Antiviral Agents

Viruses

• Obligate intracellular parasites

• Consist of a core genome in a protein shell and some are surrounded by a lipoprotein

• lack a cell wall and cell membrane

• do not carry out metabolic processes

• Replication depends on the host cell machinery

VirusesSteps for Viral Replication

1) adsorption and penetration into cell

2) uncoating of viral nucleic acid

3) synthesis of regulatory proteins

4) synthesis of RNA or DNA

5) synthesis of structural proteins

6) assembly of viral particles

7) release from host cell

Sites of Drug Action

Antiviral Agents• Block viral entry into the cell or must work

inside the cell

• Most agents are pyrimidine or purine nucleoside analogs

Sites of Drug Action

Antiherpes Agents

• Acyclovir- prototype• Valacyclovir• Famciclovir• Penciclovir• Trifluridine• Vidarabine

Mechanism of Action Acyclovir

• an acyclic guanosine derivative

• Phosphorylated by viral thymidine kinase

• Di-and tri-phosphorylated by host cellular enzymes

• Inhibits viral DNA synthesis by:1) competing with dGTP for viral DNA polymerase

2) chain termination

Mechanism of Resistance Acyclovir

• Alteration in viral thymidine kinase

• Alteration in viral DNA polymerase

• Cross-resistance with valacyclovir, famciclovir, and ganciclovir

Clinical Uses Acyclovir

• Oral, IV, and Topical formulations• Cleared by glomerular filtration and tubular

secretion• Uses:

– Herpes Simplex Virus 1 and 2 (HSV)– Varicella-zoster virus (VZV)

• Side Effects: nausea, diarrhea, headache, tremors, and delirium

Valacyclovir

• L-valyl ester of acyclovir• Converted to acyclovir when ingested• M.O.A.: same as acyclovir• Uses:

1) recurrent genital herpes2) herpes zoster infections

• Side Effects: nausea, diarrhea, and headache

Famciclovir• Prodrug of penciclovir (a guanosine

analog)

• M.O.A.: same as acyclovir

• does not cause chain termination

• Uses: HSV-1, HSV-2, VZV, EBV, and hepatitis B

• Side Effects: nausea, diarrhea, and headache

Trifluridine

• Trifluridine- fluorinated pyrimidine – inhibits viral DNA synthesis same as

acyclovir– incorporates into viral and cellular DNA– Uses: HSV-1 and HSV-2 (topically)

Vidarabine• An adenosine analog

• inhibits viral DNA polymerase

• incorporated into viral and cellular DNA

• metabolized to hypoxanthine arabinoside

• Side Effects: GI intolerance and myelosuppression

Anti-Cytomegalovirus Agents

• Gancyclovir• Valgancyclovir• Cidofovir• Foscarnet• Fomivirsen

Ganciclovir• An acyclic guanosine analog

• requires triphosphorylation for activation

• monophosphorylation is catalyzed by a phosphotransferase in CMV and by thymidine kinase in HSV cells

• M.O.A.: same as acyclovir

• Uses: CMV*, HSV, VZV,and EBV

• Side Effect: myelosuppression

Valgancyclovir

• Monovalyl ester prodrug of gancyclovir

• Metabolized by intestinal and hepatic esterases when administered orally

• M.O.A.: same as gancyclovir

• Uses: CMV*

• Side Effect: myelosuppression

Cidofovir• A cytosine analog

• phosphorylation not dependent on viral enzymes

• Uses: CMV*, HSV-1, HSV-2, VZV, EBV, HHV-6, adenovirus, and human papillomavirus

• Side Effects: nephrotoxicity (prevented by admin. of probenecid)

• Resistance: mutation in DNA polymerase gene

Foscarnet• An inorganic pyrophosphate• inhibits viral DNA polymerase, RNA polymerase,

and HIV reverse transcriptase• does not have to be phosphorylated• Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and

HIV• Resistance due to mutations in DNA polymerase

gene

• Side Effects: hypo- or hypercalcemia and phosphotemia

Fomivirsen• An oligonucleotide

• M.O.A.: binds to mRNA and inhibits protein synthesis and viral replication

• Uses: CMV retinitis

• Side effects: iritis and increased intraocular pressure

• There are five classes of antiretroviral drugs, each of which targets one of four viral processes. These classes of drugs are:

1. Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs),

2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs),

3. Protease inhibitors, 4. Entry inhibitors 5. Integrase inhibitors.

Antiretroviral Agents

HAART

Antiretroviral Agents

1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

3)Protease inhibitors

Nucleoside Reverse Transcriptase Inhibitors

• Zidovudine (AZT)• Didanosine- causes pancreatitis*

• Lamivudine- causes pancreatitis

• Zalcitabine- causes peripheral neuropathy*

• Stavudine- causes peripheral neuropathy*

• Abacavir

Mechanism of Action Zidovudine (AZT)

• A deoxythymidine analog• enters the cell via passive diffusion• must be converted to the triphosphate form by

mammalian thymidine kinase• competitively inhibits deoxythymidine

triphosphate for the reverse transcriptase enzyme

• causes chain termination

Mechanism of Resistance Zidovudine

• Due to mutations in the reverse transcriptase gene

• more frequent after prolong therapy and in persons with HIV

Clinical Uses Zidovudine

• Available in IV and oral formulations• activity against HIV-1, HIV-2, and human T cell

lymphotropic viruses• mainly used for treatment of HIV, decreases rate

of progression and prolongs survival• prevents mother to newborn transmission of HIV

Side Effects Zidovudine

• Myelosuppression, including anemia and neutropenia

• GI intolerance, headaches, and insomnia

Other NRTIs

• Didanosine- synthetic deoxy-adenosine analog; causes pancreatitis*

• Lamivudine- cytosine analog

• Zalcitabine- cytosine analog; causes peripheral neuropathy*

• Stavudine- thymidine analog;causes peripheral neuropathy*

• Abacavir- guanosine analog; more effective than the other agents; fatal hypersensitivity reactions can occur

Nucleotide Inhibitors

• Tenofovir

• Adefovir

Tenofovir• An acyclic nucleoside phosphonate analog of

adenosine• M.O.A.- competitively inhibits HIV reverse

transcriptase and causes chain termination after incorporation into DNA

• Uses – in combination with other antiretrovirals for HIV-1 suppression

Adefovir• An analog of adenosine monophosphate• Phosphorylated by cellular kinases • M.O.A. - Competitively inhibits HBV DNA

polymerase and results in chain termination after incorporation into viral DNA

• Uses - Hepatitis B• Side effects - nephrotoxicity

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Nevirapine

• Delavirdine

• Efavirenz

Mechanism of ActionNNRTIs

• Bind to site on viral reverse transcriptase, different from NRTIs

• results in blockade of RNA and DNA dependent DNA polymerase activity

• do not compete with nucleoside triphosphates• do not require phosphorylation• these drugs can not be given alone• substrates and inhibitors of CYP3A4

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Nevirapine- prevents transmission of HIV from mother to newborn when given at onset of labor and to the neonate at delivery

• Delavirdine- teratogenic, therefore can not be given during pregnancy

• Efavirenz- teratogenic, therefore can not be given during pregnancy

Protease Inhibitors

• Indinavir

• Ritonavir

• Saquinavir

• Nelfinavir

• Amprenavir

Protease Inhibitors• The protease enzyme cleaves precursor

molecules to produce mature, infectious virions• these agents inhibit protease and prevent the

spread of infection• These agents cause a syndrome of altered body

fat distribution, insulin resistance, and hyperlipidemia

Accumulation of fat at the base of the neck in a patient receiving a protease inhibitor

Indinavir and Ritonavir

• M.O.A.: Specific inhibitors of the HIV-1 protease enzyme

• M.O.R.: mediated by expression of multiple and variable protease amino acid substitutions

• Side Effects:hyperbilirubinemia• Contraindications:inhibitor/substrate for CPY3A4,

do not give with antifungal azoles

Saquinavir• A synthetic peptide-like substrate analog

• inhibits HIV-1 protease

• prevents cleavage of viral polyproteins

Nelfinavir and Amprenavir

• M.O.A.: Specific inhibitors of the HIV-1 protease enzyme

• M.O.R.: mediated by expression of multiple and variable protease amino acid substitutions

• Less cross-resistance with Amprenavir• Side Effects: diarrhea and flatulence• Amprenavir can cause Stevens-Johnson

syndrome• Contraindications: inhibitor/substrate for

CPY3A4

Fusion Inhibitors

• Enfuvirtide (T-20)- binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for fusion of the viral and cellular membranes

• By blocking fusion (entry into cell), FUZEON prevents HIV from infecting CD4 cells

Integrase Inhibitors

• Raltegravir

• M.O.A.: Inhibits the final step in integration of strand transfer of the viral DNA into our own host cell DNA.

• Side Effects: nausea, headache and diarrhea

• Raltegravir, in combination with other antiretrovirals, is approved for therapy of treatment-experienced patients with evidence of viral replication despite ongoing antiretroviral drug therapy.

Anti-Hepatitis Agents

• Lamivudine -Nucleoside Reverse Transcriptase Inhibitor (NRTI)

• Adefovir -Nucleotide Inhibitor

• Interferon Alfa

• Pegylated Interferon Alfa

• Ribavirin

Interferons• Interferon Alfa

• Endogenous proteins

• induce host cell enzymes that inhibit viral RNA translation and cause degradation of viral mRNA and tRNA

• Bind to membrane receptors on cell surface

• May also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release

Interferons

• Pegylated interferon Alfa

• A linear or branced polyethylene gylcol (PEG) moiety is attached to covalently to interferon

• Increased half-life and steady drug concentrations

• Less frequent dosing

• Tx chronic hepatitis C in combination with ribavirin

Ribavirin• A guanosine analog

• phosphorylated intracellularly by host enzymes

• inhibits capping of viral messenger RNA

• inhibits the viral RNA-dependent RNA polymerase

• inhibits replication of DNA and RNA viruses

Anti-Influenza Agents

• Amantadine

• Rimantadine

• Zanamivir

• Oseltamivir

Amantadine and Rimantadine

– cyclic amines

– inhibit the uncoating of viral RNA therefore inhibiting replication

– resistance due to mutations in the RNA sequence coding for the structural M2 protein

– used in the prevention and treatment of Influenza A

Zanamivir and Oseltamivir

• Inhibits the enzyme neuraminidase• interfere with release of progeny influenza virus

from infected to new host cells, thus halting the spread of infection within the respiratory tract .

• inhibit the replication of influenza A and Influenza B

• treats uncomplicated influenza infections• administered intranasally

Antifungal Agents

Fungal Infections

• Develop due to a loss of mechanical barriers (i.e. burns,major surgery) or immunodeficiency (chemotherapy,organ transplant, AIDS)

• fungal infections may be superficial or systemic

• Fungi possess different ribosomes, cell wall components, and discrete nuclear membrane

Fungi can infect..

Commonly isolated fungi

• Dermatophytes• Thermally dimorphic fungi• Candida• Aspergillus• Cryptococcus• Zygomycetes• ...

Pathogen Fungi

I. Yeasts (Cryptococcus Neoformans)

II. Yeast like (Candida Albicans)

III. Filamantous a- Epidermophytons, Trichophyton,Microsporum b- Aspergillus c- Penicillium mold

IV. Dimorphic (Blastomyces, Histoplasma, Coccidioid, Sprothrix)

The superficial mycoses

Dermatophytic infections:

Epidermophyton spp.,

Trichophyton spp., and

Microsporum spp.

Candidiasis:

Candida albicans

Systemic Mycosis

• Sytemic mycoses tend to be serious and

chronic.

• Many effective drugs are extremely toxic.

• Major drugs : polyenes, imidazoles and

antimetabolites

Anti-fungal agents

Anti-fungal therapy can be divided into two

categories ;

• treatment of serious systemic (deep) mycosis

• superficial mycosis involving skin and mucous

membranes

• Polyenes : Amphotericin B, nystatin

• Imidazoles : Ketoconazole, miconazole

• Antimetabolite : Flucytosine

Major drugs :

Typical infections and drugs frequently used are as follows :

• Systemic candidiasis : AmpB and/or 5-FU, Keto, Mic, Flu

• Cryptococcosis (meningitis) : AmpB + 5-FU, Mic, Flu better

• Systemic aspergillosis : AmpB and/or 5-FU • Blastomycosis : AmpB, Keto, Itra • Histoplasmosis : AmpB, Keto, Flu • Coccidioidomycosis : AmpB, Keto, Itra • Paracoccidioidomycosis : AmpB, Keto, Itra

List of drugs

Systemic :

• Amphotericin B Dapsone Fluconazole • Flucytosine Griseofulvin Itraconazole • Ketoconazole Miconazole KI

Topical drugs:

Amphotericin B Carbol-Fuchsin Ciclopirox

  Clotrimazole Econazole Haloprogin

  Ketoconazole Mafenide Miconazole

  Naftifine Nystatin Oxiconazole

  Silver sulfadiazine Sulconazole Terbinafine

Tioconazole Tolnaftate Undecylenic acid

Vaginal drugs:

Butoconazle Clotrimazole Econazole

Gentian violet Miconazole Nystatin

Terconazole Tioconazole

Fig. 1 Mode action of antifungal drugs

Site of Action of Antifungal Agents

Amphotericin B

Amphotericin B is a polyene antibiotic isolated

from Streptomyces nodosus. It contains a

macrolide ring and an aminosugar,

mycosamine.

+ a polyene

ergosterol

ergosterol withpore

Structure and chemical characteristics

• poorly water soluble

• administered by IV infusion (0.1 mg/ml) or

(0.3 mg/ml) in 5% dextrose

• extremely unstable in solution, particularly

in normal saline.

Mode of action

• affinity for membranes that have higher

content of ergosterol

• forms a channel through the membrane that

allows the passage of potassium and other

small molecules

• resistance is rare and slow to develop

Pharmacokinetics

• Poorly : crosses cell membranes, absorbed

from the gut and penetration into the eye, CSF,

and joint capsules

• For treatment of meningitis, it must be given

intrathecally

• given only via IV injection or intrathecally

Adverse effects

• renal toxicity : both predictable and dose

related

• usually reversible

• Renal function must be monitored

• Treatment : 6 to more than 24 weeks

Flucytosine

• a synthetic agent chemically related to

fluorouracil and floxuridine, both anticancer

drugs

• an antimetabolite

Mode of action

• converted to 5-fluorouracil (5-FU) which inhibits

thymidylate synthetase

• Thymidine is required for DNA synthesis.

• Vertebrate: have little of the enzyme required to

convert flucytosine to the active antimetabolite, 5-

FU.

Pharmacokinetics

• rapid and complete absorption after

oral administration

• distributes widely throughout the body

fluids, including the CSF

• treatment : meningitis caused by

Candida and Cryptococcus spp.

Adverse effects

• causes bone marrow depression and

gastrointestinal disturbances.

• Bone marrow depression : leukopenia,

anemia, and thrombocytopenia

• Gastrointestinal disturbances : nausea,

vomiting, and diarrhea

• CNS toxicity : headache, drowsiness,

confusion, vertigo, and hallucinations

• rapid development of resistance during

therapy

• not used as a single agent

Adverse effects

Azole derivatives

• subdivided into two categories: imidazoles and triazoles

• imidazoles :

- Ketoconazole and miconazole

- used to treat systemic fungal infections

• triazoles : Itraconazole and fluconazole

Acetyl CoA

Squalene

Lanosterol

(ergosterol)

Allylaminedrugs

Azoles

Squalene-2,3 oxide

Squalene monooxygenase

14--demethylase

Mode of action

• Azoles : inhibit cytochrome-P450 activity

• decreases conversion of 14-alpha-

methylsterols to ergosterol

• failure of ergosterol synthesis causes altered

membrane permeability leading to loss of ability

to maintain a normal intracellular environment.

• inhibit transformation of blastospores into

invasive mycelial form in C. albicans

• inhibit the cytochrome function may also be the

basis of their interference with steroid

biosynthesis

• higher doses : hypoadrenal cortical activity and

reduced libido

• The effects are reversible.

Effects

Clotrimazole

• intended for topical use.

• toxic when given systemically.

• useful for dermatophytic infections,

cutaneous candidiasis, and candida

infections of mucous membranes and

mucocutaneous junctions

• treatment may require two to four weeks.

• for vaginal candidiasis poor compliance with

complex, long regimens has led to using very

high doses for one to three treatments.

• Erythema, urticaria, pruritus, stinging, and

blistering may be seen.

Clotrimazole (cont.)

Ketoconazole

• a relatively new drug

• much less toxic than amphotericin B

• used orally as well as parenterally for

systemic infections

Pharmacokinetics

• is best absorbed from solutions that have

low pH

• Is rapidly absorbed and distributed

uniformly throughout the body

1. Hepatotoxicity : has been reported in 1 of 10,000 patients and usually reversible

2. Adrenocortical suppression : with high doses

- serum testosterone levels

- no specific mention of effect on estrogen or progesterone synthesis

- depression of testosterone and adrenal steroid synthesis : gynecomastia in males

Adverse effects

Miconazole• similar to ketoconazole, but less able to cross

membranes and more toxic.

• must be used by infusion for systemic effects.

• does not cause hepatotoxicity

• associated with frequent occurrence of hypersensitivity (fever and chills, skin rash or itching), and phlebitis (redness, swelling, or pain at injection site).

Itraconazole

• another imidazole that has been introduced

recently for use in human medicine

• used in veterinary medicine

Allylamines (fungicidal)

• Inhibit squalene-2,3-epoxidase–

• for dermatophytes

Terbinafine• Metabolized then excreted in urine• Inhibits squalene 2, 3- epoxidase. • Squalene is cidal to sensitive organisms.• Used orally for dermatophytes• Metabolized• Adverse effects include hepatitis and rashes.

Both are rare.

• Naftifine (for topical use)

Acetyl CoA

Squalene

Lanosterol

(ergosterol)

Allylaminedrugs

Azoles

Squalene-2,3 oxide

Squalene monooxygenase

14--demethylase

Potassium iodide

• an old drug that is still the drug of choice for

cutaneous-lymphatic sporotrichosis

• Veterinarians also use the drug for actinomycosis.

Adverse effects

• hypothyroidism and iodism

• Signs include brassy taste, rhinitis, coryza,

salivation, lacrimation, sneezing, burning of

mouth and throat, ocular irritation,

sialadenitis, and dermal lesions.

Griseofulvin

• a systemic antifungal used to treat topical

ringworm infections, e.g., onychomycosis,

Tinea capitis, Tinea pedis, etc.

• many Trichophyton spp., Microsporum spp. and

Epidermophyton spp. are susceptible.

Structure and chemistry

• derived from Penicillium griseofulvum

• is poorly water soluble and requires bile salts

for solubilization in the gut.

Mode of Action

• disrupts mitotic spindle structure to lead to

metaphase arrest.

• sufficient to inhibit growth of fungi (drug is

static), preventing them from invading.

• as the skin, hair, or nail is replaced, the fungus

is shed.

Pharmacokinetics

• used orally

• absorption is best with high fat meals to

aid in solubilizing the drug

• unabsorbed drug is eliminated in the

feces

• small amount is shed in dead skin and

hair

Adverse effects

• causes hepatomas in mice and thyroid

tumors rats

• are not common, but include confusion,

hypersensitivity (skin rash, hives, or itching),

oral thrush (soreness or irritation of mouth or

tongue), and photosensitivity

Whitfield's Ointment

• represents keratolytic agents

• consists of 3% salicylic acid plus 6%

benzoic acid.

• no significant anti-fungal activity, but

helps remove keratinous layer to aid

penetration of anti-fungals.

TargetChemical Group

ExamplesMode of Action

Cell Membrane Synthesis

AzolesMiconazole, Ketoconazole, Fluconazole

Inhibition of Ergosterol

FunctionPolyenesNystatine, Amphotericic B

Bind to Sterols in cell membrane, causing leakage of cellular components and cell death.

Properties of the important antifungal agents.

TargetChemical GroupExamplesMode of Action

Nucleic acid Synthesis

PyrimidinesFlucytosine (5-FC)Deaminated in cell to 5- fluro uracil which ultimately inhibits DNA synthesis

FunctionBenzofuransGriseofulvinAppears to inhibit nucleic acid synthesis, microtubule assembly, chitin synthesis

Properties of the important antifungal agents (cont.)

The End