Viruses

1
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

2
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

3
Sites of Drug Action
4
Antiviral Agents

• Block viral entry into the cell or must work
  inside the cell
• Most agents are pyrimidine or purine nucleoside
  analogs

5
Sites of Drug Action
6
Antiherpes Agents

• Acyclovir- prototype
• Valacyclovir
• Ganciclovir
• Famciclovir
• Cidofovir
• Idoxuridine
• Sorivudine
• Trifluridine
• Vidarabine
• Foscarnet

7
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

8
(No Transcript)
9
Mechanism of Resistance Acyclovir

• Alteration in viral thymidine kinase
• Alteration in viral DNA polymerase
• Cross-resistance with valacyclovir, famciclovir,
  and ganciclovir

10
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

11
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

12
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

13
Ganciclovir

• A guanosine analog
• requires triphosphorylation for activation
• monophosphorylation is catalyzed by a
  phosphotransferase in CMV and by thymidine kinase
  in HSV cells
• inhibits DNA polymerase
• does not cause chain termination
• Uses CMV, HSV, VZV,and EBV
• Side Effect myelosuppression

14
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

15
Idoxuridine and Trifluridine

• Idoxuridine- pyrimidine analog
• 1st antiviral agent
• used topically for herpes keratitis
• Trifluridine- fluorinated pyrimidine
• inhibits viral DNA synthesis same as acyclovir
• incorporates into viral and cellular DNA
• Uses HSV-1 and HSV-2 (topically)

16
Sorivudine

• Investigational pyrimidine analog
• competitively inhibits DNA polymerase, however,
  is not incorporated into viral DNA
• causes bone marrow suppression when administered
  with 5-FU
• Uses VZV, HSV-1, and EBV

17
Vidarabine

• An adenosine analog
• incorporated into viral and cellular DNA
• metabolized to hypoxanthine arabinoside
• Side Effects GI intolerance and myelosuppression

18
Foscarnet

• An inorganic pyrophosphate
• inhibits viral DNA polymerase, RNA polymerase,
  and HIV reverse transcriptase
• does not have to phosphorylated
• Uses HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV
• Resistance due to point mutations in DNA
  polymerase gene
• Side Effects hypo- or hypercalcemia and
  phosphotemia

19
Antiretroviral Agents

• 1) Reverse transcriptase inhibitors
• 2)Protease inhibitors

20
Reverse Transcriptase Inhibitors

• Zidovudine (AZT)
• Didanosine- causes pancreatitis
• Lamivudine- causes pancreatitis
• Zalcitabine- causes peripheral neuropathy
• Stavudine- causes peripheral neuropathy

21
Mechanism of Action Zidovudine

• 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

22
Mechanism of Resistance Zidovudine

• Due to mutations in the reverse transciptase gene
• more frequent after prolong therapy and in
  persons with HIV

23
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

24
Side Effects Zidovudine

• Myelosuppression, including anemia and
  neutropenia
• seizures may occur in people with advanced AIDS

25
Protease Inhibitors

• Indinavir
• Ritonavir
• Saquinavir

26
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 Effectshyperbilirubinemia
• Contraindicationsinhibitor/substrate for CPY3A4,
  do not give with antifungal azoles

27
Saquinavir

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

28
Other Antivirals

• 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

29
Interferons

• Endogenous proteins
• induce host cell enzymes that inhibit viral RNA
  translation and cause degradation of viral mRNA
  and tRNA
• 3 classes IFN-?, IFN-? and IFN-g

30
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

31
Antifungal Agents
32
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

33
Systemic Antifungals

• Amphotericin B
• Flucytosine
• Azoles
• Ketoconazole
• Itraconazole
• Fluconazole

34
Amphotericin B

• An amphoteric polyene macrolide
• Broad spectrum of activity
• Binds to ergosterol and alters the permeability
  of the cell by forming pores in the membrane
  leading to cell death
• Resistance occurs when ergosterol binding is
  impaired

35
Amphotericin B

• 2 categories of toxicity
• Infusion-related fever, chills, muscle spasm,
  and hypotension
• Slower toxicity renal damage

36
Flucytosine

• A pyrimidine analog
• related to fluorouracil (5-FU)
• spectrum of activity narrower than amphotericin B
• used in combination with amphotericin B

37
Flucytosine

• Enters the cell via a cytosine-specific permease
• converted to 5-FU via cytosine deaminase
• 5-FU is converted to 5-FdUMP which inhibits
  thymidylate synthase ? inhibiting DNA synthesis
• metabolized to 5-FUTP which is incorporated into
  fungal RNA, inhibiting nucleic acid and protein
  synthesis

38
Flucytosine

• Decreased levels of any of the enzymes can lead
  to resistance
• toxic effects may be related to the formation of
  5-FU including, anemia, leukopenia, and
  thrombocytopenia
• hepatic dysfunction may occur

39
Azoles

• Prototype- Ketaconazole
• interact with C-14 ?-demethylase (P450 enzyme) to
  block the demethylation of lanosterol to
  ergosterol, thereby disrupting membrane function
  and increasing permeability
• Ketaconazole has additive effect with flucytosine
  and antagonizes amphotericin B

40
Differences in Azoles

• Refer to Katzung table 48-1

41
Mucocutaneous Antifungals

• Griseofulvin
• enters fungal cells by an energy-dependent
  process
• interacts with the microtubules within the fungus
  to disrupt the mitotic spindle and inhibit
  mitosis
• resistance due to lack of energy-dependent uptake
  system
• toxicities include allergic syndrome and
  hepatitis

42
Topical Antifungals

• Nystatin
• polyene macrolide
• M.O.A. same as amphotericin B
• due to toxicity it is only used topically

43
Antiviral Agents
44
Antiherpes Agents

• Prototype- Acyclovir
• M.O.A.- Chemistry and Antiviral Activity.
  Acyclovir (9-(2-hydroxy-ethoxy)methyl-9H-guanine
  ) is an acyclic guanine nucleoside analog that
  lacks a 3-hydroxyl on the side chain
• ADD STRUCTURES