Antiviral agents Chapter 49 katzung -...

transcript

Antiviral agents

Chapter 49

katzung

Dr. Azadeh Mesripour (Ph.D)

Pharm.MUI

Antivirals

Viruses controlled by current antiviral therapy

• Cytomegalovirus (CMV)

• Hepatitis viruses

• Herpes viruses

• Human immunodeficiency virus (HIV)

• Influenza viruses (the “flu”)

• Varicella Zoster Virus ;Chickenpox, Shingles

Antiviral Agents

• Cure depends on host immune systemto eradicate.

If patients are immunocompromized, may have recurrences.

• Many need to be activated by viral and cellular enzymes before exerting antiviral effect.

Antiviral Drugs

attachment to host cell penetration

Uncoating DNA/RNA synthesis

assembley

Anti Human Herpesvirus drugs

• Acyclovir (G)

• Famciclovir (G)

• Penciclovir (G)

• Ganciclovir (G)

• Cidofovir (C)

• Foscarnet

Guanine

Acyclovir Ganciclovir

Nucleoside AnaloguesGeneral Mechanism of Action

1. Taken up by cells

2. Converted by viral and cellualr enzymes to the triphosphate form.

3. The triphosphate form:

1. Inhibits viral DNA polymerase.

2. Or it may get incorporated into growing DNAleading to abnormal proteins or breakage.

Acyclovir (Zovirax)

• Used to suppress replication of:

– HSV-1(oral herpes), HSV-2(genital herpes),

VZV (Varicella – chickenpox or shingles)

• Drug of choice for treatment of initial and

recurrent episodes of these infections.

• Oral, topical, parenteral forms

Acyclovirand Valacyclovir (prodrug, better availability)

A Guanine analogue for Herpes group (HSV-1,2 & VZV)

Acyclovir AcycloMP AcycloTP

Thymidine kinase Cellular kinases

Viral 200x affinity

of mammalian

1. Inhibits viral DNA polymerase selectively

2. Incorporated into DNA and terminates synthesis

Resistance:

1. ↓ activity of thymidine kinase

2. altered DNA polymerase

• Bioavailability of oral

acyclovir is low (15–20%).

• Acyclovir is cleared

primarily by glomerular

filtration and tubular

secretion.

• T1/2=3 h in patients with

normal renal function and

20 h in patients with anuria.

• Diffuses readily into most

tissues (ie.CNS).

Oral acyclovir has multiple uses• In first episodes of genital herpes, oral

acyclovir shortens the duration of

symptoms by 2 days, the time to lesion

healing by4 days, and the duration of viral

shedding by 7 days.

• The risk of post-herpetic neuralgia is also

reduced if treatment is initiated early

Oral acyclovir has multiple uses• In patients with varicella (if begun within

24 h after the onset).

• Acyclovir therapy significantly decreases

the total number of lesions, duration of

symptoms, and viral shedding

• However, because VZV is less susceptible

to acyclovir than HSV, higher doses are

required.

Intravenous acyclovir

• Is the treatment of choice for herpes

simplex encephalitis,

• Neonatal HSV infection, and serious HSV

or VZV infections.

Adverse effects

• Nausea, diarrhea, and headache may

occur.

• Iv infusion may be associated with

reversible renal toxicity (ie, crystalline

nephropathy or interstitial nephritis) or

neurologic effects (eg, tremors, delirium,

seizures).

• However, these are uncommon with

adequate hydration and avoidance of rapid

infusion rates. 17

Valacyclovir

• The l-valyl ester of acyclovir.

• Serum levels are 3-5 times greater than

those achieved with oral acyclovir(f=70%)

• Approximate serum levels achieved with iv

acyclovir. Oral

• Elimination half-life is 3 hours.

Famciclovir

• Famciclovir Liver Penciclovir

(Guanine)

• Mechanism is like Acyclovir (but

not chain termination)

• Against HSV-1,2 & VZV

• Bioavailability Famciclovir: 70%

• Excretion: renal

Famciclovir

• Adverse effects: headache, nausea, diarrhea

• One-day usage of famciclovir significantly

accelerates time to healing of recurrent genital

herpes and of herpes labialis.

• Penciclovir: aginst recurrent

herpes (topical)

• Docosanol inhibits fusion

between the host cell plasma

membrane and the HSV

envelope, thereby preventing

viral entry into cells.

• Topical docosanol 10% cream is

available.

Trifluridine

• phosphorylated by host cell enzymes

• Incorporation of triphosphate into both viral

and host DNA prevents its systemic use.

• Application of a 1% solution is effective in

treating keratoconjunctivitis and recurrent

epithelial keratitis due to HSV-1 or HSV-2.

AGENTS TO TREAT

CYTOMEGALOVIRUS (CMV)

INFECTIONS

• CMV infections occur

primarily in the setting

of advanced

immunosuppression .

• Clinical reactivation of

CMV infection after

organ transplantation

is still prevalent.

Ganciclovir

• Mechanism is like Acyclovir

• Active against all Herpes viruses specially CMV(100 times more than acyclovir)

• Drug of choice for CMV infections

• Low oral bioavailability (6-9%); given I.V.

• Most common adverse effect: bone marrow suppression (leukopenia 40%, thrombocytopenia 20%) and rarely CNS effects(headache, behavioral changes, psychosis, coma, convulsions).

Valganciclovir

• An L-valyl ester prodrug of ganciclovir

• After oral administration, it rapidly

hydrolyzed to ganciclovir by esterases in

the intestinal wall and liver.

• Valganciclovir is well absorbed;

• F oral valganciclovir is 60%

• It is recommended that the drug be taken

with food.

Cidofovir• A cytosine analog

• Is independent to viral enzymes,

effective against resistant strains.

• Mainly for HSV-2 & CMV

• Excretion: renal (probencid reduce

tubular secretion).

• Only IV

• Active metabolites with long t1/2

• Adverse effects:

• Nephrotoxicity(+probencid)

• Uveitis,

Foscarnet• An inorganic pyrophosphate

analog.

• Direct inhibition of DNA

polymerase, RNA polymerase and

HIV reverseTranscriptase

• Only IV

• Up to 30% of foscarnet deposits in

bone, with a half-life of several

months.

Foscarnet

• Active against:

– HSV-1,2; VZV; CMV;

– Nephrotoxicity

– Hypocalcemia (chelates divalent cations)

– CNS (tremor, irritability, seizure)

• Active against:

– HSV-1,2; VZV;

Only used for resistant virus to Acyclovir and

Ganciclovir

– genital ulcers

• In order to reduce renal toxicity;

1) Slow infusion rate

2) Preloading with N/S

3) Avoid other nephrotoxics

Antiviral Drugs for Influenza

• Are effective for both early treatment

and chemoprophylaxis of influenza

infections.

Classes of Influenza Antiviral Drugs

M2 inhibitors

• Amantadine

• Rimantadine

Neuraminidase

inhibitors

• Oseltamivir

• Zanamivir31

Amantadine, Rimantadine

• Chemically related

• Orally administered (100 mg tablets and

syrup for children)

• Activity against influenza A viruses only.

• Have comparable antiviral and clinical

activities when used for prophylaxis or

treatment.

Mechanism of Action

• Interfere with the function of the

transmembrane domain of the M2 protein

of influenza A viruses.

• Decrease the release of influenza A

viral particles into the host cell.

Treatment (3-5 days)

• Decreases length of illness due to

influenza A by about 1 day.

• Must be started within 2 days of

illness.

• Dose adjustments required for

relatively small decreases in renal

function.

Adverse Effects

Gastrointestinal: nausea, vomiting

Commonly associated with dose-related minor

CNS side effects;

– anxiousness, difficulty concentrating,

insomnia, lightheadedness

•More serious side effects (eg,delirium,

hallucinations,agitation, and seizures

Rimantadine similar reactions, but less common

than amantadine;

• in part related to lower plasma drug

concentrations.35

Neuraminidase Inhibitors

Oseltamivir, Zanamivir

Have activity against both

influenza A and influenza B

viruses.

Chemically related, but have

different routes of

administration.

Reduce the number of viral

particles released from

infected cells.36

• Oseltamivir (prodrug); Orally

administered: 75 mg tablets and syrup for

children.

•Zanamivir; Inhalational delivery of dry

powered drug.

Approved for treatment and prophylaxis

of influenza A and B

Treatment 1 year(O), 7years(Z)

Chemoprophylaxis 13 years

Oseltamivir, Zanamivir

Treatment: 5 Days

Treatment

Must be administered < 48 hours after onset of

illness.

Reduce symptoms and decrease length of

illness due to influenza A & B virus infections by

approximately 1 day.

Oseltamivir Adverse Effects

Potential adverse effects include:

• nausea, vomiting, and headache.

•Fatigue and diarrhea have also been reported

and are more common with prophylactic use

• Fewer GI symptoms if given with food.

• Only 1-2 % stop because of adverse events.

Zanamivir Adverse Effects

Nasal & throat discomfort.

Headache

Use in pts with pre-existing lower airway tract

disease associated infrequently with

bronchospasm.

Viral hepatitis

• Hepatitis B;

Adefovir, lamivudine

• Hepatitis C;

interferon alfa 2a , alfa 2b and ribavirin

INTERFERON ALFA

• Some have proven useful in both HBV and

• Interferon alfa-2a and interferon alfa-2b

may be administered either SC or IM.

• Alfa interferons are filtered at the

glomerulus and

• Liver metabolism and subsequent biliary

excretion are considered minor pathways.

• The use of pegylated interferon alfa-2a

and alfa-2b, and steadier concentrations,

thus allowing for less frequent dosing.

Adverse reactions

• flu-like syndrome, occurs within 6 hours

• Transient hepatic enzyme elevations

• during chronic therapy: neurotoxicities

myelosuppression, profound fatigue, weight

loss, rash, cough, myalgia, alopecia, tinnitus,

reversible hearing loss, retinopathy,

pneumonitis, and possibly cardiotoxicity.

• Induction of autoantibodies may occur,

causing exacerbation or unmasking of

autoimmune disease45

Contraindications & Caution

• Hepatic decompensation, autoimmune

disease, and history of cardiac arrhythmia.

• Caution is advised in psychiatric disease,

epilepsy, thyroid disease, cardiac disease,

severe renal insufficiency, and cytopenia.

drug-drug interactions

• Increased theophylline and methadone

levels.

• Co-administration with didanosine

increase risk of hepatic failure,

• Co-administration with zidovudine may

exacerbate cytopenias.

HBV therapy

The goals:

• The suppression of HBV DNA to

undetectable levels,

• Seroconversion of HBag from positive to

negative,

• Reduction in elevated hepatic transaminase

levels.

Oral drugs: now considered the

first line of therapy

HCV infection

• In contrast to the treatment of patients with

chronic HBV infection,

• The primary goal of treatment in patients

with HCV infection is viral eradication.

Adverse effects: A dose dependent

hemolytic anemia occurs in 10–20%

of patients. Other potential adverse

effects are depression, fatigue.

HIV life cycle

• Hallmark: depletion of CD4 lymphocytes

cellular immunodeficiency

• Etiology: worldwide HIV-1

west africa HIV-2

• HIV-2 is resistant to NNRTIs

• Patient is susceptible to various infections

(TB, Candidiasis, CMV) & malignancies.

Classification of

1- Attachment & fusion inhibitors

– Enfuvirtide (T20)

2- Nucleoside Reverse Transcriptase inhibitors

– Zidovudine*, Stavudine, Didanosine, Lamivudine*

3- Non-nucleoside Reverse Transcriptaseinhibitors (NNRTI)

– Delavirdine, Efavirenz, Nevirapine *

4- Protease inhibitors

– Indinavir, Saquinavir, Ritonavir*, Nelfinavir

Principles of treatment

• Life long therapy !

• Combination therapy; at least 2 drugs (otherwise ?)

• Non-adherence to regimens therapeutic

failure (recurrences), drug resistance,

limitation of future options & death

• NRTIs are the cornerstone of therapy.

• NRTIs are prodrugs: activation by

phosphorylation by host cell enzymes.

• All are inhibitors of RT (by competition).

• RNA Reverse Transcriptase DNA

• Incorporation into DNA terminates chain

elongation.

NNRTIs

• Activation by phosphorylation is not needed.

• All are inhibitors of RT (by conformational

changes).

• RNA Reverse Transcriptase DNA

• Effective just against HIV-1

• Are metabolized by CYP450 enzymes ? (drug

interactions)

Protease Inhibitors

• HIV protease is essential for viral infectivity.

• Protease cleaves the viral polyprotein into

active viral enzymes (RT, protease,

integrase).

• PIs make viruses to be immature &

noninfectious.

• Are metabolized by CYP450 enzymes

• CYP3A4 inhibitors as well.

Protease Inhibitors

– GI (nausea, vomiting, diarrhea)

– Paresthesias

– Diabetes

– Cholestrol & TG

• In prolonged administration:

– Fat redistribution (central)

Antiviral agents Chapter 49 katzung -...

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