Cardiovascular System & Its Diseases Lecture #2

1 Lecture #2 HypertensionDr. Derek Bowie,Department of Pharmacology & Therapeutics,Room 1317, McIntyre Bldg, McGill System & Its DiseasesCardiovascular System & Its Diseases :HypertensionPart 1: What Do We Know?Part 2: How Do We Treat?OverviewBackground common CV diseaseDiagnosiselevated BPAetiologyessential or secondaryNormal Regulation Of Blood PressureDrug TherapySurgical InterventionPresent In 24 % Total USA Population Source NHANES SurveyPrevalence varies with Age, Race, Education, Diet and other factorsMost Common Cardiovascular DiseaseIncreases incidence of Renal Failure, Coronary disease ,Cardiac Failure & StrokeWhat Do We Know?

2 : BackgroundCardiovascular System & Its Diseases :HypertensionRepeated (usually 3 measurements), ElevatedBlood Pressure Above Normal Levels(BP < 120/90 mm Hg)Even Mild Hypertension (BP > 140/90 mm Hg)increases risksCardiovascular System & Its Diseases :HypertensionWhat Do We Know?: DiagnosisOften Asymptomatic until overt organ damageis imminent or has occurredBlood Pressure is Age-DependentCardiovascular System & Its Diseases :HypertensionWhat Do We Know?: Diagnosis(Envelopes represent the Standard Deviation of the Mean)Essential Hypertension (cause unknown though multifactorial,most common)5 10 % Identifiable Cause (often secondary)for example,Renal Artery ConstrictionCoarctation of the Aorta (narrowing of aorta)Phaeochromocytoma(tumor of adrenal glands)Cushing s disease (hypercortisolism)Primary Aldosteronism(elevated aldosterone)Risks Factors include:HyperlipidemiaDiabetesGenetic, Family HistoryDiet(high salt)StressWhat Do We Know?

3 : AetiologyCardiovascular System & Its Diseases :HypertensionWhat Do We Know?: Secondary HypertensionCardiovascular System & Its Diseases :HypertensionHyperthyroidism:end ogenous (tumor) or drug-mimicking thyroid hormones elevate Contraceptives: reversible elevation of BP. May be related to HT associatedwith pregnancy (eclampsia) attributed to oestrogen activation of renin-angiotensin-aldosterone : due to circulating catecholamines liberated from tumorsof chromaffin tissue (adrenal medulla). Uncommon thoughscientifically interesting. Treatment by surgical excisionCoarctation of aorta: constriction of the aorta is congenital condition.

4 Constrictionsite usually in the thoracic aorta beyond the arch. Site of coarctationis compensated by large network of collateral blood involves surgical Do We Treat?: Normal Regulation Of Blood PressureCardiovascular System & Its Diseases :Hypertension** Hints At Possible Therapeutic Approaches **4 Sites Of Regulation:Blood Pressure:CardiacPeripheralXOutput Vascular ResistanceHow Do We Treat?: Drug TherapyCardiovascular System & Its Diseases :HypertensionMajor Drug Groups:DiureticsSympathoplegics(Sympatho lytic)VasodilatorsAngiotensin AntagonistsCardiovascular System & Its Diseases :HypertensionHow Do We Treat?

5 : Diuretics2 Main Actions:Reduce Blood VolumeAffect Smooth Muscle Tone2 Main Drug Classes:Thiazidesmild HTLoop Diureticssevere HTCardiovascular System & Its Diseases :HypertensionHow Do We Treat?: DiureticsThiazides( *hydrochlorothiazide):Mild/Moderate HypertensionBlock Na+/Cl-symporter, Ca2+reabsorptionOrally ActiveToxicity:K+depletion/Hypokalemia(e sp. patients with arrhythmias, infarcts etc)Loop Diuretics ( *furosemide):Moderate/Severe HypertensionBlock Na+/ K+ / 2Cl-symporter, Ca2+excretionOral & IntravenousToxicity:K+depletion/Hypokale mia* Indicates drug name should be rememberedThiazidesLoop DiureticsBlockNa+/Cl-symporter(Distal convoluted tubule)Drug ClassPharmacologyExamplesBlockNa+/K+/2Cl - symporter(Thick ascending loop)*Hydrochlorothiazide*FurosemideMild Moderate HTModerate-Severe HTDiureticsIndication* Indicates drug name should be rememberedCardiovascular System & Its Diseases .

6 HypertensionHow Do We Treat?: SympathoplegicsPharmacological Targets:1. Centrally Acting Agents2. Ganglion Blockers3. Postganglionic Sympathetic Neuron Blocker4. Adrenoceptor BlockersMain Action: Decrease Sympathetic Discharge or its effects on Cardiovascular SystemCardiovascular System & Its Diseases :HypertensionHow Do We Treat?: SympathoplegicsDrugs:*ClonidineMethyldop a(prodrug converted to methylnorepinephrine in CNS)Indication: Mild & Moderate HypertensionMechanism: Sympathoplegic effect not knownToxicity: Minimal, sudden cessation causes severe HTCentrally Acting Agents: 2-selective agonistsCardiovascular System & Its Diseases :HypertensionHow Do We Treat?

7 : SympathoplegicsGanglion Blockers: nicotinic cholinoceptor antagonistsDrugs:Trimethaphan(first agents developed for hypertension)Indication: Severe Hypertension(rapid onset)Mechanism: Blocks nAChR in autonomic gangliaToxicity: Intolerable (orthostatic hypotension, blurred vision, constipation)Used rarelyCardiovascular System & Its Diseases :HypertensionHow Do We Treat?: SympathoplegicsPostganglionic Sympathetic Neuron BlockersDrugs: *Reserpine, GuanethidineIndication: Rarely UsedMechanism: Reserpineblocks uptake;Guanethidineprevents neurotransmitter releaseToxicity: Intolerable (depression, sexual dysfunction, orthostatic hypotension) Cardiovascular System & Its Diseases :HypertensionHow Do We Treat?

8 : SympathoplegicsDrugs:*Prazosin(Block 1-receptors)*Propanolol(Block 1-receptors)Indication: Mild Hypertension( and -blockers, important monotherapy)Moderate-Severe HT ( -blocker, polypharmacy)Mechanism: Antagonism of -and -receptorsToxicity: Mild ( -blocker; marked 1stdose hypotension & mild tachycardia)Moderate( -blocker; may cause asthma, bradycardia, heart failure)Adrenoceptor Blockers: 1 and 1-receptor antagonistsCentrally Acting AgentsGanglion BlockersPostganglionic SympatheticNeuron BlockersAdrenoceptor Blockers 2-selective agonistsnAChR antagonists 1- and 1-receptorantagonistsDrug ClassPharmacologyExamplesBlock Neurotransmission*Clonidine, MethyldopaTrimethaphan*Reserpine, Guanethidine*Prazosin, *PropanololMild Moderate HTRarely usedRarely UsedMild(monotherapy)Moderate-Severe HT(polypharmacy)Sympathoplegic DrugsIndicationCardiovascular System & Its Diseases .

9 HypertensionHow Do We Treat?: VasodilatorsMain Action:Vasodilatation of arterioles by different mechanismsMechanism of VasodilationDrug ExamplesRelease of nitric oxideOpening of K+channelsAnd hyperpolarizationBlock of L-type Ca2+channelsHydralazine, *nitroprussideMinoxidil sulfate, *diazoxide*Verapamil, *Diltiazem, *NifedipineEntire Drug Class:Part of Polypharmacy for Severe HypertensionCa2+Channel Blockers:Monotherapy for Mild to Moderate HypertensionCardiovascular System & Its Diseases :HypertensionHow Do We Treat?: NitrovasodilatorsDrugs:Hydralazine*Nitro prussideIndication: Severe HT (Polypharmacy)Hypertensive Emergency (nitroprusside)Mechanism: Activate soluble GuanylateCyclase relaxing vascular smooth muscleToxicity: Excessive hypotension &tachycardia (nitroprusside)Moderate tachycardia(hydralazine) Cardiovascular System & Its Diseases :HypertensionHow Do We Treat?

10 : K+Channel Opener/AgonistDrugs:Minoxidil sulfate, *DiazoxideIndication: Severe HT (polypharmacy)Hypertensive Emergency(Diazoxide)Mechanism: Hyperpolarize the cell,causing relaxationToxicity: Severe tachycardia (Minoxidil)Mild tachycardia(Diazoxide) Cardiovascular System & Its Diseases :HypertensionHow Do We Treat?: Ca2+Channel Blockers3 classes of Ca2+channel:L-, T- and N-type familiesL-type are mainly targeted for treatment of HypertensionVasoselective:Dihydropyridin es( *Nifedipine)Cardiac & Vascular Acting:Phenylalkylamines( *Verapamil)Benzothiazines( *Diltiazem)3 main classes of blockersEach Drug Has A Distinct Allosteric Binding SiteDrugs:*Verapamil, *Diltiazem*NifedipineIndication: Mild-Moderate HT (monotherapy)Severe HT (polypharmacy)Mechanism: Voltage- & frequency-dependent blockToxicity.