- Email: [email protected]
Limitations of conventional calcium antagonists:
A
] SPECIAL SYMPOSIA
1997-VOL. 10, NO. 4, PART 2
Saturday May 31, Ballroom A, 5:30 pm Calcium Antagonists in 1997: Emerging Perspectives and Future Directions
Saturday May 31, Ballroom A, 5:3o pm Calcium Antagonists in 1997: Emerging Perspectives and Future Directions
OptfcealUtfffsattonof CalciumAntagonistsin Special HypertensivePopulations Center,Bowman John M. Flack, M.D.,M.P.H.,Hypertension Gray School ofMedicine ofWzkeForestUniversity, Winston-
EFFECTS OF CALCIUM ANTAGONISTS METABOLIC PARAM ETERS AND DYSLIPIDEMIA
Sslem,N.C.27157-1032 ‘Ilrehemodymrnic,inohopioand drrono&opiceffects of these agents differeccordingto the specific type of calciumentegonist: 1)phenylslkylemine(varapemril);2) benzotbiezepine(diltiazem); or 3) dihydropyridine(i.e., nisoldipine). Matchingthe appropriate calciumantagonisttyps with tbepatient clinical profile (i.e., conmedications) gestiveheart failure, unstablesnginsMI,concurrent represents asizable challengefor rhe clinicianwhose goal is m use this heterogemms gm.p of agents to provideoptimallyeffective thernpywhile minimizingrhepotential forhann. The dihydropyidinea appeacto be aafewhen used as adjunctivetherapy in patientswith CHFand may confer incrementalclinicalbsnefit to Afdcan-Ansedcsm and tboaewith noniaebemiccardiomyopathy. elderlyhyparrarrsiveapresentspecial tberapauticchallengesbecause of: 1)higher BP levels; 2) bigb prevzlcnceof ssltsansitivity;3) gr.eeterburdcmofprcssure-relatedtarget-organ damage;4) high ffequencyof coexistingCVD and other medical conditions;and 5) poly-phsnnacy. In individualswith severe hypesrenaion,tbeaeagents are highly useful in combinationwith odrerantih~anaive agantain achievingBP normalization. The BP loweringeffect ofcalchrn antagonistsis less attenuatedthan with other agents (excaptdiuratios)by usual levels ofdietsry sodium intake NSAIDs we commonlyprescribedmedicationsin the eldcdy. Howevsr, the BP lowsring effect ofcdciwtt aotagonisrs is ucraffkctrdbyNSAID use. Shategies will be discussed for optimizingthe use of calciumantagonistsin African-Americans, theeklady, turdhypmtensiveawitb coronarysyndromeaincluding
CHF. KeyWords;
Catcirun, .@agcmista, Elderly,Atiican Anrericens, Congestive HeartFailure
ON
JamesR. Sowers,MD, Wayne State University School of Medicine,Detroit,MI 48201 Hypertensionis offenaccompaniedby impaired glucosetokmnce, insulinresistsrrce,clinically evident type II diabetesmellitus and dyslipidemia. Impaired carbohydratemetabolismand hypertensionoccur with increeaingprevalencein relation to increasingage in industiafized societies. In these populations,factors contributingto age-relatedrises in rates of diabetes mellitusand hypertensionincludeincreasinginactivity, obesity(especiallycentralkisceral obesity)and possibly increasedutilizationofmedicationa that may impair carbohydratemetabolism. As hypertensionis often accompaniedby metabolicabnormalities,there is considerableconccrrrregardingthe metabolic effects of antihypcrtensivephsmmcologicinterventionsnd the impsct of this interventionon cardiovsscrrlsrrisk reductionresultingfromthe treatmentof hypertension. Peripheralvasculardilation appeemto be the principal mechanismoftbe long-tcnnblood pressrrrc-lowering effectsofcalciutn antagonists. Calciumantagonists appearto have beneficialeffectswith respect to maintenanceof renal blood flow and glomerularfiltration rate. Metabolicabnormalitiessuchashypokslemi~
hypercslcemiqhypemricesniqlipidchanges,and hyperglycemia% aregetteratlynotobservedwithcatcitmr antagonists. KeyWords:c~ci~
antagonists,dyslipidemia
Saturday May 31, Ballroom C, 5:30 pm Advances in Drug Therapy for Hypertension
Saturday May 31, Bsdlroom C, 5:30 pm Advances in Drug Therapy for Hypertension
Mibefradil, a new calcium antagonist with novel pharmacological properties: Results in angina pectoris
LIMITATfONSOF CONVENTIONALCALCIUMANTAGONISTS: John H. Larsgh,M.D., NewYork Hospitsl-ComellMedicelCenter
Barry M. Massie,Univ. of California,San Francisco,CA. Mibefradil(MIB) is the first of a new claw of calcium antagonists(CAS)with activityat both L-typeand T-type calcium charrnels.Unlike most CAS, its inhibition of L-channels is highly potential-dependent,so that it has little activity at -80 mV, the restingpotentialof cardiacmyocytes,but is masryfold more active at -50 mV, the usual potential of smooth muscle. It rdsois the firstknownspecificantagonistof T-typecharrnels, whichappcarto be more involvedin regulatingsmoothmuscle tone rmdcardiacautomaticitythan cardiaccontractility.These properties should produce significant rate-lowering and antihypertensiveeffects witbout depressingcardiac function, and may make mibefradilvery suitable for the treatment of angina pectoris (AP), MIB has been evaluated in 7 trials involving 1698AP patients. These studies show a consistent dose-dependentimprovementinexercisctolerrmceoverarrmge of 50 to 150mg qd, with andwithoutback~ourrdtherapywith beta-blockers or nitrates. In a psrallel comparison with arnlodipine10mg qd, MIB 100mg qd producedsignificantly greater increasesin ETT duration,time to AP, and time to 1 mm ST depression and also tended to produce greater reductionsin nrnbufatorysilentischernia.MIB 100mg qd was also at leest as effective as diltiazem SR 120 mg bid, and produced substantiallygreater decreases in exercise doubleproduct. MIB producesa similraflequencyof adverseeffects ascomparatorCAs,buta lowerincidenceofcdema. Thus,MIB is a new CA with uniquepharmacologicalpropertieswhich is rmeffectiveand well-toleratedantianginrdmedication. KeyWords:
Calciumantagonists, especiallythoaeofthedihydropyndine type,(DHP)arewidelyuaedthewotidoveraa antihypertensive agenta.Theyhavespecialappealforclinician baaeuaeoftheir inatantandpotentvasodilating actionconaequant to blockingCaentryintoarteriolarsmoothmuscle.Howaver,broadusagehas revealedproblemspertraparelatedto overdilation anda reaative hyperdynamic circulation asseaiatedwiththeiruse. Thus,it has becomeapparentthatdihydropyridine therapycanworsencongestive heartfailure,anda numberoftrialshaveshownthattheseagenta alaocanactuallyincreasetheMl recurrenceratain postMl patients. Thesefindingsare inaharpcontraatto theimpreaaive cardioprotective effeetaachievablewithaimilarvaaedilationand preaaurereduction inducedinsteadbyCEI or betsblockers.Alaoin contraatto DHP,calciumchannelblockadewithverapamilor diltiazemdoesproducesomecardioprotestion andthesetwocalcium antagoniata haveotheruniquepropetiiesfortreatingatrial arrhythmiaandhypertrophic cardiomyopathies. Twootherproblemawithcalciumantagonistdrugsin general haveemerged.Oneiatheirgeneraltendencyto promotebleeding,a propertywhichresembleaaapirintherapyin magnitudebutmightbe cauaedinateadbyoverdilation.Whateverthecase,thisriakcanbe a problemin perioperative patiantaundergoing heartaurgery,in coronarycareunitpatientaandin patientawithevolvingstrokeor a dissecting aneutysm,Thirdpoaaiblebutmoreremoteproblem,ia the statistical aaaociation in aeveralrepottaofcalciumantagonisttherapy withthesubsequent occurrenceofvarioustypeaofcancer. Thua, requireafurtherepidemiologic endlaboratoryatudybeforeitsclinical relevancecanbe defined. Altogether then,thechallengeforthefutureisto examinethe experiencetodateto developbetter, moretargetedcalcium antagonists thatpresewetheirbeneficialpropetiieswhilereducingor eliminating unattractive features.It ia alsoposaiblethatcombination of DHP’awithotheragentsmightproveto countervails unwanted effects.
Mibejiadil, angina,calciumantagonist Key Words: CslciumAntagoniata, Hypertension, Stroke,HeartAttack, Heart Failure
239A
] SPECIAL SYMPOSIA
1997-VOL. 10, NO. 4, PART 2
Saturday May 31, Ballroom A, 5:30 pm Calcium Antagonists in 1997: Emerging Perspectives and Future Directions
Saturday May 31, Ballroom A, 5:3o pm Calcium Antagonists in 1997: Emerging Perspectives and Future Directions
OptfcealUtfffsattonof CalciumAntagonistsin Special HypertensivePopulations Center,Bowman John M. Flack, M.D.,M.P.H.,Hypertension Gray School ofMedicine ofWzkeForestUniversity, Winston-
EFFECTS OF CALCIUM ANTAGONISTS METABOLIC PARAM ETERS AND DYSLIPIDEMIA
Sslem,N.C.27157-1032 ‘Ilrehemodymrnic,inohopioand drrono&opiceffects of these agents differeccordingto the specific type of calciumentegonist: 1)phenylslkylemine(varapemril);2) benzotbiezepine(diltiazem); or 3) dihydropyridine(i.e., nisoldipine). Matchingthe appropriate calciumantagonisttyps with tbepatient clinical profile (i.e., conmedications) gestiveheart failure, unstablesnginsMI,concurrent represents asizable challengefor rhe clinicianwhose goal is m use this heterogemms gm.p of agents to provideoptimallyeffective thernpywhile minimizingrhepotential forhann. The dihydropyidinea appeacto be aafewhen used as adjunctivetherapy in patientswith CHFand may confer incrementalclinicalbsnefit to Afdcan-Ansedcsm and tboaewith noniaebemiccardiomyopathy. elderlyhyparrarrsiveapresentspecial tberapauticchallengesbecause of: 1)higher BP levels; 2) bigb prevzlcnceof ssltsansitivity;3) gr.eeterburdcmofprcssure-relatedtarget-organ damage;4) high ffequencyof coexistingCVD and other medical conditions;and 5) poly-phsnnacy. In individualswith severe hypesrenaion,tbeaeagents are highly useful in combinationwith odrerantih~anaive agantain achievingBP normalization. The BP loweringeffect ofcalchrn antagonistsis less attenuatedthan with other agents (excaptdiuratios)by usual levels ofdietsry sodium intake NSAIDs we commonlyprescribedmedicationsin the eldcdy. Howevsr, the BP lowsring effect ofcdciwtt aotagonisrs is ucraffkctrdbyNSAID use. Shategies will be discussed for optimizingthe use of calciumantagonistsin African-Americans, theeklady, turdhypmtensiveawitb coronarysyndromeaincluding
CHF. KeyWords;
Catcirun, .@agcmista, Elderly,Atiican Anrericens, Congestive HeartFailure
ON
JamesR. Sowers,MD, Wayne State University School of Medicine,Detroit,MI 48201 Hypertensionis offenaccompaniedby impaired glucosetokmnce, insulinresistsrrce,clinically evident type II diabetesmellitus and dyslipidemia. Impaired carbohydratemetabolismand hypertensionoccur with increeaingprevalencein relation to increasingage in industiafized societies. In these populations,factors contributingto age-relatedrises in rates of diabetes mellitusand hypertensionincludeincreasinginactivity, obesity(especiallycentralkisceral obesity)and possibly increasedutilizationofmedicationa that may impair carbohydratemetabolism. As hypertensionis often accompaniedby metabolicabnormalities,there is considerableconccrrrregardingthe metabolic effects of antihypcrtensivephsmmcologicinterventionsnd the impsct of this interventionon cardiovsscrrlsrrisk reductionresultingfromthe treatmentof hypertension. Peripheralvasculardilation appeemto be the principal mechanismoftbe long-tcnnblood pressrrrc-lowering effectsofcalciutn antagonists. Calciumantagonists appearto have beneficialeffectswith respect to maintenanceof renal blood flow and glomerularfiltration rate. Metabolicabnormalitiessuchashypokslemi~
hypercslcemiqhypemricesniqlipidchanges,and hyperglycemia% aregetteratlynotobservedwithcatcitmr antagonists. KeyWords:c~ci~
antagonists,dyslipidemia
Saturday May 31, Ballroom C, 5:30 pm Advances in Drug Therapy for Hypertension
Saturday May 31, Bsdlroom C, 5:30 pm Advances in Drug Therapy for Hypertension
Mibefradil, a new calcium antagonist with novel pharmacological properties: Results in angina pectoris
LIMITATfONSOF CONVENTIONALCALCIUMANTAGONISTS: John H. Larsgh,M.D., NewYork Hospitsl-ComellMedicelCenter
Barry M. Massie,Univ. of California,San Francisco,CA. Mibefradil(MIB) is the first of a new claw of calcium antagonists(CAS)with activityat both L-typeand T-type calcium charrnels.Unlike most CAS, its inhibition of L-channels is highly potential-dependent,so that it has little activity at -80 mV, the restingpotentialof cardiacmyocytes,but is masryfold more active at -50 mV, the usual potential of smooth muscle. It rdsois the firstknownspecificantagonistof T-typecharrnels, whichappcarto be more involvedin regulatingsmoothmuscle tone rmdcardiacautomaticitythan cardiaccontractility.These properties should produce significant rate-lowering and antihypertensiveeffects witbout depressingcardiac function, and may make mibefradilvery suitable for the treatment of angina pectoris (AP), MIB has been evaluated in 7 trials involving 1698AP patients. These studies show a consistent dose-dependentimprovementinexercisctolerrmceoverarrmge of 50 to 150mg qd, with andwithoutback~ourrdtherapywith beta-blockers or nitrates. In a psrallel comparison with arnlodipine10mg qd, MIB 100mg qd producedsignificantly greater increasesin ETT duration,time to AP, and time to 1 mm ST depression and also tended to produce greater reductionsin nrnbufatorysilentischernia.MIB 100mg qd was also at leest as effective as diltiazem SR 120 mg bid, and produced substantiallygreater decreases in exercise doubleproduct. MIB producesa similraflequencyof adverseeffects ascomparatorCAs,buta lowerincidenceofcdema. Thus,MIB is a new CA with uniquepharmacologicalpropertieswhich is rmeffectiveand well-toleratedantianginrdmedication. KeyWords:
Calciumantagonists, especiallythoaeofthedihydropyndine type,(DHP)arewidelyuaedthewotidoveraa antihypertensive agenta.Theyhavespecialappealforclinician baaeuaeoftheir inatantandpotentvasodilating actionconaequant to blockingCaentryintoarteriolarsmoothmuscle.Howaver,broadusagehas revealedproblemspertraparelatedto overdilation anda reaative hyperdynamic circulation asseaiatedwiththeiruse. Thus,it has becomeapparentthatdihydropyridine therapycanworsencongestive heartfailure,anda numberoftrialshaveshownthattheseagenta alaocanactuallyincreasetheMl recurrenceratain postMl patients. Thesefindingsare inaharpcontraatto theimpreaaive cardioprotective effeetaachievablewithaimilarvaaedilationand preaaurereduction inducedinsteadbyCEI or betsblockers.Alaoin contraatto DHP,calciumchannelblockadewithverapamilor diltiazemdoesproducesomecardioprotestion andthesetwocalcium antagoniata haveotheruniquepropetiiesfortreatingatrial arrhythmiaandhypertrophic cardiomyopathies. Twootherproblemawithcalciumantagonistdrugsin general haveemerged.Oneiatheirgeneraltendencyto promotebleeding,a propertywhichresembleaaapirintherapyin magnitudebutmightbe cauaedinateadbyoverdilation.Whateverthecase,thisriakcanbe a problemin perioperative patiantaundergoing heartaurgery,in coronarycareunitpatientaandin patientawithevolvingstrokeor a dissecting aneutysm,Thirdpoaaiblebutmoreremoteproblem,ia the statistical aaaociation in aeveralrepottaofcalciumantagonisttherapy withthesubsequent occurrenceofvarioustypeaofcancer. Thua, requireafurtherepidemiologic endlaboratoryatudybeforeitsclinical relevancecanbe defined. Altogether then,thechallengeforthefutureisto examinethe experiencetodateto developbetter, moretargetedcalcium antagonists thatpresewetheirbeneficialpropetiieswhilereducingor eliminating unattractive features.It ia alsoposaiblethatcombination of DHP’awithotheragentsmightproveto countervails unwanted effects.
Mibejiadil, angina,calciumantagonist Key Words: CslciumAntagoniata, Hypertension, Stroke,HeartAttack, Heart Failure
239A