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



Antiviral drugs must either block entry or exit from cell or be active inside the host cell

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

ANTI-HERPES/ ANTI VZV

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:

 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

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:

 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:

 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 USES:

 ACUTE HERPES ZOSTER (SHINGLES)  SYSTEMIC ACYCLOVIR PROPHYLAXIS  HSV ENCEPHALITIS  VARICELLA ZOSTER VIRUS INFECTION  CMV PROPHYLAXIS

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

(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 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 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 EFFECTS:

 Mutagenic at high concentrations  No clinically important drug interactions have identified

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

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

 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 ACTION:

 Trifluridine monophosphate irreversibly inhibits thymidylate synthetase  Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate incorporation into DNA by DNA polymerases

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:

 Discomfort upon instillation  Palpebral edema  Hypersensensitivity reaction, irritations & superficial punctate or epithelial keratopathy

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

 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

Cont.

 3% ointment – acute keratoconjunctivitis, superficial keratitis, recurrent epithelial keratitis (HSV1 &2)  IV vidarabine – HSV encephalitis,neonatal herpes, VZV infection

ANTI-CMV AGENTS

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 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

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 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:

 Myelosuppression  CNS toxicity  Vitreous hemorrhage, retinal detachment  Neutropenia (2 nd wk)  CNS (headache, behavioral changes, convulsions, coma)  Infusion related phlebitis, azotemia, anemia, rash, fever, liver function test abnormalities

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

 (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

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 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

 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 EFFECTS:

 Nephrotoxicity  Symptomatic hypocalcemia  Saline loading may reduce the risk of nephrotoxicity  Concurrent administration with pentamidine exacerbates both nephrotoxicity & hypocalcemia

CLINICAL USES:

 CMV retinitis, colitis, esophagitis  Acyclovir- resistant HSV infection & VZV infection  HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV

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

ANTIVIRAL DRUGS – DNA & RNA VIRUSES

DRUG Acylovir Pencyclovir

MECHANISM/ VIRAL SELECTIVITY Metabolized by thymidine kinase to triphosphate

CLINICAL USE

Herpes simplex 1 & 2, varicella zoster

VIRAL RESISTANCE UNDESIRABLE SIDE EFFECTS

Produce abnormal thymidine kinase Skin irritation, burning, crystalline nephropathy

PHARMACOKINETI CS

IV/PO. Administer slowly. CNS level=50% serum level. Decrease dose w/ kidney dysfunction Topical

Valacyclovir Idoxuridine Famciclovir Ganciclovir

Oral HSV (coldsores) L-valyl ester of acyclovir converted to acyclovir Phosphorylated metabolite incorporates into DNA causing strand breaks Phosphorylated by viral thymidine kinase to penciclovir triiphosphate Metabolized by thymidine kinase to triphosphate . Preferentially phosphorylated to active drug in CMV infected cells Herpes zoster (shingles) Herpes simplex keratitis. No effect on RNA viruses Shortens duration of herpes zoster & genital herpes CMV retinitis & severe systemic CMV infections Resistance develops Some resistant strains lack thymidine kinase. Cannot activate drug.

Nausea, headache Photophobia, irritation of conjunctiva & eyelid PO. Slightly better oral absorption than acyclovir Eyedrops No clear advantage over acyclovir Drug is a halogenated derivative of deoxyuridine Minimal toxicity. Headache PO. Decrease dose with renal dysfunction.

Granulocytopenia, thrombocytopenia IV/PO. Excreted unchanged in urine. Decrease dose with renal dysfunction.

NOTES Do not coadminister zidovudine (granulocyto penia) or imipenem cilastatin (seizures)

Cidofovir

Metabolized to diphosphate form. Otherwise like ganciclovir.

CMV retinitis Nephrotoxicity may be reduced by hydration & coadministration of Probenicid. Neutropenia.

Foscarnet Amantadine

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 Prevents virus from entering susceptible cells Treatment & prophylaxis of influenza A Depression, CNS toxicity, CHF, orthostatic hypotension, urinary retention PO. Excreted unmetabolized.

Rimantadine Ribavirin

Analog of amantadine , inhibits viral uncoating Unknown mechanism Prophylaxis in children RSV Fewer CNS side effects, risk of seizure Decreased pulmonary function.

PO. Prolonged elimination w/ renal or hepatic dysfunction Aerosol administration. Absorbed systemically.

May precipitate in ventilator tubing.

ANTIRETROVIRAL AGENTS

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)

 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 USES:

 HIV – associated dementia & thrombocytopenia  Reduce rate of vertical transmission (mother-newborn) by 23%

ADVERSE EFFECTS:

 Myelosuppression – most common  Thrombocytopenia, hyperpigmentation of nails, myopathy, anxiety, confusion & tremulousness  Fatal lactic acidosis & severe hepatomegaly w/ steatosis

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 EFFECTS:

 Dose –dependent pancreatitis  Painful peripheral distal neuropathy  Diarrhea, hepatitis, esophageal ulceration, cardiomyopathy  CNS toxicity  Precipitate gouty attacks  Optic neuritis

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)

 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)

 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

 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

NUCLEOTIDE INHIBITOR

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:

 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

 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

 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

 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

 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 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

 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

 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

 Higher absorption in the fed state  Common adverse effects: diarrhea & flatulence

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

FUSION INHIBITORS

ENFUVIRTIDE (T-20)

 Newly approved antiretroviral agent  Blocks entry into the cell  Administered subcutaneously in combination with other retroviral agents

ANTI-HEPATITIS AGENTS

LAMIVUDINE

 Can be safely administered to patients with decompensated liver disease

ADEFOVIR

 Phosphorylated by cellular kinases to the active diphosphate metabolite  Competitively inhibits HBV DNA polymerase  Chain termination after incorporation into viral replication

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

 Approved for the treatment of chronic hepatitis C, AIDS associated Kaposi’s sarcoma hairy cell leukemia, chronic myelogenous leukemia

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

 Recently introduced for treatment of chronic hepatitis C  Longer termina t ½ with slower clearance

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

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

ANTI-INFLUENZA AGENTS

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

 Neuroaminidase inhibitors  Inhibits replication of both influenza A & B  5 day course regimen for both influenza A & B

UNCLASSIFIED

PALIVIZUMAB

 Prevention of RSV in high risk infants

IMQUIMOD

•Immune response modifier effective in topical treatment of external genitalia & perianal warts

ANTIVIRAL DRUGS - RETROVIRUSES

DRUG MECHANISM & VIRAL SELECTIVITY CLINICAL USE VIRAL RESISTANCE UNDESIRABLE SIDE EFFECTS PHARMACO KINETICS 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 transmissio n of HIV Mutations in reverse transcriptase Headaches, nausea, myalgias, anemia, neutropenia, macrocytosis PO. Well absorbed, rapidly metabolized by liver Acetamino phen increases risk of hematolog ic 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 Stavudine Metabolized to stavudine triphosphate w/c inhibits HIV reverse transcriptase & DNA polymerase. Prevents DNA 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 Peripheral neuropathy PO Not indicated for initial monothera py of HIV

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 interaction s due to P450 competitio n Nevirapine Delavirdene Nob-nucleoside inhibitor of HIV reverse transcriptase HIV. Never as monothera py due to rapid developme nt of resistance Rapid resistance develops due to mutations in reverse transcriptas e Severe skin rash, fever, nausea, headache PO. Well absorbed. Nevirapine crosses placenta & has better CNS penetration than Delavirdene Delavirde ne failed to show clinical efficacy when added to didanosin e in clinical trial

ANTIFUNGAL AGENTS

SYSTEMIC ANTIFUNGAL DRUGS FOR SYSTEMIC INFECTION

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:

1) 2) • • 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

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:

 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

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 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 USES:

 Candida esophagitis  Meningitis caused by coccidioides  Mucormycoses  Invasive aspergillosis  Extracutaneous sporothrichosis  Cryptococcosis  Candida cystitis  Mycotic corneal ulcers & keratitis

ADVERSE REACTIONS:

A)  INFUSION-RELATED TOXICITY: fever & chills, muscle spasms, vomiting, headache, & hypotension B) SLOWER TOXICITY:  renal damage o o Reversible renal injury Irreversible renal injury- renal tubular injury

FLUCYTOSINE (5-FC)

 Discovered in 1957  Fluorinated pyrimidine related to florouracil & floxuridine  Spectrum of activity is narrower than that of amphotericin

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 ACTION:

 Taken up by fungal cells via

CYTOSINE PERMEASE

 Converted intracellularly to 5 FU  5 fluorodeoxyuridine monophosphate & 5 fluorouridine triphosphate  inhibit RNA & DNA synthesis

5-FU

Cytosine permease

5-Flucytosine 5-FUMP

UMP pyrophosphate Ribonucleide reductase

5-FUDP 5-F-dUMP 5-FUTP RNA

Thymidine synthase

DUMP dTMP

CLINICAL USE:

 Cryptococcal meningitis  Candida species  Dermatiaceous molds that cause chromoblastomycosis

ADVERSE EFFECTS:

 Leukopenia & thrombocytopenia  Rash  Nausea/vomiting, diarrhea, severe enterocolitis

AZOLES:

 IMIDAZOLES :  Ketoconazole  Miconazole  Clotrimazole  TRIAZOLES:  Itraconazole  Fluconazole  Voriconzaole

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 USES:

 Candida species  Cryptococcus neoformans  Endemic mycoses DRUG INTERACTIONS:  All azole drugs affect mammalian cytochrome P450 systems of enzymes

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

Cont.

 Reaches the keratinocytes efficiently  Concentration in vaginal fluids is approaches that in plasma

THERAPEUTIC USES:

 Blastomycosis, histoplasmosis, coccidiodomycosis, pseudallescheriasis  Paracoccidiodomycosis, ringworm, tinea versicolor, chronic mucocutaneous candidiasis  Candida vulvovaginitis, oral & esophageal candidiasis

ADVERSE REACTIONS:

 Dose-dependent anorexia, nausea, vomiting  Inhibits steroid biosynthesis in patients endocrine abnormalities

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

      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

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

 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

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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

SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS

GRISEOFULVIN

 Practically insoluble in water  Fungistatic in vitro for dermatophytes microsporum, epidermophytom & trichophyton  No effect on bacteria & other fungi

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 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 REACTIONS:

 Allergic syndrome  hepatitis

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

 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

POLYENE ANTIFUNGAL AGENTS

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

 Topical form (Fungizone)  Cutaneous & mucocutaneous candidiasis  Lotion, ointment & cream

IMIDAZOLE & TRIAZOLE FOR TOPICAL USE:

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

 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

 Broad spectrum  Fungicidal to C. albicans, E. flocosum, M. canis, T. mentagrophytes, T. rubrum  Inhibits the growth of Malassezia furfur  Penetrates the dermis

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

 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

ANTIFUNGAL DRUGS

DRUG Amphotericin B Nystatin ACTION Disrupts plasma membrane of fungal cells, greater affinity for ergosterol CLINICAL USE DOC: systemic fungal infections, fungal meningitis & fungal urinary tract infections DOC: Intestinal candidiasis or oral thrush UNDESIRABLE EFFECTS Poor therapeutic index (toxic at therapeutic dose). Fever & chills, nephrotoxicity, nausea, headache, thrombophlebitis, anemia, hepatotoxicity, cardiotoxicity Few adverse effects PHARMACOKINETICS Slow IV for systemic infections; intrathecal for meningitis, bladder irrigation for cystitis. No need to reduce dose with renal dysfunction.

PO. Negligible absorption, fecal excretion .

NOTES CBC, urinalysis, liver enzymes, BUN, Crea, & electrolytes should be checked before and during tx Ketoconazole Fluconazole Impairs synthesis pf ergosterol Inhibits fungal cytochrome P450. Damages plasma membrane by inhibiting sterol demethylation 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 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 Follow LFTs. Stop during signs of liver abnormalities No effect on testosterone synthesis.

Itraconazole Clotrimazole Miconazole Flucytosine Griseofulvin Terbinafine Aspergillosis, histoplasmosis, coccidiomycosis, sporotrichosis, paracoccidiomyc osis, 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 unknown Deaminated to 5 FU by the fungus. Incorporated into RNA. Metabolized to 5-FdURD w/c inhibits thymidilate synthetase DOC: candida dermatophyte infections of the skin Vaginal candidiasis, severe systemic fungal infections Phlebitis, pruritus, nausea, fever, rash, vomiting Leucopenia, nausea, diarrhea, Inc LFTs, bone marrow depression topical Vaginal suppositories/ topical/IV Easily penetrates CNS. Renal excretion Fungal resistance develops 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 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

MISCELLANEOUS ANTIFUNGAL AGENTS

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

 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

 Treatment of dermatomycoses  Low efficacy

POTASSIUM IODIDE

 Treatment of mucocutaneous sporotrichosis

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Acyclovir Amantadine Zidovudine Ganciclovir Adefovir

POST-TEST

A. Antiretroviral agent B. Anti-Herpes/VZV C. Anti-CMV D. Anti-Influenza E. Anti-Hepatitis 6.

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Amphotericin B Griseofulvin Haloprogin Ketoconazole nystatin A. systemic infection B. mucocutaneous infection C. topical