1.2 Principles of Drug Toxicity

Question 1

What is the therapeutic index?

Answer 1

toxic dose / effective dose

• in licensed drugs, the toxic dose will always be higher than the therapeutic dose (TI will never be a decimal)
• the larger the difference between the two, the greater the therapeutic index will be
• as therapeutic index approaches 1, the drug becomes less and less safe

for both the toxic and therapeutic doses, the value is the dose at which 50% of animals see toxic/therapeutic effect

Question 2

What are some possible ways drug toxicity can be seen in the clinic?

Answer 2

• using drugs off lable increases the chances
• animals are not clones of the original animals in testing (these are typically healthy animals)
• mistakes in calculating doses, storing, and handling the drugs
• drug interactions

Question 3

What is the definition of adverse drug reactions?

Answer 3

unwanted effects that occur when drugs are administered for therapeutic purposes

• could broaden to encompass: a lack of efficacy in a patient where you would have expected the drug to work (e.g., resistance)

Question 4

What are the classifications of ADR?

Answer 4

• type A reactions: predictable from mechanism of action
• type B reactions: not related to mechanism of action (note: some occur so commonly that they could be predictable)

most type B reactions occur from prolonged use; however some type B reactions are truly unpredicatable (idiosyncratic)

Question 5

What factors enhance ADR?

Answer 5

• signalment (physiological factors): age, breed, gender
• disease status: hepatic, renal and cardiovascular
• concominant use of other drugs

Question 6

What are the risks of drug use in neonates vs drug use in geriatrics?

Answer 6

(1) neonate:

• decreased gut motility (drug more readily absorbed)
• increased total body water (drug concentration @ dose may be lower if water soluble)
• immature liver enzymes (drug may be cleared from plasma slower)
• decreased GFR (reduced renal excretion)

(2) geriatric: overall increased risk of ADR due to

• decreased muscle mass
• poor nutritional status
• multiple disease status
• altered compliance
• age-related changes to organ function (e.g., decreased renal excretion)

Question 7

What are the three breed specific ADRs mentioned in lecture?

Answer 7

1. monensin toxicity in horses: low first-pass metabolism c.f. ruminants
2. pyrethrum insecticide trearment of cats: inefective-metabolism
3. collies and collie-type dogs treated with ivermectin: MDR-1 deletion