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PHARMACOLOGY Feb 05, 2014 lecture

ANTIVIRAL AGENTS
I.
Acyclovir
A synthetic purine nucleoside analog
Antiviral activity essentially confined to Herpes
viruses active against :
o Herpes Symplex type I and II
o Varicella zoster- less sensitive
o EBV may be inhibited only at a very high
concentration
In vitro, more than 100x more active than Vilarabin
10x more active than Idoxuridine against HPV type 1
Activity similar to that of Vidarabine against varicella
zoster
MOA: the affinity of the viral enzymes for acyclovir is
200x greater than that of human enzymes and
phosphorelation of acyclovir by a human enzymes
process proceeds at a very evitable rate. Not toxic on
human enzymes. The synthesis of acyclovir to
acyclovir monophosphate, in viral infected cells the
local cellular enzyme catalyze sequential synthesis of
acyclovir monophosphate. The amount of acyclovir
monophosphate form in the herpes virus infected
cells is 40 100x greater than that in the uninfected
cells. Acyclovir monophosphate acts as a significant
demorpotent inhibitor of viral DNA polymerase than
that of the cellular polymerases. The drug is
incorporated in the viral DNA where it causes
determination of the biosynthesis of the DNA strand.
Mutant strains of varicella zoster virus become
resistant to acyclovir, producing altered thymidine
kinase and DNA polymerase
Eliminated through the kidneys
Elimination half life-2.5 hrs in patients with normal
renal function,Neonates-3.8 hrs
Predominantly excreted by GF and tubular secretion,
only 10% or less is recovered in the urine as inactive
metabolite
Binding to the inactive metabolite is 9carboxymethoxymethylguanine
Binding to plasma protein is only up to 15%
Peak plasma concentration is reached within 1.5 hrs
Bioavailability - approx. 20%
Available in 200mg capsule, 5% ointment and powder
for injection in vial form for IV use
Dosage for genital herpes 200mg orally every 4hrs,
5x a day for 10 days
IV 5mg/kg body wt. every 8 hrs, IV inclusion - 1 hr
period
Toxicity local irritation(most frequent), local
phlebitis, rashes, diaphoresis, n/v, hypotension,
transient renal dysfunction, evidence of
neurotoxicity(4% of patients) received BM transplantmanifestations are lethargy, coma, confusion,
hallucination, tremors and seizures.
Therapeutic uses HSV type I and II, chronic and
recurrent mucocutaneous herpes, primary and
secondary genital herpes and neonatal herpes,
Varicella zoster infections
II.

Idoxuridine
-use primarily as an ophthalmic ointment or solution

- Activity largely limited to DNA viruses primarily the


members of herpes virus group
- active against vaccemia virus, HSV, varicella virus,
CMV
- viruses resistance occurs readily
-primary clinical use hepes simplex keratitis
-Herpes simplex type II does not respond to
idoxuridine
-Given at 0.1% ophthalmic sol. 1 drop in the
conjunctival sac every 8hr during the day, every 2hrs
during the night until definite improvement appears
after which you can give 1 drop every 2hrs during the
day and every 4hrs at night.
-Ointment - 0.5% every 4hrs during the day and once
before bedtime for 3 to 5 days.
III.

Amantadine
-synthetic antiviral agent
-Inhibits the replication of influenza A virus at an early
stage of infection (stage of uncoating in the body)
-Attachment of the virus to the cells and penetration
into the cells will not be affected by amantadine.
-Almost completely absorbed from the GI tract,
approx. 90% of the orally administered drug is
excreted through the urine and 50% is excreted
within 20 hrs in an unchanged form.
-Amantadine is not metabolized in the body.
-has a prophylactic value when given to persons who
have contact with an active case of influenza A.
-does not impair immune response to influenza
vaccine. Patients can be vaccinated at the same time
that amantadine is given but it is preferred that
amantadine be discontinued after 2 weeks after
vaccination.
-dosage: 200mg per day for 5 to 7 days (stagless
disease)
*Rimantadine - analog of amantadine
*Amantadine HCl (Symmetrel) - available in 100mg
caps, 50mg/5ml syrup form, dose: 4.4-8.8mg/kg body
weight (1-9y/o) but it should not exceed of 150mg
per day. 200mg once daily or 100mg BID for older
children and adults.
-minor neurological symptoms insomnia and
difficulty in concentrating
-cerebral atherosclerosis, psychiatric disorders and
history of epilepsy observed very closely when
given with this drug.
-Pregnant and nursing mothers contraindicated
-the drug may cause less CNS toxicity but more on GI
side effects

IV.

Vidarabine
-analog of adenosine
-phosphorylated to the corresponding nucleotide
within the cells and act by inhibiting the viral DNA
polymerase
-metabolize in less active hypoxanthine arabinoside
which may act synergistically with the current
compound to inhibit the replication of the DNA
viruses.
-active in vitro against vaccinea virus, HSV, CMV and
varicella zoster viruses

-not active against DNA viruses like adenovirus or


papapoviruses nor against the RNA viruses
-use mainly for encephalitis caused by HSV, dose:
15mg/kg body weight given IV at constant rate over a
period of 12 to 24hrs daily for 10days.
-for HS keratoconjunctivitis 3% ophthalmic
ointment, applied every 3hrs.
-vial/inj: 5ml vial, contains 200mg/ml
-AE: relatively few include nausea/vomiting, diarrhea,
rashes, weakness and thromboplebitis. CNS effects:
hallucinations psychosis, ataxia, tremors and dizziness
but only seen at very high doses (above 20mg/kg BW
per day)
-the dose should be reduced in patients with renal
insufficiency, it is mutagenic and carcinogenic
-therapeutic uses HS encephalitis and HS
keratoconjunctivitis

-thymidine kinase deficient HSV are resistant to the drug


-given in IV and penetrates well to the tissues including the
eye and CNS
-Renal elimination in direct proportion to creatinine
clearance
-Oral bioavailabity - <10%, but there is an oral formulation
available for maintenance therapy
-Clinical uses use for prophylaxis and treatment of CMV
retinitis and other CMV infections esp the
immunocompromised patients
-systemic toxic effects leukopenia, thrombocytopenia,
leukocitis, hepatic dysfunction and seizures.
-severe neutropenia when used with zidovudine and other
myelosuppresant agents
-for CMV retinitis
C.

*Trifluridine/triflurothymidine new, hallogenated


pyramidine, currently being use as 1% ophthalmic
soln for topical therapy of ocular infections caused by
HS.
V.

Human interferons
-glycoproteins that have a variety of biological effects
including induction of resistance to viral infections
and the regulation of other cell functions excluding
proliferation and immunological responses.
-3 types of human interferons:
Alpha 1
Beta 1
Gamma
-Hepa B promising effect in combination with
Vidarabine

ANTI-HERPES DRUGS
A. Acyclovir Acycloguanosine
B. Foscarnet
-a phosphonoformate derivative, does not require
phosphorylation,
-inhibits viral RNA polymerase, DNA polymerase and HIV
reverse transcriptase
-there is a mechanism of resistance that involves a point
mutation in the DNA polymerase genes
-Pharmacokinetics given by IV and it penetrates well into
the tissues including the CNS. Up to 1/3 of the given dose
may be deposited in the bone
-Renal elimination direct proportion to creatinine
clearance
-prophylaxis and treatment for CMV infection (active
against ganciclovir resistant strains)
-inhibits herpes DNA polymerase (acyclovir-resistant
strains)
-those who have thymidine kinase deficiency, may
suppress resistant herpetic infections in patients with AIDS
-AE: Nephrotoxicity with disturbances in electrolyte
imbalance especially Ca and Phosphate balance,
genitourinary ulceration and CNS symptoms like headache,
hallucinations and seizures.
C. Ganciclovir
-guanine derivative, triphosphorylated to form a
nucleotide that inhibits DNA polymerase but does not
cause chain termination

Cidofovir
-activated exclusively by host cell kinases therefore
inhibits DNA polymerase of CMV, HSV, adenovirus and
papillomavirus
-Resistance - mutation in the DNA polymerase gene
-use by IV and topical administration, interal vitreal
injection of the eye
-Renal ilimination in proportion to creatinine clearance
-effective against CMV retinitis, mucocutaneous viral
infections infection including those resistant to acyclovir
and genital wart
-Nephrotoxicity-major dose limiting toxic effect of the drug

OTHER antiherpes drugs:


1. Vidarabine
2. Sorivudine
-a pyrimidine analog with activity against EBV
-approx. 1000x more potent than acyclovir against HSV
strains
-thymidine kinase deficient strains - resistant
-oral bioavailability = 50% food increases plasma levels
-plasma half-life increases to approximately 200 to 300 hrs
at steady state
-hepatic metabolism and renal excretion
-For chronic HCV infection
Other agents
1. Imiquimod
-a novel immunomodulating agent effective for topical
treatment of condyloma acuminata and other
dermatologic conditions
-lacks direct antiviral or antiproliferative effect in vitro but
induces cytokinase and chemokinase with antiviral and
immunomodulating effect
-apply topically as a 5% cream to genital warts in humans
it induces immunological responses and causes reduction
in viral load and the size of the wart when applied topically
at least 3x a week for up to 16 weeks
-associated with complete clearance with genital and
perianal warts in at least 50% of patients
-success rate: F>M
-median time of clearance of the wart: 8-10 weeks
-application causes local erythema, excoriation, burning
sensation, flaking, itching, sometimes ulceration and
erosion
ANTIVIRAL AGENTS IN CLINICAL DEVELOPMENT
A.

Hepatitis B Virus (Nucleoside inhibitors)

1.
2.
3.
4.
5.

B.

Entecavir
Clevudine
Emtricitabine
Telbivudine
Tenofovir

Hepatitis C viruses (Nucleoside Analog)


1. Viramidine
2. BILN 2061
3. NM 283

NONRETROVIRAL AGENTS
Antiherpes virus agents
VALACYCLOVIR
-the L-valyl ester prodrug of acyclovir
-converted rapidly and virtually complete to acyclovir
after oral administration especially in healthy adults
this conversion is a result from first-pass intestinal
and hepatic metabolism through enzymatic hydrolysis
-a substrate for intestinal and renal peptide
trasporters
-oral bioavailability of acyclovir increases 3 to 5x to
approx 70% following valacyclovir administration

DOCOSANOL
-long chain saturated alcohol approved for use as a
cream for treatment of recurrent orolabial herpes
-it does not inactivate HSV directly but appears to
block fusion between the cellular and viral envelope
membranes and inhibit viral entry into cell

FANCYCLOVIR AND PENCICLOVIR


-Fanciclovir is diacetyl prodrug of 5-deoxypenciclovir.
-It lacks intrinsic antiviral activity.
-Penciclovir is an acyclic guanine nucleoside analog.
-It is an inhibitor of viral DNA synthesis.
-Intracellular half life is about 720 hrs.
-Plasma half-life 2hrs
-oral bioavailability 5%, but becomes high following
oral administration of Fanciclovir- 65 77%
bioavailability
-food will slow the absorption of the drug but does
not reduce the overall bioavailability
-excreted unchanged in the urine

FOMIVIRSEN
-it is a 21-base phosphorothiote oligonucleotide
-inhibits CMV replication.
-Given by intravetreal injection in the treatment of
CMV retinitis for patients unresponsive to other
therapies
-Half life of elimination - 55 hrs

GANCICLOVIR & VALGANCICLOVIR


-Ganciclovir is an acyclic guanine nucleotide analog
-similar in structure to acyclovir except that it has an
additional hydroxymethyl group on the acyclic side
chain
-effective against chonic CMV retinitis esp in
immunocompromised patients and for prevention of
CMV in patients undergone organ transplant

-Valganciclovir is the L-valyl ester prodrug of


ganciclovir
-inhibits viral DNA synthesis
-bioavailability of ganciclovir is about 61%.
-food increases the bioavailability of the drug of
about 25% of the drug
-Plasma half-life is about 2-4 hrs
-90% is eliminated unchanged through renal
excretion through GF and tubular excretion
-myelosupressant drug, BM and CNS toxicity
ANTI-INFLUENZA AGENTS
I.
Amantadine & Rimantadine
-Amantadine is an alphamethyl derivative of
Rimantadine and uniquely confidured tricyclic amines
-they specifically inhibit the replication of influenza A
viruses
-Rimantadine is 4-10x more active than amantadine
-inhibit viral uncoating(early) and altering
hemagglutinin processing(late)
-M2 protein of the influenza virus
-Peak Plasma Conc. reached up to 0.5 to 0.8
nanograms/mL
-both are well absorbed after oral administration
-Amantadine is excreted largely unmetabolized in the
urine.
-Plasma half-life of elimination 12-18 hrs in young
adults
-metabolized by hydroxylation, conjugation and done
prior to renal excretion
-SE dose related GI and CNS complaints
-high concentration associated with serious
neurotoxic reactions
-history of seizure and psychiatric disorders be
careful in giving this drugs, might exacerbate the
disease
-teratogenic drug
-effective against Influenza A infection
-Dose- 200 mg/day in one or two divided
doses(prophylactic dose)
II.

Oseltamivir Carboxylate
-transition escape analog of sialic acid
-Potent selective inhibitory effect against influenza A
& B virus, esp neuraminidases enzymes which leads
to viral aggregation
-antiviral spectrum similar to Zanamivir
-inhibition of the neuraminidase activity will lead to
viral aggregation at the cell surface and will reduce
virus spread esp. within the respiratory tract.
-bioavailability is about 80%
-food does not decrease bioavailability but it reduces
the risk of GI tolerance to the drug
-Peak plasma concentration 2.5 to 5 hrs
-Plasma half-life 1-3 hrs for phosphate prep and 610 hrs for the carboxylate prep
-Eliminated unchanged through the kidney
-doubled plasma half life when given with Propenicid
-AE:nausea, abdominal discomfort, headache, emesis
-pregnant mothers-uncertain, do not give
-Dose-75 mg BID for 5 days

III.

Zanamivir
-sialic acid analog that inhibit neuraminidase of
Influenza A and B viruses

-MOA like Oseltamivir, inhibitor of neuraminidase


-bioavailability is low less than 5%
-Plasma half life is 2.5 to 5 hrs
-Over 90% is eliminated in the urine unchanged
-wheezing and bronchospasm (untoward effect) NOT
RECOMMENDED to patients with COPD
-no evidence of mutagenic, oncogenic or teratogenic
effects
-no significant drug interaction
-treatment of influenza A or B infection
-Dose 10 mg BID for 5 days, given by inhalation
-about 1000 times more active than acyclovir against
HSV strains

*Idoxuridine and Trifluridine


REVERSE TRANSCRIPTASE INHIBITORS:
ANTI-HIV AGENTS
A.

Zidovudine (ZDV, AZT)


-Formerly called Azidothymidine
-antimetabolite that requires phosphoryation to form a
nucleotide analog
-Inhibits reverse transcriptase of HIV-1 and HIV-2
-causes chain termination in viral DNA
-resistance is common in patients with advanced HIV
infection due to mutation
-60% bioavailability after oral dose
-Elimination - hepatic metabolism & renal excretion
-half-life = 1-3hrs
-reduce the dose in patients with uremia and cirrhosis
-clinical uses: for AIDS and AIDS related complexes
-monotherapy is not recommended. the most frequently
use in combination with other regimen
-use as a prophylaxis against HIV infection through
accidental needle prick for medical personnel and against
vertical transmission from mother to neonate
-toxicity- BM suppression,GI distress, thrombocytopenia,
myalgia, agitation and insomnia and headache
-metabolism may inhibited by azole antifungals

B.

C.

Didanosine(ddl)
-Analog of deoxyadenosine
-complete cross resistance with zalcitabine(ddc)
-only partial cross resistance with Zidovudine
-oral bioavailability reduced by food and chelating agents
-Elimination kidneys
-usually used in combination regimen
-toxic effects: Pancreatitis, peripheral neuropathy, hepatic
dysfunction

Zalcitabine(ddc)
-same as Zidovudine
-high bioavailability following oral dose
-always use in combination with other anti-HIV drugs not
as a monotherapy
-same mechanism of action as Zidovudine
-dose dependent toxic reactions including peripheral
neuropathy, pancreatitis, esopageal ulceration, stomatitis
and althralgia
-inhibitors, they do not kill the viruses

D.

Lamivudine
-active against HIV-1 and hepatitis B
-if use alone there is high level of resistance
-adjusted in patients with renal insufficiency
-mild toxic reactions

E.

Stavudine
-a thymidine analog
-cross resistance with other reverse transcriptase
inhibitors
-Use in combination with Zidovudine
-good oral bioavailability, penetrates most tissues
including the CNS
-peripheral neuropathy- major toxic dose limiting effect

NON-NUCLEOSIDES
1. Delaviridine
2. Nevirapine
ANTI-HIV AGENTS: Protease Inhibitors
Idinavir
-inhibits HIV-1 protease
-good oral bioavailability except in the presence of food
-elimination mainly hepatic, only 10% by renal excretion
-cross resistance with ritonavir and saquinavir
-toxic effects: thrombocytopenia, hyperbilirubinimia,
nephrolithiasis
-maintain good hydration to reduce renal damage
-a substrate form inhibitor of CYP460 isoform
-increase serum level by azole antifungals and decrease
by Rifampicin
-the drug increases serum level of antihistamines,
benzodiazipines and Rifampicin

Ritonavir
-Action and resistance similar to indonavir
-good oral bioavailability, should be taken with meals
-clearance via the liver, reduce the dose to those with
hepatic impairment
-GI irritation and bitter taste- most common side effects
-drug interactions drugs that increase the activity of the
cytocrome P450 will lower the serum level of Ritonavir and
drugs that inhibit this enzyme like azole antifungals,
cimetidine, and erythromycin will elevate serum level

Saquinavir
-similar to other protease inhibitors
-cross-resistance is not common
-only 4% oral bioavailability
-must taken with meals to avoid GI distress
-has synergistic effect against HIV-1 in combination with
reverse transcriptase inhibitors
-may cause headache and neutropenia
-serum level will increase by ingestion of ketoconazole,
Ritonavir and grape fruit juice

Neltinavir
-recently introduced reduction in HIV blood titer
-combine with Zidovudine

MISCELLANEOUS ANTIVIRAL AGENTS


A. Amantadine and Rimantadine
B. Interferons
IFN-alpha IFN-beta IFN-Delta
-blocks peptide chain initiation

-degrades terminal nucleotides of tRNA


-Active Rnase
C.

D.

Ribavirin
-Inhibits guanosine triphosphate formation
-Prevents capping of viral mRNA
-blocks RNA-dependent RNA polymerase
-use as a aerosol for RSV infection, may shorten the
symptoms of inlu A and B, early IV ad reduces moratality
in cases of Laisa fever and other viral hemorrhagic fever
-Dose dependent Myelosuppression systemic use
Topical Antiviral Drugs
1. Iduxuridine
2. Cytarabine
3. Trifluridine

ANTIRETROVIRAL AGENTS AND TREATMENT OF HIV INFECTION


*Nucleoside and Nucleoside reverse transcriptase inhibitors:
ABACAVIR
-a synthetic carboxylic purine analog
-the only approved antiretroviral drug that is active as a guanosine
analog
-oral bioavailability is greater than 80%
-50% bound to plasma proteins and elimination half-life of up to 21
hrs
-unique and potentially fatal adverse hypersensitivity syndrome
characterized by fever, abdominal pain and other GI complaints,
mild maculopapular rashes malaise and fatigue -most important
side effect
TENOFOVIR
-available only as a Disaproxil fumarate prodrug
-the only nucleotide analog currently marketed for treatment of HIV
infection
-active against HIV-1, HIV-2 and HBV
-tenofovir diphosphate a competitive inhibitors of viral reverse
transcriptase
-oral bioavailability of 25%, high fat meal increases oral
bioavailability to 30%
-plasma elimination half-life is 14-17 hrs
-undergoes both glomerular filtration and active tubular secretion
-should not be used together with Didanosine because both inhibit
the enzyme purine nucleoside phosphoridase
EMTRICITABINE
-Chemically related to Lamivudine
-enters to cell by passive diffusion
-Emtricitabine 5-triphosphate (active metabolite)
-low affinity for human DNA polymerases
-oral bioavailability of 93%
-elimination half life of 8-10hrs for its metabolite it is 39hrs
-excreted unchanged in the urine
-low significant adverse effects
-one of the least toxic antiretroviral drug, few AE and no effect on
mitochorial DNA
-prolonged exposure can causes hyperpigmentation of the skin
*NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
NEVIRAPINE
-a dipyridodiazepinone
-noncompetitive inhibitor, target site is HIV I specific
-readily crosses the placenta and has been found in breast milk
-Eliminated mainly by oxidative metabolism CYP3A4 and CYP2B6

-long elimination half life 25-30hrs


-recommended dose is 200mg once daily for 14 days then increase
to 200 BID if there is no adverse reaction
-single dose - HIV infected pregnant
DELAVIRDINE
-A bisheteroarylpiperazine
-no significant activity against HIV-2 and other retroviruses
-well absorbed especially at pH <2
-Achlohydria-may decrease absorption of the drug
-recommended dose: 400mg TID
-Mean elimination half life is 5.8 hrs but it ranges from 2-11 hrs
-bound to plasma albumin by as much as 98%
-penetration to CSF and semen is poor due to extensive plasma
protein binding
EFAVIRENZ
-potent activity against HIV-1 only
-non-competitive inhibitor
-reaches peak plasma concentration within 5hrs
-bioavailability increases when taken with high fat meal
-99% bound to plasma proteins
-cleared via oxidative metabolism
-elimination half-life is slow - 40-55 hrs
-AE: mainly on CNS, it is unequivocably teratogenic
HIV PROTEASE INHIBITORS
1. NELFINAVIR
-Active against both HIV-1 and HIV-2
-peak concentration achieved in 2-4 hrs
-Absorption is very sensitive to food effects, high fat meal
-oxidative metabolism in the liver primarily by CYP2C19
-Eliminated primarily in the feces
-98% bound to plasma proteins
-Most important side effect diarrhea
-no evidence of teratogenesis, well tolerated by HIV
infected pregnant
2.

AMPRENAVIR AND FOSAMPRENAVIR

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