Adverse Effects And Toxicity

Question 1

Dose-dependent toxicity

Answer 1

Dose makes the poison
1. Paracelsus (1493-1541): Father of toxicology
2. Drug effect (Cp) dictates toxic vs. therapeutic effect
3. Severity depends on length of exposure
4. Therapeutic index
5. Mechanisms
A. Pharmacological toxicity
B. Pathological toxicity
C. Genotoxicity: DNA damage

Question 2

Margin of safety

Answer 2

MOS = LD1/ED99

Question 3

Toxic dose

Answer 3

Toxic dose X% of population

1. TDx

Question 4

Drug classes w/ narrow TI

Answer 4

1. Anticoagulants (warfarin)
2. Antiarrhythmics
3. Anticonvulsants
4. Digoxin
5. Lithium carbonate
6. Oral hypoglycemics
7. Theophylline
8. Amphotericin B (amphoterrible)

Question 5

Considerations for drugs w/ narrow TI

Answer 5

1. Monitor levels of drug
2. Assess drug necessity
3. Monitor organ system health
4. Common problems:
   A. Hepatotoxicity (jaundice)
   B. Nephrotoxicity
   C. Hypersensitivity

Question 6

Pharmacological toxicity

Answer 6

1. On-target: inappropriate interaction w/ intended receptor
   A. Overdose
   B. Right receptor, wrong tissue
   C. Effects on chronic inhibition/activation
2. Off-target: unintended receptor
   A. Example: propranolol (non-selective beta-blocker)
   
   1. Used to be used for HTN
   2. Dec. bronchodilation

Question 7

Pathological toxicity

Answer 7

1. Metabolism of toxicants overwhelmed
   A. Irreversible cell injury
   B. Necrosis, cell damage, organ damage
2. Off-target bile salt export protein (BSEP) inhibition
   A. Transports bile salts from hepatocytes to bile ducts
   B. Inhibition: BS inc in hepatocytes -> necrosis (intrahepatic chleostases)
3. Acetomeniphen biotransformation
   A. Acetomeniphen -> NAPQ (toxic)
   B. OD depletes GSH (needed for detox)
   C. Hepatotoxicity

Question 8

Dose-independent toxicity

Answer 8

Allergic reactions

Question 9

Idiosyncratic toxicity

Answer 9

1. Extreme sensitivity

2. Extreme insensitivity

Question 10

Apparent dose

Answer 10

1. Patient specific factors
2. Absorption factors
   A. Slower motility
   B. Altered gastric pH
3. Distribution factors
   A. Hypoproteinemia
4. Reduced elimination factors
   A. Renal clearance
   B. Drugs
   C. PH alteration
5. Metabolism factors
6. Drug interaction factors
   A. Metabolism enzyme inhibition
   B. Metabolism enzyme induction

Question 11

Type I: Hypersensitivitiy (anaphylactic reactions)

Answer 11

1. IgE antibodies (mast cells) bind
2. Inflammation mediators released
3. Vasodilation -> edema and inflammation
4. Occurs immediately after exposure
5. Example: Red man’s syndrome
   A. Rare
   B. IV drugs
   C. Symptoms: flushing, erythema, pruritis (itching)
   D. Causes: vancomycin, ciprofloxacin, amphotericin B, rifampin