antiviral antifungal agents n.
Download
Skip this Video
Download Presentation
ANTIVIRAL/ANTIFUNGAL AGENTS

Loading in 2 Seconds...

play fullscreen
1 / 136

ANTIVIRAL/ANTIFUNGAL AGENTS - PowerPoint PPT Presentation


  • 281 Views
  • Uploaded on

ANTIVIRAL/ANTIFUNGAL AGENTS. MA. LENY ALDA G. JUSAYAN, MD Department of Pharmacology. ANTIVIRAL AGENTS. VIRUSES: Single or double stranded DNA or RNA enclosed in a protein – CAPSID Obligate intracellular parasite Replication depends on synthetic processes of the host cell

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'ANTIVIRAL/ANTIFUNGAL AGENTS' - ballari


Download Now An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
antiviral antifungal agents

ANTIVIRAL/ANTIFUNGAL AGENTS

MA. LENY ALDA G. JUSAYAN, MD

Department of Pharmacology

antiviral agents
ANTIVIRAL AGENTS

VIRUSES:

  • Single or double stranded DNA or RNA enclosed in a protein – CAPSID
  • Obligate intracellular parasite
  • Replication depends on synthetic processes of the host cell
  • Antiviral drugs must either block entry or exit from cell or be active inside the host cell
viral replication
VIRAL REPLICATION:
  • Adsorption and penetration into susceptible host cells
  • Uncoating of viral nucleic acid
  • Synthesis of early regulatory proteins
  • Synthesis of RNA or DNA
  • Synthesis of late regulatory proteins
  • Assembly (maturation) of viral particles
  • Release from cells
acyclovir
ACYCLOVIR
  • Acyclovir (9-[2-hydroxy) methyl]-9-H- guanine
  • Acyclic guanosine derivative against HSV1, HSV2, & VZV
  • Weaker activity against EBV, CMV, Human Herpes Virus 6
mechanism of action
MECHANISM OF ACTION:
  • REQUIRES 3 PHOSPHORYLATION STEPS:
    • Converted to monophosphate derivative by virus-specified thymidine kinase
    • Converted to di and triphosphate compounds by the host’s cellular enzymes
    • Acyclovir triphosphate inhibits viral DNA synthesis
slide9
Cont.
  • Acts as a chain terminator because it lacks 3’ hydroxyl group
  • Competitive inhibition of deoxyGTP for viral DNA polymerase

RESISTANCE:

  • HSV: absence of partial production of viral thymidine kinase, altered thymidine kinase substrate specificity, altered viral DNA polymerase
  • VZV: mutation in VZV thymidine kinase , mutations in viral DNA polymerase
pharmacokinetics
PHARMACOKINETICS:
  • Oral bioavailability ranges from 10-30% and decreases with increasing dose
  • Relative oral bioavailability increases to 3-5 fold approx. 70% following valacyclovir administration
  • Distributes widely in body fluids including vesicular fluid, aqueous humor & CSF
  • Concentrated in breast milk, amniotic fluid, & placenta
  • Percutaneous absorption is low
therapeutic uses
THERAPEUTIC USES:
  • First and recurrent genital herpes:
    • 200 mg 5x daily for 10 days – oral
    • 5 mg/kg per 8 hrs – IV
    • Recurrent: 400 mg 2x daily or 200 mg 3x daily
therapeutic uses1
THERAPEUTIC USES:
  • ACUTE HERPES ZOSTER (SHINGLES)
  • SYSTEMIC ACYCLOVIR PROPHYLAXIS
  • HSV ENCEPHALITIS
  • VARICELLA ZOSTER VIRUS INFECTION
  • CMV PROPHYLAXIS
side effects
SIDE EFFECTS:
  • TOPICAL PREPARATIONS- mucosal irritation & transient burning to genital lesions
  • ORAL – nausea, diarrhea, rash, headache,renal insufficiency, neurotoxicity
  • IV- renal insufficiency, CNS side effects
penciclovir
PENCICLOVIR
  • Penciclovir (9-[4-hydroxy-3-hydroxymethylbut-1-yl]guanine
  • An acyclic guanine nucleoside
  • Active metabolite of famciclovir
  • Spectrum of activity & potency against HSV & VZV is similar to acyclovir
  • Inhibitory activity to HBV
mechanism of action1
MECHANISM OF ACTION:
  • Inhibitor of viral DNA synthesis
  • Initially phosphorylated by viral thymidine kinase
  • Penciclovir triphosphate is a competitive inhibitor of viral DNA polymerase
  • 100 fold less potent in inhibiting DNA polymerase than acyclovir but present in higher concentration and prolonged periods in infected cells
therapeutic uses2
THERAPEUTIC USES:
  • Intravenous form- 5 mg/kg per 8-12 hrs for 7 days is comparable to acyclovir in tx of mucocutaneous HSV infection
  • 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
side effects1
SIDE EFFECTS:
  • Mutagenic at high concentrations
  • No clinically important drug interactions have identified
famciclovir
FAMCICLOVIR
  • Diacetyl ester prodrug of 6 deoxy penciclovir and lacks intrinsic viral activity
  • Oral form is approved for managing HSV & VZV infections
  • First episode genital herpes – 250 mg TID x 5-10 days
  • Recurrent genital herpes – 250 mg BID for 1 year
  • Herpes zoster of 3 days – 500 mg TID x 10 days is as effective as acyclovir in reducing healing time and zoster asso. pain
famciclovir1
FAMCICLOVIR:
  • Comparable to valacyclovir in treating zoster and reducing associated pain in older adults
  • 500 mg TID x 10 days is comparable to high dose of acyclovir in treating zoster in immunocompromised patients & in opthalmic zoster
  • Associated with dose-related reductions in Hepatitis B Virus DNA and transaminase levels in patients with chronic HBV hepatitis
trifluridine
TRIFLURIDINE
  • Flourinated pyrimidine nucleoside that has an in vitro inhibitory activity against HSV 1 & 2 , CMV, vaccinia certain adenoviruses
  • Inhibits viral DNA synthesis
  • Phosphorylated intracellularly into its active form by cellular enzymes
  • Incorporation into both viral and cellular DNA prevents its systemic use
mechanism of action2
MECHANISM OF ACTION:
  • Trifluridine monophosphate irreversibly inhibits thymidylate synthetase
  • Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate incorporation into DNA by DNA polymerases
clinical uses
CLINICAL USES:
  • Primary keratoconjunctivitis & recurrent epithelial keratitis due to HSV 1 & 2
  • Topical trifluridine is more active than idoxuridine & comparable to vidarabine in HSV ocular infections
adverse effects
ADVERSE EFFECTS:
  • Discomfort upon instillation
  • Palpebral edema
  • Hypersensensitivity reaction, irritations & superficial punctate or epithelial keratopathy
valacyclovir
VALACYCLOVIR
  • L- valyl ester of acyclovir
  • Rapidly converted to acyclovir after oral administration
  • Serum levels are 3-5x greater than acylcovir
  • Treatment of primary and recurrent genital herpes & herpes zoster infections
  • Prevents CMV disease in postransplant patients
vidarabine
VIDARABINE
  • Adenosine analog with an in vitro activity against HSV, VZV, & CMV
  • Phosphorylated intracellularly by host enzymes to form ara-ATP and then inhibits viral DNA polymerase
  • Vidarabine triphosphate is incorporated into both vial & cellular DNA
  • Rapidly metabolized in vivo to hypoxanthine arabinoside through removal of 6-amino group by adenosine deaminase – dec. viral activity
slide26
Cont.
  • 3% ointment – acute keratoconjunctivitis, superficial keratitis, recurrent epithelial keratitis (HSV1 &2)
  • IV vidarabine – HSV encephalitis,neonatal herpes, VZV infection
ganciclovir
GANCICLOVIR
  • (9-[1,3-dihydroxy-2-prpoxymethyl]guanine)
  • Cyclic guanosine analog that requires triphosphorylation for activation prior to inhibiting viral DNA polymerase
  • Similar structure to acyclovir except in having additional hydroxymethyl group on the acyclic side chain
mechanism of action3
MECHANISM OF ACTION:
  • Monophosphorylated intracellularly by a virus-induced enzyme
  • Phosphorylation is catalyzed by a viral thymidine kinase during HSV, phosphotransferase encoded gene during CMV infection
  • Ganciclovir di & triphosphate formed by cellular enzymes
  • Triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA, inhibits viral rather than cellular DNA polymerase
  • Viral DNA incorporation causes cessation of DNA chain elongation
pharmacokinetics1
PHARMACOKINETICS:
  • Oral bioavailability is 6-9% following ingestion with food & less in the fasting state
  • CSF concentration are approximately 50 % of those in serum
clinical uses1
CLINICAL USES:
  • Delay progression of CMV retinitis in AIDS
  • CMV colitis & esophagitis
  • CMV infection in transplant patient
  • CMV pneumonitis
  • CMV retinitis
  • CMV, HSV1, HSV2, EBV & HHV-8
adverse reactions
ADVERSE REACTIONS:
  • Myelosuppression
  • CNS toxicity
  • Vitreous hemorrhage, retinal detachment
  • Neutropenia (2nd wk)
  • CNS (headache, behavioral changes, convulsions, coma)
  • Infusion related phlebitis, azotemia, anemia, rash, fever, liver function test abnormalities
valganciclcovir
VALGANCICLCOVIR
  • L- valyl ester prodrug of ganciclovir
  • Hydrolyzed to active compound ganciclovir by intestinal & hepatic enzymes
  • Well absorbed & rapidly metabolized in intestinal walls & liver to gancilovir
  • CMV retinitis
cidofovir
CIDOFOVIR
  • (1-[(S)-3-hydroxy-2-(phosphonomethoxy)-propyl]cytosine dihydrate)
  • Cytidine nucleoside analog with inhibitory activity against human herpes, papiloma, polyoma, pox, & adenoviruses
  • Phosphorylation to active diphosphate is independent of viral enzymes
  • After phosphorylation it acts as potent inhibitor to viral DNA polymerase
pharmacokinetics2
PHARMACOKINETICS:
  • Penetration into the CNS or eye have not been well characterized
  • Terminal half-life is 2.6 hrs , cidofovir diphosphate half-life is 17-65 hrs
  • IV administration must be administered with probenicid to block active tubular secretion & decrease nephrotoxicity
clinical uses2
CLINICAL USES:
  • CMV, HSV 1, HSV 2, VZV, EBV, HHV-6, HHV-8, adenoviruses, poxvirus, poliomyxoviruses, HPV
  • CMV retinitis
  • Polyoma virus associated progressive multifocal leukoencephalopathy syndrome associated with AIDS
  • Topical – recurrent genital herpes, anogenital warts
foscarnet
FOSCARNET
  • Phosphonoformic acidinorganic pyrophosphate analog that inhibits viral DNA polymerase, RNA polymerase & HIV transcriptase directly without requiring activation by phosphorylation
  • Taken up slowly by cells & does not undergo significant intracellular metabolism
  • Reversibly blocks the pyrophosphate binding site of the viral polymerase
  • Inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates
side effects2
SIDE EFFECTS:
  • Nephrotoxicity
  • Symptomatic hypocalcemia
  • Saline loading may reduce the risk of nephrotoxicity
  • Concurrent administration with pentamidine exacerbates both nephrotoxicity & hypocalcemia
clinical uses3
CLINICAL USES:
  • CMV retinitis, colitis, esophagitis
  • Acyclovir- resistant HSV infection & VZV infection
  • HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV
fomiversen
FOMIVERSEN
  • 21mer-phosphorothioate oligonucleotide
  • First FDA approved antisense therapy Binding to target mRNA results in inhibiton of immediate early region 2 protein synthesis – inhibiting viral replication
  • Injected intravitreally in CMV retinitis
nucleoside reverse transcriptase inhibitors
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS:
  • Competitive inhibition of HIV 1 reverse transcriptase & can be incorporated into the growing viral DNA chain to cause termination
  • Bind directly to HIV reverse transcriptase, block both DNA & RNA dependent DNA polymerase activities
  • Prevent transfer of information that would allow virus to replicate & survive
  • Activity against HIV 1, HIV 2
  • Lactic acidosis & severe hepatomegaly with steatosis
zidovudine azithymidine azt
ZIDOVUDINE (Azithymidine, AZT)
  • Deoxythymidine analog
  • Decrease rate of clinical disease progression & prolong survival of HIV infected individuals
  • Well absorbed from the gut & distributed to most body tissues & fluids
  • Eliminated by renal excretion following glucorinadation in the liver
  • Combination therapy with other retroviral agents enhance potency and delay resistance
clinical uses4
CLINICAL USES:
  • HIV – associated dementia & thrombocytopenia
  • Reduce rate of vertical transmission (mother-newborn) by 23%
adverse effects1
ADVERSE EFFECTS:
  • Myelosuppression – most common
  • Thrombocytopenia, hyperpigmentation of nails, myopathy, anxiety, confusion & tremulousness
  • Fatal lactic acidosis & severe hepatomegaly w/ steatosis
didanosine ddl
DIDANOSINE (ddl)
  • Synthetic analog of deoxyadenosine
  • Activity is potentiated by hydroxyurea due to depletion of intraocular pools of dATP
  • Chewable, dispersable tablet, enteric coated
  • Contains phenylalanine & Na
  • Should be taken on an empty stomach
  • Food, fluroquinolones & tetracycline should be given 2 hrs before didanosine
adverse effects2
ADVERSE EFFECTS:
  • Dose –dependent pancreatitis
  • Painful peripheral distal neuropathy
  • Diarrhea, hepatitis, esophageal ulceration, cardiomyopathy
  • CNS toxicity
  • Precipitate gouty attacks
  • Optic neuritis
lamivudine 3tc
LAMIVUDINE (3TC)
  • Cytosine analog ,synergistic with other antiretroviral nucleoside – Stavudine, Zidovudine
  • Oral bioavailability exceeds 80% & is not food dependent
  • Used in combination therapy
  • Approved for the treatment of chronic Hepatitis B infection
zalcitabine ddc
ZALCITABINE (ddC)
  • Cytosine analog with synergistic anti-HIV1 activity with a variety of antiretrovirals against both zidovudine sensitive & resistant strains
  • Associated with dose-dependent peripheral neuropathy
  • Oral & esophageal ulcerations
  • Increase bioavailability in combination w/ probenicid or cimetidine
  • Decrease bioavailability in combination w/ antacids & metoclopramide
stavudine d4t
STAVUDINE (D4T)
  • Thymidine analog
  • High oral bioavailability, not food dependent
  • Dose-related peripheral sensory neuropathy
  • Pancreatitis, arthralgias, elevation of serum aminotransferases
  • Phosphorylation is reduced by stavudine
abacavir
ABACAVIR
  • Guanosine analog
  • Well absorbed during oral administration
  • Metabolized by alcohol dehydrogenase& glucuronosyltransferase to inactive metabolites
  • Fatal hypersensitivity reactions
  • Nausea, vomiting, diarrhea, headache, fatigue
  • Hyperglycemia, hypertriglyceridemia & lactic acidosis
tenofovir
TENOFOVIR
  • Competitively inhibits HIV reverse transcriptase & cause chain termination after incorporation to DNA
  • Indicated for use in combination with other antiretroviaral agents
non nucleoside reverse transcriptase inhibitor
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR:
  • Bind directly to a site on the HIV –1 reverse transcriptase
  • blockade of RNA & DNA dependent DNA polymerase activities
  • Binding site is near but distinct from that of the NRTI’s
  • Neither compete w/ nucleoside triphosphate nor require phosphorylation to be active
nevirapine
NEVIRAPINE
  • Oral bioavailability is > 90%
  • Not food dependent
  • Used as a component of a combination antiretroviral regimen
  • Effective in the prevention of transmission of HIV from mother to newborn
  • Causes severe life threatening rashes
delavirdene
DELAVIRDENE
  • Oral bioavailability of about 85 %
  • Metabolized to inactive metabolites by the CYP3A & CYP2D6 P450 enzymes
  • Plasma concentrations are reduced by antacids, didanosine, phenytoin, phenobarbital, carbamazepine, rifabutin, rifampin, nelfinavir & saquinavir
  • Concentrations increased by clarithromycin, fluoxetine, & ketoconazole
efavirenz
EFAVIRENZ
  • Principally metabolized by CYP3A4 &CYP2B6 to inactive hydroxylated metabolites
  • Principal adverse effects: CNS (dizziness, drowsiness, insomnia, headache, confusion, amnesia, agitation, delusions, depression, nightmares, euphoria)
  • Pyschiatric symptoms
  • rashes
protease inhibitors
PROTEASE INHIBITORS
  • Responsible for cleaving precursor molecules (immature budding particles)
  • Results in the production of immature, non-infectious viral particles
  • Block protease activity within the HIV virus – essential for the maturation
  • Associated w/ spontaneous bleeding in hemophilia A & B
saquinavir
SAQUINAVIR
  • Saquinavir H- hard gel capsule – poor bioavailability, should be taken w/n 2 hrs after a fatty meal
  • Saquinavir S – soft gel capsule – improved absorption 3x than hard gel capsule
  • Subject to first pass-metabolism by CYP3A4
  • Levels are increased by ritonavir, nelfinavir, delavirdene, indinavir, ketoconazole, clarithromycin, & grapefruit juice
ritonavir
RITONAVIR
  • An inhibitor of HIV 1 & HIV 2 proteases
  • High bioavailability that is increased with food
  • Common adverse effects: GIT disturbances, paresthesias, inc aminotransferase level, altered taste, hypertriglyceridemia
indinavir
INDINAVIR
  • Specific inhibitor of the HIV- 1 & HIV-2 proteases
  • Higher CSF penetration
  • Must be consumed in empty stomach for maximal absorption
  • Most common adverse effects are indirect hyperbilirubinemia & nephrolithiasis due to crystalization
nelfinavir
NELFINAVIR
  • Higher absorption in the fed state
  • Common adverse effects: diarrhea & flatulence
amprenavir
AMPRENAVIR
  • Rapidly absorbed from the GIT & can be taken w/ or w/o food
  • High fat meals decrease absorption
  • Common adverse effects: nausea, vomiting, diarrhea, perioral paresthesias, rash
  • Steven johnson’s syndrome
  • Inhibits CYP3A4 activity
enfuvirtide t 20
ENFUVIRTIDE (T-20)
  • Newly approved antiretroviral agent
  • Blocks entry into the cell
  • Administered subcutaneously in combination with other retroviral agents
lamivudine
LAMIVUDINE
  • Can be safely administered to patients with decompensated liver disease
adefovir
ADEFOVIR
  • Phosphorylated by cellular kinases to the active diphosphate metabolite
  • Competitively inhibits HBV DNA polymerase
  • Chain termination after incorporation into viral replication
interferon alfa
INTERFERON ALFA
  • Endogenous proteins that exert complex antiviral immunomodulatory & antiproliferative activities through cellular metabolic process
  • Enzyme induction, suppression of cell proliferation, immunomodulatory activities & inhibition of viral replication
  • Inhibition of viral penetration & uncoating
  • Treatment of both HBV & HCV
interferon alpha 2a
INTERFERON ALPHA 2a
  • Approved for the treatment of chronic hepatitis C, AIDS associated Kaposi’s sarcoma hairy cell leukemia, chronic myelogenous leukemia
interferon alpha 2b
INTERFERON ALPHA 2b
  • Only preparation licensed for treatment of HBV & acute HCV
  • Leads to loss of HbeAg, normalization of aminotransferases
  • Administered subcutaneously or intramuscularly
  • Hairy cell leukemia, malignant melanoma, follicular non-Hodgkin’s lymphoma, AIDS related kaposi’s sarcoma, & chronic hepatitis C
pegylated interferon alfa
PEGYLATED INTERFERON ALFA
  • Recently introduced for treatment of chronic hepatitis C
  • Longer termina t ½ with slower clearance
ribavirin
RIBAVIRIN
  • Guanosine analog that is phosphorylated intracellularly by host cell enzymes
  • Interferes w/ the synthesis of guanosine triphosphate
  • Inhibit capping of viral messenger RNA
  • Inhibit viral RNA dependent RNA polymerase of certain viruses
  • Influenza A, parainfluenza, RSV, paramyxoviruses, HCV & HIV 1
amantadine rimantadine
AMANTADINE/RIMANTADINE
  • (1-aminoadamantane hydrochloride)
  • -methyl derivative - rimantadine
  • Inhibits uncoating of viral RNA influenza A within infected cell thus preventing replication
  • Effectively reduce the duration of symptoms of influenza when administered w/n 48 hrs of onset
  • Primary target is M2 proteins
zanamivir oseltamivir
ZANAMIVIR/OSELTAMIVIR
  • Neuroaminidase inhibitors
  • Inhibits replication of both influenza A & B
  • 5 day course regimen for both influenza A & B
palivizumab
PALIVIZUMAB
  • Prevention of RSV in high risk infants

IMQUIMOD

  • Immune response modifier effective in topical treatment of external genitalia & perianal warts
amphotericn b
AMPHOTERICN B
  • Discovered by Gold & coworkers in 1956
  • Produced by Streptomyces nodosus
  • 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
  • Amphotericin polyene macrolide
  • Nearly insoluble in water
preparations
PREPARATIONS:
  • Colloidal suspension of amphotericin B & Na deoxycholate (DOC) –IV
    • 50 mg amphotericin B, 41 mg deoxycholate
    • Addition of electrolyte to infusion solution causes colloid to aggregate
  • Amphotericin B Colloidal Dispersion
    • contains roughly equimolar amounts of Amphotericin B & cholesteryl sulfate
    • Forms a colloidal solution when dispersed in aqueous solution
slide88
CONT.

3) Unilamellar Vessicle Formulation

  • Amphotercin B 50 mg + 350 mg of lipid in 10% molar ratio

4) Amphotericin B Lipid Complex

  • Amphotericin B 35% + dimyristolphosphatidylcholine & glycerol
antifungal activity
ANTIFUNGAL ACTIVITY:
  • Candida sp., C. neoformans, B. dermatidis, H. capsulatum, Sporothrix schenkii, C. immitis, Paracoccidioides brazilienzes, Aspergillus sp., Penicilium marneffei, Mucormycosis
  • Limited activity to Leishmania, braziliensis, Naegleria fowleri
  • No antibacterial activity
pharmacokinetics3
PHARMACOKINETICS:
  • Poorly absorbed from the GIT
  • Oral preparation is only effective in fungi within the lumen of the GIT
  • Serum t ½ is 15 days
  • Widely distributed in tissues
  • 2-3% CSF concentration
mechanism of action4
MECHANISM OF ACTION:
  • Antifungal activity depends on the binding with ERGOSTEROL
  • Alters the permeability of the cell by forming amphotericin B associated pores in the cell membrane
  • Combines with lipids along the double rich bond & associates with H2O molecules along the OH-rich side
  • Pores allow leakage of intracellular ions & macromolecules CELL DEATH
therapeutic uses3
THERAPEUTIC USES:
  • Candida esophagitis
  • Meningitis caused by coccidioides
  • Mucormycoses
  • Invasive aspergillosis
  • Extracutaneous sporothrichosis
  • Cryptococcosis
  • Candida cystitis
  • Mycotic corneal ulcers & keratitis
adverse reactions1
ADVERSE REACTIONS:
  • INFUSION-RELATED TOXICITY:
  • fever & chills, muscle spasms, vomiting, headache, & hypotension

B) SLOWER TOXICITY:

  • renal damage
    • Reversible renal injury
    • Irreversible renal injury- renal tubular injury
flucytosine 5 fc
FLUCYTOSINE (5-FC)
  • Discovered in 1957
  • Fluorinated pyrimidine related to florouracil & floxuridine
  • Spectrum of activity is narrower than that of amphotericin
pharmacokinetics4
PHARMACOKINETICS:
  • Available in oral preparation
  • Well absorbed (>90%) with serum
  • Concentration peaking 1-2 hrs
  • Poorly protein bound
  • Penetrates well body fluids & CSF
  • T ½ is 3-4 hrs
mechanism of action5
MECHANISM OF ACTION:
  • Taken up by fungal cells via CYTOSINE PERMEASE
  • Converted intracellularly to 5 FU 5-fluorodeoxyuridine monophosphate & 5-fluorouridine triphosphate inhibit RNA & DNA synthesis
slide97

Cytosine permease

5-Flucytosine

5-FU

UMP pyrophosphate

5-FUMP

5-FUDP

5-FUTP

5-F-dUMP

Ribonucleide reductase

RNA

Thymidine synthase

dTMP

DUMP

clinical use
CLINICAL USE:
  • Cryptococcal meningitis
  • Candida species
  • Dermatiaceous molds that cause chromoblastomycosis
adverse effects3
ADVERSE EFFECTS:
  • Leukopenia & thrombocytopenia
  • Rash
  • Nausea/vomiting, diarrhea, severe enterocolitis
azoles
AZOLES:
  • IMIDAZOLES :
    • Ketoconazole
    • Miconazole
    • Clotrimazole
  • TRIAZOLES:
    • Itraconazole
    • Fluconazole
    • Voriconzaole
mechanism of action6
MECHANISM OF ACTION:
  • Inhibition of sterol 14 α-demethylase
  • Impair the biosynthsesis of ergosterol for the cytoplasmic membraneaccumulation of 14-α-methylsterols
  • Impairing functions of membrane bound enzymes such as ATPase & enzymes of electron transport systeminhibits growth of fungi
  • Reduction of ergosterol synthesis by inhibition of cytochrome P450 enzymes
  • Specificity for fungal than human cytochrome P450 enzymes
clinical uses5
CLINICAL USES:
  • Candida species
  • Cryptococcus neoformans
  • Endemic mycoses

DRUG INTERACTIONS:

  • All azole drugs affect mammalian cytochrome P450 systems of enzymes
ketoconazole
KETOCONAZOLE
  • First oral azole introduced into clinical use
  • Increase propensity to inhibit mammalian cytochrome P450 enzymes
  • Less selective for fungal P450
  • Inhibition of mammalian P450 interferes with biosynthesis of adrenal & gonadal steroid hormones
  • Interaction with P450 enzymes can alter the metabolism of other drugs leading to enhanced toxicity
slide104
Cont.
  • Reaches the keratinocytes efficiently
  • Concentration in vaginal fluids is approaches that in plasma
therapeutic uses4
THERAPEUTIC USES:
  • Blastomycosis, histoplasmosis, coccidiodomycosis, pseudallescheriasis
  • Paracoccidiodomycosis, ringworm, tinea versicolor, chronic mucocutaneous candidiasis
  • Candida vulvovaginitis, oral & esophageal candidiasis
adverse reactions2
ADVERSE REACTIONS:
  • Dose-dependent anorexia, nausea, vomiting
  • Inhibits steroid biosynthesis in patients endocrine abnormalities
drug interactions
DRUG INTERACTIONS:
  • Increases cyclosporine levels
  • Enhances arrythmogenic effects of cissapride
  • H2 antagonists increases gastric pH, interfer with the absorption of ketoconazole
  • Rifamycins increased hepatic metabolism
itraconazole
ITRACONAZOLE
  • Available in capsule & solutions (oral & IV)
  • Capsule form is best absorbed in the fed state
  • Oral solution is best absorbed in the fasting state
  • Metabolized in the liver by the CYP3A4 isoenzyme system
  • Does not affect mammalian steroid synthesis
  • Reduced bioavailability when taken with rifamycins
slide109
Cont.
  • Azole of choice for dimorphic fungi histoplasma, blastomyces, sporothrix
  • Oral solution is effective for use in oropharyngeal & esophageal candidiasis
  • Onychomycosis can be treated with either 200 mg OD X 12 wks or as 200 mg BID X 1 wk out of each month
fluconazole
FLUCONAZOLE
  • Fluorinated bistriazole
  • Good water solubility & CSF penetration
  • Azole of choice in the treatment & secondary prophylaxis of cryptococcal meningitis
  • Available in oral & IV form
  • plasma concentrations of astemizole, cissapride, cyclosporine, rifampin, rifabutin, sulfonylureas, theophylline & warfarin
voriconazole
VORICONAZOLE
  • Newest triazole to enter clinical trials
  • Availabale in oral & IV
  • Well absorbed orally with bioavailability >90%
  • Low propensity to inhibit mammalian cytochrome P450
  • Same as itraconazole in its spectrum of action
  • Good activity against candida species
  • fluconazole-resistant species such as C. krusei, dimorphic fungi, pathogenic molds including aspergillus
griseofulvin
GRISEOFULVIN
  • Practically insoluble in water
  • Fungistatic in vitro for dermatophytes microsporum, epidermophytom & trichophyton
  • No effect on bacteria & other fungi
mechanism of action7
MECHANISM OF ACTION:
  • Production of multinucleate cells as`the drug inhibits fungal mitosis
  • Causes disruption of the mitotic spindle by interacting with polymerized microtubules
  • Deposited in the newly forming skin where it binds to keratin
  • Administered 2-6 wks for skin & hair infections
therapeutic uses5
THERAPEUTIC USES:
  • Mycotic disease of the skin, hair & nails due to Microsporum, Trichophyton, or Epidermophyton
  • Tinea capitis (M. canis)
  • Ringworm of the glabrous skin
  • Tinea corporis, cruris (T. rubrum, T. mentagrophytes)
  • Hyperlkeratosis (T. rubrum)
adverse reactions3
ADVERSE REACTIONS:
  • Allergic syndrome
  • hepatitis
terbinafine
TERBINAFINE
  • Synthetic allylamine
  • Available in oral formulation
  • Used in the treatment of dermatophytoses especially onychomycosis
  • Keratophillic, fungicidal
  • Inhibits the enzyme SQUALENE EPOXIDASE
  • Leads to the accumulation of the sterol squalene
  • OD X12 wks achieves 90% cure rate for onychomycosis
topical antifungal agents
TOPICAL ANTIFUNGAL AGENTS
  • Superficial fungal infections confined to the striatum corneum, squamous mucosa or cornea
  • Ringworm, candidiasis, tinea versicolor, tinea nigra, fungal keratitis
  • Not successful for mycoses of the nails & hair
  • No place for the treatment of subcutaneous mycosis
nystatin
NYSTATIN
  • Polyene macrolide
  • Structurally similar to Amphotericin B
  • Toxic for parenteral administration
  • Available in creams, ointments, suppositories
  • Oropharyngeal thrush, vaginal candidiasis, intertriginous candidal infections
amphotericin b
AMPHOTERICIN B
  • Topical form (Fungizone)
  • Cutaneous & mucocutaneous candidiasis
  • Lotion, ointment & cream
clotrimazole
CLOTRIMAZOLE
  • Available as 1% cream, lotion, & solution
  • 1% or 2% vaginal cream or vaginal tablets
  • Skin applications – BID
  • Vaginal applications – 100 mg tab OD at bedtime X 7 days or 200 mg OD X 3 days
miconazole
MICONAZOLE
  • Readily penetrates the striatum corneum of the skin
  • Persists for >4 days after application
  • Safe for use during pregnancy for vaginal use
  • Ointment, cream, solution, spray, powder or lotion
  • Vaginal cream, suppositories
  • Tinea pedis, tinea cruris, & tinea versicolor
ciclopiroxamine
CICLOPIROXAMINE
  • Broad spectrum
  • Fungicidal to C. albicans, E. flocosum, M. canis, T. mentagrophytes, T. rubrum
  • Inhibits the growth of Malassezia furfur
  • Penetrates the dermis
haloprogin
HALOPROGIN
  • Halogenated phenolic ether
  • Fungicidal to various species of Epidermophyton, Pityrosporum, Microsporum, Trichophyton & Candida
  • Poorly absorbed through the skin
  • Converted to thrichlorophenol in the body
  • Cream or solution BID X 2-4 wks
  • Principal use for tinea pedis
  • Tinea cruris, tinea versicolor, tinea corporis
naftifene
NAFTIFENE
  • Inhibit squalene-2,3- epoxidase
  • Inhibits biosynthesis of ergosterol
  • Fungicidal activity
  • 1% cream or gel
  • Topical treatment of tinea cruris & tinea corporis
  • Cutaneous candidiasis & tinea versicolor
undecyclenic acid
UNDECYCLENIC ACID
  • Yellow liquid with a characteristic rancid odor
  • Fungistatic, fungicidal w/ prolonged use
  • Foam, ointment, cream, powder, spray powder, soap & liquid
  • Ringworm, tinea pedis
benzoic acid salicylic acid
BENZOIC ACID & SALICYLIC ACID
  • Whitfield’s ointment
  • Combines fungistatic activity of benzoic acid w/ keratolytic action of salicylic acid
  • Mainly for the treatment of tinea pedis
  • Eradication occurs after the infectd stratum corneum is shed
  • Salicylate accelerates the desquamation
propionic acid caprylic acid
PROPIONIC ACID & CAPRYLIC ACID
  • Treatment of dermatomycoses
  • Low efficacy
potassium iodide
POTASSIUM IODIDE
  • Treatment of mucocutaneous sporotrichosis
post test
POST-TEST
  • Acyclovir A. Antiretroviral agent
  • Amantadine B. Anti-Herpes/VZV
  • Zidovudine C. Anti-CMV
  • Ganciclovir D. Anti-Influenza
  • Adefovir E. Anti-Hepatitis
  • Amphotericin B A. systemic infection
  • Griseofulvin B. mucocutaneous infection
  • Haloprogin C. topical
  • Ketoconazole
  • nystatin