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. Hormonal Renin-Angiotensin-Aldosterone System & 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. Vasopressin Antidiuretic 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. Vascular Remodeling Endothelial damage Stimulates growth of smooth muscle cells Vessel is thickened Lumen is narrowed Less flexible

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

12. Target Organs

13. Objectives: 1.Know mechanisms of blood pressure regulation and cardiovascular pathophysiology which chronically increase blood pressure (Review). 2.Understand types and etiologies of major forms of clinical hypertension. 3.General treatment strategy for hypertension. 4.Know major classes of anti-hypertensive agents, their general sites and mechanisms of action. 5.Identify specific, widely used, antihypertensive agents, sites of action, mechanisms of action, indications and contraindications. 6.Understand strategies for hypertension management associated with other pathologies.

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

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

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

17. 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.

18. Summary General Treatment Strategy of Hypertension 1. Diagnosis- 3- 6 independent measurements. 2. Determination of primary vs. secondary hypertension. 3. If secondary, treat underlying pathology. 5. Pharmacological treatment. 4. 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

19. ANTIHYPERTENSIVES According to their mechanism of action

20. Classes of Antihypertensive Agents 1. Diuretics 2. Peripheral  Adrenergic Antagonists 4.  Adrenergic Antagonists 3. Central Sympatholytics (  agonists) 5. Anti-angiotensin II Drugs 6. Ca++ Channel Blockers 7. Vasodilators Pharmacological Treatment

21. 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)

22. 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

23. 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

24. 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

25. Peripheral  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.

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

27. 5. Contraindications Hypersensitivity Peripheral  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

28. Central Sympatholytics (  -2 Agonists) Drugs: clonidine (Catapres), methyldopa (Aldomet) 1. Site of Action CNS medullary cardiovascular centers clonidine; direct  -2 agonist methyldopa: “false neurotrans.” CNS  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  receptors in the medulla decreases peripheral sympathetic activity, reduces tone, vasodilation and decreases TPR.

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

30. Side effects of  1 -adrenoceptor blockers First dose phenomenon Tachycardia GI effects (rare)

31. Adverse Effects of Non Specific  -Adrenoceptor Blockers Postural hypotension Reflex tachycardia Fluid retention

32. 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

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

34.  drenergic Antagonists 1. Sites of Action  2. Mechanism of Action competitive antagonist at  adrenergic receptors

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

36.  drenergic Antagonists, cont. 6. Therapeutic Considerations Selectivity nadolol (Corgard) non selective, but 20 hr 1/2 life metoprol (Lopresor)  selective, 3-4 hr 1/2 life Risky in pulmonary disease even selective , Available as mixed  blocker available-labetalol (Trandate, Normodyne) Use post myocardial infarction- protective Use with diuretic- prevent reflex tachycardia

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

38. 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 –Ca 2+ channel blockers Conduction effects on heart are additive w/ ß blockers.

39. Physiology of Renin- Angiotensin System

40. 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

41. Anti-Angiotensin II Drugs Angiotensin II Formation 2. Ang II Receptor Antagonists losartan (Cozaar); candesartan (Atacand); valsartan (Diovan) 1.Angiotensin Converting Enzyme- Inhibitors enalopril (Vasotec); quinapril (Accupril); fosinopril (Monopril); moexipril (Univasc); lisinopril (Zestril, Prinivil); benazepril (Lotensin); captopril (Capoten) Ang I Ang II ACE   Ang II Renin Angiotensinogen Ang I AT1 AT2 Lung VSM Brain Kidney Adr Gland

42. 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         – Increased regional blood flow in proportion to ang II sensitivity of the vascular bed

43. 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

44. 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+

45. 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 --Increase SymNS activity; headache; dizziness; peripheral edema

46. 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++ Na+ K+    DA

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

48. Summary Sites and Mechanisms of Action 3.  -2 agonists  -blockers Receptor antag. 2.  antag. 5. ang II antag. 7. Vasodilators 6. Ca++ antag. 1. Diuretics  -blockers Other- 5. ACE inhibitors Lung, VSM, Kidney, CNS

49. Hypertension treatment with some common co-existing conditions Heart Failure ACE inhibitors Diuretics Myocardial Infarction  -blockers ACE inhibitors Diabetes ACE Inhibitors AVOID-  blockers Isolated systolic hypertension (Older persons) Diuretics preferred calcium channel antagonist

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

51. 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.

52. Baroreflexes CO X SVR= MAP 1)MAP= set point 2)Reflexes defend set point 1)Arterial Baroreflexes 2)Pressure/Natriuresis 3)Change in MAP opposed by reflex response to maintain set pressure. 4)Hypertension- pressure resets to higher level-defended by reflex systems. CRITICAL POINT! **Multiple therapies often needed to block reflex compensation.