‫بسم ال الرحمن الرحيم‬

Anti-viral chemotherapy

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 Anti-viral chemotherapy
• Introduction
• Obligate intracellular parasites in the host
• Consist of RNA or DNA, enclosed in protein coat
• DNA-viruses enter host cell nucleus & multiply
• RNA-viruses usually remain in cytoplasm
• Do not possess their own metabolic system, utilize
metabolic system of the host
• Difficult to target them as compared to bacteria
• Drugs causing damage to viruses also damage host cells
• Resistance easy & mostly due to mutation at binding
site
• Drugs target at different stages of viral replication 2
 Stages of viral replication
Attachment
& entry Budding
Virus & release
RNA RNA
(DNA or
synth
RNA)
Uncoating
DNA
Host cell
DNA
synth Maturation
mRNA mRNA
Protein synthesis Assembly Lysis
& release
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 Mechanism & site of action of anti-viral drugs
• Replication stage Drugs affecting
• Attachment & entry Enfuvirtide
• Un-coating Amantadine, rimantadine
• Nucleic acid synth. A. Purine/pyrimidine analogs
(genom synth.) a. Guanosine derivatives
(aciclovir, ganciclovir, famciclovir)
• b. Cytosine analogs (cidofovir)
• B.↓ nucleoside reverse-transcriptase
(zidovudine, lamivudine, didanosine)
• C.↓ non-nucleoside reverse-transcriptase
• (Nevirapine, Efavirenz)

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 Mechanism & site of action (Cont.)
• Replication stage Drugs affecting
• Early protein synth. Fomiversin
(viral RNA synth.)
• Late protein synth. Protease inhibitors
(Assembly & maturation) (indinavir, saquinavir, rotinavir)
• Release Neuraminidase inhibitors
(Zanamivir)
• Multiple sites Interferons & γ-globulins

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 I. Anti-herpes simplex virus (HSV) & varicella
zoster virus (VZV) drugs
• Aciclovir Aciclovir &
• Mechanism: ganciclovir
• 1st activated by viral kinase Viral kinase
to mono-phosphate Mono-
• Then by host cell kinases phosphate
to di- & tri-phosphate Host kinases
• Activated drug ↓ DNA polymerase, Tri-
chain termination & ↓ viral division phosphate
• Kinetics:
• Given orally, IV & topically ↓ viral DNA
Polymerase
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 Aciclovir (Cont.)

• Uses:
• Herpes simplex (HSV) infections:
Labial, ano-rectal & genital herpes
Herpetic keratitis & herpetic encephalitis
• Varicella zoster (VZV) infections:
Cutaneous & visceral
• Treatment & prevention of HSV & VZV
infections in immune compromised patients

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 Aciclovir (Cont.)

• Adv. Effects:
• GI: Nausea & diarrhoea
• Neurological: Headache, tremors,
delerium & seizures
• Renal toxicity

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 II. Anti-cytomegalovirus (CMV) drugs
• Ganciclovir
• Mechanism: Similar to acyclovir
• Activated by viral kinase to mono-phosphate, then by
host cell kinases to di- & tri-phosphate
• Activated drug ↓ DNA polymerase & ↓ viral division
• Kinetics:
• Given orally, IV & intra-ocularly

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 Ganciclovir (Cont.)
• Uses:
• Treatment of CMV esophagitis, colitis,
pneumonitis & retinitis
• Reduces risk of CMV in AIDS & transplant
recipients
• Adv. Effects:
• Bone marrow: Myelosuppression
• Neurological: headach, delerium & seizures
• Intra-ocular Inj. may cause retinal detachment

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 III. Drugs for influenza virus
• Amantadine & rimantadine
• Mechanism:
• Binding to M-2 protein of viral membrane &
↓ uncoating of influenza A virus
• Uses:
• Controls fever & other complaints of influenza
(given with in 1-2 days of onset)
• Prophylactic use in influenza outbreak for risk
patients:
- Immuno-compromised & diabetics, etc

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 Amantadine (Cont.)

• Adverse effects:
• GI upset (nausea & vomiting)
• Neurological (nervousness, lack of concentration)
• Acute over dosage causes anti-cholinergic side
effects: dry mouth, blurred vision, tachycardia,
constipation, risk of glaucoma & urine retention
(elderly ?)

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 Zanamivir
• Mechanism:
↓ neuroaminidase, involved in lysis of host cell
membrane
↓ release of influenza A & B viruses
• Uses:
Used for prevention & control of influenza
• Adverse effects:
Can cause GI upset (nausea & vomiting)

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 IV. Anti retroviral drugs
for Human Immune-deficiency Virus (HIV)
A. Nucleoside Reverse Transcriptase (NRT)
Inhibitors
• Zidovudine:
• d-thymidine analog
• Mechanism:
∀ ↓ NRT & causes DNA chain termination
• Kinetics:
• Given orally & IV, mainly metabolized in liver

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 Zidovudine (Cont.)
• Uses:
• Reduces symptoms & disease progression in HIV
infection
• Reduces mother to newborn transmission of disease
• Adverse effects:
• Mylosuppression (anemia, neutropenia)
• GI-upset, lactic acidosis & hepatomegaly
• Anxiety & confusion

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 Drugs for HIV (Cont.)
B. Protease Inhibitors:
• Indinavir
• Mechanism:
• Inhibitor ↓ protien synthesis & HIV replication
• Adv. Effects:
• Kidney: Nephrolithiasis due to crystallization
• Liver: ↑ levels of bilirubin & aminotransferase (liver
damage)
• Blood: Increased bleeding in haemophilics due to
thrombocytopenia & hypoprothrombinemia
• GI-upset (nausea, vomiting & diarrhoea)
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 Drugs for HIV (Cont.)
C. Non-nucleoside reverse transcriptase inhibitors
• Efavirenz:
• Relatively safe but resistance develops more easily
D. Inhibit of viral attachement & entry
• Enfuvirtide:
• A peptide, resembles a segment of HIV protrein
(gp41); given s.c. twice daily
• Can cause more allergic reactions

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 V. Anti-hepatitis agents
• Interferon alpha & ribavirin
• Interferon alpha
• Mechanism:
• Endogenous proteins, inhibit viral replication
• Preparations & kinetics:
• Interferon alpha-2a & interferon alpha-2b
Given IM & SC, have short plasma t ½ (2-5 hrs)
• Pegylated interferon α-2a & α -2b
(poly-ethylene glycol is attached to interferon)
Given SC, have long plasma t ½ (1 week)
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 Interferon alpha (Cont.)
• Uses:
• Hepatitis B & C viral (HBV & HCV) infections
• Response rate is less than 50%
• If no improvement after 3-4 months, discontinue
• Usually given in combination with ribavirin in HCV

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 Interferon alpha (Cont.)
• Adverse effects:
• Flu like syndrome (nausea, fatigue & headache)
• Hypersensitivity (rash, arthralgia, fever &
hypotension)
∀ ↑ serum aminotransferase level (liver damage)
• Thrombocytopenia, neutropenia & alopecia

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 Ribavirin
• Mechanism:
• A guanosine analog, phosphorylated in host cells
∀ ↓ replication of DNA & RNA viruses, including:
hepatitis C (HCV) & respiratory syncytial (RSV) virus
• Uses:
• HCV, along with interferon α-2b (oral capsules)
• RSV, by inhalation as aerosol

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 Ribavirin (Cont.)

• Adverse effects:
- dose dependent haemolytic anemia
- nausea, fatigue, insomnia & depression
- rash, pruritis & cough

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