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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

2

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

6

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

12

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