PHA 6575 Lecture 21 (Drug Toxicity)

Toxicology

the study of mechanisms by which drugs and chemicals in the environment produce unwanted effects

Damage

drug toxicity refers to the level of _________ that an agent can cause to an organism

Cell Death/Tissue Injury, Altered Phenotype/Function, Immunological Hypersensitivity, and Carcinogenesis

list the four categories of drug toxicities based on the pathological effects

Dose Amount

primary cause of drug toxicity

Dose Frequency

how often exposure occurs

Dose Duration

over how long a total period of time dose exposure occurs

Natural Subject Variability

individual characteristics such as age, sex, body weight, ethnic background, and genetics

Health Status Subject Variability

whether any pre-existing health conditions such as asthma, diabetes, or hypertension may affect susceptibility to an agent

Route of Exposure

the way which the person is exposed

Ingestion, Inhalation, and Skin Contact

three most common routes of exposure

Administered Dose

the dose to which a living organism is exposed

Bioavailability

the fraction or proportion of the administered dose systemically absorbed intact

Biologically Effective Dose

amount of drug that reaches the site of action is _________________ (administered dose/internal dose/biologically effective dose).

Internal Dose

amount of drug that reaches the general circulation is _________________ (administered dose/internal dose/biologically effective dose)

AUC (Area Under the Curve) and Css (Steady State Concentration)

drug exposure can be described by _________ and ____________

Dose and Dosing Rate

drug exposure is directly related to _________ and __________

Acute

exposure is less than 24 hours

Subacute

exposure is 1 month or less

Subchronic

exposure is 1-3 months

Chronic

exposure is greater than 3 months

Type A (Augmented) Toxicity

related to the pharmacological action of the drug and consists of 85%; predictable

Type B (Bizarre) Toxicity

not directly related to pharmacological action of the drug; uncommon, unpredictable

Type A

on-target toxicity, off-target toxicity, and bioactivation/covalent modifications are examples of _________ toxicity

Type B

immune hypersensitivity and idiosyncratic responses are examples of _______ toxicity

On-Target Toxicity

toxic effect due to the drug interacting with the INTENDED target

Off-Target Toxicity

toxic effect due to the drug interacting with an UNINTENDED target

True

T/F: in on-target toxicity, the drug-receptor binding produces both the efficacious and toxic effects

Hypersensitivity

drugs react with proteins in the body to induce antibodies and immune responses

Bioactivation

drugs are converted to reactive products/metabolites

Idiosyncratic Reactions

unusual responses to a drug

Inhibition of Mevalonate Pathway in Skeletal Muscle Membrane

the main mechanism of statin-related muscular adverse effect involves the ____________________ (induction of CYP enzyme activities in the liver/inhibition of the mevalonate pathway in skeletal muscle membrane/damaging of hepatocytes)

CYP3A4

the risk of stain-induced myopathy may increase in the presence of a ____________ inhibitor

3 multiple choice options

Liver

target site of action for statins

Skeletal Muscle

which muscle is most sensitive to statins-induced inhibition of cholesterol synthesis

2 multiple choice options

Cholesterol

skeletal muscles are more susceptible to statin-induced myopathy because they rely on _______ for proper function

Rhabdomyolysis

the breakdown of muscle cells that leads to the release of muscle fiber contents into the blood, and subsequently causing kidney damage

True

T/F: rhabdomyolysis is an example of on-target toxicity

Rofecoxib (Vioxx)

selective cyclooxygenase (COX2) inhibitor that inhibits inflammation and pain by mediating the production of prostaglandins

Thromboxane/Prostacyclin Balance

the inhibition of COX-2 by rofecoxib results in a ___________ issue and is thought to cause cardiotoxicity

Potassium Channels

terfenadine induces ventricular arrhythmias due to its inhibitory effect on _________________

3 multiple choice options

IgE

type 1 immune reactions are medicated by ________

3 multiple choice options

Haptens

in type 1 reactions, __________ bind to carrier molecules to elicit an immune response

Red Blood Cells

in a type 2 reaction, an antigen binds to _________ and causes antibody-mediate hypersensitivity medicated by IgG or IgM

Soluble Toxin

in a type 3 reaction, antibodies bind to a _________ acting as an antigen and cause immune complex reactions mediated by IgG or IgM

Lymph Node

in a type 4 reaction, sensitized APCs travel to a ________ before eliciting an immune response involving T cell activation and release of inflammatory cytokines

4

allopurinol induced toxic epidermal necrolysis following allergic contact dermatitis is a type ______ immune reaction

3 multiple choice options

Antigen-Presenting Cells (APCs)

mechanism of allopurinol induced toxic epidermal necrolysis involves the sensitization of ____________________ by hapten-protein complex

3 multiple choice options