lecture 26

Question 1

Given a patient response to drug, identify the nature of the adverse reaction (side effect, augmented response, or toxic response).

Answer 1

Side effects: off target response, marginal impact on health, may impact patient compliance (ex: dry mouth with antidepressants, drowsiness with benadryl)

Augmented responses: extension of pharmacologic effect, usually dose-dependent, may seriously impair health. Cellular accumulation can cause augmented response toxicity. (ex: bradycardia with propranolol, hypotension with quinapril)

Toxic reactions: not predicted from pharmacology of drug, sometimes not drug-dependent, can seriously impact health. Reactive metabolites can impair nucleic acids, enzyme transporters, signaling proteins, receptor lipid autologous proteins –> carcinogenicity, necrosis, apoptosis, hypersensitivity (ex: carbamazepine-induced liver injury, skin rash with amoxicillin)

Question 2

Given the mechanisms by which a drug provokes a toxic response, provide potential interventions to prevent or minimize the toxic response.

Answer 2

Cellular dysfunction: cell survives, but normal metabolic processes are impaired

Cellular destruction: dysregulation by toxicant results in cell death

Genotoxicity: injury to DNA gets replicated to daughter cells

Question 3

Given the cell type that experiences genomic damage, identify the likely clinical outcome.

Answer 3

Somatic cells: cancers; depends on route of exposure
inhaled/ingested- GI and respiratory tract cancer
skin exposure- skin cancer
systemic- leukemia/lymphoma
tissue susceptibility- aflatoxin, liver cancer
ionizing radiation- thyroid/breast cancer

Germ cells: mutations in sperm/oocytes cause birth defects/childhood cancers

Developing embryo:
ionizing radiation, mutagenic chemicals, mutagenic biological agents- miscarriages, stillbirths, birth defects

Question 4

Provided a specific gestational stage for a woman, identify whether a teratogen is likely to result in 1. embryo death, 2. major congenital anomalies, or 3. functional defects and minor anomalies.

Answer 4

Period of dividing zygote, implantation, and bilaminar embryo, weeks 1-2: death of embryo and spontaneous abortion common

Main embryonic period, weeks 3-8: major congenital abnormalities
neural tube defects, mental retardation, TA, ASD, VSD, amelia, meromelia, cleft lip, low set malformed ears and deafness, microphtalima, cataracts, glaucoma, enamel hypoplasia and staining, cleft palate, masculinization of female genitalia

Fetal period, weeks 9-38: functional defects and minor anomalies
CNS, heart, upper and lower limbs, upper lip, ears, eyes, teeth, palate, external genetalia

Question 5

State the criteria for classification of an agent as a teratogen.

Answer 5

1. Exposure results in a characteristic set of malformations
2. Effect occurs with exposure at a specific stage of development
3. Effect is dose-dependent