Top veterinary pharmacology myths busted (Proceedings)


Busting the top veterinary pharmacology myths.

1) Morphine cannot be used in cats due to CNS excitement and slow metabolism

AND Morphine causes histamine release in dogs resulting in severe hypotension AND The most common adverse effects of opioids are cardiovascular and respiratory depression

Morphine is often used in cats without severe adverse effects or CNS excitement. "Morphine mania" was produced in cats by administering 5-20 mg/kg SC – a dose 20-100 times the clinically recommended dose. High doses of opioids in any species can produce CNS excitement and seizures. The plasma half-life of morphine in cats is ~1.3 hours compared to ~1 hour in dogs. Morphine is rapidly eliminated in cats, but by a different metabolic pathway (sulfate conjugation) compared to dogs and other species (glucuronide conjugation). The dose used in cats is lower (0.25 mg/kg IV, IM, SC q 2-4 hrs) because the volume of distribution in cats is lower compared to dogs. The lower volume of distribution (Vd) means higher plasma concentrations (Cp) are achieved with a given dose (Dose=Vd*Cp). The dosing interval is the same however since the half-lives are similar.

High doses of any opiate can produce bradycardia, vasodilation and subsequently hypotension. Clinically relevant doses of morphine (0.5 mg/kg IV or less) produce large increases in histamine release (~500 fold increase) but have minimal effects on blood pressure. The myth has been propagated due to high doses of morphine (3 mg/kg IV – 6 times the recommended IV dose) which result in dramatic decreases in MAP (110 mm to 30 mm Hg). The same study administered 0.3 mg/kg morphine IV and saw no significant changes in blood pressure or histamine in dogs. A separate study administered 0.5 mg/kg IV morphine to dogs with no concurrent medication which also resulted in no significant changes in blood pressure. Hypotension can be encountered and exacerbated when morphine is administered concurrently with other drugs which cause vasodilation (acepromazine, isoflurane, sevoflurane, propofol, et al) or result in decreased cardiac output (isoflurane, sevoflurane, propofol, thiopental, pentobarbital, et al).

The most common adverse effects of opioids are hypothermia, bradycardia, sedation, nausea, vomiting, panting, and defecation. Despite the pronounced bradycardia, cardiac output remains stable, due to increased stroke volume in animals administered clinically recommended dosages. A dose-dependent respiratory depression does occur with opioids, but clinically recommended dosages produce clinically insignificant respiratory depressant effects. Mild respiratory depression is a concern in animals with head trauma, some pre-existing pulmonary diseases, or when combined with other respiratory depressants.

2) Ciprofloxacin and enrofloxacin are identical antibiotics and are broad spectrum

Ciprofloxacin and enrofloxacin have significantly different pharmacokinetic properties. Fluoroquinolone efficacy is best related to the area under the curve (AUC) to minimum inhibitory concentration (MIC) ratio (AUC:MIC) with optimal dosages achieving a ratio of 125 or greater. Resistance to fluoroquinolones is minimized by achieving a maximum plasma concentration (CMAX) to MIC ratio of 8 or greater.

Ciprofloxacin administered 15 mg/kg PO q 12 hours results in an AUC of ~ 24 hr*mcg/mL per day. Therefore this dose would be optimal for bacteria with an MIC of 0.2 mcg/mL or less. The CMAX after 15 mg/kg of ciprofloxacin is ~ 2.0 mcg/mL which would decrease the potential resistance in bacteria with an MIC of 0.25 mcg/mL or less.

Enrofloxacin administered 5 mg/kg PO results in an enrofloxacin AUC of 4.5 hr*mcg/mL and a ciprofloxacin AUC 2.7 hr*mcg/mL for a total of 7.2 hr*mcg/mL sufficient for bacteria with an MIC of 0.06 mcg/mL or less. The CMAX of enrofloxacin is 1.2 mcg/mL and ciprofloxacin is 0.4 mcg/mL for a total of ~1.6 mcg/mL sufficient to delay resistance in bacteria with an MIC of 0.2 mcg/mL or less.

Fluoroquinolones typically are active against Staphylococcus spp. and gram negative aerobic bacteria (E coli, Klebsiella spp). Enrofloxacin, marbofloxacin, and ciprofloxacin have poor activity against anaerobic bacteria and Streptococcus spp. Therefore fluoroquinolones lack coverage in >1 quadrant in the typical 4 quadrant scheme of classifying bacteria. Enrofloxacin, ciprofloxacin, marbofloxacin et al are poor choices for abscesses, oral infections, and dental prophylaxis among other uses.

3) Acepromazine cannot be used in patients prone to seizures

A recent retrospective study examined the effects of acepromazine administered to 36 dogs with a previous history of seizure or to decrease seizure activity in 11 dogs. Of the 36 dogs with a previous history of seizures, zero seizures were seen up to 16 hours post acepromazine administration. Of the 11 dogs with seizure activity, 6 of the dogs were controlled for 1.5 – 8 hours post acepromazine or seizures did not recur in 2 of the dogs. Although this is NOT a definitive study stating acepromazine is 100% safe for use in dogs with seizures, it is highly suggestive that it is not absolutely contraindicated with a previous history of seizures. Diazepam and phenobarbital (loading dose) are still the treatments of choice for most status epilepticus animals.

4) Acetaminophen is toxic to dogs

Acetaminophen is considered inherently toxic to cats. The toxicity in cats is due to the formation of a reactive metabolite by cytochrome P450 metabolism (Phase 1 metabolism) of acetaminophen. Cats are deficient in the formation of glucuronide conjugates (Phase II metabolism) which is the predominant metabolism pathway in other species. Dogs form glucuronide conjugates, with minimal formation of the reactive metabolite at clinically recommended dosages. Acetaminophen in single doses of 100 mg/kg did not result in signs of toxicity in 4 experimental dogs. Clinical studies are lacking defining the appropriate dosage of acetaminophen in dogs. Dosage recommendations have been made anecdotally, 15 mg/kg PO q 8 h. However, recent pharmacokinetic studies are suggestive the dosage needs to be increased to 22 mg/kg q 6 h to achieve a plasma profile similar to that in humans given label dosages of acetaminophen.

5) Thiopental anesthesia recovery is due entirely to drug redistribution

Recovery from thiopental anesthesia is due to a combination of drug redistribution from the highly perfused CNS tissues to the less perfused tissues (i.e. muscle and fat), but is also due to hepatic metabolism. Severe liver disease or administration of inhibitors of cytochrome P450 metabolism can prolong anesthesia and recovery. Conversely administration of phenobarbital, a CYP inducer, decreases thiopental sleeping time in Greyhounds.

BONUS: COX-2 selective NSAIDs have less adverse effects than non-selective COX inhibitors

This is a partial myth. COX-2 preferential inhibitors have less GI adverse effects compared to nonselective NSAIDs. There is no evidence suggesting greater COX-2 selectivity results in less GI adverse effects. All NSAIDs, regardless of the COX selectivity have the same risk of renal and hepatic adverse effects.

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