antiviral lectures

8/3/2019 Antiviral Lectures

1/40


2/40

ANTIVIRAL DRUGS

DR/AZZA BARAKA


3/40

ANTIVIRAL DRUGS

Viruses are obligate intracellular parasites; their replicationdepends on synthetic processes of the host cell.

Because viruses share many of the metabolic processes ofthe host cell, it is difficult to find drugs that are selective for

the pathogen. However, there are some enzymes that are virus-specific and

these are potential targets for drugs.

Most currently available drugs are only effective while the

virus is replicating. Antiviral drugs do not eliminate non replicating viruses.

Clinical failure of antiviral therapy may occur with drug-sensitive viruses in immunocompromized patients or followingemergence of resistant viruses.


4/40


5/40

ANTIHERPETIC DRUGS
http://upload.wikimedia.org/wikipedia/commons/4/4c/Guanosine-acyclovir-comparison.pnghttp://www.whatdoesitlooklike.net/wp-content/uploads/2009/02/chickenpox1.jpg


6/40
http://upload.wikimedia.org/wikipedia/commons/4/4c/Guanosine-acyclovir-comparison.png


7/40

N.B. For elongation of DNA chain :Thenucleotides are joined together by

phosphate-ester bonds between the -OHon carbon #3 of one pentose and the -OHon carbon #5 of the next pentose which isreferred to as the 3'-5' phosphate linkage.


8/40

Mechanism of Action.Acyclovir is a nucleoside analogue.

1. Acyclovir, therefore, requires three phosphorylation steps for

activation. It is converted first to monophosphate derivative bythe virus-specified thymidine kinase (VTK) and then to the diand triphosphate compounds by the hosts cellular enzyme.Because it requires the VTK for the initial phosphorylation, it isselectively activated and triphosphate accumulates, only in

infected cells.2. Acyclovir triphosphate inhibits viral DNA synthesis by two

mechanisms:

A- competitive inhibition with deoxy GTP for the viral DNApolymerases with binding to the DNA template as anirreversible complex, and

B- chain termination following incorporation into the viral DNA.Acyclovir has affinity for viral DNA polymerases about 300times more than host cell DNA polymerases and this also

accounts for selective toxicity of acyclovir.


9/40


10/40

Remember: Two viral proteins

virus-specified thymidine kinase (VTK) andviral DNA polymerases


11/40


12/40

Therapeutic Uses

Acyclovir can be used topically , orally and

intravenously.

1-Topical acyclovir is used in treatment of:

-Very localized herpes simplex.

2-Oral acyclovir is used :

a-Prohylactically in:

Patients who will receive immunosuppressive drugsand are at risk of herpes virus infection due toreactivation of a latent virus.


13/40

b- Therapeutically in:

i. Treatment of herpes simplex.

ii.Treatment of chicken pox in immunocompromizedpatients.

iii-Treatment of Herpes zoster in immunocompetent

patients.Intravenous acyclovir is used in treatment of:

a- Viscerally disseminating herpes simplex .

b- Herpes zoster in severely immunocompromised

patients.


14/40

Adverse Effects:

1. GIT: nausea and diarrhea.

2. Renal insufficiency that especially occurs byrapid infusion and can be avoided by good

rehydration.3. Neurotoxicity (especially if patient has renal

impairment).

4. Phlebitis if extravasated after I.V.

administration).


15/40

Gancyclovir

Therapeutic Uses:

Treatment of CMV infections

Preemptive treatment of CMV: This is anattempt to prevent the progression ofasymptomatic infection into CMV disease.

Prophylaxis of CMV infection inimmunocompromized patients.

Side effects: bone marrow supprrssion

If resistance to gancyclovir give: foscarnet


16/40


17/40


18/40

HAART

Highlyactiveanti-retroviraltherapyHAARTis a combination of three antiretroviraldrugs belonging to first three groups. This

therapy has changed the prognosis ofpatients infected with HIV.


19/40

ZIDOVUDINE Therapeutic Uses

1-Treatment of HIV which results in:1. Decrease in HIV viral load.

2. Decrease in opportunistic infections because of an

increase in CD4 count .3. Increase in the weight of the patient.

4. Prolongation of survival.

N.B. Eradication of HIV infection cannot beachieved with available antiretroviral regimens

2- Reduce the incidence of vertical transmission of HIVfrom mother to newborn.


20/40

ZIDOVUDINE

Adverse Effects:

1. BM suppression leading to Leucopenia andanaemia.

2. Neurotoxicities.3. Myopathy

4. Lactic acidosis. (Due to mitochondrial

dysfunction with a shift toward anaerobicmetabolism leading to lactate overproduction).


21/40

When to treat an HIV patient with antiretroviral drugs:

If T-cell count is 350 or below, treatment isrecommended.

Treatment is generally not recommendedif T-cell count

is above 350.

Treatment should be initiated regardless of CD4 count:

1. If very high viral load.

2. If there are symptoms.

3. Patients with the following conditions: pregnancy , HIV-

associated nephropathy and hepatitis B virus (HBV)

coinfection.

III ANTIINFLUENZA VIRUS


22/40

III. ANTIINFLUENZA VIRUSAGENTS

Neuraminidase inhibitors:e.g. Oseltamivir(Tamiflu) and Zanamivir

(Relenza)

Both oseltamivir and zanamivir work byinhibiting an enzyme called neuraminidasethat the virus needs to replicate, but they acton different parts of the enzyme andresistance to one drug does not conferresistance to the other.


23/40

Adverse effects:

1-Nausea, vomiting, diarrhea and abdominal

pain are the most frequent adverse effect2-Headache, vertigo and insomnia.

3-Bronchospasm and a decline in lung

function have been reported after usage ofzanamivir in patients with underlyingpulmonary conditions such as asthma.

Because of the risk of these respiratoryadverse events, zanamivir is not generallyrecommended for the treatment of patientswith underlying airways disease


24/40

IV- ANTIHEPATITIS DRUGS

AntihepatitisC Antihepatitis B


25/40

HCV Lifecycle

Receptor bindingand endocytosis

Fusionand

uncoating

Transportand release

(+) RNA

Translation andpolyprotein

processing RNA replication

Virionassembly

Membranous

webER lumen

LD

LD

ER lumen

LD

protease

polymerase


26/40


27/40

Goals of treatment of chronic


28/40

Goals of treatment of chronic

hepatitis B

The goals of treatment of chronic hepatitis B are(i) Decrease viral load, to slow the progression of fibrosis to

cirrhosis;

(ii) to prevent hepatic failure; and

(iii)to prevent the development of hepatocellular carcinoma(HCC).

There is no cure for hepatitis B. HBV is maintained in areplicative form in the hepatocyte nuclei termed

covalently closed circular DNA (cccDNA) which servesas a template for viral transcription. Current therapieshave little or no direct effect on cccDNA. Hence, viralrelapse occurs once antiviral medications are

discontinued.

II i A i h i i B


29/40

II-i-Anti hepatitis B

pproved therapies include

. Standard and pegylated interferon-alfa.

. Nucleoside reverse transcriptase inhibitors:

lamivudine, adefovir and entecavir. Lamivudine,

but neither adefovir nor entecavir, are approved forchildren.

HBV has a very curious way of replicating itself

since, although it is a DNA virus, it uses an RNAproviral intermediate that has to be copied back to

DNA. For the purpose of copying RNA to DNA,

HBV like retroviruses, has a virally-encoded DNA

ol merase P called reverse transcri tase.


30/40

The main side effect of lamivudine ispancreatitis & lactic acidosis , of adefovir isnephrotoxicity & lactic acidosis.

Current therapies do not eradicate HBV so long-term

treatment is usually required.

Even with successful therapy, patients remain at risk

for reactivation of viral replication and require

lifelong monitoring


31/40

T O S S


32/40

There are three types of interferon: IFN-alpha ,IFN-beta , and IFN-gamma . IFN has antiviral,

antiproliferative and immunomodulatoryeffects.

Therapeutic Uses:

CHB, CHC. Interferon-alpha is givensubcutaneously or intramuscularly.

INTERFERONS (IFNS)

The important parameters that affect response to IFN


33/40

The important parameters that affect response to IFN

treatment are:

Viral genotype: e.g. HCV genotype 1 is the most difficult to

treat, whereas genotypes 2 and 3 are the most susceptible tointerferon therapy

Pre-treatment HCV RNA levels (viral load). A low baseline

serum viral load (


34/40

As a general rule, the success of treatment isdetermined at two time points:

1. Just as the course of treatment is completed,referred to as the end-of-treatment response(ETR);and

2. Six months after treatment is completed, referred toas the sustained virological response(SVR).

The tests that are most important at these time pointsare the liver enzyme tests and the HCV viral load. Ifa person's liver enzyme levels are back to normaland HCV viral load is undetectable at the end of

treatment, the person is said to have an effectiveETR. If a person's liver enzyme levels remainnormal and the HCV viral load is still undetectablesix months after completing treatment, he or she issaid to have an effective SVR.

Pegylated Interferons


35/40

Peginterferon alphas differ from the older, unmodified

interferon alphas in:1. A polyethylene glycol molecule, an inert compound that

slows the elimination from the body, is attached to theinterferon molecule.

2. As a result its elimination from the body is slowed and

higher.3. More constant blood levels of interferon alpha are

achieved with less frequent dosing.

4. In contrast to unmodified interferon alpha, which must be

injected three times a week to treat chronic hepatitis C,peginterferon alpha needs to be injected only once a week.

5. This results in enhanced compliance and clinicallysuperior anti-viral activity( SVR).

Pegylated Interferons

Albuferon


36/40

Albuferon

A form of interferon alfa genetically fused toalbumin.

Possible advantages compared to other formsof interferon are its very long half-life. Thus, thelower dosing frequency (every two to fourweeks rather than every week).

INTERFERONS Adverse Effects


37/40

1. Influenza like syndrome: fever, headache, nausea,vomiting, diarrhea, myalgia and arthralgia. (As a rule,

everyday symptoms people experience as aresult of HCV infection will grow worse duringtreatment).

2. Bone marrow suppression.3. Neurotoxicity (Depression).

4. Nephrotoxicity.

5. Thyroid dysfunction (Autoimmne).6. Teratogenicity.

7. Inhibition of cytochrome P450 liver enzymes.

INTERFERONS Adverse Effects


38/40

Contraindications to IFN1. Decompensated cirrhosis.

2. Pregnancy.

3. Uncontrolled depression

4. Severe cytopenias.

5. Autoimmune diseases.

Rib i i


39/40

Ribavirin

The drug is effective ( in combination with IFN) against: HCV where it helpsin decreasing viral load and increasing SVR. It is not used

alone in treatment of HCV.

Therapeutic Uses:

The addition of oral ribavirin to interferon alpha is superior

to interferon alpha alone in the treatment of chronichepatitis C

Adverse effects:

1. Hemolytic anemia because it is concentrated in RBCs

resulting in their lysis. Symptoms include: bleeding gums,blood in urine or stools.

2. Anemia, which can make heart disease worse.

3. Chest pain.

Viramadine, is a prodrug of ribavirin less likely to cause hemolyticanemia.


40/40

Contraindications To RIBAVIRIN

Absolute contraindication in

pregnancy, necessitating

reliable birth control during

treatment with this drug and

for 6 months after thismedication has been stopped .

antiviral lectures

Documents