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Antihypertensive Agents. Hypertension. High blood pressure Normal:Systolic < 130 mmHg Diastolic < 85 mm Hg. Classification of Blood Pressure. CategorySystemic BP (mm Hg)Diastolic BP (mm Hg) Normal

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  • Antihypertensive Agents

  • HypertensionHigh blood pressureNormal:Systolic < 130 mmHg Diastolic < 85 mm Hg

  • Classification of Blood PressureCategorySystemic BP (mm Hg)Diastolic BP (mm Hg)Normal
  • Classification of Blood PressurePrimary HypertensionSpecific cause unknown90% of the casesAlso known as essential or idiopathic hypertensionSecondary HypertensionCause is known (such as eclampsia of pregnancy, renal artery disease, pheochromocytoma)10% of the cases

  • Blood Pressure = CO x SVRCO = Cardiac outputSVR = Systemic vascular resistance

  • Blood Pressure = Cardiac Output X Peripheral ResistancePreload Contractility Heart Rate CirculatingFluid VolumeRenalSodiumHandlingSympatheticNervousSystemRenin AngiotensinAldosteroneSystemArteriolarVenousVasoconstrictionVenousVascular Smooth MuscleVascular remodeling

  • VVVasomotor centerAfterloadVolumeKidneysPreloadReninAng IIAldosteroneBP= CO x TPVRb1b2a1b1Resistance arteriolesCapacitance venulesTotal Peripheral Vascular Resistance (TPVR)Ang ICardiac Output Hearta2TPVRVSMCsVascularSmooth MuscleCells

  • Antihypertensive AgentsMedications used to treat hypertension

  • 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

    Antihypertensive Agents

  • Antyhepertensive Drugs New End-Points Effects on hard end-points MortalityStrokeHeart attacksEffects on end-organ damageLeft ventricular and vascular hypertophy Effects on renal functionEffects on metabolic status Blood lipids and glucose

  • Antihypertensive Agents: CategoriesAdrenergic agentsAngiotensin-converting enzyme inhibitorsAngiotensin II receptor blockersCalcium channel blockersDiureticsVasodilators

  • Antihypertensive Agents: CategoriesAdrenergic AgentsAlpha1 blockersBeta blockers (cardioselective and nonselective)Centrally acting alpha blockersCombined alpha-beta blockersPeripheral-acting adrenergic agents

  • Beta Blockers ( lol)

  • VVVasomotor centerAfterloadVolumeKidneysPreloadReninAng IIAldosteroneBP= CO x TPVRb1b2a1b1Resistance arteriolesCapacitance venulesTPVRAng ICardiac Output Hearta2b - BlockersVSMCs??

  • Beta BlockersMechanisms and Sites of ActionNegative Chronotropic& Inotropic EffectsInhibition ofRenin Release______________________________

    - 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 b2 receptors- Attenuation of pressor response to catecholamines (stress, exercise) ______________________________

  • Cardioselectivity (Beta-1 vs Beta-2 )

    Intrinsic Sympathomimetic Activity (ISA; partial agonistic activity)

    Affinity for alpha-1 adrenergic receptors (Labetalol, Carvedilol) 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 pectorisMyocardial Infarction Ventricular arrhythmiaMigraine prophylaxisHeart FailurePerioperative Hypertension

    Beta Blockers

  • Beta Blockers ( lol)Beta-1,2-Non-SelectivePropranolol [INDERAL]Nadolol [CORGARD]Carteolol [CARTROL] *Timolol [BLOCADREN]Pindolol [VISKEN] * Sotalol [BETAPACE] Penbutol [LEVATOL] *Beta-1-SelectiveAcebutolol [SECTRAL] *Atenolol [TENORMIN]Betaxolol [KERIONE]Bisoprolol [ZEBETA] Esmolol [BREVIBLOC] Metoprolol [LOPRESSOR ]

    Beta-1,2/Alpha 1SelectiveLabetalol [TRANDATE, NORMODYNE]Carvedilol [COREG]

    * - ISAXX

  • Side Effects: Bronchospasm Bradicardia/heart block Mask and prolong the symptoms of hypoglycemiaAbrupt withdrawal can precipitate MI Cold extremities, Raynauds phenomenon, intermittent claudication Decreased exercise tolerance; fatigue, depression and impotence CNS: sleep disturbance, vivid dreams, nightmares Effects of plasma lipids

    Beta Blockers

  • YES: (useful in)Younger patients Anxious patients Angina pectoris Post-MI patient Beta BlockersNo: (avoid in)Patients with COPD IDDM Pateints with peripheral vascular disease Raynauds syndrome 2nd and 3rd degree block Energetic patients

  • Antihypertensive Agents: Mechanism of ActionAdrenergic AgentsAlpha1 Blockers (peripherally acting)Block the alpha1-adrenergic receptorsThe SNS is not stimulated Result: DECREASED blood pressure Stimulation of alpha1-adrenergic receptors causes HYPERtensionBlocking alpha1-adrenergic receptors causes decreased blood pressure

  • VVVasomotor centerAfterloadVolumeKidneysPreloadReninAng IIAldosteroneBP= CO x TPVRb1Resistance arteriolesCapacitance venulesTPVRAng ICardiac Output Hearta2a1 ReceptorsBlockersb1a1a1a1a1

  • a1- Receptor BlockersInhibition of VasoconstrictionInduced by EndogenousCatecholamines atArterioles and VeinsReduced Peripheral ResistanceandReduced Preload

  • Antihypertensive Agents: Adrenergic AgentsAlpha1 Blockersdoxazosin (Cardura)prazosin (Minipress)terazosin (Hytrin)

  • Antihypertensive Agents: Mechanism of ActionAdrenergic AgentsCentral-Acting AdrenergicsStimulate alpha2-adrenergic receptorsSympathetic outflow from the CNS is decreased Result: decreased blood pressure

  • Antihypertensive Agents: Adrenergic AgentsCentral-Acting Adrenergicsclonidine (Catapres)methyldopa (Aldomet) (drug of choice for hypertension in pregnancy)

  • VVVasomotor centerAfterloadVolumeKidneysPreloadReninAng IIAldosteroneBP= CO x TPVRb1Resistance arteriolesCapacitance venulesTPVRAng ICardiac Output Hearta2Central a2 Agonistsb1VSMCXXXXX

  • Diminished CNSSympathetic OutflowAlpha-2 AgonistNE & EPIPre-synaptic NeuronAlpha-2 ReceptorAlpha-1 ReceptorBeta ReceptorPost-synapticEffectorActivation of Pre-synapticAlpha-2 Receptors ReducesNE & EPI Release at SynapseRostralVentrolateralMedullaCentral a2Agonists

  • Antihypertensive Agents: Mechanism of ActionAdrenergic AgentsAdrenergic Neuronal Blockers (peripherally acting)Inhibit release of norepinephrineAlso deplete norepinephrine storesSNS (peripheral adrenergic nerves) is not stimulated Result: decreased blood pressure

  • Antihypertensive Agents: Adrenergic AgentsAdrenergic Neuronal Blockers (peripherally acting)reserpineguanadrel (Hylorel)guanethidine (Ismelin)

  • Antihypertensive Agents: Adrenergic Agents Therapeutic UsesAlpha1 blockers (peripherally acting)Treatment of hypertensionRelief of symptoms of BPHManagement of of severe CHF when used with cardiac glycosides and diuretics

  • Antihypertensive Agents: Adrenergic AgentsTherapeutic UsesCentral-Acting AdrenergicsTreatment of hypertension, either alone or with other agentsUsually used after other agents have failed due to side effectsAlso may be used for treatment of severe dysmenorrhea, menopausal flushing, glaucomaClonidine is useful in the management of withdrawal symptoms in opioid- or nicotine-dependent persons

  • Antihypertensive Agents: Adrenergic AgentsTherapeutic UsesAdrenergic neuronal blockers (peripherally acting) Treatment of hypertension, either alone or with other agentsSeldom used because of frequent side effects

  • Antihypertensive Agents: Adrenergic AgentsSide EffectsMost common:dry mouthdrowsinesssedationconstipationOther:headachessleep disturbancesnausearashcardiac disturbances (palpitations) HIGH INCIDENCE OF ORTHOSTATIC HYPOTENSION

  • Antihypertensive Agents: CategoriesAngiotensin-Converting Enzyme Inhibitors(ACE Inhibitors)Large group of safe and effective drugsOften used as first-line agents for CHF and hypertensionMay be combined with a thiazide diuretic or calcium channel blocker

  • A n g i o t e n s i n II Peripheral resistanceRenal functionCardiovascular structure

    RapidPressor Response1. Direct vasoconstriction

    2. Enhancement of peripheral noradrenergic neurotransmission 3. Increased central (CNS) sympathetic discharge

    4. Release of catecholamines from adrenal medulla1. 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) SlowPressor ResponseCardiovascular Hypertrophy and Remodeling1. 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)

  • VVVasomotor centerAfterloadVolumeKidneysPreloadReninAng IIAldosteroneBP= CO x TPVRb1b2a1b1Resistance arteriolesCapacitance venulesTPVRAng ICardiac Output Hearta2

    ACE Inhibitors

    VSMCs

  • AngiotensinogenAng IAng IIRenin (renal)ReninAngiotensinogenAngiotensinogen Ang ImRNAAT1 Ang IIAT1 A C E ACE (autocrine)(paracrine)(endocrine)mRNAReninmRNAA C E endothelialcelltissue(VSM cells)(myocyte ) (liver)mRNAA C E mRNAmRNAReninAngiotensinogenAngiotensinogenAng IACEAng IILocal (tissue) RAS:Intrinsic; Extrinsicblood vessel

  • BradykininA C E Kallikrein ReninAngiotensin IIAngiotensin IAngiotensinogenAngiotensin Converting Enzyme ACEIsKininogens

    Inactive PeptidesBK receptorsAT-1 receptorsACEIs

  • 20 mmHgAfferentarterioleBowmanscapsuleEfferentarterioleArterialpressure+Angi