Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS
Some drugs eventually make it to the marketplace while
others fall by the wayside during any phase of drug
development. This section presents a few drugs that may
become useful for treating heart failure in the future.
Aquaretics
Aquaretics are vasopressin receptor anatagonists, e.g.
tolvaptan (OPC-41061). Tolvaptan is selective V 2 receptor
antagonist, which is showing promise in the acute
and chronic treatment of human CHF. In contrast to
loop diuretics like furosemide, V 2 receptor antagonism
has demonstrated free water excretion with little to no
sodium loss. In addition, the water loss associated with
V 2 antagonism has not been associated with activation
of the RAAS in contrast to the loop diuretics. This novel
class of agents may prove to be an addition to our
pharmacological arsenal against CHF but recent evidence
in human medicine suggests this agent is not
useful above and beyond available diuretics.
Prostacyclin analogs
Prostacyclin analogs have been shown to improve symptoms
and short-term survival in human patients with
pulmonary hypertension. Epoprostenol (Flolan®) was
the first available prostacyclin used to treat pulmonary
hypertension in humans. It is administered via continuous
rate intravenous infusion. Due to a very short halflife
abrupt withdrawal is associated with increased
morbidity and mortality. Adverse effects related to the
drug are mild and dose related while sepsis and thrombosis
are important adverse effects related to chronic
central venous access.
Treprostinil (Remodulin®) has similar hemodynamic
effects as epoprostenol but is administered as a constant
rate subcutaneous infusion which lowers the risk of
sepsis associated with direct venous access.
Intravenous iloprost has similar hemodynamic effects
as epoprostenol with a longer half-life diminishing the
adverse effects associated with abrupt withdrawal.
Inhaled iloprost is also available and has a short half-life
of 20–25 min requiring administration every 2–3 h.
Beraprost, the first orally stable prostacyclin analog,
requires administration four times a day to maintain
adequate blood levels.
Endothelin receptor antagonists
The pro-molecule big endothelin (ET)-1 is converted to
functional ET by endothelin converting enzyme. ET is
a potent vasoconstrictor and smooth muscle mitogen
resulting in vascular hypertrophy. ET levels are elevated
in humans with pulmonary hypertension and dogs with
experimentally induced dirofilariasis.
Two types of ET receptors have been identified, ET A
and ET B . ET A receptors are located on vascular smooth
muscle cells and mediate vasoconstriction and vascular
smooth muscle proliferation while ET B receptors are
located on both endothelial and vascular smooth muscle
cells and mediate vasodilation and vasoconstriction.
ET B receptors are upregulated in pulmonary
hypertension.
The ET receptor antagonist bosentan (Tracleer®)
competitively antagonizes the ET receptor types ET A
and ET B , with slightly more affinity for ET A receptors.
Optimal dosage in humans is 125 mg every 12 h. In
human studies, bosentan resulted in significant increases
in exercise capacity. A potentially important adverse
effect of bosentan therapy is elevations in hepatic
enzyme activity that typically resolve with discontinuation
of the drug but require monthly monitoring of
serum biochemistries. Bosentan was developed initially
for the treatment of heart failure but in clinical trials
did not prove useful for this indication. The selective
ET A receptor antagonists, sitaxsentan and ambrisentan,
are currently being evaluated in human clinical trials.
DRUGS USED FOR THE TREATMENT OF
CARDIAC ARRHYTHMIAS
Relevant physiology and pathophysiology
Antiarrhythmic drugs are used to manage cardiac
arrhythmias that arise as a result of an intrinsic cardiac
defect (myocardial or electrical) or because of the effect
of toxins such as drugs (e.g. digoxin toxicity) or endogenous
factors (e.g. secondary to gastric dilation and
volvulus). Different antiarrhythmic drugs have different
mechanisms of action and will have varying efficacy
depending on the type of arrhythmia present.
An understanding of the mechanisms by which action
potentials are generated in the normal heart and in
cardiac disease is essential to an understanding of the
mechanism of action of antiarrhythmic drugs.
Cardiac muscle action potentials
Myocardium (Fig. 17.1A)
● Excitation of the myocardium results in:
– influx of sodium through fast sodium channels
– influx of calcium through slow calcium
channels.
● This slow influx of calcium results in the long duration
of cardiac action potentials relative to other
excitable tissues. It also results in a long refractory
period, as the fast sodium channels cannot be reactivated
until the cell has been repolarized. Calcium
influx also causes release of calcium from intracellular
stores and activates the contractile mechanism.
● Repolarization is predominantly due to an outward
potassium current.
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