PowerPoint Presentation: Antihypertensives nurdiana Objectives:: Objectives: Know mechanisms of blood pressure regulation and cardiovascular pathophysiology which chronically increase blood pressure (Review). Understand types and etiologies of major forms of clinical hypertension. General treatment strategy for hypertension. Know major classes of anti-hypertensive agents, their general sites and mechanisms of action. Identify specific, widely used, antihypertensive agents, sites of action, mechanisms of action, indications and contraindications. Understand strategies for hypertension management associated with other pathologies. PowerPoint Presentation: Hypertension: The Silent Killer Heart Attack Stroke Kidney Failure CRITICAL POINT! Hypertension- asymptomatic Morbidity and mortality due to end organ damage PowerPoint Presentation: Determinants of Arterial Pressure Mean Arterial Pressure = X Arteriolar Diameter Blood Volume Stroke Volume Heart Rate Filling Pressure Contractility Blood Volume Venous Tone CRITICAL POINT! Change any physical factors controlling CO and/or TPR and MAP can be altered. PowerPoint Presentation:
Mechanisms Controlling CO and TPR Artery Vein 2. Hormonal Renal Ang II Adrenal Catecholamines Aldosterone 3. Local Factors 1.
SymNS PSNS CRITICAL POINTS! These organ systems and mechanisms control physical factors of CO and TPR 2. Therefore, they are the targets of antihypertensive therapy.
PowerPoint Presentation: 2. Secondary hypertension- due to specific organ pathology 1. renal artery stenosis 2. pheochromocytoma 3. aortic coarctation 4. adrenal tumor Summary-Types and Etiology of Hypertension 1. White coat hypertension office or environmental 3. Essential Hypertension No known cause. CRITICAL POINT! Pharmacological Therapy used primarily for essential hypertension. PowerPoint Presentation: Summary General Treatment Strategy of Hypertension 1. Determination of primary vs. secondary hypertension. 2. If secondary, treat underlying pathology. 4. Pharmacological treatment. 3. If primary, initiate lifestyle changes smoking cessation weight loss diet stress reduction less alcohol etc. CRITICAL POINTS! Goal- normalize pressure- decrease CO and/or TPR Strategy- alter volume, cardiac and/or VSM function PowerPoint Presentation: Classes of Antihypertensive Agents 1. Diuretics 2. Peripheral a-1 Adrenergic Antagonists 4. b- Adrenergic Antagonists 3. Central Sympatholytics ( a-2 agonists) 5. Anti-angiotensin II Drugs 6. Ca++ Channel Blockers 7. Vasodilators Pharmacological Treatment CRITICAL POINTS! Each designed for specific control system Often used in combination PowerPoint Presentation: Sites of action of the major classes of antihypertensive drugs PowerPoint Presentation: 1. Diuretics 1. Thiazides hydrochlorothiazide (HydroDIURIL, Esidrix); chlorthalidone (Hygroton) 2. Loop diuretics furosemide (Lasix); bumetadine (Burmex); ethacrynic acid (Edecrin) 3. K+ Sparing amiloride (Midamor); spironolactone (Aldactone); triamterene (Dyrenium) 4. Osmotic mannitol (Osmitrol); urea (Ureaphil) 5. Other Combination - HCTH + triamterene (Dyazide) acetazolamide (Diamox) PowerPoint Presentation: Diuretics (cont) 2. Mechanism of Action Urinary Na+ excretion Urinary water excretion Extracellular Fluid and/or Plasma Volume 3. Effect on Cardiovascular System Acute decrease in CO Chronic decrease in TPR, normal CO Mechanism(s) unknown 1. Site of Action Renal Nephron PowerPoint Presentation: Diuretics (cont) 4. Adverse Reactions dizziness, electrolyte imbalance/depletion, hypokalemia, hyperlipidemia, hyperglycemia (Thiazides) gout 5. Contraindications hypersensitivity, compromised kidney function cardiac glycosides (K+ effects) hypovolemia, hyponatremia PowerPoint Presentation: Diuretics (cont) 6. Therapeutic Considerations Thiazides (most common diuretics for HTN) Generally start with lower potency diuretics Generally used to treat mild to moderate HTN Use with lower dietary Na+ intake, and K+ supplement or high K+ food K+ Sparing (combination with other agent) Loop diuretics (severe HTN, or with CHF) Osmotic (HTN emergencies) Maximum antihypertensive effect reached before maximum diuresis- 2nd agent indicated PowerPoint Presentation: Peripheral a-1 Adrenergic Antagonists Drugs: prazosin (Minipres); terazosin (Hytrin) 1. Site of Action- peripheral arterioles, smooth muscle CRITICAL POINT! Major mechanism/site of SymNS control of blood pressure. PowerPoint Presentation: 2. Mechanism of Action Competitive antagonist at a-1 receptors on vascular smooth muscle. 3. Effects on Cardiovascular System Vasodilation, reduces peripheral resistance Peripheral a-1 Adrenergic Antagonists, cont . CRITICAL POINT! Blocking - receptors on vascular smooth muscle allows muscle relaxation, dilation of vessel, and reduced resistance. PowerPoint Presentation: 5. Contraindications Hypersensitivity Peripheral a-1 Adrenergic Antagonists, cont. 4. Adverse effects nausea; drowsiness; postural hypotenstion; 1st dose syncope 6. Therapeutic Considerations no reflex tachycardia; small 1st dose; does not impair exercise tolerance useful with diabetes, asthma, and/or hypercholesterolemia use in mild to moderate hypertension often used with diuretic, antagonist PowerPoint Presentation: Central Sympatholytics ( a -2 Agonists) Drugs: clonidine (Catapres), methyldopa (Aldomet) 1. Site of Action CNS medullary cardiovascular centers clonidine; direct a -2 agonist methyldopa: “false neurotrans.” CNS a-2 adrenergic stimulation Peripheral sympathoinhibition Decreased norepinephrine release 2. Mechanism of Action 3. Effects on Cardiovascular System Decreased NE-->vasodilation--> Decreased TPR CRITICAL POINT! Stimulation of a-2 receptors in the medulla decreases peripheral sympathetic activity, reduces tone, vasodilation and decreases TPR. PowerPoint Presentation: 5. Contraindications : mental depression 4. Adverse Effects dry mouth; sedation; impotence; with Fe 2+ absorption methyldopa (70 %) Central Sympatholytics ( a -2 Agonists); cont. 6. Therapeutic Considerations generally not 1st line drugs; prolonged use--salt/water retention, add diuretic Rebound increase in blood pressure Drug of choice for pregnancy fetus safe PowerPoint Presentation: b A drenergic Antagonists Drugs: propranolol (Inderal); metoprolol (Lopressor) atenolol (Tenormin); nadolol (Corgard); pindolol (Visken) 1. Sites of Action b-1 2. Mechanism of Action competitive antagonist at b- adrenergic receptors PowerPoint Presentation: b A drenergic Antagonists, cont. 3. Effects on Cardiovascular System a. Cardiac-- HR, SV CO b. Renal-- Renin Angiotensin II TPR 5. Contraindications asthma; diabetes; bradycardia; hypersensitivity 4. Adverse Effects impotence; bradycardia; fatigue; exercise intolerance; PowerPoint Presentation: b-A drenergic Antagonists, cont. 6. Therapeutic Considerations Selectivity nadolol (Corgard) non selective, but 20 hr 1/2 life metoprolol (Lopresor) b-1 selective, 3-4 hr 1/2 life Risky in pulmonary disease even selective b-1 , Available as mixed a/b blocker available-labetalol (Trandate, Normodyne) Use post myocardial infarction- protective Use with diuretic- prevent reflex tachycardia Effective for adolesence not aged PowerPoint Presentation: Anti-Angiotensin II Drugs Angiotensin II Formation 2. Ang II Receptor Antagonists losartan (Cozaar); candesartan (Atacand); valsartan (Diovan) Angiotensin Converting Enzyme- Inhibitors enalapril (Vasotec); quinapril (Accupril); fosinopril (Monopril); moexipril (Univasc); lisinopril (Zestril, Prinivil); benazepril (Lotensin); captopril (Capoten) Ang I Ang II ACE ACE Ang II Renin Angiotensinogen Ang I AT1 AT2 Lung VSM Brain Kidney Adr Gland PowerPoint Presentation: 3. Effect on Cardiovascular System Anti-Angiotensin II Drugs, cont Volume Aldosterone Vasopressin CO Angiotensin II Vasoconstriction TPR SymNS HR/SV Angiotensin II Norepinephrine CO SymNS PowerPoint Presentation: Anti-Angiotensin II Drugs, cont 4. Adverse Effects hyperkalemia angiogenic edema (ACE inhib); cough (ACE inhib); rash; itching; 5. Contraindications pregnancy; hypersensitivity; bilateral renal stenosis 6. Therapeutic Considerations: use with diabetes or renal insufficiency; adjunctive therapy in heart failure; often used with diuretic; Enalapril, iv for hypertensive emergency PowerPoint Presentation: Ca++ Channel Blockers Drugs: verapamil (Calan); nifedipine (Procardia); diltiazem (Cardizem); amlodipine (Norvasc) 2. Mechanism of Action- Blocks Ca++ channel decreases/prevents contraction 3. Effect on Cardiovascular system Vascular relaxation Decreased TPR 1. Site of Action- Vascular smooth muscle K+ Ca ++ Na+ PowerPoint Presentation: Ca++ Channel Blockers, cont. 5. Contraindications Congestive heart failure; pregnancy and lactation; Post-myocardial infarction 6. Therapeutic Considerations verapamil- mainly cardiac; interactions w/ cardiac glycosides nifedipine- mainly arterioles diltiazem-both cardiac and arterioles at high doses, AV node block may occur; nifedipine may increase heart rate (reflex) 4. Adverse Effects nifedipine --hypotension; tachycardi headache; dizziness; peripheral edema PowerPoint Presentation: Vasodilators Drugs: hydralazine (Apresoline); minoxidil (Loniten); nitroprusside (Nipride); diazoxide (Hyperstat I.V.); fenoldopam (Corlopam) 1. Site of Action- vascular smooth muscle 2. Mechanism of action minoxidil diazoxide hydralazine fenoldopam NO nitroprusside Ca++ Ca++ Na+ K+ DA PowerPoint Presentation: Vasodilators, Cont 3. Effect on cardiovascular system vasodilation, decrease TPR 4. Adverse Effects reflex tachycardia Increase SymNS activity (hydralazine, minoxidil,diazoxide) lupus (hydralazine) hypertrichosis (minoxidil) cyanide toxicity (nitroprusside) 5. Contraindications : fenoldopam glaucoma 6. Therapeutic Considerations nitroprusside- iv only hydralazine- safe for pregnancy diazoxide- emergency use for severe hypertension PowerPoint Presentation: Summary Sites and Mechanisms of Action 1. Can alter CO/TPR at number of sites and/or mechanisms. 2. Antihypertensives mechanistically specific, and alter blood pressure through physiologically diverse effects on CO/TPR . 3. All organ systems and/or effector mechanisms are p’col targets. 3. -2 agonists 4. b -blockers Receptor antag. 2. a- antag. 5. ang II antag. 7. Vasodilators 6. Ca++ antag. 1. Diuretics 4. b -blockers Other- 5. ACE inhibitors Lung, VSM, Kidney, CNS CRITICAL POINTS! PowerPoint Presentation: Hypertension treatment with some common co-existing conditions Heart Failure ACE inhibitors Diuretics Myocardial Infarction b -blockers ACE inhibitors Diabetes ACE Inhibitors AVOID- b- blockers Isolated systolic hypertension (Older persons) Diuretics preferred calcium channel antagonist PowerPoint Presentation: Renal Insufficiency ACE Inhibitors Angina b- blocker Calcium channel antagonists Asthma Ca++ channel blockers AVOID- b- blockers Treatment Strategy with Some Common co-existing Conditions, cont PowerPoint Presentation: Summary Important Points Hypertensive Agents Each class of antihypertensive agent: 1. has as specific mechanism of action, 2. acts at one or more major organ systems, 3. on a major physiological regulator of blood pressure, 4. reduces CO and/or TPR to lower blood pressure, 5. has specific indications, contraindications, and therapeutic advantages and disadvantages associated with the mechanism of action. Algorithm for Treatment of Hypertension: Algorithm for Treatment of Hypertension Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease) Initial Drug Choices Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. With Compelling Indications Lifestyle Modifications Stage 2 Hypertension (SBP > 160 or DBP > 100 m mHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB) Stage 1 Hypertension (SBP 140 –159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Without Compelling Indications Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist. PowerPoint Presentation: Baroreflexes CO X SVR= MAP MAP= set point Reflexes defend set point Arterial Baroreflexes Pressure/Natriuresis Change in MAP opposed by reflex response to maintain set pressure. Hypertension- pressure resets to higher level-defended by reflex systems. CRITICAL POINT! **Multiple therapies often needed to block reflex compensation. PowerPoint Presentation: Steven L. Bealer Rm 408C BPRB 7-7706 firstname.lastname@example.org ---------------------------------------------------------------- Recommended reading: Katzung, 9th Ed.; Chap. 11 (pg. 160-183) Goodman and Gilman, 11th Ed.; Chap. 30 Renin and angiotensin; pp. 789-822 Chap. 33 Therapy for Hypertension; pp. 871-900 Online; www.AccessMedicine.com