Antiviral drugs

Introduction Compared to antibacterial ,few antiviral have been developed because: - virus require host cell to replicate -most agents that interfere with reproductive process of virus are toxic to host cell as well .

Virus. are obligate intracellular parasites Contain either single or double stranded DNA or RNA enclosed in a protein coat called a capsid Some possess lipid envelop that may contain antigenic glycoprotein's Most viruses contain enzymes essential for V. replication inside host cell .

Virus Structure There are many types of virus with varying shape and structure. All virus have a central core of either DNA or RNA surrounded by a coat of regularly packed protein units. No nucleus or cytoplasm like bacteria. Diagram of an AIDS Virus 4

Effective antiviral agents inhibit virus specific replicative events or inhibit nucleic acid or protein synthesis

DNA viruses Pox v. (small pox) Herpes virus (chicken,shingles, herpes v) Adeno v.(pharyngitis) Hepadna v. (HBV) Papilloma v.(warts)

RNA viruses Rubella v. (measles) Rhabdo v. (rabies) Picorna v. (colds, hepatitis A ) Arena v. ( meningitis) Flavi v. (hepatitis C ) Orthomyxo v (influenza ) Paramyxo v , corona v (cold , RTI) Retro v (AIDs )

Virus Replication The replication of viruses can only occur if the virus has attached and penetrated the living host cell. It injects it’s DNA or RNA into the host cell’s cytoplasm. It takes over the replication mechanism of the host cell. This causes the cell to die or to be altered, which results in the symptoms of a viral infection. The host cell produces new viral DNA or RNA cells which are then released to affect other healthy cells. A virus that contains RNA rather than DNA is called a retrovirus. 10

The virus uses the cell mechanism to replicate itself Virus Replication The virus uses the cell mechanism to replicate itself 11

Antiviral Drugs Common viral infections such as the influenza, or chicken pox are usually overcome by the body’s immune system. Vaccines are often used to build up immunity before a viral inflection occurs. Medications for viral diseases are used to: relieve associated pain, reduce fever, or counteract secondary inflections Rapid replication of viruses makes it difficult to develop effective antiviral drugs. 12

Treatment of Respiratory Virus Infections

A. Neuraminidase inhibitors oseltamivir and zanamivir These drugs prevent the release of new virions and their spread from cell to cell. oseltamivir and zanamivir are effective against both Type A and Type B influenza viruses. They do not interfere with the immune response to influenza A vaccine, Administered prior to exposure

neuraminidase inhibitors prevent infection, and when administered within the first 24 to 48 hours after the onset of infection, they have a modest effect on the intensity and duration of symptoms.

Pharmacokinetics Oseltamivir (tamiflu) is an orally active prodrug that is rapidly hydrolyzed by the liver to its active form. Zanamivir, is not active orally and is either inhaled or administered intranasally. Both drugs are eliminated unchanged in the urine

Oseltamivir and Zanamivir Are neuraminidase inhibitors Taken orally. Reduce severity and duration of symptoms caused by influenza viruses and reduce incidence of respiratory complications. Given once or twice daily ,taken within 30-36 hr after the onset of symptoms

Preparations Available Oseltamivir dosage is 75 mg twice daily for 5 days for treatment and 75 mg once daily for prevention Oseltamivir (Tamiflu)    Oral: 75 mg capsules; powder to reconstitute as suspension (12 mg/mL)

Side effects Orally nausea , vomiting nasal discomfort,bronchospasm .( Zanamivir should be avoided in individuals with severe reactive asthma or chronic obstructive respiratory disease).

Tamiflu- Prevents the mature viruses from leaving the cell , It is a neuraminidase inhibitor, it works on both influenza A and B Neuraminidase is an enzyme found on the virus which cleaves sialic acid from cell membrane, leading to a more effective release of viruses.

ANTI-INFLUENZA AGENTS B.Amantadine and Rimantadine Both agents specifically inhibit the replication of influenza A viruses. Rimantadine is 4–10 times more active than amantadine.

Mech of action inhibit or delay the uncoating process that precedes primary transcription it blocks action of M2 viralprotein that facilitate dissociation of ribonucleoprotein complex preceding replication and changes that follow translation .

Pharmacokinetics : Both drugs are well absorbed orally. Amantadine distributes throughout the body and (readily penetrates into the central nervous (CNS). rimantadine does not cross the blood-brain barrier to the same extent system

Pharmacokinetics . * Amantadine is not extensively metabolized. It is excreted into the urine and may accumulat to toxic levels in patients with renal failure. *rimantadine is extensively metabolized by the liver, and both the metabolites and the parent drug are eliminated by the kidney.

Preparations Available Amantadine (generic, Symmetrel) Oral: 100 mg capsules, tablets Available in cap or syp. given orally for the prevention of influ. A Virus , can reduce infection rates by 50% Recently there is an aerosol mist of amantadine used for Rx of influenza virus

side effects amantadine and rimantadine are 1.GI(Anorexia or nausea) 2.CNS complaints, including nervousness, light-headedness, difficulty concentrating, insomnia..

C. Ribavirin is a synthetic guanosine analog. It is effective against a broad spectrum of RNA and DNA viruses. ribavirin is used in treating infants and young children with severe RSV infections. [Note: It is not indicated for use in adults.

Ribavirin *Ribavirin is also effective in chronic hepatitis C infections when used in combination with interferon *may reduce the mortality and viremia of Lassa fever. Given orally,i.v,aerosol.

Antiherpetic agents Several enzymes involved in the biosynthesis of DNA such as thymidine kinase , thymidylate kinase and DNA polymerase are inhibited by this drug

Idoxuridine It is antiviral effect is incorporating into viral DNA chromosomal breakage and altered synthesis of viral proteins . It is incorporation into DNA of normal cells is responsible of its toxicity

Idoxuridine Clinical use limited to herpes simplex keratitis. Topical application to the conjunctiva can cause local irritation ,contact dermatitis , photophobia , lacrimation and other side effects are chromosomal damage i.v.injection cause bon marrow toxicity

Antiherpetic agents Vidarabine act against DNA viruses e.g. herpes virus group(HSV1,HSV2,VZV) It is of low water solubility and poor GIT absorption therefore should be administered by prolonged IV infusion of dilute solutions

Vidarabine Uses of IV infusion is effective for Rx of herpes encephalitis and for the control of varicella – zoster virus infections in immunocompromised patients. (note: acyclovir is replaced vidarabine for these uses) Topical Rx with vidarabine oit. is useful for keratitis caused by HSV and is the drug main use.

Side effects of Vidarabine : GIT disturbances , CNS manifestation , hematologic disorders Teratogenic and carcinogenic

Acyclovir and valacyclovir It is effective against herpes viruses such as HSV , VZV and cytomegalo virus(CMV) Valacyclovir is ester of acyclovir , this prodrug is rapidly absorped after oral ingestion , then converted to acyclovir

Acyclovir The mech. Of action of acyclovir is well known : It will be phosphorelated to form acyclocvir monophosphate by herpes virus encoded thymidine kinase and further phosphorelated by other enzymes to acyclovir diphosphate and triphosphate , the last one inhibits viral DNA polymerase and terminate elongation of viral DNA chain .

Antiviral Drugs - Acyclovir Acyclovir is an antiviral drug used to treat Herpes Simplex 38

pharmacokinetic Bioavailability 20% Peak plasma conc. After 2 hr IV infusion produce higher conc. useful for resistant infection half-life is 2.5–3 hours Eliminated by kidney

Indications parenteral Rx of mucocutaneous HSV in immunocompromised patients H.ZosterV. infection herpes encephalitis Genital H.simplex H.simplex keratitis Chickenpox.

Uses in dentistry 1. Herpes labialis 2. Acute herpetic gingivostomatitis

Resistance 1- loss of viral thymidine kinase activity 2- elaboration of viral thymidine kinase with altered substrate specificity 3- altered DNA polymerase activity

Side effects - no serious toxicity with topical or oral - Rx oral for 3-5 months can cause 1. headache , diarrhea , nausea , vomiting, arthralgia , vertigo. 2. IV can induce local phlebitis , nausea , vomiting , diaphoresis , rash , hypotension,also cause nephrotoxicity and encephalopathy.

Preparations Available Acyclovir (generic, Zovirax) Oral: 200 mg capsules; 400, 800 mg tablets; 200 mg/5 mL suspension Parenteral: 50 mg/mL; powder to reconstitute for injection (500, 1000 mg/vial). Topical (5% cream) for Recurrent herpes labials Thin film covering lesion 5 times daily x 4 days

valacyclovir ester of acyclovir It is rapidly converted to acyclovir after oral administration via first-pass enzymatic hydrolysis in the liver and intestine, resulting in serum levels that are three to five times greater than those achieved with oral acyclovir and approximate those achieved with Elimination half-life is 2.5–3.3 hours.

uses treatment of recurrent genital herpes treatment for orolabial herpes. treatment for herpes zoster Once-daily dosing of valacyclovir was associated with a shorter duration of zoster-associated pain. Valacyclovir has also been shown to be effective in preventing cytomegalovirus (CMV) disease after organ transplantation when compared with placebo.

Ganciclovir and Valganciclovir Mech. Of action similar to acyclovir It is more potent than acyclovir against HSV,CMV, and VZV with greater cytotoxicity Used systemically for treatment of CMV in immunocompromized patients , Rx of HSV in resistant cases.

Ganciclovir Ganciclovir is an analog of acyclovir that has 8- to 20-times greater activity against CMV”the only viral infection for which it is approved. It is currently available for treatment of CMV retinitis in immunocompromised patients and for CMV prophylaxis in transplant patients.

Pharmacokinetics: Ganciclovir is administered intravenously and distributes throughout the body, including the CSF. .Like acyclovir, ganciclovir accumulates in patients with renal failure.

Valganciclovir Valganciclovir [is the valyl ester of ganciclovir. Like valacyclovir, valganciclovir has high oral bioavailability, because rapid hydrolysis in the intestine and liver after oral administration leads to high levels of ganciclovir. Side effects: granulocytopenia, thrombocytopenia

Side effects:

Penciclovir *Penciclovir is acyclic guanosine nucleoside derivative *active against HSV-I, HSV-2, and VZV *only administered topically *monophosphorylated by viral thymidine kinase, and cellular enzymes form the nucleoside triphosphate, which inhibits HSV DNA polymerase *Both pain and healing are shortened approximately one-half day in duration

Famciclovir *Famciclovir is a prodrug that is metabolized to the active penciclovir *The drug is effective orally *only for treatment of acute herpes zoster *Adverse effects include headaches and nausea

Foscarnet Active against HSV, CMV , HIV Inhibit herpetic DNA polymerase activity by blocking the binding site on the enzyme, it inhibits the synthesis of DNA , it is more selective for herpes virus DNA than for mammilianDNA

Foscarnet Given for treatment of Acyclovir resistant HSV infections in AIDS and CMV retinitis in immunocompromized patients,VZV and HIV -1 infections The drug is highly ionized and must be given by slow IV infusion every 8 hr

Interferon's(IFNs) Posses antiviral , immunomodulating and antiproliferative activity They are synthesized by host cell and stimulate antiviral state in cells There are 3 major classes of human IFNs ( α,β , γ) Clinically used recombinant α IFNs Interferons are host cytokines that exert complex antiviral, immunomodulatory, and antiproliferative actions ,

THERAPEUTIC USES Recombinant, natural, IFNs are approved for treatment of: 1. chronic HepatitisC Virus infection, 2.chronic(Hepatitis B Virus) 3.multiple sclerosis. 4.Papillomavirus

4- Antiretroviral agents and treatment of HIV infection human immunodeficiency virus There are two major families of HIV. Most of the epidemic involves HIV-1; HIV-2

AIDS Definition AIDS ( Acquired Immune Deficiency Syndrome) is caused by a retrovirus that contains RNA rather then DNA. This specific virus invades particular cells, that are within the immune system making the body unable to fight off infections. 61

1.reverse transcriptase inhibitors

Antiviral Drugs - AZT AZT was the first antiviral drug used to effectively treat HIV-AIDS . 64

(Zidovudine)AZT AZT combines with the enzyme that the HIV virus uses to build DNA from RNA and clogs up its active site. It acts as a reverse transcriptase inhibitor. Since only Retro-Viruses, such as HIV, use this enzyme., AZT ↓mortality & opportunistic infections, gain weight, better quality of life, delays signs and symptoms of AIDS

Adverse effect of Zidovudine (AZT) 1.Granulocytopenia and anemia: 45% in AIDS. 2.Severe headache, nausea, insomnia, myalgias