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Clinical Relevance of Drug
Metabolism
Genetic polymorphisms in the CYP and other biotransforming drugs can account for some of the variation seen in drug response between patients. Genetic polymorphisms account for hair color, eye color, skin color etc etc differences. Genetic polymorphisms in the CYP and other enzymes account for differences in drug response TERM 2
Succinylcholine (Anectin)
DEFINITION 2 muscle relaxant used prior and sometimes during surgery. Complete relaxation is required for intubation. The enzyme pseudocholinesterase biotransforms succinylcholine and the patient wakes up after the iv is stopped (the enzyme is quickly removing the drug, iv drip keeps the drug flowing and keeps up with the enzyme that is removing the drug). Patients with a genetic polymorphism of this enzyme will take much longer to biotransform succinylcholine. Stop the iv and patient does not wake up. Assisted ventilation required to keep patient breathing until the drug is finally removed from the body. GTQ (good test question). The genetic polymorphism results in an esterase enzyme that requires more time to biotransform the succinylcholine drug TERM 3
Forms that the genetic polymorphisms can
take
DEFINITION 3 When the enzyme (CYP or other) is increased (more genes than normal) then patients have more enzyme than the normal and they biotransform the drug faster. These are called ultrarapid metabolizers. When the gene is reduced in expression or absent, the enzyme is missing and the patient can not remove the drug as fast and they are slow or poor metabolizers, TERM 4
terms
DEFINITION 4 Extensive metabolizers = normal wild type metabolizers A Note about terms. In genetics the normal are called wild type. Who is to say that the slow metabolizers are not normal what ever that means. We do not say that blond hair is abnormal and black hair is normal. In genetics we use the term ethnic group. The term race is a political term with little to no scientific meaning TERM 5
allelic
variant
DEFINITION 5 When there is a well defined genetic polymorphism in a CYP enzyme, that enzyme is coded to show that it is an allelic variant, for example CYP 2C9*3 means that the liver enzyme CYP named the 2C9 has a allelic variant that has been given the number 3 and the * says an allelic variant has been identified.
SNP (single nucleotide polymorphism).
When the genetic polymorphism causes a substitution of one amino acid in a protein (CYP or other enzyme) this type of polymorphism is called a SNP (single nucleotide polymorphism). TERM 7
Individual Differences in Drug
Biotransformation
DEFINITION 7 Diet & Environmental Factors : Charcoal-broiled foods; grapefruit juice etc Age and Gender : slower rates in elderly. Drug-Drug Interactions: Induction, Inhibition. Depletion of Endogenous Compounds : Glutathione and acetaminophen. Disease Onset: Liver, kidney. Genetics: Pharmacogenomics. TERM 8
Traditional Causes of ADRs
DEFINITION 8 Drug-Drug interactionsChanges due to age (Geriatric Pharmacology)Disease factors (renal, liver etc)Lifestyle (alcohol, smoking etc)Medication and/or dosing errors.GENETIC VARIABILITY (Pharmacogenomics) TERM 9
Aspirin Pharmacogenomics
DEFINITION 9 Daily low dose aspirin (~ 80 mg po) as prophylaxis against thrombotic events.Up to 30% of individuals are aspirin resistant with 3x higher incidence of stroke and death.Aspirin target is cycloxygenase-1 (COX-1) enzyme in platelets which blocks synthesis of platelet activator thromboxane A2 Genetic polymorphisms in target enzyme account for aspirin non- responders.FDA cleared laboratory assays (platelet aggregometry) used to screen for non-responders. TERM 10
Warfarin Pharmacogenomics
DEFINITION 10 Warfarin (coumarin) oral anticoagulant inhibits activation of prothrombin and Vitamin K.Genetic polymorphisms in a liver enzyme account for ADR (bleeding) at usual dosesWarfarin (coumarin) is biotransformed to inactive metabolites by the liver enzyme CYP 2C9.CYP 2C9 genetic polymorphisms produce a liver enzyme with reduced capacity to metabolize warfarin. Dose reductions of up to 90% required to achieve therapeutic goal and prevent toxicity (bleeding).
primaquine -continued again
Mechanism: oxidative stress in RBC like from drugs, food metabolites (fava beans) and intracellular parasites leads to free radical oxidation (cell wall destruction).G6PD deficient RBCs can not protect from this cascade of metabolic damage. RBC G6PD deficiency linked to primaquine sensitivity and malarial distribution in worlds population. TERM 17
Isoniazid
DEFINITION 17 Combination: Isoniazid + Rifampin after 9 months po dosing, 95% cases cured.Rifampin blocks microbial RNA polymerase.Isoniazid blocks synthesis of mycolic acids in TB required for cell wall synthesis. Isoniazid major biotransformation is through Phase II acetylation. NAT enzyme.Block of Vitamin B6 (pyridoxine) metabolism. (add B6 to dose regimen). TERM 18
Thiopurine methyltransferase (TMP)
DEFINITION 18 cytoplasmic enzyme found in the liver (Phase II).TMP adds methyl group to -SH group on xenobiotic which inactivates the xenobioticTMP inactivates thiopurine drugs used to treat acute lymphoblastic leukemia, autoimmune disorders, inflammatory bowel disease TERM 19
FDA Guide for Product Labeling
DEFINITION 19 Include pharmacogenomic data to adjust dose based on biotransformation data (CYP enzymes). Mention possibility of side effects with greater frequency in individuals with certain genotype. Use pharmacogenomic data to identify patients as responders or non-responders
