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Dr. Florencia D. Munsayac

ANTIHYPERTENSIVE AGENTS. Dr. Florencia D. Munsayac. HYPERTENSION.

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Dr. Florencia D. Munsayac

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  1. ANTIHYPERTENSIVE AGENTS Dr. Florencia D. Munsayac

  2. HYPERTENSION • "A state of abnormal arterial function and structure associated with endothelial dysfunction, vascular smooth muscle constriction or remodeling, increased impedance to left ventricular ejection and propensity for atherosclerosis."

  3. Diagnosis: • repeated, reproducible measurements of elevated BP • Consequences: • damage to kidneys, heart & brain

  4. Etiology: • A. Primary Hypertension 1. Abnormal cardiac & peripheral hemodynamics 2. Impaired pressure natriuresis 3. Baroreceptor resetting 4. Abnormalities in the renin-angioitensin-aldosterone system 5. Abnormalities in other vasoregulatory systems a. Endothelin b. Atrial Natriuresis peptide (ANP) c. Endothelium-derived relaxation factor (EDRF)

  5. B. Secondary Hypertension 1. Renovascular hypertension 2. Renal parenchymal diseases a. Altered excretory function b. Altered renin-angiotensin-aldosterone activity 3. Endocrinologic causes a. Oral Contraceptives b. Mineralocorticosteroid excess syndrome c. Pheochromocytoma d. Miscellaneous causes (Acromegaly, Hyperparathyroidism, Hyperthyroidism, Coarctation of the aorta)

  6. Major Factors Influencing Blood Pressure • ABP = cardiac output x peripheral vascular resistance • • heart rate • arteriolar volume • contractility • blood volume • filling pressure • venous tone

  7. Genetic influences + Environmental Factors Defects in renal NA+ homeostasis Functional vasoconstriction Defects in vascular smooth muscle growth and structure Inadequate Na+ secretion Salt & water retention  Plasma & ECF volume  vascular reactivity  vascular wall thickness  cardiac output (autoregulation)  total peripheral resistance HYPERTENSION

  8. Circadian Rhythm and Blood Pressure Variability • Daytime: BP is controlled by sympathetic activity • Sleep: BP lowest sympathetic activity switch off renin level rise BP control under RAS • Early Morning Waking: BP rise as much as 30 mmHg marked increased in sympathetic activity elevated levels of renin & angiotensin II

  9. Physiological Changes Associated With Early Morning BP Elevation • Increase plasma cathecolamines & cortisol elevates myocardial oxygen demand • Increase in platelet aggregability & vascular tone; reduce myocardial oxygen supply • BP surge can cause rupture atherosclerotic plaques in coronary arteries • Promotes clot formation due to activation of coagulation process • Excess sympathetic activation results in release of adrenaline, an arrhythmic promoter

  10. Classification of Blood Pressure for Adults >/= 18 years: JNC 7

  11. Management of Hypertension in Adults Aged > / = 18 Years

  12. Classification of Antihypertensive Drugs A. Diuretics 1. Thiazides 2. Loop diuretics: Furosemide, Bumetanide 3. Potassium Sparing diuretics: Triamterene, Spirinolactone, Amiloride B. Sympathoplegic Agents 1. Centrally Acting Agents a. Acting on alpha adrenoceptor (First Generation) - methyldopa, clonidine, guanabenz, guanfacine b. Acting on imidazoline receptor (Second Generation) - moxonidine, rilmenidine 2. Ganglionic Blocking Agent - Trimetaphan 3. Adrenergic Neuron Blocking Agents - reserpin, guanethidine, guanadrel 4. Beta-adrenergic Antagonists - propranolol; metaprolol, atenolol, pindolol, acebutolol, bisoprolol 5. Alpha adrenergic Antagonists - prazocin, phenoxybenzamine, phentolamine 6. Mixed Antagonists (Alpha & Beta) - labetalol, carvedilol

  13. C. Vasodilators 1. Oral Vasodilators: hydralazine, minoxidil 2. Parenteral Vasodilators: nitroprusside, diazoxide, fenoldepam 3. Calcium Channel Blockers: Dihydropyridines - nifedipine, amlodipine, felodipine. nimodipine, nicardipine, isradipine, licidipine; Phenylalkylamines --vcrapamil; Bcnzothiazcpincs - diltiazcm D. Inhibitors of Rcnin Aogiotcnsin System: 1. Angiotensin 11 Antagonists - saralasin, losartan, valsartan 2. ACE inhibitors - captopril, qiunapril, enalapril, pcrindopril, lisinopril

  14. Loop Diuretics • furosemide, bumetamide and torsemide • act primarily on the thick ascending loop of Henle which reabsorbs 20-30% of the filtered load of NaCl • most potent diuretics in clinical use • Very steep dose-response natriuresis curve, termed high-ceiling diuretics

  15. Furosemide • Rapidly absorbed from the GIT • Binds avidly to plasma proteins • Rapidly eliminated from the body, by renal excretion (Proximal tubular secretion) • Onset of action: 30-60 min after oral administration or 2-5 min after IV • Duration of action: PO-6 hours, 2-5 min IV

  16. Thiazide Diuretics • Low ceiling, flat dose response • Slow onset of effect, long duration of action (6-12 hours) • Reduce urine calcium • Hydrochlorothiazide – sulfonamide derivative • Indapamide – new thiazide like agent with a significant vasodilating effect

  17. Potassium sparing diuretics • Spirinolactone – aldosterone antagonist in the collecting tubules has slow onset and offset of action (24-72 hours) - direct inhibitor of aldosterone at steroid receptor - Causes an increase in Na clearance & decrease in K excretion • Amiloride and triamterene – inhibitors of tubular potassium secretion, with 12-24 hrs duration of action

  18. DIURETICS Mechanism of Antihypertensive Effects of Diuretics Decreased PVR Reduction in body sodium Decrease interstitial fluid volume Fell in smooth muscle sodium concentration Decrease in 1C calcium concentration

  19. Toxicity • Potassium depletion (except K-sparing diuretics) • Magnesium depletion • Impair glucose tolerance • Increase serum lipid concentration • Increase uric acid concentration

  20. Action of Centrally - Acting Antihypertensive Agents Alpha-methyldopa Guanfacine Guanabenz Clonidine Moxonidine Rilmenidine Imidazoline receptor Alpha-adrenoceptor Nucleus Tractus Solitarius Rostral Ventrolateral Medulla Salivary Glands Nucleus Coeruleus Inhibition of Sympathetic Nerve Activity Sedation Dry mouth Inhibition of norepinephrine release Decrease in vasoconstriction Vasodilation Lower Blood Pressure

  21. Methyldopa • Mild to moderate hypertension • Decrease PVR • Extensive first pass metabolism • Effect 4-6 hours up to 24 hours • Side effects: sedation, lactation, positive coombs test

  22. Clonidine • Decrease cardiac output, HR and relaxation of capacitance vessels, decrease PVR • Decrease renal vascular resistance & maintenance of RBF • 75% bioavailability • Half-life 8-12 hours • Lipid soluble, rapidly enters brain from circulation • Toxicity: dry mouth, sedation, life threatening HTN crisis in sudden withdrawal

  23. Ganglionic-blocking Agents • Drugs that block stimulation of postganglionic autonomic neurons by Ach • No longer available because of intolerable toxicities • Trimetaphan – prototype drug, given IV, short-acting, that block the nicotine receptor

  24. Adrenergic Neuron Blocking Agents • Lower BP by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons • Guanethidine • Bethanidine • Guanadrel • Debrisoquin • reserpine

  25. Reserpine • Effective & safe for mild to moderate HTN • Enters BBB • Causes depletion of central amines  sedation, mental depression & parkinsonism symptoms • Lowers BP by decreased CO and PVR • Half-life 24-48 hours

  26. Guanethidine • Treatment of severe HTN • MOA is associated with reduce CO due to bradycardia & relaxation of capacitance vessels • Half-life 5 days, bioavailability 3-50% • 50% cleared by the kidneys • Large volume of distribution • Too polar to enter the CNS • Has none of the central effects • toxicity: postural hypotension, retrograde ejaculation

  27. BETA – ADRENOCEPTOR BLOCKING DRUGS Nonselective Selective With alpha-blocking ability Labetalol Bucindolol Carvedilol Pindolol Penbutolol Carteolol Alprenolol Dilevatol Oxyprenolol Acebutolol (Practolol) Celiprolol Atenolol Esmolol Metoprolol Bevantolol Bisoprolol Betaxolol Nadolol Propranolol Timolol Sotalol Tetralol

  28. Propranolol • Well absorbed orally • Extensive first pass metabolism • Rapidly distributed, large volume of distribution • Half-life 3-6 hours • Dose: 80-480 mg/day • Toxicity: result from blockade of cardiac, vascular & bronchial beta receptors • GIT side effects • Increase triglycerides & decrease HDL

  29. Mechanism of Action Beta-adrenoceptor blockers Decrease PVR Decreased Blood Volume Decreased in Blood Pressure

  30. Alpha-adrenergic Antagonists • Reduce arterial pressure by dilating both resistance and capacitance vessels • Cause sympathetically mediated reflex increase in HR & plasma renin activity • Long-term therapy: vasodilatation persists, but CO, HR & plasma renin activity return to normal • Selective: prazosin, terazosin, doxazosin • Non-selective: phentolamine, phenoxybenzamine

  31. Prazosin, terazosin, doxazosin • Half-life 3-4 hrs (prazosin) • Extensively metabolized but undergoes very little first-pass metabolism, half-life 12 hours, given OD (terazosin) • Doxazosin has intermediate bioavailability, half-life 22 hours, given once a day • Toxicity: first dose phenomenon, dizziness, palpitation, headache & lassitude, positive serum Antinuclear factor (prazosin)

  32. Mechanism of Action-Vasodilators • Inhibition of calcium influx into arterial smooth muscle cells  relax smooth muscle of arterioles  decreasing systemic vascular resistance  decrease arterial pressure • direct arterial dilation triggers baroreceptor, svmpathetic activation resulting in tachycardia, increase cardiac output, increase myocardial oxygen demand • cause significant fluid retention • work best in combination with other antihypertensive drugs (anti-adrenergic & diuretics) to overcome untoward effects

  33. Oral Vasodilators Hydralazine • dilate arterioles but not veins • effective in severe HTN • well absorbed from GIT • systemic bioavailability is low • half-life 1 hour • duration of action 12 hours • toxicity: immunological reactions, drug-induced lupus syndrome, serum sickness, hemolytic anemia, vasculitis & rapidly progressive glomerulonephritis

  34. Minoxidil • Metabolized by hepatic sulfotransferase to the active molecule, minoxidil N-O sulfate • Well absorbed • Half-life 3-4 hours • Duration of action 24 hours or longer • Toxicity: fluid and salt retention, hypertrichosis

  35. Parenteral VasodilatorsNitroprusside • Dilates both arterial and venous vessels • Used in treating hypertensive emergencies, severe heart failure • Rapidly lowers BP • Given by IV infusion • Effects disappear within 1-10 min after discontinuation • Eliminated by the kidney • Toxicity: metabolic acidosis, arrhythmia, hypotension, death, thiocyanate poisoning, delayed hypothyroidism, methemoglobinemia

  36. Diazoxide • Arteriolar dilator – hyperpolarizes arterial muscle cells by activating ATP sensitive K channels, this cause relaxation of the vascular smooth muscle • Used to treat hypertensive emergencies • Toxicity: hypotension

  37. Fenoldepam • Newer peripheral arteriolar dilator • Acts primarily as an agonist to dopamine D1 receptors, resulting in dilatation of peripheral arteries and natriuresis • Administered by IV infusion • Half-life 10 mins • Toxicity: reflex tachycardia, headache, flushing, increased intraocular pressure

  38. Calcium Channel Blockers • Dilate peripheral arterioles • Dihydropyridines more selective as vasodilator • less cardiac depressant effects • Verapamil greatest effect on heart, decrease heart rate and cardiac output

  39. Adverse Effects • Nifedipine: 17 - 20% of patients - hypotension, headache, peripheral edema • Verapamil: 17 - 20% of patients - cardiodepression (major), hypotension, peripheral edema (moderate), headache, constipation (minor) • Diltiazem: 2 - 5% of patients - hypotension, peripheral edema, AV block, cardiodepression

  40. ANGIOTENSIN - CONVERTING ENZYME (ACE) INHIBITORS Mechanism of Action Reduction of circulating levels of Angiotensin II Decrease aldosterone secretion; blunts increased in sympathetic activity Direct inhibition of vascular hypertrophy Enhance endothelium dependent relaxation Inhibits the degradation of bradykinin – vasodilator, weak anti-aggregant peptide, enhances synthesis of vasodilatory prostaglandins Vasodilation Decrease peripheral vascular resistance Decrease blood pressure

  41. Various ACE inhibitors

  42. Captopril • Rapidly absorbed • Bioavalability 70% with fasting, 30-40% with food • Half-life < 3 hours • Metabolized to disulfide conjugates • Eliminated in kidney • HTN in DM – diminish proteinuria & stabilize renal function

  43. Toxicity • Severe hypotension • Acute renal failure • Hyperkalemia • Dry cough sometimes with wheezing & angioedema • Contraindications • 2nd & 3rd trimester of pregnancy • Drug interaction • Potassium supplements • Potassium - sparing diuretics • NSAIDs

  44. ANGIOTENSIN II RECEPTOR -BLOCKING AGENTS • bind selectively to AT1 receptors and displace angiotensin II • blockers of the angiotensin II type 1 (AT1) receptor • 1st drugs marketed: losartan, valsatran • candesartan, eprosartan, irbesartan, & telmisartan - no effect on bradykinin metabolism  more selective blockers of angiotensin effects • SE: similar to ACE inhibitors but less cough and angioedema

  45. Thank you very much and godbless!!! Florencia G. dela Cruz, MD; RMT

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