1 / 98

Pharmacology

Pharmacology. Unit 7 HIV Care and ART: A Course for Physicians. Learning Objectives. Describe the mechanism of action of antiretroviral (ARV) drugs List the common side effects of ARVs List the standard ARV doses

bridgit
Télécharger la présentation

Pharmacology

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Pharmacology Unit 7 HIV Care and ART: A Course for Physicians

  2. Learning Objectives • Describe the mechanism of action of antiretroviral (ARV) drugs • List the common side effects of ARVs • List the standard ARV doses • Identify the ARVs that require dose adjustment for patients with renal or hepatic disease • List the ARVs that have food requirements

  3. Learning Objectives (2) • Describe the mechanisms of drug interactions relevant to ARVs • Identify commonly used drugs that may have important interactions with ARVs • Describe the principles and mechanisms of drug resistance

  4. Antiretroviral Drugs

  5. Ethiopian ART Guideline

  6. 2003 vs. 2005 WHO Guidelines

  7. Classes of Antiretrovirals • NRTIs • Nucleoside reverse transcriptase inhibitors • Nucleotide reverse transcriptase inhibitors (NtRTI) • NNRTIs – non-nucleoside reverse transcriptase inhibitors • PIs – protease inhibitors • Fusion Inhibitors

  8. ARVs and the HIV Lifecycle

  9. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) RNA DNA Nucleus Host Cell

  10. Types of NRTIs • Zidovudine (AZT) • Stavudine (d4T) • Lamivudine (3TC) • Didanosine (ddI) • Abacavir (ABC) • Zalcitabine (ddC) • Emtricitabine (FTC) • Tenofovir (TDF)-Nucleotide RTI

  11. Zidovudine (AZT, ZDV) • Dosing: 300mg BID • Food Interactions • None – can take with or without food • Food decreases AZT-related nausea

  12. Nausea Bone Marrow Suppression Anemia Neutropenia Headache Myalgia Myopathy Insomnia Pigmentation of nail beds Lactic acidosis, fatty liver ZDV: Toxicity

  13. ZDV: Bone Marrow Suppression • Correlates with drug dose & duration, marrow reserve, and stage of disease • Anemia occurs after 4-6 weeks • Neutropenia occurs after 12-24 weeks • Marrow histology shows normal or reduced RBC precursors • Management • Stop AZT if Hgb <8 gm/dl • Hgb typically recovers in 1 to 2 weeks

  14. ZDV-Related Fingernail Discoloration • Nail Hyperpigmentation • Can be seen on hands and feet after 2-6 weeks • Usually dark bluish-black vertical-line discoloration • More common among African population • This is NOT an indication to stop ZDV

  15. Lamivudine (3TC) • Dosing: 150mg BID or 300mg QD • Food Interactions: none • Toxicity: very rare • Component of all first-line regimens • Also active against Hepatitis B • Main disadvantage: rapid development of resistance

  16. Emtricitabine (FTC) • Dosing: 1 x 200mg capsule QD • Food Interactions: no food interactions • Toxicity • Mild abdominal discomfort • Occasional nausea • Emtricitabine is the fluorinated version of lamivudine

  17. Hepatitis B Co-infection • Drugs active against both HBV & HIV: 3TC, FTC, TDF • HBV develops rapid resistance to 3TC and FTC • TDF + (3TC or FTC) is the optimal NRTI backbone • Differential diagnosis of exacerbation of hepatic disease in these patients: • Development of 3TC or FTC resistance • “HBV flair” secondary to stopping 3TC or FTC • ART related hepatoxocity (AZT, d4T, ddI, EFV, NVP, All PIs) • Immune reconstitution syndrome

  18. Lamivudine + Zidovudine • Dosing: 1 tablet (150 / 300mg) BID • Food Interactions • None – with or without food is ok • Food decreases ZDV-related nausea

  19. Stavudine (d4T) • Dosing • 40 mg BID for weight > 60 kg • 30 mg BID for weight < 60 kg • Food Interactions: None • Toxicity (use lower dose to reduce risk of S/E development for patients < 60kg) • Peripheral Neuropathy (5-15%, pain, tingling, and numbness in extremities) • Lactic acidosis, fatty liver • Lipoatrophy • Pancreatitis • Hypertriglyceridemia

  20. d4T: Dose-related Side Effects • Peripheral Neuropathy: • Onset usually after 2-6 months of therapy. • If develops: discontinue d4T at onset (or reduce dose to 20mg Q12H if weight > 60kg, or 15mg Q12H if < 60kg) • Lipoatrophy: • loss of fat tissue on arms, legs, and face • Pancreatitis: • If develops, discontinue therapy. • When symptoms resolve, do not re-challenge with stavudine

  21. Facial Lipoatrophy © ITECH, 2006

  22. Abacavir (ABC) • Dosing: 1 x 300mg tablet BID • Food Interactions: no food interactions • Generally well tolerated • Toxicity • Hypersensitivity reaction • Occurs within first 6 weeks of therapy

  23. Hypersensitivity to Abacavir • Observed in approximately 5% of all patients receiving abacavir • Multi-organ system involvement • Most common signs and symptoms: • Fever (>80%) • Rash (maculopapular or urticarial) (70%) • Fatigue (>70%) • Flu-like symptoms (50%) • GI (nausea, vomiting, diarrhea, abdominal pain) (50%)

  24. Hypersensitivity to Abacavir (2) • Counsel and prepare patient for hypersensitivity symptoms and to contact provider/pharmacist immediately • Especially during first month of therapy • Provider/pharmacist determines cause of symptoms: abacavir or not • Hypersensitivity may be fatal (19 deaths) • NEVER rechallenge • Genetic predisposition • Similar to life-threatening reaction to NVP

  25. Abacavir Re-challenge • 20% risk of anaphylactic-like reaction upon re-challenge • Death can occur with hours of restarting • Symptoms may include include: • hypotension • bronchoconstriction • renal failure • Laboratory changes may include • Increased CPK • Elevated liver function tests • Reduced lymphocyte count Abacavir should never be re-challenged!

  26. Tenofovir Disoproxil Fumarate (TDF) • Dosing: 1 x 300mg tablet QD • Food Interactions: None • Very well tolerated, side effects are minimal • Toxicity • Renal insufficiency (rare) • Must dose adjust with renal failure • Also has activity against Hepatitis B • Dosed 300mg QD • Active against Lamivudine resistant HBV strains • HBV resistance 1% at 1 year • If TDF is stopped, may have HBV hepatitis flare

  27. Didanosine (ddI) • Requires a basic environment • Food Interactions: take on empty stomach • Dosing (one of the following) • 1 x 400mg enteric coated capsule QD (if <60kg: 250mg QD) • 2 x 100mg buffered tab BID or 4 x 100mg QD (if <60kg: 125 mg BID or 250mg QD) • NOTE: If use buffered tablets, 2 or more tablets must be used at each dose to provide adequate buffer • 250mg of reconstituted buffered powder BID (if <60kg: 167mg BID) • Mix pediatric powder with liquid antacid

  28. Didanosine (ddl) (2) • If taken with TDF must reduce ddI dose: • > 60 kg < 60 kg • 250 mg/d 200 mg/d • Without dose adjustment – blunted CD4 response • Toxicity • Peripheral Neuropathy • GI intolerance • Pancreatitis (7%2%) • Lactic acidosis, fatty liver

  29. NRTI Class Side Effects • As with all antiretrovirals, side effects are worst during the first 1 to 2 weeks of therapy. • Counsel patients • Potential for side effects • How to handle side effects • Don’t give up

  30. NRTI Class Side Effects (2) • Peripheral Neuropathy: ddl + d4T • With continued treatment may be irreversible • Lactic Acidosis, fatty liver: d4T > ddl > AZT • Lipoatrophy: d4T > AZT • Pancreatitis: ddl > d4T • Marrow Suppression: AZT

  31. NRTI Mitochondrial Toxicity • Inhibition of mitochondrial DNA polymerase- •  oxidative metabolism,  ATP generation • Implicated in lactic acidosis with hepatic steatosis • Other possible manifestations: • Neuropathy (d4T, ddI) • Lipoatrophy (d4T) • Pancreatitis (ddI) • Myopathy (AZT) • Cardiomyopathy (AZT)

  32. Hyperlactatemia/Lactic Acidosis • Rare but potentially fatal syndrome (1/1000 pt/yrs) • Linked to prolonged use of NRTIs, especially ddI and d4T • Acute or subacute onset • Symptoms: nausea, vomiting, weight loss, fatigue • Lab: increased anion gap (or lactate level) • Ultrasound: fatty liver • Management: discontinue NRTI – may take months to reverse. No specific treatment

  33. Neucloside Pairings

  34. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

  35. Non-Nucleoside Reverse Transcriptase Inhibitors • NNRTIs • Nevirapine (NVP) • Efavirenz (EFV)

  36. Nevirapine (NVP) • Dosing: 200 mg QD x 2 weeks, then 200 mg BID • Food Interactions: None • Toxicity • Rash (17%) • Nausea & vomiting • Hepatitis (8-18%) • Risk is greatest in first 6 weeks of therapy • Could be benign or fatal • Black Box warning by FDA (USA): • Do not use NVP in women w/ starting CD4>250 • Do not use NVP in men w/ starting CD4> 400

  37. Hepatotoxicity: NVP & PIs • NVP: • Hepatic necrosis 1st 6-16 weeks after starting Rx • Those at higher risk for hepatitis include: • Patients with a history of alcohol abuse, coinfection with hepatitis B or C and in patients who are older or are women. • Persons with higher CD4 cell counts or elevated LFTs at baseline • PI & NNRTIs: All cause ↑ ALT/AST in 10-15%

  38. Hepatotoxicity: NVP & PI (2)

  39. NVP: Hepatotoxicity “Symptomatic Hepatitis”

  40. NVP for PMTCT • Issue is RESISTANCE and EFFICACY • No SAFETY concerns

  41. Nevirapine-Induced Rash Courtesy of HIV Web Study, www.hivwebstudy.org

  42. Nevirapine-Induced Rash (2) • To reduce the risk • The dose should be escalated over the first 2 weeks • Starting at 200mg QD for 2 weeks and then increasing to 200mg BID • This dosing makes sense because nevirapine autoinduces hepatic cytochrome P450 enzymes (CYP3A4) • Which reduces its own half-life over 2 to 4 weeks from 45 to 25 hours.

  43. Efavirenz (EFV) • Dosing: 3 x 200mg capsules or 600mg tab QHS • Food Interactions • Take on an empty stomach or with low-fat meal • High-fat meals increase absorption by 50%  increases side effects • Consistent results: persistent activity after >5 years • Never surpassed in clinical trial

  44. Efavirenz Toxicity • CNS Changes (52%) • Rash (15-27%) usually does not require discontinuation • Hepatotoxicity (2-8% experience increase in LFTs > 5 ULN) • Contraindicated during pregnancy • Teratogenic—Class D

  45. Efavirenz CNS Toxicity • Symptoms: confusion, Insomnia, nightmares, poor concentration, mood change, dizziness, dysequilibrium, depression, psychosis, “disconnected” • Onset: first dose • Course: usually resolves in 2-3 weeks • Cause: Unknown • Management: warn patient

  46. Which Third Drug to Use?

  47. EFV vs. NVP

  48. NNRTI Class Effects • Side effects • Rash • Hepatotoxicity • Cross resistance: • A single mutation, the K103N, causes high-level resistance to all 3 drugs in this class: EFV, NVP, and DLV • Latent pool forever • Importance of adherence

  49. NNRTI Rash • Often diffuse, slightly raised, itchy • Vary in redness and distribution • Can be severe - Steven’s Johnson Syndrome Courtesy of the Public Health Image Library/CDC/ J. Pledger, BSS/VD

  50. Protease Inhibitors (PIs) DNA Host Cell

More Related