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Principals of anti viral Principals of anti viral and anti fungal therapy and anti fungal therapy when and where when and where Dr.saurabh joshi Dr.saurabh joshi Guide Dr.sunil rao Guide Dr.sunil rao

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Page 1: Seminar joshi

Principals of anti viral Principals of anti viral and anti fungal therapy and anti fungal therapy

when and where when and where

Dr.saurabh joshiDr.saurabh joshi

Guide Dr.sunil raoGuide Dr.sunil rao

Page 2: Seminar joshi

Introduction –Introduction – Antimycotic drugs Antimycotic drugs

Used to treat two types of fungal infection:Used to treat two types of fungal infection:– Superficial fungal infections - skin or mucous membraneSuperficial fungal infections - skin or mucous membrane– Systemic fungal infections - lungs or central nervous Systemic fungal infections - lungs or central nervous

systemsystem Fungi causing mycosis live as commensally or are

present in the environment. Earlier superficial infections were uncommon and

systemic rather rare. Recently there is increase in local as well as

systemic fungal infections. Reason for this is opportunistic infections

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Opportunistic infectionsOpportunistic infections

Immuno-suppression due to- Cancer chemotherapy

- AIDS– Corticosteroid overuse

Indiscriminate use of broad spectrum antibiotics

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Fungal infections

Superficial– Skin– Hair

– Nails

– Mucous membrane

Deep– Tissues (muscle &

connective tissue)– Organs

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Types of fungal infections - MycosesTypes of fungal infections - Mycoses Superficial mycosesSuperficial mycoses

– Affect the skin, hair and nails – ringworm/tinea or Affect the skin, hair and nails – ringworm/tinea or onychomycosisonychomycosis

Subcutaneous mycoses (tropical)Subcutaneous mycoses (tropical)– Affect the muscle and connective tissue immediately Affect the muscle and connective tissue immediately

below the skinbelow the skin Systemic (invasive) mycosesSystemic (invasive) mycoses

– Involve the internal organsInvolve the internal organs Allergic mycosesAllergic mycoses

– Affect lungs or sinuses Affect lungs or sinuses – Patients may have chronic asthma, cystic fibrosis or sinusitisPatients may have chronic asthma, cystic fibrosis or sinusitis

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MOST COMMON FUNGAL MOST COMMON FUNGAL PATHOGENSPATHOGENS

DermatophytesDermatophytes – – Microsporum, Microsporum, Epidermophyton and TrichophytonEpidermophyton and Trichophyton

CandidaCandida – – C.C. albicans, C. glabrata, C. albicans, C. glabrata, C. tropicalistropicalis

AspergillusAspergillus CryptococcusCryptococcus RhizopusRhizopus

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Causative fungiCausative fungi

Superficial infections by– Dermatophytes (ring worms): athlete`s foot or tinea

pedis, jock itch or tinea cruris, tinea capitis etc.– Candida:Candida: oral thrush, vaginitis and diaper candidiasis

etc. Deep infections are

– Candidiasis: Chronic mucocutaneous candidiasis, systemic candidiasis etc.

– Aspergillosis: broncho-pulmonary aspergillosis– Coccidiomycosis: pulmonary and disseminated

(complications – pneumonia)– Histoplasmosis:Histoplasmosis: H. capsulatum (common in HIV) H. capsulatum (common in HIV)

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TRETMENTTRETMENT

SUPERFICIAL FUNGUS ARE TRAEATED SUPERFICIAL FUNGUS ARE TRAEATED BY TOPICAL ANTIFUNGALSBY TOPICAL ANTIFUNGALS

DOC IS ORAL GRESIOFULVINDOC IS ORAL GRESIOFULVIN

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SYSTEMIC FUNGUS

S.NO. DISEASES DOC

1 INVASIVE CANDIDIASIS AMPHOTERICIN BFLUCONAZOLE,CASPOFUNGIN

2 INVASIVE ASPERGILLOSIS VORICONAZOLE,AMPHOTERICIN B

3 BLASTOMYCOSIS AMPHOTERICIN B .ITRACONAZOLE

4. COCCIDIOMYCOSISRAPIDLY PROGREESIVEINDOLENTMENINGIAL

AMPHOTERICIN BITRACONAZOLEFLUCONAZOLE

5 CRYPTOCOCCUSNON AIDSAIDS

AMPHOTERICIN BFLUCONAZOLE

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SYSTEMIC FUNGUSSYSTEMIC FUNGUS

S.NO DISEASES DOC

6 HISTOPLASMOSISPULMONARYCNS/AIDS

ITRACONAZOLEAMPHOTIRICIN BITRACONAZOLE

7. MUCORMYCOSIS AMPHOTERICIN B

8 SPOROTRICHOSISCUTANEOUSEXTRA CUTANEOUS

ITRACONAZOLEAMPHOTERICIN B

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Cell Membrane Active AntifungalCell Membrane Active Antifungal

Cell membrane1. Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical)

2. Azole antifungals Imidazoles:

• Topical: Clotrimazole, econazole, miconazole

• Systemic: KetoconazoleTriazoles: Fluconazole, itraconazole and

voriconazole

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cellwall acting anti fungals

1.Echinocandins2.pneumocandins3.Papulocandins4.Polyoxins5.Nikomycins

Nucleic acid synthesis inhibitors1.5-fluocytosin

Nuclear division inhibitorsGreseofulvin

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Local azolesLocal azoles Very popular local azoles are – Clotrimazole, Econazole

and Miconazole (For Tinea, Ring worm, Athlete’s foot, otomycosis, oral,

cutaneous & vaginal candidiasis) Mechanism of action is same as that of Ketoconazole i.e.

ergosterol inhibition by inhibiting CYP450 Clotrimazole is favoured in vaginitis because of long lasting

residual effect and once daily dosing Miconazole causes frequently vaginal irritation & pelvic

cramp. Available s lotion, cream, powder, vaginal tablet etc. Available s lotion, cream, powder, vaginal tablet etc.

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AMPHOTERICIN BAMPHOTERICIN B

Most Toxic antifungalMost Toxic antifungal Fungicide at high and static at low conc.Fungicide at high and static at low conc. Effective againstEffective against

– Candida albicansCandida albicans– Histoplasma capsulatumHistoplasma capsulatum– CryptococcusCryptococcus

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UsesUses

Broad spectrum antifungalBroad spectrum antifungal Useful forUseful for1. Candida that causes1. Candida that causes

– oraloral– vaginalvaginal– cutaneous candidiasiscutaneous candidiasis

2. Cryptococcus2. Cryptococcus3. Histoplasma3. Histoplasma4. Aspergillosis4. Aspergillosis5. Also effective for Leishmaniasis(Reserve drug for resistant 5. Also effective for Leishmaniasis(Reserve drug for resistant

cases of Kala Azar)cases of Kala Azar)

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ADRsADRs

1.1. Acute reactions -Acute reactions - occurs with each infusion occurs with each infusion– Chills, Nausea, Vomiting, Pain, Fever, Aches, DyspnoeaChills, Nausea, Vomiting, Pain, Fever, Aches, Dyspnoea– So corticosteroids are administered along with the drugSo corticosteroids are administered along with the drug

1.1. ThrombophlebitisThrombophlebitis2.2. Bone marrow depressionBone marrow depression - Reversible anemia - Reversible anemia3.3. On intrathecal injectionOn intrathecal injection – Headache, Vomiting, – Headache, Vomiting,

Nerve paralysisNerve paralysis4.4. Renal toxicity leading toRenal toxicity leading to – Azotemia, Decreased – Azotemia, Decreased

GFR, Acidosis, Hypokalemia, Inability to conc. GFR, Acidosis, Hypokalemia, Inability to conc. urineurine

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Newer Amphotericin BNewer Amphotericin B

They are developed to overcomeThey are developed to overcome1. Side effects1. Side effects2. To improve tolerability2. To improve tolerability3. To get the drug at site of action3. To get the drug at site of action4. To reduce the toxicity i.e.. Less nephrotoxic and minimal 4. To reduce the toxicity i.e.. Less nephrotoxic and minimal

anemiaanemiaFormulations are:Formulations are:1. Amphotericin B lipid complex1. Amphotericin B lipid complex2. Amphotericin B colloidal dispersion2. Amphotericin B colloidal dispersion3. Liposomal Amphotericin B3. Liposomal Amphotericin B(Only drawback of these formulations is less efficacy)(Only drawback of these formulations is less efficacy)

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Drug Interactions of Amphotericin BDrug Interactions of Amphotericin B

With Flucytocin-synergistic actionWith Flucytocin-synergistic action Rifampicin and Minocyclin – Rifampicin and Minocyclin –

– Both potentiate Amphotericin BBoth potentiate Amphotericin B Vancomycin and Aminoglycoside – Vancomycin and Aminoglycoside –

– Both increase risk of nephrotoxicityBoth increase risk of nephrotoxicity Preparation and doses:Preparation and doses:

– 50 – 100 mg four times a day orally50 – 100 mg four times a day orally– 3% ear drops3% ear drops– Systemic: 50 mg vial (one vial diluted in 500 ml of 5% Systemic: 50 mg vial (one vial diluted in 500 ml of 5%

glucose and initially 1 mg test dose followed by infusion glucose and initially 1 mg test dose followed by infusion for 4 – 8 Hrs)for 4 – 8 Hrs)

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NystatinNystatin

Similar to Amphotericin B but more Similar to Amphotericin B but more toxictoxic than than Amphotericin BAmphotericin B

Used only for superficial candidiasis ofUsed only for superficial candidiasis of

Skin, Mouth, Vagina, IntestineSkin, Mouth, Vagina, Intestine As ointment ,oral tablets & suppositoriesAs ointment ,oral tablets & suppositories Available as tablets and ointments (1 to 5 lacs U) Available as tablets and ointments (1 to 5 lacs U)

– also vaginal tablets– also vaginal tablets Orally not absorbed but can be used in monilial Orally not absorbed but can be used in monilial

diarrhoeadiarrhoea

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Other PolyenesOther Polyenes

Hamycin: Water soluble Absorption from GIT not reliable Not used for systemic fungal infections Used topically for Aspergillus, Candida, Monilial,

Trichomonas vaginalis infectionsNatamycin: Broad spectrum Used topically for – Keratitis, Monilial infections,

Trichomonas vaginalis

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Imidazoles and TriazolesImidazoles and Triazoles

Azole antifungals Imidazoles:

– Topical: Clotrimazole, econazole, miconazole– Systemic: Ketoconazole

Triazoles: Fluconazole, itraconazole and voriconazole

Remember that among imidazoles, only Remember that among imidazoles, only ketocanazole is systemic, other 3 are topical onlyketocanazole is systemic, other 3 are topical only

While, Triazoles are used systemically and largely While, Triazoles are used systemically and largely replacing ketoconazolereplacing ketoconazole

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Individual AgentsIndividual Agents

Ketoconazole:Ketoconazole: Spectrum: yeasts and moulds - poor absorption Spectrum: yeasts and moulds - poor absorption

limits its role for severe infections, generally used limits its role for severe infections, generally used in mucosal infections only (dematophytosis)in mucosal infections only (dematophytosis)

PharmacokineticsPharmacokinetics– Variable oral absorption, dependent on pH (often given Variable oral absorption, dependent on pH (often given

with cola or fruit juice)with cola or fruit juice)– T1/2 = 7-10 hoursT1/2 = 7-10 hours– Protein binding > 99%Protein binding > 99%– Hepatic, bile and kidney eliminationHepatic, bile and kidney elimination

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Ketoconazole – contd.Ketoconazole – contd.

Adverse effectsAdverse effects– N&V, worse with higher doses (800 mg/day)N&V, worse with higher doses (800 mg/day)– Hepatoxicity (2-8%), increase in transaminases, Hepatoxicity (2-8%), increase in transaminases,

hepatitishepatitis– Dose related inhibition of CYP P450 responsible Dose related inhibition of CYP P450 responsible

for testosterone synthesisfor testosterone synthesis Gynecomastia, oligosperma, decreased libidoGynecomastia, oligosperma, decreased libido

– Dose-related inhibition of CYP P450 Dose-related inhibition of CYP P450 responsible for adrenal cortisol synthesisresponsible for adrenal cortisol synthesis

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Ketoconazole – contd.Ketoconazole – contd.

Drug Interaction:Drug Interaction: Potent inhibitor of cytochrome P450 3A4Potent inhibitor of cytochrome P450 3A4

– Rifampin and phenytoin decrease ketoconazole levelsRifampin and phenytoin decrease ketoconazole levels– Ketoconazole increases cyclosporin, waKetoconazole increases cyclosporin, warrfarin, astemizole, farin, astemizole,

corticosteroid, and theophylline levelscorticosteroid, and theophylline levels– Many of these drug interactions are severeMany of these drug interactions are severe

Drugs that increase gastric pH will decrease blood levels of Drugs that increase gastric pH will decrease blood levels of ketoconazoleketoconazole– Antacids, omeprazole, H2 blockersAntacids, omeprazole, H2 blockers

Doses: Doses: – Serious infections 800 mg/day POSerious infections 800 mg/day PO– Other: 200-400 mg/day POOther: 200-400 mg/day PO

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Fluconazole - KineticsFluconazole - Kinetics Available as both IV and POAvailable as both IV and PO

– Bioavailibility > 90%Bioavailibility > 90% PharmacokineticsPharmacokinetics

– t 1/2 = ~24 hourst 1/2 = ~24 hours– Protein binding < 12%Protein binding < 12%– Vd 0.85 L/kg (widely distributed)Vd 0.85 L/kg (widely distributed)– >90% excreted unchanged through the kidney>90% excreted unchanged through the kidney

DosingDosing1.1. Mucosal candidiasisMucosal candidiasis

100-200 mg/day (150 mg tablet vulvovaginal candidiasis)100-200 mg/day (150 mg tablet vulvovaginal candidiasis)1.1. Systemic fungal infectionsSystemic fungal infections

400-800 mg q24h400-800 mg q24h >> 800 mg q24h in unstable patient, S-DD isolate, or if non- 800 mg q24h in unstable patient, S-DD isolate, or if non-albicansalbicans spp. spp.

(except (except C. kruseiC. krusei))1.1. Maintenance for cryptococcal meningitisMaintenance for cryptococcal meningitis

400 mg q24h400 mg q24h

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Fluconazole - ADRsFluconazole - ADRs

N&V, rash:N&V, rash:– More likely with high doses and in AIDS patientsMore likely with high doses and in AIDS patients– Asymptomatic increase in LFTs (7%)Asymptomatic increase in LFTs (7%)

Drug interactions:Drug interactions:– May increase phenytoin, cyclosporin, rifabutin, May increase phenytoin, cyclosporin, rifabutin,

warfarin, and zidovudine concentrationswarfarin, and zidovudine concentrations– Rifampin reduced fluconazole levels to halfRifampin reduced fluconazole levels to half

(even though FLU is not a major substrate)(even though FLU is not a major substrate)

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ItraconazoleItraconazole

Some Features:Some Features: Newer orally active triazoleNewer orally active triazole Broader spectrun than KTZ and FCZ – Broader spectrun than KTZ and FCZ –

includes moulds like aspergillusincludes moulds like aspergillus Fungistatic action but very effective in Fungistatic action but very effective in

immunocompromizrd patientsimmunocompromizrd patients Steroid hormone synthesis inhibition is Steroid hormone synthesis inhibition is

absent and no serious hepatotoxicityabsent and no serious hepatotoxicity

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Heterocyclic Nitrofurans - Heterocyclic Nitrofurans - GriseofulvinGriseofulvin

Used for superficial fungal infections by Used for superficial fungal infections by dermatophytesdermatophytes

Derived from Penicillium griseofulvum but Derived from Penicillium griseofulvum but no antibacterial activityno antibacterial activity

Effective against most dermatophytes, but Effective against most dermatophytes, but not against candida causing deep mycosisnot against candida causing deep mycosis

Dermatophytes actively concentrate it – Dermatophytes actively concentrate it – accounts for selective toxicity against themaccounts for selective toxicity against them

Taken up by newly formed keratinTaken up by newly formed keratin

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Griseofulvin - MOAGriseofulvin - MOA

Interferes with mitosis – results in Interferes with mitosis – results in multinucleated and stuntedmultinucleated and stunted hyphae hyphae

((In most fungi, hyphae are the main mode of vegetative growth, and are In most fungi, hyphae are the main mode of vegetative growth, and are collectively called a mycelium yeasts are unicellular fungi that do not collectively called a mycelium yeasts are unicellular fungi that do not grow as hyphae)grow as hyphae)

Abnormal metaphase configurations leading Abnormal metaphase configurations leading to failure of daughter nuclei to fall apartto failure of daughter nuclei to fall apart

(Colchicine and vinca alkloids also mitotic inhibitors but they cause (Colchicine and vinca alkloids also mitotic inhibitors but they cause arrest arrest of mitosis)of mitosis)

Disorientation of polymerized microtubules Disorientation of polymerized microtubules

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Griseofulvin - ADRsGriseofulvin - ADRs Safe with mild side effectsSafe with mild side effects 1. GIT upsets1. GIT upsets 2. CNS symptoms2. CNS symptoms 3. Hepatotoxicity3. Hepatotoxicity 4. Leucopenia4. Leucopenia 5. Photosensitivity5. Photosensitivity 6. Allergy etc.6. Allergy etc. Microsomal enzyme inducerMicrosomal enzyme inducer Causes decrease in activity of anticoagulantsCauses decrease in activity of anticoagulants Cause intolerance to alcoholCause intolerance to alcohol Phenobarbitone reduces its oral absorption so failure of Phenobarbitone reduces its oral absorption so failure of

therapytherapy

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FlucytosinFlucytosin Fluorinated pyrimidine related to flurouracilFluorinated pyrimidine related to flurouracil Restricted spectrum of activity.Restricted spectrum of activity. Acquired Resistance due to > result of monotherapy Acquired Resistance due to > result of monotherapy Due to:Due to: 1) Decreased uptake (permease activity)1) Decreased uptake (permease activity) 2) Altered 5-FC metabolism (cytosine deaminase or UMP 2) Altered 5-FC metabolism (cytosine deaminase or UMP

pyrophosphorylase activity)pyrophosphorylase activity)

Kinetics:Kinetics: Orally absorbedOrally absorbed Widely distributed even in CSFWidely distributed even in CSF Exc. in urine.Exc. in urine. Converted in fungal cell to 5-FU which is antimetabolite.Converted in fungal cell to 5-FU which is antimetabolite. Mammalian cells remain unaffected except few bone marrow cellsMammalian cells remain unaffected except few bone marrow cells

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FlucytosinFlucytosin

Monotherapy : NeverMonotherapy : Never

Candidiasis Candidiasis CryptococcosisCryptococcosis

?Aspergillosis?Aspergillosis } In combination with amphotericin B or

fluconazole.

Doses:1. Vaginal candidiasis: 200 mg OD for 3 days2. Dermatophytosis; 100-200 mg OD for 7-15 days3. Onychomycosis: 200 mg per day for 3 monthsADRs: 1.Mild BM depression 2. Loss of hair 3. Dose should be decreased in the presence of renal impairment

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TerbinafineTerbinafine Belongs to a newer allylamine class of antifungalsBelongs to a newer allylamine class of antifungals Given both orally & locallyGiven both orally & locally Lipophillic so widely distributedLipophillic so widely distributed Fungicidal in contrast to azoles (fungistatic)Fungicidal in contrast to azoles (fungistatic) Acts by non-competitive inhibition of Acts by non-competitive inhibition of “squalene epoxidase”“squalene epoxidase”

(early step enzyme in ergosterol synthesis accumulation of (early step enzyme in ergosterol synthesis accumulation of squalene in fungal cells – cidal effectsqualene in fungal cells – cidal effect

Used for dermatophytes & candidaUsed for dermatophytes & candida Dose is 250mg OD for 2-6 wksDose is 250mg OD for 2-6 wks Locally 1% ointmentLocally 1% ointment.

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Terbinafine – contd.Terbinafine – contd.

ADRsADRs With oralWith oral

– GIT upsetGIT upset– Hepatic dysfunctionHepatic dysfunction– RashRash– Taste disturbanceTaste disturbance– No interaction with CYP450No interaction with CYP450

Preparations and doses: Preparations and doses: – 1% cream 125/250 mg tablets etc.1% cream 125/250 mg tablets etc.– Tinea pedis: 250 mg OD for 2-6 weeksTinea pedis: 250 mg OD for 2-6 weeks– Onychmycosis: 3-12 months (alternative to fluconazole) Onychmycosis: 3-12 months (alternative to fluconazole)

• On local application -On local application - ddryness, Erythemaryness, Erythema, , Rash, Rash, itching etc. itching etc.

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DRUGS FOR NON - HIV VIRAL DRUGS FOR NON - HIV VIRAL INFECTIONSINFECTIONS

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Possible Sites of ActionPossible Sites of Action

Viral attachmentViral attachment Cell entryCell entry TranscriptionTranscription TranslationTranslation Viral assemblyViral assembly

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Drugs for HSV and VZVDrugs for HSV and VZV

Oral AgentsOral Agents– AcyclovirAcyclovir– ValacyclovirValacyclovir

– FamciclovirFamciclovir

OphthalmicOphthalmic– TrifluridineTrifluridine

Topical AgentsTopical Agents– AcyclovirAcyclovir– DocosanolDocosanol

– PenciclovirPenciclovir

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AcyclovirAcyclovir

Guanosine analogGuanosine analog Topical, oral, and intravenous formulationsTopical, oral, and intravenous formulations Spectrum: Herpes simplex 1 and 2, Spectrum: Herpes simplex 1 and 2,

varicella-zoster virus, possibly the Epstein-varicella-zoster virus, possibly the Epstein-Barr VirusBarr Virus

Treatment of choice for visceral, Treatment of choice for visceral, disseminated, or central nervous system disseminated, or central nervous system involvementinvolvement

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Acyclovir Adverse effects Acyclovir Adverse effects

PhlebitisPhlebitis Reversible renal toxicityReversible renal toxicity

– Crystalization in the renal Crystalization in the renal tubulestubules

Neurological symptomsNeurological symptoms– Encephalopathic changes Encephalopathic changes

such as somnolence, such as somnolence, hallucinations, confusion hallucinations, confusion coma coma

GI symptomsGI symptoms HeadacheHeadache TTP/HUSTTP/HUS PhotosensitivityPhotosensitivity AnemiaAnemia

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ValacyclovirValacyclovir Available orally onlyAvailable orally only Spectrum: similar to acyclovirSpectrum: similar to acyclovir Adverse effects: headache, nausea, Adverse effects: headache, nausea,

weakness, dizziness, confusionweakness, dizziness, confusion

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FamciclovirFamciclovir

Cyclic guanine analogCyclic guanine analog Available orally onlyAvailable orally only Spectrum: HSV 1 and 2, VZV, to a lesser Spectrum: HSV 1 and 2, VZV, to a lesser

extent, EBV, in vitro activity to HBVextent, EBV, in vitro activity to HBV Adverse effects: headache, GI, abnormal Adverse effects: headache, GI, abnormal

LFT’sLFT’s

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Other Topicals for HSVOther Topicals for HSV

Orolabial herpesOrolabial herpes– Penciclovir (Denavir® 1% cream)Penciclovir (Denavir® 1% cream)

Topical guanine analog similar to acyclovirTopical guanine analog similar to acyclovir Apply every 2 hours while awakeApply every 2 hours while awake

– Docosanol (Abreva® OTC)Docosanol (Abreva® OTC) Active against a broad range of lipid-envelop virusesActive against a broad range of lipid-envelop viruses MOA: interferes with viral fusion to host cellMOA: interferes with viral fusion to host cell Apply 5X per day until healing (up to 10 days)Apply 5X per day until healing (up to 10 days)

– Shortens healing time by 0.7 daysShortens healing time by 0.7 days

HSV Keratoconjuctivitis HSV Keratoconjuctivitis – Trifluridine (Viroptic® 1% ophthalmic)Trifluridine (Viroptic® 1% ophthalmic)

1 drop q2h (max 9 drops/day)1 drop q2h (max 9 drops/day) Active against acyclovir resistant strainsActive against acyclovir resistant strains Also active against vaccinia virus and smallpoxAlso active against vaccinia virus and smallpox

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Anti-CMV AgentsAnti-CMV Agents

GanciclovirGanciclovir ValganciclovirValganciclovir FoscarnetFoscarnet CidofovirCidofovir

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Foscarnet – Mechanism of ActionFoscarnet – Mechanism of Action

Trisodium phosphonoformate hexahydrateTrisodium phosphonoformate hexahydrate– Inorganic pyrophosphate analogInorganic pyrophosphate analog

Does not require thymidine kinaseDoes not require thymidine kinase– Works on HSV strains deficient of this enzymeWorks on HSV strains deficient of this enzyme

Selective inhibition at the pyrophosphate binding Selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerasesite on virus-specific DNA polymerase– Noncompetetive inhibitorNoncompetetive inhibitor– Does not affect cellular DNA polymeraseDoes not affect cellular DNA polymerase

Resistance by alterations to viral DNA polymerase Resistance by alterations to viral DNA polymerase – Not caused by thymidine kinase alterationsNot caused by thymidine kinase alterations– Does not cause cross resistance to ganciclovir or cidofovirDoes not cause cross resistance to ganciclovir or cidofovir

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FoscarnetFoscarnet

Intravenous only – controlled infusionsIntravenous only – controlled infusions Spectrum: CMV including ganciclovir resistant strains, Spectrum: CMV including ganciclovir resistant strains,

acyclovir resistant HSV or VZV, EBV, Influenza A and B, acyclovir resistant HSV or VZV, EBV, Influenza A and B, HBV, and HIVHBV, and HIV

Adverse effects: renal dysfunction (common, can require Adverse effects: renal dysfunction (common, can require dialysis), NV, anemia, CNS disturbances, electrolyte dialysis), NV, anemia, CNS disturbances, electrolyte abnormalities, seizures, arrhythmias, neutropeniasabnormalities, seizures, arrhythmias, neutropenias

Reduction of renal failureReduction of renal failure– Saline loading (adequate hydration)Saline loading (adequate hydration)– Appropriate renal dosing adjustments Appropriate renal dosing adjustments – Avoidance of concurrent nephrotoxic medicationsAvoidance of concurrent nephrotoxic medications

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CidofovirCidofovir

Available intravenous onlyAvailable intravenous only Spectrum: CMV including acyclovir and foscarnet Spectrum: CMV including acyclovir and foscarnet

resistant strains, HSV 1 and 2, VZV, EBV, HHV-6, resistant strains, HSV 1 and 2, VZV, EBV, HHV-6, HHV-8HHV-8– Also has activity against DNA viruses: papilloma virus, Also has activity against DNA viruses: papilloma virus,

polyomavirus, poxvirus, and adenoviruspolyomavirus, poxvirus, and adenovirus

Must be avoided in preexisting renal impairmentMust be avoided in preexisting renal impairment Adverse effects: nephrotoxicity (dose-limiting), Adverse effects: nephrotoxicity (dose-limiting),

neutropenia, metabolic acidosisneutropenia, metabolic acidosis Must be given with adequate hydration and PO Must be given with adequate hydration and PO

probenecid---see labeled dosing directionsprobenecid---see labeled dosing directions

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Hepatitis B AgentsHepatitis B Agents

Interferon alfa-2b/-n3/-2aInterferon alfa-2b/-n3/-2a Peginterferon alfa-2a/-2b Peginterferon alfa-2a/-2b EntecavirEntecavir AdefovirAdefovir TelbivudineTelbivudine Lamivudine/ EmtricitabineLamivudine/ Emtricitabine TenofovirTenofovir

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InterferonsInterferons

Discovered in 1957 for their antiviral effectsDiscovered in 1957 for their antiviral effects– GlycoproteinsGlycoproteins– Interferes with viral growthInterferes with viral growth– Responsible for complex antiviral, immunomodulating, and Responsible for complex antiviral, immunomodulating, and

antiproliferative effectsantiproliferative effects

Three classes (Three classes (αα, , ββ, and , and γγ))– Each distinctEach distinct– Different producer cells, inducers, and biologic effectsDifferent producer cells, inducers, and biologic effects– INF-INF-αα and – and –ββ are produced by nearly all cells in repsonse to are produced by nearly all cells in repsonse to

invasioninvasion– Only INF-Only INF-αα has been approved for viral treatment has been approved for viral treatment– INF- INF- γγ only produced by T cells and NK cells only produced by T cells and NK cells

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Hepatitis C AgentsHepatitis C Agents

RibavirinRibavirin Pegylated interferonPegylated interferon

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RibavirinRibavirin

Available orally and via inhalationAvailable orally and via inhalation– Intravenous and intraventricular available Intravenous and intraventricular available

through the CDCthrough the CDC Spectrum: RNA and DNA viruses including Spectrum: RNA and DNA viruses including

influenza A and B, mumps, measles, influenza A and B, mumps, measles, parainfluenza, HSV, togavirus, bunyavirus, parainfluenza, HSV, togavirus, bunyavirus, adenovirus, coxsackievirus, RSV, Hepatitis adenovirus, coxsackievirus, RSV, Hepatitis A, B and CA, B and C– Data also available for hemorrhagic fever, Data also available for hemorrhagic fever,

Lassa fever, and Hantaan virusLassa fever, and Hantaan virus

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Influenza AgentsInfluenza Agents

OseltamivirOseltamivir Zanamivir Zanamivir AmantadineAmantadine RimantadineRimantadine

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OseltamivirOseltamivir

Oral neuraminidase inhibitorOral neuraminidase inhibitor– Cleaves terminal sialic acid residues on Cleaves terminal sialic acid residues on

glycoconjugates and destroys receptorsglycoconjugates and destroys receptors– Newly formed virions adhere to cell surface and Newly formed virions adhere to cell surface and

limit spreadlimit spread Spectrum: Infuenza A and B in both children Spectrum: Infuenza A and B in both children

and adults, avian influenza, H5N1 diseaseand adults, avian influenza, H5N1 disease Adverse effects: NV, headacheAdverse effects: NV, headache

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ZanamivirZanamivir

Neuraminidase inhibitorNeuraminidase inhibitor Given via inhalationGiven via inhalation Spectrum: Uncomplicated influenza A and Spectrum: Uncomplicated influenza A and

B, some strains of avian influenza, possibly B, some strains of avian influenza, possibly effective for H5N1effective for H5N1

Adverse effects: nasal and throat Adverse effects: nasal and throat discomfort, bronchospasmdiscomfort, bronchospasm

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AmantadineAmantadineRamanitidineRamanitidine

MOA: Prevents the release of viral nucleic MOA: Prevents the release of viral nucleic acid into host cellacid into host cell

Spectrum: Influenza A, however resistance Spectrum: Influenza A, however resistance is frequentis frequent

Adverse effects: Seizures, anticholinergic, Adverse effects: Seizures, anticholinergic, CNS, edema, blurry visionCNS, edema, blurry vision

Not currently recommended in the USNot currently recommended in the US

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Papillomavirus OptionsPapillomavirus Options

ImiquimodImiquimod PodofiloxPodofilox Trichloroacetic AcidTrichloroacetic Acid PodophyllinPodophyllin CryotherapyCryotherapy

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ImiquimodImiquimod

Imidazoquinoline compoundImidazoquinoline compound ImmunomodulatorImmunomodulator

– Activates immune cells (monocytes, macrophages, NK cells)Activates immune cells (monocytes, macrophages, NK cells) Produces antiviral cytokines (IFN-Produces antiviral cytokines (IFN-αα, TNF-, TNF-αα, and various interleukins, and various interleukins Indirectly activates APC’s including Langerhan’s cells and T-helper Indirectly activates APC’s including Langerhan’s cells and T-helper

cellscells

Topical treatment Topical treatment – 5% cream 3X per week (for 8 hours) for 16 weeks5% cream 3X per week (for 8 hours) for 16 weeks– Can be used as adjunctive therapy with laser or surgical txCan be used as adjunctive therapy with laser or surgical tx

Spectrum: External and perianal genital warts by HPVSpectrum: External and perianal genital warts by HPV Adverse effects: Adverse effects:

– Site reactions (pain, erythema, scarring, and pruritis)Site reactions (pain, erythema, scarring, and pruritis)– No systemic reactions reportedNo systemic reactions reported

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THANKS THANKS