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Antihypertensive Agents
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  1. Antihypertensive Agents

  2. 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

  3. 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

  4. 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)

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

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

  7. Mechanism of action of beta-adrenoblockers (anaprilin, atenolol, methoprolol etc.) incase of arterial hypertension β- adrenoblockers β1-adrenoreceptors of heart Cardiac output Decreasing of blood pressure Peripheral resist- ance of vessels NO production AngiotensineΙΙ Renin Aldosterone Holding sodium and water Volume of blood circulation

  8. Afterload ? a2 Vasomotor center Volume Kidneys Cardiac Output Heart b1 Renin b1 V V Ang I Preload Ang II b2 a1 ? Aldosterone VSMCs Capacitance venules Resistance arterioles b - Blockers PVR

  9. 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

  10. 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

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

  12. Beta Blockers ( …lol) • 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 ] X X * - ISA • Beta-1,2/Alpha 1Selective • Labetalol [TRANDATE, NORMODYNE] • Carvedilol [COREG]

  13. 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

  14. 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

  15. 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

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

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

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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

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

  25. 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

  26. 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

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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. Antihypertensive Agents: Angiotensin II Receptor Blockers • losartan (Cozaar) • eposartan (Teveten) • valsartan (Diovan) • irbesartan (Avapro) • candesartan (Atacand) • telmisartan (Micardis)

  34. Antihypertensive Agents: Categories Calcium Channel Blockers • Benzothiazepines • Dihydropyridines • Phenylalkylamines

  35. Afterload a2 Vasomotor center Volume Kidneys Cardiac Output Heart b1 Renin b1 V V Ang I AV Preload Ang II BP= CO x TPVR Aldosterone Ca++ Capacitance venules L-type Ca++ channels Resistance arterioles Calcium Channel Blockers TPVR

  36. Antihypertensive Agents: Mechanism of Action Calcium Channel Blockers • Cause smooth muscle relaxation by blocking the binding of calcium to its receptors, preventing muscle contraction • This causes decreased peripheral smooth muscle tone, decreased systemic vascular resistance • Result: decreased blood pressure

  37. Calcium Channel Blockers Mechanisms and Sites of Action Block transmembrane entry of calcium into arteriolar smooth muscle cells and cardiac myocytes thus inhibiting excitation-contraction Negative Inotropic and Chronotropic Effects Produce Vasorelaxation at Arterioles L-type Ca++ channels Reduced Peripheral Resistance Nifed>Dilti+Verap Verap+Dilti>Nifed

  38. Antihypertensive Agents Calcium Channel Blockers • Benzothiazepines: • diltiazem (Cardizem, Dilacor) • Phenylalkamines: • verapamil (Calan, Isoptin) • Dihydropyridines: • amlodipine (Norvasc), bepridil (Vascor), nicardipine (Cardene) • nifedipine (Procardia), nimodipine (Nimotop)

  39. Antihypertensive Agents: Therapeutic Uses Calcium Channel Blockers • Angina • Hypertension • Dysrhythmias • Migraine headaches

  40. Antihypertensive Agents: Side Effects Calcium Channel Blockers • Cardiovascular • hypotension, palpitations, tachycardia • Gastrointestinal • constipation, nausea • Other • rash, flushing, peripheral edema, dermatitis

  41. 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 DIURETICS TPVR

  42. Diuretics Inhibition of Sodium Reabsorption Reduced Circulating Volume Reduced Preload Reduced Cardiac Output

  43. Diuretic Agents • Carbonic anhydrase inhibitors • Loop diuretics • Osmotic diuretics • Potassium-sparing diuretics • Thiazide and thiazide-like diuretics

  44. Furosemid (diuretic)

  45. Furosemid (diuretic)

  46. Triampur(triamteren + hydrochlorthiaside)diuretic

  47. Loop Diuretics: Mechanism of Action • Act directly on the ascending limb of the loop of Henle to inhibit sodium and chloride resorption. • Increase renal prostaglandins, resulting in the dilation of blood vessels and reduced peripheral vascular resistance.