cardiovascular pharmacotherapy · pharmacotherapy . overview mechanism of cardiovascular drugs...
TRANSCRIPT
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Cardiovascular Pharmacotherapy
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Overview
MechanismofcardiovasculardrugsIndicationsandclinicaluseincardiology
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Renin-Angiotensin Inhibitors: Angiotensin-Converting Enzyme Inhibitors,
Angiotensin Receptor Blockers
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ACE-I,ARB
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Cardiorenal Effects of ACE Inhibitors
• Vasodilation (arterial & venous) - reduce arterial & venous pressure - reduce ventricular afterload & preload • Decrease blood volume - natriuretic - diuretic • Depress sympathetic activity • Inhibit cardiac and vascular hypertrophy
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Therapeutic Use:
• Hypertension • Heart failure • Post-myocardial infarction
ACE-I,ARB
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• RASinhibitorsareamongthebesttoleratedoftheantihypertensivedrugs
• ReduceCVeventsandpreventingdeteriorationofrenalfunctioninhigh-riskhypertensivepatients
• “DualRASblockade”—eitherwithanACEIplusanARB—isnowcontraindicatedduetohypotension,acutekidneyinjury(AKI),andhyperkalemia
• Asmonotherapy,ACEIsaregenerallylesseffectiveinloweringBPinblackpatientsandinolderpatientswithlow-reninhypertension,buttheyarequiteeffectiveinthesegroupswhencombinedwithaCCBorlow-dosediuretic
ACE-I, ARB à Hypertension
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• ARBsconferthesamebenefitsasACEIsintreatinghypertensionwhileavoidingtheACEI-relatedcoughandangioedema
• ACEIsandARBshavebecomestandardfirst-lineantihypertensivetherapyforpatientswithdiabeticandnondiabeticCKD,butevidenceindicatesthatRASinhibitorsprovidesuperiorrenalprotectionthandootherantihypertensiveagents,mainlyfornondiabeticproteinuricCKD
ACE-I, ARB
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ACE-I, ARB à Heart failure
ThereisoverwhelmingevidencethatACEIsshouldbeusedinsymptomaticandasymptomaticpatientswithareducedEF(<40%).ACEIsstabilizeLVremodeling,improvepatientsymptoms,preventhospitalization,andprolonglife.
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Side effects
drycough(ACE-I)angioedema(ACE-I)hyperkalemiaACEIsandARBscanprovokehyperkalemiainthesettingofCKDfetalrenalagenesisandotherbirthdefects(contraindicatedinpregnancy)
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Contrindication ACE inhibitors
• Pregnancy• Historyofangioedema• Bilateralrenalarterystenosis• Knownallergicreaction/otheradversereaction(drug-specific)
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Cautions/seek specialist advice:1. Significant hyperkalemia (K+>5.0 mmol/L)2. Significant renal disfunction (creatinine >2.5 mg/dl or GFR <30 mL/min/1,73m2).3. Symptomatic or severe asymptomatic hypotension (systolic blood pressure <90 mmHg).4. Drug interactions to look out for:o K+ supplements/ K+-sparing diuretics, e.g. amiloride and triamterene (beware combination preparations with furosemide).o MRAs.o Renin inhibitorsc.o NSAIDsd.o Trimethoprim/trimethoprim-sulfamethoxazole.o ‘Low-salt’ substitutes with a high K+ content
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Beta-Adrenoceptor Antagonists (Beta-Blockers)
bind to beta-adrenoceptors and block the binding of norepinephrine and epinephrine to these receptors sympatholyticdrugsSomebeta-blockerspossessintrinsicsympathomimeticactivity(ISA)ormembranestabilizingactivity(MSA).
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Beta-Adrenoceptor Antagonists (Beta-Blockers)
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Therapeutic Indications Beta-Blockers
-hypertension-angina-myocardialinfarction-arrhythmias-heartfailure
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Beta-Blockers à Hypertension
ReducecardiacoutputAcutetreatmentwithabeta-blockerisnotveryeffectiveinreducingarterialpressurebecauseofacompensatoryincreaseinsystemicvascularresistance.Chronictreatmentwithbeta-blockerslowersarterialpressurepossiblybecauseofreducedreninreleasebythekidneysandeffectsofbeta-blockadeoncentralandperipheralnervoussystems.
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Angina and myocardial infarction • B-blockersreduceoxygendemandbydiminishheartrate,contractility,andarterialpressure
• relieveapatientofanginalpain• decreasemortalityinptsaftermyocardialinfarction
(improvingtheoxygensupply/demandratio,reducingarrhythmias,andtheirabilitytoinhibitsubsequentcardiacremodeling)
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Arrhythmias
B-blockers-classIIantiarrhythmicdrugsinhibitsympatheticinfluencesoncardiacelectricalactivitysympatheticnervesincrease:-sinoatrialnodeautomaticitybyincreasingthepacemakercurrents,whichincreasessinusrate.- conductionvelocity(particularlyattheatrioventricularnode)
- stimulatesaberrantpacemakeractivity(ectopicfoci).
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Heart failure
• Althoughitseemscounterintuitivethatcardioinhibitorydrugssuchasbeta-blockerswouldbeusedincasesofsystolicdysfunction,clinicalstudieshaveshownquiteconclusivelythatsomespecificbeta-blockersactuallyreducemortalityandmorbidityinsymptomaticpatientswithHFrEF
• reducedeleteriouscardiacremodeling
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Side effects of beta-blockers
bradycardiareducedexercisecapacityheartfailurehypotensionatrioventicularnodalconductionblockbronchoconstriction(B2)maskthetachycardiathatservesasawarningsignforinsulin-inducedhypoglycemiaindiabeticpatients
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Contra-indications: 1.Second-orthird-degreeAVblock(intheabsenceofapermanentpacemaker).2.Criticallimbischaemia.3.Asthma(relativecontra-indication):ifcardio-selectivebeta-blockersareindicated,asthmaisnotnecessarilyanabsolutecontra-indication*COPDisnotacontra-indication
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Druginteractionstolookoutfor(becauseofriskofbradycardia/atrioventricularblock):• Verapamil,diltiazem(shouldbediscontinued).b• Digoxin.• Amiodarone.• Ivabradine.
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Mineralocorticoid receptor antagonists MRAs(spironolactoneandeplerenone)blockreceptorsthatbindaldosteroneand,withdifferentdegreesofaffinity,othersteroidhormone(e.g.corticosteroids,androgens)receptors.
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MRAs
Indication:Symptomaticpatients(despitetreatmentwithanACEIandabeta-blocker)withHFrEFandLVEF≤35%àreducemortalityandHFhospitalization
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Inclusion criteria - the PARADIGM-HF trial
• symptomaticHFrEFwithLVEF≤35%• elevatedplasmaNPlevels(BNP≥150pg/mLor• NT-proBNP≥600pg/mL)• anestimatedGFR(eGFR)≥30mL/min/1.73m2ofbodysurfacearea
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Conclusion - the PARADIGM-HF trial
sacubitril/valsartan(97/103mgb.i.d.)wassuperiortoACEI(enalapril10mgb.i.d.)inreducinghospitalizationsforworseningHF,cardiovascularmortalityandoverallmortalitySideeffectsofARNI:• Symptomatichypotension• angioedema
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Drugs for treatment of hypercholesterolaemia StatinsEzetymibPCSK9inhibitors
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Statins -substantiallyreduceCVmorbidityandmortalityinbothprimaryandsecondaryprevention,inbothgendersandinallagegroups-havealsobeenshowntoslowtheprogressionorevenpromoteregressionofcoronaryatherosclerosis
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Recommendations for treatment goals for low-density lipoprotein-cholesterol
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27.09.18
R20R30R40A80
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Sideeffectsofstatins
- muscularpain - statin-inducedmyopathy - rhabdomyolysis à severemuscularpain,musclenecrosisandmyoglobinuriapotentiallyleadingtorenalfailureanddeath-elevationofalanineaminotransferase(ALT)-smallincreaseintheincidenceofdiabetes
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27.09.18
Statins+ezetymib(cholesterolabsorptioninhibitor)
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27.09.18
PCSK9inhibitors
monoclonal antibodies that reduce LDL-C levels by 60%
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DAPT–dualantiplatelettherapyAspirinP2Y12Inhibitor:clopidogrelprasugrelticagrelor
IndicationforDAPT:coronaryinterventionmyocardial infarction
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Current evidence suggests that DAPT mitigates the risk of stent thrombosis across the whole spectrum, from acute to very late event
ischaemic vs. bleeding risks for any given DAPT duration; the use of scores might prove useful to tailor DAPT duration in order to maximize ischaemic protection and minimize bleeding risks in the individual patient
DAPT–dualantiplatelettherapy
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