Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS
Pharmacokinetics
In experimental dogs, sotalol is rapidly absorbed from
the gastrointestinal tract and has a bioavailability in the
85–90% range. Less than 1% of the drug is metabolized.
Elimination is via renal clearance and is linearly
related to the glomerular filtration rate. Consequently,
the drug dose must be reduced in patients with compromised
renal function due to any cause. Sotalol is not
protein bound in plasma of dogs. The elimination halflife
is 4.8 ± l.0 h. The apparent volume of distribution
is in the 1.5–2.5 L/kg range.
Following oral administration of sotalol at 5 mg/kg
q.12 h for 3 d (when steady state is reached in experimental
dogs), the plasma concentration is in the 1.1–
1.6 mg/L range. In humans given the same dose, the
plasma concentration is in the 2–3 mg/L range. This
discrepancy probably occurs because the elimination
half-life in humans is longer (7–18 h). This suggests that
the dose in dogs should be roughly double that used in
humans. The human dosage recommendation is to
administer 40–80 mg q.12 h as an initial dose. This dose
then can be increased as necessary every 3–4 d. The
maximum dose is 320 mg q.12 h. Assuming an average
weight of 70 kg for humans means the dose starts at
approximately 0.5–1.0 mg/kg q.12 h and can achieve a
maximum dose of approximately 5 mg/kg q.12 h.
A plasma concentration of 0.8 mg/L is needed to
produce half-maximal β-adrenergic blockade in experimental
dogs. This suggests that a dose of 5 mg/kg q.12 h
PO to a dog should result in near-maximal blockade.
The plasma concentration required to prolong cardiac
refractoriness is higher. In humans, a plasma concentration
of 2.6 mg/L is necessary to increase the Q-T interval.
Doses between 2 and 5 mg/kg q.12 h PO in humans
prolong the Q-T interval by 40–100 ms. In experimental
dogs, a dose of 5 mg/kg q.12 h PO also prolongs the
Q-T interval.
Adverse effects
● Adverse effects of sotalol in humans are related to
the negative inotropic effects of sotalol and to its
ability to prolong the Q-T interval. As stated earlier,
the negative inotropic effects appear to be minor and
very few human patients experience exacerbation of
heart failure.
● The most dangerous adverse effect of sotalol in
humans is aggravation of existing arrhythmias or
provocation of new arrhythmias.
● Excessive Q-T interval prolongation can provoke
torsades de pointes in humans. Torsades de pointes
has also been produced in experimental dogs but
appears to be more difficult to invoke in dogs. For
example, one canine model requires that the dog be
bradycardic from experimentally induced thirddegree
AV block and hypokalemic (serum potassium
concentration in the 2.5 mEq/L range) before sotalol
can cause this serious arrhythmia. The arrhythmia in
this model can be terminated with intravenous
magnesium administration (1–2 mg/kg/min for
20–30 min).
● Sotalol apparently can also induce other forms of
ventricular tachyarrhythmia because of the prolongation
of the Q-T interval.
● As for any other β-blocker, withdrawal of sotalol
should be performed gradually over 1–2 weeks
because of ‘upregulation’ of β-receptors. Sudden cessation
of use can produce fatal ventricular arrhythmias.
The drug should not be used in patients with
conduction system disease such as sick sinus syndrome,
AV block or bundle branch block.
CLASS IV ANTIARRHYTHMIC DRUGS
Description and discovery
Class IV antiarrhythmic drugs are the calcium channelblocking
drugs. These are also known as calcium entry
blockers, slow channel blockers and calcium antagonists.
Verapamil, the prototype calcium channel blocker,
was discovered in 1963. It was being developed as a
coronary vasodilator and was discovered to have negative
inotropic properties. The negative inotropism could
be neutralized by the addition of calcium, β-adrenergic
agonists and digitalis glycosides – measures that increase
calcium flux into myocardial cells. It was subsequently
discovered in 1969 that verapamil and other drugs with
similar effects selectively suppressed transmembrane
calcium flow. Today, at least 29 different calcium
channel blockers are used in clinical human medicine
worldwide. In veterinary medicine, only verapamil
and diltiazem have been used with enough frequency
to make recommendations regarding therapy of
arrhythmias.
Classification and mechanism of action
Calcium channel blockers have a variety of chemical
structures. They can be classified into three groups: the
phenylalkylamines, the benzothiazepines and the dihydropyridines.
The phenylalkylamines include verapamil.
Diltiazem is a benzothiazepine. The dihydropyridines
include nifedipine and amlodipine.
The primary sites of action for calcium channel blockers
in cardiovascular medicine are the L-type calcium
channels in cardiac cells and in vascular smooth muscle
cells. In the heart, calcium channel blockers directly
decrease myocardial contractility and slow sinoatrial
depolarization and atrioventricular conduction. In vascular
smooth muscle, calcium channel blockers produce
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