drug interactions
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Identify primary drug interaction concepts Describe types and mechanisms of interactions Identify drug interactions commonly encountered with antiretroviral drugs Describe how to manage known interactions
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- 1. BY LWASAMPIJJA BAKER (bubakes2000@gmail.com) DRUG INTERACTIONS 17/09/2009
- 4. Case Study: Lake Lake, a 50 year-old male who has been HIV+ for 5 years and is stable on therapy, presents to the clinic to get more medication to treat his thrush He has been taking his brother’s medication, which seemed to help at first and then stopped working. He would like to get some more to clear the white plaques on his tongue
- 5. Case Study: Lake (2) Oral Thrush
- 7. Case Study: Lake (4) Is this an appropriate medication to use with his current ARV regimen? What are some counseling points for this patient?
- 16. CYP 2D6: Substrates Amphetamines Codeine-to-morphine Haloperidol Hydrocodone-to-morphine. Metoprolol, propranolol Phenothiazines Risperidone TCAs(amitriptyline) Inhibitors Ritonavir Cimetidine Fluoxetine Haloperidol Paroxetine Quinidine Methadone
- 17. Interactions among HIV drugs itself: NRTIs Most important are 2 types of interactions: • Do not combine 2 NRTIs that require same enzymes for intracellular phosphorylation: – d4T + AZT – ddC, FTC, 3TC • Do not combine TDF with ddI – Increased ddI toxicity – Loss of immunological response
- 18. Interactions among HIV drugs itself: NRTIs… NNRTIs are inducers of CYP3A • PIs are substrates of CYP3A • When combining NNRTIs with PIs, usually the dose of the PI is increased, for example: – LPV/r 533/133 (4 caps) BID + EFV, or – LPV/r 600/150 (3 tabs) BID + EFV
- 20. PI/ NNRTI/ Antidepressant Drug Interactions As above Levels of sertraline may be increased. ARV levels not likely to change. ritonavir, lopinavir/r, all other Pis, efavirenz Sertraline As above Levels of both fluoxetine and ARVs may be increased ritonavir, lopinavir/r, all other PIs, efavirenz Fluoxetine Start with lower dose (50%) of amitriptyline, adjust dose when addIng ritonavir . Monitor for side effects Levels of amitriptyline may be increased ritonavir, lopinavir/r, amprenavir, Amitriptyline Management Effects Potential for Interaction Antidepressant
- 21. Metabolic Characteristics of ARVs
- 23. Food-Drug Interactions A food-drug interaction can occur when the food you eat affects the ingredients in a medication you are taking, preventing the medicine from working the way it should. Food-drug interactions can happen with both prescription and over-the-counter medications, including antacids, vitamins, and iron pills.
- 24. Food-Drug Interactions… Points to note -Advise patients to take medication with a full glass of water. -Not stir medication into food or take capsules apart (unless directed by your physician). -Do not take vitamin pills at the same time you take medication (i.e, take medication 1 hour after taking vitamins). -Not mix medication into hot drinks, because the heat from the drink may destroy the effectiveness of the drug. -Never take medication with alcoholic drinks. -Ask the patient about all medications they are taking, both prescription and non-prescription.
- 27. Drug Interaction Case Studies Case I
- 28. Case Study: Endalk Endalk is 45 year-old HIV+ male presenting for routine follow-up. He has been on HAART for two years. CD4 count: 480 cells/mm3 HIV RNA < 50 copies/mL. He comes into the pharmacy after seeing a physician for his migraines. He is glad to try a new medication as his headaches have been a problem for years. He is so distraught about them that he has begun to take an herbal product to help with his mood
- 31. Case Study II: Sara Sara is a 41 year-old female with esophageal candida and has just completed a 10 day course of fluconazole. She has lost weight because symptoms of thrush made it difficult to swallow. She weighs 62 kg. She is to begin ARV therapy today.
- 33. Case Study: Lake Lake, a 50 year-old male who has been HIV+ for 5 years and is stable on therapy, presents to the clinic to get more medication to treat his thrush He has been taking his brother’s medication, which seemed to help at first and then stopped working. He would like to get some more to clear the white plaques on his tongue
- 34. Case Study: Lake (2) Oral Thrush
- 36. Case Study: Lake (4) Is this an appropriate medication to use with his current ARV regimen? What are some counseling points for this patient?
Notes de l'éditeur
- No, this is not an appropriate therapy for his thrush Ketoconazole interacts with nevirapine Ketoconazole levels are decreased by 63% Nevirapine levels are increased by 15-30% They should not be co-administered An alternative is a topical antifungal such as nystatin suspension or miconazole oral gel Ketoconazole levels are decreased by 63% and this is most likely the reason that his thrush was not responding to the medication. Ketoconazole and nevirapine should not be given concurrently due to the decrease in ketoconazole concentrations. Coadministration of nevirapine (200 mg twice daily) with ketoconazole (400 mg once daily) to 22 HIV+ individuals resulted in a 63% reduction in ketoconazole AUC and a 40% reduction in Cmax. There was a 15–28% increase in plasma concentration of nevirapine. Although interaction studies have not been performed, antifungal medicinal products which are eliminated renally (e.g. fluconazole) may be substituted for ketoconazole. Studies using human liver microsomes indicated that ketoconazole significantly inhibited the formation of nevirapine hydroxylated metabolites. Topical therapy for thrush is always preferred as first line therapy before moving to oral tablets. Lamson M, Robinson P, Lamson M et al. The pharmacokinetic interactions of nevirapine and ketoconazole. 12th World AIDS Conference, 1998, abstract 12218. Viramune Summary of Product Characteristics, 2001, Boehringer Ingelheim International. Viramune Product Information, 2000, Roxane Laboratories Inc. Counseling points Never share medication with others Always check with your physician or pharmacist BEFORE starting any medications on your own Prescription OTC Herbal
- PK drug interactions may involve : Changes in gastric pH and drug absorption: absorption is sometimes dependent upon acidity of the gut – e.g. ketoconazole requires an acid pH for adequate absorption (drugs and food may change the acidity of the gut and decrease absorption). E.g. fluroquinolones must be taken at least 2 hours prior to antacids or 6 hours after antacids to avoid formation of insoluble complex (chelation). Changes in tissue distribution: protein binding displacement – temporary increase in free drug – also results in greater clearance of drug. Altered drug metabolism mediated by induction or inhibition of CYP450, glucuronyl transferase (GT) or modulation of P glycoprotein (P-gp), an efflux protein. P-gp transports substances from cells to intestinal lumen, urine or bile for destruction. P-gp is present in intestinal epithelial cells, in the liver and kidneys, and at various blood-tissue barriers. Normal P-gp activity protects the brain from excessive accumulation of toxic drugs and metabolites, e.g. selective reduction of CNS adverse effects. P-gp can have undesirable effects, e.g. decreasing the activity of antiretrovirals within the brain. Some drugs may inhibit P-gp resulting in decreased elimination. Ritonavir has been shown to inhibit p-gp mediated transport in renal proximal tubules. Some drugs may induce P-gp (St. John’s Wort) resulting in increased elimination PIs ritonavir, nelfinavir, and amprenavir may strongly induce P-gp expression. Fluctuation in intracellular drug concentrations of active drug (D4T, ZDV) is due to impairment of phosphorylation, which is needed to change the drug to its active state. D4T and ZDV should NEVER be used together. They are antagonistic (PK). Changes in renal elimination may result in increased drug concentrations in the blood.
- PD drug interactions : result in additive effects or synergistic interactions An example of additive effects: bone marrow toxicity caused by ganciclovir and AZT An example of antagonistic effects: indinavir and saquinavir are antagonistic in vitro at higher doses. Piscitelli NEJM 2001
- Absorption of drugs from the GI tract depends on the drug's ability to pass across intestinal cell membranes, withstand the highly acidic environment of the stomach, and resist destruction in the liver (first-pass effect). In most cases drugs pass through cell membranes of intestines by simple diffusion, from an area of high concentration (inside the lumen of the intestines) to an area of lower concentration (bloodstream). Active transport across the GI mucosa, very much like a shuttle system, is another way some substances are absorbed. Other factors that may affect absorption of drugs include food and other medications that may inactivate the drug. Extensively metabolized drugs result in minimal delivery to systemic circulation. Metabolism can occur in intestine, blood, or liver. Extensive first pass metabolism of PIs through gut wall and liver may account for poor and variable bioavailability of this class. Refer participants to Handout 8.1, “ARV Effect on CYP450,” as necessary.
- Cytochrome P450 (CYP450) is a family of enzymes that accounts for the majority of oxidative metabolism conversion of endogenous substance and drugs. Approximately 50% of all drugs are substrates of CYP3A4, including HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). CYP3A4 resides in the liver and enterocytes of the gastrointestinal tract; therefore partial metabolism begins in the intestine. In humans, cytochrome enzymes are found in many tissues: CYP1A1 Lung, CYP1A2, CYP2C9, CYP2C19 Liver CYP2D6 Liver and Brain CYP3A4 Liver and Small Intestines The primary function of the CYP450 system is to alter toxins (drugs) to speed excretion of foreign bodies. Drugs metabolized by P450 enzymes can have an effect by way of three processes: by metabolism as a substrate, by inhibition or induction of enzymes, or a combination of these three: Substrate: A drug that is metabolized by one or more of the P450 enzymes is said to be a substrate of that enzyme, it is the object drug affected by inducer or inhibitor. Inducer: Increases the amount of P450 enzyme by binding directly to promoter elements in the DNA region that regulates expression of the gene. Induction persists for several days, even after the inducing drug is gone (It takes time to take effect and time to resolve) Inhibitor: This process is almost always competitive and reversible Inhibition of enzymes slows the metabolism of the substrate drug, increasing the level of the drug in the blood. This may result in increased risk of toxicity. The onset of these interactions is quick. Some P450 inhibitors are strong inhibitors, and others are poor. Protease Inhibitors: RTV >>IND>NFV>APV> SQV Knowledge of substrates, inhibitors and inducers helps predict drug interactions. This is important as PIs are metabolized 80-95% by the CYP450 isoenzymes in liver and small intestines. Example: The 20 fold increase in plasma concentration of SQV caused by RTV is probably produced by inhibition of CYP3A4 at both sites.
- The isoenzyme 3A4 is responsible for the metabolism of the PI and NNRTI class of ARVs. It is the isoenzyme that is responsible for the majority of drug interactions that are encountered by a patient on a PI or NNRTI The following two slides are lists of the common substrates of CYP 3A4. Substrates of 3A4 may be affected by either inhibition by PIs (which may result in toxic levels) or by induction from NNRTIs, which may result in loss of therapeutic efficacy. Some interactions are known and predictable, whereas others are based on theoretical considerations due to the known metabolism of the drugs. This list may be used later as a reference for the cases we will review. The isoenzyme 3A4 is responsible for the metabolism of the PI and NNRTI class of ARVs. It is the isoenzyme that is responsible for the majority of drug interactions that are encountered by a patient on potent ARVs, (which include either a PI or NNRTI)
- EFV and Ritonavir are inhibitors of 2C9 which may increase the level of certain substrates, for example: phenytoin. It is not easy to predict the outcome of the interaction between anticonvulsants and NNRTIs as the effect can be mixed. Anticonvulsants are also inducers of CYP2C9 and 2C19.
- Substrates of 2D6 may be affected by CYP2D6 inhibitors including ritonavir. Many antidepressants are metabolized by CYP2D6 and may be affected by PIs. Amitriptyline is a substrate for 2D6. It is the primary path by which it is metabolized. Ask participants, “What is the best way to manage the known drug interactions between antidepressants and ARVs? First, let’s review common inhibitors (next slide).”
- Pharmacists play a critical role in detecting drug interactions, before they happen. Pharmacists need to ask patients what other medications they are currently taking whenever dispensing a new medication to avoid potential interactions. Also, be aware that when a medication dose is changed or discontinued, that can have an effect on any other drug that it interacts with. The facilitator can ask the audience if anyone knows what red flags for potential interactions means clinically. Answer: Drugs or drug classes that are Red Flags for drug interactions are those that are known to cause significant interactions with PIs and NNRTIs and should always be approached with caution, or in some cases avoided completely with ARV medications.
- This is a summary slide of the effects of ARVs on CYP450 for reference. Remember that in general, the NNRTIs are inducers of 3A4 and the PIs are inhibitors of 3A4, to varying degrees. However, some ARV have mixed effects on different enzymes which may make it difficult to predict drug interactions, and may require close clinical monitoring.
- Concomitant use of nevirapine and ergot alkaloids such as ergotamine is predicted to result in decreased plasma concentrations of the ergot alkaloid. Caution is advised and dosage adjustments of the ergot alkaloid may be necessary. As stated in the TB unit, NVP is only to be used with rifampicin if there are no other choices available. Terfenadine and Midazolam are CYP3A4 substrates and EFV is its inducer. Midazolam and triazolam should not be combined with EFV; they can be used with NVP. St. Johns Wort is CYP3A4 inducer. Concomitant use of St. John’s wort ( Hypericum perforatum ) and nevirapine is not recommended as it results in suboptimal antiretroviral concentrations and may be associated with loss of virologic response and development of resistance. Preliminary data suggest that this drug interaction occurs because St. John’s wort is a potent inducer of CYP isoenzymes responsible for metabolism of indinavir. St. John’s wort is an extract of hypericum and contains at least 7 different components that may contribute to its pharmacologic effects, including hypericin, pseudohypericin, and hyperforin. There is evidence that hypericum extracts can induce several different CYP isoenzymes, including CYP3A4 and CYP1A2, and also may induce the p -glycoprotein transport system. Therefore, it has been recommended that concomitant use of St. John’s wort and HIV protease inhibitors or NNRTIs metabolized by CYP isoenzymes be avoided.
- Medications are recommended to be taken with food for one of two reasons: To ensure optimal absorption. e.g., Nelfinavir is best absorbed if it is taken with a meal or snack. In some instances, fat content of a meal may be an important factor affecting drug bioavailability. With lipid-soluble agents, ingestion of dietary fat results in formation of an oil or emulsion phase, which improves solubility. Ingesting a fatty meal also promotes secretion of gastric fluids, which in turn may lower gastric pH, delay stomach emptying, and decrease GI transit rates. e.g. Absorption of SQV is significantly increased when taken within 2 hours of a high-fat meal. Itraconazole caps can be taken with food or cola to increase absorption. Administration of a single 400 mg dose of ATZ with a light meal resulted in a 70% increase in AUC. Ganciclovir is poorly absorbed, if taken with food, levels are increased at best 5%. Atovaquone must be taken with a fatty meal to ensure absorption (23 g fat: 610 kcal). Amprenavir can be taken with or without meals; avoid a high fat meal which may decrease levels. IDV levels are reduced if taken with fat or high protein and should be taken on an empty stomach (at least 1 hour prior or 2 hours after a meal) or with a light, low-fat snack such as cereal with skim milk, toast and jam, fresh fruit, yogurt. ddI is destroyed by stomach acid, and therefore ddI tablets contain an antacid buffer. ddI tabs and EC caps should always be taken on an empty stomach since the presence of food interfere with action of the buffers . To reduce SE involving the stomach. Zidovudine does not need to be taken with food for adequate absorption. However, food may prevent or minimize the risk of stomach upset or nausea. INH should be taken on an empty stomach to attain peak concentration, however, it can be taken with food to decrease GI upset.
- It is essential to avoid co-administration of antacids with the following medications to ensure absorption. Protease inhibitors: Amprenavir and antacid administration have not been specifically studied. However, based on data available between antacids and other protease inhibitors, it is recommended that these drugs be taken at least one hour apart (Prod Info Agenerase, 2000). Omeprazole is contraindicated with atazanavir, only ranitidine given as 300 mg 12 hours apart from atazanavir can be used as an acid suppressing drug. Fluoroquinolones: Concurrent administration of ciprofloxacin with magnesium/aluminum antacids should be avoided. Ciprofloxacin may be taken two hours before or six hours after taking an antacid. An H2 blocker such as ranitidine may be an alternative to antacids in some clinical situations. Ketoconazole requires an acid pH for adequate absorption (drugs and food may change the acidity of the gut and decrease absorption). Aluminum antacids decrease the absorption of isoniazid (Hurwitz & Schlozman, 1974). Recommend taking antacids at least two hours after taking isoniazid. Absorption of dapsone is dependent upon an acidic pH and may be diminished with other drugs, such as ddI tablets, containing buffers
- No, this regimen is not appropriate for her. ZDV should never be used with D4T as they compete for intracellular phosphorylation The first line choice of nucleoside therapy should be ZDV + 3TC or D4T + 3TC in combination with nevirapine
- C is the correct answer However, you should inquire as to which herbal medicine he takes as some can interact with ARVs. For example, St. John’s Wort is a 3A4 inducer. It is not widely available in Ethiopia, however, if a patient indicates they take herbal medicine with ARVs, they should be closely monitored for virologic failure or toxicity. It is difficult to predict drug interactions between ARVs and herbal medicines. The next slide contains more about interaction with herbal medicines m
- She qualifies for treatment because she has Grade IV disease in the WHO staging system.
- No, this regimen is not appropriate for her. ZDV should never be used with D4T as they compete for intracellular phosphorylation The first line choice of nucleoside therapy should be ZDV + 3TC or D4T + 3TC in combination with nevirapine
- No, this is not an appropriate therapy for his thrush Ketoconazole interacts with nevirapine Ketoconazole levels are decreased by 63% Nevirapine levels are increased by 15-30% They should not be co-administered An alternative is a topical antifungal such as nystatin suspension or miconazole oral gel Ketoconazole levels are decreased by 63% and this is most likely the reason that his thrush was not responding to the medication. Ketoconazole and nevirapine should not be given concurrently due to the decrease in ketoconazole concentrations. Coadministration of nevirapine (200 mg twice daily) with ketoconazole (400 mg once daily) to 22 HIV+ individuals resulted in a 63% reduction in ketoconazole AUC and a 40% reduction in Cmax. There was a 15–28% increase in plasma concentration of nevirapine. Although interaction studies have not been performed, antifungal medicinal products which are eliminated renally (e.g. fluconazole) may be substituted for ketoconazole. Studies using human liver microsomes indicated that ketoconazole significantly inhibited the formation of nevirapine hydroxylated metabolites. Topical therapy for thrush is always preferred as first line therapy before moving to oral tablets. Lamson M, Robinson P, Lamson M et al. The pharmacokinetic interactions of nevirapine and ketoconazole. 12th World AIDS Conference, 1998, abstract 12218. Viramune Summary of Product Characteristics, 2001, Boehringer Ingelheim International. Viramune Product Information, 2000, Roxane Laboratories Inc. Counseling points Never share medication with others Always check with your physician or pharmacist BEFORE starting any medications on your own Prescription OTC Herbal