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    Antihypertensive drug 1 Antihypertensive drug 1 Presentation Transcript

    • ANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND MODE OF ACTION USESTHIAZIDEThiazides:Hydrochlorothiazide (HydroDiuril)Thiazide-like diuretics:Chlorthalidone (Hygroton)Metolazone (Zaroxolyn)Indapamide (Lozol)Quinethazone (Hydromox)Inhibit Na+-Cl- symporteron theearly distal convoluted tubule(about ascending loop of Henle)Block Na+ reabsorption↓ salt & H2O retention↓ blood volume↓ cardiac output↓ blood pressure↑ excretion of K+Acutely↑ uric acid excretion ↓uric acid excretionchronically↓ Ca2+ excretion ↑ Ca2+reabsorptionGold standard (↓ mortality)1st line therapy for treatinguncomplicatedhypertensionEffective – in African AmericanNOT useful when GFR < 30mL/min –EXCEPT Metolazone and Indapamide)Used to treat edema (associated withCongestive heart failure, liver cirrhosis,nephritic syndrome, chronic renalfailure, and glomerulonephritisReduce Urinary Ca2+ useful forcalcium nephrolithiasis andosteoporosisTreat nephrogenic diabetes insipidus(reduce urine volume by 50%)Useful for treating Br- intoxicationADVERSE EFFECTS CONTRAINDICATION DRUG INTERACTIONSHypokalemia  sudden cardiacdeath in ischemic ventricularfibrillation.HypotensionHyponatremia(low in Na+)HypomagnesmiaHyperuricemia goutHyperglycemia diabetesHyperlipidemiahigh cholesterolHypercalcemiamenopauseHypercalcemia withhydrochlorothiazideCan cause glucose intoleranceunmask latent diabetes mellitusIncrease LDL, increasetriglyceridesErectile dysfunctionIn Gout patientIn Diabetes patientIn High cholesterol patientDigoxin cause hypokalemia (low inK+)Quinidine lethal  causehypokalemia (due to prolongation of QTinterval and low in K+)NSAIDs blunt the anti-HTN effectsBile acid sequestrantsblunt theeffectiveness of ThiazidesAnti-diabetes  cause hyperglycemiaNOTESNephrogenic diabetes insipidus– use thiazides to reduce urinevolumeBr- intoxication – use thiazidesOsteoporosis – use thiazidesCalcium nephrolithiasis – usethiazides
    • ANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND MODE OF ACTION USESLOOPDIURETICSBumetanide (Bumex)Furosemide (Lasix)Torsemide (Demadex)Ethacrynic acid (Edecrin) – ONLY onehas NO Sulfur  used for sulfur-allergicpatientAct on thick ascending Loop of HenleAct on Na+-K+-2Cl-symporter toinhibit Na+, K+, and Cl- reabsorptionDecrease Ca2+ and Mg2+Lowering fluid retention induced byvasodilators such as Minoxidil.Mostly with rapid IV, especially withEthacrynic acid.USEFUL when GFR < 30mL/min &Creatinine > 2.5mg/dLTreat hypertensionTreat acute pulmonary edema (decreaseleft ventricular filling pressures)Treat chronic congestive heart failureTreat nephritic syndromeTreat edemaand ascites of hepaticcirrhosisdue to congestive heart failure orrenal insufficiencyMore effective in patients with impairedkidney function& less effective than Thiazideswith normal renal functionInduced diuresis in overdosesLoop diuretics + isotonic saline  preventvolume depletion  treat hypercalcemia(high in Ca2+)Loop diuretics + hypertonic saline  treat lifethreatening hyponatremia (low in Na+)Can be used to treat acute renal failure (byconverting oliguric ARF to nonliguric ARF)ADVERSE EFFECTS CONTRAINDICATION DRUG INTERACTIONSAdverse effects are more frequent thanThiazidesMost adverse effects due to abnormal fluid/electrolyte imbalancesHypotension, reduced GFR, circulatorycollapse, thromboembolic events, & hepaticencephalopathy in pts with liver diseaseHypokalemiaHypomagnesemia arrhythmiaHypocalcemia menopause***** Ototoxicity (tinnitus, vertigo, hearingimpairment, deafness, fullness in ear) –mostlyEthacrynic acidHyperuricemia goutHyperglycemia diabetesLipidemiasIn Gout patientIn Diabetes patientIn High cholesterol patientAminoglycosides synergism of ototoxicityCisplatin↑ototoxicityAnticoagulants↑anticoagulant activityDigitalis glycosides↑arrhythmiasLithium ↑plasma levels of lithiumPropranolol (β-blocker) ↑plasma levels ofpropranololSulfonylureas cause hyperglycemia (badfor diabetic pt)NSAIDs blunted diuretic response &salicylate toxicityProbenecid blunted diuretic reponseThiazide diuretics synergism, profounddieresisAmphotericin B↑nephrotoxicity
    • ANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND DRUG INTERACTIONS USESK+ -SPARINGDIURETICSInhibitors of renal epithelial Na+ channels:Amiloride (Midamor)Triamterene (Dyrenium)Aldosterone antagonists:Spironolactone (Aldactone)Eplerenone (Inspra)NSAIDs Very little antihypertensive effectsUsed as adjunct with Thiazides & Loop diuretics totreat hypertension & edemaPrevent hypokalemia induced by Thiazides & LoopdiureticsAmiloride – useful in lithium induced DiabetesInsipidusAerosolized amiloride↑ mucociliary clearance incystic fibrosisTreatLiddle’s syndrome – African origin havegenetic polymorphism of Na+ channel causing ↑basalactivity ↑ blood pressureSpironolactone – drug of choice in hepaticcirrhosis (reduces ventricular arrhythmias in heartfailure pts, reduces morbidity & mortality)Spironolactone – treat primary hyperaldosteronism(high in aldosterone)NOTESHepatic cirrhosis – useSpironolactoneHyperaldosteronism– useSpironolactoneDiabetes insipidus – useAmilorideADVERSE EFFECTS CONTRAINDICATION MODE OF ACTIONInhibitors of renal epithelial Na+ channels:Hyperkalemia (high in K+) cause arrhythmiaTriamterene  folic acid antagonist  folic acid& vitamin B12 deficiency  causemegaloblastic anemia fatigueTriamterene  cause N/V, leg cramps &dizziness, reduced glucose tolerance,photosensitization&renal stonesAmiloride  cause N/V, diarrhea, headacheBoth may ↑uric acid levelsAldosterone antagonists:Spironolactone has some affinity forprogesterone & androgen receptors  inducegynecomastia, impotence &menstrualirregularitiesHigh concentrations  interfere with steroidsynthesisBlockage of related gene K+ channels  anti-arrhythmic effectInduce diarrhea, gastritis, gastric bleedingCNS effects – drowsiness, lethargy, ataxia (lack ofcoordination of muscle movement), confusion,and headacheIn patients with hyperkalemiaIn patients taking ACE inhibitorsIn patients with peptic ulcersInhibitors of renal epithelial Na+ channels:Inhibits Na+ channels in the luminalmembrane of principal cells in the late distaltubule & collecting ductInhibition of Na+ channels prevents K+secretion  K+-sparingAldosterone antagonists:Deactivate membrane bound Na+ channelsNo translocationBlock De novo synthesis↓ Na+ / K+ - ATPaseNo translocation of ATPaseNo De novo synthesis of ATPase↓ Permeability of tight junctions↓ ATP production
    • ANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND MODE OF ACTION USESβ – BLOCKERSCardioselective (β1 > β2):Acebutolol (Sectral)Atenolol (Tenormin)Betaxolol (Kerlone)Bisoprolol (Zebeta)Esmolol (Brevibloc)Metoprolol (Lopressor)Nonselective (β1 + β2):Propranolol (Inderal)Nadolol (Corgard)Timolol (Blocadren)Pindolol (Visken)Penbutolol (Levatol)Drugs with additional α1-antagonistactivity:Carvedilol (Coreg)Labetalol (Transdate)New drug:Nebivolol (Bystolic)2 mechanisms:↓ β1-receptor activation in heart↓ Cardiac output↓ Blood pressureBlock rennin↓ Angiotensin II↓ Blood pressureThose with ISA (intrinsicsympathomimetic activity) – stimulatesα2 and ↓Pulmonary vascular resistance –no effect on lipids or ↑in HDLThose with α1 blocking activity – ↓PVRGold standard (↓ mortality)Use in most forms of hypertensionExcellent meds for initial therapyNormally do NOT cause water retentionLESS effective – in African AmericansCompelling indication – for post MyocardialInfarctionFavorable effects:↓Chronic stable angina↓Atrial tachyarrhythmias↓Essential tremor (in Parkison’s)↓Hyperthyroidism↓Migraine↓Anxiety (propranolol for stage fright)ADVERSE EFFECTS CONTRAINDICATION DRUG INTERACTIONS↓ myocardial contractility↓ insulin secretion↓ AV conductionWithdraw syndrome – whensudden discontinuation tachycardia↓ HDL bad↑ Triglycerides  badMasked hypoglycemia symptoms,exceptsweatingin diabetic ptsDepressionFatigueSexual dysfunctionNo β-blockers with Ca2+ channel blockers(that also treat hypertension)AVOID in asthma patientsAVOID in bronchospasm patientsAVOID in AV blockAVOID in hyperlipidemia patientsAVOID in depressed patientsAVOID in active patientsAVOID in vulnerable patientsCaution in Congestive Heart Failure (↓myocardial contractility)In diabetic patients (↓ insulin secretion)NSAIDs – blunt anti-hypertensive effects of β-blockersVerapamil & Diltiazem (Ca2+ channelblockers) cause severe decrease in heartrate & cardiac outputNOTESDiabetic & Asthma patients –usecardioselectiveB1-blockersFor congestive heart failure patients – useagents with α1-blocking activityforsynergyproperty (Labetolol, Carvedilol) totreat hypertension.
    • ANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND MODE OF ACTION USESCENTRALLYACTING α2-AGONISTSMethyldopa (Aldomet)Clonidine (Catapres)Guanfacine(Tenex)Guanabenz(Wytensin)Metyrosine (Demser)CNS:↓ sympathetic outflowPeriphery:↓PVR without much change in CO↓ renin secretion↓LDLCan be used for hypertensionpregnancyMethyldopa – used in PREGNANCYhypertensive patient↓ rennin secretion↓PVR without much change in cardiacoutputConverted to α-methyl NE – agonist ofpresynaptic α2-receptorsClonidine, Guanfacine, GuanabenzStimulates α2↓ sympathetic outflow↑ vagal tone↓ PVR&↓ Cardiac OuputUsed in Resistant HypertansionADVERSE EFFECTS ADVERSE EFFECTS (cont’) USES (cont’)No adverse effects on blood lipids↓LDL goodMethyldopa S/E:CNS sedationDry mouthExtrapyramidal symptomsHemolytic anemiaWithdrawal rebound hypertensionmust taperHyperprolactinemia milk production(can happen in males)Sexual dysfunctionIn SA node dysfunction  cause severebradycardiaClonidine, Guanfacine, GuanabenzCNS sedation, depressionBradycardia& Postural HypotensionWithdrawl rebound hypertensionSexual dysfunctionDry eyes and mouth, urinaryretention, constipation esp withclonidineContact dermatitisFluid retention & edema, also usediureticMetyrosine S/E:CrystalluriaOrthostatic hypotensionSedation, DepressionExtrapyramidal signsGI disturbancesMetyrosine – used in patients withpheochromocytoma (tumor that causes↑release of epinephrine)NOT for use in most cases of hypertensionStructural analog of L-tyrosineBinds to tyrosine hydroxylaseInhibits tyrosine hydroxylase enzymeInhibits the synthesis of DOPA andeventually epinephrine
    • ANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND MODE OF ACTION USESADRENERGICNEURONALBLOCKERSReserpine (Serpasil) Binds to adrenergic storage vesicles inneuronsInhibits vesicular monoaminetransporter (VMAT-2) preventingvesicle turnover  depletesNorepinephrine↓ PVR↓ HR↓ CO↓ Renin secretionNOT for initial therapy (because it causedepression)Used in combo with diureticAlso as an antipsychotic drugADVERSE EFFECTS CONTRAINDICATION DRUG INTERACTIONSSedationInability to concentrateDepressionGI disturbancesCLASS GENERIC / BRAND MODE OF ACTION USESα1-ADRENERGICRECEPTORANTAGONISTSPrazosin (Minipress)Terazosin (Hydrin)Doxazosin (Cardura)Selective α1-adrenergic receptorantagonistNO effect on α2-receptorsDilate arterties&↓ PVRShort term:↑ Heart rate↑ ReninLong term:Heart rate & rennin return to normalTreat hypertensionADVERSE EFFECTS FAVORABLE EFFECTSSexual dysfunctionPostural (orthostatic) hypotension –1st dose effectTreat patients that experience:HyperlipdemiaBenign prostatic hyperplasia
    • ANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND MODE OF ACTION USESACEINHIBITORSBenazepril (Lotensin) –prodrugbenazoprilat (more potentthan captopril, enalaprilat & lisinopril)Captopril (Capoten) – contains asulfhydryl groupEnalapril(Vasotec) –prodrugenalaprit (highly potent ACEI)Fosinopril (Monopril) – contains aphosphinate group –prodrugfosinoprilat (more potentthan captorpil, but less potent thanenalaprilat)Slow GI absorptionLisinopril (Zestril / Prinivil)Moexipril (Univasc)Perindopril (Aceon)Quinapril (Accupril)Ramipril(Altace)Trandolapril(Mavik)Inhibits ACE enzymeDecreased Angiotensin IIdecreased aldosteroneproduction↓ Output of sympathetic NS↑ Vasodilation of vascular smoothmuscle↓ Retention of Na+ and water↑ Levels of bradykinin↓ Preload & afterload↑ Cardiac outputOverall ↓ blood pressureTreat hypertension↓ Systemic vascular resistance (SVR)↓ Mean diastolic & systolic bloodpressureo Treat Left Ventricular SystolicDysfunctiono Hypertension + Acute myocardialinfarctiono Hypertension + Diabeteso ACEIs + thrombolytics / aspirins /adrenergic antagonists reduce inischemic CV events  renal & retinalprotection in diabetic patients.o LESS effective – in African AmericansADVERSE EFFECTS CONTRAINDICATION DRUG INTERACTIONSHypotension (1st dose - in pts withplasma renin activity)CauseCoughProteinuria (protein in urea)Dysgeusia (distortion sense of taste)NeutropeniaGlycosuria (glucose in urine)HepatotoxicityACEIs increase levels of Digoxin &LithiumMay increase hypersensitivity toAllopurinol (xanthine oxidase inhibitorNOT for hypertensive patients thatare caused by primaryaldosteronism (↑aldosterone ↓ potassium)NOT for acute renal failureseverely ↓ GFR in renal artery stenosispatientsNOT for pregnancy (Fetopathicpotential)NOT for angioedema patient (AfricanAntacids + ACEIs  antacids may reducebioavailabilityCapsaicin(release pain & itching) +ACEIs may worsen cough
    •  treat gout) American& smokers)ANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND MODE OF ACTION USESANGIOTENSINRECEPTORBLOCKERSAT1(ARBS)or(SARTANS)Candesartan (Atacand)Eprosartan (Teveten)Irbesartan (Avapro)Losartan (Cozaar)Olmesartan(Benicar)Telmisartan (Micardis)Valsartan (Diovan)Azilsartan(Edbari)Bind to AT1-receptorInhibit most biological effects ofAngiotensin II:o Contraction of vascular smoothmuscleo Pressorresponseso Vasopressin releaseo Aldosterone secretiono Release of adrenalcatecholamine’so Enhancement of noradrenergicneurotransmissiono Increase in sympathetic toneo Changes in renal functiono Cellular hypertrophy &hyperplasiaDo NOT cause coughOral availability is LOWProtein binding is HIGHLow S/EAll for hypertensionStroke prevention – use LosartanDiabetic nephropathy – use Irbersartan&LosartanHeart failure patients intolerant to ACEIs– use Valsartan & CandesartanFor heart failure – 1st line treatment – useACEI, then use ARB if intolerant orunsatisfactory responseADVERSE EFFECTS CONTRAINDICATION NOTESHyperkalemia NOT for pregnancyCaution in pts with renal functiondependent on RAS (volume depleted)AT1-antagonists ≠ ACEIsInhibition of AT1 receptors = AT1antagonistsare more effectiveActivation of AT2 receptors = AT1antagonistsare more effectiveIncreasing bradykinin levels = ACEIsaremore effectiveTo minimize hypotension in diuretic treatedpts who are elderly, volume depleted,hyponatremic or have CHF exacerbation,hold diuretic dose for 2-3 days before
    • starting ARB and use low doseANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND MODE OF ACTION USESCALCIUMCHANNELBLOCKERS(CCBs)Dihydropyridines (DHPs)Amlodipine (Norvasc)Nimodipine (Nimotop)Nifedipine (Procardia)Felodipine(Plendil)Isradipine (Dynacirc)Nicardipine (Cardene)Nisoldipine (Sular)Non-dihydropyridinesDiltiazem (Cardizem)Verapamil (Isopten)Bepridil (Vascor) – no longeravail. blocks both voltage &receptor-gated Ca2+ channelsalso blocks voltage-gated Na+channels ↓ Heart rate, ↓ PVR,↓blood pressure, ↓MVO2o Mostly used in resistantchronic stable exertionalangina (pain @ rest) & less inhypertensionInhibit voltage-gated L-type Ca2+channels↓ Ca2+ influx in vascular & cardiac cellsRelax vascular smooth musclecontraction↓ Contractility of atrial & ventricularmuscles↓ Cardiac output↓ Heart rate & contractility (Verapamil)Lowering blood pressure may stimulatecompensatory mechanisms leading tonet ↑ heart rate↓ PVRDihydropyridines>Dilatiazem>Verapamil↑ Coronary blood flow(Dihydropyridines, nicardipine>others↑ Cerebral blood flow(Nimodipine>others)Angina↑ Coronary blood flow (all CCBs)↓ O2 demand (Verapamil, Diltiazem)Hypertension↓ PVR (all CCBs)↓ Cardiac output (Verapamil,Diltiazem)Supraventricular tachyarrhythmias↓ AV nodal conduction (Verapamil)Controls ventricular rate in atrialflut& fibSubarachnoid hemorrhageCerebral vasodilation (Nimodipine)Blockade of Ca2+ channelsvasodilation (mostly DHPs)Affects arteries > veinsADVERSE EFFECTS CONTRAINDICATION DRUG INTERACTIONSDihydropyridinesHypotensionEdemaHeadachesVerapamilHypotension,CHF, Edema, Headache,Short-acting agents may ↑ mortalityHepatic dysfunction (all CCBs)LV dysfunction (Verapamil, Diltiazem)Hypotension (all CCBs)AV block (Verapamil, Diltiazem)NO calcium-channel blockers with:Concurrent β-blockers(Verapamil,Dilatazem)Digoxin(Verapamil)Antiarrhythmic drugs
    • AV block, constipationANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND MODE OF ACTION USESVASODILATORSHydralazine (Apresoline) Common mechanism:Arterial dilation ↓ PVRVenous dilation ↓ COCommon compensatory mechanism:↑ HR↑ water retentionDecrease blood pressureCommonly combined with β-blockers& diureticsEfficacy in Congestive heart failurepatients who can NOT tolerate ACEI orAT1-receptor antagonists & in thetreatment of hypertensiveemergencies in pregnant women(especially preeclampsia)ADVERSE EFFECTS CONTRAINDICATION NOTESHypotensionTachycardiaPalpitationsLupus-like syndrome of arthritisArthralgia (pain in joints)FeverPleuritisPericarditisHeadacheNauseaFlushingFluid retention  use diureticsDoes NOT dilate epicardialcoronary artery  “stealing”blood from infarct areaworsening of myocardialinfarctionHydralazine (Apresoline) – directrelaxation of arteriol SMCs↑ HR↑ Contractility↑ Renin↑ Fluid retentionNOT for monotherapy or initial therapybecause of SALT RETENTIONCHFexacerbationDoes NOT relax venous smooth muscle
    • OTHER ANTIHYPERTENSIVE DRUGSCLASS GENERIC / BRAND MODE OF ACTION USESK+ CHANNELOPENERMinoxidil(Loniten) ↑ K+ efflux from (arterial only) vascularsmooth muscle causing relaxation &hyperpolarization ↓ TPRIncreases blood flow to skin, muscle, GI& heart more than the CNSCompensatory mechanisms include:↑ HR↑ CO↑ Contractility↑ Fluid retentionDue to potent sympathetic stimulationof renin secretionVery effective in severe resistanthypertension (after trying lifestylemodification, Thiazides, β-blockers)ADVERSE EFFECTS NOTESMarked fluid retention (must use diureticto suck water out)Tachycardia (use β-blockers) – similar toHydralazine, avoid in LVH & Diastolicdysfunction, flattened & inverted T wavesHypertrichosis (↑ hair growth)Metabolized 20% K and 80% LCLASS GENERIC / BRAND MODE OF ACTION USESRENININHIBITORAliskiren (Tekturna) Directly inhibit reninMay ↑K+, creatine kinase, & uric acidTreat hypertensionADVERSE EFFECTS CONTRAINDICATION NOTESHypotensionAngioedemaDiarrheaNOT for childrenAVOID in pregnancyDecreases effects of Furosemide (loopdiuretic)CLASS GENERIC / BRAND MODE OF ACTION USESPOSTGANGLIONIC Guanethidine Postganglionic sympathetic inhibitors Little to no role in the current management of
    • SYMPATHETICINHIBITORSGuanadrel Deplete NE & block its release hypertension because of too many side effects& complications