ANTI VIRAL DRUGS pdf - د. محمد رشاد

Sunday 15 / 3 / 2015

©Ali Kareem 2014-2015

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مكتب اشور لالستنساخ

ANTI-VIRAL DRUGS

Lecture 7

Total lectures NO. 45

Dr. Mohammed Rashad

Antiviral Drugs

Dr. Mohammed Rashad

I. OVERVIEW

• Viruses are obligate intracellular parasites.

• They lack both a cell wall and a cell membrane, and they do not

carry out metabolic processes.

• Viral reproduction uses much of the host’s metabolic machinery,

and few drugs are selective enough to prevent viral replication
without injury to the host.

• II. TREATMENT OF RESPIRATORY VIRUS INFECTIONS

A.Neuraminidase inhibitors

• Orthomyxoviruses that cause influenza contain the enzyme neura-

minidase, which is essential to the life cycle of the virus.

• Viral neuraminidase can be selectively inhibited by the sialic acid

analogs,oseltamivirand zanamivir.

• 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, neuram inidase inhibitors prevent

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

1. Mode of action:

• Oseltamivir and zanamivir analogs of the sialic acid substrate and

serve as inhibitors of the enzyme activity.

2. Pharmacokinetics:

• Oseltamivir 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.

3. Adverse effects:

• The most common side effects of oseltamivir are gastrointestinal

(GI) discomfort and nausea.

• Zanamivir should be avoided in individuals with severe reactive

asthma or chronic obstructive respiratory disease, because
bronchospasm may occur with the risk of fatality.

B. Inhibitors of viral uncoating

• Amantadine and rimantadine

• is limited to influenza A infections(equally effective in both

treatment and prevention

• these drugsare 70 to 90 percent effective in preventing infection if

treatment is begun at the time of, or prior to, exposure to the
virus.

• Also, both drugsreduce the duration and severity of systemic

symptoms if started within the first 48 hours after exposure to the
virus.

1. Mode of action:

• Amantadine and rimantadine is to block the viral membrane

matrix protein,M2, which functions as a channel for hydrogen
ions.

• This channel is required for the fusion of the viral membrane with

the cell membrane that ultimately forms the endosome.

2. Pharmacokinetics:

• Both drugs are well absorbed orally.

• Amantadine penetrates into the central nervous system (CNS),

whereas rimantadine does not cross the blood-brain barrier.

3. Adverse effects:

• Minor neurologic symptoms include insomnia,dizziness, and

ataxia.

• More serious side effects, for example, hallucinations and seizures

(caution in patients with psychiatric problems)

• Rimantadine causes fewer CNS reactions

C. Ribavirin

• Ribavirin is a synthetic guanosine analog.

• Ribavirin is used in treating infants and young children with severe

RSV infections.

• Ribavirinis also effective in chronic hepatitis C infections when

used in combination with interferon-α.Ribavirin may reduce the
mortality and viremia of Lassa fever.

1. Pharmacokinetics:

• Ribavirin is effective orally and intravenously.

• Anaerosol is used in certain respiratory viral conditions such as

thetreatment of RSV infection.

2. Adverse effects:

• dose-dependent transient anemia.

• Elevated bilirubin has been reported.

• The aerosol may be safer, although respiratory function in infants

can deteriorate quickly after initiation of aerosol treatment.

III. TREATMENT OF HEPATIC VIRAL INFECTIONS

• hepatitis B and hepatitis C are the most common causes of chronic

hepatitis, cirrhosis, and hepatocellular carcinoma.

• Chronic hepatitis B may be treated with peginterferon α-2a, which

is injected subcutaneously once weekly. [Note: Interferon-α2b
injected intramuscularly or subcutaneously three times weekly]

• Oral therapy includes lamivudine, adefovir, entecavir,tenofovir, or

telbivudine.

• In the treatment of chronic hepatitis C, the preferred treatment is

the combination of peginterferon-α-2a or peginterferon-α-2b plus
ribavirin.

A.Interferon

• Interferon is a family of naturally occurring, inducible

glycoproteins that interfere with the ability of viruses to infect
cells.

• The interferons are synthesized by recombinant DNA technology.

• At least three types of interferons exist, α, β, and γ.

One of the 15 interferon-α glycoproteins, interferon-α-2b, has been
approved for:

• treatment of hepatitis B and C

• condylomataacuminate

• hairy cell leukemia

• Kaposi sarcoma.

• Interferon-β has some effectivenessin the treatment of multiple

sclerosis. In so-called “pegylated” formulations. The larger
molecular size delays absorption, lengthens the duration of action,
and decreases its clearance.

1.Mode of action:

• induction of host cell enzymes that inhibit viral RNA translation,

leading to the degradation of viral mRNA and tRNA.

2.Pharmacokinetics:

• Interferon is not active orally

• but it may be administered intralesionally, subcutaneously, or

intravenously.

3.Adverse effects:

• flu-like symptoms on injection, such as fever, chills, myalgias,

arthralgias, and GI disturbances.

• Fatigue and mental depression are common.

• dose-limiting toxicities are:

• bone marrow suppression including granuloytopenia

• neurotoxicity characterized by somnolence and behavioral

disturbances

• severe fatigue and weight loss

• autoimmune disorders suchas thyroiditis

• and, rarely, cardiovascular problems such as congestive heart

failure.

• Acute hypersensitivity reactions and hepatic failure are rare.

B.Lamivudine

• This cytosine analog is an inhibitor of:

• hepatitis B virus (HBV) DNA polymerase

• human immunodeficiency virus (HIV) reverse transcriptase

C.Adefovir

• Adefovir is a nucleotide analog

• As with other agents, discontinuation of adefovir results in severe

exacerbation of hepatitis in about 25 percent of patients.

• The drug should be used cautiously in patients with existing renal

dysfunction.

D.Entecavir

• Entecavir is a guanosine analog approved for the treatment of

HBV infections.

• Entecavir has been shown to be effective against lamivudine-

resistant strains of HBV.

• Liver inflammation and scarring are improved.

E.Telbivudine

• Telbivudine is a thymidine analog that can be used in the

treatment of HBV.

• Unlike lamivudine and adefovir, telbivudine is not active against

HIV or other viruses.

• The dose must be adjusted in renal failure.

IV. TREATMENT OF HERPESVIRUS INFECTIONS

A. Acyclovir

• Acyclovir (acycloguanosine) is the prototypic antiherpetic

therapeutic agent.It has a greater specificity than vidarabine
against herpesviruses:

• Herpes simplex virus (HSV)

• varicella-zoster virus (VZV)

• Epstein-Barr virus

• It is the treatment of choice in HSV encephalitis.

• The most common use of acyclovir is in therapy for genital herpes

infections.

• It is also given prophylactically before bone marrow and after

heart transplants.

1. Mode of action:

• 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.

• The drug is less effective against the host enzyme.

2. Pharmacokinetics:

• Administration of acyclovir can be by an intravenous (IV), oral, or

topical route.

• The drug distributes well throughout the body,including the

cerebrospinal fluid (CSF).

• Excretion into the urine occurs both by glomerular filtration and

by tubular secretion.

• Acyclovir accumulates in patients with renal failure.

3. Adverse effects:

• local irritation may occur from topical application

• headache, diarrhea, nausea, and vomiting may result after oral

administration.

• Transient renal dysfunction may occur at high doses or in a

dehydrated patient

• High-dose valacyclovir can cause GI problems and

thromboticthrombocytopenic purpura in patients with AIDS.

B. Cidofovir

• Cidofovir is approved for treatment of CMV-induce dretinitis in

patients with AIDS.

• Cidofovir is a nucleotide analog of cytosine (It inhibits viral DNA

synthesis)

• Cidofoviris available for intravitreal (injection into the eye’s

vitreous humor) and topical administration.

• Cidofovir produces significant toxicity to the kidney

• Neutropenia, metabolic acidosis.

• Probenecid must be co-administered with cidofovirto reduce the

risk of nephrotoxicity.

C. Ganciclovir

• Ganciclovir is an analog of acyclovir that has 8 to20 times greater

activity against CMV

• It is currently available for treatment of CMV retinitis in

immunocompromised patients and for CMV prophylaxis in
transplant patients.

1. Mode of action:

• Like acyclovir, ganciclovir is activated through conversion to the

nucleoside triphosphate.

• The nucleotide competitively inhibits viral DNA polymerase and

incorporated into the DNA, thereby decreasing the rate of chain
elongation.

2. Pharmacokinetics:

• Ganciclovir is administered IV and distributes throughout the

body, including the CSF.

• Excretion into the urineoccurs through glomerular filtration and

tubular secretion.

• Valganciclovir, like valacyclovir, valganciclovir has high oral

bioavailability, because rapid hydrolysis after oraladministration
leads to high levels of ganciclovir.

3. Adverse effects:

• severe, dose-dependentneutropenia.

Ganciclovir is carcinogenic as well as embryotoxic and teratogenicin
experimental animals.

D.Vidarabine (ara-A)

• Vidarabine is active against HSV‐0,HSV-2, and VZV

• its use is limited to treatment of immunocompromised patients

with herpetic and vaccinial keratitis and in HSV
keratoconjunctivitis. [Note: Vidarabine is only available as an
ophthalmic ointment.]

E.Trifluridine

• It is structurally very similar to thymidine.

• Trifluridineis active against HSV-1, HSV-2, and vaccinia virus.

• It is the drug of choice for treatment of HSV

• Because the triphosphate form of trifluridine can also incorporate

to some degree into cellular DNA, thedrug is considered to be too
toxic for systemic use.

• Therefore, the use of trifluridine is restricted to topical application

as a solution to the eye.

• A short half-life of approximately 12 minutes necessitates that the

drug be applied frequently.

• Side effects include a transient irritation of the eye and palpebral

(eyelid) edema.

V. OVERVIEW OF THE TREATMENT FOR HIV INFECTION

Prior to approval of zidovudine in 1987

• treatment of HIV infections focused on decreasing the occurrence

of opportunistic infections that caused a high degree of morbidity
and mortality in AIDS patients rather than on inhibiting HIV itself.

Today

• highly active regimen is employed that uses combinations of drugs

to suppress replication of HIV and restore the number of CD4+
cells and immunocompetence to the host.

This multidrug regimen is commonly referred to as “highly active
antiretroviral therapy,” or HAART.

There are five classes of antiretroviral drugs

• each of which targets one of four viral processes.

• nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)

• nonnucleoside reverse transcriptase inhibitors (NNRTIs),

• protease inhibitors

• entry inhibitors

• integrase inhibitors

• The current recommendation for primary therapy

• administer two NRTIs with either a protease inhibitor, an NNRTI,

or an integrase inhibitor.

• Selection ofthe appropriate combination is based on

• avoiding the use of two agents of the same nucleoside analog

• avoiding overlapping toxicities

• patient factors, such as disease symptoms and concurrent

illnesses

• impact of drug interactions

• ease of adherence to a frequently complex administration

regimen.

• The goals of therapy:

• maximally and durably suppress viral load replication

• restore and preserve immunologic function

• reduce HIV-related morbidity and mortality

• improve quality of life.

Done by

Ali Kareem