Class antiretroviral drugs
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The document discusses different classes of antiviral drugs used to treat HIV. It describes how reverse transcriptase inhibitors like nucleoside analogues (zidovudine, lamivudine) and non-nucleoside analogues (efavirenz, nevirapine) work by blocking the reverse transcriptase enzyme. Protease inhibitors like saquinavir and ritonavir prevent viral replication by inhibiting the viral protease enzyme. Integrase inhibitors like raltegravir block the integrase enzyme from integrating the viral DNA into the host cell DNA. Entry or fusion inhibitors like enfuvirtide and maraviroc inhibit viral fusion and entry into cells. The document outlines the mechanisms
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Class antiretroviral drugs
- 2. Viruses have no cell wall and made up of nucleic acid components Viruses contain envelope – antigenic in nature Viruses are obligate intracellular parasite They do not have a metabolic machinery of their own – uses host enzymes 2
- 3. Key characteristics Able to enter the cells infected with virus Interfere with viral nucleic acid synthesis and/or regulation Some drugs interfere with ability of virus to bind to cells Some drugs stimulate the body’s immune system Best responses to antiviral drugs are in patients with competent immune systems A healthy immune system works synergistically with the drug to eliminate or suppress viral activity 3
- 6. Neucleoside reverse transcriptase inhibitors(NRTIs) ZIDOVUDINE, STAVUDINE, LAMIVUDINE, ABACAVIR, ZALCITABLINE, EMTRICITABINE, DIDANOSINE Non-Nucleoside reverse transcriptase inhibitors (NtRTIs) EFAVIRENZ, NEVIRAPINE, DELAVIRDINE, ETRAVIRINE
- 7. NEUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS(NtRTIs)-TENOFOVIR PROTEASE INHIBITORS SAQUINAVIR, INDINAVIR, NELFINAVIR, AMPRENAVIR, FOSAMPRENAVIR, RITONAVIR, LOPINAVIR, ATAZANAVIR, TIPRANAVIR, DARUNAVIR ENTRY/FUSION INHIBITORS-ENFUVIRTIDE CCR5 INHIBITORS-MARAVIROC
- 8. INTEGRASE INHIBITORS RALTEGRAVIR NEWER ANTIRETROVIRAL DRUGS ELVITEGRAVIR, BEVIRIMAT, ELVUCITABINE, VICRIVIROC
- 9. When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double- stranded viral DNA. The viral DNA is then integrated into the host chromosomal DNA, which then allows host cellular processes, such as transcription and translation to reproduce the virus. RTIs block reverse transcriptase's enzymatic function and prevent completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying
- 10. 10 Nausea Bone Marrow Suppression Anemia Neutropenia Headache Myalgia Myopathy Insomnia Pigmentation of nail beds Lactic acidosis, fatty liver
- 11. 11 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
- 12. 12 Dosing: 1 x 200mg capsule QD Food Interactions: no food interactions Toxicity Mild abdominal discomfort Occasional nausea Emtricitabine is the fluorinated version of lamivudine
- 13. 13 Dosing: 1 x 300mg tablet BID Food Interactions: no food interactions Generally well tolerated Toxicity Hypersensitivity reaction Occurs within first 6 weeks of therapy
- 14. 14 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
- 15. 15 If taken withTDF must reduce ddI dose: > 60 kg < 60 kg 250 mg/d 200 mg/d Without dose adjustment – bluntedCD4 response Toxicity Peripheral Neuropathy GI intolerance Pancreatitis (7%2%) Lactic acidosis, fatty liver
- 16. PIs prevent viral replication by inhibiting the activity of proteases Protease inhibitors were the second class of antiretro viral drugs developed.
- 17. 17 Substantial GI intolerance prevents use at full, original dose Now used to boost other PIs Doses < 400 mg/day – no anti-HIV activity Nomenclature: /r (LPV/r, SQV/r) Requires refrigeration Hard to make
- 18. Saquinavir was the first protease inhibitor HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir inhibits both HIV-1 and HIV- 2 proteases.
- 19. Amprenavir , Indinavir Nelfinavir,Ritonavir Saquinavir Inhibit the protease retroviral enzyme, preventing viral replication 19
- 20. 20 Metabolic Disorders Hepatotoxicity Hyperglycemia, insulin resistance Lipid abnormalities Fat redistribution Bone Disorders GI Intolerance Drug Interactions CYP450 3A4 Inhibition: RTV, LPV > IDV = NFV = APV >SQV
- 21. Integrase inhibitors are a class of antiretoviral designed to block the action of integraace, a viral enzyme that inserts the viral genome into the DNA of the host cell. Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. The drug is metabolized away via glucuronidation
- 23. Inhibit viral fusion, preventing viral replication 23
- 24. Entry inhibitors, also known as fusion inhibitors This class of drugs interferes with the binding, fusion and entry of an HIV virion to a human cell. By blocking this step in HIV’s replication cycle, such agents slow the progression from HIV infection to AIDS
- 25. Maraviroc is an entry inhibitor. Specifically, maraviroc is a CCR5 receptor antagonist, and binds to the chemokine receptor CCR5 and blocks the HIV gp120 (V3 loop) from associating with the receptor. HIV is then unable to bind and enter human macrophages.
- 26. 26 Statins (simvistatin & lovastatin) Azole antifungals Anticonvulsants Anti-TB (Rifampicin) Warfarin Midazolam, trizolam Alternative medicine Clarithromycin Oral contraceptives Amitriptyline
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- Nausea Most common side effect for AZT Eating prior to dose helps reduce nausea Macrocytosis is common and not associated with anemia, see increase in MCV of 25-40 units after 6-24 weeks, serves as crude indicator of adherence.
- Minimal Side Effects: Best tolerated of all antiretrovirals. Resistance Low barrier to resistance: a single point mutation (M184V) is sufficient for loss of effectiveness Advantages of the M184V mutation include: Improves the susceptibility of certain ZDV-resistant viruses in some patients Impairs viral fitness Keeping 3TC as part of a combination despite proven resistance is therefore sensible because this drug will continue reduce the replicative capacity of HIV Nucleoside Analog: Cytosine analogue Mechanism of Action: It is phosphorylated 3 times by thymidine kinase to the active metabolite, 3TC-triphosphate Bioavailability (F): 86% CSF Levels: 13% of serum levels (these levels have been shown to clear HIV RNA from CSF) T1/2: 3-6 hours Intracellular T1/2: 12 hours
- The flourinated version was designed to reduce toxicity and prolong drug half-life, but clinically there does not appear to be any difference between the 2 drugs. FTC has demonstrated activity against Hepatitis B, but it is not FDA approved for this indication. Nucleoside Analog: Cytosine analogue Mechanism of Action: It is phosphorylated 3 times to the active metabolite, emtricitabine 5’-triphosphate Bioavailability (F): Good oral bioavailability. CSF Levels: Estimated to be low (in monkeys, CSF level was 4% of serum levels) T1/2: 8-9 hours Intracellular T1/2: > 20 hours
- Patients should be counseled about abacavir hypersensitivity reaction (see next slides). Reference Notes Nucleoside Analog: Guanine analogue Mechanism of Action: It is phosphorylated 3 times to the active metabolite. Bioavailability (F): 83% CSF Levels: 27%-33% of serum levels T1/2: 1.5 hours Intracellular T1/2: > 12 hours Elimination: 81% metabolized by alcohol dehydrogenase and glucouronyl transferase with renal excretion of metabolites; 16% recovered in stool, and 1% unchanged in urine. Dose does not need to be adjusted for compromised renal function. No data on hepatic failure, use usual dose. Pediatric Dose: 8mg/kg BID Pregnancy: (Category C) Crosses placenta. Drug Interaction: Alcohol increases ABC levels by 41%. Abacavir does not impact alcohol levels. Clinically, moderate alcohol use appears to be fine, do not need to adjust dose. Resistance: ABC selects for the following mutations: 65, 74, 115, and 184. The 184 mutation leads to complete cross-resistance with 3TC, but by itself does not significantly decrease ABC susceptibility. Mutations at codons 65 and 74 lead to cross-resistance to ddI and ddC. Significant resistance requires multiple mutations, usually in addition to the 184 mutation. If have M184V + at least 3 NAMS, expect ABC failure.
- Monitor for renal impairment monthly: decreasing CrCl; glucose, phosphate, or protein in urine, low serum phosphate or potassium. Renal compromise is rare, but TDF should be stopped if patient develops renal compromise Nucleotide Analog: TDF is different from nucleosides in that it has already been phosphorilated once. Mechanism of Action: Tenofovir disoproxil fumarate is a pro-drug of tenofovir. After oral administration, TDF is rapidly cleaved by nonspecific extracellular carboxyesterases into tenofovir. Once inside cells tenofovir is metabolized by adenylate cyclase and nucleoside diphosphate kinase to the active moiety, tenofovir diphosphate (PMPApp). Bioavailability (F): 25% (fasting) to 40% (with food). Bioavailability improves with food, especially high-fat meals. CSF Levels: unknown % of serum levels T1/2: 12 to 18hours Intracellular T1/2: 10 to 50 hours
- ddI is a “D” drug Use lower dose to reduce risk of S/E development for patients < 60kg. Dose-related side effects Peripheral Neuropathy: Frequency: 5%-12%. Onset usually after 2-6 months of therapy. If patient develops peripheral neuropathy discontinue ddI at onset (or reduce dose to 250mg QD). Symptoms will dissipate slowly after stopping ddI or reducing dose. Following improvement in peripheral neuropathy, can re-introduce agent at reduced dose if needed. If provider does not discontinue therapy (or reduce dose) at onset, peripheral neuropathy will become permanent and increasingly painful and debilitating. Pancreatitis: Reported in 1%-9%, fatal in 6%. Risk factors include: renal failure, alcohol abuse, morbid obesity, history of pancreatitis, increased triglycerides, gall stones, and concurrent use of d4T, hydroxyurea, allopurinol, or pentamidine. If develops, discontinue therapy. When symptoms resolve, do not re-challenge with didanosine.
- This drug is used only at a dose that alone has virtually no antiretroviral effect (that is why boosted protease combination – e.g. LPV/r - is considered “one” of the three drugs in a PI-based regimen). However, combined with other PI’s, it has a powerful effect on the other PI’s metabolism – boosting the other PI’s effect.
- Whilst many side effects develop in the first few weeks on new medication, some do not emerge until the medication has been used over the longer term. As more information becomes available about the mechanisms that cause long-term side effects, it will be more possible to develop effective interventions to prevent and treat these side effects. Metabolism A general term for the breakdown of food and production of energy within the body. Sugar and fat are sources of energy. Abnormalities in sugar and fat levels or abnormalities in the processing of fats and sugars may indicate metabolic disorders and cause physical symptoms. Metabolic disorders Have caused the greatest concern in developed countries. A number of metabolic disorders have been reported among people taking anti-HIV therapy. These include hyperlipidemia (high levels of fat in the blood); diabetes, high blood sugar (hyperglycemia), and insulin resistance; and high levels of lactate (a by-product of sugar metabolism in the body); elevated ALT (a liver enzyme); and lipodystrophy (fat redistribution). Drug interactions: In addition, PIs are known to interact with multiple other medications. The role of the pharmacist is critical for recognizing and identifying and preventing potential drug interactions through dosage adjustment or preventing co-administration of contraindicated medications.
- 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. Be aware that changing or discontinuing medications may result in altered drug levels and potential adverse outcomes.