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IVMS-CV-Pharmacology- Anti-hypertensive Agents


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Individualized Webcam facilitated and e-Classroom USMLE Step 1 Tutorials with Dr. Cray. Starting at $50.00/hr., depending on pre-assessment. 1 BMS Unit is 4 hr. General Principles and some Organ …

Individualized Webcam facilitated and e-Classroom USMLE Step 1 Tutorials with Dr. Cray. Starting at $50.00/hr., depending on pre-assessment. 1 BMS Unit is 4 hr. General Principles and some Organ System require multiple units to complete in preparation for the USMLE Step 1 A HIGH YIELD FOCUS IN Biochemistry / Cell Biology, Microbiology / Immunology and the 4 P’s-Phiso, Pathophys, Path and Pharm. Webcam Facilitated USMLE Step 2 Clinical Knowledge and Clinical Skills diadactic tutorials /1 Unit is 4 hours, individualized one-on-one and group sessions, Including all Internal Medicine sub-sub-specitialities. For questions or more information..

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  • 1. CV Pharmacology-Antihypertensive Agents Recommended Reading: Antihypertensive Drugs Formative Assessment Practice question Clinical: E-Medicine Articles Hypertension Prepared and Presented by: Marc Imhotep Cray, M.D. Professor Pharmacology
  • 2. Online Reference ResourceIVMS Online Textbook SeriesEnrolled Students click to access/download e-books 2
  • 3. Normal Control of BP Normal control of BP: sympathoadrenal axis-- response to a decrease in BP  Sensed by Central baroreceptors {heart & great arteries}  Stimulation of ß-adrenergic systems  increased heart rate (positive chronotropic response)  increased force of contraction (contractility, positive inotropic response)  increased renin secretion {juxtaglomerular renal cells}  Stimulation of a-adrenoceptor systems: causes vasoconstriction 3
  • 4. Essential HypertensionWith essential hypertension, previous slide mechanisms function inappropriately  Excessive sympathetic activation  Elevated norepinephrine may promote through vascular endothelium injury:  vascular hypertrophy  atherogenesis  ß-adrenergic receptor down-regulation  Reduced endothelium-mediated vascular relaxation  Consequence: increased vasoconstrictive tone (chronic vasoconstriction)  Excessive sympathetic activation promotes enhanced peripheral vascular resistance in hypertensive patients 4
  • 5. Hypertension Defined New Hypertension GuidelinesRe: Table in the next slide Quick Reference Card Based on recommendations of the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure s/hypertension/phycard.pdf (JNC VII)Also see: E-Medicine Article Hypertension 5
  • 6. Classification of Blood Pressure (JNC VII)Category Systemic BP (mm Hg) Diastolic BP (mm Hg)Normal <130 <85High normal 130-139 85-89Hypertension Stage 1 140-159 90-99 Stage 2 160-169 100-109 Stage 3 180-209 110-119 Stage 4  210  120 6
  • 7. Classification of HTNPrimary Hypertension Specific cause unknown 90% of the cases Also known as essential or idiopathic hypertensionSecondary Hypertension Cause is known (such as eclampsia of pregnancy, renal artery disease, pheochromocytoma) 10% of the cases 7
  • 8. Physiological FactorsInfluencing Arterial PressureArterial pressure is determined by a number of interacting factors Preload & Contractility Heart rate Peripheral resistance 8
  • 9. Physiological Factors Influencing ArterialPressurePreload & Contractility As blood volume returning to heart increases, preload increases and there is enhanced filling with ventricular dilation According to Starlings Law, increased ventricular stretch usually leads to increased contractility 9
  • 10. Physiological Factors Influencing ArterialPressurePreload & Contractility(2) Increased preload and increased contractility lead to increased stroke volume and ultimately an increase in arterial pressure, all other factors remaining equal Some antihypertensive drugs decrease preload 10
  • 11. Physiological Factors Influencing ArterialPressurePreload & Contractility(3)The Nitrates are an example of preload reducing agentsSee: IAU CV PharmacologyAnti-Anginal Agents 11
  • 12. Physiological Factors InfluencingArterial Pressure Heart RateHeart rate: Since the product of heart rate and stroke volume equals cardiac output, an increase in heart rate will increase arterial blood pressure, all other factors remaining equal Some antihypertensive agents decrease heart rate (ß-adrenergic receptor antagonists, e.g.)Heart Rate X Stroke Volume = Cardiac OutputCardiac Output X Peripheral Resistance = Arterial Pressure 12
  • 13. Physiological Factors Influencing ArterialPressure Peripheral resistancePeripheral resistance: For a given cardiac output, blood pressure depends only on peripheral resistance Some antihypertensive drugs act to reduce peripheral resistance (Also known as afterload reducing agents) 13
  • 14. Physiological Factors InfluencingArterial PressureDepending on mechanism of action, a given antihypertensive may:  Reduce preload  Reduce afterload  Decrease heart rate  Reduce peripheral resistance  Reduce contractility. Many antihypertensive drugs have multiple effects 14
  • 15. Anti-Hypertensive DrugClasses1. Diuretics2. Sympatholytics3. Vasodilators4. Calcium Channel Blockers5. Angiotensin Converting Enzyme (ACE) Inhibitor 15
  • 16. Anti-Hypertensive Drug Classes-1) DiureticsThiazides Potassium Sparing Loop Diuretics•Hydrochlorothiazide •Amiloride (Midamor) •Furosemide (Lasix),(HydroDIURIL) •Spironolactone Bumetanide (Bumex),•Chlorthalidone (Aldactone) Ethacrynic acid(Hygroton) •Triamterene (Edecrin)•Chlorothiazide (Dyrenium) •Torsemide(Diuril) (Demadex)•Indapamide (Lozol)•Metolazone(Zaroxolyn) 16
  • 17. Anti-Hypertensive Drug Classes- 2) SympatholyticsCentrally Active Adrenergic Adrenoceptor Neuron Blocker Antagonists•Clonidine(Catapres) •Guanadrel (Hylorel) • Labetalol•Methyldopa •Guanethidine (Trandate,(Aldomet) (Ismelin) Normodyne) (alpha•Guanabenz •Reserpine & beta)(Wytensin) •Prazosin (Minipress)•Guanfacine (Tenex) (alpha), Terazosin (Hytrin) (alpha) 17
  • 18. Anti-Hypertensive Drug Classes- 3) Vasodilators Nitroprusside Diazoxide Hydralazine Minoxidil sodium(Hyperstat) (Apresoline) (Loniten) (Nipride) 18
  • 19. Anti-Hypertensive Drug Classes- 4) Calcium Channel Blockers•Dihydropyridines •Non-Dihydropyridines •Amlodipine (Norvasc), •Bepridil (Vascor) Felodipine (Plendil) •Diltiazem (Cardiazem) •Nimodipine •Verapamil (Isoptin, Calan) •Isradipine •Nicardipine •Nifedipine 19
  • 20. Anti-Hypertensive Drug Classes- 5) Angiotensin Converting Enzyme Inhibitors•Benazepril (Lotensin) •Moexipril (Univasc)•Captopril (Capoten) •Quinapril (Accupril)•Enalapril (Vasotec) •Ramipril (Altace)•Fosinopril (Monopril) •Losartin (Cozaar), Irbesartin***•Lisinopril (Prinvivil, Zestril) *** ***angiotensin receptor blocker 20
  • 21. Antihypertensive Agents:Categories Discussion Adrenergic agents Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers Calcium channel blockers Diuretics Vasodilators 21
  • 22. Antihypertensive Agents:Categories Adrenergic Agents  Alpha1 blockers  Beta blockers (cardioselective and nonselective)  Centrally acting alpha blockers  Combined alpha-beta blockers  Peripheral-acting adrenergic agents 22
  • 23. Antihypertensive Agents: Mechanism of ActionAdrenergic AgentsAlpha1 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 23
  • 24. Antihypertensive Agents:Adrenergic AgentsAlpha1 Blockers doxazosin (Cardura) prazosin (Minipress) terazosin (Hytrin) 24
  • 25. Antihypertensive Agents:Mechanism of ActionAdrenergic AgentsCentral-Acting Adrenergics Stimulate alpha2-adrenergic receptors Sympathetic outflow from the CNS is decreased Result: decreased blood pressure 25
  • 26. Antihypertensive Agents:Adrenergic AgentsCentral-Acting Adrenergics clonidine (Catapres) methyldopa (Aldomet) (drug of choice for hypertension in pregnancy) 26
  • 27. Antihypertensive Agents: Mechanism of ActionAdrenergic AgentsAdrenergic Neuronal Blockers (peripherally acting) Inhibit release of norepinephrine Also deplete norepinephrine stores SNS (peripheral adrenergic nerves) is not stimulated Result: decreased blood pressure 27
  • 28. Antihypertensive Agents:Adrenergic AgentsAdrenergic Neuronal Blockers (peripherally acting) reserpine guanadrel (Hylorel) guanethidine (Ismelin) 28
  • 29. Antihypertensive Agents:Adrenergic AgentsTherapeutic 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 29
  • 30. Antihypertensive Agents: Adrenergic AgentsTherapeutic Uses Central-Acting Adrenergics  Treatment of hypertension, either alone or with other agents  Usually used after other agents have failed due to side effects 30
  • 31. Antihypertensive Agents:Adrenergic AgentsTherapeutic Uses Central-Acting Adrenergics(2)  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 31
  • 32. Antihypertensive Agents:Adrenergic AgentsTherapeutic Uses Adrenergic neuronal blockers (peripherally acting)  Treatment of hypertension, either alone or with other agents  Seldom used because of frequent side effects 32
  • 33. Antihypertensive Agents: Adrenergic AgentsSide EffectsMost common: dry mouth drowsiness sedation constipationOther: headaches sleep disturbances nausea rash cardiac disturbances (palpitations) HIGH INCIDENCE OF ORTHOSTATIC HYPOTENSION 33
  • 34. Antihypertensive Agents: Categories- (ACE Inhibitors)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 34
  • 35. Antihypertensive Agents:Mechanism of ActionACE InhibitorsRAAS: Renin Angiotensin-Aldosterone System When the enzyme angiotensin I is converted to angiotensin II, the result is potent vasoconstriction and stimulation of aldosterone 35
  • 36. Antihypertensive Agents:Mechanism of Action(2)ACE Inhibitors Result of vasoconstriction: increased systemic vascular resistance and increased afterload Therefore, increased BP 36
  • 37. Antihypertensive Agents:Mechanism of Action(3)ACE Inhibitors Aldosterone stimulates water and sodium resorption. Result: increased blood volume, increased preload, and increased B 37
  • 38. Antihypertensive Agents: Mechanism of Action(4)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 38
  • 39. Diagram illustrates the renin-angiotensin-aldosterone axis 39
  • 40. 40
  • 41. Antihypertensive AgentsACE Inhibitorscaptopril (Capoten) Short half-life, must be dosed more frequently than othersenalapril (Vasotec) The only ACE inhibitor available in oral and parenteral forms 41
  • 42. Antihypertensive Agents-ACE Inhibitors(2)lisinopril (Prinivil and Zestril)quinapril (Accupril) Newer agents, long half-lives, once-a- day dosing Several other agents available 42
  • 43. Antihypertensive Agents: Therapeutic UsesACE 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 43
  • 44. Antihypertensive Agents:Side EffectsACE Inhibitors Fatigue Dizziness Headache Mood changes Impaired taste Dry, nonproductive cough, reverses when therapy is stopped NOTE: first-dose hypotensive effect may occur!! 44
  • 45. Antihypertensive Agents:CategoriesAngiotensin II Receptor Blockers (A II Blockers or ARBs) Newer class Well-tolerated Do not cause coughing 45
  • 46. Antihypertensive Agents:Mechanism of ActionAngiotensin 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 46
  • 47. Antihypertensive Agents:Angiotensin II Receptor Blockers losartan (Cozaar) eposartan (Teveten) valsartan (Diovan) irbesartan (Avapro) candesartan (Atacand) telmisartan (Micardis) 47
  • 48. Antihypertensive Agents:Therapeutic UsesAngiotensin II Receptor Blockers Hypertension Adjunctive agents for the treatment of CHF May be used alone or with other agents such as diuretics 48
  • 49. Antihypertensive Agents:Side EffectsAngiotensin II Receptor Blockers Upper respiratory infections Headache May cause occasional dizziness, inability to sleep, diarrhea, dyspnea, heartburn, nasal congestion, back pain, fatigue 49
  • 50. Antihypertensive Agents:CategoriesCalcium Channel Blockers Benzothiazepines Dihydropyridines Phenylalkylamines 50
  • 51. Antihypertensive Agents:Mechanism of ActionCalcium 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 51
  • 52. Antihypertensive Agents- Calcium Channel Blockers Benzothiazepines:  diltiazem (Cardizem, Dilacor) Phenylalkamines:  verapamil (Calan, Isoptin) Dihydropyridines:  amlodipine (Norvasc), bepridil (Vascor), nicardipine (Cardene)  nifedipine (Procardia), nimodipine (Nimotop) 52
  • 53. Antihypertensive Agents:Therapeutic UsesCalcium Channel Blockers Angina Hypertension Dysrhythmias Migraine headaches 53
  • 54. Antihypertensive Agents: Side EffectsCalcium Channel Blockers Cardiovascular  hypotension, palpitations, tachycardia Gastrointestinal  constipation, nausea Other  rash, flushing, peripheral edema, dermatitis 54
  • 55. Antihypertensive Agents: Diuretics Decrease the plasma and extracellular fluid volumes Results: decreased preload decreased cardiac output decreased total peripheral resistance Overall effect: decreased workload of the heart, and decreased blood pressure 55
  • 56. Antihypertensive Agents: Mechanism of ActionVasodilators Directly relaxes arteriolar smooth muscle Result: decreased systemic vascular response, decreased afterload, and PERIPHERAL VASODILATION 56
  • 57. Nitrous Oxide and VasodilationAfter receptor stimulation, L-arginine-dependent metabolic pathwayproduces nitric oxide (NO) or thiolderivative (R-NO). NO causesincrease in cyclic guanosinemonophosphate (cGMP), whichcauses relaxation of vascular smoothmuscle. EDRF=endothelium-derivedrelaxing factor.From: Inhaled Nitric Oxide TherapyROBERT J. LUNN, M.D.From the Department of Anesthesiology, Mayo ClinicRochester, Rochester, Minnesota. 57
  • 58. Antihypertensive AgentsVasodilators diazoxide (Hyperstat) hydralazine HCl (Apresoline) minoxidil (Loniten, Rogaine) sodium nitroprusside (Nipride, Nitropress) 58
  • 59. Antihypertensive Agents:Therapeutic UsesVasodilators Treatment of hypertension May be used in combination with other agents Sodium nitroprusside and diazoxide IV are reserved for the management of hypertensive emergencies 59
  • 60. Antihypertensive Agents: Side EffectsVasodilators Hydralazine:  dizziness, headache, anxiety, tachycardia, nausea and vomiting, diarrhea, anemia, dyspnea, edema, nasal congestion Sodium nitroprusside:  bradycardia, hypotension, possible cyanide toxicity 60
  • 61. Stepwise Approach to Tx of Essential HTN Medication Sequence Antihypertensive beginning with a low dosage of either an ACE inhibitor, calcium channel blocker or beta blocker and proceeding, if needed to add a diuretic and ultimately additional more powerful drugs, such as centrally acting sympatholytics, peripheral vasodilators or combination. At each step dosages are reviewed and if the patients hypertension is controlled then therapy may be continued with review for possible removal of medication.Figure adapted from Harrisons "Principles of Internal Medicine, Thirteenth Edition, p. 1128 61
  • 62. ResourcesJNC GUIDELINES The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) On the JNC home page, there are a number of important resources for clinicians as well as patient resources, including: JNC 7 Complete Report: The Science Behind the New Guidelines (86 pages) JNC 7 Express Highlights "Must Know" Clinical Practice Updates (34 pages) JNC 7 Reference Card (2 pages)- A great summary of Evaluation, Treatment, 62