Antihypertensives

1. Antihypertensives Dr. Sanjita Das

2. Mechanisms Regulating Blood Pressure • Neural • Hormonal • Vascular • Vascular Remodeling

3. Neural • Triggered by hypotension & inadequate tissue perfusion • Release of epinephrine & norepinephrine causing • Constriction of blood vessels in the skin, kidney, & GI • Heart rate and force of the contraction

4. HormonalRenin-Angiotensin-AldosteroneSystem & Vasopressin • Renin is released in response to • Renin converts angiotensinogen to angiotensin I • Angiontensin-converting enzyme (ACE) produces angiontensin II

5. Renin-Angiotensin-Aldosterone

6. Angiontensin II • Strongly constricts arterioles • Increases/Decreases? peripheral vascular resistance • Increases BP by direct vasoconstriction, stimulation of the SNS, and stimulation of catecholamine release • Stimulates secretion of Aldosterone

7. Aldosterone • Kidneys retain sodium and H2O • Retention of sodium and water increases

8. VasopressinAntidiuretic Hormone (ADH) • Regulates _______ reabsorption by the kidneys • Released in response to decreased blood volume and blood pressure • Causes • Retention of fluids • vasoconstrction

9. Vascular • Endothelium damage • Production of vasoconstrictor • Inability to respond to vasodialators

10. Primary Hypertension • Unknown etiology • One or more of the compensatory mechanisms has gone awry

11. Target Organs

12. 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.

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

14. 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

15. 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.

16. 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.

17. 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

18. ANTIHYPERTENSIVESAccording to their mechanism of action

19. 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

20. 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)

21. 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

22. 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

23. 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

24. 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.

25. 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.

26. 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

27. 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.

28. Central Sympatholytics (a-2 Agonists); cont. 4. Adverse Effects dry mouth; sedation; impotence; 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

29. Side effects of a1-adrenoceptor blockers • First dose phenomenon • Tachycardia • GI effects (rare)

30. Adverse Effects of Non Specific a-Adrenoceptor Blockers • Postural hypotension • Reflex tachycardia • Fluid retention

31. Reserpine • Alkaloid from the roots of Rauwolfia serpentina. • Orally well absorbed • Slowly depletes catecholamines and serotonin from brain, adrenergic neuronesans all other tissues • Sever CNS ans Gut toxicities Loss of transmitters and fall in arterial pressure

32. Types of ß-blockers: • Non selective Prototype: Propranolol (others: nadolol, timolol, pindolol, labetolol) • Cardioselective Prototype: Metoprolol (others: atenolol, esmolol, betaxolol) • Non selective and cardioselective ß-blockers are EQUALLY effective in reducing blood pressure

33. b Adrenergic Antagonists 1. Sites of Action b-1 b-1 2. Mechanism of Action competitive antagonist at b- adrenergic receptors

34. 4. Adverse Effects impotence; bradycardia; fatigue; exercise intolerance; b Adrenergic Antagonists, cont. 3. Effects on Cardiovascular System Decrease Heart rate Force of myocardial contraction Cardiac output O2 Demand by the heart Renin release from the kidney Stimulation from SNS a. Cardiac--  b. Renal--  Renin  Angiotensin II  TPR 5. Contraindications asthma; diabetes; bradycardia; hypersensitivity

35. 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

36. Adverse Effects • Bradycardia • Heart failure • Bronchospasm • Coldness of extremities • Withdrawal effects • Glucose metabolism

37. Adverse Effects (Cont) • CNS effects • Pregnancy • Rise in plasma triglyceride concentration; decrease in HDL cholesterol • Drug interactions: • NSAID'S - can blunt effect of ß-blockers • Epinephrine - causes severe hypertension in presence of ß-blockade • Ca2+channel blockers Conduction effects on heart are additive w/ ß blockers.

38. Physiology of Renin-Angiotensin System

39. Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors) • Block the enzyme that converts angiotensin I to angiontensin II • Decrease vasoconstriction • Decrease aldosterone production • Prevent or reverse remodeling of heart and vessels

40. 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

41. Anti-Angiotensin II Drugs, cont • Increased regional blood flow in proportion to ang II sensitivity of the vascular bed 3. Effect on Cardiovascular System   Volume Aldosterone Vasopressin Angiotensin II  HR/SV Angiotensin II Norepinephrine Vasoconstriction  SymNS  SymNS  CO  TPR  CO

42. Anti-Angiotensin II Drugs, cont 4. Adverse Effects hyperkalemia angiogenic edema (ACE inhib); cough (ACE inhib); rash; itching; 10-20 % experience persistent cough Hypotension Renal failure Sexual dysfunction 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

43. 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

44. 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)

45. 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

46. 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)

47. 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

48. 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

49. 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

50. 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.