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Basic Pharmacology (2%) Basic Pharmacology (4 Questions) Types of drugs Major cardiovascular responses; Pharmacokinetics2 Cardiovascular Drugs Agonists(收缩药) restore or enhance cellular activity by mimicking natural body chemicals than bind to cell receptors Antagonists（拮抗剂） inhibit or block action by occupying a cell receptor Nitrates （硝酸酯类） dilate veins and arteries, for chest pain Inotropes (Digitalis洋地黄) the amt of intercellular Ca+, the contractile force of the myocardium Sympathomimetic (Proterenol拟交感神经类) mimic sympathic activity Sympatholytic ( blocker副交感神经类) oppose sympathetic activity3 Antiarrhythmic Drugs Vaughn Williams Classification Change the shape of the action potential by altering the flow of ions across a cardiac cell membrane Alter the automaticity, conductivity and refractoriness of cardiac tissue reduced the risk of re-entry & automaticity Bind to the channels and gates of a cell membrane Slow-binding drugs block the ioin-specific membrane channels and reduce conduction velocity Fast-binding drugs unbind quickly and have less effect on blocking a channel4 Effect on AP by Anti-arrhythmic Drugs5 Class I - Na Channel BlockersIa Quinidine奎尼奎尼丁丁A Flut & Fib, reentrant SVTs & VTBlocks Na+ / K+ , slows depolarization, prolong AP/RPQRS, QT prolongedSuppress automaticity of Purkinje/ can cause torsades de pointes （扭转性室速）（扭转性室速）Hypotension 低血压低血压Ia Procainamide普鲁卡因胺AF with fast Ventricular rate through bypass tractSimilar to Q but not as prolong AP & QT interval as QQRS, QT prolongedtorsades de pointesDrug induced SLEHypotensionIa Disopyramide丙吡胺Limited use, (-)ive inotropic & strong anticholinergic propertiesQRS, QT prolongedtorsades de pointesIb Lidocaine利多卡因利多卡因VT/VF (Popularly use) Slow depolarization & conduction velocity (shorten AP & RP) at fast HR & during ischemia, hypokalemia & acidosis, QRS prolongedQT shortenedSuppress automacticity & ealry & late afterdepolarizationsIb Mexiletine美西律Not for emergency VT/VFQRS prolongedQT shortenedCNS S.E uncoordinated movementsIb Phenytoin苯妥英VT due to digitailis toxicity HypotensionIbTocainide妥卡尼Rarely used Class I - Na Channel BlockersIC Flecainide氟卡尼AT/VT, effective for PVCs & non-sustained VTs/ AVNRT/AVRTNot 1st choice for VTSlow conduction in all parts of the heart with slow bindingautomaticityContraindicated in underlying heart disease (low EF cos life = 12 h)Risk of exacerbation of Re-entry (+) (Proarrythmic) IC Propafenone普罗帕酮Similar, a slight in RP Mild & Ca+ blocking propertiesexacerbation of Re-entry (+)(Proarrythmic)IC Moricizine莫雷西嗪Similar as Flecainide, VT/ATEffect on conduction velocity is less pronouncedAP & RPexacerbation of Re-entry (+) (Proarrythmic) 7 Class II - BlockersCarvedilol卡维地洛Metoprolol美托洛尔Terminate or prevent AVNRT, SANRT, Macro-reentrant tachySlow the ventricular response to AT, A Flut, AF(All For A) Pronounced effect in areas of rich adrenergic innervation (SAN & AVN)Bradycardia, myocardial depression, bronchoconstriction, claudation, Raynauds phenomenon, hypoglycemic effect, depression, impotency8 Class III - K+ Channel BlockersAmiodarone(Half life 100 days)胺碘酮AT , SVT or VTPAFProlong AP & RP in A & VHas all effects (Class I, II & IV) GI,Pulmonary & Thyroid, neurological & occular S.EBretylium溴苄铵Recurrent VF in emergencyProlong AP in V rather than in A, Initially adrenergic surge and later antiadrenergic effectNeed less energy for cardioversion, postural hypotension,体位性低血压 Sotalol索它洛尔Not as effective Interaction with many drugs (antibiotic/ antihistamine) May prolong the QT interval (dose related) Brady, (-)ive inotrophy, torsades de pointesIbutilide/Dofetilide伊布利特/多非利特AF or Fluttertorsades de pointes9 Class IV Ca+ Channel BlockersVerapamil维拉帕米SVT(WPW), Multifocal AT, Macro reentrant VTExercise induced and idiopathic VTsControl v rate in AF/ Flurefractoriness, depress automaticity, slow conducting in SAN & AVN(-)ive inotropic, hypotension, bradycardia, AV block, Respi failureContraindicated for HOCM, Pul diseaseDiltiazem地尔硫卓SVT, AT, AVNRT, macro reentrant VT10 Pharmacokinetics Bioavailability:生物利用度 The degree to which a drug becomes available to a target tissue after administration Affected by drug formulation, absorption, protein binding and first pass clearance in the liver11 General Pharmacology (Exam Favorites!) Loading doses do not affect time to steady state or raise concentration of steady sate Elderly patients and patients with CHF have smaller volumes of distribution and thus mandate smaller loading doses Drugs that are renally excreted require either dose reduction or less frequent dosing in renal insufficiency Cirrhosis does not increase volume of distribution, so loading doses should not be changed CHF results in decreased volume of distribution, decreased renal and hepatic blood flows, and increased risk of proarrhythmia use lower doses 12 Routes of Drug Administration13 Elimination Half- Life (t1/2) Time required for elimination of 50% of the drug from the plasma Essentially completely eliminated (90%) after 4-5 half lives Diseases that affect the organs that metabolize and excrete the drug will alter t1/214 Steady State When rate of drug elimination = rate of administration (i.e. drug effects are stable and predictable) Time to steady state is determined by the t1/2, typically 4-5 elimination half lives15 Volume of Distribution Theoretical space of drug distribution which accounts for the amount of drug that is taken up by the body tissues Affected by the affinity of different tissues for the drug and by the tissue perfusion(i.e. CHF, Elderly)和组织对药物的青睐性及组织灌注度有关16 Renally excreted AADs Class Ia Procainamide普鲁卡因胺 Disopyramide丙吡胺 Class Ic Flecainide氟卡尼 Class III Sotalol心得安, Dofetilide多非利特 Other Digoxin地高辛 All require dose reduction in RF17 AADs with Pure Hepatic Metabolism Class Ib Lidocaine利多卡因 Mexiletine美西律 Class Ic Propafenone普罗帕酮 Class II Propranolol普纳罗尔 Esmolol艾思 Class III Amiodarone胺碘酮 Class IV Verapamil维拉帕米 Diltiazem地尔硫卓 All require dose reduction in CHF and Hepatic Disease18 Drugs that affect the Pacing Threshold PacingPacingQuinidineProcainamide at high dosesFlecainide氟卡尼氟卡尼 blockers SotalolVerapamilAmiodaronePropafenoneDigitalis洋地黄19 Drugs that affect the DFT 除颤阈值除颤阈值DFTDFTLidocaineQuinidineFlecainide 佛卡尼ProparanololDiltiazem 地尔硫卓VerapamilAmiodarone with chronic oral, but IV - Digitalis 洋地黄Bretylium溴苄铵Sotalol reliably Dofetilide reliably 多多菲利特菲利特20 Proarrhythmia 致心律失常作用致心律失常作用 Low EF, CHF & Structural heart disease predict AAD efficacy and proarrhythmia Genetic predisposition based on pattern of metabolism and forme-fruste channelopathy Ischemiarisk of proarrhythmia Proarrhythmia with one AADrisk of proarr with any AAD (except amiodarone) Electrolyte abnormality and other drugs may risk Qunidine can cause idisyncratic (non-dose related) Torse de pointe21 Common S.E of Antiarrhythmic DrugsHypotensionIV Procainamide/ quinidine/ phenytoin/bretylium(-)ive Inotrophy blockers/ flecainide/ disopyramide/ VerapamilBradycardia blockers/ ca+ blockers (verapamil)/amiodaroneCNS 中枢神经 effectsAll class IB/ amiodarone/ blockers/ flecainideGI effectsAll/ quinidine/ procainamide/ class IBHepatic effectsAmiodarone/ PhenytoinPneumonitis 肺炎AmiodaroneTocainideBlood dyscrasias 不调QuinidineTocainidePhenytoinANS 自主神经系统effectsDisopyramideQuinidineblockers/ digitalis/ sotalol22 Drugs/ Electrolytes that increase the digoxin level : Quinidine奎尼丁奎尼丁FlecainidePropafenoneAmiodaroneVerapamilHypercalcimiaHypokalemia23 AF MaintenanceYes24No Heart D/SFlecainidePropafenonSotalolHyptLVHAmiodaroneDofetilideOr AblationNoAmiodaroneFlecainidePropafenoneSotalolCADHyptLVHDofetilideSotalolAmiodaroneDofetilide Other Cardiovascular drugs with AA actions Digoxin: vagal 迷走神经tone Adenosine腺苷: potent effect on blocking AVN, Slowing HR, brief effect Epinephrine 肾上腺素: and receptor agonist Dobutamine多巴酚丁胺: 1 receptor agonist Dopamine多巴胺: and receptor agonist, also dopaminergic receptors in gut & kidney25 The Autonomic Nervous System 自主神经系统自主神经系统 Consists of motor neurons that control multiple internal organs, including the heart Has 2 divisions: Sympathetic交感神经 or Adrenergic 肾上腺素 Alpha receptors peripheral arteries Arterial dilatation扩张/ constriction 收缩 Beta receptors central organs 1 Heart: HR, contractility, AV conduction. 2 Lungs: Broncho dilatation Parasympathtic 副交感神经or Cholinergic 胆碱能 Vagal activation: HR, AV conduction26 Automatically Active Drugs blockers: Metoprolol, atenolol, nadolol, pindolol Block adrenergic receptors, alpha and or beta Slow HR/ AV conduction, negatively inotropic Atropine:阿托品 Blocks vagal effects HR/ AVN conduction27 Digitalis/ Digoxin Inhibit Na- K+ ATPase pump Augment vagal activity CVRP AFlu/ AF/ AT/ Heart failure Contraindicated for VT & WPW Toxicity symptoms Anorexia, N, V, Visual blurred , yellow-green haloes, gynecomastia, VE, VT, VF, High degree AV block, accelerated junctional, AT with block28 29 The End
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