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Antiviral drugs - drdhriti

A power point presentation on Antiviral Drugs suitable for UG level medical students and others

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Antiviral drugs - drdhriti

  1. 1. ANTIVIRAL DRUGS DR. D. K. BRAHMA ASSOCIATE PROFESSOR DEPARTMENT OF PHARMACOLOGY NEIGRIHMS, SHILLONG
  2. 2. TREATMENT APPROACHES • ULTIMATE EXPRESSION OF PARASITISM • TAKES NUTRITION FROM HOST • ALSO DIRECT HOST`S METABOLIC PATHWAYS TO SYNTHESIZE VIRUS PARTICLES • CHALLENGES IN DESIGNING ANTI-VIRAL TREATMENTS: – HOST CELL MUST BE IMMUNE TO TREATMENT! (TO LIMIT OFF-TARGET TOXICITY) – VIRAL INFECTION DISEASE SYMPTOMS OFTEN ASSOCIATED WITH LATENCY PERIOD (REPLICATION AT PEAK WHEN SYMPTOMS APPEAR) – INCUBATION PERIOD THERAPY • GENERAL ANTI-VIRAL STRATEGIES ARE TO INHIBIT: 1. VIRAL ENZYMES: • DNA/RNA POLYMERASES, ETC. • REVERSE TRANSCRIPTASES, PROTEASES, ETC. 2. PENETRATION AND UNCOATING 3. REVERSE TRANSCRIPTION 4. ASSEMBLY AND MATURATION 5. RELEASE OF VIRUS
  3. 3. CLASSIFICATION • ANTI-HERPES VIRUS AGENTS: • IDOXURIDINE (IUDR), TRIFLURIDINE, ACYCLOVIR, VALACICLOVIR, FAMCICLOVIR, GANCICLOVIR, VALGANCICLOVIR, CIDOFOVIR, FOSCARNET, FOMIVIRSEN • ANTI-INFLUENZA AGENTS: • AMANTADINE, OSELTAMIVIR, PERAMIVIR, RIMANTADINE, ZANAMIVIR • ANTI-HEPATITIS VIRUSES: • FOR HEPATITIS B: LAMIVUDINE, DIPIVOXIL, TENOFOVIR • FOR HEPATITIS C: RIBAVIRIN, INTERFERON Α • ANTIRETROVIRAL AGENTS: – NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIS): ZIDOVUDINE, DIDANOSINE, STAVUDINE, LAMIVUDINE, ABACAVIR, EMTRICITABINE, TENOFOVIR – NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI’S): NEVIRAPINE, EFAVIRENZ, DELAVIRDINE – PROTEASE INHIBITORS: RITONAVIR, ATAZANAVIR, INDINAVIR, NELFINAVIR, SAQUINAVIR, AMPRENAVIR, LOPINAVIR • ENTRY (FUSION INHIBITOR): ENFUVIRTIDE • CCR5 RECEPTORINHIBITOR: MARAVIROC • INTEGRASE INHIBITOR: RALTEGRAVIR
  4. 4. ANTI-HERPES VIRUS DRUGS • EFFECTIVE AGAINST HERPES GROUP OF DNA VIRUSES • HERPES SIMPLEXVIRUS – 1 (HSV-1 ), HERPES SIMPLEXVIRUS – 2 (HSV-2), VARICELLAZO STER VIRUS (VZV), EPSTEIN-BARR VIRUS (EBV) AND CYTO MEGALO VIRUS (CMV)
  5. 5. ANTI-HERPES VIRUS DRUGS • IDOXURIDINE: 5-IODO 2-DEOXYURIDINE (IUDR) – FIRST PYRIMIDINE ANTIMETABOLITE • MOA: COMPETES WITH THYMIDINE AND GETS INCORPORATED IN DNA – FAULTY DNA FORMS WHICH BREAKS DOWN EASILY • USES: TOPICAL USES ONLY – HERPES SIMPLEX KERATITIS (SUPERFICIAL DENDRITIC KERATITIS) • WHEN RAPID ACTION REQUIRED – ACTS FASTER THAN ACYCLOVIR (MORE USEFUL WHEN STROMAL INVOLVEMENT OF CORNEA) • DRAWBACK: LOCAL TOXICITY, OCULAR IRRITATION, LOW VIRUS SELECTIVITY AND QUICK RESISTANCE • TRIFLURIDINE: FLUORINATED NUCLEOSIDE - HSV-1 , (HSV-2) AND CMV AND RELATED VIRUSES – LOW VIRUS SELECTIVITY AND INTERFERES HOST DNA SYNTHESIS – USED IN H. SIMPLEXKERATITIS
  6. 6. ACYCLOVIR • SEEN AS A “NEW AGE” IN ANTIVIRAL THERAPY, GERTRUDE ELION, ITS CREATOR, WAS GIVEN THE NOBEL PRIZE FOR MEDICINE IN 1988 • A WIDELY USED ANTIVIRAL WITH MAIN IMPLICATIONS IN THE TREATMENT OF HERPES • IT IS A NUCLEOSIDE ANALOGUE (DEOXYGUANOSINE) AND PREVENTS DNA SYNTHESIS VIRAL REPLICATION IN INFECTED CELLS • EXTREMELY SELECTIVE AND LOW IN TOXICITY
  7. 7. ACYCLOVIR – STRUCTURE • Purine Mimic • Similarity to 2`-deoxyguanosine (dGTP): lack of 3` hydroxyl
  8. 8. ACYCLOVIR - MOA Step 1: Activation Selectively taken up by virus infected cells No damage to host cells
  9. 9. ACYCLOVIR - MOA Step 2: (i) Competitive Inhibition of herpes virus DNA polymerase activity; (ii) Incorporation into growing DNA chain Inhibits DNA- polymerase irreversibly
  10. 10. ACYCLOVIR – MOA (SUMMARY) Acyclovir Acyclovir Monophosphate Acyclovir triphosphate Herpes virus specific thymidine kinase Cellular kinases Inhibits herpes virus DNA Polymerase competitively Gets incorporated in viral DNA and stops lengthening of DNA strands. The terminated DNA Inhibits DNA-polymerase irreversibly
  11. 11. ACYCLOVIR – ANTIVIRAL SPECTRUM • EFFECTIVE AGAINST THE FOLLOWING: 1.HERPES SIMPLEXVIRUS TYPE I (HSV-1) 2. HERPES SIMPLEXVIRUS TYPE II (HSV-2) 3. VARICELLA ZOSTERVIRUS (VZV) 4. EPSTEIN-BARRVIRUS (EBV) 5. CYTOMEGALOVIRUS (CMV) -- LEAST ACTIVITY • RESISTANCE: HSV – MUTANTS DEFICIENT OF THYMIDINE KINASE; VZS – CHANGE IN SPECIFICITY OF VIRUS DIRECTED ENZYME- AFFINITY FORACYCLOVIRDECREASED
  12. 12. ACYCLOVIR - PHARMACOKINETICS • POOR ORAL ABSORPTION AND IS ONLY 15 - 20% (LIPOPHILIC) AND UNAFFECTED BY FOOD • GOOD CSF PENETRATION (50% 0F PLASMA) • AFTER TOPICAL APPLICATION – PENETRATES CORNEA • EXCRETED UNCHANGED IN URINE – GLOMERULAR FILTRATION AND ACTIVE TUBULAR SECRETION • HALF-LIFE: 2-3 HRS ONLY • RENAL IMPAIRMENT – DOSE REDUCTION ADRS: LOCAL – STINGING AND BURNING SENSATION ON APPLICATION, ORAL – HEADACHE, NAUSEA MALAISE, IV – RASH, SWEATING, EMESIS, HYPOTENSION. NEUROLOGIC TOXICITY (E.G., TREMORS, DELIRIUM, SEIZURES, DISORIENTATION, HALLUCINATIONS AND COMA) DOSE DEPENDENT DECREASE IN GFR
  13. 13. ACYCLOVIR – THERAPEUTIC USES 1. GENITAL HERPES SIMPLEX: HSV – II (TOPICAL, ORAL AND IV)) – PRIMARY DISEASE: GENERALLY OINTMENT IN MILD – MORE SEVERE CASES - ORAL (1 GM/DAY IN 5 DIVIDED DOSES) – RECURRENT DISEASE: ORAL (NOT EFFECTIVE) – IV (5 MG/KG INFUSED OVER 1 HOUR Q 8 HRLY FOR 10 DAYS) (SUPPRESSIVE ORAL THERAPY 400 MG BD – PREVENT RECURRENCES – CONTINUOUS ORAL THERAPY FOR CASES WITH >8 RECURRENCES PER YEAR) 1. MUCOCUTANEOUS H. SIMPLEX: HSV - I – ACYCLOVIR CREAM – ORAL OR IV IN IMMUNOCOMPROMIZED PATIENTS (15 MG/KG/DAY FOR 7 DAYS) 1 . H. SIMPLEX ENCEPHALITIS: DOC TYPE – 1 – 10 TO 20 MG/KG/8HR X 10 DAYS 1 . H. SIMPLEX KERATITIS: SUPERFICIAL DENDRITIC CORNEAL ULCER BETTER THAN IDOXURIDINE (BETTER PENETRATION) – PREVENTION OF BLINDNESS 2. H. ZO STER – LESS SUSCEPTIBLE – USED ONLY IN IMMUNODEFICIENT PATIENTS – ALSO ORAL AND OINTMENT THERAPY 3. CHICKENPOX: WITH IMMUNODEFICIENCY – DOC - 15 MG/KG/DAY IV FOR 7 DAYS – ALSO PROPHYLACTIC VALUE
  14. 14. ACYCLOVIR SUBSTITUTES – PHARMACOKINETIC CONSIDERATION • BIOAVAILABILITY CAN BE IMPROVED BY DESIGN OF SUITABLE PRODRUGS • VALACYCLOVIR: ESTER PRODRUG OF ACYCLOVIR - DOC IN HZV • FAMCICLOVIR: ESTER PRODRUG OF GUNINE NUCLEOSIDE ANALOGUE PENCICLOVIR • CONVERTED TO TRIPHOSPHATE BY VIRAL THYMIDINE KINASE • DNA POLYMERASE INHIBITOR • INHIBITS HSV AND HZV – NOT USEFUL IN ACYCLOVIR RESISTANCE • USES: ALTERNATIVE TO ACYCLOVIR IN GENITAL AND OROLABIAL HERPES ALSO IN HEPATITIS B (HBV)
  15. 15. OTHER ANTI HERPES DRUGS • GANCICLOVIR: ACYCLOVIR ANALOGUE – EFFECTIVE AGAINST ALL HERPES – INTRACELLULAR ACTIVATION TO TRIPHOSPHATE – MOST ACTIVE AGAINST CMV • ATTAINS MUCH HIGHER CONCENTRATION IN CMV INFECTED CELLS – PLASMA HALF LIFE 2-3 HOURS BUT INSIDE CMV CELLS >24 HOURS • POOR ORAL ABSORPTION (<10%) – VALGANCICLOVIR (PRODRUG) • ADRS: BONE MARROW TOXICITY • USES: SEVERE IMMUNOCOMPROMIZED PATIENTS WITH PNEUMONIA, COLITIS, RETINITIS – IV USE AND TOPICAL – PROPHYLACTIC VALUE – PREVENTS BLINDNESS IN AIDS PATIENTS • CIDOFOVIR: DOES NOT REQUIRE VIRAL ENZYME - EFFECTIVE AGAINST HSV RESISTANT TO ACYCLOVIR AND CMV RESISTANT TO GANCICLOVIR – MONO PO4 CONVERTS TO DI PO4 • HALF LIFE 2 – 3 HOURS BUT REMAINS INSIDE CELL FOR LONG – WEEKLY THERAPY • GIVEN IV WITH PROBENECID (IMPROVES BIOAVAILABILITY) • USES: AIDS PATIENTS WITH CMV RETINITIS – GANCICLOVIR FAILED CASES; AND ALSO IN ACYCLOVIR RESISTANT MUCOCUTANEOUS HERPES SIMPLEX IN IMMUNOCOMPROMIZED PATIENTS; ADRS: KIDNEY DAMAGE AND HYPERSENSITIVITY REACTIONS
  16. 16. OTHER ANTI HERPES DRUGS – CONTD. • FOSCARNET: UNRELATED TO ANY NUCLEIC ACID • MOA: INHIBITS VIRAL DNA POLYMERASE AND REVERSE TRANSCRIPTASE • ACTION: EFFECTIVE AGAINST HSV (RESISTANT TO ACYCLOVIR), CMV (GANCICLOVIR RESISTANT), OTHER HERPES VIRUSES AND HIV • DRAWBACK: LOW VIRAL SELECTIVITY, TOXICITY HIGH, KIDNEY DAMAGE – RENAL DIABETES, ANAEMIA, PHLEBITIS, TREMOR, CONVULSION ETC. • USES: CMV RETINITIS AND OTHER CMV IN AIDS AND ACYCLOVIR
  17. 17. ANTI-INFLUENZA DRUGS • AMANTADINE, OSELTAMIVIR, RIMANTADINE, ZANAMIVIR
  18. 18. AMANTADINE - TRICYCLIC AMINE • TRICYCLIC AMINE UNRELATED TO ANY NUCLEIC ACID PRECURSOR. APPROVED BY FDA IN 1976 TO TREAT INFLUENZA A (NOT INFLUENZA B), RESISTANT TO H5N1 (AVIAN) AND H1N1 (SWINE). • MECHANISM: • INHIBITS THE UNCOATING OF THE VIRAL GENOME AND ALSO VIRAL ASSEMBLY IN LATE STEP • SPECIFICALLY TARGETS A PROTEIN CALLED M2 (AN ION CHANNEL) - INACTIVE AGAINST INFLUENZA B, WHICH LACKS M2 • PHARMACOKINETICS: • WELL ABSORBED ORALLY; CROSSES BBB • 90% EXCRETED UNCHANGED; NO REPORTS OF METABOLIC PRODUCTS • T1/2 – 16 HRS • SIDE EFFECTS: • LOW TOXICITY AT THERAPEUTIC LEVELS; NAUSEA, ANOREXIA, INSOMNIA AND SOME CNS SIDE EFFECTS (NIGHTMARES AND SCARY HALLUCINATIONS) • USES: PROPHYLAXIS OF INFLUENZA A2 (EPIDEMIC OR SEASONAL); TREATMENT OF INFLUENZA AND PARKINSONISM. DOSES: 100 MG BD OR 200 MG OD • RIMANTADINE – METHYL DERIVATIVE OF AMANTADINE
  19. 19. OSETALMIVIR (TAMIFLU) • BROAD SPECTRUM – INFLUENZA A AND B, H5N1 (BIRD FLU) AND NH1N1 (SWINE FLU) • KINETICS: OSELTAMIVIR IS A PRODRUG THAT IS ACTIVATED IN THE GUT AND LIVER (HYDROLYSED) TO O. CARBOXYLATE • WELL ABSORBED ORALLY (B - 80%) • O. CARBOXYLATE IS FURTHER METABOLIZED AND EXCRETED BY KIDNEY • T1/2 --- 6-10 HRS • MOA: NEURAMINIDASE INHIBITOR (IMPORTANT FOR VIRAL PROGENY RELEASE) • USES: BOTH PROPHYLAXIS AND TREATMENT OF INFLUENZA A AND B, H5N1 AND H1N1. REDUCES THE SEVERITY, DURATION AND COMPLICATIONS • ADRS: GASTRIC IRRITATION (NAUSEA AND VOMITING) – WITH FOOD TO TAKE. HEADACHE, WEAKNESS, SADNESS, COUGH AND INSOMNIA ETC. • DOSE: 75 MG BD FOR 5 DAYS
  20. 20. ANTI-HEPATITIS VIRUS DRUGS • SOME ANTIVIRAL DRUGS ARE VIRUS-NONSELECTIVE – INHIBIT VIRUSES BELONGING TO DIFFERENT CLASSES (DNA – RNA) • FOR HEPATITIS B: LAMIVUDINE, DIPIVOXIL, TENOFOVIR • FOR HEPATITIS C: RIBAVIRIN, INTERFERON Α • HEPATITIS B (HBV) IS A DNA VIRUS – INTEGRATE INTO HOST CHROMOSOME AND PERMANENT INFECTION • HEPATITIS C (HCV) IS RNA VIRUS – DOES NOT INTEGRATE INTO HOST CHROMOSOME CAUSE CHRONIC HEPATITIS
  21. 21. ADEFOVIRDIPIXOVIL • MONOPHOSPHATE - ANALOGUE OF AMP. EFFECTIVE AGAINST HBV AND OTHER DNA VIRUSES • KINETICS: ESTERASES IN INTESTINE AND LIVER RELEASE ACTIVE DRUG - BIOAVAILABILITY 60 % - EXCRETED IN KIDNEY – 7 HOURS HALF LIFE • MOA: AFTER ENTERING CELL - PHOSPHORYLATED TO DIPHOSPHATE – HIGH AFFINITY FOR HBV DNA POLYMERASE – NOT TO HOST DNA. POLYMERASE INHIBITED AND ADEVOFIR GETS INCORPORATED IN DNA AND TERMINATES DNA CHAIN • USES: CHRONIC HBV, LAMIVUDINE RESISTANT CASES AND HBV WITH CONCURRENT HIV INFECTION • DOSES: 10 MG/DAY FOR 1 YEAR - CLINICAL, BIOCHEMICAL, SEROLOGICAL, VIROLOGICAL, HISTOLOGICAL IMPROVEMENT (50%) – NEEDS CONTINUATION • ADRS: HEADACHE, SORE THROAT, FLU SYNDROME, NEPHROTOXICITY
  22. 22. TENOFOVIR • MONOPHOSPHATE NUCLEOTIDE RELATED TO AMP • EFFECTIVE AGAINST HBV AND HIV • LOW ORAL ABSORPTION - ADMINISTERED AS PRODRUG (TENOFOVIR DISOPROXIL) • HYDROLYSIS OF PRODRUG – CONVERTS TO TENOFOVIR DIPHOSPHATE BY CELLULAR KINASE • MOA: INHIBITS HBV DNA POLYMERASE AND ALSO HIV-REVERSE TRANSCRIPTASE (LOW AFFINITY FOR HOST DNA POLYMERASE) • KINETICS – HALF LIFE 16 HOURS (LONGER INTRACELLULAR HALF LIFE) • USES: 300 MG DAILY IN HBV INFECTION (INCLUDING LAMIVUDINE RESISTANT CASES) – 90% CURE RATE – LESSER TOXICITY
  23. 23. RIBAVIRIN (PURINE NUCLEOSIDE ANALOGUE) • BROAD SPECTRUM ANTIVIRAL ACTIVITY – INFLUENZA A AND B, RESPIRATORY SYNCITIAL VIRUSES AND MANY OTHER DNA AND RNA VIRUSES • MOA: INTRACELLULARLY GENERATES MONO- AND TRIPHOSPHATE DERIVATIVE – INHIBIT GTP AND VIRAL RNA SYNTHESIS • KINETICS: BIOAVAILABILITY 50%, ACCUMULATES IN THE BODY – HALF LIFE 10 DAYS • USES: 1) SEVERE INFLUENZA A/B AND MEASLES IN IMMUNOSUPPRESSED PATIENTS; 2) HERPES, ACUTE HEPATITIS. MONOTHERAPY – INCOMPLETE RESPONSE; 3) 1ST LINE OF DRUG IN HCV WITH PEGINTERFERONE FOR 6-12 MONTHS. NEBULIZED FORM GIVEN IN RESPIRATORY SYNCYTIAL BRONCHIOLITIS VIRUS IN INFANTS AND CHILDREN – CONGENITAL HEART DISEASE AND PREMATURITY- ALSO RARE VIRAL INFECTIOS • DOSE: 200MG QID • ADRS: ANAEMIA, BM DEPRESSION, HAEMOLYSIS AND TERATOGENICITY
  24. 24. INTERFERONE Α (IFNΑ) • LMW GLYCOPROTEIN CYTOKINES PRODUCED BY HOST CELLS IN RESPONSE TO VIRAL INFECTIONS, ALSO TNFΑ AND IL-1 – NONSPECIFIC ANTIVIRAL AND OTHER IMMUNITY AND CELL PROLIFERATION EFFECTS • MOA: BINDS TO CELL SURFACE RECEPTORS - ACT ON MULTISTEPS – VIRAL PENETRATION, VIRAL SYNTHESIS OF MRNA, ASSEMBLY, AND RELEASE • DIRECT OR INDIRECT SUPPRESSION OF VIRAL PROTEIN SYNTHESIS - TRANSLATION • JAK-STAT TYROSINE KINASE RECEPTORS – PHOSPHORYLATES CELLULAR PROTEINS – MIGRATE TO NUCLEUS – INDUCE TRANSCRIPTION OF INTERFERONE INDUCED PROTEINS – ANTIVIRAL EFFECTS • ACTION: INHIBITS MANY DNA AND RNA VIRUSES, BUT SPECIES SPECIFIC – 3 HUMAN TYPES – Α, Β, - ONLYȢ IFNΑ2A AND IFNΑ2B AVAILABLE FOR USE - IM AND SC - PEGYLATED FORMS ARE AVAILABLE FOR S.C USE • PEG IFNΑ2A LONGER DURATION THAN PEG IFNΑ2B • PHARMACOKINETICS: WELL DISTRIBUTED, DEGRADED IN LIVER. PERSISTS IN PLASMA FOR LONGER TIME 24 HRS. PEG PRODUCTS PERSISTS LONGER – THRICE WEEKLY VS WEEKLY ADMINISTRATION
  25. 25. INTERFERON (IFNΑ) – USES AND ADRS 1. CHRONIC HEPATITIS B: IFNΑ2A 2.5 TO 5 MU/M2 3 TIMES PER WEEK FOR 4-6 MONTHS. PEG PREPARATIONS 180 MCG SC WEEKLY FOR 24 TO 48 WEEKS – ALSO IFNΑ2B (5-10 MU) 2. CHRONIC HEPATITIS C: IFNΑ2B (3 MU) 3 TIMES WEEKLY FOR 6-12 MONTHS – PEGIFNS 180 MCG/WEK (MORE EFFECTIVE) – COMBINE WITH RIBAVIRIN 3. AIDS RELATED KAPOSI`S SARCOMA: HUMAN HERPES VIRUS 8 4. CONDYLOMA ACUMINATA - PAPILLOMA VIRUS 5. H. SIMPLEX, H. ZOSTER AND CMV IN IMMUNOCOMPROMISED PATIENTS – 2ND LINE OF AGENT 6. CML, MULTIPLE MYELOMA, FOLLICULAR LYMPHOMA ETC. • ADRS: FLUE LIKE SYMPTOMS, NEUROTOXICITY (NUMBNESS, NEUROPATHY, ALTERED BEHAVIOUR), MYELOSUPRESSION-DOSE DEPENDENT NUTROPENIA, AND HYPOTENSION, ARRHYTHMIA, ALOPECIA AND LIVER DYSFUNCTION ETC.
  26. 26. •REMEMBER: ACYCLOVIR, TAMIFLU AND INTERFERON - ANTI-RETROVIRUS
  27. 27. ANTI RETROVIRUS DRUGS • DRUGS USED AGAINST RETROVIRUS – HIV • USEFUL IN PROLONGING AND IMPROVING QUALITY OF LIFE – POSTPONE COMPLICATIONS OF AIDS AND ARC - DO NOT CURE THE INFECTION • CLINICAL EFFICACY – PLASMA HIV-RNA ASSAYS AND CD4 LYMPHOCYTE COUNT • SINGLE STRANDED RNA – CARRIES OUT REVERSE TRANSCRIPTION OF PROVIRAL DNA FROM VIRAL RNA (OPPOSITE OF NORMAL) – RNA DEPENDENT DNA POLYMERASE (REVERSE TRANSCRIPTASE) • ATTACKS CD4+ HELPER T- LYMPHOCYTES – LATER MACROPHAGES – DECREASED IN CD4 COUNT • >200 CELLS/µL CMI LOST – OPPORTUNISTIC INFECTIONS • DRUGS TARGET – REVERSE TRANSCRIPTASE, HIV PROTEASES (POLYPROTEINS), FUSION, CHEMOKINE CORECEPTOR (CCR5) ON HOST CELLS AND HIV-INTEGRASE – ALWAYS USED IN COMBINATION (3 OR MORE)
  28. 28. NRTIS – ZIDOVUDINE (PROTOTYPE) • THYMIDINE ANALOGUE (AZIDOTHYMIDINE, AZT) • MOA: ZIDOVUDINE TRIPHOSPHATE (PHOSPHORYLATED) – SELECTIVELY INHIBITS REVERSE TRANSCRIPTASE SSVRNA DSDNA (Proviral) Virus directed RT Integrate with host DNA Translocation to nucleus (Integrase enzyme) mRNA Genomic RNA Viral Regulatory proteins (Polyprotein) Fractionated polyprotein Protease enzyme Release of Viral particles Assemble and mature
  29. 29. ZIDOVUDINE – CONTD. • ANOTHER MOA - ZIDOVUDINE MAY ITSELF GETS INCORPORATED IN PROVIRAL DNA AND PREVENTS CHAIN ELONGATION • ZIDOVUDINE PREVENTS INFECTION OF NEW CELLS BY HIV, BUT NOT EFFECTIVE ON ALREADY INFECTED HOST CHROMOSOMES • PHARMACOKINETICS: BIOAVAILABILITY 60 %, T1/2 – 1 HR, CROSSES BBB AND PLACENTA AND IN MILK, EXCRETED IN URINE – 50% IN CSF • ADRS: ANAEMIA AND NUTROPENIA (INHIBITION OF CELLULAR MITOCHONDRIAL DNA POLYMERASE), MYOPATHY, PIGMENTATION OF NAILS, LACTIC ACIDOSIS AND ENCEPHALOPATHY • RESISTANCE: BY POINT MUTATION (ALTERATION OF RT ENZYME) • DRUGINTERACTION: PARACETAMOL INCREASES TOXICITY, STAVUDINE ANTAGONIZES EACH OTHER • USES: IN HIV INFECTED PERSONS IN COMBINATION – 1ST LINE THERAPY BY NACO – IMPROVEMENT AND REDUCTION IN KAPOSI`S LESIONS
  30. 30. DIDANOSINE AND STAVUDINE • DIDANOSINE (DDL): PURINE NUCLEOSIDE • MOA: CONVERTS TO TRIPHOSPHATE – COMPETES WITH ATP FOR INCORPORATION TO VIRAL DNA – INHIBITS RT AND TERMINATES PROVIRAL DNA • ACTION: EQUIVALENT TO AZT • TOXICITY: PERIPHERAL NEUROPATHY (STOCKING AND GLOVE), PANCREATITIS - RARELY USED NOW • STAVUDINE: THYMIDINE ANALOGUE • MOA: SAME AS ZIDOVUDINE – THYMIDINE KINASE PATHWAY • KINETICS: 1.5 HOURS HALF-LIFE • USES: COMBINATION THERAPY (NACO) • ADRS: PERIPHERAL NEUROPATHY, LIPODYSTROPHY, LACTIC ACIDOSIS, PANCREATITIS ZIDOVUDINE – NOT TO BE COMBINEDWITHSTAVUDINE AND STAVUDINE NOT TOBE COMBINEDWITHDIDANOSINE
  31. 31. LAMIVUDINE (3TC) • MOA: PHOSPHORYLATES INTRACELLULARLY AND INHIBITS – HIV RT AND ALSO HBV DNA POLYMERASE – ALSO INCORPORATION TO DNA POLYMERASE – CHAIN TERMINATION - HUMAN DNA POLYMERASE NOT AFFECTED – LOW TOXICITY • QUICKRESISTANCE: POINT MUTAION OF HIV RT AND HBV-DNA POLYMERASE • RESISTANCE STRAIN – SLOW GROWING AND LOWER VIRULENCE • KINETICS: HIGHER BIOAVAILABILITY & LONGER T1/2(6-8 HRS) – LONGER INTRACELLULARLY • USES: 1ST LINE OF DRUG IN HIV (EQUIEFFECTIVE AS ZIDOVUDINE) – SYNERGISTIC ACTION WITH OTHER NRTIS - ALSO - 1ST LINE OF DRUG IN CHRONIC HBV • LOWTOXICITY – NO HAEMATOLOGICAL TOXICITY OR NEUROPATHY • USES: HIGH PRIORITY IN COMBINATION THERAPY (HBV VIRAEMIA RETURNS AFTER 1- 4 YEARS)
  32. 32. NNRTIS - NEVIRAPINE AND EFAVIRENZ • NUCLEOSIDE UNRELATED COMPOUNDS • MOA: DIRECT INHIBITOR OF HIV REVERSE TRANSCRIPTASE (NONCOMPETITIVE) • MORE POTENT THAN AZT ON HIV-1 BUT NOT INDICATED IN HIV-2 • USED ALONE RAPID RESISTANCE AND CROSS RESISTANCE BETWEEN THE 2 – BUT NOT WITH NRTIS AND PIS • ONCE NNRTIS FAIL - SHOULD NOT BE TREATED WITH ANOTHER ONE • USES: EITHERONE OF THEM1ST LINE OF DRUG IN COMBINATION THERAPY NVP EFV Metabolism Mainly by CYP3A4 Mainly by CYP2B6 Microsomal enzyme Inducer Inducer (also inhibits CYP3A4) 2 weeks dose adjustment Doubled Not required Rifampicin (TB) Induces metabolism No induction Hepatotoxicity Yes No
  33. 33. PROTEASE INHIBITORS (PIS) • DRUGS - ATAZANAVIR, INDINAVIR, NELFINAVIR, SAQUINAVIR, AMPRENAVIR, LOPINAVIR AND RITONAVIR • MOA: AS DESCRIBED EARLIER – INHIBITION OF PROTEASE ENZYME INVOLVED IN FRACTIONATION OF POLYPROTEINS – PREVENTION OF MATURATION OF NEW VIRAL PARTICLES - BY BINDING TO THE ACTIVE SITE IN PROTEASE MOLECULE • KINETICS: VARIABLE BIOAVAILABILITY: 2- 8 HOURS, METABOLIZED BY CYP3A4, EXCEPT NFV (CYP2C19) – ALL ARE POTENT INHIBITOR OF CYP3A4 (MAINLY RITONAVIR AND LOPINAVIR) – OTHER CYP MAY BE INDUCED • ADVANTAGES: MORE EFFECTIVE THAN ZIDOVUDINE - ACT IN LAST STEP – EFFECTIVE IN NEWLY FORMED AND CHRONICALLY INFECTED CELLS - PRODUCE NON-INFECTIOUS IMMATURE VIRAL PROGENY • DRAWBACKS: UNPREDICTABLE MANY DRUG INTERACTIONS (ENZYME INDUCTION AND INHIBITION), RIFAMPICIN INTERACTION, LARGE TABLET LOAD (6-18) – LOW DOSE RITONAVIR STRATEGY • USES: COMBINATION THERAPY – BUT RESERVED (2ND LINE AGENT)
  34. 34. PROTEASE INHIBITORS – CONTD. • ADRS: GIT INTOLERANCE, HEADACHE, DIZZINESS, LIMB AND FACIAL TINGLING • LIPODYSTROPHY (ABDOMINAL OBESITY, BUFFALO HUMP WITH WASTING OF LIMB AND FACE • RAISED TRIGLYCERIDES AND CHOLESTEROL • INSULIN RESISTANCE • INDINAVIR – URINARY CALCULI
  35. 35. HIV TREATMENT GUIDELINES • COMPLEX, PROLONGED, NEEDS EXPERTISE AND STRONG MOTIVATION AND COMMITMENT OF PATIENT AND EXPENSIVE • NO MONOTHERAPY - HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) – COMBINATION OF 3 OR MORE DRUGS • AIM OF HAART – NONE ARTS CAN ERADICATE, THEREFORE: • MAXIMALLY AND DURABLY INHIBIT VIRAL REPLICATION SO THAT PATIENT CAN MAINTAIN ADEQUATE IMMUNE RESPONSE • GREATER THE SUPPRESSION LESSER IS THE CHANCE OF RESISTANCE • EFFECTIVE ART REDUCES TRANSMISSION • HAART - >99% KILLING, BUT RELAPSE
  36. 36. INITIATION OF THERAPY 1. ALL SYMPTOMATIC HIV PATIENTS 2. ASYMPTOMATICS WITH CD4 CELL COUNT BELOW 350/µL 3. HIV PATIENT COINFECTED WITH HBV/HBC 4. ALL PREGNANT HIV POSITIVE WOMEN 5. ALL PATIENT WITH HIV NEPHROPATHY ADDITIONALLY NACO: 1. ALL HIV POSITIVE IN STAGE 3 AND 4 2. HIV POSITIVE FOR 6 – 8 YEARS AGO 3. HISTORY OF TB AND HERPES ZOSTER 4. HIV INFECTED PARTNER OF AIDS PATIENTS 5. ALL HIV POSITIVE BELOW 15 YEARS OF AGE
  37. 37. THERAPEUTIC REGIMEN - NACO • 1ST LINE REGIME FOR UNTREATED PATIENTS • ALL REGIMENS SHOULD HAVE 2 NRTIS AND 1 NNRTI • INCLUDE LAMIVUDINE IN ALL REGIMENS • THE OTHER ONE CAN BE ZIDOVUDINE OR STAVUDINE • CHOSE NNRTI FROM EFAVIRENZ OR NEVIRAPINE • EFAVIRENZ IN HEPATIC DYSFUNCTION AND IN PATIENTS RECEIVING RIFAMPICIN • DO NOT USE EFAVIRENZ IN PREGNANT • TREATMENT LIFELONG
  38. 38. FIRST LINE REGIMENS • PREFERRED: LAMIVUDINE + ZIDOVUDINE + NEVIRAPINE • ALTERNATIVE: 1. LAMIVUDINE + ZIDOVUDINE + EFAVIRENZ 2. LAMIVUDINE + STAVUDINE + EFAVIRENZ (ANEMIA) 3. LAMIVUDINE + STAVUDINE + NEVIRAPINE • OTHEROPTIONS: 1. LAMIVUDINE + TENOFOVIR + NEVIRAPINE (TOXICITY AND CONTRAINDICATION) 2. LAMIVUDINE + TENOFOVIR + EFAVIRENZ (TOXICITY AND CONTRAINDICATION) 3. LAMIVUDINE + ZIDOVUDINE + TENOFOVIR (UNABLE TO TOLERATE E OR N) FOR NAÏVE PATIENTS – 2 NRTIS + 1 NNRTI PIS RESERVED FOR ADVANCED CASES – 2 NRTIS + PI OR NRTI + NNRTI + PI IF RESISTANCE – ENTIRE REGIME REPLACEMENT – NO REDUCTION OF DOSE NO DRUG HOLIDAY AND NO CONTRAINDICATION IN PREGNANCY
  39. 39. WHEN REGIME FAILED • FAILURE OF A REGIME • 6 MONTHS TREATMENT – HIV-RNA <50µL • REPEATED DETECTION OF VIRUS IN PLASMA AFTER INITIAL REDUCTION • CLINICAL DETERIORATION AND FALL IN CD4 COUNT • POST EXPOSURE PROPHYLAXIS • LOW RISK: LAMIVUDINE 150MG + ZIDOVUDINE 300 MG – TWICE DAILY FOR 4 WEEKS • HIGH RISK: LAMIVUDINE 150MG + ZIDOVUDINE 300 --- TWICE DAILY + INDINAVIR (800 MG) - THRICE DAILY – THRICE DAILY FOR 4 WEEKS • PREGNANT WOMEN: ZIDOVUDINE + LAMIVUDINE + NEVIRAPINE
  40. 40. THANK YOU Remember---- Acyclovir, Interferon, Zidovudine, and Protease inhibitors

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