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Antiviral Drugs

EWA GRABOWSKA

DEPARTMENT OF PHARMACOLOGY

MEDICAL UNIVERSITY OF LODZ

Viruses

Obligate intracellular parasites

– protein + nucleic acid (DNA/RNA)

– no metabolic processes of their own

Difficulties in designing antiviral drugs:

– difficult to descriminate between viral

reactions and host cell reactions

– few virus groups respond to treatment

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Types of Antiviral Drugs

Antiviral drugs

Drugs for

respiratory

virus infections

Drugs for herpes

and megalovirus

infections

Drugs for HIV

infections

Drugs for hepatitis

leukemia and

Kaposi’s sarcoma

Types of Antiviral Drugs

Antiviral drugs

Drugs for

respiratory

virus infections

Drugs for herpes

and megalovirus

infections

Drugs for HIV

infections

Drugs for hepatitis

leukemia and

Kaposi’s sarcoma

3

TMT of Viral Respiratory Infections

Influenza A virus

Influenza B virus

Respiratory syncytial virus (RSV)

TMT of Viral Respiratory Infections

Immunization against influenza

– prevention is better than cure:

elderly people

children

chronically ill

– (-) strain not covered by the vaccine (quick

mutations of the virus)

– ADE: rarely – allergic reactions

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Amantadine and Rimantadine

Amantadine, Rimantadine:

– MoA: (?) blockade of M

2

matrix protein

blockade of endocytosis

– TA: prevention of influenza infections

in risk groups or in case of epidemics

modest therapeutic efficacy if infection already present

must be started within first 48h of infection

– TA: Amantadine – also in the tmt of Parkinson’s

– RES: some strains resistant (modification of M

2

protein)

– SP: influenza A virus

Amantadine and Rimantadine

Amantadine:

– PK: good PO absorption
– PK: good distribution (crosses BBB)
– PK: little metabolism

excretion in urine

(!) in renal failure patients

– ADE: CNS

insomnia, dizziness, ataxia (hallucinations,

seizures)

(!) in patients with psychiatric problems, cerebral atherosclerosis,
epilepsy

Rimantadine:

– PK: good PO absorption
– PK: doesn’t cross BBB
– PK: extensive metabolism

excretion in urine

– (+): fewer CNS effects than amantadine

Both:

– CI: pregnancy, nursing mothers (teratogenic, embryotoxic)

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Ribavirin

Ribavirin

– MoA: guanosine analog

converted into RTP

(ribavirin triphosphate)

Ø mRNA synthesis

(-) ineffective against RNA viruses

– SP: RSV, influenza A, B, hepatitis A, (?) Lassa virus,

hantavirus (hemorragic fever renal syndrome)

– TA: RSV infections in children
– PK: PO, IV, aerosol
– PK: retention in tissues, no retention in CNS
– PK: elimination in urine (drug + metabolites)
– ADE: transient anemia in Lassa fever,

bilirubin (for

PO, IV)

– ADE: respiratory problems in children (for aerosol)
– CI: pregnancy (teratogenic)

Types of Antiviral Drugs

Antiviral drugs

Drugs for

respiratory

virus infections

Drugs for herpes

and megalovirus

infections

Drugs for HIV

infections

Drugs for hepatitis

leukemia and

Kaposi’s sarcoma

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TMT of Herpes and Megalovirus

Infections

Herpesviruses:

– cold sores (HSV)
– chickenpox, shingles

varicella-zoster virus (VZV)

– viral encephalitis
– genital infections

transmitted on newborn during parturition

Drugs against herpesviruses:

– effective during acute phase
– ineffective during latent phase
– MoA: purine/pyrimidine analogs

Ø of viral DNA

synthesis (exception foscarnet)

Nucleoside Analogs

Acyclovir

– MoA: guanosine analog

phosphorylated by viral

thymidine kinase

further phosphorylation by host

cell enzymes

acyclovir triphosphate

competes

with dGTP

incorporation into viral DNA

premature DNA termination, Ø of viral DNA
polymerase

– RES: altered/deficient thymidine kinase (enzyme

absent in CMV – natural resistance)

– SP: HSV-1, HSV-2, varicella-zoster virus, Epstein-

BArr virus

– TA: HSV encephalitis (more efficacious than

vidarabine)

– TA: genital herpes infections
– TA: prophylaxis

before bone marrow transplant

and after heart transplant (immunosuppressive drugs)

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Nucleoside Analogs

Acyclovir

– PK: PO, IV,

– PK: topical

??? efficacy

– PK: good distribution

– PK: partial metabolism

inactive

– PK: excretion – urine (filtration, tubular secretion)

(!) in renal failure patients

– ADE: topical

irritation

– ADE: PO

headache, diarrhea, nausea, vomiting

– ADE: IV

transient renal dysfunction (in dehydrated

patients or at high doses)

Nucleoside Analogs

Ganciclovir

– MoA: as in acyclovir; CMV

another route

– RES: some strains of CMV (? mechanism)
– TA: as in acyclovir + CMV retinitis
– PK: IV, good distribution, renal elimination
– ADE: severe neutropenia
– ADE: carcinogenic
– ADE: embryotoxic,

teratogenic

CI: pregnancy

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Nucleoside Analogs

Famciclovir

– MoA: analog of deoxyguanosine (converted

into active metabolite penciclovir)

– SP: as in ganciclovir

– TA: approved only for acute herpes zoster

infection (shingles)

– PK: PO

– ADE: headaches, nausea

Nucleoside Analogs

Penciclovir

– MoA: analog of deoxyguanosine

– SP: HSV-1, HSV-2, VZV

– TA: cold sores

– PK: topical adm

no absorption

experimental

IV

– PK: long half-life

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Nucleoside Analogs

Cidofovir

– MoA: analog of cytosine nucleotide

independent on viral enzymes

– TA: CMV-induced retinitis
– PK: PO, slow elimination
– ADE: nephrotoxicity

esp. in preexisting renal impairment/patients taking
nephrotoxic drugs (NSAIDs)

antidote

probenecid (ADE: rash, headache,

fever, nausea)

– ADE: neutropenia, metabolic acidosis, ocular

hypotony

Nucleoside Analogs

Vidarabine (ara-A)

– MoA: nucleoside analog (arabinofuranosyl adenine)

converted to ara-ATP

– SP: HSV-1, HSV-2, VZV
– TA: HSV keratitis or encephalitis , VZV infections

immunocompromised patients

(-) less effective than acyclovir

– RES: modified DNA polymerase
– PK: IV infusion (poorly soluble)

12 hours

good BBB penetration

– PK: topical

keratitis/keratoconjunctivitis

– PK: excretion

urine (native/metabolites)

– ADE: mild

in renal/hepatic failure

CNS disturbances, fluid overload

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Nucleoside Analogs

Trifluridine:

– MoA: pyrimidine

– TA: HSV keratoconjunctivitis

– PK: topical adm.

Foscarnet

Foscarnet

– MoA: pyrophosphate analog

reversible Ø

of RNA and DNA polymerases

– SP: CMV, HSV (acyclovir-resistant), VZV

(acyclovir-resistant)

– TA: cytomegalic retinitis in

immunocompromised (HIV infected) patients

– RES: mutation of polymerase structure

cross-resistance with gancyclovir

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Foscarnet

Foscarnet

– PK: IV, frequent administration

– PK: distribution into bone matrix

– PK: elimination

native form in urine

(filtration, secretion)

– ADE: nephrotoxicity, anemia, nausea, fever

– ADE: chelation with bivalent cations

hypocalcemia, hypomagnesemia

seizures,

arrhytmias

Types of Antiviral Drugs

Antiviral drugs

Drugs for

respiratory

virus infections

Drugs for herpes

and megalovirus

infections

Drugs for HIV

infections

Drugs for hepatitis

leukemia and

Kaposi’s sarcoma

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Nucleoside Analogs

Zidovudine (AZT)

– MoA: 3’-azido-3’deoxythymidine

conversion into triphosphate (mammalian
thymidine kinase)

blocks DNA synthesis by

reverse transriptase

doesn’t block host’s DNA polymerase

– MoA: Ø of dTMP

dTDP conversion

– RES: mutation of reverse transcriptase
– TA: HIV infections

slows progression

protects fetuses in infected mothers

Nucleoside Analogs

Zidovudine (AZT)

– PK: PO

good absorption

– PK: wide distribution (crosses BBB), half-life ~1 hr

– PK: glucuronidation in liver, excretion in urine

– ADE: bone marrow toxicity

anemia, leukopenia

– ADE: headaches

– ADE: seizures (in patients with advanced AIDS)

– INT: glucuronidation inhibitors: probenecid,

acetaminophen, lorazepam, indomethacin, cimetidine

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Nucleoside Analogs

Didanosine (ddI)

– MoA: dideoxyinosine

converted into ddATP

termination of chain elongation

– TA: AZT-resistant HIV infections

– RES: mutation of reverse transcriptase

(+) no cross-resistance with other nucleoside
analogs

Nucleoside Analogs

Didanosine (ddI)

– PK: PO

chewable buffered tablets or

buffered solution

– PK: good abs. in the fasting state (food

abs)

– PK: crosses BBB (less than AZT)
– PK: excretion – urine (55% unchanged)
– ADE: pancreatitis (! may be fatal)

monitoring of serum amylase

– ADE: peripheral neuropathy
– INT: buffer may

absorption of other drugs

(ketoconazole)

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Nucleoside Analogs

Zalcitabine (ddC)

– MoA: dideoxycytidine

converted into ddCTP

– TA: HIV

in conj. with AZT or instead of AZT

– RES: mutations of reverse transcriptase
– PK: PO

good abs,

by food/gastric acid

neutralizers

– PK: good distr

lower BBB penetration than AZT

– PK: metabolism (ddU), excretion

urine, some with

feces

– ADE: peripheral neuropathy (Ø mitochondrial DNA

polymerase)

– ADE: rash, stomatitis (resolve with tmt)
– ADE: pancreatitis (esp with pentamidine)

Nucleside Analogs

Stavudine (d4T)

– MoA: conversion into d4TTP

Ø RT

– PK: PO

good abs., not affected by food

– PK: BBB penetration

– PK: excretion

urine

– ADE: peripheral neuropathy (Ø mitochondrial

DNA polymerase)

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Nucleoside Analogs

Lamivudine (3TC)

– MoA: nucleoside analog

– SP: HIV, HBV (hepatitis B)

– (+): does not affect mithochondrial DNA polymerase,

does not affect bone marrow

– TA: HIV + AZT (slower development of resistance to

AZT)

– PK: PO

good abs

– PK: renal elimination

– ADE: children

pancreatitis

– INT: co-trimoxazole

bioavailability of 3TC

Nucleoside Analogs

Abacavir:

– TA: for patients who canot tolerate or do not respond

to other drugs and combinations

– RES: some cross-resistance with AZT and 3TC

– ADE: drug fever, GI symptoms, malaise, rash

in sensitized subjects

hypotension, respiratory problems

Adefovir:

– TA: as in abacavir

– SP: in vitro

HIV, herpes, HBV

– ADE: nephrotoxicity (30%)

– ADE: nausea, diarrhea, asthenia,

hepatic enzymes

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HIV Protease Inhibitors

MoA: Ø HIV protease

– viral protein

autocatalytic cleavage

generation of

viral proteins from precursor

TA: HIV infection

– in combination with AZT or 3TC

INT: Ø CYP-450

– antiarrhythmic drugs: amiodarone, quinidine
– antihistaminic drugs: astemizole, terfenadine
– antimigraine drugs: ergot derivatives
– antimycobacterial drugs: rifampin
– BZDs: midazolam, triazolam
– GI prokinetic drugs: cisapride

HIV Protease Inhibitors

ADE: lipodystrophy, hyperglycemia

– more with indinavir, ritonavir, less with

nelfinavir, saquinavir

– lipodystrophy

skinny legs, fat relocated to

abdomen and upper back

– hyperglycemia (rarely)

exacerbation or

initiation of DM

ADE:

TG,

cholesterol

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HIV Protease Inhibitors

Saquinavir

– PK: PO, low bioavailability (12%)

better with high-fat meals

– PK: good distribution

– PK: metabolism

liver; elimination

bile

lower when combined with delavirdine

– ADE: headache, fatigue, diarrhea, nausea, GI

disturbances

HIV Protease Inhibitors

Ritonavir:

– PK: PO good BA (60%), unaffected by food

taken with nutritional supplements to improve taste

– PK: metabolism

liver; excretion

bile

– ADE: nausea, vomiting, diarrhea, asthenia

– ADE: circumoral paresthesia, headache

– ADE:

aminotransferase

– ADE:

TG

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HIV Protease Inhibitors

Indinavir

– PK: good PO abs.

better in acidic gastric conditions

lower with meals

– PK: low protein binding

– PK: short half-life (1.8 hrs)

– PK: metabolism

liver

– ADE: GI disturbances, headache

– ADE: risk of nephrolithiasis

prevention by adequate hydration

– ADE: risk of reversible hyperbilirubinemia

HIV Protease Inhibitors

Nelfinavir

– PK: good PO abs.
– PK: active hydroxylated metabolite
– PK: half-life 5 hrs
– ADE: diarrhea

antidote

loperamide

Amprenavir

– PK: long half-life
– ADE: nausea, diarrhea, vomiting, oral and

perioral paresthesia, rash

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Non-nucleoside RT inhibitors

MoA: highly selective, noncompetitive
ihibitors of RT

– (+) no effect on human DNA polymerases

no effect on bone marrow

– (+) no cross-resistance with nucleoside

analogs

– (-) quick development of resistance in

monotherapy

most often used in combination with other drugs
(nucleoside RT inhibitors)

Non-nucleoside RT inhibitors

Nevirapine:

– PK: good PO absorption
– PK: good distribution (crosses BBB)
– PK: metabolism

liver; excretion

urine

– ADE: rash, fever, headache,

serum transaminases

– ADE: sever dermatologic diseases

Stevens-Johnson syndrome, toxic epidermal necrolysis

14 day titration period with ½ dose (

of risk)

– ADE: hepatotoxicity (may be fatal)
– INT: inducer of CYP3A4

metabolism of protease inhibitors

dose adjustment (

dose of indinavir and nelfinavir, do not use with saquinavir)

metabolism of other drugs: oral contraceptives,

ketoconazole, methadone, metronidazole, quinidine,
theophylline, warfarin

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Non-nucleoside RT inhibitors

Delavirdine

– PK: good PO abs. (unaffected by food)

– PK: high protein binding (98%)

– PK: extensive metabolism; elimination by feces, urine

– ADE: rash (44% of patients), nausea, dizziness,

headache

– INT: inhibitor of protease inhibitor metabolism (

plasma levels of saquinavir, indinavir)

– INT: fluoxetine, ketoconazole

plasma delavirdine

– INT: phenytoin, phenobarbital, carbamazepine

plasma delavirdine

Non-nucleoside RT inhibitors

Efavirenz

– PK: good PO abs.
– PK: high protein binding (99%)
– PK: crosses BBB
– PK: half-life 40 hrs

once-daily dosing

– ADE: CNS (50%): dizziness, headache, vivid

dreams, loss of concentration

– ADE: rash
– INT: modest CYP-450 inducer (

dosage of

indinavir)

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Types of Antiviral Drugs

Antiviral drugs

Drugs for

respiratory

virus infections

Drugs for herpes

and megalovirus

infections

Drugs for HIV

infections

Drugs for hepatitis

leukemia and

Kaposi’s sarcoma

Interferon

TA: hepatitis B and C

TA: cancer

hairy cell leukemia, Kaposi’s

sarcoma

MoA: (?) induction of host enzymes

RNA

translation

degradation of viral RNA

PK: IV, crosses BBB

ADE: fever, lehtargy, bone marrow suppression,
CV problems (CHF), hypersensitivity

ADE: hepatic failure, pulmonary infiltrates