Adverse Drug Events and Their Causes

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Questions and Answers

What percentage of American adults take five or more medications?

12%

42%

29% (correct)

55%

Which of the following drugs has the highest reported incidence of adverse drug events among patients over 65 years of age?

Statins

Anticoagulants (correct)

Opioids

Antibiotics

What is the primary cause of drug overdose deaths in the United States as reported in 2020?

Heroin

Benzodiazepines

Opioids (correct)

Alcohol

Which type of toxicity is characterized as predictable due to excessive pharmacological action?

Pharmacodynamic toxicity Signup and view all the answers

What type of adverse effect results from a person's unique genetic makeup or alterations in drug metabolism?

Idiosyncratic adverse effects Signup and view all the answers

Which of the following statements is true regarding drug interactions?

They can lead to unwanted effects when other medications are present. Signup and view all the answers

Which adverse effect is classified as potentially life-threatening?

Adverse effects Signup and view all the answers

In the treatment of diarrhea, what is considered a desirable effect of anti-histamines?

Constipation Signup and view all the answers

What is indicated by a confidence interval (CI) of the test being within 0.8 and 1.25 when determining bioequivalence?

The test drug is bioequivalent to the reference drug. Signup and view all the answers

What issue arises when switching from Drug C to Drug B based on AUC values?

There is a significant dose reduction of the active ingredient. Signup and view all the answers

Which of the following statements about the bioequivalence definition is true?

Bioequivalence is determined by the rate and extent of drug availability. Signup and view all the answers

In a scenario where Drug A has an AUC of 1, Drug B has an AUC of 0.8, and Drug C has an AUC of 1.25, which of the following is a logical conclusion?

Both Drug B and Drug C are considered bioequivalent. Signup and view all the answers

How does a phase III study help in the context of bioequivalence?

It allows for the analysis of adverse effects with a very low incidence rate. Signup and view all the answers

What was the primary reason for the withdrawal of Thalidomide from the market in 1961?

Teratogenic effects observed in humans Signup and view all the answers

Which of the following conditions has Thalidomide been used to treat today?

Hansen’s disease Signup and view all the answers

What significant regulatory change occurred after the Thalidomide tragedy in the 1960s?

Mandatory teratogenicity studies for all drugs Signup and view all the answers

What adverse effects were associated with Diethylstilboestrol (DES) upon its use?

Development of clear cell adenocarcinoma in daughters Signup and view all the answers

What was one of the roles of the Risk Evaluation & Mitigation Strategy (REMS) in relation to Thalidomide?

To monitor and mitigate its prescribed uses Signup and view all the answers

Which of the following was a factor that contributed to the source of adverse drug effects (ADEs)?

Degradation of active pharmaceutical ingredients Signup and view all the answers

What notable characteristic did Thalidomide have compared to other sedatives at its introduction?

It was deemed completely safe based on early tests Signup and view all the answers

What was the position of drug regulation during the 1950s that allowed for toxic drugs to be marketed?

Very little formal regulation with discretion to pharmaceutical companies Signup and view all the answers

What is a probable cause of API-mediated toxicity in patients?

Species-specific effects or metabolites Signup and view all the answers

How does chronic administration of certain medications affect drug metabolism?

It stimulates the production of drug-metabolising enzymes. Signup and view all the answers

What effect does the co-administration of multiple drugs with similar metabolism pathways typically have?

It may lead to apparent inhibition of drug metabolism. Signup and view all the answers

What is required for the effective treatment of paracetamol overdose?

Replenishing glutathione via oral N-acetylcysteine Signup and view all the answers

What characteristic of idiosyncratic toxicity makes it challenging to identify?

It often arises from genetic polymorphisms. Signup and view all the answers

Why was coumarin banned as a foodstuff by the FDA?

It was associated with high levels of hepatotoxicity and considered a carcinogen. Signup and view all the answers

What is a common issue with API degradation over time?

It reduces the dose of API and may produce toxic by-products. Signup and view all the answers

What consequence arises from the presence of contaminants in APIs?

They can lead to adverse drug events, including cancer. Signup and view all the answers

What is the primary reason generic drugs can differ from their branded counterparts after patent expiration?

Batch-specific by-products can occur during manufacturing. Signup and view all the answers

What is an example of a substance that acts as an inhibitor of CYP450 enzymes?

Grapefruit juice Signup and view all the answers

Study Notes

Adverse Drug Events (ADE)

82% of American adults take at least one medication, and 29% take five or more
In 2016, the age-adjusted rate for drug-poisoning deaths for males (26.2 per 100,000) was almost double that of females (13.4)
In 2020, 91,799 drug overdose deaths occurred in the United States (28.3 per 100,000 people)
75% of these involved opioids
ADEs include medication errors, allergic reactions, and overdoses.

Other Causes of ADE

The incidence of ADEs is 4 per 1000
Antibiotics account for 16% of ADEs, with allergies being the most common
Anticoagulants are responsible for 32% of ADEs in patients over 65 years of age
Warfarin, rivaroxaban, and dabigatran are among the top 10 causes of ADEs
Phenytoin (anti-seizure medication) exhibits zero-order kinetics
Opioid analgesia has a higher death rate than heroin
Insulin can also cause ADEs

Types of Toxicity - Mechanisms

Pharmacodynamic toxicity (predictable)
- Excessive pharmacological action
- Alternative pharmacological action (e.g., Aspirin can cause bleeding while having anti-inflammatory effects)
- Overdose toxicity
Pharmacokinetic (unpredictable?)
- Induction/inhibition/competition of P450 enzymes
Idiosyncratic
- Allergic response
- Hyperthermia with general anaesthetics
Withdrawal
- Steroid, beta blocker, anti epileptic, PPI withdrawal

Thalidomide

Marketed as a sedative in 1957 (Germany)
Found to be an effective antiemetic (off-label use for morning sickness)
Withdrawn in 1961 due to teratogenic effects (prevents angiogenesis)
Not tested on pregnant animals (species dependent: mice less sensitive than humans)

Thalidomide Today

Used as an immunomodulator to treat various conditions including:
- Hansen’s disease (Leprosy)
- Cancer
- Graft versus host disease in children
- HIV mouth ulcers & wasting
Prescribed under a Risk Evaluation & Mitigation Strategy (REMS, FDA)

Diethylstilboestrol (DES)

Non-steroidal oestrogen
Approved by the FDA in 1947 to prevent miscarriage, treat oestrogen deficient states, and as a post-coital contraceptive
Banned in chickens in 1959/66
Classified as a teratogen in 1971

DES Teratogenicity

DES Daughters:
- Increased risk of developing clear cell adenocarcinoma (CCA) of the vagina and cervix, breast cancer
- Pregnancy-related problems: miscarriage, stillbirth, ectopic pregnancy, premature labor, preeclampsia
DES Sons and Grandsons:
- Urogenital abnormalities (e.g., hypospadia)
DES Grandchildren:
- Infertility
- Cerebral palsy

Drug Regulation in the 1950s

Very little formal regulation, mostly at the discretion of pharmaceutical companies
No teratogenicity studies required
Thalidomide was not approved by the FDA (not used in the United States)
The thalidomide incident changed the global regulatory environment.

Source of ADEs

Active Pharmaceutical Ingredient (API)
- API-mediated toxicity is due to a species-specific effect or a metabolite, possibly species-specific
- Toxicity may only occur in a small number of patients (pharmacogenetics)
Contaminants
- Due to synthesis or degradation of API
Excipients
- Used to bulk up, stabilise, surface coat, colour, or flavour
Propellants (e.g, CFCs)
- Replaced with HFCs after the Montreal Protocol 1987

Cytochrome P450 (CYP) Enzymes

CYP enzymes metabolise medications
Chronic administration can induce hepatocytes to produce larger amounts of drug-metabolising enzymes
Enzyme induction accelerates drug metabolism, requiring larger doses of the drug or potentially leading to overdose
Apparent inhibition can occur with concurrent administration of two or more drugs that compete for the same metabolising enzymes

Bioequivalence

Generics need to show bioequivalence with approved products in a small number of healthy volunteers
Bioequivalence is usually measured by comparing Cmax and AUC between two products
Defined as a confidence interval (CI) of test within 0.8 and 1.25 of reference
Switching between generics with different AUC could significantly alter the effective dose for a patient, potentially leading to therapeutic failure or adverse effects.

Idiosyncratic Toxicity

Dose-independent
Often due to genetic polymorphisms (e.g., CYP polymorphisms)
Difficult to identify

Coumarin

High level of hepatotoxicity in rats, but low level of toxicity in humans (0.37%)
Banned as a foodstuff by the FDA in 1954 (considered a carcinogen)
Re-analysis of rat data suggests that the hepatic lesion was cholangiofibrosis (bile duct proliferation) and not cholangiocarcinoma

Generics

After a drug’s patent lapses (20 years)
Are generics the same as branded products?
Bioequivalence refers to the absence of a significant difference in the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action

Contaminants

While a very pure form of the API is used, by-products from synthesis might still exist. These can be batch specific or due to manufacturing changes
API can degrade over time influenced by storage conditions (heat, light, humidity) leading to a reduced dose and potentially toxic by-products.

Ranbaxy & Dr Reddy

Ranbaxy: Indian generic pharmaceutical company with multiple violations of regulations and product recalls.
Dr Reddy: Found to have contaminated Ranitidine, Valsartan, Losartan, and Irbesartan products with N-Nitrosodimethylamine (NDMA), a known carcinogen.

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Description

This quiz explores the various aspects of Adverse Drug Events (ADE), including their prevalence, types, and causes. Learn about the statistics surrounding drug use and the most common medications involved in ADEs. Test your knowledge on the mechanisms of toxicity related to medications.