Anti-Viral and Anti-Fungal Agents Overview

Anti-Herpes Agents

• Antiviral Drugs
    - Mechanism of Action (MOA)
      - Most drugs are antimetabolites.
      - Bioactivated via viral or host cell kinases to form active drugs.
      - Inhibit viral DNA polymerases responsible for making new DNA.

Acyclovir (Sitavig)

• MOA:
    - Guanosine analog active against:
      - Herpes Simplex Virus 1 (HSV-1)
      - Herpes Simplex Virus 2 (HSV-2)
      - Varicella Zoster Virus (VZV)
    - Activated by thymidine kinase to form acyclovir triphosphate:
      - Contains 3 phosphates to be active.
      - Viral kinase converts monophosphate to diphosphate; host kinase converts diphosphate to triphosphate, which leads to
        - Incorporation into viral DNA.
        - Termination of the growing DNA chain, thus inhibiting viral growth.
• Pharmacokinetics:
    - Short half-life.
    - Available via topical, oral, and intravenous routes.
    - Renal excretion is the primary route of elimination.
• Clinical Uses:
    - Treats mucocutaneous and genital herpes.
    - Prophylactic use in immunocompromised patients (e.g., HIV and organ transplantation).
• Toxicity:
    - Potential gastrointestinal (GI) distress, headache, delirium, tremor, seizures, hypotension, and nephrotoxicity.

Ganciclovir (Cytovene)

• MOA:
    - Guanine derivative that inhibits DNA polymerases of Cytomegalovirus (CMV) and HSV.
    - Incorporated into host DNA strand via DNA polymerase, which is indirectly conducted.
• Pharmacokinetics:
    - Hydrophobic nature allows good tissue penetration, notably into ocular and central nervous system (CNS) tissues.
    - Major route of excretion is renal.
• Clinical Uses:
    - Used for prophylaxis and treatment of CMV retinitis.
• Toxicity:
    - Causes leukopenia, thrombocytopenia, mucositis, hepatic dysfunction, and possible seizures.

Cidofovir (Vistide) and Brincidofovir (Tembexa)

• MOA:
    - Brincidofovir is a prodrug of cidofovir with a lipo chain aiding in plasma membrane incorporation.
    - Phosphonate that activates through host cell kinases.
    - The active diphosphate form inhibits DNA polymerases for various viruses including:
      - HSV, CMV, Adenovirus, HPV.
• Pharmacokinetics:
    - Effective against strains resistant to acyclovir and ganciclovir.
    - Renal excretion through the kidneys is predominant.
• Clinical Uses:
    - Effective for CMV retinitis and mucocutaneous HSV infections.
• Toxicity:
    - Nephrotoxicity is a major adverse effect.

Foscarnet (Foscovir)

• MOA:
    - Phosphonoformate derivative that does not require prior phosphorylation for antiviral activity.
    - Inhibits RNA polymerase, DNA polymerase, and HIV reverse transcriptase.
• Pharmacokinetics:
    - Good tissue penetration, including CNS.
    - Renal excretion is the major route.
• Clinical Uses:
    - Prophylaxis and treatment for CMV retinitis and other CMV infections.
• Toxicity:
    - Nephrotoxicity, hypocalcemia, genitourinary ulceration, and CNS effects (headaches, hallucinations, seizures).

Other Anti-Herpes Drugs

• Vidarabine (Vira-A):
    - Adenine analog effective against HSV, VZV, and CMV.
• Idoxuridine (Herplex) and Trifluridine (Viroptic):
    - Pyrimidine analogs targeting herpes keratitis (HSV-1).
• Fomivirsen (Vitravene):
    - Antisense oligonucleotide targeting CMV mRNA.
• Valacyclovir (Valtrex):
    - Prodrug of acyclovir, metabolized by the liver.
• Penciclovir (Denavir):
    - Direct DNA polymerase inhibitor; does not cause chain termination.
• Docosanol (Abreva):
    - Aliphatic alcohol inhibiting fusion between the HSV envelope and host plasma membranes.

Current Approaches to Antiviral Treatment

• Combination Therapy:
    - Treatment with three or more antiretroviral drugs is common.
    - Involves nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), collectively known as Highly Active Antiretroviral Therapy (HAART).
• Goals of HAART:
    - Reverse or slow increases in viral load (viral RNA).
    - Slow or reverse the decline in CD4 cells, thereby decreasing the incidence of opportunistic infections.
    - Notably, CD4 attaches to the chemokine receptor on host cells, facilitating HIV entry.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• MOA:
    - Prodrugs converted by host cell kinases into active triphosphates.
    - Lack a 3’-hydroxyl group on ribose ring, preventing attachment of the subsequent nucleotide.
    - Specifically inhibits RNA-dependent DNA polymerase (reverse transcriptase) without affecting mammalian polymerases.
• Clinical Uses:
    - Primarily utilized in anti-retroviral therapy for HIV.
• Resistance Mechanisms:
    - Commonly due to mutations in the HIV reverse transcriptase.

Individual NRTIs

• Abacavir (Ziagen):
    - MOA: Guanosine analog RT inhibitor.
    - Pharmacokinetics: Good oral bioavailability, half-life of 12-24 hours.
    - Toxicity: Hypersensitivity reactions, which can be fatal.
• Didanosine (Videx):
    - MOA: Inhibits reverse transcriptase.
    - Pharmacokinetics: Oral bioavailability reduced by food and chelating agents, renal elimination.
    - Toxicity: Pancreatitis, peripheral neuropathy, diarrhea, hepatic dysfunction, hyperuricemia, and CNS effects.
• Emtricitabine (Emtriva):
    - MOA: RT inhibitor.
    - Pharmacokinetics: Good bioavailability and renal elimination, allowing for once-daily dosing.
    - Toxicity: Asthenia, GI distress, headache, and hyperpigmentation of palms/soles.
• Lamivudine (Epivir):
    - MOA: 2’-deoxy-3’-thiacytidine RT inhibitor.
    - Pharmacokinetics: 80% bioavailability orally, kidney elimination.
    - Toxicity: GI distress, headache, insomnia, and fatigue.
• Stavudine (Zerit):
    - MOA: 2′,3′-didehydro-2′,3′-dideoxythymidine RT inhibitor.
    - Pharmacokinetics: Well-absorbed orally, good tissue penetration including the CNS.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Lactic Acidosis with Hepatic Steatosis:
    - Notable adverse effects.
• Tenofovir (Viread):
    - MOA: RT inhibitor.
    - Pharmacokinetics: Oral bioavailability 25-40%, half-life over 60 hours, renal elimination.
    - Toxicity: GI distress, asthenia, headache, acute renal failure, and Fanconi syndrome.
• Zalcitabine:
    - MOA: 2’-3’-dideoxycytidine RT inhibitor.
    - Pharmacokinetics: High oral bioavailability.
    - Toxicity: Pancreatitis, esophageal ulceration, stomatitis, and arthralgias.
• Zidovudine:
    - MOA: Azidothymidine RT inhibitor.
    - Pharmacokinetics: Orally active, distributed widely including CNS, eliminates hepatic and renal.
    - Toxicity: Bone marrow suppression causing anemia and neutropenia, GI distress, and CNS adverse effects.

NNRTI Mechanism and Resistance

• MOA:
    - Directly binds to a site on reverse transcriptase distinct from NRTIs, requires no phosphorylation for activity.
    - Does not compete with nucleoside triphosphates and has distinct resistance mechanisms.
    - Clinical Use: Anti-retroviral therapy for HIV.
    - NOTES:
      - All hypersensitivity reactions manifest as rashes.

Delavirdine (Rescriptor)

• Pharmacokinetics:
    - Subject to significant drug interactions, metabolized by CYP3A4 and CYP2D6.
    - Antacid use decreases blood levels; azole and macrolide antibiotics increase blood levels.

Protease Inhibitors

• Toxicity:
    - Skin rashes are common; some drugs are avoided in pregnancy due to teratogenicity in animals.
• Efavirenz (Sustiva):
    - Pharmacokinetics: Long half-life; absorption enhanced by fatty food.
    - Toxicity: CNS dysfunction, skin rash, elevation of plasma cholesterol.
• Etravirine (Intelence):
    - Pharmacokinetics: Second-generation with longer half-life and reduced toxicity, significant drug-drug interactions.
    - Toxicity: Skin rash, nausea, diarrhea, elevations in serum cholesterol, triglycerides, and transaminases.
• Nevirapine (Viramune):
    - Pharmacokinetics: Good oral bioavailability, good CNS penetration, half-life more than 24 hours, metabolized by hepatic CYP3A4.
    - Toxicity: Skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis.
• Rilpivirine (Edurant):
    - Pharmacokinetics: Second generation with a half-life of approximately 50 hours; interacts with antacids.
    - Toxicity: Skin rash, depression, headache, insomnia, increased serum aminotransferases, and fat redistribution syndrome.

HIV Protease Inhibitors

• Mechanism of Action:
    - Designed to inhibit the active site of the viral protease.
    - Resistance occurs due to multiple point mutations in the pol gene.
    - NOTES:
        - Resistance can lead to carbohydrate and lipid metabolism disorders (hyperglycemia, insulin resistance, hyperlipidemia, body fat distribution issues).
• Atazanavir (Reyataz):
    - Pharmacokinetics: Once-daily dosing, hepatic metabolism, penetrates cerebrospinal fluid, renal excretion.
    - Toxicity: GI distress, peripheral neuropathy, skin rash, hyperbilirubinemia.
• Darunavir (Prezista):
    - Pharmacokinetics: Used in combination with ritonavir or cobicistat, similar pharmacokinetics to Atazanavir.
    - Toxicity: GI adverse effects, rash, and possible liver toxicity.
• Fosamprenavir (Lexiva):
    - Pharmacokinetics: Prodrug converted to amprenavir; hepatic metabolism; inhibits and induces CYP3A4.
    - Toxicity: GI distress, paresthesias, rash; cross allergenicity possible with