The object of the course is to teach students an approach to the study of pharmacologic agents. It is not intended to be a review of the pharmacopoeia. The focus is on the basic principles of biophysics, biochemistry, and physiology as to the mechanisms of drug action, biodistribution and metabolis...
Harvard-MIT Division of Health Sciences and Technology
HST.151: Principles of Pharmocology
Instructor: Dr. Jeremy Ruskin
HST-151 1
Antidysrhythmics
I. Ventricular muscle cell action potential
a. Phase 0: Upstroke
b. Phase 1: Early-fast repolarization
c. Phase 2: Plateau
d. Phase 3: Repolarization
e. Phase 4: Diastole
,HST-151 2
II. Cardiac arrhythmia:
a. Abnormal impulse formation
i. Early afterdepolarizations (EADs): interrupts phase 3 -
exacerbated at slow heart rates and may contribute to development
of long QT-related arrhythmias
ii. Delayed afterdepolarizations (DADs): interrupts phase 4 - occurs
when intracellular calcium is increased; is exacerbated by fast
heart rates, may relate to digitalis excess, catecholamines, and
myocardial ischemia
b. Abnormal impulse propagation:
i. Abnormal depolarization (QRS)
ii. Abnormal repolarization (QTc)
III. Cellular mechanism of arrhythmia:
a. Enhanced automaticity: sinus and AV node, His-Purkinje system
i. Beta-adrenergic stimulation, hypokalemia, mechanical stretch
increase phase 4 slope & pacemaker rate
b. Reentry: impulse reenters and excites areas of the heart more than once
i. Obstacle for homogeneous conduction (anatomic, physiologic)
ii. Unidirectional block in conduction circuit
iii. Path length X conduction velocity > refractory period
, HST-151 3
c. Polymorphic ventricular tachycardia (Torsades de Pointes): ("twisting of
the points") or drug-induced long QT syndrome (DILQTS)
Polymorphic arrhythmia that can rapidly develop into ventricular
fibrillation
Associated with drugs that have Class III actions (potassium
channel blockers)
Also seen with other drugs such as terfenadine, cisapride,
under certain circumstances
Usually occurs within the first week of therapy
Preexisting prolonged QTc intervals may be indicator of
susceptibility
Potentiated by bradycardia
Often associated with concurrent electrolyte disturbances
(hypokalemia, hypomagnesemia)
IV. Classification of Antiarrhythmic drugs:
• Although several of the drugs used to treat cardiac arrhythmias have been used for
many years (e.g.- quinidine and digitalis since the early 1900s), most of the agents
approved for use today have only been available for a decade or less.
• Research in recent years has provided much information regarding the cellular
mechanisms of arrhythmias and the mechanisms by which some of the
antiarrhythmic drugs act, but the general approach to antiarrhythmic therapy
remains largely empirical.
• The recent results of several clinical trials, including the Cardiac Arrhythmia
Suppression Trial (CAST), have indicated that many antiarrhythmic drugs may
significantly increase mortality compared to placebo.
• All of the antiarrhythmic drugs act by altering ion fluxes within
excitable tissues in the myocardium. The three ions of primary
importance are Na+, Ca++, and K+. Antiarrhythmic drugs can be
classified by their ability to directly or indirectly block flux of one or
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