Drug Safety, Adverse Drug Reactions and Poisoning

Question 1

1. Compare and contrast graded dose-response curves and population dose-response curves and explain the use of population dose-response curves to evaluate drug safety (Therapeutic Index and Standard Safety Margin).

Answer 1

-Quantal dose-response curves measure pharmacological processes as all-or-nothing events in populations –> used to determine the minimum dose to produce the response to a single dose and tells us the fraction of the population that responds to the dose. This way we can find the dose necessary for therapeutic effect and those that gives toxicity.

• ED50 = dose that works in 50% of the population
• (In a graded response, ED50 = the dose that produces 50% of Emax).
• LD50 = lethal dose that causes death in 50% of population.
• Graded dose-response curve has many increasing doses given to one subject whose responses are measured to determine the Emax.
• The higher the therapeutic index, the safer the drug. Standard safety margin is a %; takes into account extremes?

-Extension effects = drug acting at a receptor in the target system.
-Side effects = drug acting at a receptor in a different system.
I-diosyncratic effects = immunologic/allergic or metabolic effects elicited by drug?

Question 2

2. Describe the general FDA categories for drug use in pregnancy and the implications for drug prescribing.

Answer 2

• A, B, C, D and X.
• With A, the possibility of fetal harm seems remote.
• With X, these drugs are contraindicated in pregnancy and the risks outweigh all potential benefits.
• A–> X is best –> worst.

Question 3

3. Describe the major pharmacokinetic (via effects on absorption, distribution, metabolism, and excretion) and pharmacodynamic (via pharmacologic [receptor] or physiologic effects) mechanisms underlying drug-drug and food-drug interactions and the potential for clinical significance of each.

Answer 3

DRUG-DRUG INTERACTIONS:

Pharmacokinetic Drug Interactions:

• Elevated drug concentrations and drug toxicity
• Decreases in plasma concentrations and levels below therapeutic effectiveness.

Pharmacodynamic Drug-Drug Interactions:

• pharmacologic/physiologic enhancement or antagonism of drug action.
• Narrow therapeutic index drugs to watch out for = warfarin and insulin/anti-diabetic agents.

P’kinetic interactions:

• Absorption: decreases in gastric motility slow passage of drug –> decreased absorption rate –> lower peak plasma drug levels.
• Distribution = depends on protein binding/displacement interactions.
• Metabolism: can be affected by inducers or inhibitors, especially in the CYP450 system
• Excretion: generally in kidneys; change in GFR, secretion, and urine pH can affect

P’dynamic interactions:
-can be antagonistic, synergistic/additive (when 2 drugs work together), or can result in synergistic side effects. Can also get indirect p’dyanmic effects when one drug affects the action of another.

Food-drug interactions probably happen most with impacting gastric motility?