ANTIVIRAL AGENTS

Viruses, what are they? Viruses are obligate intracellular parasites, i.e. they utilize: 􀂄 Host metabolic enzymes 􀂄 Host ribosome for protein synthesis They cannot make anything on their own, they use the cell’s materials to build themselves

Structure of viruses Virus particles (virions) consist of following parts: 􀂄 Nucleic acid core: DNA or RNA 􀂄 Often contain virus-specific enzymes 􀂄 Surrounded by protein: “capsid” 􀂄 sometimes an outer lipid “envelope”

Classification of Viruses RNA Viruses Contain an RNA genome. Virus replication: RNA-dependent RNA polymerase Reverse transcriptase (Retroviruses) Examples: Rubella virus Dengue fever virus Hepatitis A virus Hepatitis C virus HIV Influenza virus DNA viruses Contain an DNA genome. Virus replication: DNA polymerase Examples: Herpes Virus Hepatitis B virus Epstein-Barr virus

Attachment of the virus to receptors on the host cell surface; The Life Cycle of Viruses Attachment of the virus to receptors on the host cell surface; Entry of the virus through the host cell membrane; Uncoating of viral nucleic acid; Replication Synthesis of early regulatory proteins, eg, nucleic acid polymerases; Synthesis of new viral RNA or DNA; Synthesis of late, structural proteins; 5. Assembly (maturation) of viral particles; 6. Release from the cell

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Many viruses infect a specific host cell Many viral infections are self-limiting and require no medical treatment—ex. Rhinoviruses that cause common cold. Common viral infections such as the influenza, mumps, or chicken pox are usually overcome by the body’s immune system. Other viruses cause serious and even fatal disease & require aggressive therapy—ex. HIV that causes AIDS.

Vaccines are often used to build up immunity before a viral infection occurs. Common viral infections such as the influenza, mumps, or chicken pox are usually overcome by the body’s immune system. To be effective, antiviral agents must either block viral entry into or exit from the cell or be active inside the host cell. 10

Some Viral Diseases

Antiviral Medications Antiviral drugs Used to treat infections caused by viruses other than HIV Antiretroviral drugs Used to treat infections caused by HIV, the virus that causes AIDS Herpes-Simplex Viruses HSV-1 (oral herpes) HSV-2 (genital herpes) Varicella Zoster Virus Chickenpox Shingles

ANTIVIRAL DRUGS WORK BY: Altering the cell’s genetic material so that the virus cannot use it to multiply, i.e. acyclovir (inhibiting Viral enzymes, Host expression of viral proteins & Assembly of viral proteins) Preventing new virus formed from leaving the cell, i.e. amatadine.

CLASSIFICATION:- Anti-influenza Agents Amantadine · Rimantadine · Anti-herpes virus agents   Acyclovir · Famciclovir · Foscarnet · Ganciclovir · Idoxuridine · Valacyclovir · Antiretroviral Agents  NRTIs Zidovudine · Didanosine · Stavudine · Zalcitabine · Lamivudine · Abacavir · NNRTI’s Nevirapine · Efavirenz · Delavirdine Pis Saquinavir · Indinavir · Ritonavir · Nelfinavir · Amprenavir · Lopinavir · Other antiviral agents Fomivirsen · Enfuvirtide · Imiquimod · Interferon · Ribavirin · Viramidine

Anti-herpes virus agents Acyclovir / Valacyclovir Famciclovir / Penciclovir Ganciclovir / Cidofovir Foscarnet Trifluridine / Idoxuridine / Vidarabine Trifluridine

Acyclovir & Congeners : Valacyclovir is a prodrug of Acyclovir with better bioavailability. Famciclovir is hydrolyzed to Penciclovir and has greatest bioavailability. Penciclovir is used only topically whereas Famciclovir can be administered orally.

PHARMACOLOGY OF ACYCLOVIR AND CONGENERS Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir all are guanine nucleoside analogs.

Acyclovir – Structure Purine Mimic Similarity to 2`-deoxyguanosine: lack of 3` hydroxyl

Mechanism of action of Acyclovir and congeners : All drugs are phosphorylated by a viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs. The analog inhibits viral DNA-polymerase Only actively replicating viruses are inhibited

Acyclovir - MOA Step 1: Activation

Acyclovir - MOA Step 2: Incorporation into growing DNA chain Inhibits DNA-polymerase irreversibly

Figure 20.16b, c

ANTIVIRAL SPECTRUM : Acyclovir: HSV-1, HSV-2, VZV, Shingles. Ganciclovir / Cidofovir : CMV Famciclovir : Herpes genitalis and shingles Foscarnet : HSV, VZV, CMV, HIV Penciclovir : Herpes labialis Trifluridine : Herpetic keratoconjunctivitis

Pharmacokinetics of Acyclovir : Oral bioavailability ~ 20-30% Distribution in all body tissues including CNS Renal excretion: > 80% Half lives: 2-5 hours Administration: Topical, Oral , IV

Adverse effects of Acyclovir Oral: Nausea, diarrhea, and headache IV: Rashes, sweating and emesis and fall in BP Reversible renal dysfunction due to crystalline nephropathy Neurologic toxicity (eg, tremors, delirium, seizures) No Teratogenicity

Acyclovir – Therapeutic Uses Genital Herpes simplex: HSV –II Mucocutaneous H. simplex: Type - I H. simplex encephalitis: type – 1 H. simplex keratitis H. zoster Chicken pox

RESISTANCE HSV or VZV alteration in either the viral thymidine kinase or the DNA polymerase → resistance Cross-resistance to valacyclovir, famciclovir and ganciclovir Agents such as foscarnet, cidofovir, and trifluridine do not require activation by viral thymidine kinase and thus have preserved activity against the most prevalent acyclovir-resistant strains.

FAMCICLOVIR An ester prodrug of a guanine nucleoside analogue penciclovir P’kinetics:- Good oral bioavailability and prolonged intracellular t ½ of the active triphosphate metabolite. Mechanism:- Like acyclovir, it needs viral thymidine kinase for generation of the active DNA polymerase inhibitor. Spectrum:- H. simplex, H. Zoster, hepatitis B virus (HBV).

Use:- An alternative to acyclovir for genital herpes and herpes zoster. Alternative to lamivudine in chronic hepatitis B. Side effects:- Headache, nausea, loose motions, itching, rashes and mental confusion.

Other Nucleoside Analogs: 5. Cidofovir a) Cytosine analog b) Primary uses: I.V. use approved for CMV retinitis c) Side effects: Nephrotoxicity 6. Idoxuridine a) Iodinated thymidine analog b) Primary use: herpes keratitis (topically) c) Side effects: Pain, inflammation 7. Vidarabine a) Adenosine analog b) Primary uses: I.V. for herpes encephalitis and neonatal herpes (most of uses have been replaced by acyclovir)

HAART - Highly active antiretroviral therapy ANTIRETROVIRAL DRUGS HAART - Highly active antiretroviral therapy Includes at least three medications “cocktails” These medications work in different ways to reduce the viral load

RETROVIRUSES Virus has the enzyme reverse transcriptase as a part of the viral structure. A double-stranded DNA copy of the viral genome is produced. This copy can integrate into the host cell chromosome. Some retroviruses can cause tumors in animals: oncogenes Human immunodeficiency virus (HIV) is a retrovirus. This is the causative agent of AIDS.

STAGES OF HIV REPRODUCTION HIV entry into the CD4 cells HIV’s genetic information stored on a single stranded RNA instead of the double-stranded DNA HIV uses an enzyme known as reverse transcriptase to convert its RNA into DNA

HIV DNA enters the nucleus of the CD4+ cell and inserts itself into the cell’s DNA HIV DNA instructs the cell to make many copies of the original virus New virus particles assembled and leave the cell ready to infect other CD4+ cells

Antiretroviral Drugs Reverse transcriptase inhibitors (RTIs) Examples Block activity of the enzyme reverse transcriptase, preventing production of new viral DNA Nucleoside RTIs (NRTIs) Nonnucleoside RTIs (NNRTIs) Examples abacavir (Ziagen) delavirdine (Rescriptor) didanosine (Videx) lamivudine (Epivir) stavudine (Zerit) tenofovir (Viread)

Fusion inhibitors are administered by subcutaneous injection. Non-Nucleoside Reverse Transcriptase Inhibitors Nucleoside/Nucleotide Analogues Protease Inhibitors A novel class of antiretroviral agents that inhibit the fusion of HIV with target cell membranes. Fusion inhibitors are administered by subcutaneous injection. The newest class of antiretroviral agents, non-nucleoside transcriptase inhibitors (NNRTIs) Stop HIV production by binding directly onto reverse transcriptase and preventing the conversion of RNA to DNA. These drugs are called "non-nucleoside" inhibitors because even though they work at the same stage as nucleoside analogues, they act in a completely different way. The first effective class of antiretroviral drugs. They act by incorporating themselves into the DNA of the virus, thereby stopping the building process. The resulting DNA is incomplete and cannot create new virus Protease inhibitors work at the last stage of the virus reproduction cycle. They prevent HIV from being successfully assembled and released from the infected CD4+ cell.

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS ZIDOVUDINE DIDANOSINE STAVUDINE LAMIVUDINE ZALCITABINE ABACAVIR EMTRICITABINE

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Are analogs of naturally occurring nucleotides •Require phosphorylation to triphosphate form •Competitively inhibit HIV-1 (and usually HIV-2) reverse transcriptase (RT) •Are incorporated into viral DNA and cause chain termination •Net effect is inhibition of viral DNA synthesis •Block acute infection but are much less active against chronically infected cells •Usually used in combination with other anti-HIV drugs Clinical Pharmacology 2007. Gold Standard, Inc.

NRTI Mechanism of Action NRTIs mimic other nucleosides and are incorporated into the DNA strand They prevent the addition of the natural nucleosides into the DNA strand This halts the production of new virions Clinical Pharmacology 2007. Gold Standard, Inc.

reverse transcriptase Incorporated into host genome HIV integrase double helix DNA ViralRNA transcription translation Final structural proteins HIV protease Polyproteins NRTIs NNRTIs Drugs PIs

Zidovudine (Azidothymidine): AZT is a deoxythymidine analog

Zidovudine - Prototype MOA: Zidovudine triphosphate (Phosphorylated) When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double-stranded viral DNA The viral DNA is then integrated into the host chromosomal DNA Then, host cellular processes start transcribing viral RNA and mRNA to reproduce the virus Regulatory and structural proteins are produced under the direction of viral mRNA Zidovudine inhibits viral reverse transcriptase (RNA dependent DNA polymerase) Zidovudine prevents infection of new cell by HIV, but not effective on already infected host chromosomes Any of a group of viruses that, unlike most other viruses and all cellular organisms, carry their genetic blueprint in the form of RNA. Retroviruses are responsible for some cancers and viral infections of animals, and they cause at least one type of human cancer. The retrovirus HIV is the cause of AIDS in humans. The name signifies that they use RNA to synthesize DNA, the reverse of the usual cell process. This process makes it possible for genetic material from a retrovirus to enter and become a permanent part of the genes of an infected cell.

Zidovudine Resistance: Point mutation altering reverse transcriptase enzyme Kinetics: Bioavailability – 60-80%. t1/2 – 1 hour Conc. in CSF – 65% of that in plasma, crosses placenta and excreted in milk Metabolism – Most of the drug is metabolized to in the liver, excreted in the urine A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair. One can categorize point mutations as follows:

Zidovudine Unwanted effects: Blood dyscrasias – Anaemia and Neutropenia G.I disturbances – Nausea, vomiting, abdominal pain Myopathy, Myalgia Skin rash, Insomnia, Fever, Headaches, Abnormalities of liver function Drug Interaction: Paracetamol – AZT toxicity and azoles – inhibits AZT metabolism Uses: HIV infection in combination with other drugs – minimum 2 other. myelosuppression

DIDANOSINE A purine nucleoside analogue Mechanism:- After intracellular conversion to didanosine triphosphate competes with ATP for incorporation in viral DNA, inhibits HIV reverse transcriptase and terminates proviral DNA. Spectrum:-Equivalent to AZT. Mutational resistance develops. Kinetics:- Oral absorption is erratic due to acid lability. T 1/2 - 1 to 1 .5 hr. Side effects:- peripheral neuropathy and rarely pancreatitis. Diarrhoea, abdominal pain and nausea. Use:- Used only in combination regimens.

STAVUDINE Thymidine analog Mechanism: Inhibits HIV RT and causes DNA chain termination Kinetics: It is well absorbed orally and rapidly metabolised (t ½ - 1 .5 hr). Use: Advanced HIV in patients unresponsive to other therapies Resistance: Not frequently observed Side effects: Peripheral neuropathy, lipodystrophy and rarely pancreatitis

LAMIVUDINE Deoxycytidine analogue Mechanism:- Phosphorylated intracellularly and inhibits HIV reverse transcriptase as well as hepatitis B virus (HBV) DNA polymerase. Its incorporation into DNA results in chain termination. Most human DNA polymerases are not affected and systemic toxicity is low. Resistance:- Mutation in HIV reverse transcriptase and HBV-DNA polymerase gives rise to rapid lamivudine resistance.

Kinetics:- Oral bioavailability is high and plasma T ½ longer (6-8 hours). Excreted unchanged in urine. Uses:- Used in combination with other anti-HIV drugs. Frequently used for chronic hepatitis B. Side effects:- headache, fatigue, nausea, anorexia, abdominal pain. Pancreatitis and neuropathy are rare.

ZALCITABINE Deoxycytosine analog Mechanism: Inhibits HIV RT and causes DNA chain termination Bioavailability reduced by food Primary use: In combination with zidovudine (produces synergistic effects) Resistance: Viral mutation Side effects: Peripheral neuropathy; oral & esophageal ulcerations

ABACAVIR Guanosine analog Newer agent that seems to be more effective than earlier NRTIs Mechanism: Inhibits HIV RT and causes DNA chain termination Good oral oral absorption; bioavailability not reduced by food Resistance: Develops more slowly Side effects: Hypersensitivity reactions (may be fatal)

NRTI DRUG INTERACTIONS Drug (s) Interactions Abacavir Alcohol; metabolized by alcohol dehydrogenase Didanosine ↓ absorption of other drugs due to buffer (e.g. quinolones, tetracyclines, ketoconazole) ↑ levels of ribavirin; do not combine Allopurinol → ↑ levels of didanosine; do not combine Didanosine/ stavudine Agents with additive neurotoxicity (e.g. vincristine, cisplatin, isoniazid) Agents with additive pancreatoxicity (e.g. alcohol, valproic acid, ritonavir) Zidovudine Antagonism with stavudine (compete for intracellular activation) Additive bone marrow suppression (e.g. ganciclovir, valganciclovir, flucytosine)

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs) Nevirapine  Efavirenz  Delavirdine

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Bind to RT at a different site than nucleoside reverse transcriptase inhibitors (NRTIs) Do not require phosphorylation to inhibit the HIV RT Do not compete with nucleoside triphosphates for incorporation into DNA Bind to RT’s active site and block RNA- and DNA-dependent DNA polymerase cross resistance is common among different NNRTis No cross resistance with NRTIs or protease inhibitors (below) Rapid development of resistance by viral mutation

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Used in combination antiretroviral therapy Metabolized by cytochrome P450 enzyme complex Interactions with drugs which are metabolized by certain cytochrome P450 enzymes Frequently require dosage reduction in patients with compromised liver function They are more potent than AZT on HIV -1, but do not inhibit HIV - 2.

NNRTI MECHANISM OF ACTION NNRTIs also inhibit the viral reverse transcriptase enzyme but have a different mechanism of action compared to NRTIs NNRTIs bind directly to the reverse transcriptase enzyme

NEVIRAPINE (NVP) Well absorbed orally Metabolized in liver T ½ - 30 hours Modestly induce CYP 3A4, 2D6 enzymes and enhance their own metabolism as well as that of other drugs. Side effects:- Rashes (commonest), nausea, headache , Fever and rise in liver enzymes can occur. Hepatotoxic. Avoid enzyme inducers (rifampin) and enzyme inhibitors (ketoconazole). The NNRTis are indicated in combination regimens for HlV

EFAVIRENZ (EFV) Oral absorption is incomplete T ½ is longer - 48 hours Modestly induce CYP 3A4, 2D6 enzymes and enhance their own metabolism as well as that of other drugs. Side effects:-headache, rashes, dizziness, insomnia It induces the metabolism of certain drugs and inhibits that of others. Indicated in combination regimens for HlV

DELAVIRDINE Good oral bioavailability; reduced by antacids Side effects: Skin rash, can be teratogenic (avoid pregnancy during therapy)

PROTEASE INHIBITORS (PIS)

PROTEASE INHIBITORS SAQUINAVIR INDINAVIR AMPRENAVIR RITONAVIR NELFINAVIR

MECHANISM OF ACTION An aspartic protease enzyme encoded by HIV is involved in the production of structural proteins and enzymes (including reverse transcriptase) of the virus. The large viral polyprotein is broken into various functional components by this enzyme. This protease acts at a late step in HIV replication, i.e. maturation of the new virus particles when the RNA genome acquires the core proteins and enzymes. They bind to the protease molecule, interfere with its cleaving function, and are more effective viral inhibitors than AZT.

MECHANISM OF ACTION They act at a late step of viral cycle, they are effective in both newly and chronically infected cells. Under their influence, HIV-infected cells produce immature viral progeny-hence prevent further rounds of infection

PHARMACOKINETICS Oral bioavailability of Pis is variable (IDV and RTV -65 % , NFV >20%, SQV 15%) Plasma t ½ ranges from 2-5 hours. All are extensively metabolized by CYP3A4 and other CYP isoenzymes. The Pis interact with many drugs. Nelfinavir and ritonavir induce their own metabolism Monotherapy in previously AZT treated patients reduced HIV viral levels viral resistance developed slowly. Combination of NRTis with Pis more effective than either drug given alone. Current recommendations are to use a PI in combination with either two NRTis or one NRTI + one NNRTI.

ADVERSE EFFECTS Gastrointestinal intolerance, asthenia, headache, dizziness, limb and facial tingling, numbness and rashes. Lipodystrophy (abdominal obesity, buffalo hump with wasting of limbs and face) and dyslipidaemia (raised triglycerides and cholesterol) Risk of urinary calculi

1. Saquinavir a. Poor to adequate oral bioavailability b. Side effects: Fairly well tolerated with mild GI discomfort c. Usually used in combination with Ritonavir (see below) 2. Ritonavir a. Good oral bioavailability when given with food b. Side effects: GI disturbances, peripheral or oral sensations, elevated serum triglycerides and aminotransferase levels 3. Indinavir a. Excellent oral bioavailability when given on empty stomach b. Side effects: Hyperbilirubinemia and nephrolithiasis (crystals forming in the kidneys)

4. Nelfinavir a. Oral bioavailability increased with food b. Side effects: Diarrhea 5. Amprenavir a. Good oral bioavailability when given with or without food b. Efficacy increases when combined with two nucleoside RT inhibitors c. Side effects: GI disturbances & rashes

FUSION INHIBITOR

ENFUVIRTIDE Synthetic peptide Acts by binding to HIV-1 envelope glycoprotein (gp41) and preventing fusion of viral and cellular membranes. Entry of the virus into the cell is thus blocked. It is not active against HIV-2. No cross resistance with other classes of ARV drugs occurs. Administered s.c. it is used as add on drug to an optimized regimen in patients who have failed many earlier regimens.

ANTI INFLUENZA AGENTS

Antiviral Therapies for Influenza

AMANTADINE A tricyclic amine Inhibits replication of influenza A virus. Act at an early step (possibly uncoating) as well as at a late step (viral assembly) in viral replication. A protein 'M2' which acts as an ion channel is the targets of action. Resistance :- By mutation causing amino acid substitutions in the M 2 protein. Well absorbed orally and excreted unchanged in urine T ½ 16 hr.

Adverse effects:- Nausea, anorexia, insomnia, dizziness, nightmares, lack of mental concentration, hallucinations, Ankle edema Use: Prophylaxis of influenza A Parkinsonism Contraindications: Epilepsy and other CNS disease; gastric ulcer, pregnancy.

RIMANTADINE More potent Long-acting T ½ - 30 hr Better tolerated Oral bioavailability is higher and it is largely metabolized. Clinical application is similar to amantadine. Amantadine resistant virus is resistant to rimantadine as well.

Neuraminidase inhibitor Inhibit neuraminidase enzyme of influenza Enzyme essential for release of virus Examples: zanamivir and oseltamivir

OSELTAMIVIR (TAMIFLU) A broader-spectrum activity Covering influenza A (amantadine sensitive as well as resistant), influenza B and avian-influenza (bird flu) H5N1 and other strains. An ester prodrug that is rapidly and nearly complete absorption in intestine and by liver to the active form oseltamivir carboxylate. Excreted by the kidney T ½ - 6-10 hours. It acts by inhibiting influenza virus neuraminidase enzyme which is needed for release of progeny virions from the infected cell.

Indication:-For treatment of influenza A, B and bird flu. Side effects :-Nausea and abdominal pain due to gastric irritation, headache, diarrhoea, cough and insomnia, Skin reactions.

ZANAMIVIR Another influenza virus (A, B, avian strains) neuraminidase inhibitor Administered by inhalation as a powder due to very low oral bioavailability. Excreted by the kidney T ½ - 2-5 hours The mechanism of action, clinical utility and efficacy of zanamivir are similar to that of oseltamivir. side effects:-Headache, dizziness, nausea and rashes, bronchospasm. severe in asthmatics; contraindicated in them.

NONSELECTIVE ANTIVIRAL DRUGS Interferons Ribavirin Adefovir dipivoxil

RIBAVIRIN Purine nucleoside analogue Broad-spectrum activity, including influenza A and B, respiratory syncytial virus and many other DNA and double stranded RNA viruses. Its mono- and triphosphate derivatives generated intracellularly inhibit GTP and viral RNA synthesis and have other sites of action as well. No viral resistance Oral bioavailability is -50%. Accumulates in the body and persists months after discontinuation.

Indications:- Used in influenza A/B and measles in immunosuppressed patients as well as for herpes virus infections, acute hepatitis, Combined with interferon a, for chronic hepatitis C. Nebulized ribavirin used for respiratory syncytial virus broncholitis in infants and children. Shown efficacy in some rare viral infections. Adverse effects:- Anaemia, haemolysis, CNS and g.i. symptoms. Teratogenic. Irritation of mucosa and bronchospasm.

ADEFOVIR DIPIVOXIL Diester prodrug of AMP analogue Active against hepatitis B virus (HBV) and some other DNA viruses. Esterases in the intestine and liver release the active drug during absorption to attain oral bioavailability of -60%, which is then distributed in whole body water. Plasma t ½ -7 hours

Mechanism:- On entering cells, adefovir (a monophosphate) is phosphorylated to the diphosphate which has high affinity for HBV DNA polymerase. This enzyme is inhibited and adefovir itself gets incorporated in the viral DNA resulting in termination of the DNA chain. Indication:- In chronic hepatitis B, in lamivudine-resistant cases. No cross resistance Side effects :- Sore throat, headache, weakness, abdominal pain and flu syndrome. Nephrotoxicity at higher doses and in those with preexisting renal insufficiency.

Interferons Interferons (IFNs) are natural proteins produced by the cells of the immune systems in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. Antiviral, immune modulating and anti-proliferative actions Three classes of interferons – α , β, γ α and β interferons are produced by all the cells in response to viral infections γ interferons are produced only by T lymphocyte and NK cells in response to cytokines – immune regulating effects γ has less anti-viral activity compared to α and β interferons

Mechanism of action of Interferons : Induction of the following enzymes: 1) a protein kinase which inhibits protein synthesis 2) an oligo-adenylate synthase which leads to degradation of viral mRNA 3) a phosphodiesterase which inhibit t-RNA The action of these enzymes leads to an inhibition of translation

Pharmacokinetics : Interferons Oral bioavailability: < 1% Administered S.C, and I.V Distribution in all body tissues, except CNS and eye. Half lives: 1-4 hours

ADVERSE EFFECTS Flu-like symptoms-fatigue, aches and pains, fever, dizziness, anorexia, taste and visual disturbances Neurotoxicity-numbness,neuropathy, tremor, sleepiness, rarely convulsions. Myelosuppression-neutropenia, thrombocytopenia. Thyroid dysfunction (hypo as well as hyper). Hypotension, transient arrhythmias, alopecia and liver dysfunction.

THERAPEUTIC USES Chronic hepatitis B and C AIDS-related Kaposi's sarcoma Condyloma acuminata caused by papilloma virus H. simplex, H. zoster and CMV infections in immunocompromised patients Rhinoviral cold In chronic myelogenous leukaemia and multiple myeloma.

UNDESIRABLE SIDE EFFECTS ANTIVIRAL DRUGS – DNA & RNA VIRUSES DRUG MECHANISM/ VIRAL SELECTIVITY CLINICAL USE VIRAL RESISTANCE UNDESIRABLE SIDE EFFECTS PHARMACOKINETICS NOTES Acylovir Metabolized by thymidine kinase to triphosphate Herpes simplex 1 & 2, varicella zoster Produce abnormal thymidine kinase Skin irritation, burning, crystalline nephropathy IV/PO. Administer slowly. CNS level=50% serum level. Decrease dose w/ kidney dysfunction Pencyclovir Oral HSV (coldsores) Topical Valacyclovir L-valyl ester of acyclovir converted to acyclovir Herpes zoster (shingles) Nausea, headache PO. Slightly better oral absorption than acyclovir No clear advantage over acyclovir Idoxuridine Phosphorylated metabolite incorporates into DNA causing strand breaks Herpes simplex keratitis. No effect on RNA viruses Resistance develops Photophobia, irritation of conjunctiva & eyelid Eyedrops Drug is a halogenated derivative of deoxyuridine Famciclovir Phosphorylated by viral thymidine kinase to penciclovir triiphosphate Shortens duration of herpes zoster & genital herpes Minimal toxicity. Headache PO. Decrease dose with renal dysfunction. Ganciclovir Metabolized by thymidine kinase to triphosphate . Preferentially phosphorylated to active drug in CMV infected cells CMV retinitis & severe systemic CMV infections Some resistant strains lack thymidine kinase. Cannot activate drug. Granulocytopenia, thrombocytopenia IV/PO. Excreted unchanged in urine. Decrease dose with renal dysfunction. Do not coadminister zidovudine (granulocytopenia) or imipenem-cilastatin (seizures)

Cidofovir Metabolized to diphosphate form. Otherwise like ganciclovir. CMV retinitis Nephrotoxicity may be reduced by hydration & coadministration of Probenicid. Neutropenia. Foscarnet Analog of pyrophosphate. Competes for pyrophosphate site in viral but not human, DNA polymerase & reverse transcriptase Does not need phosphorylation, it is active against thymidine kinase –deficient strains Renal toxicity, seizures, hypocalcemia, fever, anemia, diarrhea, nausea IV. >80% excreted unchanged in the urine. CSF penetration variable. Reduce dose with renal dysfunction. Deposited in bone & teeth. Hydrate patient during therapy to protect the kidney Amantadine Prevents virus from entering susceptible cells Treatment & prophylaxis of influenza A Depression, CNS toxicity, CHF, orthostatic hypotension, urinary retention PO. Excreted unmetabolized. Rimantadine Analog of amantadine , inhibits viral uncoating Prophylaxis in children Fewer CNS side effects, risk of seizure PO. Prolonged elimination w/ renal or hepatic dysfunction Ribavirin Unknown mechanism RSV Decreased pulmonary function. Aerosol administration. Absorbed systemically. May precipitate in ventilator tubing.

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