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Questions and Answers
Adverse drug events (ADE) include medication errors, allergic reactions, and overdoses.
Adverse drug events (ADE) include medication errors, allergic reactions, and overdoses.
True
In 2016, the drug-poisoning death rate was higher for females than for males.
In 2016, the drug-poisoning death rate was higher for females than for males.
False
75% of drug overdose deaths in 2020 involved opioids.
75% of drug overdose deaths in 2020 involved opioids.
True
Antibiotics account for 16% of adverse drug events.
Antibiotics account for 16% of adverse drug events.
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Adverse effects of drugs are always minor and reversible.
Adverse effects of drugs are always minor and reversible.
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Pharmacodynamic toxicity is predictable and results from excessive pharmacological action.
Pharmacodynamic toxicity is predictable and results from excessive pharmacological action.
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When treating pain with opiates, constipation is considered a desirable effect.
When treating pain with opiates, constipation is considered a desirable effect.
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Insulin is associated with a significant risk of adverse drug events.
Insulin is associated with a significant risk of adverse drug events.
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Bioequivalence requires a confidence interval of the test within 0.8 and 1.25 of the reference.
Bioequivalence requires a confidence interval of the test within 0.8 and 1.25 of the reference.
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Drug A, Drug B, and Drug C have identical amounts of active pharmaceutical ingredients (API).
Drug A, Drug B, and Drug C have identical amounts of active pharmaceutical ingredients (API).
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AUC stands for Area Under the Curve, which is a measurement used to compare bioequivalence.
AUC stands for Area Under the Curve, which is a measurement used to compare bioequivalence.
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A generic drug must show bioequivalence with the approved product using a large number of healthy volunteers.
A generic drug must show bioequivalence with the approved product using a large number of healthy volunteers.
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A large phase III study may involve up to 10,000 patients to identify adverse effects.
A large phase III study may involve up to 10,000 patients to identify adverse effects.
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Thalidomide was first marketed as an antiemetic for morning sickness.
Thalidomide was first marketed as an antiemetic for morning sickness.
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DES was approved by the FDA for use in chickens.
DES was approved by the FDA for use in chickens.
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Thalidomide is currently used to treat Hansen's disease and certain cancers.
Thalidomide is currently used to treat Hansen's disease and certain cancers.
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All active pharmaceutical ingredients have no risk of contamination.
All active pharmaceutical ingredients have no risk of contamination.
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The use of thalidomide changed the global regulatory environment for drug safety.
The use of thalidomide changed the global regulatory environment for drug safety.
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DES exposure in daughters has been linked to an increased risk of breast cancer.
DES exposure in daughters has been linked to an increased risk of breast cancer.
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There were rigorous teratogenicity studies required in the 1950s before drug approval.
There were rigorous teratogenicity studies required in the 1950s before drug approval.
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CFCs were replaced with HFCs according to the Montreal Protocol.
CFCs were replaced with HFCs according to the Montreal Protocol.
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API is usually well tested in vitro and in vivo before approval.
API is usually well tested in vitro and in vivo before approval.
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Toxicity may only occur in a small number of patients and often goes undetected.
Toxicity may only occur in a small number of patients and often goes undetected.
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Cytochrome P450 enzymes always slow down drug metabolism.
Cytochrome P450 enzymes always slow down drug metabolism.
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N-Acetylcysteine is an orally active treatment for paracetamol overdose because it replenishes glutathione.
N-Acetylcysteine is an orally active treatment for paracetamol overdose because it replenishes glutathione.
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Idiosyncratic toxicity is dose-dependent and easy to identify.
Idiosyncratic toxicity is dose-dependent and easy to identify.
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Coumarin has a high level of hepatotoxicity in humans, similar to rats.
Coumarin has a high level of hepatotoxicity in humans, similar to rats.
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API degradation over time can lead to the presence of potentially toxic by-products.
API degradation over time can lead to the presence of potentially toxic by-products.
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Ranbaxy was banned by the FDA due to consistently high quality standards.
Ranbaxy was banned by the FDA due to consistently high quality standards.
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Generic drugs can be identical to branded products after a patent lapses.
Generic drugs can be identical to branded products after a patent lapses.
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Erythromycin is categorized as a substrate in drug metabolism.
Erythromycin is categorized as a substrate in drug metabolism.
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Adverse drug events include only allergic reactions and overdoses.
Adverse drug events include only allergic reactions and overdoses.
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A greater risk of serious adverse drug events is associated with the use of anticoagulants in patients over 65 years of age.
A greater risk of serious adverse drug events is associated with the use of anticoagulants in patients over 65 years of age.
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Pharmacodynamic toxicity arises from unpredictable interactions between drugs.
Pharmacodynamic toxicity arises from unpredictable interactions between drugs.
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Constipation is considered an unwanted effect when using anti-histamines.
Constipation is considered an unwanted effect when using anti-histamines.
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In 2020, drug overdose deaths in the United States had a rate of 28.3 per 100,000 people.
In 2020, drug overdose deaths in the United States had a rate of 28.3 per 100,000 people.
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Opiates have no serious adverse effects and are completely safe for all patients.
Opiates have no serious adverse effects and are completely safe for all patients.
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Idiosyncratic adverse effects are typically predictable and dose-dependent.
Idiosyncratic adverse effects are typically predictable and dose-dependent.
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The incidence of adverse drug events related to antibiotics is 1 in 1000.
The incidence of adverse drug events related to antibiotics is 1 in 1000.
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AUC stands for Area Under the Curve and is used to measure the bioequivalence of drugs.
AUC stands for Area Under the Curve and is used to measure the bioequivalence of drugs.
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Bioequivalence implies that two drugs have the same amount of active pharmaceutical ingredient (API).
Bioequivalence implies that two drugs have the same amount of active pharmaceutical ingredient (API).
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A confidence interval between 0.8 and 1.25 indicates that a generic drug is bioequivalent to a branded drug.
A confidence interval between 0.8 and 1.25 indicates that a generic drug is bioequivalent to a branded drug.
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A drug that shows a 37% reduction in dose after switching from Drug C to Drug B can lead to acceptable therapeutic outcomes.
A drug that shows a 37% reduction in dose after switching from Drug C to Drug B can lead to acceptable therapeutic outcomes.
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Phase III studies typically involve only a small number of patients to evaluate adverse effects of a drug.
Phase III studies typically involve only a small number of patients to evaluate adverse effects of a drug.
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Thalidomide was introduced as a sedative in 1957 and was found to be safe as it did not cause respiratory depression.
Thalidomide was introduced as a sedative in 1957 and was found to be safe as it did not cause respiratory depression.
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Diethylstilboestrol was banned by the FDA in 1947 for use in preventing miscarriage.
Diethylstilboestrol was banned by the FDA in 1947 for use in preventing miscarriage.
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Thalidomide acts as an immunomodulator and is still prescribed today under a Risk Evaluation & Mitigation Strategy.
Thalidomide acts as an immunomodulator and is still prescribed today under a Risk Evaluation & Mitigation Strategy.
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Des Sons and grandsons do not show any urogenital abnormalities after exposure to Diethylstilboestrol.
Des Sons and grandsons do not show any urogenital abnormalities after exposure to Diethylstilboestrol.
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In the 1950s, rigorous teratogenicity studies were required for drug approval.
In the 1950s, rigorous teratogenicity studies were required for drug approval.
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The Montreal Protocol was established to replace chlorofluorocarbons (CFCs) with hydrofluorocarbons (HFCs).
The Montreal Protocol was established to replace chlorofluorocarbons (CFCs) with hydrofluorocarbons (HFCs).
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Thalidomide's teratogenic effects were discovered after it had been tested on pregnant animals, which showed its safety.
Thalidomide's teratogenic effects were discovered after it had been tested on pregnant animals, which showed its safety.
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Drug regulation in the 1950s was primarily the responsibility of the government, with strict oversight of pharmaceutical companies.
Drug regulation in the 1950s was primarily the responsibility of the government, with strict oversight of pharmaceutical companies.
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Cytochrome P450 enzymes can induce some drugs to produce larger amounts of drug-metabolising enzymes.
Cytochrome P450 enzymes can induce some drugs to produce larger amounts of drug-metabolising enzymes.
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Idiosyncratic toxicity is typically dose-dependent and straightforward to identify.
Idiosyncratic toxicity is typically dose-dependent and straightforward to identify.
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Paracetamol's active metabolite is N-acetyl-p-benzoquinone imine.
Paracetamol's active metabolite is N-acetyl-p-benzoquinone imine.
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Coumarin is banned in the United States due to its low toxicity in humans.
Coumarin is banned in the United States due to its low toxicity in humans.
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Fluoxetine acts as an inducer in drug metabolism by CYP450 enzymes.
Fluoxetine acts as an inducer in drug metabolism by CYP450 enzymes.
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API degradation can reduce the efficacy of a drug and produce toxic by-products.
API degradation can reduce the efficacy of a drug and produce toxic by-products.
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N-Acetylcysteine is not orally active and cannot be used for paracetamol overdose treatment.
N-Acetylcysteine is not orally active and cannot be used for paracetamol overdose treatment.
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Contaminants in pharmaceuticals may arise from production variations and can potentially lead to adverse drug events.
Contaminants in pharmaceuticals may arise from production variations and can potentially lead to adverse drug events.
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All substrates in drug metabolism are completely safe and do not pose any risk of toxicity.
All substrates in drug metabolism are completely safe and do not pose any risk of toxicity.
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The presence of two drugs that compete for the same CYP450 enzymes can cause an apparent inhibition of drug metabolism.
The presence of two drugs that compete for the same CYP450 enzymes can cause an apparent inhibition of drug metabolism.
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The risk of serious adverse drug events is generally lower for patients over 65 years taking anticoagulants compared to younger patients.
The risk of serious adverse drug events is generally lower for patients over 65 years taking anticoagulants compared to younger patients.
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Antibiotics have a higher incidence of adverse drug events than opioids.
Antibiotics have a higher incidence of adverse drug events than opioids.
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Idiosyncratic adverse effects are typically linked to specific doses of medication.
Idiosyncratic adverse effects are typically linked to specific doses of medication.
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Diethylstilboestrol (DES) was approved by the FDA for use as a treatment for various types of cancer.
Diethylstilboestrol (DES) was approved by the FDA for use as a treatment for various types of cancer.
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Unwanted effects of drugs are always immediate and cannot be delayed over time.
Unwanted effects of drugs are always immediate and cannot be delayed over time.
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Contaminants in medications can significantly affect the bioequivalence of generic drugs.
Contaminants in medications can significantly affect the bioequivalence of generic drugs.
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Medication errors are included in the definition of adverse drug events.
Medication errors are included in the definition of adverse drug events.
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The drug-poisoning death rate differs notably between males and females, with males having a higher rate.
The drug-poisoning death rate differs notably between males and females, with males having a higher rate.
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A drug bioequivalence is established if the AUC of the test drug is greater than 1.25 times that of the reference drug.
A drug bioequivalence is established if the AUC of the test drug is greater than 1.25 times that of the reference drug.
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Switching from a drug with an AUC of 1.25 to one with an AUC of 0.8 leads to a reduction in the active pharmaceutical ingredient dose.
Switching from a drug with an AUC of 1.25 to one with an AUC of 0.8 leads to a reduction in the active pharmaceutical ingredient dose.
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Adverse effects of a drug identified in a phase III study with a 0.1% incidence can be considered clinically significant.
Adverse effects of a drug identified in a phase III study with a 0.1% incidence can be considered clinically significant.
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Generic drugs need to demonstrate bioequivalence in a large population of patients to be approved.
Generic drugs need to demonstrate bioequivalence in a large population of patients to be approved.
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The amount of active pharmaceutical ingredient in a drug does not influence its bioequivalence status.
The amount of active pharmaceutical ingredient in a drug does not influence its bioequivalence status.
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Thalidomide was withdrawn from the market in 1961 due to its non-teratogenic effects.
Thalidomide was withdrawn from the market in 1961 due to its non-teratogenic effects.
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Diethylstilboestrol was shown to be a teratogen after its approval in 1947.
Diethylstilboestrol was shown to be a teratogen after its approval in 1947.
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The Montreal Protocol was significant for regulating the use of hydrofluorocarbons (HFCs).
The Montreal Protocol was significant for regulating the use of hydrofluorocarbons (HFCs).
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Active Pharmaceutical Ingredients (APIs) do not require any testing for contamination.
Active Pharmaceutical Ingredients (APIs) do not require any testing for contamination.
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Thalidomide continues to be prescribed today under strict regulatory measures due to its immunomodulatory effects.
Thalidomide continues to be prescribed today under strict regulatory measures due to its immunomodulatory effects.
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Women exposed to Diethylstilboestrol in utero have an increased risk of developing certain cancers.
Women exposed to Diethylstilboestrol in utero have an increased risk of developing certain cancers.
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Contaminants in pharmaceuticals can arise solely from the synthesis process.
Contaminants in pharmaceuticals can arise solely from the synthesis process.
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Idiosyncratic reactions to drugs are always predictable and consistent among all patients.
Idiosyncratic reactions to drugs are always predictable and consistent among all patients.
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Cytochrome P450 enzymes metabolize medications, but they cannot be inhibited.
Cytochrome P450 enzymes metabolize medications, but they cannot be inhibited.
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St John’s wort is an inducer of CYP450 enzymes.
St John’s wort is an inducer of CYP450 enzymes.
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N-Acetylcysteine is ineffective in treating paracetamol overdose as it does not replenish glutathione.
N-Acetylcysteine is ineffective in treating paracetamol overdose as it does not replenish glutathione.
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Coumarin is considered safe in humans despite its high hepatotoxicity in rats.
Coumarin is considered safe in humans despite its high hepatotoxicity in rats.
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The degradation of active pharmaceutical ingredients (API) can increase the risk of adverse drug events.
The degradation of active pharmaceutical ingredients (API) can increase the risk of adverse drug events.
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Idiosyncratic toxicity is often related to specific drug doses and can be easily recognized.
Idiosyncratic toxicity is often related to specific drug doses and can be easily recognized.
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Erythromycin serves as a substrate in drug metabolism.
Erythromycin serves as a substrate in drug metabolism.
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Ranitidine was recalled due to the presence of a carcinogen known as N-Nitrosodimethylamine (NDMA).
Ranitidine was recalled due to the presence of a carcinogen known as N-Nitrosodimethylamine (NDMA).
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Drug metabolism by CYP450 enzymes always results in faster drug clearance from the body.
Drug metabolism by CYP450 enzymes always results in faster drug clearance from the body.
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Generics cannot be considered identical to branded products until a drug's patent has expired.
Generics cannot be considered identical to branded products until a drug's patent has expired.
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Study Notes
Adverse Drug Events (ADE)
- ADEs 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.
- The age-adjusted rate for drug-poisoning deaths for males (26.2 per 100,000) was almost double that of females (13.4) in 2016.
- 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 ADEs
- Antibiotics have a 1 in 1000 risk of an ADE (allergy most common).
- Anticoagulants are in the top 10 causes of ADEs, with 32% of patients >65 years of age taking them.
- Phenytoin (anti-seizure medication) has zero-order kinetics.
- Opioid analgesia has a higher death rate than heroin.
Unwanted Effects of Drugs
- Side effects are relatively minor and reversible when treatment ceases or after a short while.
- 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.
Types of Toxicity - Mechanisms
- Pharmacodynamic Toxicity (Predictable): Excessive pharmacological action, alternative pharmacological action, or overdose toxicity.
- Pharmacokinetic (Unpredictable): Induction, inhibition, or competition of P450 enzymes.
- Idiosyncratic: Allergic response or hyperthermia with general anesthetics.
- Withdrawal: Steroid, beta-blocker, anti-epileptic, or PPI withdrawal.
Thalidomide
- Marketed by Chemie Grünenthal, Germany, as a safe sedative in 1957.
- Found to be a good antiemetic for morning sickness (off-label use).
- Withdrawn in 1961 due to teratogenic effects.
- Not tested on pregnant animals.
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.
- Used to prevent miscarriage, for oestrogen deficient states, and 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 developing clear cell adenocarcinoma (CCA) of the vagina and cervix, breast cancer, and pregnancy-related problems such as miscarriage, stillbirth, ectopic pregnancy, premature labour, and preeclampsia.
- DES Sons, Grandsons: Urogenital abnormalities, such as hypospadia.
- DES Grandchildren: Infertility and cerebral palsy.
Drug Regulation in the 1950s
- Very little formal regulation.
- Thalidomide was not approved by the FDA and not used in the USA.
- The lack of regulation changed the global regulatory environment.
Source of ADEs
- Active Pharmaceutical Ingredient (API): The primary ingredient in a drug.
- Contaminants: Introduced during synthesis or due to API degradation.
- Excipients: Used to bulk up, stabilize, surface coat, color, and flavor a drug.
- Propellants: Used in inhalers and aerosols.
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.
- Pharmacogenetics plays a role.
Cytochrome P450
- CYP enzymes metabolise medications.
- Chronic administration (greater than 1-3 weeks) of some drugs stimulates hepatocytes to produce larger amounts of drug-metabolizing enzymes (inducers).
- Enzyme induction accelerates drug metabolism, potentially requiring larger doses or leading to overdose.
- Concurrent administration of drugs that compete for the same metabolising enzymes can lead to apparent inhibition.
Drug Metabolism by CYP450 Enzymes
- Inducers: Tobacco, cabbage, St John's wort, grapefruit juice, turmeric.
- Inhibitors: Fluoxetine (SSRI), St John's wort, grapefruit juice, turmeric.
- Substrates: Paracetamol, beta-blockers, theophylline, codeine, tricyclic antidepressants, warfarin, phenytoin, erythromycin, omeprazole, oestrogens.
Case Study: Paracetamol
- N-acetyl-p-benzoquinone imine is a toxic metabolite of paracetamol.
Paracetamol Overdose Treatment
- Requires replenishing glutathione (GSH).
- N-Acetylcysteine is orally active and converted to GSH to treat paracetamol overdose.
Idiosyncratic Toxicity
- Dose-independent and often due to genetic polymorphisms.
- Can be immunological and is very difficult to identify.
Coumarin Hepatotoxicity
- High level of hepatotoxicity in rats, but low level of toxicity in humans.
- Banned as a foodstuff by the FDA in 1954.
- Re-analysis of rat data suggests the hepatic lesion was cholangiofibrosis, not cholangiocarcinoma.
Coumarin Metabolism
- Humans and mice metabolize coumarin differently than rats.
- The rat metabolite is a probable hepatotoxin.
Contaminants
- By-products from synthesis may be batch-specific or due to changing conditions during manufacture.
- API degrades over time influenced by storage conditions such as heat, light, and humidity.
Ranitidine, Valsartan, Losartan, and Irbesartan Recall
- Recalled due to the presence of N-Nitrosodimethylamine (NDMA), a known carcinogen.
- NDMA is considered a contaminant.
Ranbaxy
- Indian generic pharmaceutical company that was a major supplier of generic medicines.
- Suffered multiple violations of regulations with product recalls.
- Pleaded guilty to felony charges for selling adulterated drugs in 2013 and was fined $500 million.
- Banned by the FDA from selling APIs to the US in 2014.
Dr Reddy
- Ranitidine (2019) and valsartan, losartan, and irbesartan (2019) recalls.
Generics
- After a drug's patent expires (20 years), generic versions become available.
- Bioequivalence means that the generic version releases the same amount of active ingredient into the body as the branded product.
Problems with Bioequivalence
- Generic drugs only need to show bioequivalence with approved products in a small number of healthy volunteers.
- Bioequivalence is based on Cmax and AUC, which may not reflect the drug's effect on the body.
- Switching between generic products can lead to significant differences in API dose and potential adverse effects.
Adverse Drug Events (ADEs)
- ADEs are broadly defined and include medication errors, adverse drug reactions, allergic reactions and overdoses.
- In 2016, drug-poisoning deaths were 26.2 per 100,000 in males compared to 13.4 per 100,000 in females.
- In 2020, 91,799 drug overdose deaths occurred in the US, 75% involved opioids.
Types of Drug Toxicity
- Pharmacodynamic Toxicity (predictable): Excessive pharmacological action, alternative pharmacological action (e.g., aspirin's bleeding vs. anti-inflammatory actions), and overdose toxicity.
- Pharmacokinetic (unpredictable?): Induction, inhibition, or competition of P450 enzymes - can lead to unforeseen drug effects.
- Idiosyncratic: Often dose-independent, due to genetic polymorphisms (e.g., CYP polymorphisms) or immunological reactions.
Thalidomide - A Case Study
- Thalidomide, initially marketed as a safe sedative, was later found to be teratogenic.
- Withdrawn in 1961 due to severe birth defects.
- Despite its harmful effects, Thalidomide is now used under strict controls to treat conditions like Hansen's disease and certain cancers.
Diethylstilboestrol (DES) - Another Teratogen
- DES, a non-steroidal estrogen, was approved by the FDA in 1947 for various uses including preventing miscarriages and as a post-coital contraceptive.
- It was banned in chickens in 1959/1966.
- In 1971, DES was identified as a teratogen, causing a range of birth defects in offspring.
DES Teratogenicity
- DES daughters: Increased risk of clear cell adenocarcinoma (CCA) of the vagina and cervix, breast cancer, and pregnancy-related problems.
- DES sons and grandsons: Urogenital abnormalities, such as hypospadia.
- DES grandchildren: Infertility and cerebral palsy.
Source of ADEs: Beyond the Active Pharmaceutical Ingredient (API)
- Contaminants: By-products of synthesis, degradation of the API, and excipients used in drug formulation.
- Propellants: For example, chlorofluorocarbons (CFCs) were replaced by hydrofluorocarbons (HFCs) after the Montreal Protocol 1987.
Factors Contributing to Toxic Drugs Being Allowed
- API is rigorously tested before approval.
- Species-specific effects or metabolites may only be revealed after widespread drug use.
- Pharmacogenetics: Individual genetic variations can influence drug metabolism and toxicity.
Cytochrome P450 (CYP) Enzymes - Drug Metabolism
- CYP enzymes metabolize medications.
- Some drugs induce hepatocytes to produce more drug-metabolising enzymes (inducers), leading to faster drug metabolism.
- Drug interactions can occur due to competition for the same CYP enzymes, leading to altered drug effects.
Bioequivalence: Generics and the Brand Products
- Generic drugs must show bioequivalence with the brand product by comparing the rate and extent of drug absorption.
- Bioequivalence studies are typically conducted in a small number of healthy volunteers.
Problems with Bioequivalence
- Bioequivalence studies may not adequately reflect real-world clinical scenarios.
- Patients switched between generic and brand-name versions may experience changes in drug concentration, potentially leading to unexpected drug effects.
- Example: A patient on Drug C (AUC: 1.25) switched to Drug B (AUC: 0.8) would experience a 37% reduction in drug dose.
Coumarin Toxicity - A Case of Idiosyncratic Reaction
- Coumarin displayed high levels of hepatotoxicity in rats.
- In humans, while it causes a very low level of toxicity, coumarin was still banned by the FDA as a food additive due to its carcinogenic concerns.
- The initial concerns regarding carcinogenic potential in rats were later revised to suggest cholangiofibrosis (bile duct proliferation) as the causing agent.
Coumarin Metabolism -- Species Differences
- Species differences in metabolism can lead to different toxic metabolite profiles.
- Human metabolism of coumarin leads to a different metabolite compared to mouse or rat metabolism.
Contaminated Drugs - A Major Concern
- Generic drugs are often recalled due to contaminants that result from synthesis or degradation.
- Ranitidine (H2 antagonist) and valsartan, losartan, and irbesartan (Angiotensin II Receptor Blockers) have been recalled due to the presence of N-Nitrosodimethylamine (NDMA), a known carcinogen.
Drug Companies Affected by Contamination Concerns
- Ranbaxy, an Indian generic company, has been implicated in multiple product recalls due to violations of regulations.
- Dr Reddy's Laboratories has also faced product recalls for ranitidine, valsartan, losartan, and irbesartan.
Adverse Drug Events (ADE)
- ADE is a broad term encompassing 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).
- Opioids were involved in 75% of these deaths.
- Other sources of ADEs with an incidence of 4 per 1000 include antibiotics, anticoagulants, phenytoin, opioid analgesia, and insulin.
Types of Toxicity
-
Pharmacodynamic toxicity (predictable) involves excessive or alternative pharmacological action and overdose toxicity.
- Examples include aspirin (bleeding vs. anti-inflammatory action), anti-histamines (multiple receptors).
- Pharmacokinetic (unpredictable?) involves the induction, inhibition, or competition of P450 enzymes.
-
Idiosyncratic involves allergic responses and dose-independent reactions.
- Examples include hyperthermia with general anesthetics.
- Withdrawal involves abrupt discontinuation of drugs like steroids, beta-blockers, anti-epileptics, and PPIs.
Thalidomide
- Thalidomide was marketed as a safe sedative in 1957 but was later withdrawn in 1961 due to its teratogenic effects.
- It was used off-label for morning sickness and was found to prevent angiogenesis.
- It was not tested on pregnant animals, and species sensitivity varies.
- Today, Thalidomide is prescribed under strict regulations (REMS, FDA) for conditions such as Hansen's disease, cancer, graft versus host disease, and HIV-related ulcers and wasting.
Diethylstilboestrol (DES)
- DES, a non-steroidal oestrogen, was approved by the FDA in 1947 to prevent miscarriages, manage oestrogen-deficient states, and as a post-coital contraceptive.
- It was also used in chickens until 1959/66.
- In 1971, DES was shown to be a teratogen, leading to the development of DES Daughters and Sons.
DES Teratogenicity
- DES daughters showed an increased risk of clear cell adenocarcinoma of the vagina and cervix, breast cancer, miscarriage, stillbirth, ectopic pregnancy, preterm labor, and preeclampsia.
- DES sons and grandsons experienced urogenital abnormalities like hypospadia.
- DES grandchildren exhibited infertility and cerebral palsy.
Drug Regulation 1950s
- Drug regulation was minimal in the 1950s, leaving most decisions to pharmaceutical companies.
- Teratogenicity studies were not required, and Thalidomide was not approved by the FDA.
- This situation changed after the Thalidomide tragedy, leading to a global shift in regulatory environments.
Sources of ADEs
- Active Pharmaceutical Ingredient (API): The main active ingredient in a drug.
- Contaminants: Chemicals present in the drug due to synthesis or degradation of API.
- Excipients: Inactive ingredients used in drug formulation (bulking, stabilizing, surface coating, coloring, flavoring).
-
Propellants: Used in inhalers and sprays (e.g., Chlorofluorocarbons - CFCs).
- The Montreal Protocol of 1987 phased out CFCs and replaced them with Hydrofluorocarbons (HFCs).
Why Are Toxic Drugs Allowed?
- API is usually well-tested in vitro and in vivo before approval.
- Toxicity may be species-specific or due to a metabolite that is species-specific.
- Toxicity may only occur in a small number of patients and may not be detected until many patients are treated.
- Pharmacogenetics plays a role in drug metabolism and effects.
Cytochrome P450 (CYP)
- CYP enzymes metabolize medications.
- Chronic administration (greater than 1-3 weeks) can induce hepatocytes to produce more drug-metabolizing enzymes (inducers), leading to accelerated drug metabolism.
- This can necessitate larger doses of the drug or lead to overdose.
- Concurrent administration of multiple drugs competing for the same metabolic enzymes can result in apparent inhibition.
Drug Metabolism by CYP450 Enzymes
- Several drugs act as substrates, inducers, or inhibitors of various CYP enzymes.
- Examples include: beta-blockers, codeine, tricyclic antidepressants, fluoxetine, warfarin, theophylline, phenytoin, erythromycin, omeprazole, oestrogens, St John's wort, NSAIDS, and fluconazole.
- These interactions can significantly impact drug efficacy and safety.
Case Study: Paracetamol (Acetaminophen)
- Paracetamol overdose leads to the formation of a toxic metabolite, N-acetyl-p-benzoquinone imine.
- Treatment involves replenishing glutathione (GSH), which is not orally active.
- N-acetylcysteine is an orally active precursor converted to GSH, as is 𝜓GSH.
Idiosyncratic Toxicity
- Dose-independent toxicity often related to genetic polymorphisms (e.g., CYP variations).
- Can also be immunological.
- Difficult to identify.
- Example: Coumarin, a substance with a vanilla-like smell, shows a high level of hepatotoxicity in rats but low toxicity in humans.
Coumarin Hepatotoxicity
- High hepatotoxicity in rats, but low toxicity in humans (0.37%).
- The FDA banned coumarin as a foodstuff in 1954, considering it a carcinogen.
- Re-analysis of rat data suggests the hepatic lesion was cholangiofibrosis (bile duct proliferation) and not cholangiocarcinoma.
- The metabolism of coumarin differs between species, leading to different toxic outcomes.
Contaminants
- Despite efforts to use pure API, by-products from synthesis may still be present, potentially causing ADEs, especially cancer.
- Degradation of API over time due to heat, light, or humidity can also contribute to ADEs.
Contaminants and Degradation
- The degradation of API leads to reduced API dosage and the presence of potentially toxic by-products.
- Ranitidine (H2 antagonist) and valsartan, losartan, and irbesartan (Angiotensin II Receptor Blockers) were recalled due to contamination with N-Nitrosodimethylamine (NDMA), a known carcinogen.
- Several pharmaceutical companies, including Ranbaxy and Dr Reddy's, have been involved in manufacturing and selling adulterated drugs, leading to recalls and fines.
Generics and Bioequivalence
- After a drug’s patent expires (20 years), generic versions become available.
- Bioequivalence is a regulatory standard that ensures generic drugs have the same rate and extent of absorption as the brand-name drug.
- It is determined by comparing the Cmax and AUC between the generic and the brand-name drug under similar conditions.
- 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 demonstrate bioequivalence in a small number of healthy volunteers.
Problems with Bioequivalence
- Bioequivalence does not ensure equal doses of active ingredients between generic and brand drugs.
- A patient switching between generic products with varying AUCs can experience significant changes in drug exposure and potentially adverse effects.
- This highlights the importance of considering bioequivalence in medication switching to ensure optimal therapeutic outcomes.
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Description
This quiz explores the various aspects of adverse drug events (ADEs), including their types, statistics related to medication usage, and the impact of specific drug classes. Participants will learn about the risks associated with medications, particularly opioids and antibiotics, and understand the difference between side effects and adverse effects. Engage with real-life statistics and enhance your understanding of drug safety.
