1. 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

2. 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

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

4. 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

5. Viral Infections
Types of viral infections
Influenza
Hepatitis
Herpes

6. 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

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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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.

15. 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

16. 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

17. 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

18. Antihepatic Viral Agents
Therapy includes
Interferon
lamivudine
telbivudine
Adefovir
Entecavir

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. Viral Infections
Types of viral infections
Influenza
Hepatitis
Herpes

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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