H2O retention and K+ loss from the kidney  Angiotensin II Effects on the Kidney ◦ Angiotensin II constricts the renal efferent more than afferent arteriole ◦ Increases or maintains glomerular filtration pressure ◦ Increased angiotensin II levels is often a physiological response to renal artery stenosis ACE inhibitors Block Angiotensin Converting Enzyme (ACE) ◦ reduces angiotensin II levels ◦ reduces the vasoconstrictor effects of AT-II ◦ reduces aldosterone levels ◦ Blocks breakdown of bradykinin (a potent vasodilator) ◦ Hypotensive actions presumably result from both ACE inhibition and Bradykinin buildup  ACE inhibitors BP decreases MAINLY by lowered TPVR CO is usually NOT significantly affected for some reason, reflex sympathetic stimulation DOES NOT OCCUR absence of cardio-stimulation makes these drugs safe in patients with ischemia  ACE Inhibitors Several drugs available Block ACE Blocks breakdown of bradykinin (a potent vasodilator) Hypotensive actions presumably result from both ACE inhibition and Bradykinin buildup Captopril (Capoten®) is a direct ACE blocker ACE Inhibitors Captopril: is a direct ACE blocker Enalapril is a prodrug ◦ Converted the active drug, enalaprilat Lisinopril is a lysine derivative of enalaprilat Benazepril, Fosinopril, Moexipril, Quinapril and Ramipril are long-acting, prodrugs  ACE Inhibitors Side Effects Angioedema – life-threatening Severe hypotension in volume depleted patients Acute renal failure ◦ bilateral renal artery stenosis ◦ stenosis of the renal artery of a solitary kidney Hyperkalemia ACE Inhibitors Side Effects Dry, non-productive cough – 25% incidence Alteration of taste Allergic skin rashes, drug fevers Absolutely contraindicated during 2nd and 3rd trimesters of pregnancy ◦ fetal hypotension ◦ fetal renal failure ◦ fetal malformation or death FDA Pregnancy Risk Categories Category A Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).... Category B Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well- controlled studies in pregnant women. Category C Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well- controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Category D There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Category X Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.  ACE Inhibitors Therapeutic Use Hypertension: lowers BP with relatively few side-effects Diabetic nephropathy ◦ decreases glomerular efferent resistance ◦ lowers intraglomerular pressure ◦ diminishes proteinuria ◦ preserves kidney structure and function Heart failure ◦ improves cardiac efficiency & reduces symptoms ◦ may slow hypertrophy  BENEDICT trial – Prevention of microalbuminuria in type 2 diabetes Ruggenenti, New Engl J Med (2004) 351:1941 Presentation Title 58 Date  Angiotensin Receptor Blockers Losartan (Cozaar®) Valsartan (Diovan®) Irbesartan Candesartan ◦ Agents block angiotensin type 1 receptors ◦ Have no effect on bradykinin metabolism ◦ Probably reduced cough and angioedema possibilities ◦ Contraindicated during pregnancy  Thiazide Diuretics Hydrochlorothiazide Chlorothiazide Actions Prevents Sodium reabsorption in the nephrons ◦ Initial ◦ Decreased blood volume ◦ Decreased CO ◦ Chronic – 6 to 8 weeks ◦ CO normalizes ◦ TPVR falls Thiazides Effect Mild: reduces BP 10 to 15 mm Hg Use in hypertension ◦ Alone - in mild hypertension ◦ More often used in combination – makes BP more dependent on sympathetic tone BP effects not continuous with dose Potassium Sparing Diuretics Spironolactone (Aldactone) - aldosterone antagonist Triamterene (Dyrenium) - mechanism unknown Can be found combined with thiazides in commercial preparations Loop Diuretics Examples ◦ Furosemide (Lasix) ◦ Ethacrynic acid (Edecrin) ◦ Torsemide (Demadex), etc. Use in Heart Failure ◦ patients with refractory edema ◦ patients in renal failure (GFR < 30 ml/min) ◦ BP lowering is continuous with dose Drug Therapy: things to consider ◦ lifelong disease with few symptoms ◦ symptoms only occur after years ◦ drugs must be taken daily ◦ drugs are sometimes expensive ◦ drugs can produce side-effects Diagnosis must be confirmed (not diagnosed on a single BP reading)  Drug Therapy: things to consider Patient must be educated on importance of treatment Choose the “drug(s) of choice” ◦ level of BP ◦ presence of end-organ damage ◦ age, sex, race ◦ lifestyle ◦ socioeconomic status ◦ expected compliance ◦ presence of other diseases Concomitant Disease 1. Diabetes – ACEI, CB 2. Congestive Heart Failure - ACEI 3. Angina -  blocker, CB 4. Dyslipidemia - blocker 5. Migraine -  Blocker 6. Osteoporosis -Thiazide 7. Essential tremor -  blocker 8. BPH -  Blocker Drug Therapy Initial monotherapy ◦ Diuretics* ◦ ACE inhibitors or ARB ◦ Calcium channel antagonists ◦ Beta blockers* ◦ Alpha-1 blockers Multiple drug therapy - when necessary * Shown to reduce morbidity & mortality  Rationale for Multiple Drug Therapy Additive effects Better BP lowering. Reduced side-effects Combat drug resistance  Rational Combinations ◦ Don’t give two drugs with similar mechanisms ◦ A thiazide is almost always additive with any other drug ◦ Combine drugs to reduce reflex responses ◦ Use drugs that might treat other diseases in a particular patient Vasodilators Two Types ◦ Arteriolar Hydralazine Minoxidil Diazoxide ◦ Arteriolar and Venular Nitroprusside Arteriolar Vasodilators Relax resistance vessels (arterioles) Vascular Resistance and CO maintained Relatively little postural hypotension Will elicit reflex tachycardia and water retention Examples: ◦ Hydralazine ◦ Minoxidil  Hydralazine Mechanisms ◦ generates NO near arterioles ◦ NO produces vasodilation Metabolized in part by acetylation ◦ rapid and slow acetylators among Caucasians Major side effects: ◦ salt and water retention ◦ reflex tachycardia ◦ lupus-like syndrome (higher incidence in genetically slow acetylators)  Minoxidil Mechanisms: Opens K+ channels in vascular smooth muscle Major side-effects: ◦ severe salt and water retention ◦ hypertrichosis ◦ reflex tachycardia More efficacious than hydralazine Must be used with a diuretic and sympatholytic (e.g. a beta blocker)  Hypertensive Emergencies Relatively rare Sudden, severe elevation of BP is life-threatening Most often occurs in ◦ Patient with severe, poorly controlled hypertension ◦ Patients who discontinue antihypertensives abruptly progressive vascular damage hemodynamic complications (stroke, cardiac failure, aneurysm) CNS signs severe headache mental confusion blurred vision, nausea, vomiting May progress to coma and death  Nitroprusside Major arteriolar and venular dilator Chemical name is Sodium Nitroferricyanide Releases NO when in contact with red blood cell Produces dilation of veins and arteries Rapid onset and short duration ◦ Reflex tachycardia, patient should be recumbent Given by carefully regulated IV infusion Acts within minutes; 1 to 10 mins duration upon termination of i.v. drip  Nitroprusside BP lowering effects have no floor Careful monitoring of the patient is essential!!! Converted to cyanide – monitor CN- after 2 or 3 days of use Major side effect: excessive blood pressure lowering Degraded by light. Cover IV bottle with foil; replace solutions after several hrs. Alternatives for Hypertensive Emergencies ◦ Labetalol: IV bolus or infusion Does not produce reflux tachycardia Same contraindications as β–blockers Longer t½, does not allow rapid titration ◦ Nicardipine: IV infusion Calcium channel blocker Longer t½, does not allow rapid titration