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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