Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CLASS I ANTIARRHYTHMIC DRUGS
Pharmacokinetics
Lidocaine’s half-life in dogs is 90–100 min. Total body
clearance is approximately 60 mL/min/kg. The liver primarily
metabolizes lidocaine, with less than 5% of the
clearance occurring through the kidneys. Clearance and
half-life are prolonged by liver disease or poor hepatic
perfusion (e.g. in heart failure, in shock and with propranolol
administration). The volume of distribution is
approximately 6 L/kg. Heart failure may also reduce the
volume of distribution, resulting in a higher serum concentration.
The therapeutic serum concentration is
thought to be between 2 and 6 µg/mL.
Adverse effects
● Lidocaine exerts effects on the central nervous system
when the serum concentration achieves a toxic concentration,
producing signs of drowsiness, emesis,
nystagmus, muscle twitching and seizures. Toxic
effects can be particularly severe in the cat. Dogs
administered infusion rates at the upper end of the
dosage range are commonly sedated.
● Lidocaine can depress ventricular function in severe
myocardial failure, produce atrioventricular block
in conduction system disease and exacerbate sinus
bradycardia and arrest in patients with sick sinus
syndrome. It must be used with care in dogs with
atrioventricular or ventricular conduction disorders,
if at all.
● Lidocaine produces very few electrocardiographic
changes except for a possible shortening of the Q-T
interval. Unless the sinoatrial node is diseased, lidocaine
does not affect its automaticity. It should be
avoided in dogs with sick sinus syndrome. It does
slow the rate of phase 4 depolarization in Purkinje
fibers, resulting in a slowing of the rate of escape
beats. For this reason, lidocaine (or for that matter
any other antiarrhythmic drug) should never be
administered to a patient dependent on an escape
focus, such as a patient with a third-degree AV block.
Lidocaine has fewer proarrhythmic effects than other
antiarrhythmic agents.
● Treatment for toxicity is lidocaine withdrawal and,
when necessary, intravenous diazepam administration
(0.25–0.5 mg/kg IV) for seizure control.
Known drug interactions
Prolonged lidocaine infusions during concurrent propranolol
administration prolong lidocaine’s half-life.
Special considerations
Preparations containing adrenaline (epinephrine) used
for local anesthesia should never be used intravenously.
Lidocaine is absorbed by the PVC in the plastic bags
used to store intravenous solutions.
Phenytoin
Clinical applications
Phenytoin may be effective in treating ventricular
arrhythmias due to many causes but, because of dosing
difficulties when administered intravenously, lidocaine
is generally preferred for acute termination of ventricular
arrhythmias. Phenytoin, however, may be useful for
treating digitalis intoxication although generally lidocaine
remains the preferred option. Because it can be
administered orally, phenytoin can theoretically be
administered prophylactically to patients that may
be easily intoxicated with digitalis (e.g. severe myocardial
failure patients).
Mechanism of action
Phenytoin, when used as an antiarrhythmic, shares
many properties with lidocaine. It reduces normal automaticity
in Purkinje fibers, abolishes abnormal automaticity
due to digitalis intoxication and has effects
identical to those of lidocaine on re-entrant arrhythmias.
It can repolarize abnormal, depolarized cells,
reduces sympathetic nerve effects and may modify parasympathetic
nerve activity in digitalis toxicity.
Formulations and dose rates
Phenytoin is supplied as capsules. For parenteral administration, phenytoin
sodium is supplied as injectable solutions of 50 mg/mL in 2 mL
and 5 mL ampoules or vials.
The oral phenytoin dosage is 30–50 mg/kg q.8 h. Serious arrhythmias
require intravenous treatment in intermittent doses of 2 mg/kg
administered over 3–5 min to prevent hypotension and cardiac arrest
from the propylene glycol vehicle. The total dose should not exceed
10 mg/kg. Because phenytoin in solution has a pH of 11.0, phlebitis
will occur unless it is administered via a large vein and fl ushed
immediately with normal saline.
Pharmacokinetics
Phenytoin absorption is erratic, slow and incomplete
from both the gastrointestinal tract and intramuscular
injection sites. The half-life is 3–4 h.
Adverse effects
Long-term phenytoin administration at 50 mg/kg q.8 h
results in an increase in serum alkaline phosphatase
concentration. Histological changes consist of increased
hepatic cell size. This appears to be due to increased
glycogen storage.
Known drug interactions
● The liver metabolizes phenytoin. Any drugs affecting
microsomal enzymes will, therefore, also affect
phenytoin metabolism.
● Chloramphenicol administration increases serum
phenytoin concentration and in one study increased
the half-life from 3 h to 15 h.
429