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Questions and Answers
What is the primary cause of adverse drug events (ADE)?
What is the primary cause of adverse drug events (ADE)?
Which medication class has the highest reported incidence of adverse drug events among patients over 65 years of age?
Which medication class has the highest reported incidence of adverse drug events among patients over 65 years of age?
Which of the following describes a pharmacodynamic toxicity?
Which of the following describes a pharmacodynamic toxicity?
What percentage of American adults reportedly take five or more medications?
What percentage of American adults reportedly take five or more medications?
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What type of adverse effect is described as relatively minor and reversible?
What type of adverse effect is described as relatively minor and reversible?
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Among the unintended effects of medications, which of the following best describes drug interactions?
Among the unintended effects of medications, which of the following best describes drug interactions?
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What was the reported rate of drug-poisoning deaths for males in 2016?
What was the reported rate of drug-poisoning deaths for males in 2016?
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Which drug is noted to have zero-order kinetics, indicating a unique process in metabolism?
Which drug is noted to have zero-order kinetics, indicating a unique process in metabolism?
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What was Thalidomide originally marketed as?
What was Thalidomide originally marketed as?
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What regulatory change occurred due to the issues with Thalidomide?
What regulatory change occurred due to the issues with Thalidomide?
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Which of the following is a potential risk associated with Diethylstilboestrol (DES) usage in daughters?
Which of the following is a potential risk associated with Diethylstilboestrol (DES) usage in daughters?
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What was a common issue with drugs in the 1950s regarding regulation?
What was a common issue with drugs in the 1950s regarding regulation?
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What is one of the current uses of Thalidomide?
What is one of the current uses of Thalidomide?
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Which adverse effect is associated with DES usage in sons?
Which adverse effect is associated with DES usage in sons?
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What was one primary characteristic of Thalidomide that led to its initial approval?
What was one primary characteristic of Thalidomide that led to its initial approval?
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What is noted about the teratogenicity of Thalidomide across different species?
What is noted about the teratogenicity of Thalidomide across different species?
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What is defined as bioequivalence?
What is defined as bioequivalence?
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Which parameters are typically compared to measure bioequivalence?
Which parameters are typically compared to measure bioequivalence?
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What is the acceptable confidence interval (CI) for proving bioequivalence?
What is the acceptable confidence interval (CI) for proving bioequivalence?
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What was the AUC comparison for Drug A and Drug B in the example provided?
What was the AUC comparison for Drug A and Drug B in the example provided?
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What impact did switching from Drug C to Drug B have on the dose of API?
What impact did switching from Drug C to Drug B have on the dose of API?
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What does CYP enzyme induction result in during chronic drug administration?
What does CYP enzyme induction result in during chronic drug administration?
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What is the risk associated with the concurrent administration of multiple drugs?
What is the risk associated with the concurrent administration of multiple drugs?
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What is the purpose of administering N-Acetylcysteine in the case of paracetamol overdose?
What is the purpose of administering N-Acetylcysteine in the case of paracetamol overdose?
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Which of the following is a known carcinogen that has been found as a contaminant in certain medications?
Which of the following is a known carcinogen that has been found as a contaminant in certain medications?
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What kind of toxicity is caused by genetic polymorphisms in CYP enzymes?
What kind of toxicity is caused by genetic polymorphisms in CYP enzymes?
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Why are generic drugs typically considered equivalent to branded products after patent expiration?
Why are generic drugs typically considered equivalent to branded products after patent expiration?
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What is one major consequence of API degradation over time?
What is one major consequence of API degradation over time?
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Which of the following substances acts as an inhibitor of CYP450 enzymes?
Which of the following substances acts as an inhibitor of CYP450 enzymes?
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What is the effect of coumarin toxicity in humans compared to rats?
What is the effect of coumarin toxicity in humans compared to rats?
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What might result from the presence of by-products during the synthesis of an API?
What might result from the presence of by-products during the synthesis of an API?
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What is the range of the confidence interval (CI) that defines bioequivalence?
What is the range of the confidence interval (CI) that defines bioequivalence?
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In the provided examples, what was the Area Under the Curve (AUC) for Drug B?
In the provided examples, what was the Area Under the Curve (AUC) for Drug B?
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What could be the consequence of switching a patient from Drug C to Drug B in terms of API dosage?
What could be the consequence of switching a patient from Drug C to Drug B in terms of API dosage?
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What is primarily measured to assess bioequivalence between two pharmaceutical products?
What is primarily measured to assess bioequivalence between two pharmaceutical products?
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What is a potential issue when comparing a brand drug with multiple generic drugs regarding AUC?
What is a potential issue when comparing a brand drug with multiple generic drugs regarding AUC?
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What is classified as a more serious consequence of drug administration that may be life-threatening?
What is classified as a more serious consequence of drug administration that may be life-threatening?
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Which classes of drugs contribute significantly to the incidence of adverse drug events (ADEs) in older patients?
Which classes of drugs contribute significantly to the incidence of adverse drug events (ADEs) in older patients?
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What term refers to the unwanted effects that result from the concurrent presence of other drugs?
What term refers to the unwanted effects that result from the concurrent presence of other drugs?
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In the context of drug toxicity, what type of toxicity is considered predictable due to excessive pharmacological action?
In the context of drug toxicity, what type of toxicity is considered predictable due to excessive pharmacological action?
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Which category of adverse effect is characterized as being independent of the drug's dose?
Which category of adverse effect is characterized as being independent of the drug's dose?
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Which adverse drug event is most commonly associated with antibiotic use?
Which adverse drug event is most commonly associated with antibiotic use?
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What term is used to describe conditions that may precipitate an unwanted effect when drug administration occurs?
What term is used to describe conditions that may precipitate an unwanted effect when drug administration occurs?
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What role do medication errors play in adverse drug events?
What role do medication errors play in adverse drug events?
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What was a significant reason for the withdrawal of Thalidomide in 1961?
What was a significant reason for the withdrawal of Thalidomide in 1961?
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Which condition is treated today using Thalidomide?
Which condition is treated today using Thalidomide?
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What is one of the notable effects of Diethylstilboestrol (DES) on daughters?
What is one of the notable effects of Diethylstilboestrol (DES) on daughters?
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Why were there minimal regulations on drug approvals in the 1950s?
Why were there minimal regulations on drug approvals in the 1950s?
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What action is regulated under the Risk Evaluation & Mitigation Strategy (REMS) for Thalidomide?
What action is regulated under the Risk Evaluation & Mitigation Strategy (REMS) for Thalidomide?
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What type of abnormalities have been observed in DES sons and grandsons?
What type of abnormalities have been observed in DES sons and grandsons?
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Which factor contributed to the teratogenic effects of Thalidomide during its initial use?
Which factor contributed to the teratogenic effects of Thalidomide during its initial use?
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What was one of the consequences of the 1987 Montreal Protocol regarding drug contaminants?
What was one of the consequences of the 1987 Montreal Protocol regarding drug contaminants?
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What can cause apparent inhibition of drug metabolism?
What can cause apparent inhibition of drug metabolism?
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What is true regarding idiosyncratic toxicity?
What is true regarding idiosyncratic toxicity?
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Which substance is known to act as an inducer of CYP450 enzymes?
Which substance is known to act as an inducer of CYP450 enzymes?
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What is the primary function of N-acetylcysteine in paracetamol overdose treatment?
What is the primary function of N-acetylcysteine in paracetamol overdose treatment?
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Which of the following substances has been banned due to hepatotoxicity concerns?
Which of the following substances has been banned due to hepatotoxicity concerns?
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What might be a consequence of API degradation over time?
What might be a consequence of API degradation over time?
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What impact does enzyme induction have on drug dosage requirements?
What impact does enzyme induction have on drug dosage requirements?
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What is a significant risk associated with contaminants found in pharmaceuticals?
What is a significant risk associated with contaminants found in pharmaceuticals?
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What plays a role in the variability of patient reactions to drugs?
What plays a role in the variability of patient reactions to drugs?
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What is the main reason for the recalls of certain medications like Ranitidine and Valsartan?
What is the main reason for the recalls of certain medications like Ranitidine and Valsartan?
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Study Notes
Adverse Drug Events (ADEs)
- 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.
- In 2016, drug-poisoning deaths were almost double for males (26.2 per 100,000) compared to females (13.4).
- In 2020, 91,799 drug overdose deaths occurred in the US (28.3 per 100,000 people).
- 75% of these overdoses involved opioids.
Other Causes of ADEs
- Antibiotics have a 1 in 1000 risk of an ADE, with allergies being the most common.
- Anticoagulants are used by 32% of patients over 65 years old, with Warfarin, rivaroxaban, and dabigatran being top 10 ADE causes.
- Phenytoin (anti-seizure medication) has zero-order kinetics, meaning the rate of elimination is constant regardless of the concentration.
- Opioid analgesia has a higher death rate than heroin.
Unwanted Effects of Drugs
- Side effects are relatively minor and reversible.
- 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, which is an unwanted effect when treating pain but a desirable effect when treating diarrhea.
- Anti-histamines can cause drowsiness, which is unwanted when treating allergies but desirable when preventing travel sickness.
Types of Toxicity - Mechanisms
- Pharmacodynamic toxicity is predictable and occurs due to excessive or alternative pharmacological action, or overdose.
- Pharmacokinetic toxicity is less predictable and related to enzyme induction, inhibition, or competition of P450 enzymes.
- Idiosyncratic toxicity is dose-independent and often due to genetic polymorphisms or immune responses.
- Withdrawal toxicity can occur with steroids, beta-blockers, anti-epileptics, and PPIs.
Thalidomide
- Marketed as a sedative in 1957, Thalidomide was thought to be safe as it did not cause respiratory depression.
- It was found to be effective as an antiemetic, but withdrawn in 1961 due to teratogenic effects.
- Thalidomide prevented angiogenesis, a process vital for fetal development.
- It was not tested on pregnant animals, and species sensitivity varied (mice were less susceptible than humans).
Thalidomide Today
- Thalidomide is now used as an immunomodulator to treat Hansen's disease, cancer, graft versus host disease, and HIV mouth ulcers and wasting.
- It is prescribed under a Risk Evaluation & Mitigation Strategy (REMS) by the FDA.
- Lenalidomide, a new derivative of Thalidomide, is also a teratogen.
Diethylstilboestrol (DES)
- DES is a non-steroidal estrogen approved by the FDA in 1947 to prevent miscarriage, for estrogen deficient states, and as a post-coital contraceptive.
- It was banned in chickens in 1959/66, and its teratogenic effects were shown in 1971.
DES Teratogenicity
- DES daughters have an increased risk of developing clear cell adenocarcinoma of the vagina and cervix, breast cancer, and pregnancy-related problems.
- DES sons and grandsons can experience urogenital abnormalities such as hypospadia.
- DES grandchildren may experience infertility and cerebral palsy.
Drug Regulation in the 1950's
- There was very little formal drug regulation, with most decisions left to the pharmaceutical company's discretion.
- Teratogenicity studies were not required.
- Thalidomide was not approved by the FDA and not used in the USA.
- The Thalidomide tragedy significantly changed the global regulatory environment.
Source of ADEs
- ADEs can arise from the Active Pharmaceutical Ingredient (API), contaminants, excipients, and propellants.
- Contaminants can be introduced during synthesis, degradation of the API, or through excipients.
- Propellants, such as chlorofluorocarbons (CFCs), can cause ADEs.
Why are Toxic Drugs Allowed?
- APIs are rigorously tested in vitro and in vivo before approval.
- Toxicity may be due to species-specific effects, metabolites, or occur only in a small number of patients.
- This can lead to the identification of toxic effects only after many patients have been treated.
- Pharmacogenetics plays a role in individual responses to medications.
Cytochrome P450 (CYP) Enzymes
- CYP enzymes metabolize medications, with chronic administration leading to enzyme induction in some cases.
- Induction accelerates drug metabolism, potentially requiring larger doses to achieve the desired effect or leading to overdose.
- Inhibition can occur when two or more drugs compete for the same metabolizing enzymes.
Drug Metabolism by CYP450 Enzymes
- Many common drugs are metabolized by CYP enzymes, including paracetamol, beta-blockers, codeine, tricyclic antidepressants, fluoxetine, theophylline, warfarin, and others.
- Some substances like tobacco, cabbage, grapefruit juice, and St. John's wort can act as inducers or inhibitors of CYP enzymes.
Case Study: Paracetamol
- Paracetamol overdose can lead to the formation of a highly toxic metabolite, N-acetyl-p-benzoquinone imine.
Paracetamol Overdose Treatment
- Treatment involves replenishing glutathione (GSH) levels, which is not orally active.
- N-Acetylcysteine (NAC) is orally active and converted to GSH.
- 𝜓GSH is the orally active form of GSH.
Idiosyncratic Toxicity
- Idiosyncratic toxicity is dose-independent and often due to genetic polymorphisms or immune responses.
- It is difficult to identify and can be caused by substances like coumarin.
Coumarin Hepatotoxicity
- Coumarin exhibits high hepatotoxicity in rats, but low toxicity in humans (0.37%).
- It was banned as a foodstuff by FDA in 1954 due to its carcinogenic potential, but re-analysis of rat data suggests that the hepatic lesion was not cancerous.
Coumarin Metabolism
- Coumarin metabolism differs between rats, mice, and humans, leading to a different distribution of metabolites and potential hepatotoxins.
Contaminants
- Pure APIs can still contain by-products from synthesis that may be batch-specific or emerge during manufacturing.
- These by-products can lead to ADEs, including cancer.
- APIs degrade over time, influenced by storage conditions like heat, light, and humidity.
Contaminants and Degradation
- Degradation of APIs results in reduced API concentrations and the generation of potentially toxic by-products.
- Ranitidine and valsartan, losartan, and irbesartan were recalled due to the presence of N-Nitrosodimethylamine (NDMA), a known carcinogen.
Ranbaxy and Dr Reddy
- Ranbaxy, a major supplier of generic medicines, was involved in multiple violations of regulations and product recalls, leading to a $500 million fine and an FDA ban from selling APIs to the US.
- Dr Reddy's Laboratories was involved in the recall of ranitidine in 2019 and valsartan, losartan, and irbesartan in 2019, due to NDMA contamination.
Generics
- After a drug's patent lapses, generic versions can be marketed.
- Bioequivalence describes the extent to which generic drugs are comparable to brand-name products.
- The FDA defines bioequivalence as the absence of a significant difference in the rate and extent of active ingredient availability at the site of action, after administering the same molar dose under similar conditions.
Bioequivalence Testing
- Bioequivalence is usually measured by comparing Cmax (maximum concentration) and AUC (area under the curve) between two products.
- A generic drug is considered bioequivalent if the confidence interval (CI) of the test product falls between 0.8 and 1.25 of the reference product.
Bioequivalence Problems
- Bioequivalence testing relies on a small number of healthy volunteers, and may not capture individual variations in response.
- A 10 mg tablet of brand name drug (AUC: 1) may have a bioequivalent generic with AUC of 0.8 or 1.25, leading to variations in API dosage.
- Switching between generic drugs with different AUCs can significantly alter the actual API dose.
- This may be problematic for drugs with narrow therapeutic windows and can lead to adverse effects.
Adverse Drug Events (ADE)
- ADEs are a broad term encompassing medication errors, adverse drug reactions, allergic reactions, and overdoses
- 82% of American adults take at least one medication, with 29% taking five or more
- In 2016, the age-adjusted rate for drug-poisoning deaths was almost double for males (26.2 per 100,000) compared to females (13.4)
- In 2020, 91,799 drug overdose deaths occurred in the United States (28.3 per 100,000 people), with 75% involving opioids
Causes of ADEs
- Antibiotics are a common cause of ADEs, with a 1 in 1000 risk (allergy is most common)
- Anticoagulants are another major cause, particularly in those over 65 years of age (Warfarin, rivaroxaban, and dabigatran are in the top 10 causes)
- Phenytoin, an anti-seizure medication with zero-order kinetics, is also a frequent contributor to ADEs
- Opioid analgesia has an ADE mortality rate greater than heroin
- Insulin is another class of drugs with significant ADE risk
Unwanted Effects of Drugs
- Side effects are relatively minor and typically reversible once treatment ceases or after a short period
- Adverse effects are more serious and can potentially be life-threatening
- Drug interactions occur when unwanted effects arise due to the presence of other drugs
- Contraindications are conditions that may trigger an unwanted effect
Types of Drug Toxicity
-
Pharmacodynamic toxicity (predictable):
- Excessive pharmacological action
- Alternative pharmacological action
- Overdose toxicity
-
Pharmacokinetic (unpredictable):
- Induction, inhibition, or competition of P450 enzymes
-
Idiosyncratic:
- Allergic response
- Hyperthermia with general anesthetics
-
Withdrawal:
- Steroid, beta-blocker, anti-epileptic, PPI withdrawal
Thalidomide
- Initially marketed as a safe sedative in 1957, it was later found to be an effective antiemetic for morning sickness
- Withdrawn in 1961 due to its teratogenic effects (prevents angiogenesis)
- Wasn't tested on pregnant animals, and sensitivity to its effects varied across species
- Currently used as an immunomodulator under strict regulations to treat leprosy, cancer, graft-versus-host disease, HIV mouth ulcers, and wasting
Diethylstilboestrol (DES)
- A non-steroidal estrogen approved by the FDA in 1947 for preventing miscarriage and other estrogen deficiency conditions
- Banned for use in chickens in 1959/66
- Discovered to be a teratogen in 1971
DES Teratogenicity
- DES daughters have an increased risk of clear cell adenocarcinoma (CCA) of the vagina and cervix, breast cancer, and pregnancy-related complications like miscarriage, ectopic pregnancy, and premature labor
- DES sons and grandsons can experience urogenital abnormalities such as hypospadia
- DES grandchildren may exhibit infertility, cerebral palsy, and other issues
Drug Regulation in the 1950s
- Very little formal regulation existed, leaving most decisions to pharmaceutical companies
- No teratogenicity studies were required for drug approval, and Thalidomide wasn't approved by the FDA
- This lack of stringent oversight dramatically changed the global regulatory environment following the Thalidomide tragedy
Sources of ADEs
-
Active Pharmaceutical Ingredient (API):
- Toxicity can be species-specific or due to a metabolite
- May manifest only in a small number of patients
-
Contaminants:
- Can arise from the synthesis process or degradation of the API
-
Excipients:
- Substances used to bulk up, stabilize, coat, color, or flavor drugs
-
Propellants:
- For example, CFCs were replaced by HFCs due to environmental concerns
Why Are Toxic Drugs Allowed?
- APIs are usually well-tested in vitro and in vivo before approval
- Toxicity may manifest as a species-specific effect or due to a metabolite
- ADEs may only occur in a small number of patients, requiring extensive treatment data before detection
- Pharmacogenetics also plays a significant role in susceptibility to ADEs
Cytochrome P450 (CYP) Enzymes
- CYP enzymes metabolize medications
- Chronic administration can lead to enzyme induction (increased production of drug-metabolising enzymes)
- Induction accelerates drug metabolism, potentially requiring larger doses to achieve desired effects or leading to overdose
- Apparent inhibition can happen when two drugs compete for the same metabolizing enzymes
Drug Metabolism by CYP450 Enzymes
- Drugs can be substrates, inducers, or inhibitors of CYP enzymes
- Inducers accelerate metabolism, while inhibitors slow it down, influencing drug efficacy and potential for ADEs
Case Study: Paracetamol Overdose
- Paracetamol overdose leads to N-acetyl-p-benzoquinone imine (NAPQI) formation, which depletes glutathione (GSH)
- Treatment involves replenishing GSH with N-acetylcysteine, an orally active form that converts to GSH
Idiosyncratic Toxicity
- Dose-independent toxicity often due to genetic polymorphisms, especially CYP polymorphisms
- Can have an immunological basis
- Difficult to identify and predict
Coumarin Hepatotoxicity
- Highly toxic to rats, but low toxicity in humans (0.37%)
- Banned as a food additive by the FDA in 1954 due to potential carcinogenicity
- Reanalysis of rat data suggests the hepatic lesion was cholangiofibrosis, not a neoplasm
Contaminants
- While high purity APIs are used, some by-products from synthesis may remain
- Contamination can be batch-specific or related to changes in manufacturing conditions
- Leads to ADEs, especially cancer, due to these potentially toxic by-products
- API degradation influenced by storage conditions (heat, light, humidity) can also create contaminants
Generic Drugs
- After a drug's patent expires, generics are marketed
- Generics are expected to be bioequivalent to the branded product, meaning no significant differences in their availability at the site of action
Bioequivalence
- Defined as the confidence interval (CI) of test within 0.8 and 1.25 of the reference product
- Generic drugs must demonstrate bioequivalence with the approved product in a small number of healthy volunteers
Problems with Bioequivalence
- Bioequivalence doesn't guarantee identical API doses across products
- Switching between generics with varying API amounts can significantly impact drug efficacy and risk of ADEs
Drug Regulation Today
- Drug approval processes have become drastically more stringent over the last couple of decades
- Stricter regulations, more extensive testing, and sophisticated surveillance systems are in place to minimize ADEs
- Phase III studies, involving larger numbers of patients, are crucial in identifying rare or delayed-onset ADEs
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Description
This quiz explores various aspects of Adverse Drug Events (ADEs), including medication errors, adverse drug reactions, and the implications of drug overdoses. It highlights statistics and risk factors associated with medication use in the United States, focusing on key medications such as opioids and anticoagulants. Test your knowledge on the causes and effects of ADEs and their impact on public health.