Metabolism and Excretion Flashcards
Describe the processes of Phase 1 and 2 metabolism.
Phase 1 and Phase 2 Metabolism are the two main stages of drug metabolism, primarily occurring in the liver, that modify drugs to make them easier to eliminate.
Phase 1 involves functionalization reactions like oxidation, reduction, or hydrolysis, often by CYP450 enzymes. This process either activates prodrugs or makes the drug more polar, which aids in excretion.
Phase 2 involves conjugation with larger, water-soluble molecules (e.g., glucuronidation, sulfation), making the drug even more water-soluble for excretion via urine or bile.
Together, Phase 1 and 2 metabolism increase drug solubility and reduce toxicity, but variations in these processes (e.g., genetic differences in enzyme activity) can impact drug effectiveness and safety. Drug-drug interactions and genetic polymorphisms are key factors influencing how drugs are metabolized.
Discuss the role of cytochrome P450 in drug metabolism.
Cytochrome P450 (CYP450) enzymes are crucial in Phase 1 drug metabolism, primarily responsible for oxidizing drugs to make them more water-soluble for excretion. These enzymes are found mainly in the liver and help convert lipophilic drugs into more polar forms. They also activate prodrugs and can sometimes produce toxic metabolites.
Key points include:
CYP450 enzymes play a role in drug metabolism, including the oxidation of drugs and endogenous compounds.
CYP3A4 is the most significant enzyme for drug metabolism, while others like CYP2D6 and CYP2C9 are also important for metabolizing specific drugs.
Genetic variability, drug-drug interactions, and factors like diet or age can affect CYP450 activity, influencing drug efficacy and toxicity.
Drug interactions and genetic polymorphisms can result in under-dosing or toxicity, highlighting the importance of understanding CYP450 in personalized medicine.
Overall, CYP450 enzymes are critical for safe and effective drug therapy, influencing how drugs are metabolized, activated, or inactivated in the body.
Recognise factors, including drugs, which may inhibit or induce drug metabolism and provide medically relevant examples.
Certain drugs and substances can either inhibit or induce Cytochrome P450 (CYP450) enzymes, which play a key role in drug metabolism. These interactions can affect the effectiveness and safety of medications.
Inhibitors slow down drug metabolism, potentially increasing drug levels and causing toxicity. Examples:
Grapefruit juice (CYP3A4 inhibitor) can raise levels of statins, increasing the risk of muscle toxicity.
Ketoconazole (an antifungal) inhibits CYP3A4, increasing the risk of sedation with benzodiazepines.
Inducers speed up drug metabolism, reducing drug effectiveness and increasing the risk of therapeutic failure. Examples:
Rifampin (antibiotic) induces CYP3A4 and can reduce the effectiveness of oral contraceptives.
Phenytoin (anticonvulsant) speeds up metabolism of warfarin, increasing the risk of thrombosis.
Factors like genetics, age, liver function, and diet can influence how drugs are metabolized. Understanding these interactions is crucial for preventing adverse effects and ensuring effective treatment.
Discuss, briefly, the importance of pharmacogenetics
Pharmacogenetics is the study of how genetic variations affect an individual’s response to drugs, enabling more personalized medicine. It helps:
Tailor treatments to improve drug efficacy and reduce adverse effects by considering genetic factors that influence drug metabolism and response.
Reduce adverse drug reactions (ADRs) by identifying patients at risk based on their genetic makeup.
Enhance drug efficacy by matching patients to medications that work best for their genetic profile (e.g., HER2-positive breast cancer patients benefit from trastuzumab).
Minimize drug toxicity by identifying genetic variations that affect drug metabolism, like TPMT variations in patients taking azathioprine.
Improve cost-effectiveness by reducing trial-and-error prescribing and preventing harmful reactions.
Overall, pharmacogenetics allows for more effective, safer, and individualized drug therapy.
Describe factors that influence renal excretion
Renal excretion is a key process for eliminating drugs from the body, and several factors can influence its efficiency:
Renal Blood Flow (RBF) and Glomerular Filtration Rate (GFR): Reduced blood flow or GFR (e.g., in kidney disease) can slow drug elimination, increasing the risk of toxicity.
Tubular Secretion and Reabsorption: Active transport in the kidneys can either enhance excretion (e.g., through secretion) or increase reabsorption (e.g., depending on drug ionization and urine pH).
Urine pH: Affects drug ionization and reabsorption; altering urine pH can modify drug elimination (e.g., alkalinizing urine enhances elimination of acidic drugs).
Protein Binding: Only unbound drugs can be excreted, so changes in protein binding (e.g., due to liver disease) can affect drug clearance.
Age and Disease States: Aging and conditions like chronic kidney disease reduce renal function, slowing excretion and requiring dosing adjustments.
Drug Interactions: Certain drugs can alter renal excretion by affecting transporters or urine pH.
Understanding these factors helps ensure proper drug dosing and minimize the risk of drug accumulation and toxicity.
Discuss how renal disease can increase the risk of drug toxicity and explain how this can be accounted for by alterations in the dosing strategy
Renal disease increases the risk of drug toxicity by impairing the kidney’s ability to clear drugs, leading to drug accumulation. Key factors include reduced glomerular filtration rate (GFR), impaired tubular secretion, altered protein binding, and fluid/electrolyte imbalances. These changes can cause drugs to accumulate in the bloodstream, increasing the risk of adverse effects.
To account for renal disease, dosing strategies should be adjusted by:
- Reducing drug doses or extending dosing intervals based on renal function (e.g., creatinine clearance or eGFR).
- Monitoring drug levels regularly, especially for drugs with a narrow therapeutic index (e.g., digoxin, lithium).
- Considering alternative drugs with less renal dependence or adjusting the frequency of administration.
- In some cases, using lower doses or avoiding nephrotoxic drugs altogether.
Careful management through dose adjustments and monitoring helps prevent drug toxicity in patients with renal dysfunction.
