3. Viruses
• Viruses are obligate intracellular parasites
• Viruses have no cell wall and are made up of
nucleic acid components
• Viruses containing envelope – antigenic in nature
• They do not have a metabolic machinery of their
own – use host enzymes
• Certain viruses multiply in the cytoplasm but
others do in the nucleus
• Most multiplication occurs before diagnosis
4.
5. Viral Infections
Competent immune system:
• Best response to viral infections
• A well-functioning immune system will eliminate or effectively
destroy virus replication
Immunocompromised patients have frequent viral infections
• Cancer patients, especially leukemia or lymphoma
• Transplant patients, due to pharmacologic therapy
• AIDS patients, diseases that attack immune system
6. ANTIVIRAL DRUGS: GENERAL FEATURES
- Many antiviral drugs are purine or pyrimidine analogs.
-Many antiviral drugs are prodrugs.
They must be phosphorylated by viral or cellular enzymes in order
to become active.
- Antiviral drugs typically have a restricted spectrum of antiviral
activity and inhibit a specific viral protein, most often an enzyme
involved in viral nucleic acid synthesis.
- Single nucleotide changes leading to critical amino acid
substitutions in a target protein often are sufficient to cause antiviral
drug resistance.
- Current agents inhibit active replication but do not eliminate non-
replicating or latent viruses so that viral growth may resume after
drug removal. Effective host immune response remain essential for
recovery from infection.
7. Antiviral drugs may have antiviral synergistic effects
when given concomitantly:
- gancyclovir and foscarnet;
- zidovudine and didanosine;
- zidovudine and protease inhibitors; etc.
In other cases toxic synergistic effects preclude
concurrent administration of two antiviral drugs:
- zidovudine and acyclovir--Myelosuppression
- zidovudine and gancyclovir--Myelosuppression
- Clinical efficacy of antiviral drugs depends on
achieving inhibitory concentrations within infected
cells. Therefore a clear relationship between blood
concentration and clinical response have not been
established for most antiviral agents.
8. Diagnosis of Viral Infections
• Clinical suspicion
– Is syndrome diagnostic of a specific entity?
– Is viral disease in the differential diagnosis of a presenting
syndrome?
• Knowledge of appropriate specimen(s) to send
– Blood
– Body fluids
– Lesion scraping
– Tissue
– Proper transport is essential
14. Acyclovir
• Acyclic guanosine analog
• Development represents a milestone in the field of
antiviral chemotherapy
• Valacyclovir*- prodrug of Acyclovir
• Active against - HSV, VZV and modestly CMV
Pharmacokinetics
Administered by oral, intravenous and topical
routes
– Oral bioavailability 15-30%
– T1/2 3 hrs
– Primarily renally excreted
15. Acyclovir-MOA
– Preferentially taken up by virally infected
cells
– Mono-phosphorylated by virally encoded
thymidine kinases
– Di- and tri-phosphorylation completed by
cellular kinases
– ACV-TP is the active moiety
– Competitive inhibitor of viral
DNA polymerase
– Cellular DNA polymerases
much less susceptible to
inhibition
– Leads to viral DNA chain
termination
16. Replicative cycles of herpes simplex virus, an example of a DNA virus, and the
probable sites of action of antiviral agents.
17. Acyclovir
Antiviral spectrum and resistance
• -Acyclovir: HSV-1, HSV-2, VZV.
• -Gancyclovir: HSV-1, HSV-2, VZV, EBV, CMV.
Therapeutic uses
• Acyclovir is the drug of choice for:
• -Genital HSV infections
• -HSV encephalitis
• -HSV infections in immunocompromised patient
• Gancyclovir is the drug of choice for:
• -CMV retinitis in immunocompromised patient
• -Prevention of CMV disease in transplant patients
18. Acyclovir
S/Es
– Headache, nausea
– Renal
– Neurotoxicity (1-5% of patients)
• Nephrotoxicity (crystalluria, hematuria, renal insufficiency (acyclovir,
high doses IV)
• Myelosuppression (neutropenia, thrombocytopenia) (gancyclovir)
– Teratogenic effects in animals
Resistance
– Mediated by mutations in viral thymidine kinase and/or viral DNA
polymerase genes
• TK-deficient and TK altered virus can be produced
– Clinically significant infections can be caused by drug resistant HSV and
VZV
19. Ganciclovir
• An analogue of acyclovir
• Active against all herpes viruses including H. simplex, H. zoster,
EBV, CMV.
• In fact more active than Acyclovir against CMV.
• Plasma T1/2 2-4 hours. In case of CMV infected cels > 24 hrs,
where it attains much higher concentrations.
Use– CMV infections in immunocompromised (AIDS, transplant
patients.)
Prevents blindness in CMV retinitis in AIDS patients.
Lowers HBV titres in chronic Hep B.
S/Es
Bone marrow depression, rash fever, vomiting, neuropsychiatric
disturbances.
20. HIV
Human immunodeficiency virus infection
• ELISA (enzyme-linked immunosorbent assay)
– Detects HIV exposure based on presence of human antibodies to the
virus in the blood
• Retrovirus
• Transmitted by:
– Sexual activity, intravenous drug use, perinatally from mother to child
Five Stages of HIV Infection
• Stage 1: asymptomatic infection
• Stage 2: early, general symptoms of disease
• Stage 3: moderate symptoms
• Stage 4: severe symptoms, often leading to death
WHO model stages
21. Anti- retroviral Agents
• Nucleoside reverse transcriptase inhibitors (NRTI)
• Zidovudine, abcavir, lamivudine, didanosine, stavudine
To inhibit viral replication
To delay AIDS progression
• Non-nucleoside reverse transcriptase inhibitors (NNRTI)
• Nevirapine, delavirdine, loviride,
To inhibit viral replication by a different way than NRTI,
but easily produce drug resistance
• Protease inhibitors (PI)
• Indinavir, saquinavir, ritonavir,
To inhibit HIV protease and interfere with viral maturation and
assembly
23. Zidovudine
• Azidothymidine-AZT
• Deoxy-thymidine (nucleoside) analog
• Anti-HIV-1 and HIV-2
• Well absorbed from the gut and distributed to
most body tissues and fluids, including the
cerebrospinal fluid.
• Eliminated primarily by renal excretion following
glucuronidation in the liver.
24. Zidovudine: Uses
• Initial drug of choice in AIDS patients with CD4 counts less than
500/mm3. (initially reduces morbidity and mortality)
• In asymptomatic HIV-infected individuals the drug slows the rate
of progression of AIDS.
• Decrease the rate of clinical disease progression and prolong
survival.
• Treatment of HIV-associated dementia and thrombocytopenia.
• Reduce the rate of vertical (mother-to-newborn) transmission
of HIV.
25. Zidovudine: S/Es
• Myelosuppression→ anemia or neutropenia;
• Severe anemia and leukopenia, due to bone marrow
suppression (30% of patients need transfusions)
• gastrointestinal intolerance,
• headaches, insomnia
• -Myopathy (10% of patients after long term use)
• -Encephalopathy (confusion, tremulousness), seizures (with high doses,
can be fatal)
• -Hepatic steatosis, lactic acidosis (can be fatal)
• [Toxicity is increased by concomitant use of drugs which inhibit
glucuronidation (e.g fluconazole, cimetidine) or are extensively
gucuronosylconjugated (e.g. benzodiazepines)]