Pharmacology of Antiarrhythmics (kinder) Flashcards
class Ia Na channel blockers
“Double quarter pounder”
a) Disopyramide (Norpace)
b) Quinidine
c) Procainamide ***
class I b Na channel blockers
“lettuce tomato mayo”
a) Lidocaine (Xylocaine)***
b) Mexiletine
c) Tocainide
class I c Na channel blockers
“more fries please”
moricizine,
flecainide ***
propafenone
Class II
beta adrenergic receptor blockers
esmolol
metoprolol
propranolol
class III
K+ channel blockers
“a big dog is scary”
a) Amiodarone (Cordarone) **
b) Bretylium
c) Dofetilide (Tikosyn)
d) Ibutilide
e) Sotalol (Betapace) **
Class IV
Ca channel blockers
Verapamil
Diltiazem
what is the major determinant of membrane potential in the resting cardiac cell
extracellular potassium concentration and inward rectifier channels
phase O of cell depolarization
rapid depolarization due to influx of Na
positive into the cell
phase 1
brief repolarization
(1) Transient and active K+ efflux, Ca2+ begins to move into intracellular space at about -60 mV causing slower depolarization
phase 2
plateau
ca 2+ influx continues (L channels in the myocardium)
balanced somewhat by K+ efflux
phase 3
cellular repolarization
membrane remains permeable to K+ efflux
phase 4
gradual depolarization
constant Na leak into intracellular space balanced by decreased K efflux overtime
diastolic interval (duration of diastole ) is determined by what
slope of phase 4 of action depolarization
what is early after depolarization (EAD)
when is this exacerbated
(3) Early afterdepolarization: transient depolarization that interrupts phase 3
(a) Exacerbated at slow heart rates, contributes to long QT
what is delayed after depolarization (DAD)
interrupts phase 4 - and typically occurs after a cell has repolarized
(a) Often occurs when intracellular calcium is increased, exacerbated by fast heart rates
(b) Responsible for some arrhythmias related to excess digitalis, catecholamines, and myocardial ischemia
what is reentry and what 3 conditions MUST be met for reentry to occur ?
impulse reenters and excites areas of the heart more than once
(1) 3 conditions must be met for reentry to occur
(a) Must be an obstacle, thus establishing a circuit
(b) Must be a unidirectional block
(c) Conduction time must be long enough that retrograde impulse does not encounter refractory tissues
what is the goal of pharm agents that depress autonomic properties of abnormal pacemaker cell
i) Action: decrease slope of phase 4 depolarization and/or elevate threshold potential
(1) If rate of spontaneous impulse < SA node → restoration of normal cardiac rhythm
NOTE anti-arrhythmics CAN induce arrhythmias
Type I a (sodium channel blockers) mechansim….
what is the effect on conduction velocity? refractory period?
clinical uses?
(1) Decrease conduction velocity, increase refractoriness, decrease autonomic properties of Na+ dependent conduction tissue
(2) unidirectional block transformed to bidirectional
(3) Has some potassium blocking properties
(4) Clinically effective in supraventricular and ventricular arrhythmias
intermediate kinetics
what is the mechanism of type Ib sodium channel blockers?
effect on refractoriness
effect on conduction velocity
effect on AP
clinical use?
shorten the action potential duration in some tissues in the heart and dissociate rapidly
(1) Decrease refractoriness with no effect on conduction velocity
(a) Improves antegrade conduction, eliminating area of unidirectional block
(2) However, in diseased tissue, refractoriness prolonged leading to bidirectional block
(3) Clinically effective in ventricular arrhythmias more than supraventricular arrhythmias
rapid kinetics
Type Ic sodium channel blockers
effects on AP
effect on conduction velocity
effect on refractoriness
minimal effects on action potential duration and dissociate slowly (slow kinetics)
(1) Profoundly decreases conduction velocity while leaving refractoriness
(a) Theoretically eliminate reentry by slowing conduction to the point where impulse extinguished
(2) Clinically effective for ventricular and supraventricular arrhythmias but use in ventricular arrhythmias limited due to risk of proarrhythmias
Type II sympatholytic b blockers
i) Decrease conduction velocity, increase refractoriness, decrease automacity in nodal tissues
ii) Anti-adrenergic actions
Type III potassium channel blockers….
prolong the action potential duration
i) Prolong refractoriness in atrial and ventricular tissues
ii) Delay repolarization by blocking K+ channels
type IV calcium channel blockers
slows conduction where action potential dependent on calcium (SA and AV nodes)
i) Decreases conduction, increases refractoriness, decreases automacity in calcium dependent tissues
non DHP’s
procainamide
effect on upstroke
effect on conduction
effect on QRS
effect on SA and AV nodes
Type I a
slows upstroke of action potential, slows conduction, prolongs QRS, prolong APD (a class III action due to nonspecific blockage of K+ channels), direct depressant effects on SA and AV nodes
1/2 life 3-4 hours
what occurs in toxicity with procainamide
excessive action potential prolongation
QT prolongation
induction of TdP
new arrhythmias.
Reversible lupus erythematosus like syndrome (~33%) consisting of arthralgia and arthritis (some patients experience pleuritis, pericarditis, or parenchymal pulmonary disease, rarely renal lupus).
Increased ANA titer without symptoms not an indication to stop therapy.
Nausea and diarrhea (10%), rash, fever, hepatitis (< 5%), agranulocytosis (< 0.2%).
what is the metabolite of procainamide and what action does it have>
(a) Metabolite N-acetylprocainamide (NAPA) has class III activity → accumulation implicated in TdP (especially in renal failure)
what is the therapeutic use of procainamide
atrial and ventricular arrhythmias.
Long-term therapy avoided due to frequent dosing and lupus-like adverse effects.
Used second or third line for sustained ventricular arrhythmias after MI
quinidine MOA? toxicity?
type Ia
MOA is like procainamide–> slows upstroke of AP, slows conduction, prolongs QRS, prolong ADP, depressant on SA and AV nodes
(1)Toxicity: GI [diarrhea, nausea, vomiting (33-50%)], headache, dizziness, tinnitus, rarely immunologic reactions (thrombocytopenia, hepatitis, angioneurotic edema)
Disopyramide
toxicity?
type Ia
very similar action to quinidine and procainamide
(1)Toxicity: much more pronounced antimuscarinic effects (should also administer a drug that slows AV conduction), precipitates heart failure (with preexisting depression of LV function or de novo), urinary retention, dry mouth, blurred vision, constipation.
Lidocaine
MOA
type I b
blocks activated and inactivated sodium channels with rapid kinetics
toxicity of lidocaine
least cardiotoxic of Na channel blockers
large doses may cause hypotension (especially if pre-existing heart failure)
*** most common adverse effects are neurologic (paresthesias, tremor, nausea of central origin, lightheaded, hearing disturbance, slurred speech, convulsions)
how do you administer lidocaine?
IV b/c of extensive first pass metabolism
t 1/2 is 1-2 hrs
how does lidocaine interact with alpha 1 acid glycoprotein (acute phase reactant)
(c) Occasional patients with MI or other acute illness require higher doses due to increased plasma α1-acid glycoprotein (an acute phase reactant) binding lidocaine making less free drug available
what is the therapeutic use of lidocaine?
DOC for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia. However, prophylactic use of lidocaine may increase total mortality by increasing incidence of asystole. Most administer lidocaine to those with arrhythmias
what is mexiletine
orally active congener of lidocaine
(1) PK and dosage: half-life 8-20 hrs, dosed two to three times daily
(2) Toxicity: neurologic (tremor, blurred vision, lethargy), nausea
(3) Therapeutic use: ventricular arrhythmias, off-label use for chronic pain
flecainide
therapeutic use
half life?
MOA
type Ic
potent blocker of sodium and potassium channels but does not prolong action potential or the QT interval
t1/2 is 20 hrs
therapeutic use?
supraventricular arrhythmias
toxicity of flecainide
severe exacerbation of arrhythmia even when normal doses are administered to patients with preexisting ventricular tachyarrhythmias and those with previous MI
propafenone
MOA
toxicity
uses?
Type I c
sodium channel blocking kinetics similar to flecainide but with weak b-blocking activity
does not prolong AP
(1)Toxicity: metallic taste, constipation, arrhythmia exacerbation
used for supraventricular arrhythmias
Amiodarone
MOA?
extracardiac effects?
type IIII
potassium channel blocker
markedly prolongs action potential duration (and QT interval) by blocking IKR, chronic administration results in IKS blockage
blocks AP over a wide range of heart rates
Also significantly blocks sodium channels, weak adrenergic and calcium channel blockade. Broad spectrum of activity may account for high efficacy and low incidence of TdP
Extracardiac effects–> peripheral vasodilation
what are the toxicity signs of amiodarone
symptomatic bradycardia
heart block in those with preexisting sinus of AV node disease.
Accumulates in heart (10-50x more than plasma), lung, liver, skin, and concentrates in tears.
***Most important ADR:
pulmonary toxicity, fatal pulmonary fibrosis (1%).
Abnormal LFTs, skin deposits, photodermatitis, gray-blue skin discoloration in sun-exposed areas, corneal microdeposits.
Blocks peripheral conversion of thyroxine (T4) to triiodothyronine (T3), may result in hypo- or hyperthyroidism
drug interactions of amiodarone?
MANY
increase amiodarone levels with CYP3A4 blockers (climetidine)
decreases amiodarone levels with CYP3A4 inducers (rifampin)
increased drug levels of statins, digoxin, warfarin (reduce dose by 33-50%) **
what are the therapeutic uses of amiodarone
atrial fibrillation
prevention of recurrent ventricular tachycardia
not associated with increased mortality in patients with CAD or heart failure
used as adjunct with implanted cardioverter-defibrillator (ICD) to reduce the frequency of uncomfortable discharges
Dronedarone
type III potassium channel blocker
structural analog of amiodarone with iodine atoms removed. Designed to eliminate action of parent drug on thyroxine metabolism and modify half-life of drug.
Multi-channel actions: IKr, IKs, ICa, INa, and B-blocking actions
toxicity of dronedarone
no thyroid dysfunction or pulmonary toxicity but liver toxicity has been reported (with two cases requiring transplant).
***Black box warning against use in acute decompensated or advance (class IV) heart failure
PK and dosage of dronedarone?
t 1/2 life?
t 1/2 is 24 hrs
(a) Food increases absorption two-threefold
(b) Non-renal elimination, but inhibits tubular secretion of creatinine resulting in 10-20% increase in SCr
(c) Both substrate and inhibitor of CYP3A4, should not be co-administered with potent inhibitors (azoles, protease inhibitors)
therapeutic use of dronedarone?
atrial fibrillation (restores sinus rhythm in < 15% of patients)
sotalol
type III potassium channel blocker
both β-adrengergic blocking actions and action potential prolonging actions.
Racemic mixture, L-isomer responsible for β-blocking activity, both L and D-isomers responsible for action potential prolongation. β-blocking effects not cardioselective.
what is the electrical gradient in normal cells
-90 mv inside
0 mv outside
conc of sodium intracellular and extracellular
intra–> 5-15
extra -> 135- 142
like to flow in
conc of Potassium intracellular and extracellular
intra - 135-140
extra 3-5
like to flow out
which gates of the sodium channels are open and closed during threshold, depolarization, and repolarization
threshold–> opens m gates (activation gates)
If inactivation (h) gates have not already closed, the channels are open and activated and depolarization occurs
Opening is brief . Open (m) gates very quickly followed by closure of (h) gates and channel inactivation (repolarization)
what are the ion movements during contraction ?
1) ca entry from outside the cell triggers the release of much larger quantity of Ca from the SR
2) increased Ca initiates contraction process
3) ca is removed by reuptake into the SR and by Ca/Na exchanger
Sodium balance restored by Na/K atpase
how do you reduce the rate of spontaneous discharge 4 ways
decrease phase 4 slope
increase threshold potential
increase maximum diastolic potential
increase AP duration
