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Questions and Answers
A patient with a genetic polymorphism resulting in ultra-rapid metabolism is prescribed codeine for pain management. Which of the following outcomes is most likely?
A patient with a genetic polymorphism resulting in ultra-rapid metabolism is prescribed codeine for pain management. Which of the following outcomes is most likely?
- Normal analgesic effect, as codeine metabolism is unaffected by genetic polymorphisms.
- Increased analgesic effect due to enhanced conversion to morphine. (correct)
- Prolonged analgesic effect due to slower elimination of morphine.
- Reduced analgesic effect due to rapid inactivation of codeine.
A patient who is a poor metabolizer of CYP2C19 is prescribed clopidogrel after a stent placement. What is the most probable consequence of this pharmacogenomic interaction?
A patient who is a poor metabolizer of CYP2C19 is prescribed clopidogrel after a stent placement. What is the most probable consequence of this pharmacogenomic interaction?
- Normal therapeutic effect of clopidogrel, as the alternative metabolic pathways compensate.
- Reduced effectiveness of clopidogrel, leading to a higher risk of thrombotic events. (correct)
- Increased risk of bleeding due to enhanced platelet inhibition.
- Unpredictable response to clopidogrel, necessitating frequent monitoring.
A patient with a UGT1A1 polymorphism, leading to reduced enzyme activity, is treated with irinotecan for colon cancer. Which toxicity is most likely to be exacerbated in this patient?
A patient with a UGT1A1 polymorphism, leading to reduced enzyme activity, is treated with irinotecan for colon cancer. Which toxicity is most likely to be exacerbated in this patient?
- Nephrotoxicity.
- Cardiotoxicity.
- Severe bone marrow suppression. (correct)
- Hepatotoxicity.
A patient with end-stage renal disease requires frequent drug dosing adjustments due to impaired drug elimination. Which of the following processes is least affected by renal dysfunction?
A patient with end-stage renal disease requires frequent drug dosing adjustments due to impaired drug elimination. Which of the following processes is least affected by renal dysfunction?
A drug is known to undergo both glomerular filtration and active tubular secretion. In a patient with normal renal function, what effect would probenecid (a competitive inhibitor of organic anion transporters) have on the drug's renal clearance?
A drug is known to undergo both glomerular filtration and active tubular secretion. In a patient with normal renal function, what effect would probenecid (a competitive inhibitor of organic anion transporters) have on the drug's renal clearance?
A patient is stabilized on a drug that is a weak base. If the patient's urine pH is significantly alkalinized, what is expected to happen to the drug's renal clearance?
A patient is stabilized on a drug that is a weak base. If the patient's urine pH is significantly alkalinized, what is expected to happen to the drug's renal clearance?
How does manipulating urine pH to increase drug ionization aid in treating drug overdose?
How does manipulating urine pH to increase drug ionization aid in treating drug overdose?
A patient overdoses on phenobarbital, a weak acid with a pKa of 7.4. Which intervention would most effectively increase the drug's renal clearance?
A patient overdoses on phenobarbital, a weak acid with a pKa of 7.4. Which intervention would most effectively increase the drug's renal clearance?
A drug is eliminated by first-order kinetics with a half-life of 6 hours. If the initial plasma concentration is 200 mg/L, how long will it take for the concentration to drop to 25 mg/L?
A drug is eliminated by first-order kinetics with a half-life of 6 hours. If the initial plasma concentration is 200 mg/L, how long will it take for the concentration to drop to 25 mg/L?
A new drug is found to be eliminated via zero-order kinetics. Which statement best describes its elimination?
A new drug is found to be eliminated via zero-order kinetics. Which statement best describes its elimination?
A patient is on a high dose of phenytoin, and the drug's elimination switches from first-order to zero-order kinetics. What is the most likely cause of this change?
A patient is on a high dose of phenytoin, and the drug's elimination switches from first-order to zero-order kinetics. What is the most likely cause of this change?
A drug is administered intravenously and follows first-order kinetics. After 8 hours, 75% of the drug has been eliminated. What is the approximate half-life of the drug?
A drug is administered intravenously and follows first-order kinetics. After 8 hours, 75% of the drug has been eliminated. What is the approximate half-life of the drug?
A patient is started on a medication that is known to be a substrate of CYP3A4 and also exhibits significant first-pass metabolism. Which of the following concomitant medications would most likely lead to a supratherapeutic level of the object medication?
A patient is started on a medication that is known to be a substrate of CYP3A4 and also exhibits significant first-pass metabolism. Which of the following concomitant medications would most likely lead to a supratherapeutic level of the object medication?
A novel drug predominantly binds to albumin in the plasma. A patient with hypoalbuminemia is administered this drug. What adjustments should be considered to maintain optimal therapeutic outcomes?
A novel drug predominantly binds to albumin in the plasma. A patient with hypoalbuminemia is administered this drug. What adjustments should be considered to maintain optimal therapeutic outcomes?
An elderly patient with declining renal function is prescribed a medication that is primarily cleared through glomerular filtration. What pharmacodynamic or pharmacokinetic change is most anticipated?
An elderly patient with declining renal function is prescribed a medication that is primarily cleared through glomerular filtration. What pharmacodynamic or pharmacokinetic change is most anticipated?
Flashcards
Pharmacogenomics
Pharmacogenomics
Study of genetic factors underlying drug response variations.
Extensive Metabolizer (EM)
Extensive Metabolizer (EM)
Metabolizes drugs exactly as expected, yielding expected responses.
Ultra-Rapid Metabolizer (UM)
Ultra-Rapid Metabolizer (UM)
Metabolizes drugs much faster than normal, leading to reduced drug efficacy.
Poor Metabolizer (PM)
Poor Metabolizer (PM)
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Prodrug
Prodrug
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Codeine
Codeine
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Clopidogrel
Clopidogrel
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Irinotecan
Irinotecan
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Drug Elimination
Drug Elimination
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Glomerular Filtration
Glomerular Filtration
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Organic Anion Transporter (OAT)
Organic Anion Transporter (OAT)
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Organic Base Transporter (OBT)
Organic Base Transporter (OBT)
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Urine pH & Drug Elimination
Urine pH & Drug Elimination
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First-Order Elimination
First-Order Elimination
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Zero-Order Elimination
Zero-Order Elimination
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Study Notes
Predicting the Impact of Select Genetic Polymorphisms on Drug Metabolism
- Pharmacogenomics studies genetic factors causing varied drug responses
- Also known as pharmacogenetics, and it focuses on DNA's influence on drug metabolism
- Phase one enzymes metabolize about 75% of prescription drugs
- Polymorphisms in these enzymes significantly change blood levels
Metabolic Phenotypes
- Extensive Metabolizer (EM): Normal metabolism rate, converts drugs at expected rates
- Intermediate Metabolizer (IM): Reduced metabolism efficiency, leading to toxicity risk
- Poor Metabolizer (PM): Slowest metabolism, causing drug accumulation and high toxicity risk
- Ultra-Rapid Metabolizer (UM): Fast metabolism, reducing drug efficacy (lower plasma levels)
Drug Examples
- Codeine: Pro-drug, converted to morphine by CYP2D6, morphine is more potent
- EMs experience normal pain relief
- PMs have insufficient pain relief due to poor conversion
- UMs have increased side effects like CNS and respiratory depression
- Clopidogrel: Antiplatelet drug, metabolized by CYP2C19 into an active metabolite
- PMs results in ineffective drug action against clots
- UMs have increased bleeding risk due to excessive platelet inhibition
- Irinotecan: Chemotherapy pro-drug, converted to SN-38 which inhibits cancer cell replication, SN-38 inactivated by UGT1A1
- PMs with inefficient UGT1A1, resulting in SN-38 accumulation, causing severe bone marrow suppression
Major Ways Drugs Are Eliminated
- Elimination differs from excretion
- Two main methods: Liver metabolism and kidney renal excretion
Renal Excretion
- Glomerular filtration filters free, unbound drugs, lipid solubility doesn't matter in this step
- Both ionized and non-ionized drugs are filtered
- Proximal tubular secretion actively transports drugs with OAT (for acids) and OBT (for bases)
- Distal tubular reabsorption occurs for non-ionized (lipid-soluble) drugs back into circulation, ionized drugs stay in urine
Impact of Urine pH
- Goal is to increase the ionized form of the drug to decrease reabsorption for increased elimination
- Normal urine pH is 5-8
- Manage overdose by targeting reabsorption
Urine pH Influence
- Weak Acid Drugs (HA non-ionized, A- ionized), alkalinize urine to increase A-
- Weak Base Drugs (B non-ionized, BH+ ionized), acidify urine to increase BH+
- Aspirin overdose treated with sodium bicarbonate to alkalinize urine
- Amphetamine overdose treated with ammonium chloride to acidify urine
Other Modes of Excretion
- GI tract: for unabsorbed oral drugs, useful in renal failure
- Pulmonary: For gasses and alcohol
- Milk: Concentrates lipophilic drugs, affecting nursing infants
Comparing First-Order and Zero-Order Kinetics
- Clearance: Rate of elimination / plasma drug concentration
- Volume per unit time
- First order elimination is the norm
- Zero order is the exception
First-Order Elimination
- Constant fraction of drug eliminated per unit time, half-life is constant
- Non-saturating kinetics
- Most drugs are eliminated this way
Zero-Order Elimination
- Constant amount eliminated per unit time and half-life is variable
- Saturating kinetics, enzymes work at Vmax
- High doses of aspirin, ethanol, and phenytoin
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