Adverse Effects

Question 1

1. What is an adverse drug reaction (ADR)?

Answer 1

A noxious and unintended effect of a drug, occurring at doses used for prophylaxis, diagnosis or therapy. Everything is toxic at a certain concentration, this does not include overdoses. It is generally predictable, so as long as you know the mechanism of action you can figure out what drug is providing the side effect.

Question 2

2. What are the different adverse drug reaction classifications?

Answer 2

1. Type A = explainable
2. Type B = unexplainable
3. Type C = chronic effects
4. Type D = delayed effects

Question 3

3. What is a type A adverse drug reaction?

Answer 3

This composes about 80% of all adverse drug reactions. It is an exaggerated, but otherwise expected (due to mechanism of drug) pharmacological effect of a drug.
PREDICTABLE and DOSE DEPENDENT

Question 4

4. What are examples of type A ADRs?

Answer 4

1. Toxicity of overdose – hepatic failure due to high dose acetaminophen
2. Side effects – sedation with antihistamines
3. Secondary effects – development of diarrhea with antibiotic therapy ← we give this to kill organisms, but we kill off organisms that our body needs
4. Drug interactions – theophylline toxicity in the presence of erythromycin therapy ← consumption of more than one drug

Question 5

5. What is a type B adverse drug reaction?

Answer 5

This is an UNPREDICTABLE and DOSE INDEPENDENT reaction aka idiosyncratic. You do not know who and at what dose a drug will cause an ADR.

Question 6

6. What are examples of Type B ADRs?

Answer 6

1. Intolerance – tinnitus with Aspirin use
2. Hypersensitivity – anaphylaxis with PCN administration ← allergic reaction that you cannot predict unless the person has a skin test
3. Pseudoallergic – radio contrast dye reaction (1st exposure rxn)
4. Idiosyncratic – development of anemia with use of oxidant drugs in presence of G6PD deficiency (acquired enzyme abnormalities)

Question 7

7. What is a type C ADR?

Answer 7

This is a drug reaction associated with long-term therapy. It is predictable with continued use.

Question 8

8. What are examples of Type C ADRs?

Answer 8

1. Benzodiazepine dependence – pt will become dependent on the drug and if taken off WILL go through withdrawal
2. Tardive dyskinesia with metoclopramide

Question 9

9. What is a type D ADR?

Answer 9

This is a carcinogenic or teratogenic side effect. No drug company develops a drug with these unfortunate side effects. They are generally unpredictable and unavoidable and are seen with drugs treating rare disorders that cannot be treated with anything else.

Question 10

10. What are the different mechanisms of drug toxicity?

Answer 10

1. “on target” adverse effects
2. “off target” adverse effects
3. production of toxic metabolites
4. production of harmful immune response
5. idiosyncratic response

Question 11

11. What is an “on target” adverse effect?

Answer 11

An exaggerated pharmacologic action due to increased drug at the cell receptor. This can be deliberate or accidental with dosing errors. Alterations in the pharmacokinetics of the drug can effect it for example liver and kidney failure may not clear the drug as it should keeping it around more. Alterations in the pharmacodynamics can also change with the drug-receptor interaction. An example of this change in pharmacodynamics is regarding beta-blockers. A pt on beta-blockers actually has an increased production of beta-blockers, but there is usually no effect b/c they are blocked. It is once the pt gets off the beta-blockers where there are increased numbers of receptors leading to possible cardiac issues. This is why pts need to be tapered off beta-blockers. Receptors are also not normally super specific to the a cell therefore you can get activation of the intended receptor but in a non-target tissue from drug or metabolite.

Question 12

12. What are examples of “on target” AD effects?

Answer 12

1. insulin → hypoglycemic coma
2. Anticoagulants (ex. heparin) → intracerebral bleeding
3. Anxiolytics (ex. diazepam) → sedation
4. Ex. of activation of receptor on non-target tissue → antihistamine diphenhydramine hypochloride is a H1 receptor antagonist used to treat allergic reactions. Diphenhydramine also crosses BBB to antagonize the receptors in the CNS leading to somnolence.

Question 13

13. What is an “off target” effect?

Answer 13

This is activation of an incorrect receptor in target and/or non-target tissue. It is hard to create a drug specific for a single receptor. This binding to incorrect receptors on target or non-target tissues can lead to unintended effects. Other causes may be due to entantiomers (mirror image isomers) of a drug that change effects due to differences in isomer form, and unintended activation of different receptor subtypes (B1 vs B2).

Question 14

14. What are examples of “off target” effects?

Answer 14

1. Terfenadine (antihistamine) → an effective antihistamine that also inhibits a cardiac potassium channel (hERG) leading to fatal cardiac arrhythmia causing it to be withdrawn from the market
2. Thalidomide → [R] enantiomer is an effective sedative, [S] enantiomer is a potent teratogen

Question 15

15. What are ADR caused by production of toxic metabolites?

Answer 15

This is when a drug metabolite can have an adverse effect. An example is Acetaminophen where at therapeutic dose a majority (95%) is metabolized to glucuronidation and sulfation but (5%) is oxidized by CYP450 to NAPQI. A therapeutic dose of NAPQI is conjugated to glutathione but at a non-therapeutic/toxic dose there is an NAPQI accumulation due to glutathione depletion leading to cell death.

Question 16

16. How does a harmful immune response cause ADR?

Answer 16

Drugs are xenobiotics that can be recognized by the immune system as foreign substances. This can be due to hypersensitivity (PCN, latex, poison ivy) or autoimmune reactions (methyldopa causing hemolytic anemia by eliciting autoimmune rxn against Rh antigens.

Question 17

17. What is an ADR due to idiosyncratic toxicity?

Answer 17

This is essentially a type B ADRs where there is no obvious mechanism leading to the effect but a rare adverse side effect will happen. This reaction does not normally occur on the first exposure. It is though to reflect unique individual genetic difference in the response to the drug molecules.

Question 18

18. What is a pharmacokinetic drug-drug interaction?

Answer 18

Some drugs can change the absorption, distribution, metabolism or excretion of another drug thus altering the concentration of the active drug. This is completed by inhibition or induction of cytochrome P450 enzymes or altering transporters thus affecting the transport of drugs into and out of tissues.

Question 19

19. What are classical examples of inhibitors of cytochrome P450?

Answer 19

1. cimetidine
2. ciprofloxacin
3. ketoconazole
4. clarithromycin
5. quinidine
6. grapefruit juice (ex. inhibits CYP3A4 preventing midazolam metabolism and increasing plasma concentration)
   * increased drug concentration due to decreased metabolism

Question 20

20. What are classical examples of induces of cytochrome P450?

Answer 20

1. rifampin
2. phenobarbital
3. dexamethasone
4. carbamazepine
5. tobacco
   * *decreased drug concentration due to increased metabolism

Question 21

21. What is a pharmacodynamics drug-drug interaction?

Answer 21

A pharmacodynamics interaction occurs when one drug changes the response of target or non-target tissues to another drug or when two drugs activate complementary pathways leading to exaggerated biological responses.

Question 22

22. What is the effect of co-administration of Sildenafil and nitroglycerin?

Answer 22

Sildenafil = erectile dysfunction
Nitroglycerin = angina
Sildenafil inhibits phosphodiesterase-5 prolonging action of cGMP. Nitroglycerin stimulates guanylate cyclase increasing cGMP. Coadministration of both Sildenafil and Nitroglycerin causes a large increase in cGMP leading to severe hypotension.

Question 23

23. What is the effect of co-administration of Warfarin and heparin?

Answer 23

Warfarin = antithrombotic
Heparin = antithrombotic
Coadministration of warfarin and heparin can result in supratherapeutic levels of anticoagulation resulting in a high rate of bleeding.

Question 24

24. What is a drug-herb interaction?

Answer 24

The safety and efficacy of a drug may be altered by non-pharmaceuticals (food, drink, herbal, dietary supplements). Ex. Ginkgo biloba inhibits platelet aggregation and used simultaneously with NSAIDs which also inhibits platelet aggregation increases the risk of bleeding. Another example is St. John’s wort when used in combination with SSRIs lead to mild serotonergic syndrome.

Question 25

25. What is the difference b/t acute and chronic toxicity?

Answer 25

Acute → occurs after a single dose, hours → days after admin, or immediately
Chronic → long term treatment leading to tardive dyskinesia, Hormone replacement therapy leading to endometrial cancer

Question 26

26. What is cellular toxicity?

Answer 26

1. apoptosis → cell undergoes ordered cell-destruction to eliminate damaged cells, minimal inflammation
2. necrosis → toxic insult that may be significant enough to not kill the cell but rather make it undergo necrosis, cells attract inflammatory cells and damage nearby healthy cells
3. Fibrosis → cellular injury leads to excessive deposition of collagen and extracellular matrix proteins (ex. pulmonary fibrosis can be caused by amiodarone or bleomycin)
4. Carcinogenesis → normal cells transform to neoplastic cells (ex. cytotoxic alkylating agents don’t kill cancer cells but damage normal blood cell progenitors leading to AML)
5. Teratogenesis → induction of defects in the fetus esp during 3rd-8th week of gestation (ex. vit A activates receptors regulating transcriptional events during development)

Question 27

27. What are the different FDA classifications of drugs for use in pregnancy?

Answer 27

A, B, C, D, X

Question 28

28. What is category A of the FDA classifications of drugs for use in pregnancy?

Answer 28

Adequate, well-controlled studies have been completed and there is no risk of fetal abnormalities (ex. folic acid)

Question 29

29. What is category B of the FDA classifications of drugs for use in pregnancy?

Answer 29

Animal studies reveal no evidence to harm fetus, but there are no well controlled studies in pregnant women. OR animal studies have shown an adverse effect but well-controlled studies in pregnant women have failed to demonstrate the risk to the fetus.

Question 30

30. What is category C of that FDA classifications of drugs for use in pregnancy?

Answer 30

Animal studies have shown an adverse effect and there are no adequate or well-controlled studies in pregnant women. OR no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.

Question 31

31. What is category D of the FDA classifications of drugs for use in pregnancy?

Answer 31

Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk (ex. antibiotics for meningitis).

Question 32

32. What is category X of the FDA classifications of drugs for use in pregnancy?

Answer 32

Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become pregnant.