Lecture 20_Toxicology I

Question 1

Toxicology

Answer 1

The study of the adverse effects of chemical agents on biological systems.

Question 2

What are the fields of toxicology? Give examples of each.

Answer 2

• Environmental: Pollution, residues
• Economic: Food additives, pesticides
• Legal: Forensic, regulatory
• Laboratory: Analytical
• Biomedical: Human (clinical), occupational, veterinary.

Question 3

Toxic agents themselves may be classified according to:

Answer 3

• 1.) The potential for a compound to produce toxicity
• 2.) The source of the toxin (eg. snake or spider venom)
• 3.) Chemistry of toxins
• 4.) Mechanism of action

Question 4

(T/F) The concentration response curves for the effective, toxic, and lethal doses of a drug are independent of one another.

Answer 4

TRUE.

Question 5

There are three assumptions about concentration response curves to be made.

Answer 5

• 1.) Observed response actually due to compound administered
• 2.) Degree of response related to magnitude of dose
• 3.) Response is quantifiable

Question 6

Threshold dose

Answer 6

The lowest dose that evokes a given response. For example, different doses of ASA produce g.i. bleeding, tinnitus and generalized acidosis.

Question 7

Examples of toxicities developing rapidly and reversibly, and slowly and irreversibly.

Answer 7

• Rapid and reversible: Inebriation due to methanol.

- Slow and irreversible: Methanol producing retinal nerve toxicity, leading to blindness.

Question 8

LD50 (dose required to kill 50% of exposed test animals) depends on…

Answer 8

…species, strain, sex, age, and route of drug administration.

Question 9

(T/F) Some chemicals may produce minimal acute toxicity but can have long-lasting effects (eg. carcinogens and teratogens).

Answer 9

TRUE.

Question 10

Mechanisms of toxicity

Answer 10

• 1. Receptor-mediated toxicities: Reversible binding of parent molecule and/or a stable intermediate to a receptor site.
• 2. Reactive intermediate toxicities: Bioactivation of a relatively nontoxic chemical to a highly toxic intermediate that binds to or oxidizes cellular macromolecules such as DNA, protein or lipid. This process has covalent binding and is irreversible. The parent molecule is metabolized to an intermediary that is active and toxic.

Question 11

If given at a sufficiently high concentration…

Answer 11

…most drugs can initiate reversible toxicities, primarily of the sort that stem from the predictable exaggeration of the pharmacological effect for which the drug is being employed. eg. Severe hypotension arising from an overdose of an antihypertensive.

Question 12

Most carcinogens, teratogens, and chemicals producing neurodegenerative disorders, tissue necrosis or immune system-mediated hypersensitivity reactions are thought to act…

Answer 12

…after the bioactivation of a parent drug to a reactive intermediate. The target tissue is determined by the site of bioactivation eg. liver and kidney for acetaminophen, and lung for paraquat.

Question 13

How can drug toxicity be modified?

Answer 13

• 1.) Decrease in functioning of pathways of drug elimination (primarily liver and kidney), resulting in excessive accumulation, eg. aminoglycoside antibiotics are primarily excreted unchanged by kidney.
• 2.) Enhanced pathways of bioactivation to toxic reactive intermediates.
• 3.) Reduced detoxifying or cytoprotective pathways for removing reactive intermediates.
• 4.) Decreased numbers of binding sites on plasma binding proteins (eg. the anticoagulant warfarin is 90% bound to albumin).
• 5.) Reduced pathways for repair of cellular macromolecules damaged by reactive intermediates.
  These are basically DNA repair enzymes: If errors are not caught when cell division occurs damage will replicate into future generations.

Question 14

What factors are important for drug toxicity?

Answer 14

• 1. Age
• 2. Route or site of drug administration
• 3. Duration or frequency of exposure
• 4. Nutrition
• 5. Genetic variability
• 6. Disease

Question 15

1. Age

Answer 15

Toxicity of compounds may vary with subject age because of age-dependent differences in relative organ size, maturity of enzyme systems and toxin distribution. Eg. malathion toxicity depends inversely on hepatic cyt. P450 activity. Newborns metabolic pathway not developed to deal with problem, making malathion more toxic to newborns. Adults have higher levels of beta adrenergic receptors (where DDT acts) making DDT more toxic to adults.

• Young children are less susceptible to toxicity produced by acetaminophen, digoxin and theothylline, but are more sensitive to toxicity produced by antihistamines, lead and salicylates than are adults. The very young and elderly tend to have reduced renal function which makes them more susceptible to compounds that are excreted by kidneys.

Question 16

2. Route or site of drug administration

Answer 16

Study table. Summary: intraperitoneal would need 5 times the dose compared to intravenous to reach toxic levels.

Question 17

3. Duration or frequency of exposure

Answer 17

• 1. Acute exposure (3 months)

Different exposure to the same compound can lead to different toxicities. Eg., acute exposure to benzene leads to CNS depression, while chronic exposure is associated with haematological malignancy.

Question 18

4. Nutrition

Answer 18

• Presence of food in stomach can decrease the absorption of some drugs (B-blockers and diazepam) but is beneficial for others (minimize aspirin-induced damage).
• Malnutrition can also reduce drug absorption
• Liver metabolism of drugs is also affected by nutritional state.

Question 19

5. Genetic variability

Answer 19

• A common cause of predisposition to toxicity is a genetic difference in one or more critical pathways involved in the actions of the drug.
• In the case of receptor-mediated toxicities, low or absent levels of critical enzymes such as the cytochromes P450 and N-acetyltransferases, result in drug accumulation, and lead to toxic levels.
• In the case of toxicities produced by reactive intermediates, a predisposition to toxicity may arise from genetically high activity and/or inducibility of bioactivating enzymes (eg. P450) or decreased levels of enzymes that metabolize intermediates. Egs. (1) Phenytoin metabolism by epoxide hydrolase, if impaired, can lead to liver necrosis; (2) deficiency in enzyme that produces GSH leads to increased levels of highly reactive free radical intermediates.

Question 20

6. Disease

Answer 20

• Coexisting diseases often alter susceptibility to the toxic effects of drugs, as well as compounds encountered in the environment.
• The effects of some of these diseases (eg. hepatic and renal diseases) are easily predicted.
• However, the effects of other diseases (eg. cardiovascular) may be less easy to predict. Eg., Lidocaine metabolism occurs primarily in the liver, and decreased cardiac output would affect its hepatic clearance. Diseases which affect the numbers of plasma binding proteins will affect toxicities of highly protein-bound drugs. G.I. diseases will affect the toxicities of drugs that are metabolized extensively in intestinal walls during absorption.