IVMS-CV -Pharmacology Anti-Hypertensive Agents

CV Pharmacology-Antihypertensive AgentsPrepared and Presented by: Marc Imhotep Cray, M.D.Professor PharmacologyRecommended Reading:Antihypertensive DrugsFormative AssessmentPractice questionClinical:E-Medicine ArticlesHypertension9/29/20092Normal 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 vasoconstriction9/29/20093Essential 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 patients9/29/20094Hypertension DefinedRe: Table in the next slideBased on recommendations of the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII)Also see: E-Medicine Article HypertensionNew Hypertension Guidelines Quick Reference Cardhttp://www.nhlbi.nih.gov/guidelines/hypertension/phycard.pdf9/29/20095Classification of Blood Pressure(JNC VII)Category Systemic BP (mm Hg) Diastolic BP (mm Hg)Normal<130<85High normal130-13985-89HypertensionStage 1140-15990-99Stage 2160-169100-109Stage 3180-209110-119Stage 42101209/29/20096Classification 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 cases9/29/20097Physiological Factors Influencing Arterial Pressure Arterial pressure is determined by a number of interacting factorsPreload & Contractility Heart ratePeripheral resistance9/29/20098Physiological Factors Influencing Arterial Pressure Preload & ContractilityAs blood volume returning to heart increases, preload increases and there is enhanced filling with ventricular dilation According to Starling's Law, increased ventricular stretch usually leads to increased contractility 9/29/20099Physiological Factors Influencing Arterial Pressure Preload & 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 preload9/29/200910Physiological Factors Influencing Arterial Pressure Preload & Contractility(3)The Nitrates are an example of preload reducing agentsSee: IAU CV PharmacologyAnti-Anginal Agents9/29/200911Physiological Factors Influencing Arterial 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 Output Cardiac Output X Peripheral Resistance = Arterial Pressure9/29/200912Physiological Factors Influencing Arterial Pressure 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)9/29/200913Physiological Factors Influencing Arterial 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 effects9/29/200914Anti-Hypertensive Drug Classes 1.Diuretics 2.Sympatholytics 3.Vasodilators 4.Calcium Channel Blockers 5.Angiotensin Converting Enzyme (ACE) Inhibitor9/29/200915Anti-Hypertensive Drug Classes-1) Diuretics Thiazides•Hydrochlorothiazide (HydroDIURIL) •Chlorthalidone (Hygroton) •Chlorothiazide (Diuril)•Indapamide (Lozol) •Metolazone (Zaroxolyn) Potassium Sparing•Amiloride (Midamor) •Spironolactone (Aldactone) •Triamterene (Dyrenium) Loop Diuretics•Furosemide (Lasix), Bumetanide (Bumex), Ethacrynic acid (Edecrin) •Torsemide (Demadex) 9/29/200916Anti-Hypertensive Drug Classes-2) SympatholyticsCentrally Active•Clonidine (Catapres)•Methyldopa (Aldomet)•Guanabenz (Wytensin)•Guanfacine (Tenex) Adrenergic Neuron Blocker•Guanadrel (Hylorel)•Guanethidine (Ismelin)•ReserpineAdrenoceptor Antagonists•Labetalol (Trandate, Normodyne) (alpha & beta)•Prazosin (Minipress) (alpha), Terazosin (Hytrin) (alpha)9/29/200917Anti-Hypertensive Drug Classes-3) VasodilatorsDiazoxide (Hyperstat)Hydralazine (Apresoline)Minoxidil (Loniten)Nitroprusside sodium (Nipride)9/29/200918Anti-Hypertensive Drug Classes-4) Calcium Channel Blockers•Dihydropyridines•Amlodipine (Norvasc), Felodipine (Plendil)•Nimodipine•Isradipine•Nicardipine•Nifedipine•Non-Dihydropyridines•Bepridil (Vascor)•Diltiazem (Cardiazem)•Verapamil (Isoptin, Calan)9/29/200919Anti-Hypertensive Drug Classes-5) Angiotensin Converting Enzyme Inibitors•Benazepril (Lotensin)•Captopril (Capoten)•Enalapril (Vasotec)•Fosinopril (Monopril)•Lisinopril (Prinvivil, Zestril)•Moexipril (Univasc)•Quinapril (Accupril)•Ramipril (Altace)•Losartin (Cozaar), Irbesartin*** ******angiotensin receptor blocker9/29/200920Antihypertensive Agents: Categories DiscussionAdrenergic agentsAngiotensin-converting enzyme inhibitorsAngiotensin II receptor blockersCalcium channel blockersDiureticsVasodilators9/29/200921Antihypertensive Agents: CategoriesAdrenergic AgentsAlpha1 blockersBeta blockers (cardioselective and nonselective)Centrally acting alpha blockersCombined alpha-beta blockersPeripheral-acting adrenergic agents9/29/200922Antihypertensive Agents: Mechanism of ActionAdrenergic AgentsAlpha1 Blockers (peripherally acting)Block the alpha1-adrenergic receptorsThe SNS is not stimulatedResult:DECREASED blood pressureStimulation of alpha1-adrenergic receptors causes HYPERtensionBlocking alpha1-adrenergic receptors causes decreased blood pressure9/29/200923Antihypertensive Agents: Adrenergic AgentsAlpha1 Blockersdoxazosin (Cardura)prazosin (Minipress)terazosin (Hytrin)9/29/200924Antihypertensive Agents: Mechanism of ActionAdrenergic AgentsCentral-Acting AdrenergicsStimulate alpha2-adrenergic receptorsSympathetic outflow from the CNS is decreasedResult:decreased blood pressure9/29/200925Antihypertensive Agents: Adrenergic AgentsCentral-Acting Adrenergicsclonidine (Catapres)methyldopa (Aldomet) (drug of choice for hypertension in pregnancy)9/29/200926Antihypertensive Agents: Mechanism of ActionAdrenergic AgentsAdrenergic Neuronal Blockers(peripherally acting)Inhibit release of norepinephrineAlso deplete norepinephrine storesSNS (peripheral adrenergic nerves) is not stimulatedResult:decreased blood pressure9/29/200927Antihypertensive Agents: Adrenergic AgentsAdrenergic Neuronal Blockers(peripherally acting)reserpineguanadrel (Hylorel)guanethidine (Ismelin)9/29/200928Antihypertensive 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 diuretics9/29/200929Antihypertensive 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 effects9/29/200930Antihypertensive 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 persons9/29/200931Antihypertensive Agents: Adrenergic AgentsTherapeutic UsesAdrenergic neuronal blockers (peripherally acting) Treatment of hypertension, either alone or with other agentsSeldom used because of frequent side effects9/29/200932Antihypertensive Agents: Adrenergic AgentsSide EffectsMost common:dry mouthdrowsinesssedationconstipationOther:headachessleep disturbancesnausearashcardiac disturbances (palpitations)HIGH INCIDENCE OF ORTHOSTATIC HYPOTENSION9/29/200933Antihypertensive 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 blocker9/29/200934Antihypertensive 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 aldosterone9/29/200935Antihypertensive Agents: Mechanism of Action(2)ACE InhibitorsResult of vasoconstriction: increased systemic vascular resistance and increased afterload Therefore, increased BP9/29/200936Antihypertensive Agents: Mechanism of Action(3)ACE InhibitorsAldosterone stimulates water and sodium resorption.Result: increased blood volume, increased preload, and increased B9/29/200937Antihypertensive 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, bradykininResult:decreased systemic vascular resistance (afterload), vasodilation, and therefore, decreased blood pressure9/29/200938Diagram illustrates the renin-angiotensin-aldosterone axis 9/29/2009399/29/200940Antihypertensive AgentsACE Inhibitorscaptopril (Capoten)Short half-life, must be dosed more frequently than othersenalapril (Vasotec)The only ACE inhibitor available in oral and parenteral forms9/29/200941Antihypertensive Agents-ACE Inhibitors(2)lisinopril (Prinivil and Zestril) quinapril(Accupril)Newer agents, long half-lives, once-a-day dosingSeveral other agents available9/29/200942Antihypertensive 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 diabetesDrugs of choice in hypertensive patients with CHF9/29/200943Antihypertensive Agents: Side EffectsACE InhibitorsFatigueDizzinessHeadacheMood changesImpaired tasteDry, nonproductive cough, reverses when therapy is stoppedNOTE: first-dose hypotensive effect may occur!!9/29/200944Antihypertensive Agents: CategoriesAngiotensin II Receptor Blockers(A II Blockers or ARBs)Newer classWell-toleratedDo not cause coughing9/29/200945Antihypertensive 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 aldosterone9/29/200946Antihypertensive Agents:Angiotensin II Receptor Blockerslosartan (Cozaar)eposartan (Teveten)valsartan (Diovan)irbesartan (Avapro)candesartan (Atacand)telmisartan (Micardis)9/29/200947Antihypertensive Agents: Therapeutic UsesAngiotensin II Receptor BlockersHypertensionAdjunctive agents for the treatment of CHFMay be used alone or with other agents such as diuretics9/29/200948Antihypertensive Agents: Side EffectsAngiotensin II Receptor BlockersUpper respiratory infectionsHeadacheMay cause occasional dizziness, inability to sleep, diarrhea, dyspnea, heartburn, nasal congestion, back pain, fatigue9/29/200949Antihypertensive Agents: CategoriesCalcium Channel BlockersBenzothiazepinesDihydropyridinesPhenylalkylamines9/29/200950Antihypertensive 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 pressure9/29/200951Antihypertensive Agents-Calcium Channel BlockersBenzothiazepines:diltiazem (Cardizem, Dilacor)Phenylalkamines:verapamil (Calan, Isoptin)Dihydropyridines:amlodipine (Norvasc), bepridil (Vascor), nicardipine (Cardene)nifedipine (Procardia), nimodipine (Nimotop)9/29/200952Antihypertensive Agents: Therapeutic UsesCalcium Channel BlockersAnginaHypertensionDysrhythmiasMigraine headaches9/29/200953Antihypertensive Agents: Side EffectsCalcium Channel BlockersCardiovascularhypotension, palpitations, tachycardiaGastrointestinalconstipation, nauseaOtherrash, flushing, peripheral edema, dermatitis9/29/200954Antihypertensive Agents: DiureticsDecrease the plasma and extracellular fluid volumesResults:decreased preloaddecreased cardiac outputdecreased total peripheral resistanceOverall effect:decreased workload of the heart, and decreased blood pressure9/29/200955Antihypertensive Agents: Mechanism of ActionVasodilatorsDirectly relaxes arteriolar smooth muscleResult:decreased systemic vascular response, decreased afterload, andPERIPHERAL VASODILATION9/29/200956Nitrous Oxide and VasodilationAfter receptor stimulation, L-arginine-dependent metabolic pathway produces nitric oxide (NO) or thiol derivative (R-NO). NO causes increase in cyclic guanosine monophosphate (cGMP), which causes relaxation of vascular smooth muscle.EDRF=endothelium-derived relaxing factor. From: Inhaled Nitric Oxide TherapyROBERT J. LUNN, M.D.From the Department of Anesthesiology, Mayo Clinic Rochester, Rochester, Minnesota.http://www.mayoclinicproceedings.com/inside.asp?ref=7003sc9/29/200957Antihypertensive AgentsVasodilatorsdiazoxide (Hyperstat)hydralazine HCl (Apresoline)minoxidil (Loniten, Rogaine)sodium nitroprusside (Nipride, Nitropress)9/29/200958Antihypertensive Agents: Therapeutic UsesVasodilatorsTreatment of hypertensionMay be used in combination with other agentsSodium nitroprusside and diazoxide IVare reserved for the management of hypertensive emergencies9/29/200959Antihypertensive Agents:Side EffectsVasodilatorsHydralazine:dizziness, headache, anxiety, tachycardia, nausea and vomiting, diarrhea, anemia, dyspnea, edema, nasal congestionSodium nitroprusside:bradycardia, hypotension, possible cyanide toxicity9/29/200960Stepwise Approach to Tx of Essential HTN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 patient's hypertension is controlled then therapy may be continued with review for possible removal of medication.Figure adapted from Harrison's "Principles of Internal Medicine, Thirteenth Edition, p. 1128Antihypertensive Medication Sequence9/29/200961ResourcesJNC 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,