Lecture 19_ADRs

Question 1

Why are drugs tested before released to market? What was a major impetus in the study of adverse reactions?

Answer 1

• To determine their efficacies and pharmacological profiles.
• The thalidomide disaster of 1961.

Question 2

Thalidomide Disaster

Answer 2

• 1961, outbreak of children born with deformities of upper portion of limb being absent or poorly developed (phocomelia).
• Birth defects associated with hypnotic thalidomide.
• Use in the first trimester (where forelimb buds developed) caused deformities.
• All of this led to re evaluation of methodology and regulations applied to the testing of the safety of drugs.

Question 3

Preclinical trials

Answer 3

Done in vitro and in vivo on animals. Produce evidence that the drug may have effect in humans, test for toxicity and provide estimate of doses to try in human trials.

Question 4

Clinical trials

Answer 4

• Phase 1: Dose-ranging to determine therapeutic doses (

Question 5

ADE v. ADR

Answer 5

Some patients develop unwanted signs or symptoms during drug therapy (called adverse drug events; ADE). But is this due specifically to the drug therapy? If so, the reaction is called an adverse drug reaction (ADR).

• Adverse Drug Events are due to correlation.
• Adverse Drug Reactions are due to causation.

Question 6

How does one determine causation?

Answer 6

Challenge-dechallenge-rechallenge: Give drug, take away drug, give back drug. See if anything changes.

Question 7

What is considered to be an ADR?

Answer 7

An ADR is any noxious, unintended or undesired effect of a drug that is observed at doses usually administered therapeutically. This does not include cases of drug overdose (accidental or on purpose), drug abuse or therapeutic errors.

Question 8

Levels of severity of ADRs

Answer 8

• 1. Mild: No antidote, therapy, or prolongation of hospital stay is required.
• 2. Moderate: requires a change in drug therapy, although not necessarily discontinuation of the use of the drug. It may prolong hospitalization and require specific treatment.
• 3. Severe: Potentially life-threatening, requires discontinuation of the drug and specific treatment of the ADR.
• 4. Lethal: Directly or indirectly contributes to the death of the patient.

Question 9

The adequate assessment and classification of ADRs require…

Answer 9

…a knowledge of the mechanisms by which they are produced.

Question 10

ADRs are the result of…

Answer 10

…the interplay between the characteristics of the administered drug and some inherent or acquired characteristic of the susceptible patient.

Question 11

Reactions to a drug are due to…

Answer 11

…some physicochemical or pharmacokinetic property of the drug (its formulation or the dosing regimen) in combination with some characteristic of the patient (his genetic makeup or something unusual or pathological about his physiology).

Question 12

Some ADRs are dose-related.

Answer 12

(eg., CNS depression by sedative hypnotics) and are by far the most common occurrences of ADRs (95%). These ADRs, which can be prevented by adjusting the patient’s dose, may be due to impairment of drug elimination by renal disease (for drugs such as digoxin that are predominantly excreted by the kidney) or due to liver dysfunction (for drugs eliminated after biotransformation by the liver). The ADR may be either an extension of the usual pharmacological effects of the drug or an unusual toxicity caused by the drug and/or its metabolites.

Question 13

Other ADRs are not dose-related.

Answer 13

These are less common and are due to an increased susceptibility of the patient. The ADR usually manifests as a qualitative change in the patient’s response to the drug and may be caused by a pharmacogenetic variant or an acquired drug allergy. ADRs resulting from a pharmacogenetic basis are typically detected only after the patient is exposed to the drug.

Question 14

Features of dose-related ADR

Answer 14

• Nature of abnormality is quantitative
• Incidence is high
• Predictable
• Possibly related to liver/kidney dysfunction
• Preventable by adjusting dose
• Treated by adjusting dose
• Mortality rate is low

Question 15

Features of non dose-related ADR

Answer 15

• Nature of abnormality is qualitative
• Incidence is low
• Not predictable
• Not affected by liver/kidney dysfunction
• Preventable by avoiding drug
• Treated by discontinue use of drug
• Mortality rate is usually high

Question 16

Anaphylactic

Answer 16

Immediate hypersensitivity reactions involving interaction of allergen (drug) and IgE antibody on the surface of basophils and mast cells. This causes the release of histamine, kinins and prostaglandins that lead to capillary dilation, contraction of smooth muscle and edema. This reaction may be limited to a weal, but can also result in life-threatening anaphylaxis (shock and bronchoconstriction) or asthma.
Anaphylactic reactions may occur after injection of penicillin or other antimicrobials.
Up to a quarter of asthmatic patients are intolerant of ASA, which may cause severe bronchospasms, by a mechanism unrelated to IgE.

Question 17

Frequencies of ADRs

Answer 17

• ADRs are seen about 10% of hospitalized patients
• 3-5% of all patients are admitted because of an ADR, and 10-20% of those are severe.
• ADR lethality occurs in 0.5-0.9% of those hospitalized for ADRs.
• Most ADRs are caused by cardiac glycosides, diuretics, antimicrobials, anticoagulants, and NSAIDs.
• Patients admitted to hospital for ADRs are typically older.

Question 18

Risk factors associated with ADRs

Answer 18

• Age. Older subjects (>60) are more susceptible to ADRs. They are more likely to bleed during heparin treatment, and are more sensitive to analgesics and more likely to develop digitalis toxicity. Impaired drug elimination and increased receptor drug sensitivity are proposed mechanisms. However, older patients also tend to have more diseases and to receive more drugs than younger patients. Newborns are also more sensitive to some ADRs (eg., chloramphenicol).
• Gender. Women are more likely than men to develop ADRs, especially drug-induced g.i. symptoms and problems with digoxin toxicity.
• Other factors: patients on multi-drug therapy, patients with histories of allergic disorders, previous presentation with an ADR., disease state (especially liver & renal).

Question 19

Sample size required for detecting ADRs, and limitations with this.

Answer 19

Clinical trials are usually short-term studies conducted on perhaps 1,000- 2,000 patients before the drug is marketed. Therefore, only the most common ADRs would be detected.
This approach obviously has its limitations. Eg., clozapine (an antipsychotic) was introduced in Finland in 1975. Within 6 months, 17 cases of serious haematological reactions had occurred, from approximately 3200 users (prevalence of 0.6-0.7%). Clozapine was withdrawn from the market.
Temafloxacin (antibiotic) was withdrawn from the market after only 15 weeks because of ADRs.
These examples illustrate the importance of postmarketing monitoring of new drugs.