4.2.2_Pharm

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sirchubbsalot13
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12810
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4.2.2_Pharm
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2010-04-04 00:12:00
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viral and fungal drugs
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4.2.2_Pharm
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  1. Prevent or reduce transmission (hygiene, public health, nosocomial prevention)
    Immunization
    Controlling viral disease
  2. Effective against many viruses, directed against surface antigens
    Monoclonal: Palivizumab for RSV
    Polyclonal: CMV ___ ___, hep B ___ ___, Rabies ___ ___, and varicella-zoster ___ ___ are used to prevent viral infection in exposed Pt's.
    Usefulness: acute, serious dz administered w/ nucleoside antiviral to obtain synergistic effect; post exposure prophylaxis
    IV-IG to obtain high titer of antiviral antibodies
    Immune Globulin
  3. Lead to rapid secondary immune response
    Effective for HPV (Gardacil for HPV 6,11,16,18), Hep A (Havrix) and B, Polio, Rabies, yellow fever, VZV (Varivax); MMR, Flu (effective for 6 mo. or longer)
    Side effects: fever, achy muscles, malaise
    Administered IV or orally
    Vaccines
  4. 3 classes of antiviral chemotherapy
    • Immune modulators (Vaccines, immune globulin, IFNs)
    • Inhibitors of viral replication
    • Inhibitors of viral entry

    Goal is to inhibit virus w/out causing cell toxicity
  5. Viruses: influenza A & B
    Mech: inhibits neuraminidase (enables virus to be released from cell)
    Notable ADME: (1) inhalation poorly adsorbed), (2) oral prodrug, hepatic metabolism
    Adverse effects: Psychiatric bx, bronchospasm (1), d/n and sinusitis
    • (1) Zanamivir
    • (2) Oseltamivir

    Neuraminidase inhibitors
  6. Viral uncoating inhibitors
    Influenza A
    Mech: inhibits M2 ion channel; inhibits uncoating of virus endosome
    (1) Hepatic clearance; (2) renal clearance
    Resistance since 2005 (no longer used)
    Adverse effects: GI, CNS
    (2) Exhibits some anti-parkinsons activity
    (1) Rimantadine; (2) Amantadine)
  7. Activity: HSV, VZV (limited use for CMV and EBV)
    Mech: converted by viral thymidine kinase; Tri-PO4 cmpd inhibits viral DNA synthesis
    higher affinity for viral DNA polymerase, competes w/ guanine, incorporated into growing DNA chain of virus => terminating synthesis
    Resistance: Deficient TK, altered TK, altered DNA polymerase
    Side effects: n/v, rash, phlebitis, CNS & nephrotoxicity in renal impaired Pt's
    Acyclovir and Valacyclovir
  8. Activity: CMV (much greater the acyclovir), HSV, VZV, human herpes virus 6
    Mech: less dependent on viral TK
    More toxic than acyclovir; myelosuppression
    Ganciclovir
  9. Similar to acyclovir but longer duration of action
    cross resistance w/ acyclovir
    Side effects: headache, GI
    Famciclovir
  10. Activity: CMV, HSV, VZV, EBV, HHV-6 (secondary to gancyclovir and acyclovir in compromised Pt's)
    Mech: Cytosine analog, inhibits viral DNA synthesis (not dependent on TK)
    DLT: nephrotoxicity
    Resistance due to mutations in viral DNA polymerase
    Administered IV (not orally)
    Cidofovir
  11. Activity: HSV, VZV, CMV, HHV-6, HIV
    Mech: inhibits DNA polymerase (mimics pyrophosphate)
    Side effects: many, Headache, tremor, irritability, seizures, hallucinations (due to changes in Ca levels)
    DLT: nephrotoxicity and hypocalcemia
    ADME: IV, accumulates in bone (but no myelosuppression)
    Foscarnet
  12. Activity: against herpes viruses, but lack specificity for viral infections.
    Mech: following phosphorylation trifluidine inhibits viral DNA synthesis through inhibition of thymidylic phosphorylase (Lacks selectivity -- mammalian incorperation)
    ADME: (1) only ophthalmic preperations (2) topical tx
    (1) Idoxuridine and (2) Trifluridine
  13. CMV retinintis
    First anti-sense therapy for viral infection
    Inhibits CMV replication through sequence specific & nonspecific mechs including inhibiting viral binding
    Fomivirsen
  14. HSV (cold sores)
    Long chain fatty acid alcohol
    presumably inhibits membrane fusion
    May shorten healing by about 1 day
    Docosanol
  15. RNA and DNA viruses
    Mech: mimic antiviral response (made by recombinant DNA technology)
    Inhibit transcription, translation, protein processing and viral maturation
    Clinicl usefulness: Hep B,C; combo therapy w/ ribavirin for Hep C; Genital warts, common cold, RNA tumor viruses
    Given mainly IM or IV, inhalent for cold
    Interferon
  16. Activity: combo therapy for HCV with INF, also used for HSV, ZVZ & RSV
    Mech: purine nucleoside (inhibits 5' capping of mRNA, interferes w/ guanine nucleotide synthesis)
    ADME: half-life dependent on delivery mode
    Side effects: Mild conjuctival irritation, rash, wheezing, myelosuppression, may be teratogenic, embryotoxic, oncogenic, or gonadotoxic
    Systemic administration limited to serious infections due to many side effects
    Ribavirin
  17. Adefovir - failed as HIV drug (AMP nucleotide analog that inhibits reverse transcriptase)
    Main benefit is longer time to develop resistance
    Lamivudine -- still used to combat HIV (nucleoside reverse transcriptase inhibitor)
  18. FDA approved for HPV infections
    Mech: dependent on TLR7, induces secretion of pro-inflammatory cytokines (IFN & TNF & interleukins)
    Topical Admin
    Imaquimod
  19. A few histo images
  20. Mech: Increases fungal membrane permeability (selective to ergosterol)
    Uses: Most fungi that cause myoceses it is the mainstay of Rx against serious systemic infections and the most reliable agent. The drug of choice in treatment of primary amebic meningoencephalitis caused by Naegleria and an alternate in treatment of American cutaneous or mucocutaneous leishmoniasis.
    Duration of therapy is usually 6-12 weeks so a costly hospital stay is required.
    ADME: Does not cross BBB
    Toxocity: Oral application [essentially a topical application for enteral mycoses]: N/V/D. Intravenous administration: N/V/D plus frequent *fever & chills (50%) & *nephrotoxicity (80%). Other common side effects are headache, hypotension, & rapid breathing. Nephrotoxicity and infusion-related reactions are less frequent if the drug is infused over a 24 hr period rather than over the usual 4 hr. Intrathecal administration: Also causes *unique CNS-related toxicities including headache, n/v, radiculitis, paresis, paresthesias, and visual impairment.
    Nephrotoxicity is frequently the limiting factor in determining the duration of therapy. Changes may be reversible up to a total dose of 4 gm. Sodium loading with normal saline is recommended if pts can tolerate the fluid load as it seems to prevent/ameliorate this adverse effect.
    There are also 3 lipid formulations available, all are less toxic, and all cost much more.
    Amphotericin B

    (Liposomal Ampho B, Ampho B lipid complex, Ampho B colloidal disersion-- L-AmB is probably the best but costs $1,318 per day)
  21. Mech: ________ is selective for fungi because cytosine deaminase doesn’t exist in man. Strictly fungistatic rather than fungicidal.
    Uses: Useful clinical spectrum is extremely narrow. ________ monotherapy is only the drug of choice for initial therapy of Chromomycosis. ________ is used with amphoB against Cryptococcus (including cryptococcal meningitis in AIDS patients) as their effects are superadditive & the combo is safer than a full dose of amphoB. ________ is used as an alternate for Rx of urinary Candidiasis. Resistance can occur during therapy causing therapeutic failure.
    ADME: Well absorbed orally & enters the CSF (75%), aqueous humor, bronchial secr. Excreted by glomerular filtration without prior metabolism. t1/2 = 3-4 hours. Dose must be adjusted if renal function is compromised. Half time with complete renal failure = 200 hours.
    Toxicities: *Potentially lethal as the principal toxicity is dose-related bone marrow toxicity (leukopenia & thrombocytopenia). *Keeping plasma concentration below 50-100 μg/ml decreases toxicity but this is hard to maintain in patients with renal insufficiency and getting test results often take too long. *Use with nephrotoxic amphoB can increase the toxicity of flucytosine by decreasing its renal excretion. *Enterocolitis with severe diarrhea can result, esp. if used in combination with amphoB.
    Flucytosine
  22. 1. They interfere with ergosterol biosynthesis by inhibition of one or more fungal enzymes in the cytochrome P450 microsomal enzyme system.
    2. Low concentrations are fungistatic, while higher concentrations are fungicidal.
    3. They have a broad spectra of action against dermatophytes, Candida (most), Crypto- coccus, Coccidioides, Histoplasma, Blastomyces, & Paracoccidioides. Aspergillus & Fusarium are only moderately sensitive except to voriconazole. Zygomycetes such as Mucor are insensitive except to posaconazole.
    4. *The systemic antifungal azoles cause very numerous drug interactions as a result of inhibition of specific human cytochrome P450 enzymes; ketoconazole and itraconazole are potent inhibitors of CYP3A4, fluconazole is a moderate blocker of CYP3A4 and a stronger blocker of CYP2C9, and voriconazole is a blocker of CYP2C19, CYP2C9, & CYP3A4. As a result, use of these agents with other drugs metabolized by any of these pathways can increase the concentration of other drugs, potentially to toxic levels. Conversely, use of certain drugs metabolized by specific pathways can either increase or decrease the concentration of the antifungal azole.
    5. *All are teratogenic if administered to pregnant women. In infants exposed to fluconazole during gestation, a pattern of craniofacial & cardiac anomalies has been reported similar to those seen in animals. (Amphotericin B is preferred for systemic fungal infections in this situation.)
    6. The major advantages of the newer azoles are that: a. They are better tolerated than amphoB or flucytosine. b. They can generally be given orally rather than IV even for serious infections. c. They do not require hospitalization.
    ITRA-, FLU-, VORI-, POSA- & KETOCONAZOLE (systemic antifungal azoles)
  23. 1. Therapeutic Uses: It has a broader spectrum of activity than closely related fluconazole. It is the first drug of choice for eight indications and is an effective alternate for five other indications ranging from superficial to systemic mycoses. It has no activity against Fusarium or Mucor. Agent of choice for both acute treatment and chronic suppression of histoplasmosis in immunocompromised patients (requires daily doses). Approved for oral Rx of dermatophytic infections of the fingernails and toenails (onychomycoses).
    2. Absorption, Distribution and Excretion: It is readily absorbed orally if stomach contents are sufficiently acidic. It is extensively metabolized by the liver where it undergoes saturable metabolism; renal excretion of active drug is <0.03% of dose. Never used for fungal meningitis as doesn’t enter the CSF. It passes into breast milk.
    3. Toxicity & Adverse Effects: It is well tolerated at the usual oral dose but 10-15% experience N/V and abdominal discomfort; headache (4%); *skin rash (possibly including Stevens-Johnson syndrome) or pruritus are common (ca 11%); hepatitis can occur. *Hypocalcemia, edema, hypertension and worsening myocardial function can also occur. Congestive heart failure has occurred and it shouldn’t be used in pts with ventricular dysfunction.*Itraconazole is teratogenic in rats (pregnancy category C). *IV _____ contains cyclodextrin which accumulates in patients with creatinine clearance 30 ml/min.
    4. Drug Interactions With Itraconazole: *It is a strong inhibitor of CYP3A4 and co-administration with any substrate of CYP3A4 will increase the plasma concentration of the substrate; this interaction can be potentially serious and even life threatening. Use with quinidine can cause cardiac arrhythmias or death while use with lovastatin or simvastatin can cause rhabdomyolysis. *Since it is also a substrate of CYP3A4, co-administration of itraconazole with any inducer of CYP3A4 (rifampin, phenytoin, others) will decrease the plasma concentration of the azole. In addition, coadministration with any inhibitor of CYP3A4 will increase the plasma concentration of it. Co-administration of it with *digoxin can, by a different mechanism, increase the serum concentration of digoxin and cause serious cardiac toxicity. Use with many other drugs such as *oral contraceptives will decrease the contraceptive action while co-administration with a benzodiazepine can enhance its action causing prolonged sedation and respiratory depression.
    ITRACONAZOLE [SPORANOX]
  24. 1. Therapeutic Uses: Agent of choice for eight fungal indications & alternate for five others .Agent of choice for chronic suppression of (1) cryptococcal infections (including meningitis), (2) frequent or severe oral or esophageal candidiasis esp. in HIV patients, or (3) systemic or vaginal candidiasis is any population.Single-dose therapy for vaginal yeast infections: A unique application involving 1 x 150 mg. yielding progressive recovery over the next several days.
    2. Absorption, Distribution, and Excretion: 80% of a dose appears in the urine unchanged. Secreted in milk.
    3. Toxicity: is generally well tolerated, most common adverse effects include headache and GI effects (dry mouth, N/V/D; 2-4%) and skin rash (2%). Patients have rarely developed *exfoliative skin disorders (Stevens-Johnson syndrome). *It is teratogenic in animals (pregnancy category C)
    4. Drug Interactions: *is a moderate inhibitor of CYP 3A4 & a strong inhibitor of CYP2C9. *concentrations are decreased by co-administration with inducers such as rifampin (CYP3A4, CYP2A9) or barbiturates (CYP2A9).
    FLUCONAZOLE
  25. Therapeutic uses: Similar to itraconazole, exept it has greater activity against aspergillus and some species of candida. Tx of potentially lethal invasive aspergillosis (better than ampho b), active against fusarium, agent of choice for 3 systemic fungal infections and alternate for 2 others.
    ADME: same if given orally or IV, primarily metabolized by CYP2C19-- slow metabolizers experience a 4x greater exposure. Dosage must be reduced 50% in pts with cirrhosis.
    Toxicity: visual defects (blurred vision, photophobia, altered color or image perception), photosenitivity, rash (stevens-johnson syndrome), confusion, hallucinations, it is a teratogenic in animals.
    Drung interactions: metabolized by CYP2C19, 2C9, & 3A4. Is contraindacated for those taking rifampin, rifabutin, ergot alkaloids, long-acting barbituates, carmamazepine, pimozide, quinidine.
    VORICONAZOLE
  26. It is structurally similar to itraconazole and its antifungal spectrum is, in general, similar to that of itraconazole. It is approved for prophylaxis of invasive Aspergillus and Candida. It is unique among azoles in that it is active against Zygomycetes such as Mucor. It is unique among azoles in that it must the taken with high-fat meals in order to obtain adequate absorption. Prophylaxis is better than that by flu- or itraconazole has also been used successfully in treatment of mycoses that are often refractory to commonly used antifungal agents (aspergillosis, coccidioidomycosis, zygomycosis, oropharyngeal and esophageal candidiasis).
    Its adverse effects are similar to those of fluconazole (see above). It inhibits CYP3A4 and therefore, if coadministered with drugs metabolized by CYP3A4 such as cyclosporine or tacrolimus, their doses should be reduced.
    POSACONAZOLE
  27. No longer is a first drug of choice for any systemic infection but it is a cheap backup in several cases (tables on p. 1-2). Other agents are preferred, largely because of their superior toxicity profiles. *Unique among the azoles in that it can cause a dose-dependent decrease in serum testosterone in man, oligospermia, gynecomastia, loss of libido, loss of potency and, in women, menstrual irregularities. Commonly causes anorexia, nausea and vomiting; taking ketoconazole with food and/or at bedtime improves tolerance. Not used for fungal meningitis as it doesn’t penetrate well into the CSF. Not used in nursing moms as it is excreted in breast milk or in pregnant momsas it is teratogenic in animals (pregnancy category C). Very numerous drug interactions that are similar to those of itraconazole. Most significantly, it is a potent inhibitor of CYP3A4.
    KETOCONAZOLE
  28. 1. Therapeutic Uses: All are newer once-daily IV antifungal drugs which have activity against most Candida species (even if resistant to azoles) and against Aspergillus. Their efficacies and safety profiles are similar. All are alternate 1st place drugs of choice for esophageal candidiasis, candidemia, & some other infections due to Candida. (1) serves as an alternate drug for Rx of invasive aspergillosis for pts refractory to or intolerant of other therapies. (2) is also FDA-approved for prevention of invasive Candida infections in patients undergoing hematopoietic stem cell transplantation (HSCT). Results are comparable to those of AmBisome (L-AmB).
    2. Mechanism of Action: They are the first agents in a new class of antifungal drugs that blocks synthesis of (1,3)-D-glucan, a major polysaccharide component of the fungal cell wall of susceptible pathogenic fungi. Their selectivity & low toxicity arise from the fact that mammalian cells lack cell walls and, consequently, lack enzymes involved in glucan synthesis.
    3. Distribution, Metabolism, and Excretion: Distribution rather than metabolism or excretion is the main mechanism of clearance. It is found in milk so concern about using it in nursing moms. Slowly metabolized by hydrolysis and N-acetylation to inactive metabolites which are excreted in feces and urine. No dosage adjustment is required for moderate renal or hepatic insufficiency.
    4. Toxicity: Generally well tolerated but can cause *phlebitis at the injection site. Occasionally causes rash, pruritus, fever, headache, n/v/d, mild hepatic toxicity. *All are embryotoxic/teratogenic (pregnancy category C) Anaphylaxis & hemolysis are occasionally observed.
    5. Drug Interactions: *It could be used in combination with amphotericin B and,*unlike azoles, it does not inhibit any cytochrome P450 enzyme.
    (1) CASPOFUNGIN, (2) MICAFUNGIN & ANIDULAFUNGIN
  29. What antifungal is the first choice to treat: Aspergillosis, Fusariosis, pseudallscheriasis
    and the 2nd option to treat: Candidiasis
    Voriconazole
  30. What antifungal is the 1st choice for these fungi: Aspergillosis, Candidiasis (systemic), Cryptococcis, Zygomycosis, Blastomycosis, Coccidioidomycosis, Fusariosis, Histoplasmosis, Parcoccidioidomycosis, and Sporotrichosis (systemic)
    Amphotericin B
  31. Fluconazole is the 1st choice for what infections?
    Is it the 2nd choice for any infections?
    • 1st) Candidiasis (systemic and urinary), Cryptococcosis, coccidioidomycosis.
    • 2nd) Blastomycosis, Histoplasmosis.
  32. Name the fungi that Flucytosine is the 1st and 2nd choice for.
    • 1st) Cryptococcus (with Ampho B), Chromomycosis
    • 2nd) Candidiasis (urinary)
  33. What drug is the 1st choice for Paracoccidioidomycosis, Hisoplasmosis, Coccidioidomycosis, Blastomycosis; and the 2nd choice for Pseudallescheriasis, Cryptococcosis, and Aspergillosis
    Itraconazole

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