Lecture 17: Adverse Drug Events, Hypersensitivity, Mutagenicity & Teratogenicity Notes

What is an adverse event (AE)?

Any harmful or negative outcome occurring while a patient receives medical care, including procedures, surgery, or medications

What is an adverse drug event (ADE)?

An injury resulting from medical intervention related to a drug.

What can ADEs include?

ADRs, allergic reactions, side effects, overmedication/overdose, and medication errors.

What is a medication error?

Inappropriate use of a drug that may or may not cause harm.

At which steps can medication errors occur?

Prescribing, transcribing, dispensing, administration, adherence, or monitoring.

What is an adverse drug reaction (ADR)?

Harm directly caused by a drug given at normal doses.

What factors increase ADR risk?

Advanced age, polypharmacy, dose, route, duration, bioavailability, sex, ethnicity, genetics, coexisting disease, and geographic factors.

What is the inpatient impact of ADEs?

About 1 in 3 hospital visits involves an AE; ADEs affect about 2 million hospital stays yearly and may extend stays by 1.7–4.6 days.

What is the outpatient impact of ADEs?

Over 3.5 million office visits, about 1 million ED visits, and about 125,000 hospital admissions yearly.

What are social determinants of health (SDOH)?

Nonmedical conditions that affect health, well-being, quality of life, medication access, and safe medication use.

What are examples of SDOH that can affect ADE risk?

Housing, transportation, income, education, food access, discrimination, pollution, language, and health literacy.

How can SDOH increase ADE risk?

Barriers such as limited transportation, low health literacy, or inability to afford medications can lead to medication errors or unsafe medication use.

What percentage of ADRs are Type A?

More than 80%.

What percentage of ADRs are Type B

Less than 20%.

How is Type A ADR pharmacology related?

It is related to the drug’s known pharmacologic effects.

How is Type B ADR pharmacology related?

It is not explained by the drug’s known pharmacology

Are Type A ADRs dose-dependent?

Yes—usually dose-dependent.

Are Type B ADRs dose-dependent?

Usually not; dose dependence is low.

What causes Type A ADRs?

Predictable pharmacologic actions, including ADME and receptor effects.

What causes Type B ADRs?

Off-target receptor activation, immune responses, or genetic susceptibility.

When do Type A ADRs usually occur?

Within hours to days.

When can Type B ADRs occur?

Immediately, after a delay, or variably

Who can experience a Type A ADR?

Anyone at a sufficiently high dose.

Who usually experiences a Type B ADR?

Susceptible individuals.

Compare morbidity and mortality of Type A vs. Type B ADRs.

Type A: higher morbidity but lower mortality. Type B: lower morbidity but potentially higher mortality.

What is a Type A drug overdose?

Toxicity caused by consuming an excessive amount of a drug.

Give examples of Type A overdose toxicity.

Acetaminophen → liver failure; warfarin → bleeding; opioids → respiratory depression.

What is a drug side effect?

A predictable, dose-dependent effect unrelated to the primary therapeutic effect.

Give examples of drug side effects.

NSAIDs → gastritis; aminoglycosides → nephrotoxicity; antibiotics → diarrhea; doxycycline → phototoxicity.

What is a drug interaction

When a drug’s effect is altered by another drug, food, supplement, or disease.

Give examples of Type A drug interactions.

Theophylline + macrolides; warfarin + vitamin K intake; benzodiazepines + opioids → respiratory depression.

What are Type B hypersensitivity reactions?

Immune or inflammatory reactions to a drug.

What are other immunologic Type B reactions?

Immune-mediated reactions that are not classic hypersensitivity, such as drug-induced autoimmune disease or fixed drug eruptions.

What is an idiosyncratic reaction?

An unpredictable reaction, often due to genetic variation.

What is an example of an idiosyncratic reaction?

Hemolysis from dapsone in a patient with G6PD deficiency.

What is a pseudoallergic reaction?

A reaction that resembles allergy but is not immune-mediated, often from direct mast-cell activation.

What are examples of pseudoallergic reactions?

Vancomycin infusion reaction; reactions to fluoroquinolones or neuromuscular blockers.

What is haptenation?

Covalent binding of a small drug molecule to a large protein, creating an immunogenic drug-protein complex.

What size are drugs that commonly act as haptens?

Usually less than 1,000 Da.

In which hypersensitivity type is haptenation especially important?

Type IV hypersensitivity, although it can also contribute to Types I–III.

What triggers mediator release in immediate hypersensitivity?

Cross-linking of adjacent IgE molecules bound to a cell by a free drug or drug-protein conjugate.

Why can beta-lactam antibiotics cause hypersensitivity?

Their strained beta-lactam rings can open and covalently bind proteins.

How can epoxides contribute to hypersensitivity?

They are electrophilic metabolites, often formed by aromatic epoxidation, that react with cellular nucleophiles/proteins.

How do α,β-unsaturated carbonyls react with proteins?

They react with thiol groups through Michael addition.

How do aromatic amines/anilines become reactive?

N-hydroxylation forms hydroxylamines, which can be oxidized to reactive nitroso compounds.

What do nitroso compounds react with on proteins?

Sulfhydryl (–SH) groups.

How can sulfhydryl-reactive metabolites contribute to hypersensitivity?

They bind cysteine thiols on proteins, altering protein function or creating antigenic complexes.

What is mutagenesis?

The ability of a chemical to cause DNA changes that are transmitted during cell division.

What is a germline mutation?

A mutation in sperm or ova that can be passed to future generations.

What is a somatic mutation?

A mutation in nonreproductive body cells that is not inherited by offspring but may cause cell death or pass to daughter cells during mitosis.

What common chemical groups can be mutagenic?

Epoxides, alkylating agents, DNA base analogs, aromatic amines/anilines, and planar PAHs.

What are nitrogen mustards, and how do they cause mutations?

Chloroethylamine-containing cytotoxic compounds that nonspecifically alkylate DNA, causing mutations and cell death.

How do DNA base analogs cause mutations?

They resemble normal purines or pyrimidines, become incorporated into DNA, and can pair incorrectly.

How does 5-bromouracil cause a mutation?

It can replace thymine; after tautomeric shift, it pairs with guanine and causes an A-T → G-C transition.

What are PAHs, and where are they found?

Mutagenic/carcinogenic products of incomplete combustion found in tobacco smoke, car exhaust, coal tar, asphalt production, and some foods.

What are the key teratogenesis and thalidomide facts?

A teratogen disrupts fetal development, especially during organogenesis (about day 20 through the end of the first trimester). Thalidomide’s S-enantiomer is teratogenic, R is sedating, and racemization means giving only R is not fully protective.