Module 8 Flashcards
Patients taking a combination of interferon-alpha and telaprevir for the treatment of viral hepatitis have a significant risk of a life-threatening rash. What are some possible mechanisms by which interferon-a could increase the risk of a telaprevir-induced rash?
○ Telaprevir-induced skin rash is presumably immune mediated. Interferon-alpha can promote inflammation and immune responses; therefore, it may help to induce an immune response to telaprevir.
○ Interferon-alpha inhibits protein synthesis. Therefore, it may decrease the levels of P450s and transporters involved in the clearance of telaprevir and increase telaprevir blood levels.
Many drugs are metabolized by the same P450 isozyme, and this can lead to drug interactions because of competitive inhibition of the enzyme. What factors determine when such interactions will be important?
○ The relative affinity of the two drugs for the enzyme, i.e. if the inhibiting drug has a lower affinity than the primary drug it will not significantly inhibit the metabolism of the other drug.
○ Whether the P450 that is being inhibited is the major mode of clearance of the other drug.
Whether the drug whose metabolism is being inhibited has a narrow therapeutic index, i.e. would increasing its concentration likely lead to toxicity
How could drinking alcohol increase or decrease the risk of acetaminophen hepatotoxicity, and what would determine whether it is an increase or decrease?
○ Acetaminophen-induced liver injury is the major cause of liver failure in North America. Liver failure results in death unless the patient undergoes a liver transplant.
○ Most, but not all, acetaminophen-induced liver failure is caused by a large overdose
○ acetaminophen toxicity is caused by a reactive imidoquinone metabolite formed by CYP2E1.
○ Alcohol is also metabolized by CYP2E1, and at high concentrations it is an effective competitive inhibitor of the formation of the acetaminophen reactive metabolite.
○ Therefore, in theory, if you drink alcohol at the same time as you take acetaminophen it should decrease the acetaminophen hepatotoxicity. However, with chronic use, alcohol causes induction of CYP2E1, which would result in an increase in the production of the toxic metabolite of acetaminophen.
Chronic alcohol use also decreases hepatic glutathione, the major detoxication system for acetaminophen and can cause liver injury by itself.
What is the rationale for using ritonavir at subtherapeutic doses in the treatment of HIV infections?
Ritonavir is a very potent inhibitor of P450 and increases the half-life of other anti-HIV drugs thereby making them more effective
Name some drug interactions that can lead to pregnancy in someone on birth control pills.
aromatic anticonvulsants (e.g. carbamazepine and phenytoin) increase the clearance of ethinyl estradiol and other agents such that they may be decreased to subtherapeutic levels. ○ In addition, a major mode of clearance of the hormones in BC pills is transport of conjugates (glucuronides and sulfates) into bile. These conjugates are cleaved by gut bacteria leading to reabsorption of the hormone (enterohepatic cycling). If the bacteria are killed, less of the conjugates are hydrolyzed, and this leads to a decrease in the blood level of the hormones.
The combination of digoxin and quinidine was used for decades in patients with cardiovascular disease before it was discovered that quinidine caused a marked increase in digoxin levels, often to toxic levels. Digoxin was known to be cleared both by metabolism and renal clearance of the parent drug, and yet quinidine had little effect on either. How does quinidine affect digoxin blood levels?
○ What was not known at the time is that a significant mode of digoxin clearance involves transport into the gut by P-glycoprotein. Quinidine is a strong competitive inhibitor of P-glycoprotein, and when given with digoxin, inhibits this mode of clearance resulting in higher, and sometimes toxic, blood levels of digoxin.
