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Antihypertensives. Steven L. Bealer Rm 408C BPRB 7-7706 steve.bealer@deans.pharm.utah.edu ---------------------------------------------------------------- Recommended reading: Katzung, 9th Ed.; Chap. 11 (pg. 160-183) Goodman and Gilman, 11th Ed.;

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  1. Antihypertensives Steven L. Bealer Rm 408C BPRB 7-7706 steve.bealer@deans.pharm.utah.edu ---------------------------------------------------------------- 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

  2. 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.

  3. Stroke Kidney Failure Heart Attack Hypertension: The Silent Killer CRITICAL POINT! Hypertension- asymptomatic Morbidity and mortality due to end organ damage

  4. Determinants of Arterial Pressure Blood Volume Mean Arterial Pressure = X Arteriolar Diameter Stroke Volume Heart Rate CRITICAL POINT! Change any physical factors controlling CO and/or TPR and MAP can be altered. Contractility Filling Pressure Blood Volume VenousTone

  5. 1. Neural SymNS PSNS 2.Hormonal Renal Ang II Adrenal Catecholamines Aldosterone 3. Local Factors Artery Vein Mechanisms Controlling CO and TPR CRITICAL POINTS! 1. These organ systems and mechanisms control physical factors of CO and TPR 2. Therefore, they are the targets of antihypertensive therapy.

  6. Summary-Types and Etiology of Hypertension 1. White coat hypertension office or environmental 2. Secondary hypertension- due to specific organ pathology 1. renal artery stenosis 2. pheochromocytoma 3. aortic coarctation 4. adrenal tumor 3. Essential Hypertension No known cause. CRITICAL POINT! Pharmacological Therapy used primarily for essential hypertension.

  7. 1. Diagnosis- 3- 6 independent measurements. 2. Determination of primary vs. secondary hypertension. 3. If secondary, treat underlying pathology. Summary General Treatment Strategy of Hypertension 4. If primary, initiate lifestyle changes smoking cessation weight loss diet stress reduction less alcohol etc. 5. Pharmacological treatment. CRITICAL POINTS! Goal- normalize pressure- decrease CO and/or TPR Strategy- alter volume, cardiac and/or VSM function

  8. Pharmacological Treatment Classes of Antihypertensive Agents 1. Diuretics 2. Peripheral a-1 Adrenergic Antagonists 3. Central Sympatholytics (a-2 agonists) 4. b-Adrenergic Antagonists 5. Anti-angiotensin II Drugs 6. Ca++ Channel Blockers 7. Vasodilators CRITICAL POINTS! Each designed for specific control system Often used in combination

  9. 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)

  10. Diuretics (cont) 1. Site of Action Renal Nephron 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

  11. 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

  12. 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

  13. 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.

  14. Peripheral a-1 Adrenergic Antagonists, cont. 2. Mechanism of Action Competitive antagonist at a-1 receptors on vascular smooth muscle. 3. Effects on Cardiovascular System Vasodilation, reduces peripheral resistance CRITICAL POINT! Blocking -receptors on vascular smooth muscle allows muscle relaxation, dilation of vessel, and reduced resistance.

  15. Peripheral a-1 Adrenergic Antagonists, cont. 4. Adverse effects nausea; drowsiness; postural hypotenstion; 1st dose syncope 5. Contraindications Hypersensitivity 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

  16. 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.” 2. Mechanism of Action CNS a-2 adrenergic stimulation Peripheral sympathoinhibition Decreased norepinephrine release 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.

  17. Central Sympatholytics (a-2 Agonists); cont. 4. Adverse Effects dry mouth; sedation; impotence; 5. Contraindications 6. Therapeutic Considerations generally not 1st line drugs; methyldopa drug of choice for pregnancy prolonged use--salt/water retention, add diuretic Rebound increase in blood pressure

  18. b Adrenergic Antagonists Drugs: propranolol (Inderal); metoprolol (Lopressor) atenolol (Tenormin); nadolol (Corgard); pindolol (Visken) 1. Sites of Action b-1 b-1 2. Mechanism of Action competitive antagonist at b- adrenergic receptors

  19. 4. Adverse Effects impotence; bradycardia; fatigue; exercise intolerance; b Adrenergic Antagonists, cont. 3. Effects on Cardiovascular System a. Cardiac--  HR,  SV CO b. Renal--  Renin  Angiotensin II  TPR 5. Contraindications asthma; diabetes; bradycardia; hypersensitivity

  20. b-Adrenergic Antagonists, cont. 6. Therapeutic Considerations Selectivity nadolol (Corgard) non selective, but 20 hr 1/2 life metoprol (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

  21. 2. Ang II Receptor Antagonists losartan (Cozaar); candesartan (Atacand); valsartan (Diovan) Anti-Angiotensin II Drugs Angiotensin II Formation Angiotensin Converting Enzyme- Inhibitors enalopril (Vasotec); quinapril (Accupril); fosinopril (Monopril); moexipril (Univasc); lisinopril (Zestril, Prinivil); benazepril (Lotensin); captopril (Capoten) Angiotensinogen Ang I ACE Lung VSM Brain Kidney Adr Gland  Ang I AT1 Ang II ACE AT2  Ang II Renin

  22. Anti-Angiotensin II Drugs, cont 3. Effect on Cardiovascular System   Volume Aldosterone Vasopressin Angiotensin II  HR/SV Angiotensin II Norepinephrine Vasoconstriction  SymNS  SymNS  CO  TPR  CO

  23. 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

  24. Ca++ Channel Blockers Drugs: verapamil (Calan); nifedipine (Procardia); diltiazem (Cardizem); amlodipine (Norvasc) 1. Site of Action- Vascular smooth muscle 2. Mechanism of Action- Blocks Ca++ channel decreases/prevents contraction K+ Ca++ Na+ 3. Effect on Cardiovascular system Vascular relaxation Decreased TPR

  25. Ca++ Channel Blockers, cont. 4. Adverse Effects nifedipine --Increase SymNS activity; headache; dizziness; peripheral edema 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)

  26. NO 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 nitroprusside fenoldopam DA    minoxidil diazoxide K+ Na+ Ca++ Ca++ hydralazine

  27. 6. Therapeutic Considerations nitroprusside- iv only hydralazine- safe for pregnancy diazoxide- emergency use for severe hypertension 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

  28. 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. Summary Sites and Mechanisms of Action 3. -2 agonists Receptor antag. 2. a-antag. 5. ang II antag. 7. Vasodilators 6. Ca++ antag. 4. b-blockers 1. Diuretics 4. b-blockers Other- 5. ACE inhibitors Lung, VSM, Kidney, CNS CRITICAL POINTS!

  29. 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

  30. Treatment Strategy with Some Common co-existing Conditions, cont Renal Insufficiency ACE Inhibitors Angina b-blocker Calcium channel antagonists Asthma Ca++ channel blockers AVOID- b-blockers

  31. 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.

  32. Baroreflexes • 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. CO X SVR= MAP

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