Drug Toxicity Flashcards
Three types of inadvertent consequences drugs may elicit
- Side effects
- Adverse effects
- Toxic effects
Inadvertent consequences are a function of. . .
- Mechanism of drug action
- Drug dose
- Characteristics and health status of the patient
Margin of safety
Range between the dose required for efficacy and the dose that causes side effects
ED50, TD50, LD50, and the Therapeutic Index
When it comes to TD50, a ____ number is better.
When it comes to TD50, a larger number is better.
“On-Target” Adverse Effects
Adverse effects that are the result of the drug binding to its intended target receptor
“Off-Target” Adverse Effects
Adverse effects that are the result of the drug binding to a receptor for which it is not intended
Most adverse effects are mediated by ___.
Most adverse effects are mediated by the immune system.
“On-Target” adverse effects may be “off target” in a sense, in that they may be ____.
“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.
Pathways to toxicity
Class effects
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.
Diphenhydramine
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.
hERG channels
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.
As a condition of marketing approval, new drugs are evaluated clinically for the ability to alter ____.
As a condition of marketing approval, new drugs are evaluated clinically for the ability to alter the electrocardiogram.
Promiscuous β1-blockers are contraindicated in ______.
Promiscuous β1-blockers are contraindicated in patients with asthma.
(Due to bronchoconstriction caused by β2 blocking)
haptenization
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.
Types of hypersensitivity reaction
Methyldopa immune reactions
Can cause hemolytic anemia by eliciting an autoimmune reaction against the Rhesus antigens (Rh factors)
Hydralazine, isoniazid, and procainamide immune reactions
Can cause a lupus-like syndrome by inducing antibodies to myeloperoxidase (hydralazine and isoniazid) or DNA (procainamide).
Stevens-Johnson syndrome
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.
Immunotoxicity
Broad term for toxicity effects mediated by the immune system
Acetominophen metabolism
Hepatotoxic metabolite of acetominophen
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.
Antidote for acetominophen toxicity
N-acetylcysteine
Which replenishes glutathione stores.
Acetominophen toxicity is responsible for ___% of acute hepatic failure in the US.
Acetominophen toxicity is responsible for 50% of acute hepatic failure in the US.
___ is used to measure renal necrosis.
serum creatine is used to measure renal necrosis.
Gentamicin and aminoglycoside nephrotoxicity
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.
amphotericin B mechanism of action
Damages fungal cell membranes by interacting with ergosterol and forming membrane pores through which potassium leaks, leading to cell death.
amphotericin B nephrotoxicity
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
Contrast media toxicity
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
Peripheral neuropathy has been associated with. . .
vinca alkaloids (e.g., vincristine, vinblastine), taxanes (e.g., paclitaxel), and platinum compounds (e.g., cisplatin).
Drug classes associated with skeletal muscle injury include. . .
. . . statins and corticosteroids.
Three Mechanisms of Drug-Induced Cardiovascular Toxicity
- ) Cardiac potassium channel interactions causing arrhythmia
- ) Direct toxicity to cardiac myocytes
- ) Iron interactions resulting in ROS production and subsequent mitochondrial and membrane lipid damage (Fenton chemistry)
Two Mechanisms of Drug-Induced Pulmonary Toxicity
- ) β2 receptor antagonism leading to bronchoconstriction
- ) Chronic inflammation resulting in lung fibrosis
“all substances are poison; there is none which is not a poison. The right dose differentiates a poison and a remedy.”
Paracelsus, 1500’s CE
MDR1
Multidrug resistance 1
The gene which encodes P-glycoprotein
organic anion transporting polypeptide 1 (OATP1)
mediates uptake of drugs into hepatocytes for metabolism and transport of drugs across the tubular epithelium of the kidney for excretion
probenecid
Inhibitor of renal tubule transport. May be given with some drugs, including penicillin, to increase their halflife within the blood.
naloxone
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
Filgrastim
recombinant human GM-CSF
May be given along with chemotherapy to sustain PMN levels.
Period of organogenesis in human fetus
3rd-8th week of gestation
This is the period during which teratogens have their greatest effect
FDA pregnancy categories
A, B, C, D, X
Category A
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).
Category B
Animal reproduction studies have failed to demonstrate a risk to the fetus, but there are no adequate and well-controlled studies in pregnant women.
Category C
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.
Category D
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.
Category X
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
N-acetylcysteine antidote time-dependency for NAPQI hepatotoxicity
Therapeutic window vs index plot
Vd
dose / Cplasma
___ is the p450 enzyme which produces NAPQI.
CYP2E1 is the p450 enzyme which produces NAPQI.
Human children are already born with a robust ___.
Human children are already born with a robust repertoire of detoxifying liver enzymes.
Any malnourished patient is likely to have lower stores of ___.
Any malnourished patient is likely to have lower stores of glutathione.
Alcohol and CYP2E1 interacitons
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.
To prevent tylenol toxicity, tylnenol may be taken with . . .
. . . NAC or ethylene glycol.
Both inhibit 2E1 and thus prevent any possible toxicity.
Flumenazil
Competitive antagonist of benzodiazepene binding sites on GABA receptors.
Think of it as the naloxone of benzodiazepenes. It is an antidote.
Anticholinergic mnemonic
Hot as a hare
Blind as a bat
Dry as a bone
Red as a beet
Mad as a hatter
Sarin
Neurotoxin. A nicotinic agonist. Causes mostly muscarinic symptoms but also fasciculations.
The antidote for sarin poisoning is atropine.
