Slide Anti-Virals Antimicrobials

Pharmacology:
Antiviral Agents
With Dr. Pravin J. Shukle
Anubhav Mishra, anmishra013@gmail.com

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Pharmacology An Overview of Antiviral Activity
Entry and fusion inhibitors Mammalian cell
Penetration
Viral attachment Amantadine,
and entry Interferon-α Uncoating rimantadine
Blocked by Early protein synthesis

neuraminidase inhibitors Reverse
(influenza) transcriptase
Nucleic acid synthesis inhibitors
Packaging and Late protein Blocked by

Viral release assembly synthesis and protease
processing inhibitors
Blocked by maturation
inhibitors

Pharmacology Antiviral Agents by Target Organism
Antiviral agents
Anti-HIV agents Anti-herpes agents Drugs for influenza Anti-hepatitis drugs
Entry inhibitors Acyclovir Amantadine INF-α

Reverse Ganciclovir Zanamivir Others
transcriptase
Foscarnet
inhibitors
Integrase inhibitors
Maturation
inhibitors
Protease inhibitors
Others

CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus, PD
Pharmacology Anti-HIV Agents
Tat Trans-activator of
transcription (Tat)
Lipid membrane Regulatory protein
Matrix protein that enhances the
efficiency of viral
Capsid transcription
Nucleocapsid
Atropos235, HI-Virion, https://commons.wikimedia.org/wiki/File:HI-Virion.svg, CC BY 2.5, edited

Tat
Viral RNA genome
Lipid membrane
Matrix protein
Capsid
Nucleocapsid

Reverse transcriptase
Enzyme used to
generate comple-
mentary DNA (cDNA)
from RNA template
Reverse
(reverse transcription)
transcriptase

Integrase
Enzyme produced by a
retrovirus that enables
its genetic material to Integrase
be integrated into DNA
Reverse
of the infected cell
transcriptase

Protease
Protease
An enzyme that helps
break proteins; in this
case used to package
up the proteins for viral Integrase
assembly Reverse
transcriptase

Glycosylation
Proteins of Env-glyco-
host cell gp120
protein complex
gp41
gp120 and gp41
Viral surface proteins

that act to bridge
between the virus and
host cell walls

Glycosylation
Proteins of Env-glyco-protein
host cell gp120
complex
gp41
Tat
Viral RNA genome
Lipid membrane
Protease
Matrix protein
Capsid
Integrase
Nucleocapsid
Reverse
transcriptase

CCR5 What Is It?
• C-C chemokine receptor type 5
• Integral membrane protein
• Protein on the surface of T cells,

macrophages, dendritic cells, eosinophils
• Provide a method of entry for HIV into cells
Pleiotrope, PD
CCR5 What Is It?
• Gp120 binds to CCR5 or

CXCR4 at the same time it
binds to the CD4 complex.
• Gp41 subunit spans the

membrane and can bind to
CCR5 or CXCR4.
US National Institutes of Health - National Institute of Allergy and Infectious Diseases, PD-USGov-NIH, PD
CCR5 What Is It?
• If the gp120 molecule binds

to CD4 without any protein
binding to CCR5, the gp120
is shed and fusion cannot
happen.
• CCR5 is essential for the

spread of the R5 strain of
HIV-1.
US National Institutes of Health - National Institute of Allergy and Infectious Diseases, PD-USGov-NIH, PD
Antiviral agents
Anti-HIV agents
Gp41 Inhibitors
Entry inhibitors
Reverse CCR5 Inhibitors
transcriptase
inhibitors
Integrase inhibitors Gp120 Binders
Maturation
inhibitors CD4 Binders
Protease inhibitors
Others

Gp41 Inhibitor Enfuvirtide
• Estimated cost: $25,000 per year

• Little used due to price; injectable
Mechanism of action
• Binds to gp41 and interferes with the ability to
create an entry pore for the viral capsid
• Active against HIV-1 only
Adverse events
• Injection site reactions
• Cough, dyspnea, arthralgia

CCR5 Antagonists Maraviroc, Vicriviroc, Cenicriviroc
• CCR5: transmembrane chemokine receptor

involved in HIV envelope binding
• Targets CCR5; able to bind with gp120
(cenicriviroc also targets another receptor,
CCR2)
• If HIV particle uses CXCR4 receptor, these

agents will not work
• A Trofile assay can be done to see
if maraviroc will work

CCR5 Antagonists Maraviroc, Vicriviroc, Cenicriviroc
Resistance
• No cross-resistance
• Will be through mutations in the env gene
Side effects of maraviroc

• Can cause serious, life-threatening side effects:
• Hepatitis
• Allergic reactions (this may precede hepatotoxic

reactions)

Gp120 Binders Fostemsavir
• Experimental
• Drug trials finish in 2022
• Targets a highly conserved protein
• Resistance should be low
• Fostemsavir is a prodrug of temsavir
Vaccinationist, PD
CD4 Antagonists Ibalizumab
• Approved in 2019 for multidrug-resistant HIV

(trade name Trogarzo®)
• Monoclonal antibody (humanized)
• Binds to CD4 receptor on the surface of the

CD4 cell
Trogarzo
• Study: 48 weeks; 59% of patients achieved viral
suppression
• Administered by professionals every 14 days

Antiviral agents
Anti-HIV agents
Nucleoside Reverse Transcriptase Inhibitors (NsRTIs)
Entry inhibitors
Reverse Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)
transcriptase
inhibitors
Integrase inhibitors Non-nucleoside 1st generation

reverse transcriptase
Maturation inhibitors (NNRTIs)
inhibitors 2nd generation
Protease inhibitors
Others

Remember: Nucleosides do not
have a phosphate group!
• Abacavir • Apricitabine
• Didanosine • Censavudine
• Emtricitabine • Elvucitabine
• Lamivudine • Racivir
• Stavudine • Stampidine
• Zidovudine • Zalcitabine
• Amdoxovir
Go to https://www.nih.gov/ for the most recent regimens.

• Mostly anti-metabolic drugs
• Use 3 or more drugs from different drug

classes before symptoms appear
• HAART: highly active anti-retroviral therapy
• Shown to reduce or reverse the decrease

of CD4
• Shown to reduce morbidity and mortality

• Viral reverse transcriptase is different from

mammalian reverse transcriptase.
• -hydroxyl group on the ribose

ring so the next nucleotide cannot bind.
• NsRTIs are converted by host cell kinases to
•
d-site of RT.
• All NsRTIs may cause lactic acidosis and severe

hepatomegaly.
• Watch aminotransferase levels closely!

Abacavir (ABC) (guanosine analogue):
• Good oral availability
• Cell half-life of 12 24 h
• Resistance unlikely; requires several point

mutations
• Hypersensitivity reactions; occasionally fatal

occur in 5 % of HIV patients
Yikrazuul, PD
Didanosine (ddI):
• Reduce dose based on kidney function
• Resistance is unlikely; requires several point

mutations
Adverse effects:
• High degree of pancreatitis (up to 30 %)

watch carefully for cases
• Peripheral neuropathy
NEUROtiker, PD
Emtricitabine (FTC):
• Good oral availability, renal elimination:

consume doses once daily
• Contraindicated in children, and patients with

hepatic dysfunction
Yikrazuul, PD
Lamivudine (3TC):
• Used in HAART for HIV and in hepatitis
Toxicity and adverse events:
• GI/GU: (mild) gastric distress
• Neuro: (mild) headache, insomnia, fatigue
Vaccinationist PubChem, PD
Stavudine (d4T):
• Renal elimination; adjust dose based on

renal function
• Peripheral neuropathy, increases the risk

of lactic acidosis/steatohepatitis
compared to others
NEUROtiker, PD
Zalcitabine (ddC):
• Distributed to most tissues including the CNS
• Renal excretion; dose reduction in renal

disease
• Metabolized through CYP450; rifampicin

(Rifampin) increases clearance, whereas
azoles decrease clearance
Yikrazuul, PD
Zalcitabine (ddC):
• GI/GU: pancreatitis, esophageal ulcerations,

stomatitis
• Neuro: dose limits peripheral neuropathy
Yikrazuul, PD
Zidovudine (ZDV):
• Formerly called azidothymidine (AZT)
• Distributed to most tissues, and eliminated

via both the kidney and liver
• Bone: bone marrow suppression/anemia,

and neutropenia
• GI/GU: gastric distress, syndrome
• Neuro: headache, insomnia, fatigue

Jü, CC0
Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)
Remember: Nucleotides do
have a phosphate group!
• Tenofovir disoproxil (TDF)
• Tenofovir alafenamide (TAF)
Go to https://www.nih.gov/ for the most recent regimens.

Tenofovir disoproxil (Viread®):
• Used in both hepatitis and HIV
• Used for needlestick prophylaxis
• Can be used in pregnancy
• Excreted renally
• Prodrug; converted to tenofovir diphosphate

(actually a triphosphate)
• When taken with fatty food, the AUC is

increased by 40%
Anypodetos, CC0
Interactions:
• Increases concentration of didanosine
• Lead to pancreatitis and neuropathy
• Decreases concentrations of protease

inhibitors (atazanavir)
• May impede renal clearance of acyclovir and

ganciclovir
Anypodetos, CC0
• Nausea, rash, diarrhea, headache, pain,

depression, weakness
• High blood lactate, hepatomegaly
• syndrome
• Neuro: headache, insomnia, fatigue
Anypodetos, CC0
Tenofovir alafenamide (Vemlidy®):
• Used in HIV and hepatitis
• Greater antiviral activity
• Better lymphoid tissue penetration
• Studies show similar activity with fewer

side effects
• Often sold as a component to many fixed-

dose combination products
Vaccinationist PubChem, CC0
Tenofovir alafenamide (Vemlidy®):
Interactions:
• Increases concentration of didanosine
• Lead to pancreatitis and neuropathy
• Decreases concentrations of protease

inhibitors (atazanavir)
Vaccinationist PubChem, CC0

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• Binds to a site other than the NNTIs
• Do not require phosphorylation to be activated
• No cross resistance with NRTIs
• If used as monotherapy, resistance would occur

rapidly via a mutation in the pol gene

1st Generation Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz (EFV) Nevirapine (NVP) Delavirdine (DLV)

Efavirenz (EFV):
• Can be given once daily
• Metabolized by CYP and drug interactions

are common
• Neuro: CNS dysfunction
• Skin: skin rash
• Pregnancy: teratogenic in first trimester
• Lipids: increases blood cholesterol

Shizhao, PD
Nevirapine (NVP):
• Commonly used in 3 drug regimens
• Effective in preventing vertical transmission
• Skin
• Skin rash 15 20% of patients
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
Roland1952, PD
Delavirdine:
• Drug interactions are a major concern

(CYP3A4, 2D6)
• Blood levels are increased

by azoles and macrolides
• Blood levels are decreased

by antacids, ddI, phenytoin,
rifampin and nelfinavir
• Will affect warfarin levels
Emeldir, PD
Delavirdine:
• Skin: skin rash in 20% of patients
• Pregnancy: teratogenic
Emeldir, PD
2nd Generation Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Etravirine (ETR) Rilpivirine (RPV) Doravirine

2nd Generation Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Etravirine (ETR):
• Substrate and inducer of CYP3A4,

inhibits 2C9 and 2C19
• GI: diarrhea
• Skin: skin rash
• Pregnancy: teratogenic in first trimester
• Blood: increases blood cholesterol,

triglycerides, serum transaminases
Antiviral agents
Anti-HIV agents
Raltegravir (RAL)
Entry inhibitors
Reverse Dolutegravir (DTG)
transcriptase
inhibitors Elvitegravir (EVG)
Cabotegravir
Maturation
inhibitors Bictegravir
Protease inhibitors
MK2048
Others

Integrase Strand Transfer Inhibitors
• Treatment-naive patients
• Not metabolized by cytochrome; undergoes

glucuronidation
• If used with rifampin (induces UDP glucuronosyl

transferase), doses should be doubled
• Binds with integrase that is both common and

essential to HIV-1 and HIV-2
• Inhibits strand transfer
• Integration of rDNA into host cells is inhibited

Maturation Inhibitors
• Bebirimat (MPC4326)
• Isolated from a Chinese herb
• Not approved for use
• Normal viral replication requires the cleavage of a

capsid protein from the spacer protein.
• Bevirimat blocks this cleavage by entering

the growing virus bud.
• As the capsid remains bound, normal virus

particle core compression cannot happen.
• Result: immature, non-infectious particle

Maturation Inhibitors
Resistance:
• Gag-mutations cause resistance; 50% of

patients have mutations
• 50% of patients responded well to the

drug.

Antiviral agents
Anti-HIV agents
Entry inhibitors
Reverse
transcriptase
inhibitors
Maturation
inhibitors
Protease inhibitors
Others

Protease Inhibitors
• Used commonly in HAART
• Significant disorders in carbohydrate

metabolism
• May be due to inhibition of lipid regulating

proteins
• Have sites similar to HIV protease

Protease Inhibitors
disease) in 50% of patients on PIs (protease

inhibitors) for one year
•
gynecomastia
• Facial and peripheral lipodystrophy
• Hyperglycemia and insulin resistance
• Elevated lipids

Protease Inhibitors
Atazanavir:
• Dosing occurs once daily and requires an
acidic environment
• Penetrates barriers; CNS, seminal fluid
• Excreted in bile

• GI/GU: GI distress, elevated bilirubin but
NOT elevated cholesterol/triglycerides
• Neuro: peripheral neuropathy
• Skin: skin rash
Unknown, PD
Anti-HIV Drugs Protease Inhibitors
Darunavir (DRV), cobicistat-boosted darunavir

(DRV/c), ritonavir-boosted darunavir(DRV/r):
• Used in combination with other drugs to
boost effectiveness
• Used with caution in patients suffering from

the sulfa allergy

• GI/GU: liver toxicity
• Skin: skin rash
Fvasconcellos, PD
Anti-HIV Drugs Protease Inhibitors
Fosamprenavir/amprenavir:
• Fosamprenavir: prodrug to amprenavir
• Used in combination with other drugs, like

ritonavir, to boost effectiveness
• Use with caution in patients with sulfa allergy

• GI/GU: GI distress
• Skin: skin rash and paresthesias
• Pregnancy: contains propylene glycol and
should not be used in pregnancy or children
Fvasconcellos, PD
Protease Inhibitors
Ritonavir:
• Take with meals, clearance by the liver
•
due to its ability to inhibit metabolism
• Subtherapeutic doses inhibit the

metabolism of other protease inhibitors like
indinavir, lopinavir, and saquinavir
Yikrazuul, PD
Protease Inhibitors
Ritonavir:
• GI/GU: GI irritation, bitter taste, elevation of

transaminases, cholesterol, triglycerides
Yikrazuul, PD
Protease Inhibitors
Saquinavir:
• Combined with ritonavir
• Both a substrate and an inhibitor of

cytochrome
• GI/GU: nausea, vomiting, diarrhea,

dyspepsia
Protease Inhibitors
Tipranavir:
• Newer drug, combined with ritonavir
• Substrate and inducer of CYP3A4 and

P glycoprotein
• Increased risk of rhabdomyolysis with HMG-
• GI/GU: nausea, vomiting, liver toxicity

Leyo, PD
Antiviral agents
Anti-HIV agents
Entry inhibitors Uncoating inhibitors TRIM5α

Reverse
transcriptase Transcription
TAT Oyi vaccine
inhibitors (TAT) inhibitors
Integrase inhibitors Translation inhibitors Trichosanthin

Maturation
inhibitors DNA polymerase
Foscarnet
inhibitor
Protease inhibitors
Others Others ZFTF, CRSPR

Case: 44-year-old Woman with Abdominal Pain and Elevated Amylase
A 44-year-old female prostitute is HIV positive and is seen with abdominal

pain and elevated amylase and lipase levels. She is diagnosed with
pancreatitis. She is following a 3 drug HAART protocol (didanosine, ritonavir,
and zidovudine). She was also placed on terbinafine for a foot fungal
infection. Which of these drugs is most likely to have caused the pancreatitis?
A. Didanosine
B. Ritonavir
C. Zidovudine
D. Terbenifine


A. Didanosine
B. Ritonavir
C. Zidovudine
D. Terbenifine


A question very similar to this one has been on the USMLE and MCCQE
A. Didanosine
exam each year. Unfortunately, you just have to memorize the facts on this
question.
B. Ritonavir
Didanosine is well known to cause pancreatitis. Up to 30% of recipients will
C. Zidovudine
develop it. It is a feared and potentially fatal disease if unrecognized. You
should be aware
D. Terbenifine of this fact simply because of the high incidence.

Case: 32-year-old Woman with Polyuria, Polydipsia, and Dehydration
A 32-year-old HIV positive woman presents with polyuria, polydipsia,

dehydration, and confusion. She has bloodwork done, which shows acidosis,
hypokalemia, and hyperchloremia. The patient is on HAART therapy with
zidovudine, nevirapine, and ritonavir. Which drug is most likely to present
those symptoms?
A. The NRTI zidovudine
B. The NNRTI nevirapine
C. The PI ritonavir


those symptoms?
B. The NNRTI nevirapine
C. The PI ritonavir


those symptoms?
The purpose of this question is to reinforce that NRTIs are associated

with increasing the risk of lactic acidosis.
Nevirapine is an NNRTI. It is well known to be associated with skin side
effects
B. The such
NNRTI asnevirapine
rash (in 15 20%), a Stevens-Johnson syndrome, or toxic
epidermal necrolysis.
C. The PI ritonavir
Ritonavir is associated with multiple GI symptoms and skin rash.
-HIV medications.

Antiviral agents

transcriptase
Foscarnet
inhibitors
Maturation
inhibitors
Protease inhibitors
Others

Anti-Herpes Drugs Thymidine Kinase Dependant
Acyclovir, ganciclovir Monophosphate
• Active against HSV-1, HSV-2, VZV Host

kinases
• Short half-life; administered three to five
times daily Diphosphate
• Renal excretion; adjust dose in renal failure
Triphosphate
Incorporation Competitive inhibition of

info viral DNA viral DNA polymerase
Chain Inhibition of viral

termination DNA synthesis

Acyclovir, ganciclovir Monophosphate
Acyclovir, Virus-specified
Mechanism of action ganciclovir enzymes (e.g. Host
1. Competitive substrate for DNA polymerase thymidine kinases
kinase, UL97)
2. Leads to chain termination after Diphosphate
incorporation
Triphosphate



Valacyclovir
Monophosphate
ganciclovir enzymes (e.g. Host
thymidine kinases
kinase, UL97)
Valacyclovir (ValtrexR) is a prodrug of acyclovir
Diphosphate
• 3 5 x greater levels, that lasts much longer

Triphosphate



Valacyclovir
Monophosphate
thymidine kinases
Penciclovir inhibits DNA polymerase kinase, UL97)
Pencyclovir Diphosphate
• Does not cause chain termination

Famciclovir Triphosphate
• Famciclovir converted to penciclovir by liver


Valacyclovir
Monophosphate
Ganiciclovir a guanine derivative (acyclovir is a Acyclovir, Virus-specified

guanosine derivative) ganciclovir enzymes (e.g. Host
thymidine kinases
kinase, UL97)
• Inhibits DNA polymerase in CMV and HSV Pencyclovir Diphosphate
• CMV retinitis, other CMV infections in

immunocompromised hosts Famciclovir Triphosphate
• Toxicity: leukopenia, thrombocytosis, Competitive inhibition of

Incorporation
mucositis info viral DNA viral DNA polymerase


Valacyclovir
Monophosphate
thymidine kinases
Valganciclovir is a prodrug of ganciclovir Valganicyclovir kinase, UL97)
Pencyclovir Diphosphate
• High bioavailability
Famciclovir Triphosphate
• Longer half-life


Acyclovir, penciclovir, ganciclovir, famciclovir
Toxicity
• GI/GU: GI distress, nephrotoxicity
• Neuro: headache, delirium, tremor, seizures
• Bone: no significant effects on bone marrow

Acyclovir, penciclovir, ganciclovir, famciclovir
Resistance occurs in 2 ways
1. Changes in viral DNA polymerase
2. Some strains lack thymidine kinase
• Viral specific phosphorylation of acyclovir

• Will be cross resistant to each other

Anti-Herpes Drugs Host Kinase Dependant
Cidofovir Monophosphate
• Activated by host cell kinases
Trifluridine
• HSV, CMV, adenovirus, HPV Host
cidofovir
kinases
• Does not require viral kinase; active against
many resistant viruses Diphosphate
Activity
Triphosphate
• CMV retinitis, mucocutaneous HSV, genital warts
• Toxicity viral DNA polymerase
info viral DNA
• Nephrotoxicity

Anti-Herpes Drugs RNA Polymerase Inhibitors
Foscarnet Monophosphate
• Does not require phosphorylation for activity
• NOT an antimetabolite Host

kinases
• Inhibits DNA and RNA polymerase
• Inhibits HIV reverse transcriptase Diphosphate
• Inhibits DNA polymerase in acyclovir resistant

strains that are thymidine kinase deficient Triphosphate
Foscarnet
Adverse events: severe
• GI/GU: nephrotoxicity (30 %), GU ulceration
• Neuro: headache, hallucinations, seizures termination DNA synthesis

Anti-Herpes Drugs Others
Vidarabine
• Adenine analog
• Systemic infections of HSV, VZV, CMV
• No effect on genital lesions

Anti-Herpes Drugs Others
Vidarabine
Fomivirsen
• Anti-sense oligonucleotide
• Used intravitreally, for treatment of CMV retinitis
• Toxicity: iritis, vitreitis, increased intraocular pressures
Idoxuridine, trifluridine: herpes keratitis topical treatment

Fomivirsen

Pharmacology A Review
Pyrimidine analogues Adenine analogues Guanine derivative Guanosine derivative

• Idoxuridine • Vidarabine • Ganciclovir • Acyclovir
• Trifluridine
Antisense oligonucleotide Phosphonoformate derivative Aliphatic alcohol

• Fomivirsen • Foscarnet • Doscanol

Anti-Influenza Agents
Amantadine, rimantadine Blocked by amantadine,

rimantadine (influenza)
Mechanism of action
1. Inhibits decloaking of the influenza Viral attachment
and entry Penetration
A virus
Uncoating
2. Binds to a proton channel to prevent
acidification of the virus core Early protein synthesis
3. Without acidification, RNA Mammalian cell

Nucleic acid synthesis
transcriptase cannot activate!
Late protein
Packaging and synthesis and
Does NOT act on the influenza B virus assembly processing
Viral release

Amantadine, rimantadine Blocked by amantadine,

rimantadine (influenza)
• Note that amantadine is also an
antiparkinsonian medication! Viral attachment
• Rimantadine does not require dosage
adjustment in renal failure Uncoating
Early protein synthesis

Toxicity Mammalian cell
• GI irritation
• Slurred speech, dizziness, ataxia Late protein

assembly processing
Viral release

Oseltamivir (TamifluR), zanamivir

Neuraminidases act by
• Cleaving sialic acid residues Viral attachment
• Prevent clumping of newly released
Uncoating
virions
Blocked by Early protein synthesis
These agents inhibit neuraminidases neuraminidase
Mammalian cell
inhibitors Nucleic acid synthesis
• Impedes viral spread (influenza)
• Active against Influenza A and B Late protein

assembly processing
• Active against H3N2 and H1N1 strains Viral release
Worldwide resistance rare; due to

mutations of neuraminidases
Anti-Hepatitis Drugs
Viral attachment
Blocked by Uncoating
• Anti-hepatitis B drugs are interferon-α
suppressive, not curative. (HBV, HCV)
• Anti-hepatitis C drugs are Mammalian cell

targeted for viral eradication.
Late protein
assembly processing
Viral release

Interferon-α (INF-α) JAK-
1. Cytokine acting though Janus kinases STAT
• Janus kinases phosphorylate STAT
(Signal Transducers and Activators
of Transcription)
• Increased production of antiviral

proteins. JAK
2. Specific activation of a ribonuclease Y Y ~P
that degrades viral mRNA
3. Promotes formation of natural killer STAT

cells that destroy infected liver cells

Interferon-α (INF-α)
• Intramuscular injections; formulations may vary
• Absorption is slow, given 2- or 3-times per week

• Pegylated forms can be given once a week
• Elimination through hydrolysis and proteolysis in the kidney
Uses
• Chronic HBV
• Acute HCV with ribavirin

Pharmacology Anti-Infectives 6
Interferon-α
Adefovir
DNA polymerase inhibitors
Entecavir
Anti -
Hepatitis Nucleoside inhibitors Lamivudine
drugs
Broad spectrum
Ribavirin
replication inhibitors
Telbivudine
Miscellaneous
Tenofovir
Sofosbuvir
Boceprevir

Adefovir dipivoxil
(the prodrug of adefovir)
• Inhibits DNA polymerase of HBV Viral attachment
• Results in chain termination after
incorporation Uncoating
• Good oral bioavailability, Early protein synthesis

unaffected by foods Mammalian cell
• Dose reductions in renal
dysfunction Late protein
assembly processing
Viral release

Adefovir, entacavir
• Inhibits DNA polymerase of HBV
Viral attachment
• Results in chain termination after and entry Penetration
incorporation
Uncoating
• Good oral bioavailability,
unaffected by foods Early protein synthesis
Mammalian cell
• Dose reductions in renal Nucleic acid synthesis
dysfunction
Late protein
• Works well against lamivudine Packaging and synthesis and
resistant strains of HBV assembly processing
Viral release

Lamivudine
Nucleoside inhibitor
• Inhibits HIV reverse transcriptase Viral attachment
• Very long-acting in HBV infected
cells (compared to HIV infected Uncoating
cells)
• Used as monotherapy Mammalian cell
• Very nontoxic
• Rapid suppression of HBV Late protein

replication assembly processing
Viral release

Ribavirin
Inhibits replication of a wide range
of DNA/RNA Viral attachment
• Influenza A and B, parainfluenza,
RSV Uncoating
• Paramyxoviruses Early protein synthesis
• Hepatitis C, HIV Mammalian cell

Late protein
assembly processing
Viral release

Ribavirin
Mechanisms of action (largely
unknown) Viral attachment
1. Inhibits guanine triphosphate
Uncoating
2. Prevents capping of viral mRNA
3. Block RNA dependent
polymerases Mammalian cell
Late protein
assembly processing
Viral release

Ribavirin
• Avoid antacids; absorbed better
in acidity Viral attachment
• Eliminated by kidney dose reductions
Uncoating
• Used with INF-α in chronic Hepatitis C
• Monotherapy is not effective
Mammalian cell
Toxicity
Late protein
• Dose dependent hemolytic anemia Packaging and synthesis and
assembly processing
Viral release
• Contraindicated in pregnancy

Anti-Hepatitis Drugs Newer Drugs in HBV
Telbivudine Nucleoside analogue, inhibits DNA polymerase
Tenofovir Approved for lamivudine- and entecavir-resistance
Sofosbuvir Inhibits RNA polymerase in HCV; 95 % cure rates with ribavirin
Boceprefir Protease inhibitor, used with ribavirin

Overview
Virus Primary drugs Alternative or adjunctive drugs

CMV Ganciclovir, valganciclovir Cidofovir, foscarnet, fomivirsen
HSV, VZV Acyclovir Cidofovir, foscarnet, vidarabine
HBV IFN-a, lamivudine Adefovir dipivoxil, entecavir,

lamivudine, telbivudine
HCV IFN-a, sofosbuvir Ribavirin
Influenza A Oseltamivir Amantadine, rimantadine, zanamivir
Influenza B Oseltamivir Zanamivir

Overview CMV Retinitis
Sight-treatening Intravitreal injections

lesions (adjacent • Ganciclovir (2mg/injection) or foscarnet (2.4 mg/injection);
to the optic nerve 1 4 doses over 7 10 days (AIII)
or fovea) plus
Systemic CMV therapy

Preferred systemic therapy
• Valganciclovir 900 mg PO (BID for 14 21 days,
then once daily) (AI)
Alternative systemic therapy

• Ganciclovir 5 mg/kg IV q12h for 14 21 days,
then 5 mg/kg IV daily (AI)
Peripheral Administer one of the systemic therapy agents

lesions

Case Study 3: Hepatitis B Drugs
A 63-year-old hemophiliac had contracted hepatitis B from contaminated
advice three months ago, and presents with fulminant transaminitis and
jaundice.
The following is/are true statement/s about Hepatitis B medications.
A. Interferon-α acts through tyrosine kinase receptors.
B. Interferon-α is quickly absorbed at the injection site.
C. Interferon-α inhibits a ribonuclease that degrades viral mRNA.
D. Interferon-α promotes the formation of natural killer cells.

Case Study 3: Hepatitis B Drugs
A 63-year-old hemophiliac had contracted hepatitis B from contaminated
advice three months ago, and presents with fulminant transaminitis and
jaundice.
The following is/are true statement/s about Hepatitis B medications.
A. Interferon-α acts through tyrosine kinase receptors.
B. Interferon-α is quickly absorbed at the injection site.
C. Interferon-α inhibits a ribonuclease that degrades viral mRNA.
D. Interferon-α promotes the formation of natural killer cells.

Question 2: Got the Flu Bug
A 45-year-old male has contracted Influenza B.

The following statements are true:
A. Zanamivir is an intranasal spray that may be beneficial for this patient if taken
within 24 hours of the onset of symptoms.
B. Amantadine may be used as a prophylaxis for this patient.
C. Rimantidine may be beneficial for this patient if taken within 24 hours of the
onset of symptoms.
D. Amantadine is an inhibitor of neuraminidase.
E. Zanamivir acts through blockage of a proton port in the cell wall that prevents
acidification of the interior.


within 24 hours of the onset of symptoms.
B. Amantadine may be used as a prophylaxis for this patient.
C. Rimantidine may be beneficial for this patient if taken within 24 hours of the
onset of symptoms.
E. Zanamivir acts through blockage of a proton port in the cell wall that prevents


B iswithin
incorrect because
24 hours of theamantadine is not useful against Influenza B.
onset of symptoms.
C
B.isAmantadine
incorrect because rimantadine
may be used also is not
as a prophylaxis useful
for this against Influenza B.
patient.
D
C.isRimantidine
incorrect because amantadine
may be beneficial is apatient
for this blocker of a proton
if taken pump
within 24 hoursinofthe
the
vesicle wall,
onset that would have allowed transcription with an acidic
of symptoms.
environment.
E is incorrect because Zanamivir is a neuraminidase inhibitor.
ItE.does
Zanamivir acts
not act onthrough blockage
a proton port. of a proton port in the cell wall that prevents

Image: National Eye Institute, NIH
A 34-year-old male presents with a painful left eye. The funduscopic image is
displayed on the left.
The appropriate treatment would be:
A. Valganciclovir 900 mg PO bid for 21 days, then once daily
B. Intravitreal injections of ganciclovir or foscarnet over 7 10 days, then

valganciclovir 900 mg PO bid for 21 days or resolution
C. Gancyclovir 5 mg/kg IV Q 12 h for 21 days
D. Oral valganciclovir 900 mg PO bid for 7 days

The appropriate treatment would be:
A. Valganciclovir 900 mg PO bid for 21 days, then once daily
B. Intravitreal injections of ganciclovir or foscarnet over 7 10 days, then

valganciclovir 900 mg PO bid for 21 days or resolution
C. Gancyclovir 5 mg/kg IV Q 12 h for 21 days
D. Oral valganciclovir 900 mg PO bid for 7 days

Comment The appropriate treatment would be:

For some reason, examination boards love CMV retinitis. It is a good disease
to know. This patient is having retinitis that is threatening his optic nerve. He
has loss of vision. Systemic therapy would not be enough in most situations
like this.
An intravitreal injection of a strong anti-viral like ganciclovir would be

advised. Usually it is given every second day for 7 days, followed by
systemic therapy; either oral valganciclovir for 21 days or ganciclovir IV for
21 days. Treatment would obviously be under the care of an eye specialist
experienced in this disease.
Ganciclovir intraocular implants are sometimes used.

Antiviral agents

transcriptase
Foscarnet
inhibitors
Maturation
inhibitors
Protease inhibitors
Others

This document is a property of: Anubhav Mishra
Note: This document is copyright protected. It may not be copied, reproduced, used, or
distributed in any way without the written authorization of Lecturio GmbH.


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Pharmacology:

With Dr. Pravin J. Shukle

Anubhav Mishra, anmishra013@gmail.com

Blocked by Early protein synthesis

Packaging and Late protein Blocked by

Anubhav Mishra, anmishra013@gmail.com

Anti-HIV agents Anti-herpes agents Drugs for influenza Anti-hepatitis drugs

Entry inhibitors Acyclovir Amantadine INF-α

Anubhav Mishra, anmishra013@gmail.com

Atropos235, HI-Virion, https://commons.wikimedia.org/wiki/File:HI-Virion.svg, CC BY 2.5, edited

Atropos235, HI-Virion, https://commons.wikimedia.org/wiki/File:HI-Virion.svg, CC BY 2.5, edited

Atropos235, HI-Virion, https://commons.wikimedia.org/wiki/File:HI-Virion.svg, CC BY 2.5, edited

Atropos235, HI-Virion, https://commons.wikimedia.org/wiki/File:HI-Virion.svg, CC BY 2.5, edited

Atropos235, HI-Virion, https://commons.wikimedia.org/wiki/File:HI-Virion.svg, CC BY 2.5, edited

gp120 and gp41

Viral surface proteins

Atropos235, HI-Virion, https://commons.wikimedia.org/wiki/File:HI-Virion.svg, CC BY 2.5, edited

Atropos235, HI-Virion, https://commons.wikimedia.org/wiki/File:HI-Virion.svg, CC BY 2.5, edited

• C-C chemokine receptor type 5

• Integral membrane protein

• Protein on the surface of T cells,

• Provide a method of entry for HIV into cells

• Gp120 binds to CCR5 or

• Gp41 subunit spans the

• If the gp120 molecule binds

• CCR5 is essential for the

Integrase inhibitors Gp120 Binders

Anubhav Mishra, anmishra013@gmail.com

• Estimated cost: $25,000 per year

Anubhav Mishra, anmishra013@gmail.com

• CCR5: transmembrane chemokine receptor

• If HIV particle uses CXCR4 receptor, these

Anubhav Mishra, anmishra013@gmail.com

Side effects of maraviroc

• Allergic reactions (this may precede hepatotoxic

Anubhav Mishra, anmishra013@gmail.com

• Drug trials finish in 2022

• Targets a highly conserved protein

• Resistance should be low

• Fostemsavir is a prodrug of temsavir

• Approved in 2019 for multidrug-resistant HIV

• Monoclonal antibody (humanized)

• Binds to CD4 receptor on the surface of the

• Administered by professionals every 14 days

Anubhav Mishra, anmishra013@gmail.com

Integrase inhibitors Non-nucleoside 1st generation

Anubhav Mishra, anmishra013@gmail.com

Go to https://www.nih.gov/ for the most recent regimens.

Anubhav Mishra, anmishra013@gmail.com

• Mostly anti-metabolic drugs

• Use 3 or more drugs from different drug

• HAART: highly active anti-retroviral therapy

• Shown to reduce or reverse the decrease

• Shown to reduce morbidity and mortality

Anubhav Mishra, anmishra013@gmail.com

• Viral reverse transcriptase is different from

• -hydroxyl group on the ribose

• NsRTIs are converted by host cell kinases to

• All NsRTIs may cause lactic acidosis and severe

Anubhav Mishra, anmishra013@gmail.com

Abacavir (ABC) (guanosine analogue):

• Good oral availability

• Resistance unlikely; requires several point