Chapter 43 Antifungal and Antiviral Agents

Department of pharmacology

Liu xiaokang( 刘小康）2010,3

Antifungal Agents

• Drugs categorized multiple bases: (1) Type of infection: (a) Systemic (Deep) Fungal infections. (b) Topical (Dermatophytic) Fungal infections. (c) Mucous membranes -- Yeast infections. (2) Route/Site of action. (3) Mechanism of action. (4) Chemical nature.

ANTIFUNGAL DRUGS

DrugInfection Type

Route/Site MechanismChemical Group

Amphotericin B Deep/DermIV for Systemic/Topical

Cell membrane

Polyene

NystatinDerm/Yeast

PO for GI/Topical/Vaginal

Cell membrane

Polyene

Itraconazole Deep PO for SystemicCell membrane

Azole

Fluconazole Deep IV,PO for SystemicCell membrane

Azole

Ketoconazole Deep/DermPO for Systemic/Topical

Cell membrane

Azole

Miconazole Deep/DermIV for Systemic/Topical

Cell membrane

Azole

Sulconazole 硫康唑 Derm Topical

Cell membrane

Azole

ANTIFUNGAL DRUGS

DrugInfection Type Route/Site

Mechanism

Chemical Group

Clotrimazole Derm/Yeast Topical/Vaginal

Cell Membrane

Azole

Enilconazole 恩康唑 Derm Topical

Cell Membrane

Azole

Econazole 益康唑

Derm/Yeast Topical/Vaginal

Cell membrane

Azole

Oxiconazole 奥昔康唑

Derm/Yeast Topical/Vaginal

Cell membrane

Azole

Tioconazole 噻康唑

Derm/Yeast Topical/Vaginal

Cell membrane

Azole

Flucytosine Deep PO for Systemic Nuclear Pyrimidine

Griseofulvin Derm PO for Topical Nuclear Other

Terbinafine Derm TopicalCell membrane

Allylamine

• Basis for some selectivity: • Bacteria: Prokaryotes, Have cell wall, Ke

y membrane lipid = hydroxylated glycerols

• Fungi: Eukaryotes, Have cell wall, Key membrane lipid = ergosterol

• Vertebrates: Eukaryotes, NO cell wall, Key membrane lipid = cholesterol

Amphotericin B

• Structure and chemical characteristics: • (1) Poorly water soluble. • (2) Unstable in saline -- must use 5% dext

rose. • (3) Large, charged molecule, polyene deri

vative.• (4) Nystatin related and similar, but mor

e systemic toxicity

• Mechanism of Action: • (1) Affinity for membranes with ergosterol. • (2) Forms channel through membrane. • (3) Small molecules leak. • (4) Cell dies.• (5) Resistance is rare and slow to develop.

• Pharmacokinetics: • Crosses membranes poorly by diffusion a

nd must inject where need, e.g., intrathecal, IV.

• Clinical uses: Deep infection of various fungal.

• Adverse Effects: Many adverse effects, some serious.

Azole Derivatives

• Overview: Much less toxic than amphotericin B

• Mechanism of Action: • Inhibit ergosterol synthesis: Inhibits key

cytochrome P450 step and Lanosterol( 羊毛甾醇 )alpha-C14-demethylase

  Ketoconazole

Fluconazole

Itraconazole

Spectrum NarrowExpanded

Expanded

Route(s) of Adm Oral Oral, IV Oral

t1/2 (hr) 6-9 30 30-40

CSF penetration No Yes No

Renal excretion No Yes No

Interaction with other drugs FrequentOccasional

Occasional

Inhibition of mammalian sterol synthesis

Dose-dependent inhibitory effect

No inhibition

No inhibition

Figure 34.5: Summary of azole fungistatic drugs. P342, Mycek, Harvey & Champe [Pcol-Lipp2nd97]

Ketoconazole

• Broad spectrum antifungal agent.• Pharmacokinetics: Used PO for system

ic effect. Dose-related kinetics, PO doses. Hepatic biotransforming enzymes approach saturation. Half-life after stated oral dose: 6.5 hr -- 100 mg tablet, 8.1 hr -- 200 mg tablet, 9.6 hr -- 300 mg tablet

• Clinical uses: various fungal infection.

• Adverse effects:

• (1) Most common -- anorexia, nausea, vomiting. divided doses have been used to reduce GI side effects.

• (2) Hepatocellular toxicity.

• (3) Adrenocortical suppression

Itraconazole

• Antifungal activity: 5 - 100 times greater in vitro potency and broader antifungal activity than ketoconazole. Good activity against Aspergillus spp. Activity vs meningeal cryptococcus.

• Clinical uses: • Broad antifungal spectrum. Drug of choi

ce for blastomycosis. May be effective in aspergillosis, candidemia, coccidioidomycosis, and cryptococcosis.

• Adverse effects: • Fewer adverse side effects than ketocona

zole. Nausea and vomiting, Rash (especially in immunocompromised patient), Hypokalemia, Hypertension, Edema, Headache.

Fluconazole

• In vivo potencies are 100-fold ketoconazole. Similar with itraconazole

Antiviral Agents • Amantadine• Mechanism: Inhibit early viral processes.

• Pharmacokinetics: PO, Well absorbed, Eliminated unchanged in urine.

• Uses: Highly selective, Influenza A viruses (H1 N1, H2, N2, and H3 N2), NOT clinically active versus influenza B viruses.

• Adverse Effects: Dose related and appear above 1-5 mcg/mL, CNS toxicity, nervousness, confusion, hallucinations, and coma.

• Acyclovir• Antiviral activity: Effective against herpes si

mplex virus (HSV).

• Mechanism of action: Relatively large margin of safety. It is a Prodrug -- must be activated.

• (1) Activated by herpesvirus thymidine kinase (TK).

• (2) Binds to herpes virus thymidine kinase 200 times more strongly than to host TK.

• (3) Inhibits viral DNA polymerase.

• Pharmacokinetics: PO and IV. Widely distributed, including CSF.

• Therapeutic application: • (1) Essentially only for herpesviruses (esp

ecially H.simplex type 1). • (2) Topical, Mucotaneous herpesvirus inf

ections, May be useful for primary genital herpes, less for recurrent (PO better), Herpes simplex keratitis.

• Adverse effects: • Few side effects in humans, Nausea with P

O, Tissue irritation if extravasation on IV.

• Ganciclovir: • Conceptually similar to acyclovir. Lower

margin of safety than acyclovir. Highly efficacious and important drug.

• Mechanism of action: Prodrug, Activated drug incorporated into both host and viral DNA.

• Adverse effects: • Predict toxicity by rapidly dividing

tissues, bone marrow, GI mucosa, and gonads (at all doses tested).

• Uses: • Potent and broad spectrum vs herpes vir

uses, especially Cytomegalovirus (CMV ).

• Ribavarin: • Effective against BOTH DNA and RNA v

iruses. Prodrug that must be phosphorylated. Phosphorylated derivatives inhibit viral nucleic acid synthesis. Generally low toxicity.

• Zidovudine:

• The first and most important drug for palliation of AIDS, Active against HIV-1 and other mammalian retroviruses.

• Mechanism of action: • (1) Decreases reverse transcriptase activity i

n cultured cells at 0.013 mcg/mL • (2) Inhibits replication of HIV-1 virus• (3) Prodrug that must be phosphorylated: P

hosphorylated to triphosphate by cellular enzymes, inhibits viral RNA-directed DNA polymerase (transcriptase), Triphosphate binds more strongly to viral than eukaryotic DNA polymerase.

• (4) DNA chain termination: azidothymidine triphosphate can be incorporated into DNA, hence nucleotides cannot be added to modified 3'-position.

• (5) Mammalian DNA polymerases: Alpha-DNA polymerase relatively resistant to incorporating azido-TP, Gamma DNA polymerase in mitochondria does incorporate -- source of toxicity?

• Resistant strains: Isolated from AIDs patients treated 6 months or more, Still sensitive to dideoxycytidine( 双脱氧胞苷 ) and foscarnet ( 膦甲酸 ).

• Pharmacokinetics: PO, F=60-65%. Peak concentration 30 to 90 minutes. Wide distribution. Usual dosage is 200 mg q4h!! continuously!!

• Adverse effects:

• (1) Hematologic: Granulocytopenia and anemia in up to 45% of patients. (2) Other effects: occur sometimes, Gastrointestinal disturbances, paresthesia, skin rash, insomnia, fever, headaches, abnormalities of liver function, Myopathy, Confusion, anxiety, depression, and flu-like syndrome

• Clinical uses:

• (1) HIV positive patients before onset of AIDS, Delays progession of disease by 12-18 months. (2) Patients with AIDS – can reduces opportunistic infections, e.g., Pneumocystis carinii pneumonia, stabilizes weight, reduces HIV-associated thrombocytopenia, stabilizes HIV-associated dementia.

• (The end)