Antiviral Drugs: Acyclovir

Antiviral Drugs

Acyclovir

• Guanosine derivative, selective for herpesviruses
• Metabolized to monophosphate via thymidine kinase, then converted to triphosphate, which inhibits viral DNA polymerase
• Widely distributed throughout body tissues and fluids, including the brain, semen, and CSF
• Excreted by kidneys through glomerular filtration and tubular secretion
• Used to treat ocular and respiratory infections of herpes virus 1 in cats, and active against equine herpes virus type-1 in vitro
• Adverse effects: low WBC, leukopenia, anemia in cats, and necrosis at injection site in birds

Amantadine

• 1-aminoadamantane, binds to M2 protein and blocks its ion channel activity, inhibiting viral uncoating and replication
• N-methyl-D-aspartate (NMDA) receptor antagonist, important in pain sensation
• Used to treat influenza viruses, replicate within host cells, and M2 protein
• Therapeutic use: adjunct treatment to chronic pain in dogs and cats, and treatment of equine-2 influenza via IV
• Pharmacokinetics: variable absorption, bioavailability 40-60%, excretion renal, half-life ~3.5 hours
• Adverse effects: agitation, loose stools, flatulence, diarrhea, contraindications: hypersensitivity, untreated angle-closure glaucoma, liver and renal diseases, CHF, active psychoses, eczematoid dermatitis, seizure disorders
• Drug interactions: anticholinergics, CNS stimulants, urinary acidifiers, TMPS

Famciclovir

• Converted to penciclovir, which is phosphorylated to penciclovir monophosphate, then triphosphate, inhibiting herpes virus DNA polymerase
• Used to treat feline herpes (FHV-1), and active against varicella zoster virus
• Pharmacokinetics: cats require higher doses due to poor conversion to penciclovir
• Contraindications: hypersensitivity, patients with renal problems
• Adverse effects: not well documented, but well tolerated when used up to three weeks

Interferons

• Human recombinant IFN-α, feline recombinant IFN-ω
• MOA: released by host cells in response to viral infection, attached to receptors on adjacent cells, increasing transcription of host cell DNA and activating endonuclease, increasing cell resistance to virus infection
• Used to treat non-neoplastic Feline Leukemia (FeLV) disease, and oral administration for ocular herpes infection
• Effects: antiviral, antiproliferative, immunomodulating, well distributed throughout the body except in CNS
• Adverse effects: dose-related, malaise, fever, allergic reactions, myelotoxicity, myalgia, hyperthermia, vomiting, decrease RBCs, platelets, WBCs, increase ALT, soft feces, mild diarrhea, transient fatigue, anorexia, and weight loss

Oseltamivir phosphate

• Ester prodrug converted to its active metabolite, oseltamivir carboxylate, by hepatic esterases
• Competitive inhibitor of the enzyme neuraminidase, used by influenza viruses for budding of replicative viral particles from infected cells
• May be effective for parvovirus infections in dogs, and mixed bacterial/viral infections
• Public health issues: prohibited by the FDA for extralabel drug use in poultry due to fear of resistance that avian influenza virus would develop against oseltamivir

Zidovudine (AZT)

• Analog of thymidine, phosphorylated by host cell enzymes to AZT 5-triphosphate, which competes with host 5-thymidine, essential for proviral DNA formation by reverse transcriptase of the virus
• Antiretroviral agent, virustatic effect, converted to active metabolite- triphosphate, inhibiting viral RNA-directed DNA polymerase
• Used to treat FIV, and as adjunct treatment for FeLV
• Pharmacokinetics: well absorbed orally, 90% bioavailability in cats, widely distributed including the CSF, metabolized in liver by glucuronide conjugation, excreted in urine, t ½ = 1.5 hours
• Adverse effects: anemia, reduction in hemoglobin, diarrhea, weakness, bone marrow, renal or hepatic dysfunction
• Drug interactions: antifungals, azole, atovaquone, doxorubicin, interferon alfa, probenecid, rifampin, myelo-/cytotoxic drugs

Other Antiviral Agents

• Trifluorothymidine (TFT): thought to have higher affinity for viral DNA than mammalian, and is more potent
• Idoxuridine: thymidine analogs active against DNA viruses, herpesvirus, and poxvirus

Interferon-ω (Omega) / Cat Omega Interferon

• Produced by genetic engineering, type 1 interferon closely related to alpha interferon
• Half-life: 1-2 hours in dogs and cats
• Mechanism of action: Acts on virus-infected cells by inhibiting mRNA synthesis and translation proteins, leading to inhibition of viral replication
• Used to treat cat viral infections, including calici virus, FeLV, FIV, and others, as well as canine parvovirus
• Adverse effects: Hyperthermia, vomiting, decrease in RBCs, platelets, and WBCs (myelotoxicity), increase in ALT, soft feces/mild diarrhea, transient fatigue, anorexia, and weight loss

Oseltamivir Phosphate

• Ester prodrug converted to active metabolite, oseltamivir carboxylate by hepatic esterases
• Mechanism of action: Competitive inhibitor of the enzyme neuraminidase, which influenza viruses use for budding and release of viral particles
• May be effective for parvovirus infections in dogs and other mixed bacterial/viral infections
• Public health controversy: use in veterinary medicine may lead to resistance in avian influenza virus

Zidovudine (AZT)

• Analog of thymidine, phosphorylated by host cell enzymes to AZT 5-triphosphate, which competes with host 5-thymidine for proviral DNA formation by reverse transcriptase
• Antiretroviral agent with virustatic effect, inhibiting viral RNA-directed DNA polymerase
• Used to treat FIV, with clinical improvement seen 14 days after treatment
• Pharmacokinetics: Well absorbed orally, widely distributed, metabolized in liver, and excreted in urine, with a half-life of 1.5 hours
• Adverse effects: Non-regenerative anemia, diarrhea, and weakness

Other Antiviral Agents

• Trifluorothymidine (TFT): Thought to have higher affinity for viral DNA than mammalian DNA, making it more potent
• Idoxuridine: Thymidine analog active against DNA viruses, including herpesvirus and poxvirus

Acyclovir

• Guanosine derivative selective for herpesviruses
• Metabolized to monophosphate via thymidine kinase, then converted to triphosphate, which inhibits viral DNA polymerase
• Used to treat ocular and respiratory infections of herpes virus 1 in cats
• Adverse effects: Low WBC, leukopenia, and anemia in cats; necrosis at injection site in birds

Amantadine

• 1-aminoadamantane, binds to M2 protein, and blocks its ion channel activity, inhibiting viral uncoating and replication
• Used as an adjunct treatment for chronic pain in dogs and cats, and for equine-2 influenza via IV
• Pharmacokinetics: Not described in dogs and cats, but has variable absorption and bioavailability of 40-60% in horses
• Adverse effects: Agitation, loose stools, flatulence, and diarrhea

Famciclovir

• For feline herpes (FHV-1), converted into penciclovir, which inhibits herpes virus DNA polymerase
• Pharmacokinetics: Cats require higher doses due to poor conversion to penciclovir
• Contraindication: Hypersensitivity
• Adverse effects: Not well documented, but well-tolerated when used up to three weeks

Interferon-ω (Omega) / Cat Omega Interferon

• Produced by genetic engineering, type 1 interferon closely related to alpha interferon
• Half-life: 1-2 hours in dogs and cats
• Mechanism of action: Acts on virus-infected cells by inhibiting mRNA synthesis and translation proteins, leading to inhibition of viral replication
• Used to treat cat viral infections, including calici virus, FeLV, FIV, and others, as well as canine parvovirus
• Adverse effects: Hyperthermia, vomiting, decrease in RBCs, platelets, and WBCs (myelotoxicity), increase in ALT, soft feces/mild diarrhea, transient fatigue, anorexia, and weight loss

Oseltamivir Phosphate

• Ester prodrug converted to active metabolite, oseltamivir carboxylate by hepatic esterases
• Mechanism of action: Competitive inhibitor of the enzyme neuraminidase, which influenza viruses use for budding and release of viral particles
• May be effective for parvovirus infections in dogs and other mixed bacterial/viral infections
• Public health controversy: use in veterinary medicine may lead to resistance in avian influenza virus

Zidovudine (AZT)

• Analog of thymidine, phosphorylated by host cell enzymes to AZT 5-triphosphate, which competes with host 5-thymidine for proviral DNA formation by reverse transcriptase
• Antiretroviral agent with virustatic effect, inhibiting viral RNA-directed DNA polymerase
• Used to treat FIV, with clinical improvement seen 14 days after treatment
• Pharmacokinetics: Well absorbed orally, widely distributed, metabolized in liver, and excreted in urine, with a half-life of 1.5 hours
• Adverse effects: Non-regenerative anemia, diarrhea, and weakness

Other Antiviral Agents

• Trifluorothymidine (TFT): Thought to have higher affinity for viral DNA than mammalian DNA, making it more potent
• Idoxuridine: Thymidine analog active against DNA viruses, including herpesvirus and poxvirus

Acyclovir

• Guanosine derivative selective for herpesviruses
• Metabolized to monophosphate via thymidine kinase, then converted to triphosphate, which inhibits viral DNA polymerase
• Used to treat ocular and respiratory infections of herpes virus 1 in cats
• Adverse effects: Low WBC, leukopenia, and anemia in cats; necrosis at injection site in birds

Amantadine

• 1-aminoadamantane, binds to M2 protein, and blocks its ion channel activity, inhibiting viral uncoating and replication
• Used as an adjunct treatment for chronic pain in dogs and cats, and for equine-2 influenza via IV
• Pharmacokinetics: Not described in dogs and cats, but has variable absorption and bioavailability of 40-60% in horses
• Adverse effects: Agitation, loose stools, flatulence, and diarrhea

Famciclovir

• For feline herpes (FHV-1), converted into penciclovir, which inhibits herpes virus DNA polymerase
• Pharmacokinetics: Cats require higher doses due to poor conversion to penciclovir
• Contraindication: Hypersensitivity
• Adverse effects: Not well documented, but well-tolerated when used up to three weeks

Antifungal Drugs

• Antifungal drugs are used to treat fungal infections in animals.
• Fungi can be unicellular or multicellular, and are classified into molds, mushrooms, and yeasts.

Azoles

• Azoles are a group of antifungal drugs that include imidazoles and triazoles.
• Azoles have antibacterial, antifungal, antiprotozoal, and anthelmintic activity.
• Azoles are poorly water-soluble, except for fluconazole.
• Azoles can be divided into imidazoles (e.g., clotrimazole, miconazole, econazole) and triazoles (e.g., ketoconazole, itraconazole, fluconazole).

Ketoconazole

• Ketoconazole is an imidazole antifungal drug used for systemic fungal infections.
• Mechanism of action: inhibits synthesis of ergosterol in fungal cytoplasmic membranes by blocking cytochrome P-450 enzymes.
• Pharmacokinetics: well-absorbed orally, widely distributed, and metabolized in the liver.

Itraconazole

• Itraconazole is a triazole antifungal drug used for systemic fungal infections.
• Mechanism of action: inhibits synthesis of ergesterol in fungal cytoplasmic membranes.
• Indications: systemic mycoses, including aspergillosis, blastomycosis, and histoplasmosis.
• Adverse effects: fewer side effects than ketoconazole, but can cause hepatic toxicity, anorexia, weight loss, and vomiting.

Fluconazole

• Fluconazole is a triazole antifungal drug used for systemic fungal infections.
• Mechanism of action: inhibits synthesis of ergosterol in fungal cytoplasmic membranes.
• Indications: systemic mycoses, including cryptococcal meningitis, blastomycosis, and histoplasmosis.
• Pharmacokinetics: well-absorbed orally, widely distributed, and excreted in the urine.

Miconazole

• Miconazole is an imidazole antifungal drug used topically or orally for fungal infections.
• Indications: fungal keratitis in horses, canine and feline dermatophytoses.

Polyene Macrolides

• Polyene macrolides are a group of antifungal drugs that include amphotericin B, nystatin, and natamycin.
• Mechanism of action: binds to ergosterol in fungal membranes, forming pores and causing leakage of cellular contents.

Amphotericin B

• Amphotericin B is a polyene macrolide antifungal drug used for systemic fungal infections.
• Mechanism of action: binds to ergosterol in fungal membranes, forming pores and causing leakage of cellular contents.
• Pharmacokinetics: not absorbed orally, distributed to most tissues except CNS, eye, and bone, and excreted in the urine.
• Adverse effects: renal toxicity, renal vasoconstriction, and decreased renal glomerular filtration.

Nystatin

• Nystatin is a polyene macrolide antifungal drug used topically or orally for fungal infections.
• Indications: candidiasis, dermatophytosis, and gastrointestinal fungal infections.

Natamycin

• Natamycin is a polyene macrolide antifungal drug used topically for fungal eye infections.
• Indications: fungal keratitis in horses and humans.

Flucytosine

• Flucytosine is a fluorinated pyrimidine antifungal drug used orally for systemic fungal infections.
• Mechanism of action: inhibits synthesis of DNA and RNA in susceptible fungi.
• Indications: cryptococcosis, aspergillosis, and candidiasis.
• Pharmacokinetics: well-absorbed orally, widely distributed, and excreted in the urine.

Griseofulvin

• Griseofulvin is a benzofuran antifungal drug used orally for dermatophytic infections.
• Mechanism of action: binds to microtubules, inhibiting spindle formation and mitosis in dermatophytes.
• Pharmacokinetics: absorbed orally, distributed to keratin precursor cells, and metabolized in the liver.

Terbinafine

• Terbinafine is an allylamine derivative antifungal drug used orally or topically for fungal infections.
• Mechanism of action: inhibits synthesis of ergosterol by blocking the enzyme squalene monooxygenase.
• Indications: dermatophytic infections in dogs and cats, and aspergillosis in birds.

Other Antifungals

• Chlorhexidine, iodine, tolnaftate, benzoic acid, salicylic acid, and thiabendazole are other antifungal drugs used topically or orally for various fungal infections.

Antifungal Drugs

• Itraconazole: Delivered by subconjunctival route, used for systemic mycoses (Aspergillosis, Cryptococcal meningitis, Blastomycosis, Histoplasmosis), no effects on hormone synthesis.
  • Can cause hepatic toxicity, anorexia, weight loss, and vomiting.

Polyene Macrolides

• Amphotericin B: Mechanism of action: binds to ergosterol of fungal membrane, forming pores or channels that result in leakage of cellular contents, fungicidal or fungistatic.
  • Used for systemic mycoses in dogs, cats, horses, and birds.
  • Can be combined with ketoconazole, fluconazole, or itraconazole to reduce toxicity.
  • Adverse effects: renal toxicity, renal vasoconstriction, decreased renal glomerular filtration, and damage to tubular epithelium.
• Nystatin: Fungistatic or fungicidal, used for candidiasis in small animals and birds.
  • Combined with other drugs: neomycin, thiostrepton, and triamcinolone acetonide.
• Natamycin: Ophthalmic preparation approved as an antifungal for eyes, used for fungal dermatitis (Fusarium keratomycosis) in horses.

Other Antifungals

• Flucytosine: Fluorinated pyrimidine, mechanism of action: inhibits thymidylate synthetase, inhibits DNA and RNA synthesis in susceptible fungi.
  • Well absorbed orally, widely distributed, and excreted unchanged in the urine.
  • Effective against Cryptococcus, Candida, and Aspergillus spp.
  • Adverse side effects: low toxicity, mild gastrointestinal disturbances, and rare bone marrow depression.
• Terbinafine: Allylamine derivative, mechanism of action: inhibits the synthesis of ergosterol by blocking the enzyme squalene monooxygenase.
  • Fungicidal vs. dermatophytes, fungistatic vs. yeast.
  • Can be administered orally or topically, useful for treating dermatophytic infections in dogs and cats.

Griseofulvin

• Griseofulvin: From Penicillium griseofulvum, actively taken up by growing dermatophytes, binds to microtubules, inhibiting spindle formation and mitosis.
  • Fungistatic vs. Microsporum spp. and Trichophyton spp.
  • Action is slow, infected cells shed and replaced with uninfected cells.
  • Absorption: high oral absorption, high-fat foods, and preparation of micronized particles.
  • Pharmacokinetics: distributed to keratin precursor cells of the skin, hair shafts, and nails, metabolized in the liver, and excreted in urine.

Azoles

• Azoles: Have antibacterial, antifungal, antiprotozoal, and anthelmintic activity, poorly water soluble except for fluconazole.
  • Divided into Imidazoles and Triazoles.
  • Mechanism of action: alter cell membrane permeability of susceptible yeasts and fungi, block synthesis of ergosterol, and inhibit other enzyme systems.
• Ketoconazole: Imidazole antifungal for systemic use, mechanism of action: inhibits synthesis of ergosterol in fungal cytoplasmic membranes by blocking cytochrome P-450 enzymes.
  • Fungistatic, often given orally, and topical preparations available.
• Fluconazole: Synthetic, water soluble, fungistatic, and excreted via kidney.
  • Mechanism of action: cell membrane alteration, leakage of cellular contents, and impaired uptake of purine and pyrimidine precursors.
  • Indications: systemic mycoses, cryptococcal meningitis, blastomycosis, and histoplasmosis.

Antifungal Drugs

• Flucytosine:
  • Inhibits thymidylate synthetase
  • Inhibits DNA and RNA synthesis in susceptible fungi
  • Effective against Cryptococcus, Candida, and Aspergillus
  • Well absorbed orally, widely distributed, and excreted unchanged in the urine
  • Therapeutic uses: combined with amphotericin B for cryptococcosis, aspergillosis, and candidiasis
  • Adverse side effects: low toxicity, mild gastrointestinal disturbances, and rare bone marrow depression

Terbinafine

• Allylamine derivative
• MOA: inhibits the synthesis of ergosterol by blocking squalene monooxygenase
• Fungicidal vs dermatophytes and fungistatic vs yeast
• Can be administered orally or topically for treating dermatophytic infections and systemic mycotic infections

Other Antifungals

• Chlorhexidine
• Iodine
• Tolnaftate
• Benzoic acid
• Salicylic acid
• Thiabendazole

Griseofulvin

• MOA: binds to microtubules, inhibiting spindle formation and mitosis
• Fungistatic against Microsporum spp. and Trichophyton spp.
• Action is slow, and infected cells shed and are replaced with uninfected cells
• Pharmacokinetics: high oral absorption, distributed to keratin precursor cells, metabolized in the liver, and excreted in the urine
• Administration and use: PO in dogs, cats, and horses for multifocal dermatophyte infections
• Adverse effects: rare, idiosyncratic reaction in kittens, leukopenia, and anemia

Azoles

• Have antibacterial, antifungal, antiprotozoal, and anthelmintic activity
• Divided into Imidazoles and Triazoles
• MOA: alter cell membrane permeability, block synthesis of ergosterol, and inhibit other enzyme systems
• Fungistatic against Blastomyces, Coccidioides, Cryptococcus, and Histoplasma spp.

Ketoconazole

• Imidazole antifungal for systemic use
• MOA: inhibits synthesis of ergosterol in fungal cytoplasmic membranes by blocking cytochrome P-450 enzymes
• Fungistatic
• Often given orally or topically

Itraconazole

• For systemic mycoses: aspergillosis, cryptococcal meningitis, blastomycosis, and histoplasmosis
• No effects on hormone synthesis
• Adverse effects: hepatic toxicity, anorexia, weight loss, and vomiting

Polyene Macrolides

• From various strains of Actinomyces
• Include Amphotericin B, Nystatin, and Pimaricin (natamycin)
• Poorly soluble in water

Amphotericin B

• Polyene macrolide
• MOA: binds to ergosterol of fungal membrane, forming pores or channels, leading to leakage of cellular contents
• Fungicidal or fungistatic
• Spectrum of activity: systemic mycoses of dog, cats, horses, and birds
• Pharmacokinetics: not absorbed in the GIT, distributed to most tissues except CNS, eye, and bone, and secreted unchanged in the urine
• Adverse effects: renal toxicity, renal vasoconstriction, and decreased renal glomerular filtration

Nystatin

• Fungistatic or fungicidal
• From Streptomyces noursei
• Combined with other drugs: Neomycin, Thiostrepton, and Triamcinolone acetonide
• For candidiasis infecting the skin, mucous membranes, and intestinal tract of small animals and birds
• Adverse side effects: rare

Natamycin

• Ophthalmic preparation: approved antifungal for eyes
• Poorly water soluble
• For fungal dermatitis and Fusarium keratomycosis in horses