Antifungals And Antivirals Drugs

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List the three major classes of antifungal drugs

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3 major antifungal classes:

1) Polyene (nystatin, amphotericin B)

2) Azole (ketocon-, itracon-, flucon-, voriconazole)

3) Allylamine (terbinafine)

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Types of Antifungal Mechanism of Action

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#1 Antifungals whose mechanism involves Ergosterol
(Polyenes, Azoles, and Allylamines)
#2 Antifungals that interfere with fungal cell-wall synthesis (Echinocandins)
#3 Miscellaneous Antifungals (Flucytosine)

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Polyenes

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Nystatin, Amphotericin B
Antifungal drugs the bind to ergosterol in the cell membrane of fungi and yeasts. This binding allows the drug to form pores or channels in the membrane. Sodium and potassium leak out of these channels distrupting the internal environment and leading to fungistatic or fungicidal effects.

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Nystatin

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Polyene antifungal drug.
Binds to ergosterol --> form pores--> Na and K leak out --> kills fungi
-Too toxic to be used systemically so used locally
Uses: Thrush in mouth
Adverse Effects: Nephrotoxic

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Amphotericin B

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Polyene antifungal drug.
Binds to ergosterol --> form pores--> Na and K leak out --> kills fungi
Gold Standard for treating serious systemic fungal infections.
IV, mostly metabolized, long half life of 15 days.
Uses: treatment of life-threatening fungal infections in patients with impaired defense mechanisms.
Adverse effects: Hypersensitivity reactions, anaphylaxis, Infusion related side effects (fever, chills, headache, nausea, vomiting). Tolerance is usually developed to these minor issues with continued use. 80% of patients experience decreased renal function that doesn't return after drug stopped.

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Azoles

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Ketoconazole, Itraconazole, Fluconazole, Voriconazole
-Inhibit lanosterol 14-alpha-demethylase which is required for the conversion of lanosterol to ergosterol. Depletion of ergosterol in the fungal cell membrane leads to failure of the membrane and fungal cell death.
Resistance to Azoles: Efflux pump, altered target protein (14-alpha-demethylase), and increase target protein expression.
Azoles have broad spectrum of antifungal activity

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Ketoconazole

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Azole Antifungal
Inhibits 14-alpha-demethylase. Decreases Ergosterol.
Adverse Effects: Hepatotoxicity (monitor liver enzymes) with rare fatalities, Anaphylaxis after first dose.
Drug interactions: Potent inhibitor of cytochrome P450 3A4 so inhibits metabolism of Astemizole and Cisapride which may prolong QT intervals.
High doses demonstrated to lower testosterone and ACTH-induced corticosteroid serum levels.

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Itraconazole

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Azole Antifungal
Inhibits 14-alpha-demethylase. Decreases Ergosterol.
Drug can be detected in nailbeds for 6-9 months. Metabolized into 30 metabolites including hydroxy itraconazole which active.
Drug interactions: cytochrome P450 3A4 inhibitor but P450 inducers can also decrease effectiveness of itraconazole.
Contraindications:Not used for treatment of onychomycosis in patients with congestive heart failure.

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Fluconazole

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Azole Antifungal
Inhibits 14-alpha-demethylase. Decreases Ergosterol.
Over 90% oral bioavailability. Distributes well into body tissues including CSF (meningitis), saliva, sputum, nail, blister, vaginal secretion.
Drug Interactions: Potent inhibitor of CYP2C9 and mod inhibitor of CYP3A4.
Very high doses can be teratogenic in pregnant women.

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Voriconazole

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Azole Antifungal -Second generation (improved target activity and specificity)
Inhibits 14-alpha-demethylase. Decreases Ergosterol.
Uses: treatment of invasive fungal infections, including aspergillosis in kids who didn't respond to conventional antifungal therapy.
Drug Interactions: Inhibitor of CYP2C19, CYP2C9 and CYP3A4 (but less so than Ketoconazole and Itraconazole).

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Terbinafine

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Allylamine Antifungal
-Noncompetitive inhibitor of fungal squalene epoxidase which prevents squalene expoxiation which is an important step in ergosterol synthesis.
Active against wide range of fungi.
Synergistic effect with Azoles and Amphotericin B

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Echinocandins

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Anidulafungin, Caspofungin, Micafungin
Inhibit the synthesis of beta-1,3-D-diglucans, an essential component of fungal cell wall.
Uses: treatment of invasive aspergillosis inpatients not responding to other antifungals.

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Andiulafungin

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Echinocandin Antifungal
Inhibit the synthesis of beta-1,3-D-diglucans, an essential component of fungal cell wall.
Uses: treatment of invasive aspergillosis inpatients not responding to other antifungals.

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Caspofungin

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Echinocandin Antifungal
Inhibit the synthesis of beta-1,3-D-diglucans, an essential component of fungal cell wall.
Uses: treatment of invasive aspergillosis inpatients not responding to other antifungals.

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Micafungin

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Echinocandin Antifungal
Inhibit the synthesis of beta-1,3-D-diglucans, an essential component of fungal cell wall.
Uses: treatment of invasive aspergillosis inpatients not responding to other antifungals.

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Flucytosine

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Antifungal (miscellaneous)
-Taken up by fungus-specific enzyme cytosine permease and converted by cytosine deminase to 5-fluorouracil --> causes RNA miscoding and inhibits DNA synthesis.
Oral.Widely distributed to body tissues.
Resistance develops if given by itself.
Adverse Effects: potentially lethal bone marrow depression, GI upset, rash, and hepatic dysfunction.
Synergistic with Amphotercin B so can lower Amph B dose so it's less toxic.

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Anti-influenza Drugs (Antivirals for respiratory viruses)

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Amantadine, Rimantadine, Oseltamivir, Zanamivir, Ribavirin

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Amantadine

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Anti-influenza drug.
Symmetric tricyclic amines that inhibit the replication of influenza A viruses at low concentrations by blocking action of M2 protein. M2 protein - membrane protein required for efficient necleocapsid release (viral uncoating) after viral fusion with the endosomal membrane.
Uses: prophylaxis during influenza A virus epidemic (nursing homes).
Adverse Effects: confusion, hallucination, seizure and coma.

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Rimantadine

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Anti-influenza drug.
Symmetric tricyclic amines that inhibit the replication of influenza A viruses at low concentrations by blocking action of M2 protein. M2 protein - membrane protein required for efficient necleocapsid release (viral uncoating) after viral fusion with the endosomal membrane.
Uses: prophylaxis during influenza A virus epidemic (nursing homes).
Adverse Effects: significantly less CNS stimulation than Amantadine.

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Oseltamivir

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Anti-influenza Drug (antiviral)
Inhibit viral enzyme neuraminidase.
Active against influenza A and B and H1N1.
Oral.
Adverse Effects: self-injury and delirium in children.
Use: decreases severity and duration (by 1-2days) of disease and decrease viral shedding if taken within 36 hrs of first symptom.

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Zanamivir

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Anti-influenza Drug (antiviral)
Inhibit viral enzyme neuraminidase.
Active against influenza A and B and H1N1.
Administered by inhalation.
Adverse Effects: Bronchospasm.
Use: decreases severity and duration (by 1-2days) of disease and decrease viral shedding if taken within 36 hrs of first symptom.

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Ribavirin

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Antiviral drug
Activity against influenza viruses, respiratory syncytial virus, parainfluenza viruses and adenoviruses.
-Guanosine analog that inhibits influenza virus RNA polymerase activity and competitively inhibits guanosine triphosphate-dependent 5'-capping of influenza viral messenger RNA.
Ribavirin in combo with pegylated interferon-alpha-2b = treatment of chronic Hepatitis C infection.

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Drugs for Non-HIV viral infections

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#1Synthetic Nucleosides that require metabolic activation - Acyclovir, Valacyclovir, Famciclovir, Ganciclovir, Valaganciclovir
#2 Non-nucleoside antivirals - Foscarnet

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Acyclovir

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Nucleoside Analog Antiviral
Required metabolic activation to the triphosphate to exert antiviral activity. Drug only activated in infected cells by Herpes virus thymidine kinase.
Triphosphate then: inhibits viral DNA polymerase and incorporation of triphosphate into viral DNA leads to premature chain termination.
Resistance: Loss of thymidine kinase activity = no activation (cross resistance to valacyclovir and famciclovir)
Uses: Active against Herpres Simplex Virus (HSV-1, HSV-2), VZV and EBV. Treatment of serious HSV and VZV infections.
Given IV
Adverse Effects: headaches, GI disturbances, renal dysfunction due to crystalline nephropathy (IV form)

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Valacyclovir

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Nucleoside Analog Antiviral
-Valacyclovir is metabolized to acyclovir after oral administration.
Required metabolic activation to the triphosphate to exert antiviral activity. Drug only activated in infected cells by Herpes virus thymidine kinase.
Triphosphate then: inhibits viral DNA polymerase and incorporation of triphosphate into viral DNA leads to premature chain termination.
Resistance: Loss of thymidine kinase activity = no activation (cross resistance to valacyclovir and famciclovir)
Uses: Active against Herpres Simplex Virus (HSV-1, HSV-2), VZV and EBV. Treatment of serious HSV and VZV infec
Adverse Effects: headaches, GI disturbances,

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Famiciclovir

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Nucleoside Analog Antiviral
-A prodrug converted to penciclovir (active).
Required metabolic activation to the triphosphate to exert antiviral activity. Drug only activated in infected cells.
Triphosphate then: inhibits viral DNA polymerase.
Resistance: Loss of thymidine kinase activity = no activation (cross resistance to valacyclovir and famciclovir)
Uses: Active against Herpres Simplex Virus (HSV-1, HSV-2), VZV and EBV. Treatment of serious HSV and VZV infections.

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Ganciclovir

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Nucleoside Analog Antiviral
-Similar to acyclovir but enhanced activity against CMV.
Required metabolic activation to the triphosphate to exert antiviral activity. Drug only activated in infected cells by Herpes virus thymidine kinase.
Triphosphate then: inhibits viral DNA replication in HSV.
Adverse Effects: dose-limiting toxicities - granulocytopenia and thrombocytopenia
Uses: Treats cytomegalovirus (CMV) retinitis, CMV colitis, and CMV esophagitis in AIDS patients and to prevent or treat CMV disease in allogenic transplant patients.

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Valaganciclovir

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Prodrug of ganciclovir.

Treats CMV.

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Foscarnet

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Non-nucleoside antiviral
-Binds to phosphate binding site of viral DNA or RNA polymerase and HIV reverse transcriptase and inhibits the enzyme.
Uses: treats resistant CMV retinitis and acyclovir-resistant HSV and VZV. (less well tolerated than ganciclovir).
Adverse Effects: Renal dysfunction which is usually reversible althought renal failure with dialysis may occur.

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HAART

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Treatment regimen for HIV.
Highly Active AntiRetroviral Therapy.
1. HIV rapidly becomes resistant if only a single drug is used.
2. survivorship is inversely related to the circulating level of HIV RNA in the blood
3. Survivorship is positively correlated with CD4 count.
Uses multiple drugs (usually 3) and tries to reduce blood level of HIV RNA and maintain CD4 count.
Class Sparing = They always hold back one class of drug so that if a resistance to class develops they will have backups.

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Classes of Drugs used to Treat HIV

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1. Nucleoside reverse transcriptase inhibitors (nRTI)
2. Non-nucleoside reverse transcriptase inhibitors (nnRTI)
3. HIV protease inhibitors (PI)
4. Fusion inhibitor (secondary drug)
5. Entry inhibitor (secondary drug)
6. Integrase inhibitor

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nRTIs (nucleoside reverse transcriptase inhibitors)

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Emtricitabine, Tenofovir, Abacavir, Lamivudine, Didanosine, Zidovudine
Purine or pyrimidine analogs that must be metabolically activated into a triphosphate. The triphosphate then competitively inhibits HIV reverse transcriptase and are incorporated into the DNA chain causing chain termination.
Adverse Effects: Lactic acidosis (stop drug), hepatic steatosis, peripheral neuropathy, myopathy, and lipoatrophy. Side effects due to inhibiting mitochondrial DNA polymerase - y

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Emtricitabine

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Newer nRTI drug
Purine or pyrimidine analogs that must be metabolically activated into a triphosphate. The triphosphate then competitively inhibits HIV reverse transcriptase and are incorporated into the DNA chain causing chain termination.
Adverse Effects: Lactic acidosis (stop drug), hepatic steatosis, peripheral neuropathy, myopathy, and lipoatrophy. Has fewer Side effects due to less inhibition mitochondrial DNA polymerase - y

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Tenofovir

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Newer nRTI drug
Purine or pyrimidine analogs that must be metabolically activated into a triphosphate. The triphosphate then competitively inhibits HIV reverse transcriptase and are incorporated into the DNA chain causing chain termination.
Adverse Effects: Lactic acidosis (stop drug), hepatic steatosis, peripheral neuropathy, myopathy, and lipoatrophy. Has fewer Side effects due to less inhibition mitochondrial DNA polymerase - y

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Abacavir

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nRTI Drug
Purine or pyrimidine analogs that must be metabolically activated into a triphosphate. The triphosphate then competitively inhibits HIV reverse transcriptase and are incorporated into the DNA chain causing chain termination.
Adverse Effects: Lactic acidosis (stop drug), hepatic steatosis, peripheral neuropathy, myopathy, and lipoatrophy. Side effects due to inhibiting mitochondrial DNA polymerase - y

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Lamivudine

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nRTI Drug
Purine or pyrimidine analogs that must be metabolically activated into a triphosphate. The triphosphate then competitively inhibits HIV reverse transcriptase and are incorporated into the DNA chain causing chain termination.
Adverse Effects: Lactic acidosis (stop drug), hepatic steatosis, peripheral neuropathy, myopathy, and lipoatrophy. Side effects due to inhibiting mitochondrial DNA polymerase - y

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Didanosine

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nRTI Drug
Purine or pyrimidine analogs that must be metabolically activated into a triphosphate. The triphosphate then competitively inhibits HIV reverse transcriptase and are incorporated into the DNA chain causing chain termination.
Adverse Effects: Peripheral neuropathy in 20%, Lactic acidosis (stop drug), hepatic steatosis, myopathy, and lipoatrophy. Side effects due to inhibiting mitochondrial DNA polymerase - y

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Zidovudine

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nRTI Drug
Purine or pyrimidine analogs that must be metabolically activated into a triphosphate. The triphosphate then competitively inhibits HIV reverse transcriptase and are incorporated into the DNA chain causing chain termination.
Adverse Effects: Neutropenia (2%), Anemia (1%), Lactic acidosis (stop drug), hepatic steatosis, peripheral neuropathy, myopathy, and lipoatrophy. Side effects due to inhibiting mitochondrial DNA polymerase - y.

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nnRTIs (non-nucleoside reverse transcriptase inhibitors)

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Efavirenz, Nevirapine
Do not require metabolic activation. They bind to site close to the active site on reverse transcriptase and lock the enzyme into the inactive state.
Active against HIV-1 except subtype O and inactive against HIV-2.
HIV that is resistant to nRTIs and protease inhibitors remain sensitive to nnRTI. There is cross-resistance within nnRTIs.
Adverse Effects: Rash (most common side effect) that can become severe.
nnRTIs are metabolized by P450 enzymes so drug interactions with protease inhibitors

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Efavirenz

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nnRTI
Use: component of HIV therapy
Adverse effect: Rash, CNS or pysch problems (vivid dreams, hallucinations, etc), tetratogenic so contraindicated for pregnant women.

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Nevirapine

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nnRTI
Use: component of HIV therapy
Adverse Effects: Rash that can be severe

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HIV Protease Inhibitors

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Atazanavir, Darunavir, Fosamprenavir, Lopinavir, Ritonavir, Saquinavir
As mature HIV virions are produced the bud off the cell surface and gag and gag-pol polyprotein precursors are cleaved by proteases. This process is essential for maturation of infectious virus.
PIs bind to the active site of HIV protease and inhibit both HIV-1 and HIV-2.
Resistance: develops rapidly is used as single drug, cross resistance within PIs.
Adverse Effects: GI disturbances, increased aminotransferase activity, increased bleeding in hemophiliacs, new or worsening diabetes, insulin resistance, fat wasting and resdistribution (buffalo hump).
Drug Interactions: PIs are metabolized by P450 enzymes . Rifampin is a CYP34A inducer so decreases effectiveness of PIs.

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Atazanavir

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HIV Protease Inhibitor
PIs bind to the active site of HIV protease and inhibit both HIV-1 and HIV-2.
Resistance: develops rapidly is used as single drug, cross resistance within PIs.
Adverse Effects: GI disturbances, increased aminotransferase activity, increased bleeding in hemophiliacs, new or worsening diabetes, insulin resistance, fat wasting and resdistribution (buffalo hump).
Drug Interactions: PIs are metabolized by P450 enzymes . Rifampin is a CYP34A inducer so decreases effectiveness of PIs.

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Darunavir

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HIV Protease Inhibitor
PIs bind to the active site of HIV protease and inhibit both HIV-1 and HIV-2.
Resistance: develops rapidly is used as single drug, cross resistance within PIs.
Adverse Effects: GI disturbances, increased aminotransferase activity, increased bleeding in hemophiliacs, new or worsening diabetes, insulin resistance, fat wasting and resdistribution (buffalo hump).
Drug Interactions: PIs are metabolized by P450 enzymes . Rifampin is a CYP34A inducer so decreases effectiveness of PIs.

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Fosamprenavir

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HIV Protease Inhibitor
PIs bind to the active site of HIV protease and inhibit both HIV-1 and HIV-2.
Resistance: develops rapidly is used as single drug, cross resistance within PIs.
Adverse Effects: GI disturbances, increased aminotransferase activity, increased bleeding in hemophiliacs, new or worsening diabetes, insulin resistance, fat wasting and resdistribution (buffalo hump).
Drug Interactions: PIs are metabolized by P450 enzymes . Rifampin is a CYP34A inducer so decreases effectiveness of PIs.

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Lopinavir

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HIV Protease Inhibitor
PIs bind to the active site of HIV protease and inhibit both HIV-1 and HIV-2.
Resistance: develops rapidly is used as single drug, cross resistance within PIs.
Adverse Effects: GI disturbances, increased aminotransferase activity, increased bleeding in hemophiliacs, new or worsening diabetes, insulin resistance, fat wasting and resdistribution (buffalo hump).
Drug Interactions: PIs are metabolized by P450 enzymes . Rifampin is a CYP34A inducer so decreases effectiveness of PIs.

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Ritonavir

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HIV Protease Inhibitor Booster
**Very potent inhibitor of P450 so given at a subtherapeutic dose with a different PI to slow the elimination of the PI

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Saquinavir

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HIV Protease Inhibitor
PIs bind to the active site of HIV protease and inhibit both HIV-1 and HIV-2.
Resistance: develops rapidly is used as single drug, cross resistance within PIs.
Adverse Effects: GI disturbances, increased aminotransferase activity, increased bleeding in hemophiliacs, new or worsening diabetes, insulin resistance, fat wasting and resdistribution (buffalo hump).
Drug Interactions: PIs are metabolized by P450 enzymes . Rifampin is a CYP34A inducer so decreases effectiveness of PIs.

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Raltegravir

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Integrase Inhibitor
Blocks insertion of HIV DNA into host (human) DNA.
This drug is well tolerated.

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Enfuvirtide

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Fusion Inhibitor
Prevents the HIV envelope from fusing the cell membrane of CD4 cells and thereby blocks viral entry and replication.
Use: used in patients that have failed all other HIV therapy.

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Maraviroc

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Entry Inhibitor
Binds to CCR5 on the surface of CD4 cells. CCR5 is a coreceptor for HIV and blocking it prevents entry into the cell.
Resistance: HIV that uses CXCR4 as the coreceptor is resistant to the drug.
Use: used in patients that have failed other HIV therapy.

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Long term Effects of AntiHIV therapy

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HIV Lipodystrophy Syndrome
-Fat redistribution (buffalo hump)
-Elevated cholesterol
-Elevated triglycerides
-Hyperglycemia (insulin resistance)

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Malaria

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Malaria is caused by the protozoa Plamodium. (P. vivax, P. falciparum, P. malariae and P. ovale).
P. falciparum causes the most severe form of malaria and is frequently drug resistant.
Sporozoites in the salivary gland of mosquitos are injected into blood of host. Sporozoites invade the liver and infect the parenchymal cells of the liver and divide into exoerthrocytic merozoites. The RBCs rupture releasing merozoites into the bloodstream that can go infect other RBCs.Pyogenic factors are released which cause fever and other sequela of malaria. P.vivax and P. ovale can remain dormant in the liver as hypnozoites until they are later reactivated.

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Anti-malarials

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Chloroquine, Mefloquine, Quinine, Primaquine, Pyrimethamine + sulfadoxine, Atovaquone/Proguanil

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Chloroquine

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Antimalarial Drug.
Gold standard
Uses: prophylaxis for individuals traveling to area of malaria endemic. Taken while in the area and for 1-2 wks after return.
Adverse Effects: Overdosage can cause reversible corneal damage and permanent damage (Bull's eye). Toxic doses can cause visual disturbances, hyperexcitability, convulsions, and heart block.

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Mefloquine

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Antimalarial
Uses: prophylaxis for travelers. Has activity against species resistant to other drugs.
Adverse Effects: Contrindicated if history of epilepsy, psychiatric disorder, arrhythmia, cardiac conduction defect or sensitivity to quinidine.

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Primaquine

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Antimalarial
Only drug available against liver hypnozoites (take for awhile once you get home)
Adverse Effects:Hemolytic anemia especially in pts deficient in G6PD.
Contraindications: pts with connective tissue disorders or history of granulocytopenia or methemoglobinemia

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Quinine

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Antimalarial
Uses: treats chloroquine-resistant P. falciparum
Adverse Effects: toxic dose may cause Cinchonism (tinnitus, headache, nausea and visual disturbances

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Pyrimethamine

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Antimalarial
A folic acid antagonist --> inhibits DNA synthesis.
Uses: used in combination with sulfadoxine for treatment of chloroquine-resistant P. falciparum.

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Atovaquone/Proguanil

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Antimalarials
Atovaquone - disrupts the mitochondrial electric transport. (used in malaria and Pneumocytis jiroveci)
Proguanil - inhibits dihydrofolate reducatase --> inhibit DNA synthesis.

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Entamoeba Hystolytica Treatments

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Asymptomatic - Iodoquinol
Symptomatic (mild) - Metronidazole + Iodoquinol
Severe or hepatic abscess - Metronidazole + Iodoquinol

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Tichomonas Vaginalis Treament

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Metronidazole

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Pneumocystis jiroveci treatment

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Trimethoprim-sulfamethoxazole (TMP-SMZ) .
But lots of AIDS patients can't tolerate TMP-SMZ so give them Pentamidine

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Toxoplasma gondii treatment

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Pyrimethamine + Trisulfapyrimidines

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Giardia lamblia

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Metronidazole