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Antiviral drugs - drdhriti
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Antiviral Lecture

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Antiviral Lecture

  2. 2. ANTIVIRAL AGENTS <ul><li>VIRUSES: </li></ul><ul><li>Single or double stranded DNA or RNA enclosed in a protein – CAPSID </li></ul><ul><li>Obligate intracellular parasite </li></ul><ul><li>Replication depends on synthetic processes of the host cell </li></ul><ul><li>Antiviral drugs must either block entry or exit from cell or be active inside the host cell </li></ul>
  3. 3. VIRAL REPLICATION: <ul><li>Adsorption and penetration into susceptible host cells </li></ul><ul><li>Uncoating of viral nucleic acid </li></ul><ul><li>Synthesis of early regulatory proteins </li></ul><ul><li>Synthesis of RNA or DNA </li></ul><ul><li>Synthesis of late regulatory proteins </li></ul><ul><li>Assembly (maturation) of viral particles </li></ul><ul><li>Release from cells </li></ul>
  5. 7. ANTIHERPES/VZV AGENTS <ul><li>ACYCLOVIR </li></ul><ul><li>FAMCICLOVIR </li></ul><ul><li>VALACYCLOVIR </li></ul><ul><li>PENCICLOVIR </li></ul><ul><li>TRIFLURIDINE </li></ul><ul><li>VIDARABINE </li></ul><ul><li>DOCOSANOL </li></ul>
  6. 8. ACYCLOVIR <ul><li>Acyclovir (9- [2-hydroxy) methyl]-9-H- guanine </li></ul><ul><li>Acyclic guanosine derivative against HSV1, HSV2, & VZV </li></ul><ul><li>Weaker activity against EBV, CMV, Human Herpes Virus 6 </li></ul>
  7. 9. MECHANISM OF ACTION: <ul><li>REQUIRES 3 PHOSPHORYLATION STEPS: </li></ul><ul><ul><li>Converted to monophosphate derivative by virus-specified thymidine kinase </li></ul></ul><ul><ul><ul><li>Selective activation of acyclovir </li></ul></ul></ul><ul><ul><ul><li>Active metabolites accumulates only in infected cells </li></ul></ul></ul><ul><ul><li>Converted to di and triphosphate compounds by the host’s cellular enzymes </li></ul></ul>
  8. 10. EFFECTS: <ul><li>Acyclovir triphosphate inhibits viral DNA synthesis </li></ul><ul><li>Acts as a chain terminator because it lacks 3’ hydroxyl group </li></ul><ul><li>Competitive inhibition of deoxyGTP for viral DNA polymerase = binds to DNA template as irreversible complex </li></ul>
  9. 11. Cont. <ul><li>RESISTANCE: </li></ul><ul><li>HSV: absence of partial production of viral thymidine kinase, altered thymidine kinase substrate specificity, altered viral DNA polymerase </li></ul><ul><li>VZV: mutation in VZV thymidine kinase, mutations in viral DNA polymerase </li></ul>
  10. 12. PHARMACOKINETICS: <ul><li>Oral bioavailability ranges from 15-20 % and decreases with increasing dose, unaffected by food </li></ul><ul><li>Relative oral bioavailability increases to 3-5 fold approx. 70% following valacyclovir administration </li></ul><ul><li>Distributes widely in body fluids including vesicular fluid, aqueous humor & CSF </li></ul><ul><li>Concentrated in breast milk, amniotic fluid, & placenta </li></ul><ul><li>Percutaneous absorption is low </li></ul>
  11. 13. <ul><li>Half-life: 3 hours (normal renal function) </li></ul><ul><li> 20 hours (anuria) </li></ul><ul><li>Readily cleared by dialysis but not by peritoneal dialysis </li></ul><ul><li>IV- treatment of choice for herpes simplex </li></ul><ul><li>Oral – herpes labialis </li></ul><ul><li>Topical – high concentration in herpetic lesions </li></ul>
  12. 14. THERAPEUTIC USES: <ul><li>First and recurrent genital herpes: </li></ul><ul><ul><li>200 mg 5x daily for 10 days – oral </li></ul></ul><ul><ul><li>5 mg/kg per 8 hrs – IV </li></ul></ul><ul><ul><li>Recurrent: 400 mg 2x daily or 200 mg 3x daily </li></ul></ul>
  13. 15. THERAPEUTIC USES: <ul><li>ACUTE HERPES ZOSTER (SHINGLES) </li></ul><ul><li>SYSTEMIC ACYCLOVIR PROPHYLAXIS </li></ul><ul><li>HSV ENCEPHALITIS </li></ul><ul><li>VARICELLA ZOSTER VIRUS INFECTION </li></ul><ul><ul><li>higher doses </li></ul></ul><ul><li>CMV PROPHYLAXIS </li></ul>
  14. 16. SIDE EFFECTS: <ul><li>TOPICAL PREPARATIONS- mucosal irritation & transient burning to genital lesions </li></ul><ul><li>ORAL – nausea, diarrhea, rash, headache,renal insufficiency, neurotoxicity </li></ul><ul><li>IV- renal insufficiency (crystalline nephropathy), CNS side effects </li></ul>
  15. 17. PENCICLOVIR <ul><li>Penciclovir (9- [4-hydroxy-3-hydroxymethylbut-1-yl]guanine) </li></ul><ul><li>An acyclic guanine nucleoside </li></ul><ul><li>Active metabolite of famciclovir </li></ul><ul><li>Recurrent herpes labialis </li></ul><ul><li>Topical – 1% cream </li></ul>
  16. 18. MECHANISM OF ACTION: <ul><li>Inhibitor of viral DNA synthesis </li></ul><ul><li>Initially phosphorylated by viral thymidine kinase </li></ul><ul><li>Penciclovir triphosphate is a competitive inhibitor of viral DNA polymerase </li></ul><ul><li>100 fold less potent in inhibiting DNA polymerase than acyclovir but present in higher concentration and prolonged periods in infected cells </li></ul>
  17. 19. THERAPEUTIC USES: <ul><li>Intravenous form- 5 mg/kg per 8-12 hrs for 7 days is comparable to acyclovir in tx of mucocutaneous HSV infection </li></ul><ul><li>Topical 1% penciclovir cream applied every 2 hrs while awake for 4 days shortens healing time and symptoms by about 1 day in recurrent labial HSV </li></ul>
  18. 20. SIDE EFFECTS: <ul><li>Mutagenic at high concentrations </li></ul><ul><li>No clinically important drug interactions have identified </li></ul>
  19. 21. FAMCICLOVIR <ul><li>Diacetyl ester prodrug of 6 deoxy penciclovir and lacks intrinsic viral activity </li></ul><ul><li>Rapidly converted to by first pass metabolism to PENCICLOVIR </li></ul><ul><li>HSV-1, HSV-2, VZV, EBV, HBV </li></ul>
  20. 22. FAMCICLOVIR: <ul><li>Comparable to valacyclovir in treating zoster and reducing associated pain in older adults </li></ul><ul><li>500 mg TID x 10 days is comparable to high dose of acyclovir in treating zoster in immunocompromised patients & in opthalmic zoster </li></ul><ul><li>Associated with dose-related reductions in Hepatitis B Virus DNA and transaminase levels in patients with chronic HBV hepatitis </li></ul>
  21. 23. <ul><li>Rapidly converted by first-pass metabolism to penciclovir </li></ul><ul><li>Does not cause chain termination </li></ul><ul><ul><li>Lower affinity for viral DNA polymerase than acyclovir triphosphate </li></ul></ul><ul><li>Achieves a higher intracellular concentrations & more prolonged intracellular effect </li></ul>
  22. 24. PHARMACOKINETICS: <ul><li>70% bioavailability after oral administration </li></ul><ul><li>Intracellular half life: 10 hrs – HSV 1 </li></ul><ul><li> 20 hrs – HSV 2 </li></ul><ul><li> 7 hrs- VZV </li></ul>
  23. 25. TRIFLURIDINE (Trifluorothymidine) <ul><li>Flourinated pyrimidine nucleoside that has an in vitro inhibitory activity against HSV 1 & 2 , CMV, vaccinia certain adenoviruses </li></ul><ul><li>Inhibits viral DNA synthesis </li></ul><ul><li>Does not require activation by viral thymidine kinase </li></ul><ul><li>Phosphorylated intracellularly into its active form by host cellular enzymes </li></ul><ul><li>Competes with thymidine triphosphate for incorporation by viral DNA polymerase </li></ul><ul><li>Incorporation into both viral and cellular DNA prevents its systemic use </li></ul>
  24. 26. MECHANISM OF ACTION: <ul><li>Trifluridine monophosphate irreversibly inhibits thymidylate synthetase </li></ul><ul><li>Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate incorporation into DNA by DNA polymerases </li></ul>
  25. 27. CLINICAL USES: <ul><li>Topical : 1% solution </li></ul><ul><li>Primary keratoconjunctivitis & recurrent epithelial keratitis due to HSV 1 & 2 </li></ul><ul><li>Topical trifluridine is more active than idoxuridine & comparable to vidarabine in HSV ocular infections </li></ul><ul><li>Combination with Interferon alfa – acyclovir resistant HSV infections </li></ul>
  26. 28. ADVERSE EFFECTS: <ul><li>Discomfort upon instillation </li></ul><ul><li>Palpebral edema </li></ul><ul><li>Hypersensensitivity reaction, irritations & superficial punctate or epithelial keratopathy </li></ul>
  27. 29. VALACYCLOVIR <ul><li>L- valyl ester of acyclovir </li></ul><ul><li>Rapidly converted to acyclovir after oral administration </li></ul><ul><li>Serum levels are 3-5x greater than acylcovir IV or oral </li></ul><ul><li>Treatment of primary and recurrent genital herpes & herpes zoster infections </li></ul><ul><li>Prevents CMV disease in postransplant patients </li></ul><ul><li>Oral preparation </li></ul>
  28. 30. <ul><li>Elimination half-life: 2.5-3.0 hours </li></ul><ul><li>High dose: </li></ul><ul><ul><li>gastrointestinal intolerance </li></ul></ul><ul><ul><li>Thrombotic microangiopathies (TTP, hemolytic-uremic syndrome) </li></ul></ul>
  29. 31. VIDARABINE <ul><li>Adenosine analog with an in vitro activity against HSV, VZV, & CMV </li></ul><ul><li>Phosphorylated intracellularly by host enzymes to form ara-ATP and then inhibits viral DNA polymerase </li></ul><ul><li>Vidarabine triphosphate is incorporated into both viral & cellular DNA </li></ul><ul><li>Decreases viral activity </li></ul>
  30. 32. Cont. <ul><li>3% ointment – acute keratoconjunctivitis, superficial keratitis, recurrent epithelial keratitis (HSV1 &2) </li></ul><ul><li>IV vidarabine – HSV encephalitis,neonatal herpes, VZV infection </li></ul>
  31. 33. DOCOSANOL <ul><li>Saturated 22-carbon aliphatic alcohol </li></ul><ul><li>Inhibits fusion between the plasma membrane & HSV envelope </li></ul><ul><li>Prevents viral entry into cells & subsequent viral repliction </li></ul><ul><li>10% topical cream- 5x daily </li></ul>
  33. 35. ANTI-CMV AGENTS <ul><li>GANCICLOVIR </li></ul><ul><li>CIDOFOVIR </li></ul><ul><li>FOMIVERSEN </li></ul><ul><li>VALGANCICLOVIR </li></ul><ul><li>FOSCARNET </li></ul>
  34. 36. GANCICLOVIR <ul><li>(9- [1,3-dihydroxy-2-prpoxymethyl]guanine) </li></ul><ul><li>Acyclic guanosine analog that requires triphosphorylation for activation prior to inhibiting viral DNA polymerase </li></ul><ul><li>Similar structure to acyclovir except in having additional hydroxymethyl group on the acyclic side chain </li></ul>
  35. 37. MECHANISM OF ACTION: <ul><li>Monophosphorylated intracellularly by a virus-induced enzyme </li></ul><ul><li>Phosphorylation is catalyzed by a viral thymidine kinase during HSV, phosphotransferase encoded gene during CMV infection </li></ul><ul><li>Ganciclovir di & triphosphate formed by cellular enzymes </li></ul><ul><li>Triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA, inhibits viral rather than cellular DNA polymerase </li></ul><ul><li>Viral DNA incorporation causes cessation of DNA chain elongation </li></ul>
  36. 38. PHARMACOKINETICS: <ul><li>Oral bioavailability is 6-9% following ingestion with food & less in the fasting state </li></ul><ul><li>CSF concentration are approximately 50 % of those in serum </li></ul><ul><li>IV, oral, intraocular implant </li></ul>
  37. 39. <ul><li>Elimination half life: 4 hours </li></ul><ul><li>Intracellular half-life: 18 hours </li></ul><ul><li>Cleared by hemodialysis </li></ul>
  38. 40. CLINICAL USES: <ul><li>Delay progression of CMV retinitis in AIDS – IV ( foscarnet ) </li></ul><ul><li>CMV colitis & esophagitis - IV </li></ul><ul><li>CMV infection in transplant patient - IV/oral </li></ul><ul><li>CMV pneumonitis </li></ul><ul><li>CMV retinitis – intraocular implant/intravitreal administration </li></ul><ul><li>CMV, HSV1, HSV2, EBV & HHV-8 </li></ul>
  39. 41. ADVERSE REACTIONS: <ul><li>Myelosuppression </li></ul><ul><li>CNS toxicity </li></ul><ul><li>Vitreous hemorrhage, retinal detachment </li></ul><ul><li>Neutropenia (2 nd wk) </li></ul><ul><li>CNS (headache, behavioral changes, convulsions, coma) </li></ul><ul><li>Infusion related phlebitis, azotemia, anemia, rash, fever, liver function test abnormalities </li></ul>
  40. 42. DRUG INTERACTION: <ul><li>Additive myelosuppression </li></ul><ul><ul><li>Zidovudine, azathioprine or mycophenolate mofetil </li></ul></ul><ul><li>Increase levels </li></ul><ul><ul><li>Probenicid, trimethoprim </li></ul></ul><ul><li>Increase levels of didanosine </li></ul>
  41. 43. VALGANCICLOVIR <ul><li>L- valyl ester prodrug of ganciclovir </li></ul><ul><li>Hydrolyzed to active compound ganciclovir by intestinal & hepatic enzymes </li></ul><ul><li>Well absorbed & rapidly metabolized in intestinal walls & liver to gancilovir </li></ul><ul><li>CMV retinitis </li></ul><ul><li>CMV disease in high risk kidney, heart, & kidney-pancreas transplant patients </li></ul>
  42. 44. PHARMACOKINETICS: <ul><li>Bioavailability after oral administration: 60% </li></ul><ul><li>Should be taken with food </li></ul><ul><li>Elimination - renal </li></ul>
  43. 45. CIDOFOVIR <ul><li>(1- [(S)-3-hydroxy-2-(phosphonomethoxy)-propyl]cytosine dihydrate) </li></ul><ul><li>Cytosine nucleoside analog with inhibitory activity against human herpes, papiloma, polyoma, pox, & adenoviruses </li></ul><ul><li>Phosphorylation to active diphosphate is independent of viral enzymes </li></ul><ul><li>After phosphorylation it acts as potent inhibitor of and as an alternative substrate to viral DNA polymerase </li></ul><ul><li>Competitively inhibits DNA synthesis & becoming incorporated into viral DNA chain </li></ul>
  44. 46. PHARMACOKINETICS: <ul><li>Penetration into the CNS or eye have not been well characterized </li></ul><ul><li>Terminal half-life is 2.6 hrs , cidofovir diphosphate half-life is 17-65 hrs </li></ul><ul><li>Poor CSF penetration </li></ul><ul><li>IV administration must be administered with probenicid (2-3 hours before infusion) to block active tubular secretion & decrease nephrotoxicity </li></ul>
  45. 47. CLINICAL USES: <ul><li>CMV, HSV 1, HSV 2, VZV, EBV, HHV-6, HHV-8, adenoviruses, poxvirus, poliomyxoviruses, HPV </li></ul><ul><li>CMV retinitis </li></ul><ul><li>Polyoma virus associated progressive multifocal leukoencephalopathy syndrome associated with AIDS </li></ul>
  46. 48. FOSCARNET <ul><li>Phosphonoformic acid inorganic pyrophosphate analog that inhibits viral DNA polymerase , RNA polymerase & HIV reverse transcriptase directly without requiring activation by phosphorylation </li></ul><ul><li>Taken up slowly by cells & does not undergo significant intracellular metabolism </li></ul><ul><li>Reversibly blocks the pyrophosphate binding site of the viral polymerase but not in human & transcriptase enzyme </li></ul><ul><li>Inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates </li></ul>
  47. 49. SIDE EFFECTS: <ul><li>Nephrotoxicity </li></ul><ul><li>Symptomatic hypocalcemia or hypercalcemia </li></ul><ul><li>Hyper or hypophosphatemia </li></ul><ul><li>hypomagnesemia </li></ul><ul><li>Saline preloading may reduce the risk of nephrotoxicity </li></ul><ul><li>Concurrent administration with pentamidine exacerbates both nephrotoxicity & hypocalcemia </li></ul>
  48. 50. DRUG INTERACTION: <ul><li>Nephrotoxic potential </li></ul><ul><ul><li>amphotericin B, pentamidine, aminoglycosides </li></ul></ul><ul><li>Hypocalcemia </li></ul><ul><ul><li>pentamidine </li></ul></ul><ul><li>Penile ulcerations </li></ul><ul><ul><li>foscarnet </li></ul></ul><ul><li>Anemia </li></ul><ul><ul><li>zidovudine </li></ul></ul><ul><li>CNS toxicity </li></ul><ul><ul><li>imipenem </li></ul></ul><ul><li>Chromosomal damage </li></ul><ul><ul><li>foscarnet </li></ul></ul>
  49. 51. CLINICAL USES: <ul><li>CMV retinitis, colitis, esophagitis </li></ul><ul><li>Acyclovir- resistant HSV infection & VZV infection </li></ul><ul><li>HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV </li></ul>
  50. 52. FOMIVERSEN <ul><li>21mer-phosphorothioate oligonucleotide </li></ul><ul><li>First FDA approved antisense therapy Binding to target mRNA results in inhibiton of immediate early region 2 protein synthesis – inhibiting viral replication </li></ul><ul><li>Injected intravitreally in CMV retinitis </li></ul>
  51. 53. ANTIVIRAL DRUGS – DNA & RNA VIRUSES DRUG MECHANISM/ VIRAL SELECTIVITY CLINICAL USE VIRAL RESISTANCE UNDESIRABLE SIDE EFFECTS PHARMACOKINETICS NOTES Acylovir Metabolized by thymidine kinase to triphosphate Herpes simplex 1 & 2, varicella zoster Produce abnormal thymidine kinase Skin irritation, burning, crystalline nephropathy IV/PO. Administer slowly. CNS level=50% serum level. Decrease dose w/ kidney dysfunction Pencyclovir Oral HSV (coldsores) Topical Valacyclovir L-valyl ester of acyclovir converted to acyclovir Herpes zoster (shingles) Nausea, headache PO. Slightly better oral absorption than acyclovir No clear advantage over acyclovir Idoxuridine Phosphorylated metabolite incorporates into DNA causing strand breaks Herpes simplex keratitis. No effect on RNA viruses Resistance develops Photophobia, irritation of conjunctiva & eyelid Eyedrops Drug is a halogenated derivative of deoxyuridine Famciclovir Phosphorylated by viral thymidine kinase to penciclovir triiphosphate Shortens duration of herpes zoster & genital herpes Minimal toxicity. Headache PO. Decrease dose with renal dysfunction. Ganciclovir Metabolized by thymidine kinase to triphosphate . Preferentially phosphorylated to active drug in CMV infected cells CMV retinitis & severe systemic CMV infections Some resistant strains lack thymidine kinase. Cannot activate drug. Granulocytopenia, thrombocytopenia IV/PO. Excreted unchanged in urine. Decrease dose with renal dysfunction. Do not coadminister zidovudine (granulocytopenia) or imipenem-cilastatin (seizures)
  52. 54. Cidofovir Metabolized to diphosphate form. Otherwise like ganciclovir. CMV retinitis Nephrotoxicity may be reduced by hydration & coadministration of Probenicid. Neutropenia. Foscarnet Analog of pyrophosphate. Competes for pyrophosphate site in viral but not human, DNA polymerase & reverse transcriptase CMV retinitis Does not need phosphorylation, it is active against thymidine kinase –deficient strains Renal toxicity, seizures, hypocalcemia, fever, anemia, diarrhea, nausea IV. >80% excreted unchanged in the urine. CSF penetration variable. Reduce dose with renal dysfunction. Deposited in bone & teeth. Hydrate patient during therapy to protect the kidney Amantadine Prevents virus from entering susceptible cells Treatment & prophylaxis of influenza A Depression, CNS toxicity, CHF, orthostatic hypotension, urinary retention PO. Excreted unmetabolized. Rimantadine Analog of amantadine , inhibits viral uncoating Prophylaxis in children Fewer CNS side effects, risk of seizure PO. Prolonged elimination w/ renal or hepatic dysfunction Ribavirin Unknown mechanism RSV Decreased pulmonary function. Aerosol administration. Absorbed systemically. May precipitate in ventilator tubing.
  54. 56. STAGES OF HIV REPRODUCTION <ul><li>HIV entry into the CD4 cells </li></ul><ul><li>HIV’s genetic information stored on a single stranded RNA instead of the double-stranded DNA </li></ul><ul><li>HIV uses an enzyme known as reverse transcriptase to convert its RNA into DNA </li></ul>
  55. 57. <ul><li>HIV DNA enters the nucleus of the CD4+ cell and inserts itself into the cell’s DNA </li></ul><ul><li>HIV DNA instructs the cell to make many copies of the original virus </li></ul><ul><li>New virus particles assembled and leave the cell ready to infect other CD4+ cells </li></ul>
  56. 59. Fusion Inhibitors Non-Nucleoside Reverse Transcriptase Inhibitors Nucleoside/Nucleotide Analogues Protease Inhibitors <ul><li>A novel class of antiretroviral agents that inhibit the fusion of HIV with target cell membranes. </li></ul><ul><li>Fusion inhibitors are administered by subcutaneous injection. </li></ul><ul><li>The newest class of antiretroviral agents, non-nucleoside transcriptase inhibitors (NNRTIs) </li></ul><ul><li>Stop HIV production by binding directly onto reverse transcriptase and preventing the conversion of RNA to DNA. </li></ul><ul><li>These drugs are called &quot;non-nucleoside&quot; inhibitors because even though they work at the same stage as nucleoside analogues, they act in a completely different way. </li></ul><ul><li>The first effective class of antiretroviral drugs. </li></ul><ul><li>They act by incorporating themselves into the DNA of the virus, thereby stopping the building process. </li></ul><ul><li>The resulting DNA is incomplete and cannot create new virus </li></ul><ul><li>Protease inhibitors work at the last stage of the virus reproduction cycle. </li></ul><ul><li>They prevent HIV from being successfully assembled and released from the infected CD4+ cell. </li></ul>
  57. 60. NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS: <ul><li>Competitive inhibition of HIV 1 reverse transcriptase & can be incorporated into the growing viral DNA chain to cause termination </li></ul><ul><li>Bind directly to HIV reverse transcriptase, block both DNA & RNA dependent DNA polymerase activities </li></ul><ul><li>Prevent transfer of information that would allow virus to replicate & survive </li></ul><ul><li>Activity against HIV 1, HIV 2 </li></ul><ul><li>Mitochondrial toxicity – inhibition of mitochondrial DNA polymerase gamma </li></ul><ul><li>Lactic acidosis & severe hepatomegaly with steatosis </li></ul>
  58. 61. NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS: <ul><li>ZIDOVUDINE </li></ul><ul><li>DIDANOSINE </li></ul><ul><li>STAVUDINE </li></ul><ul><li>LAMIVUDINE </li></ul><ul><li>ZALCITABINE </li></ul><ul><li>ABACAVIR </li></ul><ul><li>EMTRICITABINE </li></ul>
  59. 62. ZIDOVUDINE (Azithymidine, AZT) <ul><li>Deoxythymidine analog </li></ul><ul><li>Decrease rate of clinical disease progression & prolong survival of HIV infected individuals </li></ul><ul><li>Well absorbed from the gut & distributed to most body tissues & fluids </li></ul><ul><li>Eliminated by renal excretion following glucorinadation in the liver </li></ul><ul><li>Combination therapy with other retroviral agents enhance potency and delay resistance </li></ul>
  60. 63. CLINICAL USES: <ul><li>HIV – associated dementia & thrombocytopenia </li></ul><ul><li>Reduce rate of vertical transmission (mother-newborn) by 23% - 14 and 34 weeks of gestation and during labor </li></ul><ul><li>Newborn – syrup from birth – 6 weeks </li></ul>
  61. 64. ANTIRETROVIRAL AGENTS IN PREGNANCY: <ul><li>NRTIs: Zidovudine, lamivudine, didanosine, stavudine, abacavir, emtricitabine </li></ul><ul><li>NNRTIs: Nevirapine </li></ul><ul><li>PROTEASE INHIBITORS: Nelfinavir, saquinavir S, indinavir, lopinavir, ritonavir </li></ul>
  62. 65. ADVERSE EFFECTS: <ul><li>Myelosuppression – most common </li></ul><ul><li>Thrombocytopenia, hyperpigmentation of nails, myopathy, anxiety, confusion & tremulousness </li></ul><ul><li>Fatal lactic acidosis & severe hepatomegaly w/ steatosis </li></ul>
  63. 66. DIDANOSINE (ddl) <ul><li>Synthetic analog of deoxyadenosine </li></ul><ul><li>Chewable, dispersable tablet, enteric coated </li></ul><ul><li>Contains phenylalanine ( 36.5 mg) & Na (1380 mg) </li></ul><ul><li>Should be taken on an empty stomach </li></ul><ul><li>Food, fluroquinolones & tetracycline should be given 2 hrs before didanosine </li></ul><ul><li>Buffered powder (oral solution), chewable tablests, enteric coated tablets </li></ul>
  64. 67. DRUG INTERACTION <ul><li>Interferes with the absorption of the ff. drugs: (powder and tablets) </li></ul><ul><ul><li>indinavir, delavirdene, dapsone, itraconazole </li></ul></ul>
  65. 68. PRECAUTIONS: <ul><li>Phenylketonuria </li></ul><ul><li>Na restricted diets </li></ul>
  66. 69. ADVERSE EFFECTS: <ul><li>Dose –dependent pancreatitis </li></ul><ul><li>Painful peripheral distal neuropathy </li></ul><ul><li>Diarrhea, hepatitis, esophageal ulceration, cardiomyopathy </li></ul><ul><li>CNS toxicity </li></ul><ul><li>Precipitate gouty attacks </li></ul><ul><li>Optic neuritis </li></ul>
  67. 70. LAMIVUDINE (3TC) <ul><li>Cytosine analog ,synergistic with other antiretroviral nucleoside – Stavudine, Zidovudine </li></ul><ul><li>Oral bioavailability exceeds 80% & is not food dependent </li></ul><ul><li>Used in combination therapy </li></ul><ul><li>Approved for the treatment of chronic Hepatitis B infection </li></ul>
  68. 71. RESISTANCE: <ul><li>M184V mutation in regimens that are not fully suppressive </li></ul><ul><li>K65R mutation is associated with reduced susceptibility to lamuvudine, abacavir, tenofovir and emcitricitabine </li></ul>
  69. 72. ADVERSE EFFECTS: <ul><li>Headache, insomnia, fatigue, gastrointestinal discomfort </li></ul>
  70. 73. DRUG INTERACTION: <ul><li>Increase lamivudine bioavailability </li></ul><ul><ul><li>trimethoprim-sulfamethoxazole </li></ul></ul><ul><li>Inhibit intracellular phosphorylation of one another in vitro (decrease potency) </li></ul><ul><ul><li>zalcitabine </li></ul></ul>
  71. 74. ZALCITABINE (ddC) <ul><li>Cytosine analog with synergistic anti-HIV1 activity with a variety of antiretrovirals against both zidovudine sensitive & resistant strains </li></ul><ul><li>Associated with dose-dependent peripheral neuropathy </li></ul><ul><li>Oral & esophageal ulcerations </li></ul><ul><li>Increase bioavailability in combination w/ probenicid or cimetidine </li></ul><ul><li>Decrease bioavailability in combination w/ antacids & metoclopramide </li></ul>
  72. 75. STAVUDINE (D4T) <ul><li>Thymidine analog </li></ul><ul><li>High oral bioavailability, not food dependent </li></ul><ul><li>Dose-related peripheral sensory neuropathy </li></ul><ul><li>Pancreatitis, arthralgias, elevation of serum aminotransferases </li></ul>
  73. 76. ABACAVIR <ul><li>Guanosine analog </li></ul><ul><li>Well absorbed during oral administration (83%) </li></ul><ul><li>Unaffected by food </li></ul><ul><li>Metabolized by alcohol dehydrogenase & glucuronosyltransferase to inactive metabolites </li></ul><ul><li>Fatal hypersensitivity reactions </li></ul><ul><li>Nausea, vomiting, diarrhea, headache, fatigue </li></ul><ul><li>Hyperglycemia, hypertriglyceridemia & lactic acidosis </li></ul>
  74. 77. RESISTANCE: <ul><li>Requires at least 2 or 3 concomitant mutations: </li></ul><ul><ul><li>M184V, L74V, D67N </li></ul></ul><ul><ul><li>develop slowly </li></ul></ul><ul><li>K65R </li></ul><ul><ul><li>reduced susceptibility to lamivudine, abacavir, tenofovir and emtricitabine </li></ul></ul>
  75. 78. EMTRICITABINE (FTC) <ul><li>Flourinated analog of lamivudine </li></ul><ul><li>Long intracellular half-life (>39 hours) </li></ul><ul><li>Contains propylene glycol </li></ul><ul><li>Oral solutions contraindicated in children, pregnant women, patients with renal & hepatic failure, using metronidazole & disulfiram </li></ul>
  76. 79. ADVERSE EFFECTS: <ul><li>Headache, diarrhea, nausea & asthenia </li></ul><ul><li>Hyperpigmentation of the palms/soles </li></ul>
  77. 80. USE OF ANTITRETROVIRAL DRUGS IN PREGNANCY: <ul><li>NRTIs </li></ul><ul><ul><li>zidovudine, lamivudine </li></ul></ul><ul><ul><li>Didanosine, emtricitabine, stavudine, abacavir </li></ul></ul><ul><li>NNRTIs </li></ul><ul><ul><li>nevirapine </li></ul></ul><ul><li>Protease inhibitors </li></ul><ul><ul><li>nelfinavir, saquinavir-S </li></ul></ul><ul><ul><li>Indinavir, lopinavir, ritonavir </li></ul></ul>
  79. 82. TENOFOVIR <ul><li>Competitively inhibits HIV reverse transcriptase & cause chain termination after incorporation to DNA </li></ul><ul><li>Indicated for use in combination with other antiretroviral agents </li></ul>
  80. 83. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR: <ul><li>Bind directly to a site on the HIV –1 reverse transcriptase </li></ul><ul><li>Blockade of RNA & DNA dependent DNA polymerase activities </li></ul><ul><li>Binding site is near but distinct from that of the NRTI’s </li></ul><ul><li>Neither compete w/ nucleoside triphosphate nor require phosphorylation to be active </li></ul>
  81. 84. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS: <ul><li>NEVIRAPINE </li></ul><ul><li>EFAVIRENZ </li></ul><ul><li>DELAVIRDENE </li></ul>
  82. 85. NEVIRAPINE <ul><li>Oral bioavailability is > 90% </li></ul><ul><li>Not food dependent </li></ul><ul><li>Used as a component of a combination antiretroviral regimen </li></ul><ul><li>Effective in the prevention of transmission of HIV from mother to newborn </li></ul><ul><li>Causes severe life threatening rashes </li></ul>
  83. 86. DELAVIRDENE <ul><li>Oral bioavailability of about 85 % </li></ul><ul><li>Metabolized to inactive metabolites by the CYP3A & CYP2D6 P450 enzymes </li></ul><ul><li>Plasma concentrations are reduced by antacids, didanosine, phenytoin, phenobarbital, carbamazepine, rifabutin, rifampin, nelfinavir & saquinavir </li></ul><ul><li>Concentrations increased by clarithromycin, fluoxetine, & ketoconazole </li></ul>
  84. 87. EFAVIRENZ <ul><li>Principally metabolized by CYP3A4 &CYP2B6 to inactive hydroxylated metabolites </li></ul><ul><li>Principal adverse effects: CNS (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria) </li></ul><ul><li>Pyschiatric symptoms </li></ul><ul><li>rashes </li></ul>
  85. 88. PROTEASE INHIBITORS <ul><li>Responsible for cleaving precursor molecules (immature budding particles) </li></ul><ul><li>Results in the production of immature, non-infectious viral particles </li></ul><ul><li>Block protease activity within the HIV virus – essential for the maturation </li></ul><ul><li>Associated w/ spontaneous bleeding in hemophilia A & B </li></ul>
  86. 89. PROTEASE INHIBITORS: <ul><li>SAQUINAVIR </li></ul><ul><li>INDINAVIR </li></ul><ul><li>AMPRENAVIR </li></ul><ul><li>LOPRENAVIR/RITONAVIR </li></ul><ul><li>TIPRANAVIR </li></ul><ul><li>RITONAVIR </li></ul><ul><li>NELFINAVIR </li></ul><ul><li>ATAZANAVIR </li></ul><ul><li>FOSAMPRENAVIR </li></ul>
  87. 90. SAQUINAVIR <ul><li>Saquinavir H- hard gel capsule – poor bioavailability, should be taken w/n 2 hrs after a fatty meal </li></ul><ul><li>Saquinavir S – soft gel capsule – improved absorption 3x than hard gel capsule </li></ul><ul><li>Subject to first pass-metabolism by CYP3A4 </li></ul><ul><li>Levels are increased by ritonavir, nelfinavir, delavirdene, indinavir, ketoconazole, clarithromycin, & grapefruit juice </li></ul>
  88. 91. RITONAVIR <ul><li>An inhibitor of HIV 1 & HIV 2 proteases </li></ul><ul><li>High bioavailability that is increased with food </li></ul><ul><li>Common adverse effects: GIT disturbances, paresthesias, inc aminotransferase level, altered taste, hypertriglyceridemia </li></ul>
  89. 92. INDINAVIR <ul><li>Specific inhibitor of the HIV- 1 & HIV-2 proteases </li></ul><ul><li>Higher CSF penetration </li></ul><ul><li>Must be consumed in empty stomach for maximal absorption </li></ul><ul><li>Most common adverse effects are indirect hyperbilirubinemia & nephrolithiasis due to crystalization </li></ul>
  90. 93. NELFINAVIR <ul><li>Higher absorption in the fed state </li></ul><ul><li>Common adverse effects: diarrhea & flatulence </li></ul>
  91. 94. AMPRENAVIR <ul><li>Rapidly absorbed from the GIT & can be taken w/ or w/o food </li></ul><ul><li>High fat meals decrease absorption </li></ul><ul><li>Common adverse effects: nausea, vomiting, diarrhea, perioral paresthesias, rash </li></ul><ul><li>Steven johnson’s syndrome </li></ul><ul><li>Inhibits CYP3A4 activity </li></ul>
  92. 95. LOPRINAVIR/RITONAVIR <ul><li>Combination that subtherapeutic doses of ritonavir inhibit the CYP3A mediated metabolism of lopinavir </li></ul><ul><li>Maintains potent viral suppression & prevents resistance </li></ul><ul><li>Ritonavir – pharmacokinetic enhancer </li></ul>
  93. 96. TIPRANAVIR <ul><li>Bioavailability is increased when taken with a fatty meal </li></ul><ul><li>Should be taken with ritonavir </li></ul><ul><li>Contraindicated in liver insufficiency, sulfa allergy </li></ul>
  95. 98. ENFUVIRTIDE (T-20) <ul><li>Newly approved antiretroviral agent </li></ul><ul><li>Blocks entry into the cell </li></ul><ul><li>Administered subcutaneously in combination with other retroviral agents </li></ul>
  97. 100. ANTIHEPATITIS AGENTS: <ul><li>LAMIVUDINE </li></ul><ul><li>INTERFERON ALFA </li></ul><ul><li>INTERFERON ALFA 2b </li></ul><ul><li>ENTECAVIR </li></ul><ul><li>ADEFOVIR DIPIVOXIL </li></ul><ul><li>INTERFERON ALFA 2a </li></ul><ul><li>PEGYLATED INTERFERON </li></ul>
  98. 101. LAMIVUDINE <ul><li>Can be safely administered to patients with decompensated liver disease </li></ul>
  99. 102. ADEFOVIR <ul><li>Phosphorylated by cellular kinases to the active diphosphate metabolite </li></ul><ul><li>Competitively inhibits HBV DNA polymerase </li></ul><ul><li>Chain termination after incorporation into viral replication </li></ul>
  100. 103. INTERFERON ALFA <ul><li>Endogenous proteins that exert complex antiviral immunomodulatory & antiproliferative activities through cellular metabolic process </li></ul><ul><li>Enzyme induction, suppression of cell proliferation, immunomodulatory activities & inhibition of viral replication </li></ul><ul><li>Inhibition of viral penetration & uncoating </li></ul><ul><li>Treatment of both HBV & HCV </li></ul>
  101. 104. INTERFERON ALPHA 2a <ul><li>Approved for the treatment of chronic hepatitis C, AIDS associated Kaposi’s sarcoma hairy cell leukemia, chronic myelogenous leukemia </li></ul>
  102. 105. INTERFERON ALPHA 2b <ul><li>Only preparation licensed for treatment of HBV & acute HCV </li></ul><ul><li>Leads to loss of HbeAg, normalization of aminotransferases </li></ul><ul><li>Administered subcutaneously or intramuscularly </li></ul><ul><li>Hairy cell leukemia, malignant melanoma, follicular non-Hodgkin’s lymphoma, AIDS related kaposi’s sarcoma, & chronic hepatitis C </li></ul>
  103. 106. PEGYLATED INTERFERON ALFA <ul><li>Recently introduced for treatment of chronic hepatitis C </li></ul><ul><li>Longer terminal t ½ with slower clearance </li></ul>
  104. 107. Interferon-  Interferon- β Interferon-  Chronic hepatitis B & C Relapsing-remitting multiple sclerosis Chronic granulomatous disease Genital warts caused by papilloma virus Hairy- cell leukemia Kaposi’s sarcoma
  105. 108. RIBAVIRIN <ul><li>Guanosine analog that is phosphorylated intracellularly by host cell enzymes </li></ul><ul><li>Interferes w/ the synthesis of guanosine triphosphate </li></ul><ul><li>Inhibit capping of viral messenger RNA </li></ul><ul><li>Inhibit viral RNA dependent RNA polymerase of certain viruses </li></ul><ul><li>Influenza A, parainfluenza, RSV, paramyxoviruses, HCV & HIV 1 </li></ul>
  107. 111. AMANTADINE/RIMANTADINE <ul><li>(1-aminoadamantane hydrochloride) </li></ul><ul><li> -methyl derivative - rimantadine </li></ul><ul><li>Inhibits uncoating of viral RNA influenza A within infected cell thus preventing replication </li></ul><ul><li>Effectively reduce the duration of symptoms of influenza when administered w/n 48 hrs of onset </li></ul><ul><li>Primary target is M2 proteins </li></ul>
  108. 112. ZANAMIVIR/OSELTAMIVIR <ul><li>Neuroaminidase inhibitors </li></ul><ul><li>Inhibits replication of both influenza A & B </li></ul><ul><li>5 day course regimen for both influenza A & B </li></ul><ul><li>Delivered by inhalation – ZANAMIVIR </li></ul><ul><li>Oral - OSELTAMIVIR </li></ul>
  109. 113. UNCLASSIFIED
  110. 114. PALIVIZUMAB <ul><li>Prevention of RSV in high risk infants </li></ul>IMQUIMOD <ul><li>Immune response modifier effective in topical treatment of external genitalia & perianal warts </li></ul>
  111. 115. ANTIVIRAL DRUGS - RETROVIRUSES DRUG MECHANISM & VIRAL SELECTIVITY CLINICAL USE VIRAL RESISTANCE UNDESIRABLE SIDE EFFECTS PHARMACOKINETICS NOTES Zidovudine (AZT) Thymidine analog is incorporated into DNA of hyman immunodeficiency viirus causing termination of the viral DNA chain HIV. Prevention of maternal-fetal transmission of HIV Mutations in reverse transcriptase Headaches, nausea, myalgias, anemia, neutropenia, macrocytosis PO. Well absorbed, rapidly metabolized by liver Acetaminophen increases risk of hematologic toxicity Didanosine (ddl) Zalcitabine (ddC) Lamivudine -Metabolized intracellularly to dideoxynucleotide triphosphate that inhibits reverse transcriptase & incorporates into viral DNA. -Nucleotides fail to bind to ddATP bec it lacks free 3’ OH group HIV Mutations in reverse transcriptase Peripheral neuropathy, pancreatitis, diarrhea, headache, insomnia, vomiting, nausea, rash, abdominal pain IV/PO. Partially metabolized in liver, excreted in the urine. Toxicity may be enhanced by renal or hepatic dysfunction. Limited utility as a single agent therapy because of viral resistance Stavudine Metabolized to stavudine triphosphate w/c inhibits HIV reverse transcriptase & DNA polymerase. Prevents DNA elongation. HIV Peripheral neuropathy PO Not indicated for initial monotherapy of HIV
  112. 116. Ritonavir Indinavir Saquinavir Nelfinavir Inhibts HIV protease . Results in immature virion HIV Mutations in protease sequence reduce affinity of protease inhibitors GI distress, headache, neurologic symptoms. Indinavir associated w/ increase risk for kidney stones PO. Metabolized by P450 in liver. Reduce dose in patients with liver disease. Poor CNS penetration Potentially serious drug interactions due to P450 competition Nevirapine Delavirdene Nob-nucleoside inhibitor of HIV reverse transcriptase HIV. Never as monotherapy due to rapid development of resistance Rapid resistance develops due to mutations in reverse transcriptase Severe skin rash, fever, nausea, headache PO. Well absorbed. Nevirapine crosses placenta & has better CNS penetration than Delavirdene Delavirdene failed to show clinical efficacy when added to didanosine in clinical trial
  113. 117. POST-TEST <ul><li>Inhibits step # 1 in HIV replication: </li></ul><ul><li>A. NRTI B. fusion inhibitors </li></ul><ul><li>2. Inhibits step #2 in HIV replication: </li></ul><ul><li>A. fusion B. NNRTIs </li></ul><ul><li>3. Inhibits step # 3 in HIV replication: </li></ul><ul><li>A. protease inhibitors B. NRTIs </li></ul><ul><li>4. Inhibits step #4 in HIV replication: </li></ul><ul><li>A. protease inhibitors B. NRTIs </li></ul><ul><li>5. Virus that undergoes endocytosis: </li></ul><ul><li>A. HIV B. influenza </li></ul>
  114. 118. <ul><li>6. Enzyme inhibited by antiretroviral agents: </li></ul><ul><li>A. reverse transcriptase B. DNA polymerase </li></ul><ul><li>7. Drug for influenza A infection: </li></ul><ul><li>A. Amantadine B. zidovudine </li></ul><ul><li>8. Drug used for HIV that is used in the tx of HBV: </li></ul><ul><li>A. lamivudine B. amantadine </li></ul><ul><li>9. Drug used in the treatment of RSV: </li></ul><ul><li>A. amantadine B. rimantadine </li></ul><ul><li>10. Drug used in the treatment of perianal warts: </li></ul><ul><li>A. imquimod B. amantadine </li></ul>
  117. 122. AMPHOTERICN B <ul><li>Polyene antifungal </li></ul><ul><li>Discovered by Gold & coworkers in 1956 </li></ul><ul><li>Produced by Streptomyces nodosus </li></ul><ul><li>Heptane macrolide w/ 7 conjugated double bonds in the trans position & 3-amino-3,6- dideoxymannose connected to the main ring by a glycoside bond </li></ul><ul><li>Amphotericin polyene macrolide </li></ul><ul><li>Nearly insoluble in water </li></ul>
  118. 123. PREPARATIONS: <ul><li>Colloidal suspension of amphotericin B & Na deoxycholate (DOC) –IV </li></ul><ul><ul><li>50 mg amphotericin B, 41 mg deoxycholate </li></ul></ul><ul><ul><li>Addition of electrolyte to infusion solution causes colloid to aggregate </li></ul></ul><ul><li>Amphotericin B Colloidal Dispersion </li></ul><ul><ul><li>contains roughly equimolar amounts of Amphotericin B & cholesteryl sulfate </li></ul></ul><ul><ul><li>Forms a colloidal solution when dispersed in aqueous solution </li></ul></ul>
  119. 124. CONT. <ul><li>3) Unilamellar Vessicle Formulation </li></ul><ul><ul><ul><li>Amphotercin B 50 mg + 350 mg of lipid in 10% molar ratio </li></ul></ul></ul><ul><li>4) Amphotericin B Lipid Complex </li></ul><ul><ul><ul><li>Amphotericin B 35% + dimyristolphosphatidylcholine & glycerol </li></ul></ul></ul>
  120. 125. ANTIFUNGAL ACTIVITY: <ul><li>Candida sp., C. neoformans, B. dermatidis, H. capsulatum, Sporothrix schenkii, C. immitis, Paracoccidioides brazilienzes, Aspergillus sp., Penicilium marneffei, Mucormycosis </li></ul><ul><li>Limited activity to Leishmania, braziliensis, Naegleria fowleri </li></ul><ul><li>No antibacterial activity </li></ul>
  121. 126. PHARMACOKINETICS: <ul><li>Poorly absorbed from the GIT </li></ul><ul><li>Oral preparation is only effective in fungi within the lumen of the GIT </li></ul><ul><li>Serum t ½ is 15 days </li></ul><ul><li>Widely distributed in tissues </li></ul><ul><li>2-3% CSF concentration </li></ul>
  122. 127. MECHANISM OF ACTION: <ul><li>Antifungal activity depends on the binding with ERGOSTEROL </li></ul><ul><li>Alters the permeability of the cell by forming amphotericin B associated pores in the cell membrane </li></ul><ul><li>Combines with lipids along the double rich bond & associates with H2O molecules along the OH-rich side </li></ul><ul><li>Pores allow leakage of intracellular ions & macromolecules  CELL DEATH </li></ul>
  123. 129. THERAPEUTIC USES: <ul><li>Candida esophagitis </li></ul><ul><li>Meningitis caused by coccidioides </li></ul><ul><li>Mucormycoses </li></ul><ul><li>Invasive aspergillosis </li></ul><ul><li>Extracutaneous sporothrichosis </li></ul><ul><li>Cryptococcosis </li></ul><ul><li>Candida cystitis </li></ul><ul><li>Mycotic corneal ulcers & keratitis </li></ul>
  124. 130. ADVERSE REACTIONS: <ul><li>INFUSION-RELATED TOXICITY: </li></ul><ul><li>fever & chills, muscle spasms, vomiting, headache, & hypotension </li></ul><ul><li>B) SLOWER TOXICITY: </li></ul><ul><li>renal damage </li></ul><ul><ul><li>Reversible renal injury </li></ul></ul><ul><ul><li>Irreversible renal injury- renal tubular injury </li></ul></ul>
  125. 131. FLUCYTOSINE (5-FC) <ul><li>antimetabolite </li></ul><ul><li>Discovered in 1957 </li></ul><ul><li>Fluorinated pyrimidine related to florouracil & floxuridine </li></ul><ul><li>Spectrum of activity is narrower than that of amphotericin </li></ul>
  126. 132. PHARMACOKINETICS: <ul><li>Available in oral preparation </li></ul><ul><li>Well absorbed (>90%) with serum </li></ul><ul><li>Concentration peaking 1-2 hrs </li></ul><ul><li>Poorly protein bound </li></ul><ul><li>Penetrates well body fluids & CSF </li></ul><ul><li>T ½ is 3-4 hrs </li></ul>
  127. 133. MECHANISM OF ACTION: <ul><li>Taken up by fungal cells via CYTOSINE PERMEASE </li></ul><ul><li>Converted intracellularly to 5 FU  5-fluorodeoxyuridine monophosphate & 5-fluorouridine triphosphate  inhibit RNA & DNA synthesis </li></ul>
  128. 135. 5-FU 5-Flucytosine Cytosine permease UMP pyrophosphate 5-FUMP 5-FUDP 5-FUTP Ribonucleide reductase 5-F-dUMP RNA Thymidine synthase DUMP dTMP
  129. 136. CLINICAL USE: <ul><li>Cryptococcal meningitis </li></ul><ul><li>Candida species </li></ul><ul><li>Dermatiaceous molds that cause chromoblastomycosis </li></ul>
  130. 137. ADVERSE EFFECTS: <ul><li>Leukopenia & thrombocytopenia </li></ul><ul><li>Rash </li></ul><ul><li>Nausea/vomiting, diarrhea, severe enterocolitis </li></ul>
  131. 138. AZOLES: <ul><li>IMIDAZOLES : </li></ul><ul><ul><li>K etoconazole </li></ul></ul><ul><ul><li>M iconazole </li></ul></ul><ul><ul><li>C lotrimazole </li></ul></ul><ul><li>TRIAZOLES: </li></ul><ul><ul><li>I traconazole </li></ul></ul><ul><ul><li>F luconazole </li></ul></ul><ul><ul><li>V oriconzaole </li></ul></ul>
  132. 139. MECHANISM OF ACTION: <ul><li>Inhibition of sterol 14 α -demethylase </li></ul><ul><li>Impair the biosynthsesis of ergosterol for the cytoplasmic membrane  accumulation of 14- α -methylsterols </li></ul><ul><li>Impairing functions of membrane bound enzymes such as ATPase & enzymes of electron transport system  inhibits growth of fungi </li></ul><ul><li>Reduction of ergosterol synthesis by inhibition of cytochrome P450 enzymes </li></ul><ul><li>Specificity for fungal than human cytochrome P450 enzymes </li></ul>
  133. 141. CLINICAL USES: <ul><li>Candida species </li></ul><ul><li>Cryptococcus neoformans </li></ul><ul><li>Endemic mycoses </li></ul>DRUG INTERACTIONS: <ul><li>All azole drugs affect mammalian cytochrome P450 systems of enzymes </li></ul>
  134. 142. KETOCONAZOLE <ul><li>First oral azole introduced into clinical use </li></ul><ul><li>Increase propensity to inhibit mammalian cytochrome P450 enzymes </li></ul><ul><li>Less selective for fungal P450 </li></ul><ul><li>Inhibition of mammalian P450 interferes with biosynthesis of adrenal & gonadal steroid hormones </li></ul><ul><li>Interaction with P450 enzymes can alter the metabolism of other drugs leading to enhanced toxicity </li></ul>
  135. 143. Cont. <ul><li>Reaches the keratinocytes efficiently </li></ul><ul><li>Concentration in vaginal fluids is approaches that in plasma </li></ul>
  136. 144. THERAPEUTIC USES: <ul><li>Blastomycosis, histoplasmosis, coccidiodomycosis, pseudallescheriasis </li></ul><ul><li>Paracoccidiodomycosis, ringworm, tinea versicolor, chronic mucocutaneous candidiasis </li></ul><ul><li>Candida vulvovaginitis, oral & esophageal candidiasis </li></ul>
  137. 145. ADVERSE REACTIONS: <ul><li>Dose-dependent anorexia, nausea, vomiting </li></ul><ul><li>Inhibits steroid biosynthesis in patients endocrine abnormalities </li></ul>
  138. 146. DRUG INTERACTIONS: <ul><li>Increases cyclosporine levels </li></ul><ul><li>Enhances arrythmogenic effects of cissapride </li></ul><ul><li>H2 antagonists increases gastric pH, interfere with the absorption of ketoconazole </li></ul><ul><li>Rifamycins increased hepatic metabolism </li></ul>
  139. 147. ITRACONAZOLE <ul><li>Available in capsule & solutions (oral & IV) </li></ul><ul><li>Capsule form is best absorbed in the fed state </li></ul><ul><li>Oral solution is best absorbed in the fasting state </li></ul><ul><li>Metabolized in the liver by the CYP3A4 isoenzyme system </li></ul><ul><li>Does not affect mammalian steroid synthesis </li></ul><ul><li>Reduced bioavailability when taken with rifamycins </li></ul>
  140. 148. Cont. <ul><li>Azole of choice for dimorphic fungi histoplasma, blastomyces, sporothrix </li></ul><ul><li>Oral solution is effective for use in oropharyngeal & esophageal candidiasis </li></ul><ul><li>Onychomycosis can be treated with either 200 mg OD X 12 wks or as 200 mg BID X 1 wk out of each month </li></ul>
  141. 149. FLUCONAZOLE <ul><li>Fluorinated bistriazole </li></ul><ul><li>Good water solubility & CSF penetration </li></ul><ul><li>Azole of choice in the treatment & secondary prophylaxis of cryptococcal meningitis </li></ul><ul><li>Available in oral & IV form </li></ul><ul><li> plasma concentrations of astemizole, cissapride, cyclosporine, rifampin, rifabutin, sulfonylureas, theophylline & warfarin </li></ul>
  142. 150. VORICONAZOLE <ul><li>Newest triazole to enter clinical trials </li></ul><ul><li>Availabale in oral & IV </li></ul><ul><li>Well absorbed orally with bioavailability >90% </li></ul><ul><li>Low propensity to inhibit mammalian cytochrome P450 </li></ul><ul><li>Same as itraconazole in its spectrum of action </li></ul><ul><li>Good activity against candida species </li></ul><ul><li>fluconazole-resistant species such as C. krusei, dimorphic fungi, pathogenic molds including aspergillus </li></ul>
  143. 151. ECHINOCANDINS <ul><li>Large cyclic peptides linked to a long chain fatty acid </li></ul><ul><li>Caspofungin, micafungin, anidulafungin </li></ul><ul><li>Candida and aspergillus but not cryptococcus neoformans </li></ul><ul><li>IV forms only </li></ul>
  144. 152. MECHANISM OF ACTION <ul><li>Inhibits the synthesis of β (1-3) glucan </li></ul><ul><li>Disruption of the fungal cell wall and cell death </li></ul><ul><li>The glucan synthesis inhibitors are, collectively, agents that are presumed to block fungal wall synthesis </li></ul><ul><li>Inhibition of this enzyme results in depletion of glucan polymers in the fungal cell, resulting in an abnormally weak cell wall unable to withstand osmotic stress </li></ul>
  145. 154. CLINICAL USE: <ul><li>CASPOFUNGIN </li></ul><ul><li>Disseminated mucocutaneous candida infections </li></ul><ul><li>Empiric antifungal therapy during febrile neutropenia </li></ul><ul><li>MICAFUNGIN </li></ul><ul><li>Mucocutaneous candidiasis </li></ul><ul><li>Prophylaxis of candida infections in bone marrow transplant patients </li></ul>
  146. 155. <ul><li>ANIDULAFUNGIN </li></ul><ul><ul><li>esophageal candidiasis </li></ul></ul><ul><ul><li>Invasive candidiasis </li></ul></ul><ul><ul><li>septicemia </li></ul></ul>
  148. 157. GRISEOFULVIN <ul><li>Practically insoluble in water </li></ul><ul><li>Fungistatic in vitro for dermatophytes microsporum, epidermophytom & trichophyton </li></ul><ul><li>No effect on bacteria & other fungi </li></ul>
  149. 158. MECHANISM OF ACTION: <ul><li>Production of multinucleate cells as the drug inhibits fungal mitosis </li></ul><ul><li>Causes disruption of the mitotic spindle by interacting with polymerized microtubules – critical step in cellular division </li></ul><ul><li>Deposited in the newly forming skin where it binds to keratin </li></ul><ul><li>Administered 2-6 wks for skin & hair infections </li></ul>
  150. 159. THERAPEUTIC USES: <ul><li>Mycotic disease of the skin, hair & nails due to Microsporum, Trichophyton, or Epidermophyton </li></ul><ul><li>Tinea capitis (M. canis) </li></ul><ul><li>Ringworm of the glabrous skin </li></ul><ul><li>Tinea corporis, cruris (T. rubrum, T. mentagrophytes) </li></ul><ul><li>Hyperlkeratosis (T. rubrum) </li></ul>
  151. 160. ADVERSE REACTIONS: <ul><li>Allergic syndrome </li></ul><ul><li>hepatitis </li></ul>
  152. 161. TERBINAFINE <ul><li>Synthetic allylamine </li></ul><ul><li>Available in oral formulation </li></ul><ul><li>Used in the treatment of dermatophytoses especially onychomycosis </li></ul><ul><li>Keratophillic, fungicidal </li></ul><ul><li>Inhibits the enzyme SQUALENE EPOXIDASE </li></ul><ul><li>Leads to the accumulation of the sterol squalene </li></ul><ul><li>Allylamines work in a conceptually similar fashion to azole antifungals by inhibiting the synthesis of ergosterol </li></ul><ul><li>Allylamines act at an earlier step in the ergosterol synthesis pathway </li></ul><ul><li>OD X12 wks achieves 90% cure rate for onychomycosis </li></ul>
  153. 162. TOPICAL ANTIFUNGAL AGENTS <ul><li>Superficial fungal infections confined to the striatum corneum, squamous mucosa or cornea </li></ul><ul><li>Ringworm, candidiasis, tinea versicolor, tinea nigra, fungal keratitis </li></ul><ul><li>Not successful for mycoses of the nails & hair </li></ul><ul><li>No place for the treatment of subcutaneous mycosis </li></ul>
  155. 164. NYSTATIN <ul><li>Polyene macrolide </li></ul><ul><li>Structurally similar to Amphotericin B </li></ul><ul><li>Toxic for parenteral administration </li></ul><ul><li>Available in creams, ointments, suppositories </li></ul><ul><li>Oropharyngeal thrush, vaginal candidiasis, intertriginous candidal infections </li></ul>
  156. 165. AMPHOTERICIN B <ul><li>Topical form (Fungizone) </li></ul><ul><li>Cutaneous & mucocutaneous candidiasis </li></ul><ul><li>Lotion, ointment & cream </li></ul>
  158. 167. CLOTRIMAZOLE <ul><li>Available as 1% cream, lotion, & solution </li></ul><ul><li>1% or 2% vaginal cream or vaginal tablets </li></ul><ul><li>Skin applications – BID </li></ul><ul><li>Vaginal applications – 100 mg tab OD at bedtime X 7 days or 200 mg OD X 3 days </li></ul>
  159. 168. MICONAZOLE <ul><li>Readily penetrates the striatum corneum of the skin </li></ul><ul><li>Persists for >4 days after application </li></ul><ul><li>Safe for use during pregnancy for vaginal use </li></ul><ul><li>Ointment, cream, solution, spray, powder or lotion </li></ul><ul><li>Vaginal cream, suppositories </li></ul><ul><li>Tinea pedis, tinea cruris, & tinea versicolor </li></ul>
  160. 169. CICLOPIROXAMINE <ul><li>Broad spectrum </li></ul><ul><li>Fungicidal to C. albicans, E. flocosum, M. canis, T. mentagrophytes, T. rubrum </li></ul><ul><li>Inhibits the growth of Malassezia furfur </li></ul><ul><li>Penetrates the dermis </li></ul>
  161. 170. HALOPROGIN <ul><li>Halogenated phenolic ether </li></ul><ul><li>Fungicidal to various species of Epidermophyton, Pityrosporum, Microsporum, Trichophyton & Candida </li></ul><ul><li>Poorly absorbed through the skin </li></ul><ul><li>Converted to thrichlorophenol in the body </li></ul><ul><li>Cream or solution BID X 2-4 wks </li></ul><ul><li>Principal use for tinea pedis </li></ul><ul><li>Tinea cruris, tinea versicolor, tinea corporis </li></ul>
  162. 171. NAFTIFENE <ul><li>Inhibit squalene-2,3- epoxidase </li></ul><ul><li>Inhibits biosynthesis of ergosterol </li></ul><ul><li>Fungicidal activity </li></ul><ul><li>1% cream or gel </li></ul><ul><li>Topical treatment of tinea cruris & tinea corporis </li></ul><ul><li>Cutaneous candidiasis & tinea versicolor </li></ul>
  163. 172. ANTIFUNGAL DRUGS DRUG ACTION CLINICAL USE UNDESIRABLE EFFECTS PHARMACOKINETICS NOTES Amphotericin B Disrupts plasma membrane of fungal cells, greater affinity for ergosterol DOC: systemic fungal infections, fungal meningitis & fungal urinary tract infections Poor therapeutic index (toxic at therapeutic dose). Fever & chills, nephrotoxicity, nausea, headache, thrombophlebitis, anemia, hepatotoxicity, cardiotoxicity Slow IV for systemic infections; intrathecal for meningitis, bladder irrigation for cystitis. No need to reduce dose with renal dysfunction. CBC, urinalysis, liver enzymes, BUN, Crea, & electrolytes should be checked before and during tx Nystatin DOC: Intestinal candidiasis or oral thrush Few adverse effects PO. Negligible absorption, fecal excretion . Ketoconazole Impairs synthesis pf ergosterol DOC: P. brasiliensis, thrush, chronic mucocutaneous candidiasis, dermatophytes Nausea, diarrhea, headaches, rsh, dizziness, fatal hepatic necrosis, gynecomastia. Risk of cardiac arrhythmia with Terfenadine PO. Acid pH required for dissolution. Absorption decreased by food, antacids, cimetidine Follow LFTs. Stop during signs of liver abnormalities Fluconazole Inhibits fungal cytochrome P450. Damages plasma membrane by inhibiting sterol demethylation Systemic histoplasmosis, blastomycosis, coccidiomycosis or sporotrichosis. Opportunistic cryptococcosis, candidiasis, candidal thrush, vaginitis, esophagitis Nausea, headache, rash, vomiting, diarrhea PO/IV. Long half life. Excellent penetration of CSF, eye, urine. Hepatic metabolism No effect on testosterone synthesis.
  164. 173. Itraconazole Aspergillosis, histoplasmosis, coccidiomycosis, sporotrichosis, paracoccidiomycosis, tinea or candidal infections Nausea, edema, hepatitis. No gynecomastia or breast pain. Risk of fatal cardiac arrhythmias w/ terfenadine PO. Requires acidic environment for absorption No effect on testosterone synthesis Clotrimazole unknown DOC: candida dermatophyte infections of the skin topical Miconazole Vaginal candidiasis, severe systemic fungal infections Phlebitis, pruritus, nausea, fever, rash, vomiting Vaginal suppositories/ topical/IV Flucytosine Deaminated to 5-FU by the fungus. Incorporated into RNA. Metabolized to 5-FdURD w/c inhibits thymidilate synthetase Leucopenia, nausea, diarrhea, Inc LFTs, bone marrow depression Easily penetrates CNS. Renal excretion Fungal resistance develops Griseofulvin Interferes w/ synthesis & polymerization of nucleic acids Dermatophytes of hair, skin, & nails. Up to 6 months tx may be required Headaches, GI upset, dec memory & judgement, leucopenia, teratogenic PO. Water insoluble, powder absorbed fairly well, administration w/ fatty meal aids absorption Contraindicated w/ pregnant women. Drug binds to keratin of growing tissues Terbinafine Inhibits squalene epoxidase that converts squalene to ergosterol in fungi Toenail infection due to trichophyton species Neutropenia, skin infections, ophthalmic toxicity PO. Long half life. Good tissue penetration Monitor blood counts
  166. 175. UNDECYCLENIC ACID <ul><li>Yellow liquid with a characteristic rancid odor </li></ul><ul><li>Fungistatic, fungicidal w/ prolonged use </li></ul><ul><li>Foam, ointment, cream, powder, spray powder, soap & liquid </li></ul><ul><li>Ringworm, tinea pedis </li></ul>
  167. 176. BENZOIC ACID & SALICYLIC ACID <ul><li>Whitfield’s ointment </li></ul><ul><li>Combines fungistatic activity of benzoic acid w/ keratolytic action of salicylic acid </li></ul><ul><li>Mainly for the treatment of tinea pedis </li></ul><ul><li>Eradication occurs after the infectd stratum corneum is shed </li></ul><ul><li>Salicylate accelerates the desquamation </li></ul>
  168. 177. PROPIONIC ACID & CAPRYLIC ACID <ul><li>Treatment of dermatomycoses </li></ul><ul><li>Low efficacy </li></ul>
  169. 178. POTASSIUM IODIDE <ul><li>Treatment of mucocutaneous sporotrichosis </li></ul>
  170. 179. GOOD LUCK !!!
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