Podcast
Questions and Answers
What is the primary metric used to assess bioequivalence between two pharmaceutical products?
What is the primary metric used to assess bioequivalence between two pharmaceutical products?
What percentage of American adults take at least one medication?
What percentage of American adults take at least one medication?
What does the confidence interval (CI) range of 0.8 to 1.25 indicate in bioequivalence studies?
What does the confidence interval (CI) range of 0.8 to 1.25 indicate in bioequivalence studies?
Which of the following statements about generic drugs and bioequivalence is true?
Which of the following statements about generic drugs and bioequivalence is true?
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Which of the following medications is NOT commonly associated with adverse drug events (ADEs)?
Which of the following medications is NOT commonly associated with adverse drug events (ADEs)?
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If a patient optimized on Drug C (AUC: 1.25) switches to Drug B (AUC: 0.8), what is the consequence regarding the active pharmaceutical ingredient (API)?
If a patient optimized on Drug C (AUC: 1.25) switches to Drug B (AUC: 0.8), what is the consequence regarding the active pharmaceutical ingredient (API)?
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What is a common characteristic of idiosyncratic adverse effects?
What is a common characteristic of idiosyncratic adverse effects?
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What is the potential issue when switching a patient from Drug B to Drug C according to the data provided?
What is the potential issue when switching a patient from Drug B to Drug C according to the data provided?
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Which drug class is associated with a higher rate of adverse effects among patients over 65 years of age?
Which drug class is associated with a higher rate of adverse effects among patients over 65 years of age?
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What defines adverse drug reactions compared to side effects?
What defines adverse drug reactions compared to side effects?
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Which factor does NOT contribute to adverse drug events?
Which factor does NOT contribute to adverse drug events?
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How does the use of opioids affect the death rate compared to heroin?
How does the use of opioids affect the death rate compared to heroin?
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What is an example of a desirable effect from a medication?
What is an example of a desirable effect from a medication?
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What was Thalidomide originally marketed as in 1957?
What was Thalidomide originally marketed as in 1957?
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What led to the withdrawal of Thalidomide from the market in 1961?
What led to the withdrawal of Thalidomide from the market in 1961?
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Which of the following medications is associated with teratogenic effects, similar to Thalidomide?
Which of the following medications is associated with teratogenic effects, similar to Thalidomide?
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What significant change did the Thalidomide incident have on drug regulation?
What significant change did the Thalidomide incident have on drug regulation?
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What is a known side effect of Diethylstilboestrol (DES) exposure in daughters?
What is a known side effect of Diethylstilboestrol (DES) exposure in daughters?
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Which drug is used today as an immunomodulator to treat Hansen’s disease?
Which drug is used today as an immunomodulator to treat Hansen’s disease?
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What type of compounds are propellants used in drug formulations, such as CFCs?
What type of compounds are propellants used in drug formulations, such as CFCs?
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What was one of the reasons for the low regulation of drugs in the 1950s?
What was one of the reasons for the low regulation of drugs in the 1950s?
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What causes API-mediated toxicity?
What causes API-mediated toxicity?
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Which statement about drug metabolism and CYP450 enzymes is correct?
Which statement about drug metabolism and CYP450 enzymes is correct?
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Which of the following is NOT a characteristic of idiosyncratic toxicity?
Which of the following is NOT a characteristic of idiosyncratic toxicity?
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What is the significant consequence of drug degradation over time?
What is the significant consequence of drug degradation over time?
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What was a reason for the ban of coumarin as a foodstuff by the FDA?
What was a reason for the ban of coumarin as a foodstuff by the FDA?
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Which of these drugs is considered an inhibitor of CYP450 enzymes?
Which of these drugs is considered an inhibitor of CYP450 enzymes?
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What impact do contaminants have on drug safety when APIs degrade?
What impact do contaminants have on drug safety when APIs degrade?
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How do genetic polymorphisms influence idiosyncratic toxicity?
How do genetic polymorphisms influence idiosyncratic toxicity?
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What major action did the FDA take against the Indian generic pharmaceutical company Ranbaxy?
What major action did the FDA take against the Indian generic pharmaceutical company Ranbaxy?
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What role does N-acetylcysteine play in paracetamol overdose treatment?
What role does N-acetylcysteine play in paracetamol overdose treatment?
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Study Notes
Adverse Drug Events
- Adverse drug events (ADE) include medication errors, adverse drug reactions, allergic reactions, and overdoses.
- 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.
Other Causes of ADE
- The incidence of ADE is 4 per 1000.
- Antibiotics (16%) have a 1 in 1000 risk of an ADE (with allergies being the most common); a 1 in 4000 chance of preventing a serious complication of an upper respiratory tract infection.
- Anticoagulants (32% of patients over 65 years of age) including warfarin, rivaroxaban, and dabigatran are in the top 10 causes of ADEs.
- Phenytoin (an anti-seizure medication) has zero-order kinetics.
- Opioid analgesia has a death rate greater than that of heroin.
Unwanted Effects of Drugs
- Side effects are relatively minor and reversible when treatment ceases.
- Adverse effects are more serious and may be life-threatening.
- Drug interactions are unwanted effects that occur in the presence of other drugs.
- Contraindications are conditions that may precipitate an unwanted effect.
Unwanted vs Desirable Effects
- Opiates can cause constipation when treating pain, but this is a desirable effect when used to treat diarrhea.
- When treating allergy, drowsiness is an unwanted effect of anti-histamines, but it can be desirable when used to prevent travel sickness.
Types of Toxicity - Mechanisms
-
Pharmacodynamic Toxicity (Predictable):
- Excessive pharmacological action
- Alternative pharmacological action
- Overdose toxicity
-
Pharmacokinetic (Unpredictable?):
- Induction/inhibition/competition of P450 enzymes
-
Idiosyncratic:
- Allergic response (often genetically mediated)
- Hyperthermia with general anesthetics
-
Withdrawal:
- Steroid, beta-blocker, anti-epileptic, PPI withdrawal
Thalidomide
- Marketed by Chemie Grünenthal, Germany
- Introduced as a sedative in 1957.
- Found to be a good antiemetic (off-label use for morning sickness).
- Withdrawn in 1961 due to teratogenic effects.
- Not tested on pregnant animals (species dependent: mice less sensitive than humans).
Thalidomide Today
- Used as an immunomodulator to treat Hansen’s disease/leprosy, cancer, graft versus host disease in children, HIV mouth ulcers, and wasting.
- Prescribed under a Risk Evaluation & Mitigation Strategy (REMS, FDA).
- Lenalidomide, a new derivative, is also a teratogen.
Diethylstilboestrol (DES)
- Non-steroidal oestrogen.
- Approved by the FDA in 1947 to:
- Prevent miscarriage
- Treat oestrogen deficient states
- Act as a post-coital contraceptive
- Banned in chickens in 1959/66.
- Shown to be a teratogen in 1971.
DES Teratogenicity
-
DES Daughters:
- Increased risk of clear cell adenocarcinoma (CCA) of the vagina and cervix, breast cancer.
- Pregnancy-related problems: miscarriage, stillbirth, ectopic pregnancy, premature labour, preeclampsia.
-
DES Sons, 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 but was used in the USA.
- The thalidomide tragedy changed the global regulatory environment.
Source of ADEs
-
Active Pharmaceutical Ingredient (API):
- Species-specific effects
- Metabolites, possibly species-specific
- Toxicity may only occur in a small number of patients.
-
Contaminants:
- Due to synthesis or degradation of API.
-
Excipients:
- Used to bulk up, stabilize, surface coat, color, or flavor.
-
Propellants:
- E.g., CFCs (chlorofluorocarbons) replaced with HFCs (hydrofluorocarbons) due to the Montreal Protocol 1987.
Why are Toxic Drugs Allowed?
- API is usually well tested in vitro and in vivo before approval.
- Toxicity may only occur in a small number of patients.
- Toxicity could be discovered after many patients are treated (pharmacogenetics).
Cytochrome P450 (CYP) Enzymes
- CYP enzymes metabolise medications.
- With chronic administration, some drugs stimulate hepatocytes to produce larger amounts of drug-metabolising enzymes (inducers).
- Enzyme induction accelerates drug metabolism and can lead to the need for larger doses of the drug or a drug overdose.
- Apparent inhibition may occur with concurrent administration of two or more drugs that compete for the same metabolising enzymes.
Drug Metabolism by CYP450 Enzymes
-
Inducers:
- Tobacco, cabbage, St. John’s wort, grapefruit juice, turmeric.
-
Inhibitors:
- Fluoxetine (SSRI), erythromycin, fluconazole.
-
Substrates:
- Paracetamol, beta-blockers, theophylline, codeine, tricyclic antidepressants, warfarin, phenytoin, oestrogens, NSAIDS.
Case Study: Paracetamol
- N-acetyl-p-benzoquinone imine (NAPQI) is a toxic metabolite of paracetamol.
Paracetamol Overdose Treatment
- Requires replenishing glutathione (GSH).
- GSH is not orally active.
- N-Acetylcysteine is orally active and is converted to GSH.
Idiosyncratic Toxicity
- Dose-independent.
- Often due to genetic polymorphisms (e.g., CYP polymorphisms).
- Can be immunological.
- Very difficult to identify.
Coumarin
- Used for its smell of "vanilla."
- Found in vanilla grass, tonka bean, cinnamon, strawberries.
- High level of hepatotoxicity in rats (dose-dependent).
- Low level of toxicity in humans (0.37%).
- Banned as a foodstuff by the FDA in 1954 because it was considered a carcinogen.
- Re-analysis of rat data suggests that the hepatic lesion was cholangiofibrosis (bile duct proliferation) not cholangiocarcinoma.
Coumarin Metabolism Differences
- Rat metabolism: produces a probable hepatotoxin.
- Human and mouse metabolism: differ from the rat.
Contaminants
- By-products from synthesis may cause ADE, especially cancer.
- API degrades over time (influenced by storage conditions such as heat, light, humidity), leading to a reduced dose of API and potentially toxic by-products.
Examples of Recalled Medications Due to Contaminants
- Ranitidine (H2 antagonist) and valsartan, losartan, and irbesartan (Angiotensin II Receptor Blockers) were recalled due to the presence of N-Nitrosodimethylamine (NDMA), a known carcinogen.
Generic Pharmaceuticals
- After a drug's patent lapses, generics become available.
- Generics need to demonstrate bioequivalence to the branded product.
Bioequivalence
- "The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." (FDA)
- Usually measured by comparing Cmax and AUC between two products.
- Bioequivalence is defined as a confidence interval (CI) of the test within 0.8 and 1.25 of the reference.
- Generic drugs only need to show bioequivalence with the approved product in a small number of healthy volunteers.
Problems with Bioequivalence
- Patients switching from different generics of the same medication may experience significant variation in the amount of API they are receiving.
- This can lead to sub-therapeutic (too low) or supratherapeutic (too high) dosing.
- Adverse effects may become more frequent in patients who switch between generic products.
- Large phase III studies identify adverse effects with an incidence of 0.1%.
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Description
This quiz covers the important aspects of Adverse Drug Events (ADE), including their definitions, statistics on medication use, and specific causes such as opioids and antibiotics. Test your knowledge on the impact of ADEs and their association with various medications. Understand the significance of monitoring drug use and preventing adverse effects.
