Drug Toxicity

Question 1

on target effects

Answer 1

• exaggeration of desired pharmacologic action due to alteration in exposure to drug

Question 2

off target effects

Answer 2

• adverse effects that occur when a drug interacts with unintended target (multiple receptors)
• enantiomers of drugs can cause off target effects

Question 3

pharmacokinetic interactions

Answer 3

• one drug changes absorption, distribution, metabolism, or excretion of another drug
• P450 isozyme system is central to this concept, especially CYP3A4
• displacement of a drug from plasma proteins (albumin) via a second drug may increase bioavailability of displaced drug especially in liver failure, malnutrition or nephrotic syndrome

Question 4

pharmacodynamic interactions

Answer 4

• one drug changes the response of target or nontarget tissues to another drug
• toxic interactions occur when two drugs activate complementary pathways leading to exaggerated effect (viagra and nitroglycerin)

Question 5

type 1 hypersensitivity

Answer 5

• immediate response or anaphylaxis results from production of IgE after exposure to foreign protein or hapten modified endogenous protein
• subsequent exposure results in IgE cross link of antigen causing mast cell degranulation releasing inflammatory mediators promoting vasodilation, bronchoconstriction, and inflammation - wheal and flare reaction in skin, conjunctivitis, and rhinitis in upper respiratory tract

Question 6

type II hypersensitivity

Answer 6

• antibody dependent cytotoxic response occurs when drug binds to cells (usually RBCs) which are then recognized by antibodies (usually IgG) resulting in complement fixation, phagocytosis, or cytolysis by cytotoxic T cells

Question 7

type III hypersensitivity

Answer 7

• immune complex mediated occurs when antibodies (usually IgG or IgM) are formed against soluble antigens
• antigen/antibody complexes are deposited in tissues such as kidneys, joints and lungs

Question 8

type IV hypersensivity

Answer 8

• delayed response that results from the activation of TH1 and cytotoxic T cells
• no response with first exposure but subsequent dermal exposure activates Langerhans cells which migrate to regional lymph nodes and activate T cells which return to site and initiate immune response
• poison ivy and latex allergy are well known examples

Question 9

autoimmune reaction caused by methyldopa

Answer 9

• hemolytic anemia by eliciting autoimmune reaction against Rh factors

Question 10

drugs that can lupus like symptoms

Answer 10

• hydralizine, isoniazid, and procainamide can cause lupus like syndrome by inducing antibodies to myeloperoxidase (hydralazine, isoniazid) and DNA (procainamide)

Question 11

cause of red man syndrome

Answer 11

• vancomycin
• direct effect on mast cells causing degranulation
• wheals and urticaria relatively localized to neck, arms and upper trunk
• management involves antihistamines and slowing infusion

Question 12

common causes of Steven Johnsons

Answer 12

• barbiturates, sulfonamides, antiepileptics (phenytoin, carbamazepine), NSAIDs (ibuprofen, celecoxib) and allopurinol
• skin eruptions and skin sloughs off

Question 13

drug induced hepatotoxicity

Answer 13

• tylenol depletes glutathione stores

- administration of N-acetylcysteine replenishes glutathione stores

Question 14

drugs associated with renal toxicity

Answer 14

• ACE inhibitors
• NSAIDs
• progressive increase in serum creatinine is hallmark

Question 15

drugs associated with neurotoxicity

Answer 15

• chemotherapeutic medicines

Question 16

drugs associated with skeletal muscle toxicity

Answer 16

• HMG-CoA reductase (statins)
• corticosteroids (dexamethasone, hydrocortisone)
• zidovudine

Question 17

three major mechanisms of drug induced cardiotoxicity

Answer 17

• cardiac potassium channel blockade leading to prolonged QTc
• direct toxicity to cardiac myocytes
• toxicity to heart valves

Question 18

drugs associated with cardiotoxicity

Answer 18

• fenfluramine

- causes proliferation of valvular fibroblasts that form myxoid plaques on AV valves

Question 19

drugs associated with pulmonary toxicity

Answer 19

• bleomycin

Question 20

carcinogenesis due to drug therapy

Answer 20

• tamoxifen

Question 21

drugs associated with increased risk of serious infection

Answer 21

• rituximab targets CD20+ B cells which are involved in non-Hodgkin’s lymphoma and rheumatoid arthritis
• potentially adverse effects are progressive multifocal leukoencephalopathy, infection from polyomavirus, the JC virus, and hepatitis B reactivation with fulminant hepatitis

Question 22

Hy’s rule of drug induced hepatotoxicity

Answer 22

• ALT greater than 3X upper limit combined with bilirubin 2X upper limit associated with mortality rate of at least 10%