Calcium AntagonistsPowerPoint PresentationSlide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Other UsesSlide 19Slide 20Slide 21Calcium AntagonistsTatyana [email protected]+Ca2+Na+Ca2+-ATPaseNa+ -driven Ca2+ antiport2 mMCa2+Ca2+ATPADPCa2+MitochondriaCa2+-bindingproteinsCa2+-ATPaseCa2+-sequestering compartmentsRegulation of Ca2+ extrusion100 nMRGqPLCIP3DAGReceptor-dependent Ca2+ entryRegulation of Ca2+ entryVoltage-dependent Ca2+ channelPolarizedDepolarizedClosedOpen-activeOpen-inactive1 2SSSubunit composition of L-type Ca2+ channel•L-type (long-lasting)-excitation/contraction coupling of cardiac myocytes (nifedipine, verapamil, diltiazem)•T-type (transient) - participate in pace making, highly expressed in sinusal cells (mibefradil)•N-, P-type - expressed in neurons, are not affected by Ca2+ antagonistsACTIVATIONINACTIVATIONSELECTIVITYVOLTAGE SENSORDILTIAZEMNIFEDIPINEVERAPAMILPPPPPPSTRUCTURE OF THE L-TYPE CHANNEL ALPHA SUBUNITE/C COUPLING4CalmodulinCa2+ channels blockersCa2+ channelsCa2+ (intracellular)Ca2+ - calmodulin complexMLCKMyosin light chainPMyosin-actin interactionContractionControl of smooth muscle contraction and the site of action of calcium channel-blocking drugsCalcium Antagonists•Bind to specific sites on the alpha1 subunit of the L-type Ca2+ channel•Reduce the probability of channel opening rather then calcium current flow through an open channel•Tissue selectivity is one of the most beneficial properties of Ca2+ antagonists•In general, skeletal muscle, bronchial, tracheal, and intestinal smooth muscle and neuronal tissue are relatively insensitive to Ca2+ antagonistsSMOOTH MUSCLE Relaxation due to Ca2+ decrease•Decrease in blood pressure•Decrease in vascular resistanceCARDIAC MUSCLE * Excitation/contraction* Impulse generation in sinoatrial node* Conduction in atrioventricalar nodeRequire Ca2+ influxDECREASE IN OXYGEN REQUIREMENTVASCULAR SELECTIVITYINCREASED CORONARY PERFUSIONIMPROVED OXYGEN SUPPLYDECREASED PERIPHERAL RESISTANCECONTRACTION ENERGY SAVINGIMPROVED HEART PERFORMANCEFLOWAFTERLOADBPmyocardium vessels sino-atrial nodeverapamildiltiazemnifedipinenimodipinefelodipinenisoldipineamlodipine++++++++++++++++++++++++++++-----Degree of tissue selectivity of calcium antagonist in clinical useAmlodipine is currently the most commonly prescribed calcium blocker for hypertensionAngina and Calcium Antagonists•Angina is a chest pain that occurs when coronary blood flow is inadequate to supply the oxygen required by heart•Classic angina is caused by atherosclerosis•Angiospastic or variant angina is caused by vasospasmAngina and Calcium Antagonists•VASODILATIONCan be used in Prinzmetal’ anginaEffective at coronary vasospasmNot recommended in unstable angina or MI•INCREASED OXYGEN SUPPLYMyocardial oxygen extraction is almost maximal ~75% of the available oxygen under no stress condition, thus there is no reserve to meet increased demand. The increased demand is me by increasing coronary blood flow•DECREASE OXYGEN DEMANDThree major determinants of the myocardial oxygen uptake are heart rate, blood pressure, and the contractile status of the myocardiumAngina and Calcium AntagonistsCalcium Antagonists•Reduce blood pressure because of peripheral vasodilation•Reduce heart rate, especially diltiazem and verapamil•Decrease contractility thereby reducing the oxygen demandHypertension and Calcium Antagonists•Mechanism of action is VASODILATION•Nifedipine is used commonly because is 10 times more selective to vascular smooth muscle cells than to myocardial cells•Often used in patients with contraindications to beta-antagonistsArrhythmia and Calcium AntagonistsArrhythmia results from•Abnormal pacemaker activity•Abnormal impulse propagationAim of therapy•To reduce ectopic pacemaker activity•To modify impulse propagationArrhythmia and Calcium AntagonistsSupraventricular dysrhythmia(diltiazem, verapamil)•Mechanism of action is selectivity for pacemaker and nodal cells. Blocks Ca2+-dependent conduction in AV node, thereby reducing atrioventricular conduction•Restores synapse rhythm in 75% casesOther Uses•Migraine•Prevent development of atheromatous lesions•Pulmonary artery hypertensionSide EffectsDiltiazem•Edema•Headache•Depresses sinoatrial nodal function because of high degree atrioventricular nodal blockNifedipine•Dizziness is the result of acute vasodilation and rapid blood pressure fall•Headaches is the result of vasodilation•Ankle edema is caused by precapillary vasodilationVerapamil•May increase digoxin level when used in combination•Absolutely contraindicated in digoxin toxicity because will cause high grade AV block•High rate of constipation up to 30%, presumably due to a specific interaction of verapamil with calcium channels in smooth muscle cells of the gut•Depresses sinoatrial nodal function, may cause high degree atrioventricular nodal blockContraindications• Patients with low baseline blood pressure -may develop hypotension• Patients with decreased left ventricular systolic function - may worsen the heart failure•Arrythmias with antegrade conduction down a bypass tract, such as syndrome Wolff-Parkinson-WhiteDRUG INTERACTIONDRUG AFFECTEDMECHANISMPHARMACOKINETICEFFECTCTPOTENTIALCLINICALEFFECTDigoxinDecreasedclearanceIncreased serumdigoxin concentrationDigoxin toxicityCarbmazepineDecreasedclearanceIncreased serumcarbmazepineconcentrationNeurotoxicity(dizziness,headache, ataxia)AntihistaminesDecreasedclearanceIncreased exposure toactive drugVentriculararrhythmiaHMG-CoAreductase inhibitorsDecreasedclearanceIncreased exposure toactive drugMyopathyImmunosuppressivedrugsDecreasedclearanceIncreased exposure toactive drugNephrotoxicityBeta-blockersDecreasedclearanceIncreased exposure toactive
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