Antihypertensive Agents

1. Antihypertensive Agents

2. Hypertension High blood pressure • Normal: Systolic < 130 mm Hg Diastolic < 85 mm Hg

3. Classification of Blood Pressure Category Systemic BP (mm Hg) Diastolic BP (mm Hg) Normal <130 <85 High normal 130-139 85-89 Hypertension Stage 1 140-159 90-99 Stage 2 160-169 100-109 Stage 3 180-209 110-119 Stage 4  210  120

4. Classification of Blood Pressure Primary Hypertension • Specific cause unknown • 90% of the cases • Also known as essential or idiopathic hypertension Secondary Hypertension • Cause is known (such as eclampsia of pregnancy, renal artery disease, pheochromocytoma) • 10% of the cases

5. Blood Pressure = CO x SVR • CO = Cardiac output • SVR = Systemic vascular resistance

6. Blood Pressure = Cardiac Output X Peripheral Resistance Preload Contractility Heart Rate Vasoconstriction Venous Arteriolar Venous Circulating Fluid Volume Renin Angiotensin Aldosterone System Vascular Smooth Muscle Renal Sodium Handling Sympathetic Nervous System Vascular remodeling

7. Afterload a2 Vasomotor center Volume Kidneys Cardiac Output Heart b1 Renin b1 V V Ang I Preload Ang II b2 a1 BP= CO x TPVR Aldosterone VSMCs Vascular Smooth Muscle Cells Capacitance venules Resistance arterioles TPVR Total Peripheral Vascular Resistance (TPVR)

8. Antihypertensive Agents • Medications used to treat hypertension

9. Antihypertensive Agents • Therapeutic goals in hypertension To lower the high blood pressure and reduced cardiovascular morbidity and mortality by least intrusive means. • For most of the HTN patients: life-long treatment of an asymptomatic disease

10. Antyhepertensive DrugsNew End-Points • Effects on hard end-points • Mortality • Stroke • Heart attacks • Effects on end-organ damage • Left ventricular and vascular hypertophy • Effects on renal function • Effects on metabolic status • Blood lipids and glucose

11. Antihypertensive Agents: Categories • Adrenergic agents • Angiotensin-converting enzyme inhibitors • Angiotensin II receptor blockers • Calcium channel blockers • Diuretics • Vasodilators

12. Antihypertensive Agents: Categories • Adrenergic Agents • Alpha1 blockers • Beta blockers (cardioselective and nonselective) • Centrally acting alpha blockers • Combined alpha-beta blockers • Peripheral-acting adrenergic agents

13. Beta Blockers ( … lol)

14. Afterload ? a2 Vasomotor center Volume Kidneys Cardiac Output Heart b1 Renin b1 V V Ang I Preload Ang II b2 a1 ? BP= CO x TPVR Aldosterone VSMCs Capacitance venules Resistance arterioles b - Blockers TPVR

15. Beta BlockersMechanisms and Sites of Action ______________________________ - Reduction in cardiac output - Inhibition of renin release - CNS effects - Reduction in venous return and plasma volume - Reduction in peripheral resistance - Improvement in vascular compliance - Resetting of baroreceptor levels - Effects on prejunctional b2receptors - Attenuation of pressor response to catecholamines (stress, exercise) ______________________________ Negative Chronotropic & Inotropic Effects Inhibition of Renin Release

16. Beta Blockers • Cardioselectivity (Beta-1 vs Beta-2 ) • Intrinsic Sympathomimetic Activity (ISA; partial agonistic activity) • Affinity for alpha-1 adrenergic receptors (Labetalol, Carvedilol)

17. Beta Blockers • There are 15 Beta blockers on the market in the US • Approved for hypertension (13) and for one or more of following indications: • Angina pectoris • Myocardial Infarction • Ventricular arrhythmia • Migraine prophylaxis • Heart Failure • Perioperative Hypertension

18. Beta-1,2-Non-Selective Propranolol [INDERAL] Nadolol [CORGARD] Carteolol [CARTROL] * Timolol [BLOCADREN] Pindolol [VISKEN] * Sotalol[BETAPACE] Penbutol [LEVATOL] * Beta-1-Selective Acebutolol [SECTRAL] * Atenolol [TENORMIN] Betaxolol [KERIONE] Bisoprolol [ZEBETA] Esmolol [BREVIBLOC] Metoprolol [LOPRESSOR ] Beta Blockers ( …lol) X X * - ISA • Beta-1,2/Alpha 1Selective • Labetalol [TRANDATE, NORMODYNE] • Carvedilol [COREG]

19. Beta Blockers • Side Effects: • Bronchospasm • Bradicardia/heart block • Mask and prolong the symptoms of hypoglycemia • Abrupt withdrawal can precipitate MI • Cold extremities, Raynaud’s phenomenon, intermittent claudication • Decreased exercise tolerance; fatigue, depression and impotence • CNS: sleep disturbance, vivid dreams, nightmares • Effects of plasma lipids

20. Beta Blockers • No: (avoid in) • Patients with COPD • IDDM • Pateints with peripheral vascular disease • Raynaud’s syndrome • 2nd and 3rd degree block • Energetic patients • YES: (useful in) • Younger patients • Anxious patients • Angina pectoris • Post-MI patient

21. Antihypertensive Agents: Mechanism of Action Adrenergic Agents Alpha1 Blockers (peripherally acting) • Block the alpha1-adrenergic receptors • The SNS is not stimulated Result: DECREASED blood pressure • Stimulation of alpha1-adrenergic receptors causes HYPERtension • Blocking alpha1-adrenergic receptors causes decreased blood pressure

22. Afterload a2 Vasomotor center Volume Kidneys Cardiac Output Heart b1 Renin V V b1 Ang I Preload Ang II a1 a1 BP= CO x TPVR Aldosterone a1 a1 Capacitance venules Resistance arterioles a1 Receptors Blockers TPVR

23. a1- Receptor Blockers Inhibition of Vasoconstriction Induced by Endogenous Catecholamines at Arterioles and Veins Reduced Peripheral Resistance and Reduced Preload

24. Antihypertensive Agents: Adrenergic Agents Alpha1 Blockers • doxazosin (Cardura) • prazosin (Minipress) • terazosin (Hytrin)

25. Antihypertensive Agents: Mechanism of Action Adrenergic Agents Central-Acting Adrenergics • Stimulate alpha2-adrenergic receptors • Sympathetic outflow from the CNS is decreased Result: decreased blood pressure

26. Antihypertensive Agents: Adrenergic Agents Central-Acting Adrenergics • clonidine (Catapres) • methyldopa (Aldomet) (drug of choice for hypertension in pregnancy)

27. X Afterload a2 Vasomotor center Volume Kidneys Cardiac Output Heart b1 X Renin X V V b1 Ang I X Preload X Ang II BP= CO x TPVR Aldosterone VSMC Capacitance venules Resistance arterioles Central a2 Agonists TPVR

28. Central a2–Agonists Activation of Pre-synaptic Alpha-2 Receptors Reduces NE & EPI Release at Synapse Diminished CNS Sympathetic Outflow Alpha-2 Agonist Post-synaptic Effector Rostral Ventrolateral Medulla Pre-synaptic Neuron Alpha-1 Receptor Beta Receptor Alpha-2 Receptor NE & EPI

29. Antihypertensive Agents: Mechanism of Action Adrenergic Agents Adrenergic Neuronal Blockers (peripherally acting) • Inhibit release of norepinephrine • Also deplete norepinephrine stores • SNS (peripheral adrenergic nerves) is not stimulated Result: decreased blood pressure

30. Antihypertensive Agents: Adrenergic Agents Adrenergic Neuronal Blockers(peripherally acting) • reserpine • guanadrel (Hylorel) • guanethidine (Ismelin)

31. Antihypertensive Agents: Adrenergic Agents Therapeutic Uses • Alpha1 blockers (peripherally acting) • Treatment of hypertension • Relief of symptoms of BPH • Management of of severe CHF when used with cardiac glycosides and diuretics

32. Antihypertensive Agents: Adrenergic Agents Therapeutic Uses • Central-Acting Adrenergics • Treatment of hypertension, either alone or with other agents • Usually used after other agents have failed due to side effects • Also may be used for treatment of severe dysmenorrhea, menopausal flushing, glaucoma • Clonidine is useful in the management of withdrawal symptoms in opioid- or nicotine-dependent persons

33. Antihypertensive Agents: Adrenergic Agents Therapeutic Uses • Adrenergic neuronal blockers (peripherally acting) • Treatment of hypertension, either alone or with other agents • Seldom used because of frequent side effects

34. Antihypertensive Agents: Adrenergic Agents Side Effects Most common: dry mouth drowsiness sedation constipation Other: headaches sleep disturbances nausea rash cardiac disturbances (palpitations) HIGH INCIDENCE OF ORTHOSTATIC HYPOTENSION

35. Antihypertensive Agents: Categories Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors) • Large group of safe and effective drugs • Often used as first-line agents for CHF and hypertension • May be combined with a thiazide diuretic or calcium channel blocker

36. A n g i o t e n s i n II Peripheral resistance Renal function Cardiovascular structure 1. Non-hemodynamic effects: - Increased expression of proto-oncogenes - Increased production of growth factors - Increased synthesis of extracellular matrix proteins 2. Hemodynamic effects: - Increased afterload (cardiac) - Increased wall tension (vascular) 1. Direct vasoconstriction 2. Enhancement of peripheral noradrenergic neurotransmission 3. Increased central (CNS) sympathetic discharge 4. Release of catecholamines from adrenal medulla 1. Increases Na+ reabsorption 2. Releases aldosterone from adrenal cortex 3. Altered renal hemodynamics: - renal vasoconstriction - increased noradrenergic neurotransmission in kidney - Increased renal sympathetic tone (CNS) Rapid Pressor Response Slow Pressor Response Cardiovascular Hypertrophy and Remodeling

37. Afterload a2 Vasomotor center Volume Kidneys Cardiac Output Heart b1 Renin b1 V V Ang I Preload Ang II b2 a1 BP= CO x TPVR Aldosterone VSMCs Capacitance venules Resistance arterioles ACE Inhibitors TPVR

38. mRNA mRNA mRNA Angiotensinogen A C E Renin Local (tissue) RAS: Intrinsic; Extrinsic Ang I Ang II Angiotensinogen Angiotensinogen (myocyte ) Renin (VSM cells) tissue A T1 A T1 endothelial cell ACE (autocrine) blood vessel Ang I Renin (renal) Ang II (paracrine) ACE Ang I Angiotensinogen Ang II (liver) (endocrine) A C E mRNA mRNA mRNA Angiotensinogen Renin A C E

39. Angiotensin Converting Enzyme Angiotensinogen Kininogens Kallikrein Renin Angiotensin I Bradykinin ACEIs ACEIs A C E Angiotensin II Inactive Peptides BK receptors AT-1 receptors

40. ACEIs : Prevention of renal disease INTRAGLOMERULAR PRESSURE Angiotensin II Arterial pressure Angiotensin II + + + + Afferent arteriole Efferent arteriole 20 mmHg excess glomerular pressure hyperfiltration microalbuminuria Bowman’s capsule

41. Antihypertensive Agents: Mechanism of Action ACE Inhibitors RAAS: Renin Angiotensin-Aldosterone System • When the enzyme angiotensin I is converted to angiotensin II, the result is potent vasoconstriction and stimulation of aldosterone • Result of vasoconstriction: increased systemic vascular resistance and increased afterload • Therefore, increased BP

42. Antihypertensive Agents: Mechanism of Action ACE Inhibitors • Aldosterone stimulates water and sodium resorption. • Result: increased blood volume, increased preload, and increased B

43. Antihypertensive Agents: Mechanism of Action ACE Inhibitors • ACE Inhibitors block the angiotensin-converting enzyme, thus preventing the formation of angiotensin II. • Also prevent the breakdown of the vasodilating substance, bradykinin Result: decreased systemic vascular resistance (afterload), vasodilation, and therefore, decreased blood pressure

44. Antihypertensive Agents ACE Inhibitors • captopril (Capoten) • Short half-life, must be dosed more frequently than others • enalapril (Vasotec) • The only ACE inhibitor available in oral and parenteral forms • lisinopril (Prinivil and Zestril) and quinapril (Accupril) • Newer agents, long half-lives, once-a-day dosing • Several other agents available

45. Antihypertensive Agents: Therapeutic Uses ACE Inhibitors • Hypertension • CHF (either alone or in combination with diuretics or other agents) • Slows progression of left ventricular hypertrophy after an MI • Renal protective effects in patients with diabetes Drugs of choice in hypertensive patients with CHF

46. Antihypertensive Agents: Side Effects ACE Inhibitors • Fatigue Dizziness • Headache Mood changes • Impaired taste Dry, nonproductive cough, reverses when therapy is stopped NOTE: first-dose hypotensive effect may occur!!

47. Antihypertensive Agents: Categories Angiotensin II Receptor Blockers (A II Blockers or ARBs) • Newer class • Well-tolerated • Do not cause coughing

48. ACE Inhibitors vs AT1 Antagonists Example: Fibrinolytic System Angiotensinogen Kininogens Bradykinin Inactive Peptides Kallikrein Renin A C E Is Angiotensin I A C E Angiotensin II tPA PAI-1 Plasminogen Activators PAI-1 + + Endothelial Cell

49. Afterload a2 Vasomotor center Volume Kidneys Cardiac Output Heart b1 Renin b1 V V Ang I Preload Ang II Ang II b2 a1 BP= CO x TPVR Aldosterone VSMCs Capacitance venules Ang II Resistance arterioles Ang II Receptor Blockers TPVR

50. Antihypertensive Agents: Mechanism of Action Angiotensin II Receptor Blockers • Allow angiotensin I to be converted to angiotensin II, but block the receptors that receive angiotensin II • Block vasoconstriction and release of aldosterone