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.

-competitive inhibition of enzymes by a drug

How can selective organ uptake cause an adverse drug reaction?

Organ selectively accumulates drug in cells.

-aminoglycosides nephrotoxicity

What are the two groups of macrolide endectocides?

Avermectins and milbemycins.

Which drugs are listed as avermectins?

Ivermectin, selamectin, doramectin, and eprinomectin.

Which drugs are listed as milbemycins?

Milbemycin Oxime, Moxidectin

What are macrolide endectocides used as?

Anthelmintics and heartworm preventatives.

-applied through injection, PO, topicals, topical drops

-cats, dogs, sheep, cattle, horses, 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

• in mammals, GABA-gated chloride channels in the CNS are “safely” protected from blood by the BBB containing P-glycoprotein

How do macrolide endectocides act when they can 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.

Mechanism of macrolide endectocide toxicity in mammals

These drugs are substrates for p-glycoprotein but cannot be transported out of the brain and back into the capillary lumen if MDR-1 mutation → 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)

• in collies/collie mixed breeds or other dogs genetically pre-disposed to toxicity

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 clinical signs occur in turtles with macrolide endectocide toxicity?

• Extreme paresis, flaccid paralysis

• often die within several days

• severe fatty changes in liver

How is macrolide endectocide toxicity diagnosed from history?

• History of administration/exposure

  • use of horse paste wormer on dog

  • use of cattle injectable in small animals

  • administration of drug to collie-related breed

• toxicology testing: liver, adipose tissue, serum

• 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.

-takes a long time to leave a dog - comatose dog (7 weeks - recovered)

What additional care is used to treat macrolide endectocide toxicity?

Symptomatic/supportive care.

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

PU/PD.

-others: THC, benzos, barbiturates

How do corticosteroids cause PU/PD?

Partial inhibition of antidiuretic hormone (vasopressin) secretion.

-ADH decreases production of urine by 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).

-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.

-treating 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 type of toxicity causes sardonic "grin"?

Strychnine

-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?

1. Diluted venom is injected into a horse, sheep, or rabbit;

2. Animal has immune response and produces antibodies against venom

3. Blood is collected from animal → serum isolated and antibodies purified and lyophilized (freeze dried)

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.

dispositional antagonism = _____ _______ _______

preventing toxicant absorption

What does “activated” mean in activated charcoal?

“activated” = petroleum or vegetable origin, not mineral/animal

What does activated charcoal do in the GI tract?

Adsorbs toxin/toxicant in GI tract → fecal excretion.

-decreases systemic absorption

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

Immediately.

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.

What acts as “blockers” for receptor antagonism drug interactions?

Naloxone competes with morphine-like drugs for same receptor

What causes carbon monoxide poisoning?

Incomplete combustion of fuels.

How strongly does carbon monoxide bind hemoglobin compared with oxygen?

More than 200x more affinity than oxygen → carboxyhemoglobin

How is supplemental oxygen administered for carbon monoxide poisoning?

Supplemental 100% O2 via endotracheal tube.

What does Naloxone do in receptor antagonism?

-known as blockers

-competes with opioids for same receptor