ANTIMICROBIAL THERAPY 2 ANTIVIRAL DRUGS

ANTIMICROBIAL

THERAPY 2

ANTIVIRAL DRUGSDR AMADIN A. OLOTU

Outline

Introduction

Classification of Antiviral Drugs

Drugs Indicated for the Treatment of non HIV viral infections

Drugs Indicated for the Treatment of HIV infection

Introduction

Viruses consist of nucleic acid (DNA or RNA) surrounded

by a protective coat of protein.

Some viruses in addition have this protein coat enclosed

in an outer partially host derived lipid membrane or

envelope

Viruses are:

Obligate intracellular parasites

Their replication is dependent on synthetic processes of

host cell

Introduction

Antiviral Drugs:

Have to be active inside host cells

To inhibit viral replication they either:

Block viral entry

Block viral exit

Inhibit any of the steps in between

May need to be activated by viral and cellular enzymes before exerting antiviral effect

Are virustatic: do not eliminate non-replicating or latent virus

Single nucleotide mutations in target viral protein may cause drug resistance

Adapted from Basic & Clinical Pharmacology 14th Edition Editor Bertram G. Katzung, MD, PhD

MAJOR SITES OF ACTION OF ANTIVIRAL DRUGS


Anti-herpesvirus Agents

• Nucleoside Analogs

Acyclovir

Valacyclovir

Famciclovir

Penciclovir

Trifluridine

Ganciclovir

Valganciclovir

Cidofovir

• Others

Docosanol

Foscarnet

Anti-influenza Agents

Oseltamivir

Zanamivir

Amantadine

Rimantadine

Anti-hepatitis Agents

Nucleoside Analogs

Lamivudine

Adefovir

Entecavir

Tenofovir

Telbivudine

Interferon alfa-2b

Others

Pegylated interferon alfa – 2a

Pegylated interferon alfa – 2b

Ribavirin

Anti-HIV Agents

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTI)

NonNucleoside Reverse Transcriptase Inhibitors (NNRTI)

Protease Inhibitors

Entry Inhibitors

Integrase Strand Transfer Inhibitor



1. Anti-herpesvirus Agents

2. Anti-influenza Agents

3. Anti-hepatitis Agents


1. Nucleoside Reverse Transcriptase Inhibitors (NRTI)

2. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI)

3. Protease Inhibitors (PI)

4. Entry Inhibitors

5. Integrase Strand Transfer Inhibitors

Nucleoside Analogs

General Mechanism of Action:

Taken up by host cells

Most converted by viral and cellular enzymes to the active triphosphate form

The triphosphate form inhibits:

DNA polymerase

Reverse transcriptase

RNA polymerase

Additionally, some antivirals get incorporated into nascent DNA leading to chain termination

Viral resistance





Mechanism of action of antiherpes agents

Adapted from Basic & Clinical Pharmacology 14th Edition Editor Bertram G. Katzung, MD, PhD



(Thymidine kinase)

Mechanism of action of aciclovir

Mode of activation and action of

aciclovir (ACV). ACVMP, aciclovir

monophosphate; ACVDP, aciclovir

diphosphate; ACVTP, aciclovir

triphosphate; dATP, deoxyadenosine

triphosphate; dTTP, deoxythymidine

triphosphate; dCTP, deoxycytidine

triphosphate; vDNA, viral

deoxyribonucleic acid

Adapted from Medical Microbiology (18th Edition), 2012 . Greenwood, W.L. Irving

Acyclovir: acyclic guanosine derivative



Nucleoside Analogs

Mechanism of action: Phosphorylated thrice, first by viral thymidine kinase, then by host cell enzymes inhibits viral DNA synthesis by 2 mechanisms: (1) competition with deoxyGTP for viral DNA polymerase forming an irreversible complex with the DNA

(2) DNA chain termination after incorporation into viral DNA

Pharmacology: Bioavailability 15-20%, excreted by glomerular filteration and tubular secretion, ½ life: 2.5-3 hours normal 20 hours in anuria, diffuses into most tissues and fluids, CSF conc 20-50% of serum

Indications:

treatment of HSV and VZV infections, treatment of chickenpox (VZV) in children, prophylactic for CMZ infections

Therapeutic Effects:

for HSV: shortens healing time of lesions; reduces viral shedding

for VZV: shortens acute pain; reduces severity of postherpetic neuralgia

Adverse effects:

GI, headache, rash

Valacyclovir



Nucleoside Analogs

Mechanism of action: same as acyclovir

L-valyl ester of acyclovir, converted to acyclovir by 1st pass effect then acts same as acyciclovir

Pharmacology:, serum levels 3-5x > acyclovir. Oral bioavailability 54-70%, CSF levels 50% of serum, ½ life 2.5-3.3 hours.

Indications:

treatment of HSV and VZV infections

prophylactic for CMV infections




Adverse effects:

GI, headache, rash

Famciclovir



Nucleoside Analogs

Mechanism of action:

diacetyl ester prodrug of 6 deoxypenciclovir, an acyclic guanosineanalogue undergoes 1st pass effect to penciclovir, competitive inhibition of viral DNA polymerase, blocks DNA synthesis but doesn’t cause chain termination.

Pharmacology: Bioavailability 70%, prolonged intracellular ½ life 7-20hours, excreted in urine

Indications:

treatment of HSV and VZV infections




Adverse effects:

GI, headache, rash

Penciclovir



Nucleoside Analogs

Mechanism of action: guanosine analogue

inhibit viral DNA polymerase by competition with nucleosides

Indications:

treatment of HSV in topical formulation



Adverse effects:

rash



Nucleoside Analogs Trifluridine (

trifluorothymidine)

Mechanism of action: fluorinated pyrimidine nucleoside phosphorylated intracellularlly to trifluridine triphosphate by host enzymes then inhibits viral DNA synthesis by competition with nucleosides for incoporation by viral DNA polymerase

Indications:

for HSV infections causing herpetic keratoconjunctivitis and epithelial keratitis


topical only formulation for treatment of ocular herpesvirus infections

Adverse effects:

ocular irritation, redness, itching

Ganciclovir



Nucleoside Analogs


Phosphorylated thrice, first by viral protein kinase phosphotransferaseUL97 in CMV infected cells and then by host cell enzymes, then inhibits viral DNA synthesis by competition with nucleosides and inhibits viral DNA polymerase also causes chain termination.

Pharmacology: poor oral bioavailability given IV or as intraocular implant

CSF conc 50% of serum, intracellular ½ life prolonged 16-24 hours

Indications:

drug of choice for CMV infections: retinitis, pneumonitis, colitis, esophagitis

100X more active against CMV than acyclovir


treat or prevent cytomegalovirus (CMV) infections

available in slow-release gel for intravitreous administration

Adverse effects:

Myelosuppression, headache, nausea, diarrhea, peripheral neuropathy.

Valganciclovir



Nucleoside Analogs

Mechanism of action: L-valyl ester prodrug of ganciclovir administered orally rapidly hydrolyzed to ganciclovir by esterases in intestinal wall and liver

Pharmacology:

Bioavailability 60%

Indications:

CMV infections: retinitis, pneumonia, colitis CMV in HIV


treat or prevent cytomegalovirus (CMV) infections

Adverse effects:

Myelosuppression, headache, nausea, diarrhea, peripheral neuropathy

Cidofovir



Nucleoside Analogs

Mechanism of action: cytosine nucleotide analog, phosphorylation to an active diphosphate independent of viral enzymes. Cidofovir diphosphate as a potent inhibitor of viral DNA polymerase competitively inhibits DNA synthesis, and as an alternative substrate for the enzyme is incorporated into viral DNA

Pharmacology: terminal half life 2.6 hours, prolonged intracellular half life of 17-65 hours for active metabolite cidofovir diphosphate poor CSF penetration eliminated by active renal tubular secretion. Must be administered with probenicid which blocks active tubular secretion and decreases nephrotoxicity. Aggressive hydration indicated. Contraindicated in renal impairment.

Indications:

for CMV retinitis, infections resistant to ganciclovir


treat CMV prevent CMV infections

Adverse effects:

Dose dependent proximal tubular nephrotoxicity, proteinuria, azotemia and metabolic acidosis

Mechanism of action: inhibits viral DNA polymerase, an inorganic pyrophosphate analog blocks pyrophosphate-binding sites on viral DNA polymerase and inhibits cleavage of pyrophosphate from deoxynucleotidetriphosphates preventing attachment of nucleotide precursors

Pharmacology: IV only, poor oral bioavailability, CSF conc 43-67% serum values, mean plasma half life of 3-7 hours but up to 30% may be deposited in bone. renal clearance. Give with large volume of fluids

Indications:

for use in CMV and HSV infections resistant to first-line drugs


treatment of CMV and HSV infections in immunocompromised ptx

Adverse effects:

nephrotoxicity, hypo/hypercalcemia, hypo/hyperkalemia, CNS toxicity



Others

Foscarnet (Phosphonoformic acid)

Mechanism of action: a saturated 22 carbon aliphatic alcohol that inhibits fusion between the HSV envelope and the cells plasma membrane preventing viral entry and replication

Pharmacology: Topical use as 10% cream

Indications:

for use in orolabial herpes



Others

Docosanol



Amantadine (1 aminoadamantane hydrochloride)

Mechanism of action: Tricyclic amine of the adamantane family

blocks M2 proton ion channel of the virus particle preventing uncoating of viral RNA within infected host cells preventing replication

Pharmacology: well absorbed, 67% protein bound, plasma half life 12-18hours, CSF levels 52-96% serum levels, excreted unchanged in urine.

Indications:

prevention and treatment of influenza A infections only


decrease in the severity and length of influenza A infections

Adverse effects:

Nausea, anorexia, nervousness and insomnia. Agitation, seizures hallucination Teratogenic.



Rimantadine (alpha methyl derivative of amantadine)


blocks M2 proton ion channel of the virus particle preventing uncoating of viral RNA within infected host cells preventing replication

Pharmacology: 4-10 time more active than amantadine in vitro. 40% protein bound, half life 24-36 hours, concentrations in nasal mucus 50% > than plasma. Extensively metabolized by hydroxylation, conjugation and glucoronidation before renal excretion.

Indications:

prevention and treatment of influenza A (only) infections


decrease in the severity and length of influenza A infections

Adverse effects:

GI, and CNS effects including nausea, anorexia, nervousness and insomnia. Agitation, seizures hallucination ( CNS effects less than with amantadine) Teratogenic



Oseltamivir

Mechanism of action: Neuraminidase inhibitor

Competitively and reversibly inhibits neuroaminidases of both influenza A and B viruses preventing release of virions from infected cells causing virions to clump to each other and membranes of infected cells

Pharmacology: An orally administered prodrug, activated by hepatic esterasesand is widely distributed, 80% bioavailability low plasma binding. Must be administed early within 36-48 hours of symptom onset Half life 6-10 hours excretion by glomerular filteration and tubular secretion

Indications:

prevention and treatment of influenza A and B


decrease in the severity and length of influenza A and B infections

Adverse effects:

nausea, vomitting abdominal pain, headache, fatigue and diarrhea



Zanamivir


Neuraminidase inhibitor

Competitively and reversibly inhibits neuroaminidases of both influenza A and B viruses preventing release of virions from infected cells causing virions to clump to each other and membranes of infected cells

Pharmacology: Directly delivered to respiratory tract by inhalation, giving very high concentrations pulmonary half life of 2.8 hours

Indications:

prevention and treatment of influenza A and B


nasal spray only formulation; decreases in the severity and length of influenza A and B infections

Adverse effects:

cough. Brochospasm, reversible decrease in pu;monary function not recommended for patients with underlying airway disease



Adefovir dipivoxil (NRTI)


diester prodrug of adefovir, an acyclic phosphoated adenine nucleotide analog it is converted to active diphosphate form by cellular enzymes then competively inhibits HBV DNA polymerase ( and HIV RT), is incorporated into viral DNA and causes chain termination.

Pharmacology: 59% oral bioavailability, unaffected by meals, <5% protein bound, prolonged intracellular half life of 5-18hours thus OD dosing

Indications:

treatment of chronic HBV infections


reduces viral load of serum HBV, glomerular and tubular excretion

normalizes liver histology and enzymes by 48 weeks

Adverse effects:

nephrotoxicity, lactic acidosis, hepatic steatosis, headache, diarrhea and abdominal pain



Lamivudine


nucleoside analog that inhibits both HIV RT and HBV DNA polymerase by competing with deoxycytidine-3p results in chain termination

host cell kinases convert to active triphosphate form

Pharmacology: 80% oral bioavailability, serum half life 2-.5hours, intracellular half life 11-14hours, eliminated unchanged in urine.

Indications:

treatment of chronic hepatitis B (HBV) infections (also used in antiretroviral therapy)


HBV DNA levels decreasing by approximately 97% after 2 weeks of therapy and 98% by 1 year. However, evidence of viral replication recurs in over 80%upon discontinuation of therapy.normalizes liver histology and enzymes

Adverse effects:

mild: neutropenia, headache and nausea



Tenofovir is a nucleotide adenosine 5′-monophosphate derivative that,

because of poor oral bioavailability, is commercially available as the

prodrug tenofovir disoproxil fumarate (TDF)


adenosine nucleotide analog activated to triphosphate form by host cell

kinases inhibits HBV DNA polymerase function incorporation into viral DNA

causes chain termination

Pharmacology: Oral bioavailability increased following high-fat meal,

prolonged serum half life 12-17 hours allowing OD dosing

Indications:

treatment of Chronic HBV infections


reduces HBV viral load more than lamivudine and adefovir less resistance.

Adverse effects:

mild; nausea, diarrhea and flatulence



Ribavirin


guanosine analog that inhibits viral replication of RNA and DNA viruses

host cell kinases convert to active monophosphate and triphosphate form

monophosphate: inhibits GTP synthesis

triphosphate: inhibits 5’ capping of viral mRNA

Pharmacology: oral bioavailability 45-64%,↑ with fatty meals

Indications:

treatment of chronic hepatitis C (HCV) infections (with pegIFN alfa-2)

treatment of respiratory syncytial virus (RSV) in children in aerosol

effective in wide variety of other viruses Lassa fever


reduces viral load of serum HBC

normalizes liver enzymes

Adverse effects:

oral: reversible anemia; aerosol: rash, wheezing, decreased lung function

Non-Retroviral Antiviral Agents


Interferons IFN alfa, pegIFN alfa 2a, 2b) (peg-polyethylene glycol complexed)


antiviral, immunomodulating and antiproliferative actions induces

endogenous chemokines, and signals several sites of action in viral cycle;

inhibit viral penetration, translation translation, viral protein processing

maturation and release

inhibits both hepatitis B and C viruses

Pharmacology: half life 2-5 hours, filtered at glomerulus and undergoes

proteolytic degradation during tubular reabsorption, pegylated moiety reduces

clearance

Indications:

treatment of chronic HBV and HCV infections

treatment of condylomata acuminata (genital warts) due to HPV

(also for Kaposi’s sarcoma in HIV ptx; malignancies, and multiple sclerosis)


in combination with ribavarin, reduces viral load of serum HBV and HCV

intralesion injections for genital warts effective in 50% of ptx

Adverse effects: flu-like syndrome, bone marrow suppression; CNS

Drugs Indicated for the Treatment of HIV

infection


1. Nucleoside Reverse Transcriptase Inhibitors (NRTI)

2. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI)

3. Protease Inhibitors (PI)

4. Entry Inhibitors

5. Integrase Strand Transfer Inhibitors

Sites in the HIV replication cycle where the different antiviral agents available act are shown in HIV therapy combinations of the different drugs are used.

Adapted from Mandel, Douglas and Bennetts’ principles and practice of infectious diseases. 9th ed.Philadelphia. Churchhill Livingstone Elsevier

THE HIV REPLICATION CYCLE AND SITE OF ACTION OF ANTIRETROVIRAL DRUGS


Nucleoside Reverse Transcriptase Inhibitors (NRTI)

Zidovudine (azidothymidine:AZT) Zidovudine (ZDV; 3′-azido-3′-deoxythymidine [AZT])

is a thymidine analogue that is administered orally as a 300-mg pill twice daily


nucleoside analog activated to triphosphate form by host cell kinases inhibits

HIV RT function incorporation by HIV RT into proviral DNA causes chain

termination

Pharmacology: oral bioavailability of 64%, should never be co-administered

with stavudine (d4T) because of antagonism,

Indications:

treatment of HIV infections

prevention of maternal to infant HIV transmission


in combination with other antiretroviral drugs, reduces viral load of HIV and increases CD4 cells↓mortality and opportunistic infections, gain weight, better quality of life, delays signs and symptoms of AIDS

Adverse effects: interference of zidovudine with the normal function of mitochondrial DNA pol-γ. Lactic acidosis, hepatic steatosis, peripheral neuropathy, lipodystrophic/lipoatrophic changes, and myopathy



Lamivudine [(−)2′,3′-dideoxy-3′-thiacytidine (3TC)] is a cytosine analogue


nucleoside analog that inhibits both HIV RT and HBV DNA polymerase

host cell kinases convert to active triphosphate form

Indications:

treatment of HIV infections in combination with other antiretroviral agents

(also used in treatment of chronic hepatitis B (HBV) infections)


in combination with other antiretroviral drugs, reduces viral load of HIV and increases CD4 cells

Adverse effects:

mild: neutropenia, headache and nausea



Stavudine(2′,3′-didehydro-2′,3′-dideoxythymidine [d4T]) is a thymidine analogue

DidanosineDidanosine (2′,3′-dideoxyinosine [ddI]) is functionally an adenosine

analogue that is administered in a delayed-release enteric-coated form


nucleoside analogs activated to triphosphate form by host cell kinases

inhibits HIV RT function

incorporation by HIV RT into proviral DNA causes chain termination

Indications:



usually not first-line treatment


↓mortality and opportunistic infections, gain weight, better quality of life, delays signs and symptoms of AIDS

Adverse effects:

peripheral neuropathy; HIV lipodystrophy syndrome (fat wasting)

didanosine also pancreatitis



Abacavir [(1S, cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl)]-2-cyclopentene-

1-methanol (ABC)]





Indications:






Adverse effects:

hypersenstivity rx; repeat exposure often fatal



Emtricitabine





antiviral activity 10-fold greater than lamivudine

Indications:

treatment of HIV infections in combinations with other agents




Adverse effects:

mild; pigmentation of skin



Tenofovir





Indications:

treatment of HIV infections in combinations with other agents


It is part of the first-line treatment



Adverse effects:

mild; flatulence

Nucleoside and Nucleotide Reverse-

Transcriptase Inhibitors

Tenofovir

Lamivudine

Emtricitabine

Zidovudine

Abacavir

Didanosine

Stavudine


Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

Nevirapine


non-competitively binds to allosteric site on HIV RT enzyme

causes conformational change which inhibits HIV RT function

no host cell activation required as in NRTIs

Indications:





Adverse effects:

rash; Stevens-Johnson syndrome rarely


Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

Efavirenz


non-competitively binds to allosteric site on HIV RT enzyme

causes conformational change which inhibits HIV RT function

no host cell activation required as in NRTIs

Indications:





Adverse effects:

CNS: dizziness, insomnia, impaired concentration, psychotic episodes

Nonnucleoside Reverse-TranscriptaseInhibitors

Efavirenz

Etravirine

Nevirapine

Delavirdine


Protease Inhibitors (PI)

Saquinavir


peptide-like agent that inhibits HIV protease

selective for homodimer of HIV protease; homolog in host are monomer

blocks cleavage of gag-pol precursor proteins and prevents maturation

Indications:





Adverse effects:

GI including N/V, diarrhea, anorexia and taste perversion

HIV lipodystrophy syndrome



Atazanivir





Indications:





Adverse effects:

hyperbilirubinemia not associated with other hepatotoxicity

less likely to cause HIV lipodystrophy syndrome



Ritonavir





Indications:


most potent inhibitor of CYP3A4 so used in boosted therapy with other PI




Adverse effects:





Lopinavir



selective for homodimer of HIV protease; protease in host cell is monomer


similar to Ritonavir but 10-fold more potent

Indications:





Adverse effects:



Protease inhibitors

Atazanavir

Darunavir

Fosamprenavir

Indinavir

Lopinavir

Ritonavir

Saquinavir

Tipranavir


Entry Inhibitors

Enfuvirtide


large peptide that binds to HIV gp 41 and blocks fusion

i.v. route of administration

Indications:

treatment of HIV infections in combination with other antiretroviral drugs


usually not first-line treatment, used when other drugs ineffective



Adverse effects:

injection site irritation


Entry Inhibitors

Maraviroc


antagonist of CCR5 co-receptor on CD4 cells

prevents binding of HIV glycoproetin 120 (gp120) to CCR5 co-receptor

inhibits CCR5-tropic HIV entry (HIV can also use CXCR4 co-receptor)

Indications:

treatment of HIV infections in combination with other antiretroviral drugs





Adverse effects:

Hepatotoxicity; may be preceded by systemic allergic reaction


Integrase Strand Transfer Inhibitors

Dolutegravir


recruits divalent cation binding to core area of HIV integrase

prevents HIV integrase from integrating viral DNA into host DNA

Indications:



It is now the first-line treatment


Adverse effects:

headache, GI and N/V

Entry Inhibitors and Integrase Inhibitors

Dolutegravir

Raltegravir

Enfuvirtide

Maraviroc

Highly Active Antiretroviral Therapy

(HAART)/ Antiretroviral Therapy (ART)

HIV rapidly develops resistance on monotherapy

This led to the use of HAART – 3 drugs from at least 2

different classes of antiretroviral drugs for HIV therapy

1 Integrase strand transfer inhibitor(INSTI) and 2 Nucleoside

Reverse Transcriptase Inhibitors (NRTI) or 1 Non Nucleoside

Reverse Transcriptase Inhibitor (NNRTI) and 2 NRTIs

ART is the term in common use today and means HAART

ART Firstline

1st choice: Dolutegravir, Tenofovir, Lamivuine

2nd choice: Effavirenz, Tenofovir, Lamivudine

BIBLIOGRAPHY AND

REFERENCES Mandel, Douglas and Bennetts’ principles and practice of

infectious diseases. 9th ed.Philadelphia. Churchhill Livingstone

Elsevier

Jawetz, Melnink and Adelberg’s medical microbiology. 28th edition

Medical Microbiology, 4th edition Editor: Samuel Baron.

Basic & Clinical Pharmacology 14th Edition Editor Bertram G.

Katzung, MD, PhD

Rang & Dale's Pharmacology 9th Edition

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ANTIMICROBIAL THERAPY 2 ANTIVIRAL DRUGS

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