Page 260 - Basic _ Clinical Pharmacology ( PDFDrive )

246 SECTION III Cardiovascular-Renal Drugs

Pharmacokinetics & Dosage MISCELLANEOUS
The half-life of verapamil is approximately 4–7 hours. It is ANTIARRHYTHMIC AGENTS &
extensively metabolized by the liver; after oral administration, its OTHER DRUGS THAT ACT ON
bioavailability is only about 20%. Therefore, verapamil must be
administered with caution in patients with hepatic dysfunction or CHANNELS
impaired hepatic perfusion.
In adult patients without heart failure or SA or AV nodal Certain agents used for the treatment of arrhythmias do not fit
disease, parenteral verapamil can be used to terminate supraven- the conventional class 1–4 organization. These include digitalis
tricular tachycardia, although adenosine is the agent of first choice. (see Chapter 13), adenosine, magnesium, and potassium. It is
Verapamil dosage is an initial bolus of 5 mg administered over also becoming clear that certain nonantiarrhythmic drugs, such
2–5 minutes, followed a few minutes later by a second 5 mg bolus as drugs acting on the renin-angiotensin-aldosterone system, fish
if needed. Thereafter, doses of 5–10 mg can be administered every oil, and statins, can reduce recurrence of tachycardias and fibril-
4–6 hours, or a constant infusion of 0.4 mcg/kg/min may be used. lation in patients with coronary heart disease or congestive heart
Effective oral dosages are higher than intravenous dosage failure.
because of first-pass metabolism and range from 120 mg to
640 mg daily, divided into three or four doses. ADENOSINE

Therapeutic Use Mechanism & Clinical Use

Supraventricular tachycardia is the major arrhythmia indication Adenosine is a nucleoside that occurs naturally throughout the
for verapamil. Adenosine or verapamil is preferred over older body. Its half-life in the blood is less than 10 seconds. Its cardiac
treatments (propranolol, digoxin, edrophonium, vasoconstrictor mechanism of action involves activation of an inward rectifier K
+
agents, and cardioversion) for termination. Verapamil can also current and inhibition of calcium current. The results of these
reduce the ventricular rate in atrial fibrillation and flutter (“rate actions are marked hyperpolarization and suppression of calcium-
control”). It only rarely converts atrial flutter and fibrillation dependent action potentials. When given as a bolus dose, adenos-
to sinus rhythm. Verapamil is occasionally useful in ventricular ine directly inhibits AV nodal conduction and increases the AV
arrhythmias. However, intravenous verapamil in a patient with nodal refractory period but has lesser effects on the SA node. Ade-
sustained ventricular tachycardia can cause hemodynamic collapse. nosine is currently the drug of choice for prompt conversion of
paroxysmal supraventricular tachycardia to sinus rhythm because
DILTIAZEM of its high efficacy (90–95%) and very short duration of action. It
is usually given in a bolus dose of 6 mg followed, if necessary, by
Diltiazem appears to be similar in efficacy to verapamil in the a dose of 12 mg. An uncommon variant of ventricular tachycardia
management of supraventricular arrhythmias, including rate is adenosine-sensitive. The drug is less effective in the presence of
control in atrial fibrillation. An intravenous form of diltiazem is adenosine receptor blockers such as theophylline or caffeine, and
available for the latter indication and causes hypotension or brady- its effects are potentiated by adenosine uptake inhibitors such as
arrhythmias relatively infrequently. dipyridamole.

The Nonpharmacologic Therapy of Cardiac Arrhythmias

It was recognized over 100 years ago that reentry in simple therapy can often permanently cure atrial fibrillation, and because
in vitro models (eg, rings of conducting tissues) was perma- it does not involve adverse effects of drugs, it has become a very
nently interrupted by transecting the reentry circuit. This concept common treatment for chronic atrial fibrillation.
is now applied in cardiac arrhythmias with defined anatomic Another form of nonpharmacologic therapy is the implant-
pathways—eg, atrioventricular reentry using accessory pathways, able cardioverter-defibrillator (ICD), a device that can auto-
atrioventricular node reentry, atrial flutter, and some forms of ven- matically detect and treat potentially fatal arrhythmias such as
tricular tachycardia—by treatment with radiofrequency catheter ventricular fibrillation. ICDs are now widely used in patients who
ablation or extreme cold, cryoablation. Mapping of reentrant have been resuscitated from such arrhythmias, and several trials
pathways and ablation can be carried out by means of catheters have shown that ICD treatment reduces mortality in patients
threaded into the heart from peripheral arteries and veins. Studies with coronary artery disease who have an ejection fraction
have also shown that paroxysmal and persistent atrial fibrillation ≤ 30% and in patients with class II or III heart failure and no prior
may arise from one or more of the pulmonary veins. Both forms history of arrhythmias. The increasing use of nonpharmacologic
of atrial fibrillation can be cured by electrically isolating the pul- antiarrhythmic therapies reflects both advances in the relevant
monary veins by radiofrequency or cryotherapy catheter ablation technologies and an increasing appreciation of the dangers of
or during concomitant cardiac surgery. Because catheter ablation long-term therapy with currently available drugs.