Adverse Drug Reactions and Antagonism

What is an adverse drug reaction?

Any toxic or unintended response to a drug that occurs at appropriate therapeutic doses.

When do adverse drug reactions occur due to over-accumulation of a drug?

"In-flow exceeds out-go."

How can renal disease decrease the ability to eliminate a drug?

Decreased filtration, decreased renal secretion.

How can hepatic disease alter drug metabolism?

Decreased hepatic elimination.

How can competitive inhibition alter drug metabolism?

Competitive inhibition of enzymes by a drug.

How can selective organ uptake cause an adverse drug reaction?

Organ selectively accumulates drug in cells.

What is an example of toxicity caused by selective organ uptake of a drug?

Aminoglycoside nephrotoxicity.

What dose measurements are shown on the adverse drug reaction dose-response graph?

ED50, TD50, and LD50.

What are the two groups of macrolide endectocides?

Avermectins and milbemycins.

Which drugs are listed as avermectins?

Ivermectin, selamectin, doramectin, and eprinomectin.

Which products are listed under ivermectin?

Heartgard® and Ivomec®.

Which product is listed under selamectin?

Revolution.

Which drugs are listed as milbemycins?

Milbemycin oxime and moxidectin.

Which products are listed under milbemycin oxime?

MilbeMite®, Sentinel®, Trifexis®, and Interceptor®.

What are macrolide endectocides used as?

Anthelmintics and heartworm preventatives.

What conditions are macrolide endectocides used to treat or prevent?

Heartworm, intestinal parasites, skin parasites, and mange.

Through which routes are macrolide endectocides applied?

Injection, PO liquid/tablets, pour-on topicals, and topical drops.

In which animals are macrolide endectocides used?

Cats, dogs, sheep, cattle, horses, and pigs.

What is the mechanism of action of macrolide endectocides in parasites?

Bind glutamate receptors on chloride channels in the cell membranes of neurons in parasite.

What happens after macrolide endectocides bind glutamate receptors in parasites?

Increased cell permeability to chloride ions (Cl-).

How do chloride ions cause paralysis in parasites?

Chloride ions move into cell → hyperpolarization → paralysis.

Why do macrolide endectocides generally have a wide margin of safety in mammals?

Mammals do not have glutamate-gated chloride channels.

Which chloride channels do mammals have in the brain?

GABA-gated chloride channels.

How are GABA-gated chloride channels in the mammalian CNS protected?

The blood-brain barrier containing P-glycoprotein.

How do macrolide endectocides act when they penetrate the blood-brain barrier?

Macrolide endectocides act as GABA agonists when they bind GABA receptor in animals.

Which animals may be deficient in the multi-drug resistance gene (MDR1)?

Some collies/dogs and chelonians (turtles).

What does MDR1 encode for?

P-glycoprotein.

What is the function of P-glycoprotein at the blood-brain barrier?

Functions as an efflux drug transport pump at the blood-brain barrier - prevents entry of drug.

Which dogs display the sensitive phenotype?

Dogs that are homozygous for the mdr-1 deletion mutation.

How does an MDR-1 mutation cause macrolide endectocide toxicity?

Drug accumulates in brain causing CNS depression.

When can macrolide endectocides penetrate the mammalian CNS?

In young animals, in chelonians, in severe overdoses (extra-label use), and in collies/collie mixed breeds or other dogs genetically pre-disposed to toxicity.

Which dog breed has the highest listed frequency of the MDR1 mutation?

Collie: 55-57%.

How common is homozygosity for the MDR-1 mutation in U.S. collies?

1 in 3 or 4 collies in the U.S.

How much ivermectin can dogs with no P-glycoprotein deletion tolerate without clinical signs?

Up to 2.5 mg/kg.

How much ivermectin can dogs with a P-glycoprotein deletion tolerate without clinical signs?

Up to 0.1 mg/kg.

What are the clinical signs of macrolide endectocide toxicity?

Ataxia; depressed, disoriented; bradycardia, hypotension; hypersalivation; blindness; mydriasis; vomiting, diarrhea; tremors, seizures; hypoventilation.

What is distinctive about blindness caused by macrolide endectocide toxicity?

Especially in cats; reversible.

What clinical signs occur in turtles with macrolide endectocide toxicity?

Extreme paresis, flaccid paralysis.

What may happen to turtles with macrolide endectocide toxicity?

Often die within several days; severe fatty changes in liver.

How is macrolide endectocide toxicity diagnosed from history?

History of administration/exposure.

What exposure examples support a diagnosis of macrolide endectocide toxicity?

Use of horse paste wormer on dog; use of cattle injectable in small animals; administration of drug to Collie-related breed.

Which samples are used for toxicology testing for macrolide endectocides?

Liver, adipose tissue, serum.

Which test identifies an animal's MDR1 genotype?

PCR test for MDR1 genotype.

How are seizures from macrolide endectocide toxicity managed?

Phenobarbital or propofol (if not responding to phenobarb).

Which drugs should be avoided for seizure treatment in macrolide endectocide toxicity?

Benzodiazepines.

Why may repeated doses of activated charcoal be indicated for macrolide endectocide toxicity?

Drug is recirculated by enterohepatic recirculation - in system longer.

What additional care is used to treat macrolide endectocide toxicity?

Symptomatic/supportive care.

How long should macrolide endectocide toxicity be treated?

Treat long enough!

What non-toxic adverse drug reaction can corticosteroids cause in dogs?

PU/PD.

Which other drugs can cause PU/PD?

THC, benzodiazepines, barbiturates.

How do corticosteroids cause PU/PD?

Partial inhibition of antidiuretic hormone (vasopressin) secretion.

How does ADH decrease urine production?

Increasing water reabsorption in renal tubules.

What is the therapeutic use of diphenhydramine?

Antihistamine for allergy treatment.

How does diphenhydramine act at the histamine H1 receptor?

Inverse agonist of histamine H1 receptor; binds same receptor as histamine.

What is a beneficial effect of diphenhydramine?

Sedative effect (sleep aid, anxiolytic).

How does diphenhydramine produce its sedative effect?

Mild inhibitor of reuptake of serotonin; crosses BBB antagonizing central H1 receptors.

What are the four types of drug antagonism?

Functional, chemical, dispositional, and receptor.

What is antagonism?

An interaction between two or more drugs that have opposite effects on the body.

How is antagonism exploited in toxicology and medicine?

Antidotes.

What is functional antagonism?

An interaction between two or more drugs (or drugs + poison) that produce opposite effects on the same physiological function.

What does functional antagonism treat?

The clinical signs observed.

Where does strychnine come from?

Alkaloid toxin from Strychnos nux-vomica plant.

What is the mechanism of toxicity of strychnine?

Blocks the inhibitory neurotransmitter glycine → CNS stimulation.

What signs result from strychnine toxicity?

Excess sensory input & exaggerated responses, rigor; sardonic "grin"; seizures, convulsions.

What is a sardonic "grin" in strychnine toxicity?

Sustained facial muscle spasms.

Which drugs are used to treat strychnine toxicity?

Methocarbamol, pentobarbital, and propofol.

What is chemical antagonism?

A chemical interaction (reaction) that occurs between two drugs (or drug + poison) that produces a less toxic product.

What is an example of chemical antagonism?

Chelation therapy and heavy metal toxicity.

Which heavy metals are listed as targets of chelation therapy?

Arsenic, mercury, and lead.

Which chelation drug is listed for arsenic, mercury, and lead?

Dimercaprol (BAL).

What percentage of lead in blood is bound to hemoglobin?

97-99%.

To which tissues is lead distributed?

Liver, brain, kidney, and bone.

What is the goal of chelation therapy?

Give a drug that chemically binds to the toxic metal in order to form a less toxic complex for excretion in urine.

How was chelation therapy first used during World War II?

As antidote for arsenic-based chemical weapons and to treat lead poisoning in service men painting naval ships with Pb-based paints.

What are the toxic blood lead levels listed for cats and cows?

Greater than 0.3 ppm.

What is the toxic blood lead level listed for dogs?

Greater than 0.6 ppm.

How does anti-venom act through chemical antagonism?

Antibodies against venom.

What is anti-venom given to counteract?

Envenomation by poisonous snakes.

How is anti-venom made?

Diluted venom is injected into a horse, sheep, or rabbit; serum is isolated and antibodies are purified and lyophilized.

What is dispositional antagonism?

Alteration of absorption, distribution or excretion of a poison or drug such that the concentration or duration of time at the target organ is diminished.

Which treatments are listed as examples of dispositional antagonism affecting absorption?

Administration of activated charcoal/cathartic and apomorphine.

What does activated charcoal do in the GI tract?

Adsorbs toxin/toxicant in GI tract → fecal excretion.

What does activated charcoal decrease?

Systemic absorption.

When should activated charcoal be implemented for maximal adsorption to poison?

Immediately.

What does "activated" mean for activated charcoal?

Petroleum or vegetable origin, not mineral/animal.

What is receptor antagonism?

When two or more drugs (or drug + poison) bind the same receptor and produce less toxicity than when given separately.

How is carbon monoxide poisoning treated through receptor antagonism?

Administration of O2 to displace CO from hemoglobin.

How does naloxone act as a receptor antagonist?

Competes with morphine-like drugs for same receptor.

What causes carbon monoxide poisoning?

Incomplete combustion of fuels.

What are examples of sources of carbon monoxide poisoning?

Malfunctioning space heaters, fireplaces.

How strongly does carbon monoxide bind hemoglobin compared with oxygen?

More than 200x more affinity than oxygen.

What forms when carbon monoxide binds hemoglobin?

Carboxyhemoglobin.

How is supplemental oxygen administered for carbon monoxide poisoning?

Supplemental 100% O2 via endotracheal tube.

How does supplemental 100% oxygen affect recovery from carbon monoxide poisoning?

4-fold faster recovery against high affinity CO bound to hemoglobin.

What is the brand name of naloxone?

Narcan®.