مادة االدوية

المرحلة الثالثة

محمد غدير حاتم. م. م

2016-2017

ANTIVIRAL AGENTS

VIRUS are obligate intracellular parasite

Replication depend on RNA DNA of host cell

•virus replication consist of • 1. Adsorption and penetration of

susceptible cells

• 2 .Synthesis of early ,Non structural proteins, eg :nucleic acid polymerase.

.

3.Synthesis of RNA and DNA

4- integration into host genome in cell nuclease and transcription , translation.

5-.Synthesis of late, structural protein

.

6-.Assembly (maturation )of viral particles and their release from the cells.

Inhibition of adsorption and penetration of susceptible cells

• A- Gamma Globulin : • Interfere with entry of viral into cell.

• I.M during incubation of measles ,hepatitis,poliomylitis effect last2-3 wks

• :

Amantadine and Rimantadine

• Both are tricyclic amines with similar pharmacology profile

• Inhibit the replication of : *the influenza A and C virus

Mechanisim of action

inhibit or delay the uncoating

process that precedes primary transcription ,it blocks action of M2 viral protein that facilitate dissociation of ribonucleoprotein complex preceding replication and changes that follow translation .

• Peak plasma conc. Are reached within 2-4 hr

• 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 are dose related include nervousness, drowsiness , insomnia and depression

Preparations Available

Amantadine (generic, Symmetrel)

Oral: 100 mg capsules, tablets; 50 mg/5

mL syrup

Preparations Available

Amantadine (generic, Symmetrel)

Oral: 100 mg capsules, tablets; 50 mg/5

mL syrup

Inhibition of nucleic acid synthesis

Ribavirin

Inhibit mRNA synthesis

Uses in influnza A –B infection

Acute hepatitis

IV ,erosol

SIDE EFFEC

Anaemia

Teratogenic effect

Pyramiding and purine analogues

VIDARABINE

Antiherpetic agents

•Vidarabine act against DNA viruses (e.g. herpes virus

group , pox viruses(oncorna viruses)

It is of low water solubility and poor GIT absorption therefore should be administered by prolonged IV infusion of dilute solutions

Cont.

• 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 application for recurrent herpes labialis and herpes genitalis

• Side effects : GIT disturbances , CNS manifestation , hematologic disorders

• Teratogenic and carcinogenic

Acyclovir and valacyclovir

• Acyclovir designed to mimic substrates for adenosine deaminase an enzyme essential to nucleic acid metabolism (it is analogue)

• 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

Antiviral Drugs Nucleoside and Nucleotide Analogs

Cont.

• The mech. Of action of acyclovir is well known :

It will be phosphorelated to form acyclocvir monophosphate by herpes virus encoded thymidine kinase and furter phosphorelated by other enzymes to acyclovir diphosphate and triphosphate , the last one inhibits viral DNA polymerase and terminate elongation of viral DNA chain .

Cont.

• Bioavailability 20%

• Peak plasma conc. After 2 hr

• IV infusion produce higher conc. useful for resistant infection

• Eliminated by kidney

Cont.

• Indications

- topical for symtomatic relief of recurent herpes labialis in patients with normal immune systems.

-oral for prevention of recurrent herpes genitalis and Rx of primary and recurrent herpes genitalis and VZV infection , also in prevention of reactivation of HSV in immunosuppressed patients .

- parenteral Rx of mucocutaneous HSV in immunocompromised patients , VZV infection and herpes encephalitis

Cont.

• Because acyclovir is in extensive clinical use , there is resistance against it by spesific mechanisms:

1- loss of viral thymidine kinase activity

2- elaboration of viral thymidine kinase with altered substrate specificity

3- altered DNA polymerase activity

Cont.

• Side effects

- no serious toxicity with topical or oral

- Rx oral for 3-6 months can cause headache , diarrhea , nausea , vomiting, arthralgia , vertigo

- 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% ointment

Foscarnet

• Active against HSV, CMV , HIV -1 • 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

• 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

Cont.

• It cause problems

- renal toxicity

- electrolytes disturbances

- nausea , vomiting , fatigue , headache ,

genital ulcers , CNS disturbances , anemia ,

leukopenia , liver dysfunction

Antiherpetic agents

• Idoxuridine Several enzymes involved in the

biosynthesis of DNA such as thymidine kinase , thymidylate kinase and DNA polymerase are inhibited by this drug

It is antiviral effect is related to the adverse biological consequences of incorporating idoxuridine into viral DNA chromosomal breakage and altered synthesis of viral proteins

Antiherpetic agents

• It is incorporation into DNA of normal cells is responsible of its toxicity

• Viral resistance develops during therapy due to rapid inactivation of idoxuridine by viral enzymes

• Topical application to the conjunctiva can cause local irritation ,contact dermatitis , photophobia , lacrimation and other side effects are chromosomal damage .

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 , also Rx of HSV in resistant cases

• Side effects:

granulocytopenia, thrombocytopenia

• Plasma half life 3 hr

• Excreated by urine

Revers transcripitase inhibitors

Zidovudine (AZT)

• Act on viral DNA polymerase of AIDS so

replication inhibited

• Given orally and I.V

• Short half life (1h)

Interferons(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 • Mech. Of action bind to specific cellular

receptors , stimulate transcription of specific genes lead to synthesis of proteins that contribute to antiviral effect at different stages of viral infection.

Cont.

• IFNs effects

1- transcription inhibition

a- activate specific cellular protein

b- block mRNA synthesis

2- translation inhibition

a- reduce mRNA methylation

b- cleaves viral RNA

c- inhibit mRNA translation

d- block tRNA function

3- protein processing inhibition

4- virus maturation inhibition and blocks budding.

Cont.

• IM or SC injection of IFN α , reach peaking 4-8 hr

• t 1\2 3-8 hr

• Side effects : fever,chills,headache,myalgia,arthralgia,nausea,

vomiting and diarrhea

• Dose limiting toxicities :

myelosuppression , neurotoxicity , confusion , depression.

Antiviral therapy in the oral cavity

• HSV causes ;

• Herpetic gingivostomatitis

• Intraoral herpes simplex

• Human papilloma virus

• Herpes labials

• Oral hairy leukoplakia is an early sign of HIV

Dental Implications

• Most cases of HSV-1 infections are self limited

• HSV-1 infections can be Rx by topical penciclovir

• HSV-1 infections that is complicated type and in management of immunocompromized patients systemic Acyclovir (oral or parenteral ) should be added(400 mg \3-5 times daily \ for 10 days)

• Or 2 gm of valacyclovir at the onset of symptoms and 2 g \12 hr later

• Or 500 mg \3 times \ day for 5 days of famciclovir can reduce healing time

Cont.

• If acyclovir intolerant or resistant cases are present , they should be treated by foscarnet

(40 mg/kg every 8 hours for 7 days or longer)

• Topical agents effective during the early stage of herpes out break