HTN.pptx
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Antihypertensives Advanced Pharmacology Dru Riddle Objectives 1. List the antihypertensive agents used in the clinical management of essential hypertension. 2. Describe the mechanisms of action of the drugs used clinically in the management of essential hypertension. 3. List the advantages, disadv...
Antihypertensives Advanced Pharmacology Dru Riddle Objectives 1. List the antihypertensive agents used in the clinical management of essential hypertension. 2. Describe the mechanisms of action of the drugs used clinically in the management of essential hypertension. 3. List the advantages, disadvantages and possible adverse reactions encountered with each of the antihypertensive agents used in the clinical management of idiopathic hypertension. 4. Correlate the properties of drugs to their use in various types and degrees of hypertension. 5. Describe the rationale for combinations of antihypertensive drugs. 6. List the possible drug interactions encountered with the clinical use of antihypertensive agents. 7. List the agents used in the clinical management of hypertensive crisis. 8. Describe the mechanisms and durations of action of the drugs used in the clinical management of hypertensive crisis. 9. List the adverse reactions encountered with the agents used in the clinical management of hypertensive crisis. Drugs • Diuretics • Thiazides: hydrochlorothiazide, chlorthalidone, indapamide, metolazone • Loops: furosemide, bumetanide, torsemide, ethacrynic acid • K-sparing: spironolactone, eplerenone, amiloride, triamterene Drugs • Ca++ Channel Blockers (CCB) • dihydropyridines (nifedipine, entire series of “ipine” drugs that are generally preferred for treating hypertension over verapamil and diltiazem). • Amlodipine, clevidipine, felodipine, isradipine, nicardipine, nisoldipine • Non-dihydropyridines: verapamil or diltiazem Drugs • Alpha blockers • prazosin, terazosin, doxazosin • Beta Blockers • • • • • • • Propranolol, nadolol, timolol (non-selective) 1st gen Pindolol, penbutolol (non-selective) 1st gen Atenolol, bisoprolol, esmolol, metoprolol, (beta1-selective) 2 nd gen Acebutolol (beta1-selective) 2nd gen Carvedilol (non-selective) 3rd gen Carteolol, labetalol (non-selective) 3° gen Nebivolol (beta1-selective with direct vasodilating (NO) 3rd gen • Alpha/Beta Blockers • labetalol, carvedilol Drugs • Direct renin inhibitor • Aliskiren • ACE Inhibitors • captopril, benazepril, enalapril, fosinopril, lisinopril, moexipril, quinapril, perindopril, ramipril, trandolapril (drugs that end “pril”) • Angiotensin II Receptor Blockers (ARB) • Losartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, valsartan • Arterial Dilators • hydralazine, minoxidil • Arteriovenodilators • nitroprusside, nitroglycerin Drugs • Anti-NE • reserpine • Central Acting • methyldopa • clonidine • Drugs in Hypertensive Crisis • • • • • labetalol nitroprusside nitroglycerin hydralazine fenoldopam Hypertension Defined and Therapy New Guidance on Blood Pressure Management in Low-Risk Adults with Stage 1 Hypertension 2021, American College of Cardiology Identifiable Causes • Sleep apnea • Drug-induced or drug-related • Chronic kidney disease • Primary aldosteronism • Renovascular disease • Chronic steroid therapy and Cushing syndrome • Pheochromocytoma • Coarctation of the aorta • Thyroid or parathyroid disease Non-Drug Treatment • Diet modification • decrease fat (unhealthy?) and cholesterol • decrease Na+ • behavior modification (handle stress better) • avoid tobacco • decrease alcohol intake • decaffeinate the diet (mainly an acute effect) • Exercise and physical activity Hypertension 101 • BP=CO X PVR • Arterial blood pressure is directly proportional to the product of blood flow and resistance to the passage of blood through precapillary arterioles • In order to treat BP, you need to adjust this equation Antihypertensives • In general, drugs will make patients feel worse • Patient compliance is an issue • Lifestyle changes are critical • ACE inhibitors • ARB • Beta-blockers • Calcium-channel blockers • Diuretics (thiazides) • Direct renin inhibitor • Alpha-blockers • Combined alpha/beta blockers • Centrally acting alpha2 agonists • NOT vasodilators BP Control and How to Interfere with that Control • Sympathetics • Moment to moment • Prevent orthostatic hypotension • Deliver blood to skeletal muscles • Renin/Angiotensin II/Aldosterone (RAA) • Key role of ACE = kininase 2 • “On going” tone and volume regulation Katzung, 15th ed., pg. 178 Basic Pharmacology 1. Diuretics: depleting body of sodium and volume 2. Block production/action of angiotensin: reduce peripheral vascular resistance and possible volume 3. Direct vasodilators: reduce pressure by relaxing the vascular smooth muscle 4. Sympathoplegic agents: reducing vascular resistance, inhibiting cardiac function, increasing venous pooling in capacitance vessels • MOA is different, thus combination therapy is often useful Katzung, 15th ed., pg. 180 Diuretics • Remain ’first line’ therapy for many patients • Deplete body of sodium stores • Initially reduce Bp by reducing blood volume and CO • After 6-8 weeks, CO returns to normal with PVR declines • Often seen used in combination with other agents (see a 10-15mmHg drop when used alone) Diuretics: Mechanism of Action • Enhanced Na+ loss leads to: • H2O loss • blood volume • CO effect is usually slight • BP (change is more than can be accounted for from preceding effects) • Chronic effects: • Na loss causes • responsiveness of arterioles to NE • arteriolar resistance Selecting a Diuretic • Usually thiazides first ie. HCTZ, chlorthalidone, or indapamide • least potential for harm • satisfactory for mild and moderate hypertension • Loop diuretics for severe hypertension; used i.v. for hypertensive emergency • K+-sparing in combination with thiazides or loop diuretics Some Side-Effects (all for thiazides; first two for Loop) • Hypokalemia • Hyperuricemia • Hypertriglyceridemia • Hypercholesterolemia • Glucose Intolerance Diuretics: Advantages Frequently effective by themselves Combat Na+ retention (many antihypertensive drugs promote Na+ retention) Potentiate effects of other antihypertensive drugs African-Americans and elderly respond well Minimal hypotension Loop diuretics are effective in renal failure Renin AntagonistAliskiren • Mechanism and Effects • Blocks the action of renin upon conversion of angiotensinogen to angiotensin 1 • Similar in adverse reaction to ACE inhibitors Katzung, 15th ed., pg. 184 ACE Inhibitors Captopril and other “pril” drugs • Mechanism and Effects • Block conversion of angiotensin I to angiotensin II • angiotensin II-mediated release of aldosterone • breakdown of bradykinin • overly active SNS • Overall result is preload, afterload BP Captopril • Uses include • Hypertension • Useful in conditions of renal insufficiency and when plasma renin high (but no clear correlation between plasma renin and antiHTN response) • Preferred in diabetes mellitus (proteinuria) • The preferred drug in HF (will get more coverage of these drugs in HF lecture) Captopril: Advantages • predictable, typically mild, dose-related sideeffects • blunts hypokalemia caused by diuretics • little orthostatic hypotension or SNS activation • no effect on triglycerides, cholesterol Captopril: Disadvantages • Initial dose BP problem, esp. if hypovolemic • cough (3-15%) • skin rashes/neutropenia (is enalapril better than captopril?) • acute renal failure in renal artery stenosis • angioedema • African-Americans and elderly may not respond well (combine with diuretic) • contraindicated in pregnancy • hyperkalemia possible (esp. if combined with other drugs that increase K) Other ACE drugs Enalapril • pro-drug converted to active compound, enalaprilat, in liver by hydrolysis • no SH groups (less allergy?) All other “prils” • pro-drugs ( all except Lisinopril), converted to an active agent in liver • long duration of action Angiotensin II Receptor Antagonists • Losartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, valsartan • Block AT1 subtype of the ATII receptors • Effects and side-effects similar to ACE inhibitors (remember that side-effects are pretty benign), although no cough • Avoid during pregnancy • ACE inhibitors generally prescribed first b adrenergic receptor blockers b-Receptor Review · b1 stimulation causes • • • • • HR contractility AV conduction electrical excitability of the heart renin release · b2 stimulation causes • • • • • bronchodilation arteriole dilation relaxation of the uterus insulin release glycogenolysis b-Blockers Pharmacodynamics • Cardiac function • • • • contractility HR CO Immediate and on going effect • Peripheral Resistance • block of b2 can lead to increased in BP (usually does not) • block of renin release decreases total peripheral resistance (usual effect) • Renin regulates angiotensin II and aldosterone Propranolol • Non-selective beta-blocker • Advantages: cheap, efficacious, extensive history • Disadvantages: • Contraindicated in asthma, acute decompensated HF, and AV conduction problems • Inhibits glycogenolysis, impairs recovery from hypoglycemia, also blocks tachycardia/tremors typically seen with hypoglycemia, which are warning signs for diabetics Pindolol • Non-selective beta blocker • Intrinsic sympathomimetic activity • partial agonist, predominately efficacious at b2 • “The vasodilating beta blocker”, more notable decrease in peripheral resistance b1-selective Metoprolol or Atenolol • Preferred in individuals who also have: • asthma • diabetes • peripheral vascular disease Side Effects of b Blockers • AV block • Severe Bradycardia • Bronchospasm and respiratory distress • Exacerbation of CHF and pulmonary edema • Delay recovery from hypoglycemia • triglycerides; HDL (these effects with beta blockers that do not have intrinsic sympathomimetic activity or ISA) • Beta-blockers with ISA stimulate the beta-adrenergic receptors and oppose the action of epinephrine released Calcium Channel Blockers • Know nitrendipine or amlodipine (nifedipine) (“ipine”), and contrast usefulness to verapamil/diltiazem • “ipine” drugs are relatively selective for smooth muscle calcium channels (L-type) • Verapamil/diltiazem relatively selective for cardiac muscle Ca channels (L-type) • Ca++ influx, resulting in smooth muscle relaxation • at the heart, decrease cardiac contractility and CO CCBs Mechanism Katzung, 15th ed., pg. 201 Ca ++ Channel Blockers: Uses • hypertension • Angina (Prinzmetal variant for “ipines”) • Verapamil and diltiazem for arrhythmias • Advantages • efficacious • low incidence of side-effects • Disadvantages • headache; flushing • potential problem of verapamil and diltiazem if used with betablockers Alpha1 Antagonists: Prazosin • Block post-synaptic alpha1 receptors • SNS effect on vasculature • preload; afterload BP Alpha1 Antagonists: Uses • Not first-line drugs (side-effects) • Use in combination with other classes • Useful in benign prostatic hypertrophy (BPH) • Being replaced by tamsulosin (alpha1A selective) • Advantages • don’t adversely affect serum lipids • benign prostatic hypertrophy • Disadvantages • • • • increased risk for HF (ALLHAT trial) first-dose hypotension (severe) salt and water retention (must use diuretic) fatigue and light headedness Vasodilato rs • Reduce BP by decreasing systemic vascular resistance • Hypotension (orthostatic) is a difficult side-effect for most patients Katzung, 15th ed., pg. 182 Arteriolar Vasodilators • Dilate arterioles • PR • compensatory responses (initiated by baroreceptors) • Sympathetic Nervous System • Renin/Angiotensin System Arterial Dilators • Consequences of SNS and RAS activation • • • • HR renin release Na+ and H2O retention SNS with arterial “block” but venous constriction • Consequences (continued) • • • • antihypertensive effectiveness myocardial O2 consumption (angina) myocardial work (CHF) hypotension side-effects such as palpitation, pounding headache, edema, orthostatic hypotension • Must be combined with a b blocker and a diuretic • Use only with caution in angina or HF Hydralazine • Mechanism is unknown • Uses • severe hypertension • pregnancy • Adverse Effects • Tachyphylaxis (see often in anesthesia uses) • headache, palpitation, GI • systemic lupus (high doses, slow acetylators, reversible) Venoarterial Dilators Nitroprusside • NO-cGMP Mechanism • Dilates arteries and veins (probably mainly veins) • Mechanism/Effects • NO formation cGMP relaxation • dilates arterioles and veins • myocardial oxygen demand Katzung, 15th ed., pg. 202, Fig. 12-2 Nitroprusside • Uses • hypertensive emergencies • CHF (with hydralazine) • Surgery (controlled hypotension) • Adverse Effects • excessive hypotension • cyanide/thiocyanate toxicity Sympatholytic Agents • Adrenergic neuronal depleting agents • Reserpine • Central adrenergic agonists • Clonidine, methyldopa Adrenergic Neuronal Depleting Agents: Reserpine • Mechanism: blocks vesicular uptake and storage of NE (and others). • Result is depletion of catecholamines throughout the body • Long lasting effect • Inexpensive Katzung, 15th ed., pg. 100, Fig. 6-4 Reserpine • Generally unacceptable side effects • CNS -- depression, nightmares (seldom used) • don’t use if history of depression • nasal stuffiness • unopposed parasympathetic activity: miosis, bradycardia, aggravation of ulcers, diarrhea • fluid retention Central Adrenergic Agonists • Clonidine, methyldopa • Reduce sympathetic outflow from brainstem sites • reduce peripheral vascular resistance • Stimulate alpha2 receptors Central Adrenergic Agonists Clonidine • Part of effect may be via imidazoline receptors in brainstem • decreases heart rate and CO more than methyldopa • Not first-line • Give with diuretic (Na retention) • Useful in opioid withdrawal • Adverse effects • CNS: drowsiness, dry mouth, depression • Rebound hypertension Methyldopa • Pro-drug • Not first-line • CNS: dry mouth, sedation, fatigue, depression, nightmares • sexual dysfunction • hemolytic anemia, hepatitis (rare) Hypertensive Crisis • Get diastolic pressure to 100-110, then move it to “normal” over the next few days • Avoid excessive decrease in BP • Avoid too rapid of decrease in BP • Both can result in cerebral or cardiac hypoperfusion • Use drugs parenterally in emergencies • Use drugs parenterally and occasionally orally for urgencies Drugs • Labetalol • Nitroprusside • Nitroglycerin • Hydralazine • Fenoldopam (D1 receptor agonist) • increases renal blood flow, despite hypotensive effect Precautions • Overly aggressive therapy is associated with severe hypotensive problems. • Insufficient therapy is associated with endorgan damage, including stroke.
