Lecture 8 - Individual Variation in Drug Response

‭The “Standard” Dose‬ ‭●‬ ‭Standard dose: Median effective dose (ED50)‬ ‭●‬ ‭Generally, dose selected for initial treatment‬ ‭●‬ ‭Not everyone response the same way to the‬ ‭standard dose‬ ‭ uestion:‬‭Why do nurses need to know the therapeutic‬ Q ‭effects as well as potential adverse drug reactions?‬ ‭●‬ ‭Patient education‬ ‭●‬ ‭Knowing what to monitor for‬ ‭●‬ ‭Being prepared for a possible intervention‬ ‭Individual Variability in Drug Response: Nursing Implications‬ ‭●‬ ‭Standard doses are an approximation, the dose may vary based on patient response‬ ‭●‬ ‭Anticipate response, but don’t assume‬ ‭●‬ ‭Evaluation:‬‭The possibility of variability emphasizes‬‭the necessity of assessing patients’‬ ‭responses to ensure patient safety, well-being, and monitoring for therapeutic response‬ ‭●‬ ‭Documentation/Communication:‬‭Document/report patient’s‬‭response to the prescriber‬ ‭so appropriate adjustments may be made‬ ‭ uestion:‬‭Dose requirements for drugs with a narrow‬‭therapeutic index are most accurately‬ Q ‭calculated based on the patient’s…‬ ‭a.‬ ‭Body weight‬ ‭b.‬ ‭Height‬ ‭c.‬ ‭Body mass index‬ ‭d.‬ ‭Body surface area‬ ‭Sources of Individual Variation Affecting Pharmacokinetics/dynamics‬ ‭Morphometric‬ ‭●‬ ‭Body size: Body surface area most accurate way to calculate drug dose‬ ‭●‬ ‭Body composition‬ ‭○‬ ‭Muscle mass‬ ‭○‬ ‭Adiposity: Affects distribution and drug concentration at site of action‬ ‭■‬ ‭Impacts patient response‬ ‭○‬ ‭Malnourishment → lower albumin → increased “free drug”‬ ‭Drug Specific‬ ‭●‬ ‭Dose and schedule: More frequent → more likely to improperly administer (timing)‬ ‭●‬ ‭Formulation: Oral, IV, IM, SQ, topical, transdermal‬ ‭○‬ ‭Oral: Most variability‬ ‭‬ E ■ ‭ nteric coated: Pass through stomach and absorbed in the SI‬ ‭■‬ ‭Extended/sustained release: Designed to release drug over time, less doses‬ ‭needed‬ ‭Environment‬ ‭●‬ ‭Drug-drug interactions‬ ‭●‬ ‭Drug-food interactions‬ ‭●‬ ‭Drug-supplement interactions (ex. fiber)‬ ‭●‬ ‭Drug-CAM interactions‬ ‭○‬ ‭Complimentary alternative medicine‬ ‭○‬ ‭Ex. herbal supplements‬ ‭○‬ ‭Limited data on effects; no FDA approval‬ ‭Physiologic‬ ‭●‬ ‭Disease‬ ‭●‬ ‭Hepatic function: Metabolism‬ ‭○‬ ‭Impaired → more drug available‬ ‭○‬ ‭Ex. cirrhosis, cancer, hepatitis‬ ‭●‬ ‭Renal function: Excretion‬ ‭●‬ ‭Acid-base imbalance: pH-dependent ionization‬ ‭●‬ ‭Altered electrolytes:‬ ‭○‬ ‭Impacts effect on cellular level‬ ‭○‬ ‭Ex. low potassium affects digoxin’s ability‬ ‭to cause dysrhythmias‬ ‭ uestion:‬‭Which of the following is a decreased responsiveness‬‭to a drug brought on by‬ Q ‭repeated drug administration over longer periods of time?‬ ‭a.‬ ‭Bioavailability‬ ‭b.‬ ‭Physical dependence‬ ‭c.‬ ‭Tolerance‬ ‭d.‬ ‭Tachyphylaxis‬ ‭Tolerance‬ ‭●‬ ‭A decreased responsiveness to a drug after repeated administration over time‬ ‭●‬ ‭Pharmacodynamic:‬‭Result of adaptive processes due‬‭to chronic receptor occupation‬ ‭○‬ ‭Increased MEC → higher drug level to produce an effect‬ ‭●‬ ‭Metabolic:‬‭Result of accelerated drug metabolism;‬‭rids body of drug quickly‬ ‭●‬ ‭Tachyphylaxis:‬‭Rapidly diminishing responses to successive‬‭doses of drug‬ ‭○‬ ‭Common in drugs affecting the CNS (ex. aphrin)‬ ‭Patient Characteristics‬ ‭●‬ ‭Age: Very young or old‬ ‭●‬ ‭Ethnicity/genetic origin‬ ‭○‬ ‭Metabolism (East Asian vs. European)‬ ‭●‬ ‭Sex: Male vs. female‬ ‭○‬ ‭More studies done on males‬ ‭○‬ ‭May be related to genetics or hormone response‬ ‭Genetics‬ ‭●‬ ‭Variations in metabolic enzymes, transporters, receptors, etc.‬ ‭●‬ ‭Pharmacogenetics:‬‭Study of genetic influence on drug‬‭response‬ ‭●‬ ‭Pharmacogenomics:‬‭Study of how genomic variation influences‬‭drug response, looking‬ ‭at variation across the genome; includes lifestyle and environment‬ ‭Genetic Variation‬ ‭●‬ ‭Pharmacogenomics (PGx):‬‭Study of variations in human‬‭DNA sequence and how‬ ‭genetic factors might influence how individuals respond to drugs‬ ‭○‬ ‭Pharmacokinetic variation (metabolism, enzymes)‬ ‭○‬ ‭Pharmacodynamic variation (receptors)‬ ‭○‬ ‭Quicken or slow down drug response‬ ‭●‬ ‭Precision medicine:‬‭Approach to finding effective‬‭strategies for treating similar groups‬ ‭of patients with specific genetics, lifestyles, and environmental factors‬ ‭○‬ ‭Could result in maximal benefit and minimal adverse effects‬ ‭Application of Pharmacogenomics‬ ‭●‬ ‭Tests can be used to guide treatment‬ ‭●‬ ‭Tests look at gene characteristics (‬‭biomarkers‬‭) related‬‭to drug responses‬ ‭○‬ ‭How genes response to and metabolize certain medications‬ ‭○‬ ‭Measurable substance indicating ab/normal processes, diseases, or conditions‬ ‭●‬ ‭Testing can be done using blood, saliva, urine, amniotic fluid, tissue, or hair‬ ‭●‬ ‭High importance in medications with a narrow therapeutic index‬ ‭●‬ ‭Rapidly expanding business‬ ‭●‬ ‭Cost can be prohibitive (> $1,000)‬ ‭Cytochrome P450‬ ‭●‬ ‭Superfamily of enzymes (> 55 genes)‬ ‭●‬ ‭CYP2C9, CYP2C19, CYP2D6, CYP3A4 are involved in the metabolism of > 80% of‬ ‭OTC medications‬ ‭●‬ ‭Gene nomenclature: [Human]CYP2D6*5‬ ‭○‬ ‭Superfamily: CYP‬ ‭‬ ○ ‭○‬ ‭○‬ ‭○‬ ‭ amily: 2‬ F ‭Subfamily: D‬ ‭Isoform: 6‬ ‭Allele: 5‬ ‭Phenotype: Prediction from Genotype Data‬ ‭●‬ ‭Refers to metabolizer status; four groups‬ ‭●‬ ‭Ultra rapid metabolizer (UM):‬‭Rapid breakdown of medication‬ ‭○‬ ‭May be removed from system too quickly to provide symptom relief‬ ‭●‬ ‭Extensive/normal metabolizer (EM):‬‭Normal rate of‬‭metabolism‬ ‭○‬ ‭Normal amount of medication at standard doses‬ ‭●‬ ‭Intermediate Metabolizer (IM):‬‭Slow rate of metabolism‬ ‭○‬ ‭May have too much medication at standard doses‬ ‭○‬ ‭Potentially causing side effects‬ ‭●‬ ‭Poor metabolizer (PM):‬‭Medication is broken down very‬‭slowly‬ ‭○‬ ‭More available; may experience side effects at standard doses‬ ‭○‬ ‭If prodrug, no activation‬ ‭CYP2D5 and Codeine‬ ‭●‬ ‭Codeine metabolizes into morphine, which is more potent‬ ‭●‬ ‭Poor metabolizer:‬‭Avoid due to possibility of diminished‬‭analgesia‬ ‭●‬ ‭Ultrarapid metabolizer:‬‭Avoid due to potential for‬‭toxicity‬ ‭○‬ ‭Respiratory depression with morphine overdose‬ ‭CYP2C9 and Warfarin/Coumadin‬ ‭●‬ ‭Variants in the gene that codes for CYP2C9 can increase risk of toxicity‬ ‭●‬ ‭Warfarin has a narrow therapeutic index‬ ‭●‬ ‭Patients with altered CYP2C9 genes produce a form of the enzyme that decrease the‬ ‭metabolism of warfarin → increased effect and excessive bleeding‬ ‭●‬ ‭FDA now recommends patients be tested for variants of CYP2C9‬