Drug Toxicities

Pharmacology

scientific discipline that studies the mechanisms by which drugs alter biological systems in an attempt to improve health and alleviate disease

Toxicology

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

Drug toxicity

level of damage that a therapeutic agent can cause to an organism

Drug toxicity categories

1. cell death/tissue injury

2. altered phenotype/function

3. immunological hypersensitivity

4. carcinogenesis

Sources of drug toxicity

• drug overdose

• drug-drug interactions

• adverse effects at therapeutic doses

• idiosyncratic reactions

Determinants of Drug Toxicity

• Dose amount (primary cause)

• dose frequency

• dose duration

• subject variability (natural and health status)

• route of exposure

Dose Amount

• measure of magnitude of dose

• measured quantity of therapeutic agent that comes into contact with a living organism or some part of a living organism

• primary cause of drug toxicity

Administered dose

dose to which a living organism is exposed

Internal dose

amount of drug that reaches systemic circulation

Biologically effective dose

amount of drug that reaches the site of action

Dose Frequency

how often exposure occurs

dose duration

total period of time of dose exposure

subject variability

• natural: individual characteristics

  • age

  • sex

  • body weight

  • ethnic background

  • genetics

• health: pre-existing conditions

  • asthma

  • diabetes

  • hypertension

Route of exposure

• way person is exposured

• most common: ingestion, inhalation, skin contact

How can drug exposure be described?

• drug levels achieved in body after drug administration

• area under the drug concentration-time curve (AUC) or drug concentration at steady state (Css)

• directly related to dose and dosing rate

Acute exposure

exposed <24 hours

Subacute exposure

< 1 month

Subchronic exposure

1-3 months

Chronic exposure 1

>3 months

Classification of drug toxicity

• Type A (augmented): related to the pharmacological action of the drug

  • common, predictable

• Type B (bizarre): not directly related to pharmacological action of the drug

  • uncommon, unpredictable

• unacceptable drug toxicities are repsonse for the high attrition of drug candidates and high cost of drug dev

Mechanisms of drug toxicity

• on-target toxicity (A)

• off-target toxicity (A)

• immune hypersensitivity (B)

• bioactivation/covalent modification (A)

• idiosyncratic responses (B)

On-target toxicity

• due to interaction of drug with same target that produces desired pharmacological response

• not inhibition or induction but rather drug-receptor binding produces both efficacious and toxic effects

Off-target toxicity

• binding to an alternate target due to complexity of biological regulatory pathways and multi-gene families

Hypersensitivity and immune responses

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

Bioactivation

• drugs converted to reactive products/metabolites

Stain-Induced Myopathy

• on-target toxicity

• statins share HMG-like moeity that binds to HMG-CoA reductase and inhibit the mevalonate pathway that mediates biosynthesis of cholesterol from acetyl CoA

• liver is target site of action for statins

• inhibition of CYP3A4 and/or CYP2C9 in intestine and liver results in increased oral bioavailability and decreased metabolism of statins

• increased statin exposure leads to increased statin distribution in other tissues other than the liver (skeletal muscle)

• skeletal muscle is more sensitive to statin than myocardium and smooth muscle

• skeletal muscle relies more on cholesterol for function bc transverse tubules of skeletal muscle cells have high cholesterol levels

• inhibition of cholesterol synthesis in skeletal muscle leads to damage to integrity and function of cell membrane

• Rhabdomyolysis: breakdown of muscle cells that leads to the release of muscle fiber contents into the blood, subsequently kidney damage

• reversed when med discontinued

Rofecoxib-induced cardiotoxicity

• on-target toxicity

• increases risk of cardiovascular prothrombotic events

• selective COX-2 inhibitor

  • COX-2 mediates prostaglandin production responsible for inflammation and pain

• cardiotoxicity may be associated with the inhibition of prostacyclin synthesis that results in a shift of the thromboxane/prostacyclin balance

  • production of thromboxane A2 involves COX1

• thromboxane A2: platelet aggregation and vasoconstriction

  • produced by COX1

• Prostacyclin: inhibits platelet aggregation and vasodilation

  • produced by COX2

Terfenadine-induced cardiotoxiciy

• off-target toxicity

• cause prolongation of QT interval, leading to ventricular arrhythmia

• Terfenadine is peripherally selective antagonist of histamine H1 receptor

• also acts as potassium channel blocker

  • K channels encoded by human ether-a-go-go-related gene (hERG)

  • unintended inhibition may lead to fatal cardiac arrhythmias

Hypersensitivity Reactions

• type B toxicity

• often unpredictable and dose independent

• usually mediated by immune system

• Type I hypersensitivity reactions:

  • IgE-mediated immediate hypersensitivity

  • Haptens bind to carrier molecules to elicit immune response

  • ex. Penicillin induced anaphylaxis: penicillin acts as haptens

• Type II: antibody-mediated cytotoxic

  • IgG or IgM mediated

  • antigen binds to red blood cells

  • penicillins, cephalosporins, hydrochlorothiazide, methyldopa

  • lead to anemia and thrombocytopenia

• Type III: immune complex reactions

  • IgG or IgM mediated

  • when antibodies bind to soluble toxin acting as antigen

  • treatment with penicillin leads to nephritis

• Type IV: T-cell mediated, delayed

  • hapten binds to protein

  • hapten-protein complex phagocytosed by antigen-presenting cells

  • sensitized APCs travel to a regional lymph node and present the antigen to T cells and activate the T cells

  • migrate to region and release inflammatory cytokines

  • ex. allopurinol-induced toxic epidermal necrolysis