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25 Cards in this Set
- Front
- Back
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How would the distribution for acetylation of a drug be different from distribution for "normal response" to a drug?
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"normal response"--> bell-shaped curve
acetylation--> bimodal/atypical |
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What was one early way to determine if drug metabolism was genetic?
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Twin studies-->
hereditary coefficient(HC) is equal to [var(fraternal)- var(identical)] divided by var(fraternal) HC=0 no genetic contribution, HC=1complete genetic contribution |
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Why is the HC of bishydroxycoumarin important?
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The high HC lets us know that there is a genetic contribution and we can then dose them accordingly.
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What are the mechanisms of the genetic actions?
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- receptor site abnormalities (Vit D)
-drug metabolism disorders (CYTp450) -tissue metabolism disorders (G-6-D) -anatomic abnormalities - effect of drugs on genotype (drugs causing mutagenesis) |
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Clinical Vignette I
58 y/o hispanic female diagnosed with TB sensitive to anti-TB agents. Started on isoniazid, rifamipin, ethambutol. Develops fulminant hepatitis after two months (flu-like sx and right upper quad pain) What is etiology of fulmhep, risk of mortality, and how to prevent? |
Isoniazid is normally metabolized by acetylation in phase II and patient must be a slow acetylator so drug can not be excreted and reactive intermediates build-up in the liver.
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Why are drugs acetylated?
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To make them water soluble and make excretion more efficient.
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What are consequences of slow acetylation?
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-hepatotoxicity
-isoniazid-induced hepatitis -peripheral neuropathy -phenyoin CNS toxicity -SLE |
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Clinical Vignette II
Pt in for hernia repair and give following: Pre-anesthesia relaxation--> short-acting benzodiazapene Paralysis--> succinylcholine General anesthesia--> halothane Pt fails to resume spontaneous respiration... what's wrong? |
Patient has an altered psuedocholinesterase
normally high activity leads to high dosing to compensate for low half-life. atypical enzyme is much less active. pt has atypical psuedocholinesterase so succinylcholine stays around for a long time in this patient. |
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How do you test for atypical psuedocholinesterase?
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Dibucaine test:
dibucaine inhibits the atypical enzyme less than the normal enzyme. |
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Clinical Vignette (altered oxidation of CYTp450 enzyme)
Pt goes into ER for closed angle glaucoma and treated with IV acetazolamide to reduce intraocular fluid production and topical timolol to cause miosis. Intraocular pressure drops, but patient exhibits SOB, weakness, lightheadedness. BP is 80/50 and HR is 40 and he begins wheezing. Pt goes into acute cardiopulmonary arrest and you resuscitate him. What happened and why? |
Patient has abnormal CYTp2d6 which is the CYTp450 enzyme that metabolizes beta-blockers such as Timolol.
(known as Sperteen-Bursaquin polymorphism) |
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What are other drugs metabolized by CYTp2d6?
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CODEINE metabolized to morphine.
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What can be learned from the actions of the drug paroxetine?
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-variations in clearance are small compared to a drug's large therapeutic index
-there may be more effective competetive inhibition for other substrates metabolized by the same enzyme -the mutant enzyme may be more susceptible to saturation kinetics. |
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What drug metabolism is influenced by mutant CYTp2c19?
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Mephenytoin
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What action do poor metabolizers of mephenytoin lack?
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Hydroxylation of mephenytoin prior to glucuronidation and urinary excretion causing sedation and ataxia.
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What drug metabolisms are influenced by CTYp2c9?
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tolbutamide and warfarin
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What is another important genetic site of influence in the metabolism of warfarin?
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Vitamin K epoxide reductase...this is a tissue metabolism disorder.
Epoxide is responsible for regenerating Vitamin K. Excess reductase means they are warfarin resistant. |
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Clinical Vignette (tissue metabolism)
19 yo male born in Sicily presents with SOB, weakness, fatigue. had a meal of meat and fava beans. No smoking or alcohol. Dark urine and low hematocrit so he has hemolytic anemia. This is classic G6PD deficiency. |
Makes patients resistant to malaria.
G6PD functions in RBC to generate glutathione. Also there is a low ratio of NADPH/NADP in deficient patients. Drugs push the ratio further down by causing oxidative stress. |
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What drug causes problems if patient has G6PD deficiency?
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Primaquine
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Clinical Vignette
45 yo black man has cardiac transplant. On a regimen of azathiprine, steroids, and cyclosporine to suppress rejection. Develops hyperuricemia with excess urate which is treated with allopurinol. Develops infection with gram negative org. Patient dies despite antimicrobial therapy. CBC reveals patient is myelosuppressed with absolute neutrophil count <500. What's wrong? |
patient has thiopurine methyltransferase deficiency.
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How is azothioprine affected by this thiopurine methyltransferase?
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Azothioprine metabolized to mercaptopurine which is then metabolized ot inactive metabolite by methylation by TPMT.
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What is the alternate metabolism pathway for azothioprine?
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Metabolism into uric acid via xantine oxidase.
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What is the genetic component of malignant hyperthermia?
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Some pts have an altered calcium channel and when there is uncontrolled release of calcium you get this. Treated with dantrolene which is a muscle relaxant that decreases calcium release.
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What is the cause of hereditary methhemeglobinemia?
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Deficient NADH methhemoglobin reductase.
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What is a pharmacogenetic cause of hepatic porphyria?
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Excess production of porphyrins induced by phenobarbital.
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Why would a patient develop coumarin resistance?
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Excess vitamin K epoxide reductase.
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