School of Pharmacy, University of Nizwa Anti-Viral Drugs Course Coordinator Jamaluddin Shaikh, Ph.D. School of Pharmacy, University of Nizwa Lecture 10 March 11, 2013

What is Virus? Intracellular parasites that use many of the host cell’s biochemical mechanisms and products to sustain their viability A mature virus (virion) can exist outside a host cell and retain its infective properties For reproduction, virus must enter the host cell, take over the host cell’s mechanisms for DNA and protein synthesis, and direct the host cell to make new virus

Overview of Antiviral Therapy Three basic approaches are used to control viral diseases: 1.Vaccination 2. Antiviral chemotherapy 3. Stimulation of host resistance mechanisms

Antiviral Chemotherapy The chemotherapy of viral infections may involve interference with any or all of the steps in the viral replication cycle Disadvantage: Because viral replication and host cell processes are so intimately linked, the main problem in the chemotherapy of viruses is finding a drug that is selectively toxic to the virus

Viral Infections Types of viral infections Influenza Hepatitis Herpes

Influenza Virus Influenza is responsible for several thousand deaths each year Individuals over the age of 65, and patients with long-term health problems are at highest risk for severe influenza and complications Yearly vaccination can prevent influenza infection and minimize the severity of symptoms in those who do contract this disease However, infection can occur in immunized persons, because influenza viruses mutate rapidly

Antiinfluenza Agents Neuraminidase inhibitors Oseltamivir Zanamivir Inhibitors of viral uncoating Amantadine Rimantadine Ribavirin

Neuraminidase Inhibitors Orthomyxoviruses that cause influenza contain the enzyme neuraminidase, which is essential to the life cycle of the virus Viral neuraminidase can be selectively inhibited by oseltamivir and zanamivir These drugs prevent the release of new virions and their spread from cell to cell Effective against both Type A and B influenza viruses

Neuraminidase Inhibitors: Mechanism of Actions Neuraminidase enzyme is essential for the life cycle of the virus Oseltamivir and zanamivir are transition-state analogs of sialic acid substrate and serve as inhibitors of the neuraminidase enzyme activity Neuraminidase Inhibitors: Pharmacokinetics Oseltamivir is an orally active prodrug that is rapidly hydrolyzed by the liver to its active form Zanamivir, on the other hand, is not active orally and is either inhaled or administered intranasally Both drugs are eliminated unchanged in the urine

Neuraminidase Inhibitors: Adverse Effects The most common side effects of oseltamivir are GI discomfort and nausea Zanamivir is not associated with GI disturbance, because it is administered directly to the airways Zanamivir should be avoided in individuals with severe reactive asthma or chronic obstructive respiratory disease, because bronchospasm may occur Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles

Inhibitors of Viral Uncoating The therapeutic spectrum of the amantadine and rimantadine is limited to influenza A infections Both drugs reduce the duration and severity of systemic symptoms if started within the first 48 hours after exposure to the virus Treatment is particularly useful in high-risk patients who have not been vaccinated and during epidemics

Inhibitors of Viral Uncoating: Mechanism of Actions Amantadine and rimantadine inhibit an early step in viral replication, probably viral uncoating; for some strains, they also have an effect on a late step in viral assembly

Inhibitors of Viral Uncoating : Pharmacokinetics Both drugs are well absorbed orally Amantadine distributes throughout the body and readily penetrates into the CNS, whereas rimantadine does not cross the blood-brain barrier to the same extent Amantadine is not extensively metabolized, and excreted into the urine and may accumulate 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

Inhibitors of Viral Uncoating : Adverse Effects The side effects of amantadine are mainly associated with the CNS, symptoms include insomnia, dizziness, and ataxia. The drug should be employed cautiously in patients with psychiatric problems, renal impairment, or epilepsy Rimantadine causes fewer CNS reactions, because it does not efficiently cross the blood-brain barrier They should be used with caution in pregnant and nursing mothers, because they have been found to be embryotoxic and teratogenic in rats Ataxia describes a lack of coordination while performing voluntary movements. It may appear as clumsiness, inaccuracy, or instability Teratogenic: relating to, or causing malformations of an embryo or fetus.

Ribavirin: Mechanism of Actions Synthetic guanosine analog Effective against a broad spectrum of RNA and DNA viruses Ribavirin: Mechanism of Actions Ribavirin converted to ribavirin-triphosphate, which exerts its antiviral action by inhibiting guanosine triphosphate formation, which blocks RNA-dependent RNA polymerase

Ribavirin: Pharmacokinetics Effective orally and intravenously Absorption is increased if it is taken with a fatty meal Studies of drug distribution in primates have shown retention in all tissues, except brain The drug and its metabolites are eliminated in the urine Ribavirin: Adverse Effects Side effects reported for oral or parenteral use of ribavirin have included dose-dependent transient anemia Elevated bilirubin has been reported Because of teratogenic effects in experimental animals, ribavirin is contraindicated in pregnancy

Hepatic Virus Infections Hepatitis viruses thus far identified as A, B, C, D, and E, each have a pathogenesis specifically involving replication in and destruction of hepatocytes Hepatitis B and hepatitis C are the most common causes of chronic hepatitis, and are the only hepatic viral infections for which therapy is currently available

Antihepatic Viral Agents Therapy includes Interferon lamivudine telbivudine Adefovir Entecavir

Interferon: Mechanism of Actions The antiviral mechanism is incompletely understood It appears to involve the induction of host cell enzymes that inhibit viral RNA translation, ultimately leading to the degradation of viral mRNA and tRNA

Interferon: Pharmacokinetics Not active orally, but it may be administered subcutaneously, or intravenously Very little active compound is found in the plasma Negligible renal elimination occurs

Interferon: Adverse Effects Adverse effects include flu-like symptoms on injection, such as fever, chills, and GI disturbances Fatigue and mental depression are common. These symptoms subside with subsequent administrations The principal dose-limiting toxicities are bone marrow suppression, neurotoxicity, severe fatigue and weight loss, and autoimmune disorders

Adefovir An acyclic phosphonate nucleotide analog of adenosine monophosphate Clinical use is limited to HBV infections Oral adefovir dipivoxil shows dose-dependent inhibition of hepadnavirus replication in animal models

Adefovir: Mechanism of Actions Adefovir is converted by cellular enzymes to the diphosphate, which acts as a competitive inhibitor of viral DNA polymerases and reverse transcriptases and also serves as a chain terminator of viral DNA synthesis

Adefovir: Pharmacokinetics The parent compound has low oral bioavailability, whereas the dipivoxil prodrug is absorbed rapidly Adefovir bioavailability is approximately 30% to 60% Food does not affect bioavailability Eliminated unchanged by renal excretion through a combination of glomerular filtration and tubular secretion

Adefovir: Adverse Effects Adefovir dipivoxil causes dose-related nephrotoxicity and tubular dysfunction, glycosuria, and proteinuria The lower dose (10 mg/day) used in chronic HBV infection patients has been associated with few adverse events, e.g., headache, abdominal discomfort, diarrhea

Lamivudine Inhibitor of both hepatitis B virus (HBV) DNA polymerase and HIV reverse transcriptase Phosphorylated by host cellular enzymes to the triphosphate. This compound competitively inhibits HBV DNA polymerase Well absorbed orally and is widely distributed Plasma half-life is about 9 hours Seventy percent is excreted unchanged in the urine Dose reductions are necessary when there is moderate renal insufficiency

Viral Infections Types of viral infections Influenza Hepatitis Herpes

Herpes Virus Infection with herpes simplex virus type 1 (HSV-1) typically causes diseases of the mouth, face, skin, esophagus, or brain Herpes simplex virus type 2 (HSV-2) usually causes infections of the genitals, rectum, skin, hands Both cause serious infections in neonates

Antiherpesvirus Agents Drugs that are effective against herpes viruses exert their actions during the acute phase of viral infections Except a few, all are purine or pyrimidine analogs that inhibit viral DNA synthesis Few antiherpesvirus agents acyclovir penciclovir ganciclovir

Acyclovir A high specificity for herpes simplex and varicella-zoster viruses Herpes simplex can cause cold sores, conjunctivitis, mouth ulcers, genital infections The most common use of acyclovir is in therapy for genital herpes infections

Acyclovir: Pharmacokinetics Given orally, intravenously or topically When it is given orally, only 20% of the dose is absorbed and peak plasma concentrations are reached in 1-2 hours Drug is widely distributed, reaching concentrations in the CSF that are 50% of those in the plasma Excreted by the kidneys, partly by glomerular filtration and partly by tubular secretion

Acyclovir: Mechanism of Actions Acyclovir action depends on interaction with two distinct viral proteins: HSV thymidine kinase and DNA polymerase Acyclovir is converted to the di- and triphosphate forms by the host cells. Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase and is itself incorporated into the viral DNA, causing premature DNA-chain termination

Acyclovir: Adverse Effects Unwanted effects are minimal Renal dysfunction has been reported when acyclovir is given intravenously; slow infusion reduces the risk Nausea and headache can occur