ADR

What is an adverse drug reaction (ADR), and how does it differ from an adverse drug experience?

An ADR is an unintended or unexpected response to a drug; an adverse drug experience includes any associated problem, even without confirmed drug causation.

Which events may qualify as ADRs beyond unexpected toxicity?

Unexpected injection-site reactions, violative residues in edible tissues, or failure to achieve an expected therapeutic response.

What is the difference between Type A and Type B ADRs?

Type A is dose-dependent and predictable from known pharmacology; Type B is unpredictable, generally dose-independent, and often immune-mediated.

An animal with impaired renal clearance develops toxicity at a normal dose. Which ADR type is most likely?

Type A: reduced elimination augments the drug's expected effects.

How do Type C and Type D ADRs differ?

Type C is chronic, dose- and time-dependent (e.g., phenobarbital); Type D is delayed and may occur long after treatment (e.g., chemotherapy).

What is veterinary pharmacovigilance?

Monitoring, detecting, assessing, understanding, and preventing unrecognized or changing adverse effects of veterinary drugs.

What distinguishes on-target from off-target adverse drug actions?

On-target effects relate to the drug's principal pharmacological action and may be shared by its class; off-target effects involve other actions or chemical features.

Which drug classes or drugs are associated with neurotoxicity, nephrotoxicity/ototoxicity, arrhythmias, and pancytopenia?

Avermectins: neurotoxicity; aminoglycosides: nephrotoxicity/ototoxicity; digoxin: arrhythmias; estrogens: pancytopenia.

How do pharmaceutical and pharmacological drug interactions differ?

Pharmaceutical interactions occur outside the body (chemical/physical incompatibility); pharmacological interactions occur inside the body (pharmacokinetic/pharmacodynamic).

What medication errors commonly cause Type A ADRs?

Incorrect dose, route, or formulation; look-alike drug names/containers; transcription and decimal-point errors.

What can happen when incompatible injectable medications are mixed?

Precipitation or separation; examples include diluted diazepam, lidocaine with propofol, and tetracycline/ceftriaxone with calcium.

How can liver or kidney disease increase the risk of Type A ADRs?

Reduced hepatic metabolism, GFR, renal clearance, or biliary elimination can increase drug plasma concentrations.

Why can decreased plasma albumin increase drug toxicity?

Reduced protein binding increases the unbound fraction of drugs, especially acidic drugs.

Which patient factors can influence drug metabolism and ADR susceptibility?

Breed/genetics, age, organ disease, diet/nutrition, sex, endocrine status, and drug interactions.

How can CYP450 metabolizer phenotypes affect drug dosing?

For the lecture's example: poor/intermediate metabolizers need lower doses; extensive metabolizers may need higher doses; ultra-rapid metabolizers need higher doses.

What is the significance of CYP1A2 in canine drug metabolism?

It is involved in Phase I metabolism of approximately 8–10% of clinical drugs; genetic variation may alter drug disposition.

Why are sighthounds predisposed to ADRs involving certain drugs?

CYP2B11 deficiency reduces Phase I metabolism of some drugs.

Why are Collies and other herding breeds predisposed to drug-induced neurotoxicity?

MDR1/ABCB1 mutations reduce P-glycoprotein efflux, increasing drug accumulation in the CNS and reducing biliary clearance.

What does the ABCB1 (MDR1) gene encode, and what mutation was described?

P-glycoprotein, a drug efflux transporter; a four-base-pair deletion can produce a nonfunctional transporter.

Can P-glycoprotein-related toxicity occur in dogs or cats without an MDR1 mutation?

Yes. Multiple P-glycoprotein substrate drugs can saturate or impair efflux, increasing drug accumulation.

Which breed is predisposed to sulfonamide hypersensitivity, and what ADR type does it represent?

Doberman pinschers; Type B ADR.

Why do very young and very old animals have increased ADR susceptibility?

They often have reduced drug metabolism; immature animals cannot simply be treated as smaller adults.

What pharmacokinetic mechanisms can cause drug-drug interactions?

Competition for protein binding or transport, and induction or suppression of drug-metabolizing enzymes.

How can chronic CYP450 induction or suppression alter drug exposure?

It changes drug metabolism and plasma AUC; these time-dependent interactions are often Type C rather than Type A.

Which pharmacodynamic interactions reduce versus enhance drug effects?

Reduce: competitive/noncompetitive antagonism, negative allosteric modulation, functional antagonism. Enhance: additive effects, positive allosteric modulation, synergism.

What distinguishes additive effects from synergism?

Additive: combined effect equals the sum of individual effects; synergism: combined effect exceeds that sum.

Which hypersensitivity mechanisms are associated with Type B ADRs?

Types I–IV hypersensitivity and idiosyncratic reactions, many with an immune basis.

Why might an initially classified Type B reaction later be considered Type A?

A genetic polymorphism affecting drug metabolism or disposition may explain the previously unpredictable reaction.

Which drugs are associated with hepatic necrosis, sulfonamide hypersensitivity, and self-excoriation?

Oral diazepam: hepatic necrosis; potentiated sulfonamides: hypersensitivity; oral methimazole: self-excoriation, hepatotoxicity, and thrombocytopenia.

Which drug classes most commonly cause cutaneous adverse drug reactions (toxidermias)?

Antibiotics, especially beta-lactams and sulfonamides, and NSAIDs.

How can reactive drug metabolites cause Type B ADRs?

Oxidative enzymes generate reactive metabolites that cause oxidative injury or form drug haptens, triggering humoral/T-cell responses affecting liver, skin, or bone marrow.

What factors should be evaluated before prescribing drugs to minimize ADR risk?

Risks versus benefits, therapeutic index, concurrent medications, and drug-drug, drug-disease, or drug-nutrition interactions.

How does the number of medications administered influence ADR risk?

ADR incidence increases as the number of drugs administered increases.

What are the initial steps in managing a suspected ADR?

Stop the implicated drug, investigate causes, reconsider treatment, and assess injury using physical examination, CBC, and other laboratory tests.

How should serious ADRs and medication errors be reported?

Report serious unexpected events to the manufacturer/FDA CVM; voluntary reporting of medication errors is encouraged even when no patient harm occurs.