Drug Toxicity Flashcards
What are on-target effects?
Adverse effect may be an exaggeration of the desired pharmacological action, such as observed in drug overdose
What is an example of on-target effects?
CNS depression is predictable in dose-dependent fashion
- progression of clinically effects go from anxiolysis to sedation to somnolence to coma
What is an example of how duration of a drug can have on-target effects?
Tardive dyskinesia, an extrapyramidal motor disorder associated with use of antipsychotic medications, may be dependent upon duration of exposure
What are off-target effects?
Drug designed to bind to target A for therapeutic efficacy, but also binds to target B leading to toxicity
What is an example of off-target effects?
Antihistamine terfenadine – H1 antagonist – therapeutic site - also binds to hERG which causes cardiac arrhythmia.
Thalidomide with its 2 different enantiomers.
Beta-blockers for the heart can block the beta receptors that lead to the dilation of airways, leading to toxicity for asthmatic patients in particular.
What is idiosyncratic toxicity?
Toxicity that is unpredictable and mechanism is unknown
Interaction of absorption
A drug may cause increase or decrease in absorption of a second drug from the intestinal lumen
Interaction with protein binding
Drugs can be highly protein bound in the plasma binding sites can become saturated in physiological states that lead to hypoalbuminemia
Interaction of metabolism
Drug can influence the metabolism of another drug
Ex: Ethanol and acetaminophen
How does alcohol affect acetaminophen metabolism?
A small amount of acetaminophen is metabolized by CYP2E1 to N-acteyl-p-benzoquinoneimine (NAPQI) which is toxic.
Some ethanol is metabolized by CYP2E1 as well which can induce CYP2E1 expression that can cause NAPQI to reach toxic levels if acetaminophen is taken with alcohol.
Interaction of receptor binding
Antagonists can be used to block the effects of receptor drugs
Interaction of therapeutic action
Drugs with overlapping effects can lead to toxicity
Ex: Aspirin and heparin
Additive
Combined effect of two drugs equals sum of effect of each drug given alone
Synergistic
Combined effect exceeds the sum of effects of each drug given alone
Potentiation
Creation of a toxic effect from one drug due to presence of another drug
Antagonism
Interference of one drug with the action of another
Function or physiological antagonism
Two drugs have opposite effect on the same physiological function
Chemical antagonism
Chemical reaction between two drugs to neutralize their effects – chelation therapy
Dispositional antagonism
Alter absorption/distribution/excretion (i.e. disposition) so that less drug gets to site of action
Ex: Protein binding of the drug
Receptor antagonism
Block drug binding to receptor with another drug
What is Type I Hypersensitivity?
Allergic reactions mediated by IgE
What is Type II Hypersensitivity?
Ab directed against tissue Ag mediated by IgG
What is Type III Hypersensitivity?
Immune complex mediated disease caused by Ag-IgG complexes
What is Type IV Hypersensitivity?
Delayed hypersensitivity mediated by T cells
Red Man Syndrome
Drugs acting directly on mast cells, causing cell to degranulate and is like Type I but NOT mediated by IgE.
Stevens-Johnson Syndrome
Most severe type of skin rash; can be life-threatening
Indirect Immunotoxicity
Non-selective cancer drugs target or kill proliferating neoplastic cells also damage the cells in the bone marrow, lymphoid tissues, intestines and hair follicles at therapeutic doses
Direct Immunotoxicity
Immune system can be targeted directly to dampen immune system such as with the use of corticosteroids
What is an example of drugs causing liver drug toxicity?
Acetaminophen overdose will lead to NAPQI accumulation
What is an example of drugs causing renal toxicity?
NSAID
What is an example of drugs causing neurotoxicity?
Anti-cancer drugs
What is an example of drugs causing skeletal muscle toxicity?
Statins
