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Antiarrhytmic drugs (Basic concept of cardiac electrophysiology (Working…

- - - - Hyperpolarization induced Na inflow by funny Na channels (phase 4 - slope)
- - - - General
        
        moderate inhibition of phase 0 depolarization
        
        moderate steady-state Na+ block owing to intermediate duration of channel blockade
        
        intermediate time constant of dissociation - 1 sec
      - additional K+ channel block -> prolonged repolarization
        
        good thing
        
        additional reduction of automaticity and increase in refractory period
        
        Bad thing
        
        QT prolongation -> EAD -> torsades de pointes (pro-arrhythmic action)
      - use dependence -> bind preferentially to active channels (effect in tachyarrhythmia)
      - significant autonomic actions
      - used mainly in supraventricular arrhythmia
      - Quinidine
        
        stereoisomer of the antimalarial alkaloid quinine
        
        strong α-block and antimuscarinic action (autonomic effects)
        
        paradoxical heart effects
        
        positive chronotropic and dromotropic effects
        
        extracardiac side effects
        
        diarrhea
        
        muscle weakness
        
        immunothrombocytopenia
        
        photophobia
        
        good oral absorption + extensive metabolism
      - procainamide
        
        less prominent autonomic actions compared to quinidine -> best for supravetricular arrhythmia
        
        eliminated by acetylation in the liver (fast acetylation)
        
        in slow acetylators, SLE-like syndrome may develop (upon prolonged use)
        
        in fast acetylators, torsades de pointes (pro-arrhythmic action) may develope
        
        used i.m. / i.v. for emergency (orally not -> because of SLE provocation)
    - - general
        
        slight inhibition of phase 0 depolarization
        
        mild steady-state Na+ block owing to short duration of single channel blockade
        
        very short time constant of dissociation – 0.1sec
        
        slightly shortened repolarization (but not that significant)
        
        use dependence -> bind preferentially to active channels (effect in tachyarrhythmia)
        
        state dependence -> blind also inactive channels
        
        higher effect in hypoxic tissue, mainly in ventricular fiber
        
        no autonomic actions but less expressed heart effect (short time of dissociation – 0.1sec)
        
        used mainly in ventricular tachyarrhythmia caused by ischemic heart disease
      - lidocaine
        
        only slight cardiac action : negative dromotropic and inotropic effects
        
        extracardiac side effects
        
        paresthesias
        
        Tremor
        
        Convulsions
        
        high first-pass metabolism
        
        used only in i.v. (emergency) -> T1/2 : 1-2hours
        
        used to treat ventricular arrhythmia associated with AMI
      - mexiletine
        
        similar cardiac action as with lidocaine
        
        good oral bioavailability + long T1/2 (difference from lidocaine)
    - - General
        
        strong inhibition of phase 0 depolarization
        
        strong steady-state Na+ block owing to sustained single channel blockade
        
        long time constant of dissociation – 10sec
        
        pro-arrhythmic action (slower conduction may activate latent reentry -> pro-arrhythmic effect)
        
        no effect on repolarization but prolonged refractory period
        
        use dependence -> bind preferentially to active channels (higher effect in case of tachyarrhythmia)
        
        strong negative dromotropic and inotropic effects + pro-arrhythmic action
      - flecainide
        
        I.v. used in resistant case of supraventricular tachyarrhythmia
        
        may cause serious ventricular arrhythmia in patient with previous AMI or preexisting ventricular ectopy
        
        good oral bioavailability + long T1/2
        
        Withdrawn
      - propafenone
        
        additional slight K+ channel block + β-blocker activity
        
        low first pass metabolism -> orally used
        
        metabolite : blocks Na+ channels but not β-receptor
  - - - diminish the slope of SDD -> reduce automaticity and heart rate
      - slow AV conduction (negative dromotropic effect) and increase AV node refractoriness (inhibition of reentry)
        
        negative dromotropic effect is good for supraventricular tachycardia / atrial flutter & fibrillation
      - inhibit both EAD and DAD
      - drug choice in ventricular arrhythmia
        
        β-blockers can protect against sudden cardiac death caused by ventricular fibrillation
      - very effective in catecholamine-induced arrhythmia
        
        Pheochromocytoma
        
        Hyperthyroidism
        
        Amphetamine overdose
      - β1-selective drugs having no intrinsic sympathomimetic activity are used
    - - β1-selective drugs (cario-selective) with minimal β2-receptor inhibition
  - - - block K+ channels responsible for repolarization -> phase 3 is prolonged
        
        reduced automaticity + increased refractory period, inhibiting reentry
      - but prolongation of QT time may lead to torsades de pointes (pro-arrhythmic action)
      - used in both supraventricular and ventricular arrhythmia
    - - pure K+ channel blockers (only for supraventricular)
      - excreted unchanged by the kidney
      - orally used in atrial fibrillation and flutter
    - - pure K+ channel blockers (only for supraventricular)
      - used i.v. for atrial fibrillation and flutter (high first pass metabolism)
    - - structurally related to thyroid hormone (contains iodine)
      - additional Na+ & Ca2+ channel / α & β receptor blocking actions -> highly effective drug (complex electrophysiological effect)
      - used for both supraventricular and ventricular arrhythmia (oral or i.v.)
        slight positive heart effect but no torsades de pointes, although it is expected (other activity inhibit it)
      - extracardiac side effects (really bad)
        
        Pulmonary fibrosis
        
        Photosensitive skin
        
        hepatic & thyroid dysfunction
        
        Hypotension
      - very lipophilic
        
        slow accumulation in adipose tissue and other tissue
        
        plasma T1/2 is 1 month (loading dose is needed)
      - extensive metabolism + inhibition of CYP3A4 and p-glycoprotein -> numerous drug interactions
    - - analog of amiodarone but has no iodine -> fewer side effects
      - shorter T1/2 -> favorable pharmacokinetics
      - used in atrial fibrillation
    - - additional β receptor blocking actions -> torsades de pointes (pro-arrhythmic action)
      - Used orally
      - excreted unchanged by the kidney
  - - - β1-recptors facilitate voltage-gated Ca2+ channel by PKA-mediated phosphorylation -> some properties are similar to class II & III
      - expressed effect in nodal tissue (Ca2+ channel is responsible for upstroke) -> used for supraventricular!!
      - bind to both active and inactive channels -> use-dependence + state-dependence
      - reduce slope of SDD -> reduce automaticity and heart rate
      - slow AV conduction (negative dromotropic) + increased AV node refractoriness
      - inhibit both EDA and DAD
      - used in supraventricular tachycardia / atrial flutter & fibrillation (nodal tissue!!)
    - - given orally or i.v. (dihydropiridines are not used -> for vascular smooth muscles)
  - - - muscarinic antagonist
      - may be used in sinus bradycardia and AV block (not cause arrhythmia)
    - - synthetic catecholamine
      - but may cause arrhythmia (unlike atropine)
      - may be used in sinus bradycardia and AV block
    - - positive inotropic drug
      - may be used in atrial fibrillation in patient with systolic heart failure
    - - via A1 adenosine receptor (Gi-coupled protein), it inhibits Ca2+ channels and activates K+ channels mainly in AV node
        
        produces negative dromotropic effect
      - used to stop supraventricular tachycardia (i.v.) -> less than 1 min T1/2 due to active cellular uptake
      - side effects
        
        hypotension
        
        transient bronchospasm
      - Indication
        
        caffeine / theophylline -> antagonize adenosine receptor
        
        dipyridamole -> inhibits adenosine uptake
- - - - higher nomotopic pacemaker rate or ectopic impulse formation due to
        
        shortening of the action potential (e.g. faster repolarization) -> always tachyarrhythmia
        
        shortening of the diastolic interval (phase 4, SDD) by change of 3 parameters
        
        increase minimum diastolic potential
        
        increased slope
        
        decreased of activation threshold
    - - prolong of the action potential (phase 3) or SDD (phase 4) -> opposite of pathological changes
      - Principle
        
        time point between two upstroke phase = duration of the action potential(AP) + duration of the diastolic period (SDD)
      - 3 ways to prolong the SDD (combination form is used) to reduce automaticity
        
        make membrane potential more negative (staring point of SDD is lowered) -> e.g. -80 to -100mV
        
        decrease of SDD slope (more time is needed to reach action potential threshold)
        
        increased action potential threshold
        
        increase action potential duration -> plateau phase is longer
  - - - early after-depolarization
        
        during phase 2 (plateau) of the action potential (by QT prolongation!!!)
        
        Provoking factor
        
        AP prolongation
        
        Bradycardia
        
        hypokalemia
        
        May lead to torsades de pointes
      - delayed after - depolarizaition
        
        during phase 4 (following the AP)
        
        provoking factors
        
        Elevate the IC Ca lvl
        
        Tachycardia
    - - elevation of action activated treshold
  - - - Obstacle of homogensous impulse conduction
      - Unidirectional conduction block on the branches
      - Retrograde impulse must arrive when the refractory period is over
    - - Production is bidirectional block by slowing AP conduction or prolongation of the refractory period
  - - - Increased vagal tone
      - Beta 1 block
    - - Pacemaker
      - Beta 1 agonist
      - Atropine
- - - - IA - moderate Na channel block -> prolonged repolarization
      - IB - Mild Na channel block -> Shortened repolarization
      - IC - Marked Na channel block - No change in repolarization
    - - action potential (repolarization) prolonging durgs
  - - - aim of Na+ channel blocker : to prolong refractory period
      - principle of Na+ channel blocker
        
        under the same resting membrane potential, there are no Na+ available (in drug effect)
        
        so, more negative membrane potential is required to achieve same number of Na+ channel under the drug effect
        
        and to lower the membrane potential, time is needed for further K+ outflow
        
        by this principle, Na+ channel blocker can prolong refractory period
    - - starting point : fewer Na+ channels are available for activation
        
        activation threshold in increased -> automaticity↓
        
        slope of SDD is decreased -> automaticity↓
        
        slope of phase 0 is reduced -> slower conduction (negative dromotropic effect)
        
        slower conduction may activate latent reentry -> pro-arrhythmic effect
        
        voltage dependent of the recovery of the inactive Na+ channel is shifted in the direction of hyperpolarization -> refractory period↑
        
        increased refractory period can inhibit reentry
        
        extent of the negative inotropic effect depends on steady-state Na+ channel block (the power of Na+ block)
        
        determinant of the extent of the steady-state of Na+ channel block
        
        a. frequency of channel openings (i.e. heart rate) -> use dependent
        
        stronger block with higher frequency -> selective inhibition of tachyarrhythmic foci
        
        reason : higher affinity for the active state of the Na+ channel
        
        b. resting membrane potential (with drugs) -> state-dependence (opposite to use dependence)
        
        stronger block in less repolarized tissue -> selective inhibition of ischemic ventricular cells (less complete repolarization)
        
        reason : higher affinity for the inactive state of the Na+ channel
        
        c. time constant dissociation of the drug from the Na+ channels
        
        time point of drugs from binding to channel and dissociation from channel
        
        long time binding -> strong effect
        
        slow dissociation rate increased Na+ block
        
        tachycardia increases Na+ block (short time for dissociation -> no complete dissociation then start action potential
        
        1 more item...
        
        short time binding -> weak effect
- - - - Act on nodal tissue
        
        Prolong degree AP to some degree
        
        Drugs
        
        Na channel blocker
        
        Beta receptor antagonist
        
        Ca channel blocker
    - - Direct effect
      - K channel blocker