Drug Toxicity

Question 1

causes of drug toxicity

Answer 1

• mechanism of drug action
• characteristics and health status of patient
• size of drug dose

Question 2

margin of safety

Answer 2

• dose efficacy vs dose toxicity
• can be impacted by characteristics and health status of the patient and genetics
• new medicines are initiated at the lowest possible doses to avoid toxicity

Question 3

mechanism of drug toxicity

Answer 3

• on-target adverse effects
• off-target adverse effects
• idiosyncratic effects = mechanism not known

Question 4

on-target adverse effects

Answer 4

• adverse effects may be exaggeration of intended action due to too high of concentration/dose
• long duration of drug exposure can cause effects

Question 5

off target adverse effects

Answer 5

• can get off target receptor within same cell, off target receptor within different cell, or intended target receptor but in a different cell
• ex. anti-histamine Terfenadine (H1 agonist -therapeutic site) binds to hERG (Ik potassium channels in the heart) and inhibits potassium currents to increase QT interval and can cause arrhytmias and death. All new drug candidates tested for binding to hERG invitro and if drug makes it to clinical trial it is evaluated for its ability to prolong the QT interval
• ex #2 = non-selective beta-blockers can also affect beta receptors in smooth muscle cells in the airway and vasculature, so they are contraindicated in asthmatics
• ex #3 enantiomers: thalidomide, R-enantiomer = sedative and S-enantiomer = birth defects. Now enantiomers are evaluated by the FDA as separate entities

Question 6

idiosyncratic effects of drugs

Answer 6

• unknown cause that are specific to individuals — polymorp0hisms
• if they cause organ failure or death then they are removed from the market

Question 7

interactions of absorption

Answer 7

a drug may cause incr or decr in absorption of a second drug from the intestinal lumen

Question 8

dispositional antagonism

Answer 8

if the distribution, the metabolism, or the elimination of the drug can be altered in such a way that the drug is either transformed into a less toxic substance or is eliminated from the body more rapidly, then the observed effects will be less than the expected ones

Question 9

dangerous metabolism of acetaminophen

Answer 9

• most of it undergoes phase I reactions but some of it undergoes phase I reactions that produces a highly reactive product = NAPQI made from CYP2E1 enzyme.
• at low levels, it can be converted with GSH and excreted, but if there is too much, it can cause cell death
• alcoholics can be more susceptible to this because they have more CYP enzymes
• acetaminophen can cause organ damage within 20-40 hours!

Question 10

positive or negative allosteric modulators

Answer 10

• enhance (P) or decrease (N) agonist binding to the site of action
• PAMs = potentiation

Question 11

additive/synergistic drugs

Answer 11

-2 drugs with distinct mechanisms of action but same therapeutic effect

Question 12

Drug-drug interaction types (5)

Answer 12

1) interaction of absorption
2) interaction with protein binding
3) interaction of metabolism
4) interaction of receptor binding
5) interaction of therapeutic action

Question 13

immunotoxicity

Answer 13

• due to stimulating the immune system
• can compromise the immune system and have secondary effects leading to increased risk of infection
• immune reactions classed into type I-IV
• syndromes that mimic some features of the immune response
• skin rashes

Question 14

some drugs can induce _____-like syndrome

Answer 14

lupus

Question 15

red-man syndrome

Answer 15

• cause = drugs acting directly on mast cells leading to degranulation
• linked to IV infusion of drugs
• not caused by IgE
• cutaneous wheals and urticarial to neck, arms and upper trunk
• can proceed to angioedema and hypotension in rare cases
• antihistamines prophylactically

Question 16

erythema multiforme

Answer 16

skin rashes from drug immunotoxicity

Question 17

steven-johsons syndrome

Answer 17

• most severe type of skin rash– can be life threatening
• morphologic appearance of mucous mb and skin inflammation
• blisters and separation of the epidermis from the dermis
• observed with many commonly prescribed and OTC drugs

Question 18

drugs and an indirect effect on the immune system

Answer 18

• damage cells in the bone marrow, lymphoid tissues, intestines, and hair follicles in addition to the neoplasm at therapeutic doses
• safety margin is low for cancer drugs
• increased risk of infection if white blood cells are compromised

Question 19

drugs and direct effect on the immune system

Answer 19

-ex corticosteroids which will reduce the overal immune response and incr the risk of pneumonia

Question 20

renal toxicity from drugs

Answer 20

• caused by certain antibiotics and NSAIDs
• inhibition of lysosomal hydrolases in the proximal tubule
• changed lysosomal structure- lysosomes burst and cells die by necrosis
• may be reversible by stopping treatment

Question 21

teratogenesis

Answer 21

• induction of structural defects in the fetus caused by a drug
• maternal absorption, distribution, metabolism, and excretion will dictate drug exposure to fetus

Question 22

teratogenesis category A

Answer 22

• controlled studies

- no risk to fetus in first trimester and no evidence of risk throughout pregnancy

Question 23

teratogenesis category B

Answer 23

no risk observed in preclinical studies, but no studies have been done in women

Question 24

teratogenesis category C

Answer 24

risk observed in preclinical studies but no studies have been done in women
-benefit may outweigh risk

Question 25

teratogenesis category D

Answer 25

-some evidence of risk to the the fetus but the benefit may outweigh the risk

Question 26

teratogenesis category X

Answer 26

clear evidence of risk to the fetus but risk clearly outweighs the benefit