Pharmacology / Dr. Samer
Lec. 42
College of Medicine Baghdad University
2
Disopyramide:
Pharmacologic Effects: are similar to quinidine, but unlike quinidine and
procainamide it produces a greater reduction in Vmax at a depressed
membrane potentials than at normal resting potentials. Concentration of
disopyramide that does not affect conduction velocity of ERP can reduce
automaticity in atrial and ventricular Ts.
ECG changes are similar to quinidine but mild.
Dispyramide has –ve inotropic effect which can be troublesome in patients
with pre-existing heart disease.
It can cause vasoconstriction and has an atropine like action.
Therapeutic Uses: it is used as an alternative to quinidine and
procainamide.
Pharmacokinetics: well absorbed after oral administration. 50% excreted
unchanged in urine. t
1/2
5-7hrs.
Adverse Effects: it may cause conduction disturbances, CHF,
anticholinergic side effects.
Class I-B Drugs
Lidocaine:
The I-B agents rapidly bind and unbind from Na channels, therefore their
action is manifested when the cardiac cell is depolarizing rapidly. Those drugs
are particularly useful in treating ventricular arrhythmia. Lidocaine is the drug of
choice in emergency treatment of ventricular arrhythmia after M.I.
Pharmacokinetics: it is an amide L.A., 1
st
pass effect is 70%, t
1/2
1
1/2
hrs.
not effective orally.
Pharmacologic Effects: it depresses the rate of phase 4 depolarization in
ventricular and purkinjie fibers. Unlike quinidine which suppresses
arrhythmia caused by ↑normal automaticity, lidocaine suppresses
arrhythmia caused by abnormal automaticity, it suppresses or abolishes
ventricular reentry.
Lidocaine reduces the duration of AP of purkinjie fibers.
Unlike quinidine, lidocaine produces few ECG changes.
Pharmacology / Dr. Samer
Lec. 42
College of Medicine Baghdad University
3
It has little effect on the elect. phys. of the atria, thus it has little effect on
atria on AV junc. arrhythmia.
Therapeutic Uses: because of its rapid onset and short duration of action, it
is particularly useful in treating ventricular arrhythmia arising in
emergency situations: 1. Open heart surgery 2.M.I. 3. Dig intoxication.
Route of administration: it is given I.V. to abolish the arrhythmia then
followed by continuous infusion because t
1/2
is short, steady state
concentration can be reached quickly. It can also be given I.M.
Adverse Effects:
1. It has wide toxic/therap. ratio.
2. It shows little impairment of LVF and has no –ve inotropic effect.
3. CNS effects include: drowsiness, slurred speech, parasthesia,
confusion, and convulsions.
4. Cardiac arrhythmia may also occur.
Mcxiletene and Tocainide:
They are class I-B similar to lidocaine but are effective orally and are used for
chronic treatment of chronic symptomatic ventricular arrhythmia.
Side Effect: include: 1. GIT disturbances 2. Neurologic side effects
3. Tocainide may produce pulmonary fibrosis.
Phenytoin:
As anti-arrhythmic, it resembles lidocaine, most useful in treating
ventricular arrhythmia associated with dig toxicity and acute M.I.
Pharmacology / Dr. Samer
Lec. 42
College of Medicine Baghdad University
4
Class I-C Drugs
Flecainide, Moricizine, Propafenone:
These drugs slowly dissociate from Na
+
channels and show prominent
effects even at normal heart rates. They markedly slow phase 0 depolarization
causing marked conduction slowing, but only little effect on AP duration or
ventricular ERP. They are approved only for refractory arrhythmia (ventricular).
They have –ve inotropic effects and can aggravate CHF. They can ppt cardiac
arrest. Also approved for AV node tachy in WPW syndrome.
Class II Drugs
(Propranolol, metoprolol (β
1
-selective) and pindolol (ISA),
Acebutalol (β
1
-sel.) and Esmolol)
Propranolol:
(β
1
, β
2
blocker)
Effect results from β-blockade + direct membrane stabilizing effect. These
drugs ↓phase 4 depolarization, thus depress SA node firing → bradycardia.
Automaticity is also depressed in purkinjie fibers. They cause a substantial ↑in
ERP of AV node prolonging AV conduction. The refractoriness of SA node,
atrial and ventricular m. is not as a greatly affected.
ECG Effects: ↑PR interval by its action on AV node.
Therapeutic Uses of
β-blockers:
1. Useful for ventricular arrhythmia caused by ↑sympathetic activity
(emotional stress, exercise, thyrotoxicosis).
2. Useful for AF and atrial flutter and for AV nodal reentrant tachy
by slowing conduction through AV node.
3. It is used sometimes to abolish ventricular arrhythmia caused by
dig toxicity.
4. It reduces the incidence of sudden arrhythmic death after M.I.
5. May be used in WPW syndrome.
Esmolol:
Is very short acting
β
1
-selective blocker used I.V. in acute arrhythmia
occurring during surgery or emergency situations.
Pharmacology / Dr. Samer
Lec. 42
College of Medicine Baghdad University
5
Class III Drugs
Satolol:
Prolongs repolarization (class III effect) by blocking the K
+
outward
current and prolongs the duration of the AP and lengthening of the ERP in all
cardiac fibers. It has also a non-selective
β-blocking activity (class II). The D-
isomer of satolol lacks the β-blocking effect while retaining the effect on
prolonging the ERP.
Uses of satolol:
1. It is effective in preventing life threatening ventricular arrhythmia.
2. May be useful for treatment of SV arrhythmia.
Satolol is better tolerated than Na
+
channel blocker and probably more effective
in preventing arrhythmia recurrence. However, satolol has a proarrhythmic effect
in prolonging the QT interval and may cause torsades de points (3-4 %), t
1/2
=12
hrs, completely absorbed after oral administration excreted unchanged.
Amiodarone:
It contains iodine and is structurally related to thyroxine. It has complex
effects slowing class I, II, III, IV effects.
Pharmacologic Effects:
1. It ↑the AP duration and ERP in atrial and ventricular m, AV node
automaticity.
2. It ↓the SA node automaticity.
3. It ↑the PR, QRS, and QT intervals.
4. It induces α and β adrenergic blockade (by non-competitive
antagonism), therefore it can cause sys. And coronary vasodilation.
Uses of Amiodarone: it is considered the most powerful anti-arrhythmic
available for the treatment and prevention of both atrial and ventricular
arrhythmia.Side effects are frequent even with short term use, therefore, its
use is reserved for the treatment of life threatening arrhythmia refractory to
other anti-arrhythmias. It is the drug of 1
st
choice in WPW syndrome.
Pharmacokinetics: highly lipid soluble. t
1/2
= 20-100 days, full clinical
effects may not be achieved until 6 weeks after initiation of therapy.
Pharmacology / Dr. Samer
Lec. 42
College of Medicine Baghdad University
6
Adverse Effects: with prolonged use, it occurs in 50% of patients which
may lead to discont. Of the drug:
1. Pulmonary fibrosis (usually reversible).
2. Cardiac effects: AV block, sinus brady. and torsades de pointes.
3. Corneal microdeposits and blurred vision.
4. Photosensitivity.
5. Bluish discoloration of skin due to iodine accumulation.
6. Hyper- or hypo- thyroidism due to interference with conversion of
T
4
to T
3
.
7. Neurological: ataxia, dizziness, tremor, peripheral neuropathy and
myopathy.
8. GIT intolerance –nausea, vomiting and anorexia.
9. Serum levels of dig, diltiazem, and quinidine are ↑ with
amiodarone use.
Dronedarone:
same as amiodarone but lacks iodine atoms t half is only 24 hrs .Has no
thyroid or pulmonary toxicity
Bretylium:
Is an adr. neuronal blocker, has no. of direct and indirect actions, the most
prominent of which is prolongation of the ERP and duration of AP in atrial,
ventricular m. and AV node. It also ↑the VF threshold and AV node. It also has
ECG effects: ↑PR and QT intervals.
Uses of bretylium: reserved for life threatening arrhythmia refractory to
other therapy.
Side Effects: hypotension, n and v after rapid I.V. administration.
DOFETILIDE
Dofetilide has class 3 action potential prolonging action. This action is effected
by a dose-dependent blockade of the rapid component of the delayed rectifier
potassium current, I
Kr
. Dofetilide is 100% bioavailable. Dofetilide is approved
for the maintenance of normal sinus rhythm in patients with atrial fibrillation. It
is also effective in restoring normal sinus rhythm in patients with atrial
fibrillation.It increases QT interval.
Pharmacology / Dr. Samer
Lec. 42
College of Medicine Baghdad University
7
IBUTILIDE
Ibutilide slows cardiac repolarization by blockade of the rapid component (I
Kr
) of
the delayed rectifier potassium current. Intravenous ibutilide is used for the acute
conversion of atrial flutter and atrial fibrillation to normal sinus rhythm. The
drug is more effective in atrial flutter than atrial fibrillation, with a mean time to
termination of 20 minutes. The most important adverse effect is excessive QT
interval prolongation and torsade de pointes. Patients require continuous ECG
monitoring for 4 hours after ibutilide infusion or until QT
c
returns to baseline.
Class IV Agents
Ca
+
channel blockers:
(verapamil and diltiazem)
They block the inward current carried by Ca
+
resulting in the ↓ in the rate
of phase 4 depolarization. They slow conduction and ↑ERP in Ts dependant on
Ca
+
current e.g. AV node. They shorten the AP. These drugs bind only to open
depolarization channels. They are therefore used dependent (i.e. they block most
effect where the heart is rapidly (use or state dependence)
Use of Class IV drugs:
1. Are more effective against atrial than ventricular arrhythmia.
2. Very effective in the termination of SVT due to AV re-entry when
given I.V.
3. They reduce ventricular rate in atrial flutter or AF and may enhance
the effect of digoxin in this regard.
Adverse Effects:
1. Because of its effect on AV node, they should not be used in patients
with AV nodal dysfunction.
2. They depress M. contractility, therefore care should be taken when
used in patients with CHF.
3. It is contraindicated in patients with AF who have the WPW
syndrome.
4. Hypotension.
5. Leg edema.
Pharmacology / Dr. Samer
Lec. 42
College of Medicine Baghdad University
8
Adenosine:
Is naturally occurring nucleoside, but at high doses it decreases conduction
velocity and prolongs the Ref period and ↓automaticity in AV node. I.V.
adenosine has become the drug of choice for abolishing SVT and is replacing
verapamil in this regard. It has low toxicity, but causes flushing, chest pain and
hypotension. It has an extremely short duration of action (15 seconds).
MAGNESIUM
Originally used for patients with digitalis-induced arrhythmias who were
hypomagnesemic, magnesium infusion has been found to have antiarrhythmic
effects in some patients with normal serum magnesium levels. The mechanisms
of these effects are not known, but magnesium is recognized to influence Na
+
,K
+
ATPase, sodium channels, certain potassium channels, and calcium channels.
Magnesium therapy appears to be indicated in patients with digitalis-induced
arrhythmias if hypomagnesemia is present; it is also indicated in some patients
with torsade de pointes even if serum magnesium is normal. The usual dosage is
1 g (as sulfate) given intravenously over 20 minutes and repeated once if
necessary