Drug Interactions
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This document discusses pharmacokinetics and important drug interactions for treating HIV. It describes the four components of pharmacokinetics - absorption, distribution, metabolism and excretion - and explains how the liver's cytochrome P450 system plays a key role in drug metabolism. It provides examples of cytochrome P450 inducers and inhibitors and how they can affect substrate drugs. Specifically, it notes that the antibiotic rifampin is a strong inducer that significantly decreases levels of protease inhibitors, NNRTIs, methadone and antifungals by inducing cytochrome P450. Managing interactions is important for successful HIV treatment.
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Drug Interactions
- 1. 1 Pharmacokinetics and Drug Interactions HAIVN Harvard Medical School AIDS Initiative in Vietnam
- 2. 2 Learning Objectives By the end of this session, participants will be able to: Describe 4 components of pharmacokinetics Explain importance of the liver’s P450 system in drug metabolism Explain how an inducer and an inhibitor affect the blood level of CYP450 substrates Describe the most important drug-drug interactions
- 3. 3 What is Pharmacokinetics? The study of how drugs enter, interact with, and leave the body, including: • Absorption • Distribution • Metabolism • Excretion Or, “what the body does to the drug”
- 4. 4 Drug Absorption The movement of a drug from its site of administration (stomach, vein, skin, etc.) into the bloodstream
- 5. 5 Factors Affecting Drug Absorption Alterations in gastric pH: • some drugs are absorbed better in an acidic environment (itraconazole) • other drugs are absorbed better in a higher pH environment (ddI) Presence or absence of food or other medications: • Buffered ddI decreases the absorption of itraconazole, ketoconazole, indinivir
- 6. 6 Drug Distribution Following absorption or systemic administration into the bloodstream, a drug distributes into interstitial and intracellular fluids and then finally into the body tissue
- 7. 7 Factors Affecting Drug Distribution Cardiac output and blood flow to organs and tissues Drug permeability and accumulation in tissues Protein binding: • Protein binding varies among ARVs • Protein levels may vary between and within patients
- 8. 8 What is Drug Metabolism? The process of transforming active drugs into inactive metabolites that can be more readily excreted from the body
- 9. 9 Drug Excretion Drugs are eliminated from the body either unchanged or as metabolites: • Kidney • Liver-Intestines Factors affecting drug excretion include: • Renal insufficiency and/or failure • Alkalinization or acidification of urine • Liver failure
- 11. 11 Role of CYP450 in Metabolism
- 12. 12 Cytochrome P450 Enzymes The cytochrome P450 (CYP) enzyme family is the major enzyme system involved in drug metabolism CYP-mediated metabolism occurs mostly in the liver CYP3A is the most important enzyme • responsible for the breakdown and clearance of the largest number of drugs including most PIs and NNRTIs
- 13. 13 Drug Effects on CYP450 Activity of CYP450 enzymes can be affected by many medications Drugs that affect CYP450 are categorized as either inducers or inhibitors Drugs that are metabolized by CYP450 (substrates) may be affected by the presence of an inducer or an inhibitor
- 14. 14 Examples of CYP450 Inducers and Inhibitors Inducers: • Rifampin • NVP • EFV Inhibitors: • Ritonavir • Ketoconazole • Itraconazole
- 15. 15 Examples of Common CYP450 Substrates ARVs: NVP, EFV, LPV/r (Aluvia) Rifampin Methadone Ketoconazole & Itraconazole Clarithromycin & Erythromycin Simvastatin & Lovastatin Birth control pills
- 16. Example: How a CYP450 Inducer affects Substrates 16 Substrates CYP450 Rifampin LPV and other PIs, NVP, EFV: • decreased concentrations • increased activity of CYP450 • faster breakdown and clearance of other drugs Inducer
- 17. Example: How a CYP450 Inhibitor affects Substrates 17 Substrates CYP450 Ritonavir The 2nd PIs: •increased & prolonged concentrations • decreased activity of CYP450 • slower breakdown and clearance of other drugs Inhibitor
- 18. 18 Drug Effects on CYP450 Advantages: Use of Ritonavir (inhibitor) with another PI leads to: • higher, prolonged blood levels • decreases required amount of 2nd PI Disadvantages: The use of Rifampin with many ARVs leads to leads to unacceptably low blood levels of these ARVs
- 19. 19 Key Drug Interactions with ARVs
- 20. 20 Rifampin and HIV Medications By inducing the CYP450 enzyme, Rifampin decreases blood levels of: • PI • NNRTI (NVP, EFV) • Methadone • Antifungal drugs
- 21. 21 Rifampin and ARV Blood Levels SQV IDV NFV LPV NVP EFV Rifampin 84% 89% 82% 75% 37% 25% Finch et al. Arch Intern Med 2002;162:985-92 Do not use PIs with Rifampin
- 22. 22 Rifampin and NNRTIs (1) Rifampin and NVP NVP levels decreased by 20- 58% Clinical significance of this is debated Risk of hepatotoxicity with NVP and TB therapy is also a concern Rifampin and EFV EFV levels decreased by 26% Not felt to have a significant effect on clinical outcomes MOH guidelines recommend EFV at standard dosing (600 mg/day) when used with RIF
- 23. 23 Rifampin and NNRTIs (2) In patients on TB therapy, EFV is the preferred NNRTI Patients on NVP at the time of TB diagnosis should be changed to EFV if possible If EFV is not available, not tolerated or contraindicated, NVP can be used at standard doses
- 24. 24 Rifampin and LPV/r RIF decreases LPV levels by > 75% **Combination should be avoided if possible Patients who require RIF-based TB therapy and PI-based ART can be treated with “superboosted” LPV/r • LPV 400 mg + RTV 400 mg twice daily • Available by referral to provincial-level OPC
- 25. 25 Case Study: Hung Hung, a 26 year old HIV-positive man presents to HIV OPC • Has been on ART for about 3 months with AZT, 3TC, NVP • Baseline CD4 count was 67; Hb and ALT normal • Developed pulmonary TB and was recently started on TB therapy (RHEZ) Should his ART regimen be altered? If so, how and why?
- 26. 26 Antifungals + ARVs: ITRA Interactive pair Result Management ITRA + NVP ↓ ITRA levels (↓ AUC by 61%) •Monitor closely •Consider ↑ ITRA dose ITRA + EFV ↓ ITRA levels (↓ AUC by 39%) •Monitor closely •Consider ↑ ITRA dose ITRA + LPV/r ↑ ITRA levels Limit ITRA to 200 mg/day
- 27. 27 Methadone + ARVs ARV Effect Comment EFV ↓ methadone levels (by 52%) Can precipitate withdrawal symptoms May require increase in methadone doseNVP ↓ methadone levels (by 41%) LPV/r ↓ methadone levels (by 26 to 53%) • Opioid withdrawal unlikely but may occur • Usually no adjustment in methadone required AZT ↑ AZT levels (by 29-43%) Monitor for AZT side effects (e.g. anemia) ↓ ddI levels Use with caution Source: US Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, January 10, 2011.
- 28. 28 Hormonal Contraceptives + ARVs ARV Effect on hormonal contraceptive Comment EFV ↑ ethinyl estradiol Use alternative or additional methods NVP ↓ ethinyl estradiol 20% LPV/r ↓ ethinyl estradiol 42%
- 29. 29 Interactions among NRTIs NRTI Pair Results of Interaction Recommen- dation DDI + D4T •Increased toxicities Avoid combination D4T + AZT •Antagonistic effect (require same enzymes for intracellular phosphorylation) TDF + DDI • Increased DDI toxicity • Loss of CD4 responses after time • Suboptimal antiviral response in regimens with EFV
- 30. 30 How Can You Recognize and Avoid Drug Interactions? Review patient’s full medication list at every visit Recognize: • drugs most commonly associated with interactions (PIs, itraconazole, rifampin, etc.) • medications with overlapping toxicities • dietary restrictions with certain medications Select agents with fewer drug interactions if clinically appropriate Simplify drug regimens whenever possible
- 31. 31 Look it Up! When prescribing a new drug to a patient, always look it up to make sure there aren’t any drug interactions References: MOH Guidelines for the Diagnosis and Treatment of HIV/AIDS www.HIV-druginteractions.org www.AIDSinfo.nih.gov
- 32. 32 Key Points 4 components of pharmacokinetics • All can affect success of drug therapy Drug interactions are common when treating PLHIV • Many related to effects of the P450 liver enzymes • Important to recognize and avoid drug interactions
Editor's Notes
- M2-07-Pharmacokinetics and Drug Interactions-EN HAIVN Module 2, Revised April 2012
- Note that this slide is animated. Do not click through the answers on the slide until AFTER asking participants the question in the title. ASK participants “What is pharmacokinetics?” ALLOW time for them to answer, then click to show the answer.
- ASK participants “What factors might affect drug distribution?” ALLOW time for them to answer, then move to the next slide.
- GIVE more examples of drugs absorbed better in an acidic environment: Itraconazole Ketoconazole Indinivir Atazanavir EXPLAIN that when prescribing drugs which are absorbed better in acidic environment, patients should be counseled to: avoid antacids consider taking the medication with acidic drinks such as carbonated soft-drinks EXPLAIN that ddI is better absorbed in a low acid environment. This is why it is formulated with a built in antacid (buffered) or protective coating (enteric coated). The buffered formulation can decrease the absorption of other drugs because of the built-in antacid. So when prescribing itraconazole, ketoconazole or indinavir with buffered ddI, the drug should be taken at least 1 hour apart.
- EXPLAIN that distribution is the movement of the drug from the blood throughout the body. The action of most drugs is in the cells, not the blood, so distribution is how the drug gets from the blood to the site of action. For most ARV, the site of action is in the cells infected by HIV, such as the CD4 cells and others.
- EXPLAIN that in general, drugs that have high protein binding have longer half-lives. However, the clinical relevance of changes in protein levels and protein binding is uncertain.
- Note that this slide is animated. Do not click through the answers on the slide until AFTER asking participants the question in the title. ASK participants “What is drug metabolism?” ALLOW time for them to answer, and then click to show the answer on the screen. EXPLAIN that metabolites can be active (have desired effects) or be inactive (have no medicinal effects). EXPLAIN that we will discuss drub metabolism in more detail later in the session
- EXPLAIN that all drugs must eventually be eliminated from the body. The kidney and the liver are the primary organs for drug excretion. For metabolism through the liver and intestine: drugs can be excreted in the bile, or secreted directly into the intestinal tract GIVE an example of how alkalinization of the urine affects drug excretion: increasing the pH of the urine from 6 to 8 will increase aspirin excretion by 4-6 times.
- GIVE brief summary of what happens when a drug enters the body in general.
- EXPLAIN that the Cytochrome P450 enzymes are one of the primary pathways for metabolizing drugs and toxins in the body. Many drugs used in HIV infection, including ARV, TB, and anti-fungal drugs, are metabolized this way.
- EXPLAIN that CYP450 enzymes metabolize many drugs but the enzyme activity itself can also be affected by drugs.
- STRESS that the most important inducer to know if Rifampin. We will see examples shortly of how it leads to serious drug interactions. Generally rifampin leads to decreased concentrations of other drugs and thus decreased effectiveness of those drugs.
- EXPLAIN that many drugs are both inducers or inhibitors and also substrates of CYP450 themselves.
- EXPLAIN this diagram: An inducer, for example rifampin, affects CYP450 enzymes, leading to: increased activity of CYP450 enzymes faster breakdown and clearance of other drugs decreased concentrations of other drugs EXPLAIN that the most important inducer to know if Rifampin. Generally rifampin leads to decreased concentrations of other drugs and thus decreased effectiveness of those drugs
- EXPLAIN this diagram: An inhibitor, for example ritonavir, affects CYP450 enzymes, leading to: decreased activity of CYP450 enzymes slower breakdown and clearance of other drugs increased and prolonged concentrations of other drugs EXPLAIN that the most important inhibitor to know is ritonavir. Generally ritonavir leads to increased concentrations of many medications and thus increased risk of toxicity.
- STRESS that induction or inhibition of CYP450 can have both advantages and disadvantages.
- INTRODUCE that now you will review some important drug-drug interactions. Many of these are mediated through induction or inhibition of the CYP450 system.
- EXPLAIN that Rifampin has interactions with many other drugs because it is a very strong inducer of the CP450 enzymes.
- STRESS that PIs should not be used with Rifampin because the blood levels will be too low and ineffective.
- EXPLAIN that some studies have demonstrate reduced virological outcomes with the use of NVP-containing ART and RIF-containing TB therapy while others have not. EXPLAIN that some experts recommend increasing the dose of EFV to 800 mg/day in patients who weigh more than 60 kg, but most suggest that no dosage adjustment is necessary
- GIVE an example of contraindication of EFV: patient is in the 1st trimester of pregnancy CONCLUDE that it is OK to use NVP in a patient taking Rifampin EXPLAIN that the Vietnam MOH HIV/AIDS guidelines recommend using EFV in patients who are also taking Rifampin, but allow using NVP if EFV is not available or if the patient can not take EFV. If using NVP with RIF, monitor closely for clinical symptoms of hepatitis and check liver enzyme level every 2 weeks
- EXPLAIN that LPV/r is Lopinavir/Ritonavir . REMIND that combination of RIF and a PI should be avoided whenever possible. However, in some cases these drugs must be used together. For example, a patient on second-line ART (TDF/3TC/LPV-r) who develops active TB. In this situation, the patient can be referred to the provincial level for superboosted LPV/r therapy. Superboosting LPV involves providing additional ritonavir to counteract the decreased LPV levels caused by RIF. The dose is LPV 400 mg / RTV 400 mg BID. GIVE an example of how to get the superboosted dose: Aluvia 2 tabs + Ritonavir 3 tabs twice a day STRESS that patients should be monitored very closely for liver toxicity and may have significant GI side effects on this regimen.
- HAVE a participant read the case study and question presented on this slide. ALLOW time for participants to discuss this question. EXPLAIN that Hung’s ART regimen should be changed. NVP should be changed to EFV This is due to the interaction between Rifampin and NVP where-by Rifampin lowers NVP blood levels It is also due to the higher risk of liver toxicity when using NVP and TB therapy together If the patient cannot tolerate EFV, it is then acceptable to switch back to NVP
- EMPHASIZE that interactions between ARVs and itraconazole are very important in Vietnam because of the incidence of penicillium marneffei infection. Patients on Itraconazole for treatment of PM should be monitored closely for non-response and/or recurrence when NNRTI-based ART is given concomitantly. Consideration should be given to increasing the dose of Itraconazole (especially during the maintenance phase; 200 mg/day to 400 mg/day) in this scenario. EXPLAIN that similar concerns exist with the use of Itraconazole and Rifampin-based TB therapy. Rifampin significantly decreases Itraconazole levels (decreased AUC by 80-90%) as well. The combination should be avoided if possible. MENTION that Ketoconazole has similar interactions as Itraconazole (decreased levels with NVP/EFV and increased with Aluvia) BACKGROUND: ITRA: Itraconazole REF: - Pharmacokinetic study of the interaction between itraconazole and nevirapine. Eur J Clin Pharmacol (2007) 63:451–456 - US DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. March 27, 2012
- EXPLAIN that Methadone levels are decreased with co-administration with EFV, NVP, and LPV/r. Methadone dosing may need to be increased to avoid withdrawal symptoms.
- EXPLAIN that ART affects levels of oral hormonal contraception. Patients should be advised to use additional methods especially when on EFV (risk of teratogenicity).
- Note that this slide is animated. Do not click through the answers on the slide until AFTER asking participants the question in the title. ASK participants “How can you recognize and avoid drug interactions?” ALLOW time for them to answer, and then click to show the answer. REMIND participants to review medications prescribed at other clinics (i.e. TB), private pharmacies, home remedies, etc. GIVE example of medications with overlapping toxicities: INH-D4T DDI-D4T AZT-ribavirin GIVE example of dietary restrictions with certain medications: DDI-empty stomach EFV-empty stomach
- EMPHASIZE that there are many drugs used to treat HIV patients and the number of potential interactions is too many to remember them all. If you are not sure about drug interactions between ARV and other drugs, then you can look it up. REFER participants to Handout M2S7.1: Important Drug Interactions so that they can see further detail on drug interactions.