Transcript MEDICAL, HEALTH AND SOCIAL ASPECTS OF HIV/AIDS / …
ميحرلا نمحرلا الله مسب
Treatment of HIV/AIDS In : Medical, health and social aspects of HIV/AIDS
Alex Shnyra 2003
Nucleoside RT Inhibitors (NRTI)
•
A class of nucleoside analogs
•
Require an activation (phosphorylation) by cells
•
Mechanism of action:
– –
A: competitive inhibition of HIV RT B: if incorporated – causes stop of DNA elongation
ZIDOVUDINE
(zye-DOE-vue-deen)
O H N H O O O N N 3 CH 3 • • • • • •
Azidothymidine (AZT) or deoxythymidine analog Active against HIV-1 and other mammalian retroviruses Well absorbed the tissues (CSF:>60% of blood level) and distributed in Serum T1/2 ~ 1hr , but intracellular – 3.3 hrs Excretion – primarily uremic patients renal after glucuronidation by the liver. Clearance is reduced by 50% in Drug resistance (mutations in RT gene) may limit its efficacy when used as monotherapy
ZIDOVUDINE: Use and Dosage
Agent Route Use Adult Dosage ZIDOVUDINE ORAL HIV 200 mg q3d or 300 mg q2d I.V.
During labor 1-2 mg/kg/h (to prevent mother-to newborn infection)
• • •
Decrease the rate of clinical disease progression Prolongs survival of HIV-infected patients Used for treatment of HIV associated dementia and thrombocytopenia
ZIDOVUDINE:
Adverse Effects
• • • •
Common Myelosuppression (anemia and neutropenia) Gastrointestinal intolerance Headache Insomnia
• • •
Uncommon Thrombocytopenia Hyperpigmentation of nails Myopathy,High doses may cause anxiety, confusion.
•
Rare Fatal lactic acidosis, severe hepatomegaly (check aminotransferase levels)
ZIDOVUDINE: Drug Interactions
•
Increased serum levels of Zidovudine may occur with simultaneous administration of:
– – – – –
Fluconazole Probenecid Phenytoin Methadone Valproic acid
• •
Zidovudine may decrease the levels of Phenytoin Potentiating hematologic toxicity of other cytotoxic agents and myelosuppressive drugs
DIDANOSINE
(di-DAN-oe-seen)
H N H O O N O N N •
Didanosine (ddI) is a synthetic analog of deoxyadenosine.
•
Activated by acidic pH via hydrolysis of the glycosidic bond.
•
Plasma protein binding is low.
•
Excretion by renal system 0.6-1.5 h.
- T1/2
•
Activated intracellular T1/2 12-24 h !
Contains phenylalanine (phenylketonuria) and Na (Na-restricted diets)
DIDANOSINE: Use and Dosage
•
A chemical buffer is needed to increase absorption ; proper buffer dosing depends on taking drug on an empty stomach (AUC is reduced by 55% if taken 2 h after a meal)
•
Resistance occurs due to mutation in the viral RT gene Agent Route Use Adult Dosage DIDANOSINE ORAL Antiretrovir al HIV 200 mg q12h (> 60 kg) 125 mg q12h (< 60 kg)
DIDANOSINE:
Adverse Effects
•
Common Anxiety, diarrhea.
•
Uncommon Nausea and vomiting; stomach pain; pain in the hands or feet.
•
Rare Convulsions (seizures); fever and chills; shortness of breath; skin rash
DIDANOSINE: Drug Interactions
•
Decreases absorption of: !
NB! Avoid alcohol
– – – –
Dapsone (Use with Didanosine may increase the chance of peripheral neuropathy) Ketoconazole Quinolones (Didanosine decreases concentration of antibiotics via chelation effects) Tetracycline (use with Didanosine may increase the chance of pancreatitis)
•
Increased risk of pancreatitis with I.V. Pentamidine or Ganciclovir
LAMIVUDINE: (la-MI-vyoo-deen)
NH 2 N H O O S N O •
Lamivudine (3TC) is a cytosine analog.
•
Synergistic with other antiretroviral nucleoside analogs.
•
Oral bioavailability ~ 80% dependent).
(not food-
•
Excretion: unchanged by renal system T ½ ~ 2.5h.
•
Intracellular T1/2 ~ 10-15h.
•
High level resistance occurs – best when used in combination
LAMIVUDINE: Use and Dosage
• •
For treatment of HIV infection /AIDS or hepatitis B infection Side effects are typically mild gastrointestinal).
(headache, insomnia, Agent Route Use Adult Dosage LAMIVUDINE ORAL Antiretrovir al HIV 150 mg q12h ( > 50 kg) 2 mg/kg q12h (< 50 kg)
ZALCITABINE (zal-SITE-a-been)
H O O NH 2 N N O • • • • • • •
Zalcitabine – a cytosine analog high bioavailability ~ 80% with If taken with food or antacid – plasma concentration drops Excretion – T1/2 ~ 2 h by renal system – reduce the dosage in patients with renal insufficiency T1/2 intracellular ~ 10 h Resistance has been described – use in combination regimens (effective with Zidovudine) Only 4% is plasma protein bound CSF ~ 20% plasma concentration
ZALCITABINE: Use and Dosage
Agent Route Use Adult Dosage
•
ZALCITABIN E ORAL Antiretrovir al HIV 0.75 mg q8h Drug interactions:
–
Any drug with potential risk of peripheral neuropathy ddI, Cloramphenicol, INH, Dapsone, Phenytoin etc.).
–
Any drug which increases risk of pancreatitis Pentam) (e.g., IV (e.g.,
– –
Antacids decrease ddC absorption.
Probenecid and Cimetidine decrease elimination of ddC and may increase chance of toxicity.
ZALCITABINE:
Adverse Effects
•
Common Dose-dependent neuropathy, tingling, burning, numbness, or pain in the hands, arms, feet, or legs
•
Less common Fever; joint pain; muscle pain; skin rash; ulcers in the mouth and throat.
•
Rare Fever and sore throat; nausea and vomiting; stomach pain (severe); yellow eyes or skin
STAVUDINE (STAV-yoo-deen)
O H N H O O O N CH 3 • • • • • • • •
A thymidine analog Oral bioavailability ~ 86% Blood T1/2 ~ 1.22 h T1/2 intracellular ~ 3.5h
CFS ~ 55% of blood concentration Excretion – renal Resistance occurs (mutations in RT gene) Side Effects:
–
peripheral sensory neuropathy (may increase when used with other drugs, e.g. ddC ddI)
–
Pancreatitis
ABACAVIR (a-BAK-a-veer)
NH N H 2 N H O N N N • • • • • • • • •
A guanidine analog in the group) (the most effective drug Oral bioavailability food ~ 83%, not affected by ~50% is protein bound form Blood T1/2 ~ 1.5 h T1/2 intracellular ~ 3.5h
CFS ~ 30% of blood concentration Excretion – renal – after alcohol dehydrogenase inactivation High level resistance RT gene) occurs (mutations in Side Effects:
–
Hypersensitivity, gastrointestinal – resolves quickly with discontinuation
–
Nausea, vomiting, headache, fatigue.
NONNUCLEOSIDE RT INHIBITORS
•
The NNRTIs directly interact with RT – block RNA- and DNA dependent DNA polymerase .
•
Do not require activation for the activity.
•
Specific for RT of HIV-1.
•
Rapid resistance (cross-resistance with other NNRTIs) occurs due to mutations in viral RT gene – use in combination regiments.
•
No cross-resistance between NNRTIs and NRTIs or the protease inhibitors
NEVIRAPINE (ne-VYE-ra-peen)
• • • • •
A highly lipophilic drug Excellent bioavailability ~ 90% which is not food-dependent ~ 60% as protein-bound CSF concentration ~ 45% of the blood levels Metabolized by P450 – excretion primarily in urine Agent Route Use Adult Dosage NEVIRAPINE ORAL Antiretrovir al HIV 200 mg/d for 2 w then 200 mg q12h Newborn from infected mother – 2 mg/kg oral
NEVIRAPINE: Drug Interaction
• • •
ATNTAGONIZES: ketoconazole methadone (not recommended) oral contraceptives (use nonhormonal contraception)
•
Concentration is increased by: Coadministration with
• •
Cimetidine Macrolide agents Inhibitors of CYP3A Monitor: Rifampin , Rifabutin and other drugs metabolized by CYP3A4 or CYP2B6.
NEVIRAPINE: Adverse Effects
•
COMMON Skin rash (17%). Sometime severe – toxic epidermal necrolysis; hepatoxicity (fatal hepatic necrosis), abnormal liver function tests; chills, fever, or sore throat.
•
LESS COMMON Aching joints and muscles; bleeding or crusting sores on lips; dark urine; loss of appetite; nausea; vomiting; weakness; yellow skin or eyes
•
RARE Pain in arms, legs, or feet; sleepiness or unusual drowsiness; sores or ulcers in the mouth.
DELAVIRDINE (de-la-VIR-deen)
• • • • •
Good bioavailability ~ 85% which is reduced by antacids ~ 98% as protein-bound CSF concentration only 0.4 % of the blood levels Metabolized by CYP3A and CYP2D6 P450 (monitor liver tests) Can inhibit its own metabolism via inhibition of CYP3A Agent Route Use Adult Dosage DELAVIRDINE ORAL Antiretroviral HIV 400 mg q8h
DELAVIRDINE: Drug Interaction
Delavirdine may increase plasma concentrations of:
• • • •
Indinavir , Saquinavir , Amprenavir , Rifabutin Antihistamines.
Sedative hypnotics Calcium channel blockers Delavirdine concentration may be decreased by:
•
Antacids, Didanosine , Phenytoin, Phenobarbital, Carbamazepine, Rifabutin , Rifampin . Delavirdine concentration may be increased by:
• • •
Ketoconazole Clarithromycin Fluoxetine
EFAVIRENZ (ef-FAH-ver-enz)
• Oral administration gives ~ 45% bioavailability , food-dependent • T1/2 40-55 hrs with peak 3-5 hrs after administration • Highly protein bound (>99%) • Steady plasma concentration is established after 6-10 days of use • Hydroxylated by CYP3A4 and CYP2B6 • Low CSF concentration (0.3-1.2 % blood levels) Agent Route Use Adult Dosage
EFAVIRENZ
ORAL Antiretroviral HIV 600 mg/d
EFAVIRENZ: Adverse Effects
Usually occur in the first days of therapy !
COMMON
• •
Psychiatric effects – depression, aggression, confusion Skin rash or itching LESS COMMON
•
Blood in urine; difficult or painful urination; pain in lower back RARE
EFAVIRENZ: Drug Interaction
!
Induces CYR3A4 – induction of its own metabolism + other drugs Efavirenz may decrease the amount of:
• • •
Indinavir Saquinavir Rifabutin Efavirenz levels may be decreased by:
• •
Rifampin Rifabutin High rates of fetal abnormalities in primates: should be avoided in pregnancy.
Protease Inhibitors
•
Act on late stages of HIV growth cycle.
•
Proteases are responsible for conversion (cleaving) of the proteins in to mature forms which are the components of virion core.
•
Prevent new waves of infection.
•
Resistance is emerging and associated with mutations (at least 4) in the genes encoding viral proteases.
SAQUINAVIR (sa-KWIN-a-veer)
• • • • • •
Oral administration: old formulation (hard) only 4 % bioavailability; new formulation (soft) ~ 12% bioavailability Absorption is food-dependent before or after meals (fat). Drug should be taken 2h Highly protein bound (~ 98%) Low CSF concentrations T1/2 12 hrs; Excretion in the feces Metabolized in the liver by CYP3A4 Agent Route Use Adult Dosage SAQUINAVIR ORAL Antiretroviral HIV 600 mg q8h
SAQUINAVIR: Drug Interaction
Saquinavir concentration is increased by:
•
Ritonavir, Nelfinavir, Delavirdine, Indinavir, Ketoconazole, Clarithromycin, grapefruit juice.
Saquinavir is decreased by:
•
Efavirenz, Nevirapine, Rifampin, Rifabutin, Phenobarbital, Phenytoin, Dexamethasone, Carbamazepine.
Contraindications:
•
Concomitant Rifampin: not recommended.
SAQUINAVIR: Adverse Effects
Selective drug RARE:
•
Burning or prickling sensation; confusion; dehydration; dry or itchy skin; fruity mouth odor; nausea; unusual tiredness; weight loss
RITONAVIR (ri-TOE-na-veer)
• • • • •
An inhibitor of HIV-1 and HIV-2 proteases High bioavailability (~ 75%) – increased with food Excretion – primarily in the feces.
A potent inhibition of CYP3A and CYP 2D6 P450 ( patients with hepatic insufficiency ).
Resistance is emerging.
Agent RITONAVIR Route Use Adult Dosage ORAL Antiretrovir al HIV 600 mg q12h
RITONAVIR: Drug Interaction
Dosage adjustment is required Concentrations are reduced by:
•
Phenobarbital, Carbamazepine, Dexamethasone, Phenytoin, Rifampin, Nevirapine, tobacco use.
Concentration are increased by:
•
Fluconazole, Efavirenz, Delavirdine, Clarithromycin Contradictions:
•
Cardiac drugs - Amiodarone, Encainide
• • • •
Analgesics – Meperidine, Propoxyphene Anti-depressants – Bupropion, Desipramine Neuroleptics – Clozapine, Pimozide Sedatives – Diazepam, Chlorazepate !
RITONAVIR: Adverse Effects
•
COMMON GI upset, asthenia, abdominal pain, headache, anorexia
•
UNCOMMON Numbness or tingling feeling around the mouth; numbness or tingling feeling in the hands or feet
•
RARE Confusion; dehydration; dry or itchy skin; fatigue; nausea; vomiting; weight loss
INDINAVIR (in-DIN-a-veer)
• • • • • • • •
A specific inhibitor of HIV-1 and HIV-2 proteases Oral bioavailability ~ 65%, but must be taken on empty stomach ~ 60% of drug is protein-bound CSF ~ 75% - is the highest levels among protease inhibitors Metabolized by liver ( CYP3A4 ) – excretion in the feces Cirrhosis and other hepatic diseases Indinavir cause the higher AUC for Resistance - due to multiple codon substitutions Indinavir is a substrate and inhibitor of CYP3A4 Agent Route Use Adult Dosage INDINAVIR ORAL Antiretrovir al HIV 800 mg q8h
INDINAVIR: Drug Interaction
!
Numerous complex drug interactions Concentrations are reduced by:
•
Rifabutin (substantially decreases AUC for Indinavir), Amprenavir, Nevirapine, Efavirenz, Fluconazole, grapefruit juice Concentration are increased by:
•
Zidovudine, Ritonavir, Nelfinavir, Delavirdine, Ketoconazole, Contradictions:
•
Concomitant Cisapride, Triazolam, Midazolam, Ergot derivatives.
INDINAVIR: Adverse Effects
COMMON
•
Blood in urine; sharp back pain just below ribs UNCOMMON
•
Asymptomatic hyperbilirubinemia, GI upset, abdominal pain, headache, fatigue, insomnia.
RARE
•
Confusion; dehydration; dry or itchy skin; fatigue; nausea; vomiting; weight loss.
NELFINAVIR (nel-FIN-a-veer)
• • • • • •
A specific inhibitor of HIV-1 and HIV-2 proteases Absorption is food-dependent Nelfinavir) (food increases AUC for Bioavailability in humans is unknown Extensively protein-bound (>98%) Plasma T1/2 is 3.5-5 h Resistance is emerging Agent NELFINVIR Route Use Adult Dosage ORAL Antiretrovir al HIV 750 mg q8h with food
NELFINAVIR: Drug Interaction
!
Nelfinavir is an inducer and an inhibitor of the CYP3A Concentrations are reduced by:
•
Rifabutin and Rifampin (substantially decreases AUC for Nelfinavir) May be reduced by Carbamazepine, Phenobarbital, Phenytoin Concentration are increased by:
•
Indinavir, Ritonavir, Saquinavir, Delavirdine, Efavirenz, Ketoconazole Contradictions:
•
Cisapride, Triazolam, Midazolam, ergot derivatives.
NELFINAVIR: Adverse Effects
COMMON
•
Diarrhea, flatulence, redistribution of body fat .
LESS COMMON
•
Intestinal gas; skin rash, diabetes, hyperglycemia. RARE
•
Other side effects not listed above may also occur in some patients.
AMPRENAVIR (am-PREN-a-veer)
• • • •
Rapidly absorbed from the GI (food-independent) Plasma T1/2 is 7-10 hrs Especially effective in a combination with NRTIs (at least two) Resistance occurs but cross-resistance with other protease inhibitors is less prevalent Agent Route Use Adult Dosage AMPRENAVIR ORAL Antiretrovir al HIV 1200 mg q12h b.w. > 50kg 20 mg/kg q12h b.w. < 50 kg
AMPRENAVIR: Adverse Effects
COMMON
•
Dry or itchy skin; fatigue; increased hunger; increased thirst; increased urination; skin rash LESS COMMON
•
Burning or prickling sensation in arms or legs; depression; mood or mental changes RARE
•
Fever; general feeling of discomfort or illness; unexplained weight loss
AMPRENAVIR: Drug Interaction
!
Nelfinavir is an inhibitor of the CYP3A4 Concentrations are reduced by:
•
Rifampin and Efavirenz Contradictions:
•
Triazolam, Cisapride, Midazolam, ergot derivatives, Amiodarone, Warfarin, tricyclic antidepressants, Lovastatin, NB! Use of antacids or may keep Amprenavir from working properly.