1. Antiviral Agents

2. 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

3. Viruses Steps 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

4. Sites of Drug Action

5. Antiviral Agents
Block viral entry into the cell or must work inside the cell
Most agents are pyrimidine or purine nucleoside analogs

6. Sites of Drug Action

7. Antiherpes Agents Acyclovir- prototype Valacyclovir Famciclovir
Penciclovir
Trifluridine
Vidarabine

8. 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

11. Mechanism of Resistance Acyclovir
Alteration in viral thymidine kinase
Alteration in viral DNA polymerase
Cross-resistance with valacyclovir, famciclovir, and ganciclovir

12. 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

14. Valacyclovir L-valyl ester of acyclovir
Converted to acyclovir when ingested
M.O.A.: same as acyclovir
Uses:
1) recurrent genital herpes
2) herpes zoster infections
Side Effects: nausea, diarrhea, and headache

15. 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

16. Trifluridine Trifluridine- fluorinated pyrimidine
inhibits viral DNA synthesis same as acyclovir
incorporates into viral and cellular DNA
Uses: HSV-1 and HSV-2 (topically)

17. Vidarabine An adenosine analog inhibits viral DNA polymerase
incorporated into viral and cellular DNA
metabolized to hypoxanthine arabinoside
Side Effects: GI intolerance and myelosuppression

18. Anti-Cytomegalovirus Agents
Gancyclovir
Valgancyclovir
Cidofovir
Foscarnet
Fomivirsen

19. 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

20. 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

21. 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

22. 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

23. 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

27. Antiretroviral Agents
There are five classes of antiretroviral drugs, each of which targets one of four viral processes. These classes of drugs are:
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs),
Non-nucleoside reverse transcriptase inhibitors (NNRTIs),
Protease inhibitors,
Entry inhibitors
Integrase inhibitors.

29. HAART

30. Antiretroviral Agents
1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
3)Protease inhibitors

31. Nucleoside Reverse Transcriptase Inhibitors
Zidovudine (AZT)
Didanosine- causes pancreatitis*
Lamivudine- causes pancreatitis
Zalcitabine- causes peripheral neuropathy*
Stavudine- causes peripheral neuropathy*
Abacavir

32. 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

33. Mechanism of Resistance Zidovudine
Due to mutations in the reverse transcriptase gene
more frequent after prolong therapy and in persons with HIV

34. 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

35. Side Effects Zidovudine
Myelosuppression, including anemia and neutropenia
GI intolerance, headaches, and insomnia

36. 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

37. Nucleotide Inhibitors
Tenofovir
Adefovir

38. 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

39. 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

40. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Nevirapine
Delavirdine
Efavirenz

41. Mechanism of Action NNRTIs
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

42. 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

43. Protease Inhibitors Indinavir Ritonavir Saquinavir Nelfinavir
Amprenavir

44. 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

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

46. 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

47. Saquinavir A synthetic peptide-like substrate analog
inhibits HIV-1 protease
prevents cleavage of viral polyproteins

48. 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

49. 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

51. 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.

52. Anti-Hepatitis Agents
Lamivudine -Nucleoside Reverse Transcriptase Inhibitor (NRTI)
Adefovir -Nucleotide Inhibitor
Interferon Alfa
Pegylated Interferon Alfa
Ribavirin

54. 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

55. 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

56. 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

58. Anti-Influenza Agents
Amantadine
Rimantadine
Zanamivir
Oseltamivir

59. 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

61. 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

63. Antifungal Agents

64. 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

66. Fungi can infect..

67. Commonly isolated fungi
Dermatophytes
Thermally dimorphic fungi
Candida
Aspergillus
Cryptococcus
Zygomycetes
...

68. Pathogen Fungi 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)

69. The superficial mycoses
Dermatophytic infections:
Epidermophyton spp.,
Trichophyton spp., and
Microsporum spp.
Candidiasis:
Candida albicans

70. Systemic Mycosis Sytemic mycoses tend to be serious and chronic.
Many effective drugs are extremely toxic.
Major drugs : polyenes, imidazoles and antimetabolites

71. 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

72. Major drugs : Polyenes : Amphotericin B, nystatin
Imidazoles : Ketoconazole, miconazole
Antimetabolite : Flucytosine

73. 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

74. List of drugs Systemic : Amphotericin B Dapsone Fluconazole
Flucytosine Griseofulvin Itraconazole
Ketoconazole Miconazole KI

75. Topical drugs :
Amphotericin B Carbol-Fuchsin Ciclopirox
  Clotrimazole Econazole Haloprogin
  Ketoconazole Mafenide Miconazole
  Naftifine Nystatin Oxiconazole
  Silver sulfadiazine Sulconazole Terbinafine
Tioconazole Tolnaftate Undecylenic acid

76. Vaginal drugs :
Butoconazle Clotrimazole Econazole
Gentian violet Miconazole Nystatin
Terconazole Tioconazole

77. Fig. 1 Mode action of antifungal drugs
Site of Action of Antifungal Agents
Fig Mode action of antifungal drugs

78. Amphotericin B
Amphotericin B is a polyene antibiotic isolated from Streptomyces nodosus. It contains a macrolide ring and an aminosugar, mycosamine.

79. + a polyene
ergosterol
ergosterol with
pore

80. 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.

81. 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

82. 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

83. Adverse effects renal toxicity : both predictable and dose related
usually reversible
Renal function must be monitored
Treatment : 6 to more than 24 weeks

84. Flucytosine
a synthetic agent chemically related to fluorouracil and floxuridine, both anticancer drugs
an antimetabolite

85. 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.

86. 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.

87. Adverse effects
causes bone marrow depression and gastrointestinal disturbances.
Bone marrow depression : leukopenia, anemia, and thrombocytopenia
Gastrointestinal disturbances : nausea, vomiting, and diarrhea

88. Adverse effects
CNS toxicity : headache, drowsiness, confusion, vertigo, and hallucinations
rapid development of resistance during therapy
not used as a single agent

89. Azole derivatives
subdivided into two categories: imidazoles and triazoles
imidazoles :
- Ketoconazole and miconazole
- used to treat systemic fungal infections
triazoles : Itraconazole and fluconazole

90. Allylamine drugs Azoles Acetyl CoA Squalene Squalene-2,3 oxide
Lanosterol
(ergosterol)
Allylamine
drugs
Azoles
Squalene-2,3 oxide
monooxygenase
14-a-demethylase

91. 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.

92. Effects
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.

93. Clotrimazole intended for topical use. toxic when given systemically.
useful for dermatophytic infections, cutaneous candidiasis, and candida infections of mucous membranes and mucocutaneous junctions

94. Clotrimazole (cont.) 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.

95. Ketoconazole a relatively new drug much less toxic than amphotericin B
used orally as well as parenterally for systemic infections

96. Pharmacokinetics is best absorbed from solutions that have low pH
Is rapidly absorbed and distributed uniformly throughout the body

97. Adverse effects
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

98. 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).

99. Itraconazole
another imidazole that has been introduced recently for use in human medicine
used in veterinary medicine

100. Allylamines (fungicidal)
Inhibit squalene-2,3-epoxidase–
for dermatophytes

101. Terbinafine Naftifine (for topical use)
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)

102. Allylamine drugs Azoles Acetyl CoA Squalene Squalene-2,3 oxide
Lanosterol
(ergosterol)
Allylamine
drugs
Azoles
Squalene-2,3 oxide
monooxygenase
14-a-demethylase

103. Potassium iodide
an old drug that is still the drug of choice for cutaneous-lymphatic sporotrichosis
Veterinarians also use the drug for actinomycosis.

104. 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.

105. 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.

106. Structure and chemistry
derived from Penicillium griseofulvum
is poorly water soluble and requires bile salts for solubilization in the gut.

107. 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.

108. 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

109. 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

110. 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.

111. Properties of the important antifungal agents.
Target
Chemical Group
Examples
Mode of Action
Cell Membrane Synthesis
Azoles
Miconazole, Ketoconazole, Fluconazole
Inhibition of Ergosterol
Function
Polyenes
Nystatine, Amphotericic B
Bind to Sterols in cell membrane, causing leakage of cellular components and cell death.

112. Properties of the important antifungal agents (cont.)
Target
Chemical Group
Examples
Mode of Action
Nucleic acid Synthesis
Pyrimidines
Flucytosine (5-FC)
Deaminated in cell to 5- fluro uracil which ultimately inhibits DNA synthesis
Function
Benzofurans
Griseofulvin
Appears to inhibit nucleic acid synthesis, microtubule assembly, chitin synthesis

113. The End