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*What happens to drug Lipid solubility after it is metabolized?
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*Drug becomes more hydrophilic less lipid soluble so they can be excreted.
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*CHRONIC alcohol use induces P450 which is located on?
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* Chronic alcohol use INDUCES P450 (CYP2E1) which functions In SER(SMOOTH ER involved in detoxification and lipid metabolism)*Acute alcohol use actually inhibits P450(Thus INCREASES Concentration of other drugs metabolized by this system)
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*Displacement of drug from tissue proteins will do what to Volume of distribution and what will happen to effect of drug?
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*Transient increase in effect of drug.*Volume of distribution Decreases(Vd=Theoretical Concentration of drug in whole body/Concentration of drug in plasma.(As you displace it from tissue proteins more drug enters plasma so the ratio will decrease)
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*Azole antifungal drugs were cause of increased toxicity of older antihistamine drugs, why?
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*Azoles are inhibitors of P450 system, thus they increase concentration of drugs metabolized by this system(Thus increased intensity of side effects is a possibility)*Remember:
Azoles target fungal cell wall by inhibiting Ergosterol synthesis.These drugs also inhibits another enzyme-this effect is responsible for antiandrogenic effects>GynecomastiaThis enzyme is *Cholesterol Desmolase.*Don't forget that it also Hepatotoxic drug. |
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*Why ritonavir would be awesome addition to Therapy for HIV?
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*Ritonavir is a Protease Inhibitor(Prevents maturation of virions) it inhibits P450 so you can reduce the dose needed of other drugs(Like indinavir), but don't forget to decrease dose as inhibition of P450 can actually can cause Increase in intensity of side effects.
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*Patient on warfarin gets severe bleeding episode, which class of antiarrhythmic he is most likely on, what function tests should you check?
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*Class III (patient is most likely on Amiodarone) which inhibits P450 and thus can increase warfarin concentration(Thus more inhibition of Epoxide reductase which now can't convert VitK to active form-hydroxyquinone>Less Ycarboxylation of 2,7,9,10,protein C and S > Thus increased bleeding chance).*When patient is on amiodarone you should check Pulmonary,Liver,Thyroid function tests.*So if they describe patient with Cold intolerance,bradychardia(HYPOthyroidism) or palm swearing, tachycardia(HYPERthyroidsim) don't get confused.*On ECG you might see AP,ERP,QT prolongation.
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What reaction but more importantly which PHASE METABOLISM, is responsible for toxic affects of acetaminophen(Focal to massive hepatic necrosis)?
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Even though it is mainly eliminated after conjugation reactions in liver(Phase 2), NAPQ(Toxic metabolite that depletes gluathione) is formed by OXIDATION reaction during phase ONE metabolism by P450 enzymes.*Reverse by Nacetylcysteine(Regenerates glutathione)*Remember you first loose phase 1 metabolism as you age You stop being HOR (Hydroylation,Oxidation,Reduction) and have More GAS (Methylation,Glucoronidation,Acetylation,Sulfation as you age)*Also remember that CHRONIC alcohol use can increase toxicity(REDUCING HEPATOTOXIC DOSE) due to INDUCTION of P450 and thus INCREASING toxic metabolite formation.(Cyp2E1).*P450 system induction is often manifested by increased synthesis of Smooth ER.
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*Ethanol is special because bioavailability(Amount of drug that reaches plasma without being changed) varies by gender while effect on P450 depends on usage, can you elaborate?
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*Bioavailability is Lower in males Due to greater First-pass effect in Stomach, alcohol is also metabolized in liver.Chronic alcohol use induces P450 system thus SER synthesis, decreasing concentration of drug thus increasing needed dose for particular effect.Acute alcohol use Inhibits P450 thus decreasing dose needed for effect, due to increase in concentration of drug as a result of decreased drug metabolism.*Acetaminophen toxicity is Increased by induction(Chronic aclohol use-inducing Cyp2E1) because its METABOLITE is what depletes glutathione by communicating with it by sulfhydryl groups.(remember glutathione is needed for free radical neutralization,specifically H2O2)
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*P-glycoprotein(MDR1 protein) takes out toxins and chemotherapy out of cell, decreasing intracellular concentration, which drug inhibits P-glycoprotein and is often used to enhance cytotoxic effects of methotrexate?*Note this protein is ATP dependent and decreases INTRAcellular concentration by pumping thing OUT thus potentially Increasing concentration in Extracellular space.
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*Verapamil(Non-dihydropyridine Ca channel blocker with side-effects of:*Gingival hyperplasia,Gynecomastia, edema,constipation,Hypotension AV block)*Verapamil blocks P-glycoprotein>Increased cytotoxicity of Methotrexate(DHR inhibitor)*Do not confuse this with Lecuovorin administration with methotreaxate to treat myelosupression by regenerating Thymidine levels for proper DNA,RNA synthesis.
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Why you don't give PM,EM,UM with genotype of CYP2C19 clopidogrel what are alternatives?Note:Clopidogrel is IRREVERSIBLE inhibitor of ADP receptor mediated platelet aggregation that lasts for Lifespan of platelet.
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*Well Poor metabolizer would have insufficient inhibition of platelets because Clopidogrel is a prodrug that is metabolized to active form by CYP2C19.*Extensive Metabolizers or Ultrarapid Metabolizers have higher risk of bleeding(due to excessive effect)*Prasugrel and Ticagrelor are alternatives as they don't need activation By P450 system.
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Guy who develops extensive rash after being on Abacavir(NRTI-Guanine analog that inhibits HIV reverse transcriptase enzyme) is determined to be Extensive metabolizer with genotype of?
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HLAB B*57:01 thus he is also prone to develop liver damage if he will be on flucloxacillin(he might be treated for urinary tract infection by this bactericidal antibiotics that inhibit DNA topoisomerase II( preventing unwinding and supercoilling of DNA>no replication)
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Everyone can figure out that G6PD-A(canon) polymorphism is associated with increased risk of hemolysis and increased resistance to malaria, but is it a gain of function or loss of function?
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*it is due to Reduced function of the allele> Reduced intracellular glutathione(Not enough NADH generated by G6PD>Not enough NADPH for Glutathione reductase>Not enough glutathione to detoxify free radicals)>Increased risk of hemolysis but also less risk of malaria(RBC can't live long enough for parasite to take over.)*Remember that G6PD is X-linked recessive disease more common in African Americans.(hemolysis is often precipitated by Primaquine,anti-TB drugs,sulfonamides,Fava beans, INFECTION.)Characterized by heinz bodies(Denatured hemolgobin due to free radicals creates cytoplasmic inclusions) and Bite cells( when splenic macrophages bite out these inclusions of denatured hemoglobin you get these abnormally shaped RBC's).AND NO IT IS NEVER TOO MUCH TO REPEAT THIS DISEASE and ITS ASSOCIATION WITH DRUGS.(PLEASE)
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*Everyone knows that grapefruit juice inhibits P450, but how they will confuse you?
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*They will just give you Furanocoumarins as an option(Component in the juice that inhibits P450)*So it can increase conc/toxicity of drugs .
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