Drug Toxicity

Question 1

Three types of inadvertent consequences drugs may elicit

Answer 1

• Side effects
• Adverse effects
• Toxic effects

Question 2

Inadvertent consequences are a function of. . .

Answer 2

• Mechanism of drug action
• Drug dose
• Characteristics and health status of the patient

Question 3

Margin of safety

Answer 3

Range between the dose required for efficacy and the dose that causes side effects

Question 4

ED₅₀, TD₅₀, LD₅₀, and the Therapeutic Index

Answer 4

Question 5

When it comes to TD₅₀, a ____ number is better.

Answer 5

When it comes to TD₅₀, a larger number is better.

Question 6

“On-Target” Adverse Effects

Answer 6

Adverse effects that are the result of the drug binding to its intended target receptor

Question 7

“Off-Target” Adverse Effects

Answer 7

Adverse effects that are the result of the drug binding to a receptor for which it is not intended

Question 8

Most adverse effects are mediated by ___.

Answer 8

Most adverse effects are mediated by the immune system.

Question 9

“On-Target” adverse effects may be “off target” in a sense, in that they may be ____.

Answer 9

“On-Target” adverse effects may be “off target” in a sense, in that they may be binding to the right receptor in the wrong tissue.

Question 10

Pathways to toxicity

Answer 10

Question 11

Class effects

Answer 11

The “on-target” effects of a drug class, which tend to be shared by all drugs within the class. It is the “off-target” effects which vary.

Question 12

Diphenhydramine

Answer 12

1st Generation H₁ receptor antagonist

Like all 1st generation, it blocks H₁ at its target tissues (endothelium), but also crosses the blood-brain barrier and produces off-target effects by blocking histaminergic neurons in the brain.

2nd Generation H₁ antagonists have since been designed which do not cross the blood-brain barrier.

Question 13

hERG channels

Answer 13

Cardiac potassium channels. Unfortunately, a common site of off-target effects, leading to delayed repolarization and arrhythmia and possibly in sudden death. Several antihistamines have been taken off of the market due to discovered interactions with these channels.

Question 14

As a condition of marketing approval, new drugs are evaluated clinically for the ability to alter ____.

Answer 14

As a condition of marketing approval, new drugs are evaluated clinically for the ability to alter the electrocardiogram.

Question 15

Promiscuous β1-blockers are contraindicated in ______.

Answer 15

Promiscuous β1-blockers are contraindicated in patients with asthma.

(Due to bronchoconstriction caused by β2 blocking)

Question 16

haptenization

Answer 16

When a small molecule compound reacts with a self or foreign protein, resulting in antigenicity of a self protein or increased antigenicity of a foreign protein.

Question 17

Types of hypersensitivity reaction

Answer 17

Question 18

Methyldopa immune reactions

Answer 18

Can cause hemolytic anemia by eliciting an autoimmune reaction against the Rhesus antigens (Rh factors)

Question 19

Hydralazine, isoniazid, and procainamide immune reactions

Answer 19

Can cause a lupus-like syndrome by inducing antibodies to myeloperoxidase (hydralazine and isoniazid) or DNA (procainamide).

Question 20

Stevens-Johnson syndrome

Answer 20

Reported with barbiturates, sulfonamides, antiepileptics, NSAIDs, allopurinol, among some other drugs.

Morphologic appearance of mucous membrane and skin inflammation, with the development of blisters and separation of the epidermis from the dermis, is consistent with an immune etiology.

Question 21

Immunotoxicity

Answer 21

Broad term for toxicity effects mediated by the immune system

Question 22

Acetominophen metabolism

Answer 22

Question 23

Hepatotoxic metabolite of acetominophen

Answer 23

N-acetyl-p-benzoquinoneimine (NAPQI)

If left to build up (in the absence of conjugation to glutathione), it will damage many hepatocyte structures, especially mitochondria, resulting in hepatocyte necroptosis.

Question 24

Antidote for acetominophen toxicity

Answer 24

N-acetylcysteine

Which replenishes glutathione stores.

Question 25

Acetominophen toxicity is responsible for ___% of acute hepatic failure in the US.

Answer 25

Acetominophen toxicity is responsible for 50% of acute hepatic failure in the US.

Question 26

___ is used to measure renal necrosis.

Answer 26

serum creatine is used to measure renal necrosis.

Question 27

Gentamicin and aminoglycoside nephrotoxicity

Answer 27

Cause renal injury in part through its inhibition of lysosomal hydrolases (sphingomyelinase, phospholipases) in proximal tubules of the kidney, leading to lysosomal storage disease.

Lysosomal rupture leads to cell death in the form of acute tubular necrosis. Renal tubular injury by gentamicin and other aminoglycoside antibiotics is reversible upon cessation of treatment, provided that the initial injury is not too severe.

Question 28

amphotericin B mechanism of action

Answer 28

Damages fungal cell membranes by interacting with ergosterol and forming membrane pores through which potassium leaks, leading to cell death.

Question 29

amphotericin B nephrotoxicity

Answer 29

Damages renal tubular cells via a similar mechanism to how it damages fungal cells, with initial binding of drug to sterols in the membrane

Because the mechanism responsible for efficacy is shared by the mechanism responsible for toxicity, there is a small margin between the exposures required for antifungal activity and those required for renal injury

Question 30

Contrast media toxicity

Answer 30

Cause renal injury both by direct toxicity to renal tubular epithelial cells and by constriction of the vasa recta leading to reduced renal medullary blood flow

Question 31

Peripheral neuropathy has been associated with. . .

Answer 31

vinca alkaloids (e.g., vincristine, vinblastine), taxanes (e.g., paclitaxel), and platinum compounds (e.g., cisplatin).

Question 32

Drug classes associated with skeletal muscle injury include. . .

Answer 32

. . . statins and corticosteroids.

Question 33

Three Mechanisms of Drug-Induced Cardiovascular Toxicity

Answer 33

1. ) Cardiac potassium channel interactions causing arrhythmia
2. ) Direct toxicity to cardiac myocytes
3. ) Iron interactions resulting in ROS production and subsequent mitochondrial and membrane lipid damage (Fenton chemistry)

Question 34

Two Mechanisms of Drug-Induced Pulmonary Toxicity

Answer 34

1. ) β2 receptor antagonism leading to bronchoconstriction
2. ) Chronic inflammation resulting in lung fibrosis

Question 35

“all substances are poison; there is none which is not a poison. The right dose differentiates a poison and a remedy.”

Answer 35

Paracelsus, 1500’s CE

Question 36

MDR1

Answer 36

Multidrug resistance 1

The gene which encodes P-glycoprotein

Question 37

organic anion transporting polypeptide 1 (OATP1)

Answer 37

mediates uptake of drugs into hepatocytes for metabolism and transport of drugs across the tubular epithelium of the kidney for excretion

Question 38

probenecid

Answer 38

Inhibitor of renal tubule transport. May be given with some drugs, including penicillin, to increase their halflife within the blood.

Question 39

naloxone

Answer 39

pharmacologic antagonist of the opioid receptor

By competitively binding to opioid receptors, naloxone prevents or reverses the toxic effects of natural or synthetic opioids, including respiratory depression, sedation, and hypotension

Question 40

Filgrastim

Answer 40

recombinant human GM-CSF

May be given along with chemotherapy to sustain PMN levels.

Question 41

Period of organogenesis in human fetus

Answer 41

3rd-8th week of gestation

This is the period during which teratogens have their greatest effect

Question 42

FDA pregnancy categories

Answer 42

A, B, C, D, X

Question 43

Category A

Answer 43

Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).

Question 44

Category B

Answer 44

Animal reproduction studies have failed to demonstrate a risk to the fetus, but there are no adequate and well-controlled studies in pregnant women.

Question 45

Category C

Answer 45

Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Question 46

Category D

Answer 46

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Question 47

Category X

Answer 47

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Category X drugs include not only teratogens but also drugs that have no proper use in pregnant patients. Statins are in this category, for example, because the normal physiologic increase in serum cholesterol that occurs during pregnancy should not be suppressed

Question 48

N-acetylcysteine antidote time-dependency for NAPQI hepatotoxicity

Answer 48

Question 49

Therapeutic window vs index plot

Answer 49

Question 50

Vd

Answer 50

dose / C_plasma

Question 51

___ is the p450 enzyme which produces NAPQI.

Answer 51

CYP2E1 is the p450 enzyme which produces NAPQI.

Question 52

Human children are already born with a robust ___.

Answer 52

Human children are already born with a robust repertoire of detoxifying liver enzymes.

Question 53

Any malnourished patient is likely to have lower stores of ___.

Answer 53

Any malnourished patient is likely to have lower stores of glutathione.

Question 54

Alcohol and CYP2E1 interacitons

Answer 54

Alcohol chronically upregulates 2E1 and decreases glutathione levels, but also acutely inhibits 2E1.

So ironically, while chronic alcoholism is a major risk factor for acetominophen toxicity, if an alcoholic takes acetominophen with alcohol they are protected.

Question 55

To prevent tylenol toxicity, tylnenol may be taken with . . .

Answer 55

. . . NAC or ethylene glycol.

Both inhibit 2E1 and thus prevent any possible toxicity.

Question 56

Flumenazil

Answer 56

Competitive antagonist of benzodiazepene binding sites on GABA receptors.

Think of it as the naloxone of benzodiazepenes. It is an antidote.

Question 57

Anticholinergic mnemonic

Answer 57

Hot as a hare

Blind as a bat

Dry as a bone

Red as a beet

Mad as a hatter

Question 58

Sarin

Answer 58

Neurotoxin. A nicotinic agonist. Causes mostly muscarinic symptoms but also fasciculations.

The antidote for sarin poisoning is atropine.