Soloist at the Heartbreak Hotel Class I (A, B, C) Antiarrhythmics – Na-Channel Blockers

4.1 – “Soloi “Soloist st at the Heartbreak Hotel”: Cl Class ass I (A, B, C) Antiarrhyth Antiarrhythmics mics – Na-channel blockers Physiology of ar arrhythmias rhythmias • Arrhythmias are the result of abnormal pacemaker activity or AP propagation (heartbreak hotel). Can be caused or exacerbated acid/base disturbances, electrolyte abnormalities, ischemia, hypoxia. Antiarrhythmics decrease automaticity of ectopic pacemakers, inhibit conduction, a/o ↓excitability of cardiac tissue. • Ion channels can assume 3 different states: o Open. o Inactivation gate swings shut. o Channel is refractory to reactivation in the absence of excessive stimulation. • Normal cardiac myocyte action potential (AP) (shape as effected by Class I antiarrhythmics shown by the solo singer’s cord): o Phase 4: resting potential (diastole). determined primarily by membrane permeability to K+ ions while in the resting state at -90mV. o Phase 0: rapid depolarization (Upstroke). AP onset occurs when voltage-gated Na+ channels open and causes Na current into the cell. o Phase 1: initial rapid repolarization. Rapid closure of Na+ channels o Phase 2: plateau. Opening of L-type Ca-channels and the closure of some K+ channels; results in membrane highly permeable to Ca ions, minimally permeable to K ions. Ca-current dominated. Na-channels are inactivated. o Phase 3: late rapid repolarization. Closures of Ca++ channels and opening of K-channels. Efflux of K from cell restores resting potential. K-current dominated (longest state). Class 1 ant antiarrhythmics iarrhythmics (solo (solo-singer). -singer). • Block inactivated Na-channels (peanut butter jar) o bind to open but inactivated Na-channels) → decreased slope of phase 0 upstroke, slowing action potential conduction through the tissue (demonstrated by microphone & wire) ▪ Many also act on K+ current, and therefore length of refractory period o Note that these act only on the myocytes & transmission systems, not on the nodal currents (which rely on Ca-channels initially) • Demonstrate use-dependence d/t binding to inactivated channels (i.e. more effective in rapidly depolarizing tissue, as e.g. in tachyarrhythmias) (ticking heart watch!). Stronger binding = more strongly use-dependent • Type I antiarrhythmics all slow down conduction velocity of action potential → widening QRS on ECG (wide QRS). Because of use-dependence, QRS widening intensifies with elevated HR • Binding strength: Class IC > IA > IB Class IA • Include Quinidine (dining prom queen), Procainamide (prom king), Disopyramide (“disappears!” headline) • Intermediate use dependence → moderate slowing of AP upstroke (gal loosely holding peanut butter jar) • Block K+ channels → longer depolarization phase & prolonged effective refractory period (banana curtain pushed away) • Clinical indications o used in supraventricular & ventricular arrhythmias (Top & bottom of heart lighted) o WPW syndrome (an SVT) ( • Side effects/toxicities o All: QT prolongation d/t prolongation of cardiac AP because of blockage of K-channels (→ longer depolarization period) (twisted streamers) o Quinidine: ▪ cinchonism (a syndrome of tinnitus, headache, dizziness) (tin cans for tinnitus). ▪ Rare: immune reaction → thrombocytopenia (broken plates) o Procainamide: ▪ long-term may cause ↑ANA titer & may cause drug-induced lupus (SSx: arthritis, arthralgias; less common: pleuritis, pericarditis, parenchymal interstitial lung disease) (lupus wolf) o Disopyramide: ▪ can exacerbate or cause HF d/t negative inotropic effects at high concentration (heart balloon past newspaper headline) Class IB • Include lidocaine (“You LIED” sign), mexiletine (Mexican flag). Phenytoin has some 1B antiarrhythmic properties (friendly towing). • Low binding affinity for Na-channel (peanut butter jar not held at all) o low use dependence. o Binding occurs and falls off so rapidly that cumulative effect over multiple cardiac cycles is minimal, with minimal effect on phase 0. o Shorten Phases 2 & 3 → shortened action potential (drawing banana curtain closed) o Highly selective for channels that stay in resting state longer (i.e. those in the ventricles & His-Purkinje system & dead tissue) (“DEAD to me” sign) • Used to treat ventricular arrhythmias, esp. in ischemic tissue d/t ↓membrane resting potential delays Na-channel transition from inactivated back to resting state (broken atrial light; “DEAD” sign). This is one of the most common causes of death postMI. • Side effects/toxicities o Neuro adverse effects/toxicities including paresthesias, tremor, convulsions, CNS depression (brain hat on tow guy) Class IC • Flecainide (corn flakes), propafenone (purple phone) • Strong binding affinity for Na-channel o Ergo strong use dependence and drastic slowing of phase 0. Slowest to dissociate. Have more dramatic effect on QRS duration. o Do not effect AP duration or refractory period (banana curtain looks like a normal myocyte action potential) • Can be used to treat both ventricular & supraventricular arrhythmias (top & bottom of heart lit up) • Restores normal rhythm in a-fib; can be used for cardioversion (remote to change channel). Can be used to maintain normal rate & sinus rhythm in A-fib (a-fib television). • Side effects/toxicities o Can cause a delay in conduction speed out of proportion to prolongation of refractory period. Can cause arrhythmias, particularly in structural HD (e.g. post MI) o Contraindicated in structural or ischemic HD (healthy heart cereal)