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Antivirals & antifungals

Dr S.A Jayaratne
Dept of Pharmacology

Virion
Lipid membrane

Viruses have no cell wall and made up of


nucleic acid components (DNA or RNA)
Surrounded by a protein capsid sometimes an
outer lipid envelop
Viruses are obligate intracellular parasite
They do not have a metabolic machinery of
their own uses host enzymes

Certain viruses multiply in the cytoplasm but


others do in the nucleus

Most multiplication take place before


diagnosis is made

Antiviral agents
Replication of the virus peaks at or before the
manifestation of clinical symptoms in many
viral infections
chemoprophylaxis or early initiation of therapy
may be key.
In chronic illnesses such as viral hepatitis or
HIV infection, potent inhibition of viral
replication is crucial in limiting the extent of
systemic damage
Viral replication consists of several steps.

Stages of viral replication


SCell entry attachment

- penetration
Uncoating of viral nucleic acid
Synthesis of early regulatory proteins
eg- synthesis of RNA or DNA
Synthesis of late structural proteins
Assembly of virion components
Release

Viral replication
penetration
viral attachment

uncoating
Early protein synthesis

& entry

Nucleic acid synthesis


Viral release

Packaging &
assembly

Late protein synthesis

Antiviral drugs
Current anti-viral agents do not eliminate nonreplicating or latent virus
Effective host immune response remains
essential for the recovery from the viral
infection
Clinical efficacy depends on achieving
inhibitory conc. at the site of infection within
the infected cells

Therapy difficulties
Antiviral agents can target any steps in the
replication process
Current anti-viral agents do not eliminate nonreplicating or latent virus
Effective host immune response remains
essential for the recovery from the viral infection
Clinical efficacy depends on achieving inhibitory
conc. at the site of infection within the infected
cells

Antiviral drugs
Many antiviral drugs are Purine or Pyrimidine
analogs.
Many antiviral drugs are Prodrugs. They must
be phosphorylated by viral or cellular enzymes
in order to become active.
Anti-viral agents inhibits active replication so
the viral growth resumes after drug removal.

Aciclovir
Mechanism of action
Aciclovir is phophorylated to triphosphate
compound by host cell enzymes thimidine
kinase
Aciclovir triphosphate inhibit viral DNA
polymerase & so prevent formation of viral
DNA
Because it requires the viral kinase for initial
phosphorylation, active metabolite
accumulates, only in infected cells

Acyclovir is thus selectively activated in cells


infected with herpes virus.
Uninfected cells do not phosphorylate
acyclovir

Aciclovir contd--

Pharmocokinetics
Given orally bioavailability is 15-20% Given 5 times a
day
Given iv for viral enchephalitis
Distributed readily into most body tissue & fluid
CSF -50% of plasma concentration
Excretion by glomerular filteration & secretion(dose
reduced in renal impairment

Aciclovir contd-

Clinical uses
I) Herpes simplex
Oral preparations
Non-genital herpes
Genital herpes
Treatment & prevention of recurrent genital
herpes
Prophylaxis in immunocompromised

Acyclovir contd--

Herpes simplex
IV aciclovir
Treatment of herpes simplex in
immunocompromised
Treatment of severe initial genital herpes
Treatment herpes simplex encephalitis
Prophylaxis of herpes simplex encephalitis in
immunocompromised

Clinical uses of aciclovir contd--

Topical aciclovir
Skin
Initial and recurrent labial and genital
herpes simplex
Eye
Herpes simplex producing dendritic corneal
ulcers

Clinical uses contd--

II)Chickenpox & herpes zoster


o Neonates with chickenpox (iv)
o Immunocompromised & those at special risk
(severe CVS or respiratory diseases or severe skin
diseases) 10days with at least of 7 days parenteral.
o Herpes zoster ( shingles), chickenpox &
prophylaxis ( orally)
Aciclovir reduce severity, duration of pain &
complications if started within 24hrs of onset of
rash

Aciclovir contd-III epstein barr virus infection


IV Cytomegalovirus-least activity

Adverse effects of aciclovir


Refer BNF
Precautions
Adequate hydration during intravenous aciclovir
Avoid rapid infusion rates
Avoid concurrent use of nephrotoxic agents
Avoid concurrent use of other agent which
interfere with drug excretion
Probencid

Famciclovir refer BNF

Agents to treat cytomegalovirus (CMV)


infections
CMV infections occur primarily in the setting
of advanced immunosuppression and are
typically due to reactivation of latent infection

Agents to treat c(CMV) infections contd--

Ganciclovir
Mechanism of action
The drug is activated by converting to a triphosphate

the virus-specified protein kinase in CMV-infected


cells.
The activated compound competitively inhibits viral

DNA polymerase and causes termination of viral


DNA elongation

Ganciclovir contd--

Uses
Life threatening or sight threatening CMV
infections in immunocompromised patients
Prevention of CMV disease during
immunosupressive therapy following organ
transplantation
Local treatment of CMV retinitis

Agents used in the management of influenza


virus infections

Amantadine
Oseltamivir (Tamiflu)
Zanamivir (Relenza)
Current influenza A subtypes that are circulating
among people worldwide include H1N1, H1N2,
and H3N2

Amantadine
Effective only against influenza A
Not recommended for avian influenza/ H1N1
H1N1 is resistant to amantadine
Mechanism of action
inhibit uncoating of the viral RNA within
infected host cells, thus preventing its release of
viral genome

Amantadine contd--

When begun within 12 days after the onset of


illness, the duration of fever and systemic
symptoms is reduced by 12 days.

Oseltamivir (Tamiflu)
A neuraminidase inhibitors
Enzyme neuraminidase which is essential for
the replication of the virus.
prevent the release of new virions and their
spread from cell to cell.

Oseltamivir (Tamiflu)
Effective against both influenza A, B & avian infuenza
(broad spectrum)
Used in treatment & prophylaxis
When initiated early within 36-48hrs reduce the
duration severity & incidence of complications of the
disease
Is not recommended for post exposure prophylaxis or
treatment of healthy individuals with influenza

Oseltamivir contd--

Recommended for post exposure prophylaxis of


at risk individuals over 13yrs (Nice guidance)
At risk patients: Those with chronic respiratory & CVS
diseases
Chronic renal diseases
Immunosuppressed
Diabetes mellitus

Pharmacokinetics
Given orally
Food reduces side effects but does not interfere
with absorption
Excretion glomeruler filtration and tubular
secretion
Dose has to be adjusted in renal failure

Drugs used in the management of HIV infections

There is no cure
There are drugs that slow the progression of
the disease
Antiretrovirals increase quality of life the life
expectancy

Principles of treatment of HIV


Aim:Reduce viral load
Delay disease progression
Reduce the rate of opportunistic infections
Prolong survival
Reduces the risks of onward transmission to
sexual partners and the unborn children of HIVinfected mothers

Principles of treatment of HIV contd--

Should be started before the immune system is


irreversibly damaged
Early treatment should be balanced against
toxicity
Regimen chosen should take into account patient
tolerance
Development of drug resistance is reduced by
using combinations of drugs
Such combinations should have synergistic &
additive effects without additive toxic effects

Antiretroviral agents
Four classes of antiretroviral agents are available
for use:
1. nucleoside/nucleotide reverse transcriptase
inhibitors (NRTIs)
2. non-nucleoside reverse transcriptase inhibitors
(NNRTIs)
3.protease inhibitors (Pi)
4 fusion inhibitors

Antiretroviral agents contd--

Combination therapy with maximally efficacious


and potent agents will
reduce viral replication to the lowest possible
level
decrease emergence of resistance.
Highly active antiretroviral therapy (HAART)
Combination of 34 antiretroviral agents
(Combinations should be tailored to the individual)

Zidovudine(Retrovir)(NRTI)
First anti-HIV drug
HIV replicates by converting single stranded
RNA into double standard DNA by the
enzyme reverse transcriptase
This is incorporated into host DNA
Zidovudine inhibit reverse transcriptase

When HIV infects a cell


Viral single stranded RNA
double stranded DNA
reverse transcriptase
viral DNA is then integrated into host chromosomal
DNA
Host cellular processes start transcribing viral RNA to
reproduce the virus

Zidovudine(Retrovir)(NRTI) contd--

Given orally or iv
Metabolically inactivated
20% excreted in urine
Concentration in CSF is 50% of that in plasma
Adverse effects :Git symptoms, Hach, dizziness
Anaemia , neutropenia, myopathy
Rarely hepatic necrosis & lactic acidosis

Antifungals
Fungal infections both systemic as well as
cutaneous have increased in incidence and
severity in recent years, owing mainly to
advances in surgery
cancer treatment
and critical care accompanied by increases in
the use of broad-spectrum antimicrobials
HIV epidemic.

Classification of Antifungal agents


I) Drugs that disrupt the fungal cell membrane:
Polyenes: amphotericin B, nystatin
Azoles:
Imidazoles: ketoconazole, miconazole,
Clotrimazole
triazoles: fluconazole, itraconazole
Allylamine: terbinafine
II) Drugs that inhibit mitosis: griseofulvin
III) Drugs that inhibit DNA synthesis:
flucytosine

Polyene Antibiotics
Amphotericin A & B are produced by
Streptomyces nodosus
Amphotricin A is not used clinically

Amphotericin B
Mechanism of action
They bind to the ergosterol in the fungal cell
membrane
This causes deformity of the cell membrane
Leakage of intracellular ions & enzymes

Causes cell death

Pharmacokinetics of amphotericin B
Poorly absorbed from the gut
Effective for fungi in the gut lumen
After stopping treatment persist in the body for
several weeks
Long t1/2of about 15 days
90% bound to serum proteins
Given iv for systemic infections
Used in life threatening fungal infections
Topical-corneal ulcers, artheritis-intra-articular

Adverse effects of amphotericin B


Nephrotoxicity
reversible at early stages
Adequate hydration
Hypokalaemia
GI symptoms
Muscle and joint pains
febrile reactions
Rarely anaphylaxis

Nystatin
Too toxic for systemic use
not absorbed from the GI tract
Clinical uses
prevent or treat superficial candidiasis of the
mouth, oesophagus or intestinal tract (as
suspension, tablets or pastilles)
Vaginal candidiasis (pessaries)
Cutaneous infection (cream, ointment or
powder)

Antifungal Azoles
Mechanism of action of azoles
They interfere with fungal cell wall synthesis
Imidazoles-ketoconazole, ticonozole,
miconazole, clotrimazole
Triazoles-fluconazole, itraconazole
Triazoles are more selective in their action and
cause less endocrine disturbances than
imidazole

Ketoconozole
Well absorbed from gut
Effective by mouth for systemic mycosis
Absorption is reduced by drugs that reduce
gastric acid secretion eg antacids, histamine H 2
receptor blockers
Is an inhibitor of cytochrome P450 isoenzymes
Interferes with drugs like phenytoin, rifampicine

Ketoconozole contd--

Adverse effects
N/V giddiness, photophobia

Hepatotoxic (transient to severe toxicity)


Impairs testosterone synthesis & cause
gynaecomastia reduced libido in males
(clinically used to bone pain in patients with
androgen depended prostatic cancer)

Griseofulvin
Prevent fungal growth by inhibiting mitosis
It binds to keratin as it is being formed in cells
of the nail bed, hair follicles & skin
Has no effect on established fungal growth
Prevent infection of new keratin
Duration of treatment depends on the time
taken for infected keratin to be shed
Duration of treatment-hair & skin-4-6wks
toe nail-1yr

Griseofulvin contd--

Given orally
Absorption enhanced by fat in food
Metabolised by liver
Inducer of hepatic enzymes
Effective against all superficial
ringworm(dermatophyte) infections