Module 10: Adverse Drug Reactions and Medication Errors Flashcards
What is an adverse drug reaction?
Adverse drug reactions (ADRs) are the unintended and undesired responses from drugs
- Adverse drug reactions are an enormous societal health problem
Adverse drug reactions can include (7):
- Side effects
- Drug toxicity
- Allergic Reaction
- Idiosyncratic Reaction
- Carcinogenic Effects
- Mutagenic Effects
- Teratogenic Effects
Adverse Drug Reactions
Side effects:
- Definition
- When do they occur?
- What are they often due to?
- Examples
Side effects are secondary to the main therapeutic effect of the drug and are expected.
- Side effects occur at normal therapeutic doses and are often unavoidable.
- Side effects are often due to poor specificity or selectivity of the drug.
Example: Anti-histamines
- Antihistamines act by blocking H1 histamine receptors to prevent the symptoms of allergy (i.e. runny nose, watery eyes)
- Side effects include drowsiness, dry mouth and urinary retention
- Histamine binding to the histamine receptor in sinuses causes vasodilation which results in runny nose and watery eyes
- Antihistamines act by blocking the effect of histamine
- Side effects occur when antihistamines bind to either histamine receptors or other receptors in the brain
- This produces sedation, dry mouth and urinary retention
- These are side effects of antihistamines
Adverse Drug Reactions
Drug Toxicity:
- Defined as?
- Mediated by?
Drug toxicity can be considered as any severe adverse drug event.
- Drug toxicity is often mediated by overdose where patients unintentionally or intentionally take too much medication.
These types of reactions are often extensions of the therapeutic effect.
- For example, a patient who takes too much insulin will experience hypoglycemia (low blood glucose).
Adverse Drug Reactions
Allergic Reaction:
- Mediated by?
- Requires?
- When does it occur?
- What occurs during?
- Intensity?
Allergic reactions are mediated by the immune system.
- Allergy requires a prior sensitization where a patient is exposed to the allergen (i.e. drug)
- Upon subsequent exposure to the drug an allergic reaction will occur.
- During allergic reactions, mast cells release chemical mediators such as histamine
- The intensity of allergic reactions are independent of dosage size - Therefore small doses can produce severe allergy.
How many drugs cause allergic reactions?
- Most common?
~ 10% of all ADRs are related to drug allergy.
- Very few drugs cause allergic reactions
The most common drug class to cause drug allergy are the penicillins
Sulfonamides (an antibiotic) and nonsteroidal anti-inflammatory drugs (NSAID) are also known to cause drug allergy.
Adverse Drug Reactions
Idiosyncratic Reaction:
- What is it?
- What causes it?
- Future?
These are reactions that occur rarely and unpredictably in the population.
Recent evidence suggests that genetic polymorphisms account for the majority of idiosyncratic reactions.
- The majority of polymorphisms causing idiosyncratic reactions occur in drug metabolizing enzymes and drug transport proteins.
It is hoped that one day, routine blood test will be able to determine people at risk for idiosyncratic reactions due to genetic polymorphisms
- This already occurs in some centres for the drugs warfarin and 6-mercaptopurine which are metabolized by CYP2C9 and thiopurine methyltransferase (TPMT) respectively.
List examples of genetic polymorphisms that cause idiosyncratic reactions:
A. CYP2C9 – Approximately 15% of Caucasians have a polymorphism that decreases metabolism.
B. CYP2D6 – 10% of Caucasian and African Americans are poor metabolizers. These patients do not experience pain relief when they take codeine. Codeine is a prodrug that is metabolized by CYP2D6 to morphine.
C. Thiopurine methyltransferase (TPMT) – Approximately 10% of patients have decreased activity and 0.3% have no activity. Treatment with thiopurine drugs in patients with low or absent TPMT can result in life threatening bone marrow suppression.
D. OATP1B1 – An uptake drug transporter in the liver. 15% of Asian and Caucasian patients have a polymorphism that decreases function. This leads to an increase in plasma drug concentrations. This polymorphism has been implicated in causing myopathy (muscle toxicity) in patients taking statin drugs.
E. Glucose 6-Phosphate dehydrogenase deficiency (G6PDH) – An enzyme important in red blood cell metabolism. Deficiency is common in people of African and Middle Eastern descent. Patients with deficiency may have red blood cell hemolysis following treatment with certain analgesics (i.e. Aspirin) or anti-malarial drugs.
Adverse Drug Reactions
Carcinogenic Effects:
- Defintion
- How to determine if a drug is carcinogenic?
- Example
Carcinogenic means the ability of a drug to cause cancer - relatively few drugs are carcinogenic.
- Determining whether a drug is carcinogenic is difficult because it normally takes years after the initial dose to appear.
- The drug diethylstilbestrol (DES) used to be prescribed to prevent spontaneous abortion in high risk pregnancies; Years later it was determined that the female offspring developed vaginal or uterine cancer.
Adverse Drug Reactions
Mutagenic Effects:
- Definition
- It is also… (2)
- How are these approved?
- How are they tested?
If a drug is mutagenic it is able to change DNA.
- Often when a drug is mutagenic it is also carcinogenic or teratogenic.
- Sometimes drugs that are mutagenic are not carcinogenic or teratogenic; These drugs may receive approval for use from regulatory agencies if there is sufficient evidence of safety from preclinical studies.
- Drugs are tested for their potential as mutagens by the Ames test; The Ames test evaluates the ability of the test compound (i.e. a drug) to cause a mutation in specialized strains of bacteria.
Adverse Drug Reactions
Teratogenic Effects:
- What are they?
- What do birth defects include? (3)
- Sensitivity occurs when?
- When do malformations occur?
- What occurs with exposure in 2/3 trimester?
- When is placental drug transfer the greatest?
Compounds that are teratogens are known to produce birth defects or impair fertility.
- Typically we think of birth defects as major physical malformations, but birth defects also include behavioural and metabolic defects.
Sensitivity to teratogens changes during development
- Gross malformations typically occur when exposure to a teratogen is in the 1st trimester.
- Teratogen exposure during the second and third trimesters usually disrupts function as opposed to gross anatomy.
- Transfer of drugs across the placenta is thought to be greatest in the third trimester because as the placenta develops, the surface area for transfer between maternal and fetal circulation increases. - In addition, the placental-fetal barrier becomes progressively thinner.
Pregnancy Risk Categories:
- Describe A, B, C, D, X
A:
- Well controlled human studies have failed to show risk to the fetus during the 1st trimester
- No evidence of harm later in pregnancy
B:
- Animal reproduction studies have failed to show harm to the fetus and there are no well controlled studies in pregnant women, OR
- Animal studies have shown an adverse effects but well controlled studies in pregnant women fail to show any harm
C:
- Animal studies have shown harm to the fetus but there are no well-controlled studies in pregnant women
- Potential benefits of the drug outweigh the potential risk
D:
- Clear evidence of risk to the fetus from studies in humans
- Potential benefits of the drug outweigh the potential risk
X:
- Studies in animals and humans clearly demonstrate risk to the fetus
- Risks of using the drug clearly outweigh the benefits
- These drugs should never be used in pregnant women
T/F
Many drugs exhibit toxicity to a specific organ
True
Organ specific toxicity can occur to… (6)+
… the kidney, lung, heart, liver, muscle and inner ear amongst others.
The most common and important organ specific toxicity is observed in the … (2)
… liver and heart.
