Antiviral Agents

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Antiviral Agents
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Viruses

• Obligate intracellular parasites
• Consist of a core genome in a protein shell and
  some are surrounded by a lipoprotein
• lack a cell wall and cell membrane
• do not carry out metabolic processes
• Replication depends on the host cell machinery

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Viruses

• Steps for Viral Replication
• 1) adsorption and penetration into cell
• 2) uncoating of viral nucleic acid
• 3) synthesis of regulatory proteins
• 4) synthesis of RNA or DNA
• 5) synthesis of structural proteins
• 6) assembly of viral particles
• 7) release from host cell

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Sites of Drug Action
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Antiviral Agents

• Block viral entry into the cell or must work
  inside the cell
• Most agents are pyrimidine or purine nucleoside
  analogs

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Sites of Drug Action
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Antiherpes Agents

• Acyclovir- prototype
• Valacyclovir
• Famciclovir
• Penciclovir
• Trifluridine
• Vidarabine

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Mechanism of Action Acyclovir

• an acyclic guanosine derivative
• Phosphorylated by viral thymidine kinase
• Di-and tri-phosphorylated by host cellular
  enzymes
• Inhibits viral DNA synthesis by
• 1) competing with dGTP for viral DNA polymerase
• 2) chain termination

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Mechanism of Resistance Acyclovir

• Alteration in viral thymidine kinase
• Alteration in viral DNA polymerase
• Cross-resistance with valacyclovir, famciclovir,
  and ganciclovir

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Clinical Uses Acyclovir

• Oral, IV, and Topical formulations
• Cleared by glomerular filtration and tubular
  secretion
• Uses
• Herpes Simplex Virus 1 and 2 (HSV)
• Varicella-zoster virus (VZV)
• Side Effects nausea, diarrhea, headache,
  tremors, and delirium

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Valacyclovir

• L-valyl ester of acyclovir
• Converted to acyclovir when ingested
• M.O.A. same as acyclovir
• Uses
• 1) recurrent genital herpes
• 2) herpes zoster infections
• Side Effects nausea, diarrhea, and headache

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Famciclovir

• Prodrug of penciclovir (a guanosine analog)
• M.O.A. same as acyclovir
• does not cause chain termination
• Uses HSV-1, HSV-2, VZV, EBV, and hepatitis B
• Side Effects nausea, diarrhea, and headache

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Trifluridine

• Trifluridine- fluorinated pyrimidine
• inhibits viral DNA synthesis same as acyclovir
• incorporates into viral and cellular DNA
• Uses HSV-1 and HSV-2 (topically)

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Vidarabine

• An adenosine analog
• inhibits viral DNA polymerase
• incorporated into viral and cellular DNA
• metabolized to hypoxanthine arabinoside
• Side Effects GI intolerance and myelosuppression

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Anti-Cytomegalovirus Agents

• Gancyclovir
• Valgancyclovir
• Cidofovir
• Foscarnet
• Fomivirsen

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Ganciclovir

• An acyclic guanosine analog
• requires triphosphorylation for activation
• monophosphorylation is catalyzed by a
  phosphotransferase in CMV and by thymidine kinase
  in HSV cells
• M.O.A. same as acyclovir
• Uses CMV, HSV, VZV,and EBV
• Side Effect myelosuppression

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Valgancyclovir

• Monovalyl ester prodrug of gancyclovir
• Metabolized by intestinal and hepatic esterases
  when administered orally
• M.O.A. same as gancyclovir
• Uses CMV
• Side Effect myelosuppression

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Cidofovir

• A cytosine analog
• phosphorylation not dependent on viral enzymes
• Uses CMV, HSV-1, HSV-2, VZV, EBV, HHV-6,
  adenovirus, and human papillomavirus
• Side Effects nephrotoxicity (prevented by admin.
  of probenecid)
• Resistance mutation in DNA polymerase gene

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Foscarnet

• An inorganic pyrophosphate
• inhibits viral DNA polymerase, RNA polymerase,
  and HIV reverse transcriptase
• does not have to be phosphorylated
• Uses HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV
• Resistance due to mutations in DNA polymerase
  gene
• Side Effects hypo- or hypercalcemia and
  phosphotemia

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Fomivirsen

• An oligonucleotide
• M.O.A. binds to mRNA and inhibits protein
  synthesis and viral replication
• Uses CMV retinitis
• Side effects iritis and increased intraocular
  pressure

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Antiretroviral Agents

• There are five classes of antiretroviral drugs,
  each of which targets one of four viral
  processes. These classes of drugs are
• Nucleoside and nucleotide reverse transcriptase
  inhibitors (NRTIs),
• Non-nucleoside reverse transcriptase inhibitors
  (NNRTIs),
• Protease inhibitors,
• Entry inhibitors
• Integrase inhibitors.

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HAART
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Antiretroviral Agents

• 1) Nucleoside Reverse Transcriptase Inhibitors
  (NRTIs)
• 2) Nonnucleoside Reverse Transcriptase Inhibitors
  (NNRTIs)
• 3)Protease inhibitors

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Nucleoside Reverse Transcriptase Inhibitors

• Zidovudine (AZT)
• Didanosine- causes pancreatitis
• Lamivudine- causes pancreatitis
• Zalcitabine- causes peripheral neuropathy
• Stavudine- causes peripheral neuropathy
• Abacavir

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Mechanism of Action Zidovudine (AZT)

• A deoxythymidine analog
• enters the cell via passive diffusion
• must be converted to the triphosphate form by
  mammalian thymidine kinase
• competitively inhibits deoxythymidine
  triphosphate for the reverse transcriptase enzyme
• causes chain termination

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Mechanism of Resistance Zidovudine

• Due to mutations in the reverse transcriptase
  gene
• more frequent after prolong therapy and in
  persons with HIV

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Clinical Uses Zidovudine

• Available in IV and oral formulations
• activity against HIV-1, HIV-2, and human T cell
  lymphotropic viruses
• mainly used for treatment of HIV, decreases rate
  of progression and prolongs survival
• prevents mother to newborn transmission of HIV

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Side Effects Zidovudine

• Myelosuppression, including anemia and
  neutropenia
• GI intolerance, headaches, and insomnia

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Other NRTIs

• Didanosine- synthetic deoxy-adenosine analog
  causes pancreatitis
• Lamivudine- cytosine analog
• Zalcitabine- cytosine analog causes peripheral
  neuropathy
• Stavudine- thymidine analogcauses peripheral
  neuropathy
• Abacavir- guanosine analog more effective than
  the other agents fatal hypersensitivity
  reactions can occur

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Nucleotide Inhibitors

• Tenofovir
• Adefovir

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Tenofovir

• An acyclic nucleoside phosphonate analog of
  adenosine
• M.O.A.- competitively inhibits HIV reverse
  transcriptase and causes chain termination after
  incorporation into DNA
• Uses in combination with other antiretrovirals
  for HIV-1 suppression

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Adefovir

• An analog of adenosine monophosphate
• Phosphorylated by cellular kinases
• M.O.A. - Competitively inhibits HBV DNA
  polymerase and results in chain termination after
  incorporation into viral DNA
• Uses - Hepatitis B
• Side effects - nephrotoxicity

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Non-nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)

• Nevirapine
• Delavirdine
• Efavirenz

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Mechanism of Action NNRTIs

• Bind to site on viral reverse transcriptase,
  different from NRTIs
• results in blockade of RNA and DNA dependent DNA
  polymerase activity
• do not compete with nucleoside triphosphates
• do not require phosphorylation
• these drugs can not be given alone
• substrates and inhibitors of CYP3A4

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Nonnucleoside Reverse Transcriptase Inhibitors
(NNRTIs)

• Nevirapine- prevents transmission of HIV from
  mother to newborn when given at onset of labor
  and to the neonate at delivery
• Delavirdine- teratogenic, therefore can not be
  given during pregnancy
• Efavirenz- teratogenic, therefore can not be
  given during pregnancy

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Protease Inhibitors

• Indinavir
• Ritonavir
• Saquinavir
• Nelfinavir
• Amprenavir

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Protease Inhibitors

• The protease enzyme cleaves precursor molecules
  to produce mature, infectious virions
• these agents inhibit protease and prevent the
  spread of infection
• These agents cause a syndrome of altered body fat
  distribution, insulin resistance, and
  hyperlipidemia

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Accumulation of fat at the base of the neck in a
patient receiving a protease inhibitor
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Indinavir and Ritonavir

• M.O.A. Specific inhibitors of the HIV-1 protease
  enzyme
• M.O.R. mediated by expression of multiple and
  variable protease amino acid substitutions
• Side Effectshyperbilirubinemia
• Contraindicationsinhibitor/substrate for CPY3A4,
  do not give with antifungal azoles

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Saquinavir

• A synthetic peptide-like substrate analog
• inhibits HIV-1 protease
• prevents cleavage of viral polyproteins

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Nelfinavir and Amprenavir

• M.O.A. Specific inhibitors of the HIV-1 protease
  enzyme
• M.O.R. mediated by expression of multiple and
  variable protease amino acid substitutions
• Less cross-resistance with Amprenavir
• Side Effects diarrhea and flatulence
• Amprenavir can cause Stevens-Johnson syndrome
• Contraindications inhibitor/substrate for CPY3A4

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Fusion Inhibitors

• Enfuvirtide (T-20)- binds to the gp41 subunit of
  the viral envelope glycoprotein, preventing the
  conformational changes required for fusion of the
  viral and cellular membranes
• By blocking fusion (entry into cell), FUZEON
  prevents HIV from infecting CD4 cells

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Integrase Inhibitors

• Raltegravir
• M.O.A. Inhibits the final step in integration of
  strand transfer of the viral DNA into our own
  host cell DNA.
• Side Effects nausea, headache and diarrhea
• Raltegravir, in combination with other
  antiretrovirals, is approved for therapy of
  treatment-experienced patients with evidence of
  viral replication despite ongoing antiretroviral
  drug therapy.

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Anti-Hepatitis Agents

• Lamivudine -Nucleoside Reverse Transcriptase
  Inhibitor (NRTI)
• Adefovir -Nucleotide Inhibitor
• Interferon Alfa
• Pegylated Interferon Alfa
• Ribavirin

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Interferons

• Interferon Alfa
• Endogenous proteins
• induce host cell enzymes that inhibit viral RNA
  translation and cause degradation of viral mRNA
  and tRNA
• Bind to membrane receptors on cell surface
• May also inhibit viral penetration, uncoating,
  mRNA synthesis, and translation, and virion
  assembly and release

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Interferons

• Pegylated interferon Alfa
• A linear or branced polyethylene gylcol (PEG)
  moiety is attached to covalently to interferon
• Increased half-life and steady drug
  concentrations
• Less frequent dosing
• Tx chronic hepatitis C in combination with
  ribavirin

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Ribavirin

• A guanosine analog
• phosphorylated intracellularly by host enzymes
• inhibits capping of viral messenger RNA
• inhibits the viral RNA-dependent RNA polymerase
• inhibits replication of DNA and RNA viruses

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Anti-Influenza Agents

• Amantadine
• Rimantadine
• Zanamivir
• Oseltamivir

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Amantadine and Rimantadine

• cyclic amines
• inhibit the uncoating of viral RNA therefore
  inhibiting replication
• resistance due to mutations in the RNA sequence
  coding for the structural M2 protein
• used in the prevention and treatment of Influenza
  A

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Zanamivir and Oseltamivir

• Inhibits the enzyme neuraminidase
• interfere with release of progeny influenza virus
  from infected to new host cells, thus halting the
  spread of infection within the respiratory tract
  .
• inhibit the replication of influenza A and
  Influenza B
• treats uncomplicated influenza infections
• administered intranasally

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Antifungal Agents
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Fungal Infections

• Develop due to a loss of mechanical barriers
  (i.e. burns,major surgery) or immunodeficiency
  (chemotherapy,organ transplant, AIDS)
• fungal infections may be superficial or systemic
• Fungi possess different ribosomes, cell wall
  components, and discrete nuclear membrane

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Fungi can infect..
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Commonly isolated fungi

• Dermatophytes
• Thermally dimorphic fungi
• Candida
• Aspergillus
• Cryptococcus
• Zygomycetes
• ...

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Pathogen Fungi

• Yeasts (Cryptococcus Neoformans)
• II. Yeast like (Candida Albicans)
• III. Filamantous a- Epidermophytons,
  Trichophyton,Microsporum b- Aspergillus c-
  Penicillium mold
• IV. Dimorphic (Blastomyces, Histoplasma,
  Coccidioid, Sprothrix)

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• The superficial mycoses
• Dermatophytic infections
• Epidermophyton spp.,
• Trichophyton spp., and
• Microsporum spp.
• Candidiasis
• Candida albicans

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Systemic Mycosis

• Sytemic mycoses tend to be serious and chronic.
• Many effective drugs are extremely toxic.
• Major drugs polyenes, imidazoles and
  antimetabolites

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Anti-fungal agents

• Anti-fungal therapy can be divided into two
  categories
• treatment of serious systemic (deep) mycosis
• superficial mycosis involving skin and mucous
  membranes

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Major drugs

• Polyenes Amphotericin B, nystatin
• Imidazoles Ketoconazole, miconazole
• Antimetabolite Flucytosine

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Typical infections and drugs frequently used are
as follows

• Systemic candidiasis AmpB and/or 5-FU, Keto,
  Mic, Flu
• Cryptococcosis (meningitis) AmpB 5-FU, Mic,
  Flu better
• Systemic aspergillosis AmpB and/or 5-FU
• Blastomycosis AmpB, Keto, Itra
• Histoplasmosis AmpB, Keto, Flu
• Coccidioidomycosis AmpB, Keto, Itra
• Paracoccidioidomycosis AmpB, Keto, Itra

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List of drugs

• Systemic
• Amphotericin B Dapsone Fluconazole
• Flucytosine Griseofulvin Itraconazole
• Ketoconazole Miconazole KI

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Topical drugs

• Amphotericin B Carbol-Fuchsin Ciclopirox
•   Clotrimazole Econazole Haloprogin
•   Ketoconazole Mafenide Miconazole
•   Naftifine Nystatin
  Oxiconazole
•   Silver sulfadiazine Sulconazole Terbinafine
  
• Tioconazole Tolnaftate Undecylenic
  acid

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Vaginal drugs

• Butoconazle Clotrimazole Econazole
• Gentian violet Miconazole Nystatin
• Terconazole Tioconazole

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Fig. 1 Mode action of antifungal drugs
Site of Action of Antifungal Agents
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Amphotericin B

• Amphotericin B is a polyene antibiotic isolated
  from Streptomyces nodosus. It contains a
  macrolide ring and an aminosugar, mycosamine.

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Structure and chemical characteristics

• poorly water soluble
• administered by IV infusion (0.1 mg/ml) or (0.3
  mg/ml) in 5 dextrose
• extremely unstable in solution, particularly in
  normal saline.

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Mode of action

• affinity for membranes that have higher content
  of ergosterol
• forms a channel through the membrane that allows
  the passage of potassium and other small
  molecules
• resistance is rare and slow to develop

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Pharmacokinetics

• Poorly crosses cell membranes, absorbed from
  the gut and penetration into the eye, CSF, and
  joint capsules
• For treatment of meningitis, it must be given
  intrathecally
• given only via IV injection or intrathecally

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Adverse effects

• renal toxicity both predictable and dose
  related
• usually reversible
• Renal function must be monitored
• Treatment 6 to more than 24 weeks

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Flucytosine

• a synthetic agent chemically related to
  fluorouracil and floxuridine, both anticancer
  drugs
• an antimetabolite

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Mode of action

• converted to 5-fluorouracil (5-FU) which inhibits
  thymidylate synthetase
• Thymidine is required for DNA synthesis.
• Vertebrate have little of the enzyme required to
  convert flucytosine to the active antimetabolite,
  5-FU.

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Pharmacokinetics

• rapid and complete absorption after oral
  administration
• distributes widely throughout the body fluids,
  including the CSF
• treatment meningitis caused by Candida and
  Cryptococcus spp.

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Adverse effects

• causes bone marrow depression and
  gastrointestinal disturbances.
• Bone marrow depression leukopenia, anemia,
  and thrombocytopenia
• Gastrointestinal disturbances nausea, vomiting,
  and diarrhea

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Adverse effects

• CNS toxicity headache, drowsiness, confusion,
  vertigo, and hallucinations
• rapid development of resistance during therapy
• not used as a single agent

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Azole derivatives

• subdivided into two categories imidazoles and
  triazoles
• imidazoles
• - Ketoconazole and miconazole
• - used to treat systemic fungal infections
• triazoles Itraconazole and fluconazole

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Mode of action

• Azoles inhibit cytochrome-P450 activity
• decreases conversion of 14-alpha- methylsterols
  to ergosterol
• failure of ergosterol synthesis causes altered
  membrane permeability leading to loss of ability
  to maintain a normal intracellular environment.

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Effects

• inhibit transformation of blastospores into
  invasive mycelial form in C. albicans
• inhibit the cytochrome function may also be the
  basis of their interference with steroid
  biosynthesis
• higher doses hypoadrenal cortical activity and
  reduced libido
• The effects are reversible.

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Clotrimazole

• intended for topical use.
• toxic when given systemically.
• useful for dermatophytic infections, cutaneous
  candidiasis, and candida infections of mucous
  membranes and mucocutaneous junctions

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Clotrimazole (cont.)

• treatment may require two to four weeks.
• for vaginal candidiasis poor compliance with
  complex, long regimens has led to using very high
  doses for one to three treatments.
• Erythema, urticaria, pruritus, stinging, and
  blistering may be seen.

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Ketoconazole

• a relatively new drug
• much less toxic than amphotericin B
• used orally as well as parenterally for systemic
  infections

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Pharmacokinetics

• is best absorbed from solutions that have low pH
• Is rapidly absorbed and distributed uniformly
  throughout the body

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Adverse effects

• 1. Hepatotoxicity has been reported in 1 of
  10,000 patients and usually reversible
• 2. Adrenocortical suppression with high doses
• - serum testosterone levels
• - no specific mention of effect on estrogen
  or progesterone synthesis
• - depression of testosterone and adrenal
  steroid synthesis gynecomastia in males

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Miconazole

• similar to ketoconazole, but less able to cross
  membranes and more toxic.
• must be used by infusion for systemic effects.
• does not cause hepatotoxicity
• associated with frequent occurrence of
  hypersensitivity (fever and chills, skin rash or
  itching), and phlebitis (redness, swelling, or
  pain at injection site).

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Itraconazole

• another imidazole that has been introduced
  recently for use in human medicine
• used in veterinary medicine

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Allylamines (fungicidal)

• Inhibit squalene-2,3-epoxidase
• for dermatophytes

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Terbinafine

• Metabolized then excreted in urine
• Inhibits squalene 2, 3- epoxidase.
• Squalene is cidal to sensitive organisms.
• Used orally for dermatophytes
• Metabolized
• Adverse effects include hepatitis and rashes.
  Both are rare.
• Naftifine (for topical use)

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Potassium iodide

• an old drug that is still the drug of choice for
  cutaneous-lymphatic sporotrichosis
• Veterinarians also use the drug for
  actinomycosis.

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Adverse effects

• hypothyroidism and iodism
• Signs include brassy taste, rhinitis, coryza,
  salivation, lacrimation, sneezing, burning of
  mouth and throat, ocular irritation,
  sialadenitis, and dermal lesions.

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Griseofulvin

• a systemic antifungal used to treat topical
  ringworm infections, e.g., onychomycosis, Tinea
  capitis, Tinea pedis, etc.
• many Trichophyton spp., Microsporum spp. and
  Epidermophyton spp. are susceptible.

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Structure and chemistry

• derived from Penicillium griseofulvum
• is poorly water soluble and requires bile salts
  for solubilization in the gut.

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Mode of Action

• disrupts mitotic spindle structure to lead to
  metaphase arrest.
• sufficient to inhibit growth of fungi (drug is
  static), preventing them from invading.
• as the skin, hair, or nail is replaced, the
  fungus is shed.

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Pharmacokinetics

• used orally
• absorption is best with high fat meals to aid in
  solubilizing the drug
• unabsorbed drug is eliminated in the feces
• small amount is shed in dead skin and hair

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Adverse effects

• causes hepatomas in mice and thyroid tumors rats
• are not common, but include confusion,
  hypersensitivity (skin rash, hives, or itching),
  oral thrush (soreness or irritation of mouth or
  tongue), and photosensitivity

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Whitfield's Ointment

• represents keratolytic agents
• consists of 3 salicylic acid plus 6 benzoic
  acid.
• no significant anti-fungal activity, but helps
  remove keratinous layer to aid penetration of
  anti-fungals.

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Properties of the important antifungal agents.
Target Chemical Group Examples Mode of Action
Cell Membrane Synthesis Azoles Miconazole, Ketoconazole, Fluconazole Inhibition of Ergosterol
Function Polyenes Nystatine, Amphotericic B Bind to Sterols in cell membrane, causing leakage of cellular components and cell death.
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Properties of the important antifungal agents
(cont.)
Target Chemical Group Examples Mode of Action
Nucleic acid Synthesis Pyrimidines Flucytosine (5-FC) Deaminated in cell to 5- fluro uracil which ultimately inhibits DNA synthesis
Function Benzofurans Griseofulvin Appears to inhibit nucleic acid synthesis, microtubule assembly, chitin synthesis
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The End