B.5 Flashcards
Phases of the pacemaker potential
phase 4: pacemaker potential
Phase 0: upstroke
Phase 3: repolarization
Phase 4: Pacemaker potential
influx of Na+ and Ca++, efflux of K+ until the cell reaches the threshold, then transition to phase 0
Phase 0: upstroke
depolarization due to rapid Ca++ influx
Phase 3: repolarization
K+ efflux
Phases of the ventricle potential
Phase 0: fast depolarization (Na+ influx)
Phase 1: partial repolarization (Notch) (rapid K+ efflux)
Phase 2: plateau (Ca++ influx)
Phase 3: repolarization (K+ influx)
Phase 4: resting membrane potential
Drugs influencing cardiac electrophysiology
Class I: Lidocaine (Ib), Propafenone (Ic)
Class II: Sotalol, Esmolol
Class III: Amiodarone, Sotalol
Class IV: Verapamil
Class V: Adenosine, Digoxin, Mg2+
Cardiac electrophysiology
Physiological conduction pathway:
1. AP is generated by the SA node and is transmitted to the atria and the AV node → 2. The AV node transmits the impulse to the Purkinje fibers → 3. Purkinje fibers conduct the impulse to the ventricles
effective refractory period
The shortest period of time after which the myocardial cell becomes excitable again following the previous AP. Also called ARP (Absolute refractory period)
The most common cardiac arrhythmia
A.fib
A.fib can lead to
- Transition to V.fib
- Persistently high ventricular rate
- Cerebral embolism
Lidocaine
Class I
MOA: Subclass I/b. weak Na+ channel blocker, they act selectively in ventricles (not atria!), and in ischemic tissue they also bind inactive channels (due to state dependence);
IND: treatment of post-infarction arrhythmias, VENTRICULAR TACHYCARDIA (used primarily to treat VTs occuring in the hospital phase of AMI) - Amiodarone mostly replaced it;
Pharmacokinetics: p.o BA is low→ due to strong first pass efefct → can be given i.v or i.m., ↑plasma protein binding, hepatic metabolism by CYP3A4, short T1/2- 2h; SEs: sedation, excitation (→tremor, convulsions, sensory disturbances);
Contra-IND: MI and HF;
Special point: Important phenomenon of “use” dependence- they bind primarily to active channels→ heart rate dependent, greater efficacy in tachyarrhythmic foci:
Propafenone
Class I
MOA: subclass I/C. strong Na+ channel blocker, mild β-blocker activity;
IND: SVT (conversion of A.fib, WpW syndrome), if no structural heart disease present!!;
Pharmacokinetics: p.o or i.v adm., metabolized in the liver (2 active metabolites, T1/2: 5-6h or 15-20h depending on the metabolizer);
SEs: (-) chronotropy and inotropy., Proarrhythmic potential, visual disturbances, GI symptoms, seizures, impotence;
Contra-IND: HF and MI;
Special point: Important phenomenon of “use”dependence - they bind primarily to active channels→ heart rate dependent. greater efficacy in tachyarrhythmias
Esmolol
MOA: class II. β-blocker;
Pharmacokinetics: only parenterally!, fast onset, short duration (10-15min), does NOT cross BBB;
IND: used in acute cases (SVT, A.fib, perioperative HTN/Tachycardia);
Drug-interactions: increased toxicity if combined with class IV. agents (can stope pacemaker activity of SA node)
Amiodarone
MOA:
-Class III. K+ channel blocker (prolonged AP, inhibition of repolarization),
-subclass I/A-like effect (Na+ channel blocker, fast dissociation kinetics),
-class IV-like effect (Ca2+ channel blocker →slower AV conduction),
-class II-like effect (→non-competitive β-blocker - may be bradycadizing in chronic use), Low arrhythmogenicity;
IND: used in almost any type of SVT and VT; Pharmacokinetics: p.o BA 60%, ↑plasma protein binding, accumulated in tissues - saturation dose needed (in order to reach steady state cc), metabolized in the liver (active metabolite: desethyl-amiodarone), long T1/2: 60-100days;
SEs: accumulation in tissues: can form deposits in skin (blue discoloration), photosensitivity, cornea (visual impairment), Lungs (fibrosis- can be fatal, must be monitored), Thyroid dysfunction, tremor, hair loss, hepatic dysfunction;
Contra-IND: IODINE ALLERGY, hyperthyreosis due to iodine content; Special point: has reverse use-dependence (greater effect on slower HR→less potent as high beating frequencies
Sotalol
MOA: Class II and III., K+ channel blocker, β-blocker (D,L-Sotalol has mixed β and K+ channel blocker, pure K+ channel blocker is D-Sotalol);
IND: ventricular and SV arrhythmias (A.fib); Pharmacokinetics: p.o or i.v adm., renal excretion in unchanged form;
SEs: Proarrhythmic effect (→due to excessive prolongation of repolarization (TdP), (-) inotropy, bradycardia, hypotension due to β-blocker effect
Verapamil
MOA: class IV.
-L-type Ca2+ channel blocker (IC Ca2+↓→ (-) inotropy, dromotropy→inhibiton of SA pacemaker activity and inhibition of AV-conduction),
-α-blocker as well;
IND: PSVT, supraventricular arrhythmias (AVNRT, AVRT), WpW syndrome (prolongation of PR interval), rate control in chronic A.fib, Migraine;
Kinetics: Use-dependence (potency increases with HR) p.o adm., good BAp.o, administered 3x/daily (b/c of short duration action), ↑plasma protein binding (might increase Digoxin toxicity), metabolized by the liver, excreted in urine;
SEs: (-) cardiac effects AV block, bradycardia, decreased pump function, hypotension, transient asystolia can occur at i.v adm.;
Contra-IND: can cause V.fib in WPW or LGL syndrome, A.fib, Digitalis intoxication, AV-block (cannot be administered in combination with β-blockers), severe LV failure, hypotension
Adenosine
MOA: Class V. Adenosine A1-R activaiton in SA and AV nodes blockage: (-) dromotropic effect, Ca2+ block, K+ opening;
IND: treatment of paroxysmal SVT (tachycardia with narrow QRS complex);
Kinetics: Short DOA (10sec), administered in fast i.v bolus (6-12mg), weaker effect if combined with theophylline and caffeine (Adenosine-R antagonists); SEs: can cause asystolia (AV-block), flushes, headache, nausea, hypotension, bronchoconstriction;
Contra-IND: WPW syndrome, AV-block, asthma bronchiale
Digoxin
MOA: Class V. strong cardioselective vagus stimulation and inhibition of AV-conduction;
IND: A.fib and A.flutter in HF - treatment of pulse deficit;
Extra: Ca2+ channel blockers and Adenosine significantly replaced its use
Mg2+
MOA: Class V. Ca2+ channel blocker;
IND: 1st line treatment for TdP, i.v. for digitalis induced arrhythmias, prevent preterm labor
PSVT
Paroxysmal Supraventricular Tachycardia
“Use” dependence phenomenon
- In active and inactive states the affinity of drugs for the receptor is high, and this binding dominates
- In restinge state, affinity is low, and thus dissociation becomes prominent
- At high heart rates or early ES (Extra Systole), the effect of Na+ channel inhibitors is strengthened (“use” dependence), and at slow HR it is wekened or may disappear
- Dissociation kinetics presumabely depend on lipid solubility and molecular weight of the drug molecules
Treatment of Arrhythmias
- None
- Treatment of underlying cause
- Maneuvers
- Medications
- Implantable devices
- Surgery/ablation
Updated Vaughan-Williams Classification of antiarrhythmic Agents
0.: HCN channel mediated pacemaker current (If ) inhibitors
I.: Na+ channel blockers:
I/A. al (Quinidine, Disopyramide, Procainamide, Ajmaline, Prajmaline)
I/B. al (Lidocaine, Mexiletine, Phenytoin)
I/c. al (Flecainide, Propafenone)
II.: β-Blockers:
Non selective: (Propanolol, Sotalol)
Cardioselective (Esmolol, Metoprolol, Bisoprolol, Atenolol)
III.: K+ channel blockers:
Amiodarone, Dronedarone, Sotalol, Bretylium, Ibutilidw, Dofetilide, Vernakalant::2 we have to know
IV.: Ca2+ channel blockers:
Verapamil, Diltiazem
V.: Others:
Adenosine, Digoxin, Mg2+, Atropine
HCN
hyperpolarization activated cyclic nucleotide channels
types of Ca2+ channels exists in the heart
T-type (transient) and L-type (late)
note: L-type has pharmacological importance.
The activity of L-type Ca2+ channels is greatly increased by β-R stimulation, while PSY excitation inhibits it
types of K+ channels exist in the heart
IK1: Inward rectifier K+ current;
hERG,
IKr: Fast delayed rectifier K+ channel;
IKs: Slow late rectifier K+ current;
ATP-dependent-K+ channels: opens in response to reduced ATP level (hypoxia/ischemia), K+ efflux from the cell results in significant repolarization shortening
