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Pharmacology > Lecture 14 - Antivirals > Flashcards

Lecture 14 - Antivirals Flashcards

1
Q

Describe the background of virus biology

A
  • Obligate intracellular parasites
  • No cell wall or plasmamembrane
  • No metabolism - so tough to target
  • Few drugs block reproduction selectively
  • Pharmacology focused on late symptoms
  • Few virus groups can be effectively treated with drugs
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2
Q

Describe cytopathic effects of virus

A
  • Host cell metabolism hijacked
  • Viral-induced suppression of host homeostasis
  • Viral proteins induce lysis or apoptosis
  • Viral proteins trigger host immune response
  • Inflammatory rxn kills host
  • All above involve lytic cycle - generation of new virus
  • Virus can become latent - host cell survives
  • No overt immune response
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3
Q

Describe virus groups that are available for treatment

A
  • Herpes/Varicella zoster/Cytomegalovirus (CMV)
  • HIV-1 and HIV-2
  • Respiratory infection - influenza A/B
  • Hepatic - hepatitis A-E (B and C most common - HBV and HCV)
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4
Q

Describe Herpes simplex virus (HSV)

A
  • Neurotropic
  • Complex dsDNA viruses - at least 8 members
  • HSV-1 (cold sores), HSV - 2 (genital herpes)
  • Chicken pox (Varicella zoster - VZV), shingles, cytomegalovirus (CMV)
  • Close contact transmission
  • Latent infection
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5
Q

Describe HSV - life cycle

A
  • Lytic cycle in epithelial cells; 80 genes in cascade
  • Viral progeny spread to sensory neurons
  • Retrogradely transported to cell body
  • Latent - circular episcopal DNA (nucleosome)
  • No immune signature
  • No cytotoxic effect
  • Stress-related reactivation
  • Anterograde transport
  • Shingles - Varicella zoster rash and pain (neuralgia)
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6
Q

Describe HSV - replication

A
  • Viral DNA enters nucleus and circularizes
  • Immediate early genes - use host RNA pol (2-4 hour post infection)
  • Host transcription factors
  • VP16 viral activator
  • Binds host cell factor that activates OCT1 (host)
  • IEG trigger early genes
  • E proteins control viral DNA replication
  • DNA replication initiates alte genes - viral structure and assembly
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7
Q

Describe HSV - acyclovir (Zovirax)

A
  • Synthetic nucleoside analog
  • Viral thymidine kinase converts to acyclovir-GMP
  • Acyclo-GTP inhibitor of viral DNA polymerase (x100 over host)
  • Viral DNA chain termination
  • Treatment for genital herpes, shingles, cold sores and chicken pox
  • Oral or intravenous
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8
Q

Other HSV drugs include?

A

Famciclovir: a prodrug of 6-deoxypenciclovir - 1st pass metabolism convert to penciclovir. Active against HSV-1, HSV-2 and VZC. Oral or topical

Penciclovir: guanosine analogue; topical formulation

Docasonal: inhibitor of fusion of HSV-1 virus with host cell. Topical formulation.

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9
Q

Describe CMV

A
  • CMV a major problem in immune-compromised patients (organ transplantation)
  • Can lead to liver failure, colitis and retinitis (inflammation of retina)
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10
Q

Describe the drugs to treat CMV

A

Ganciclovir: analog of acyclovir; x20-100 more effective against CMV; targets virus specific protein kinase phosphor-transferase UL97. Intravenous

Valganciclovir: prodrug of ganciclovir. Oral administration

Foscarnet: reversible inhibitor of viral DNA/RNA polymerases; CMV infection and resistant HSV; range of side effects (intravenous only)

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11
Q

Describe Human Immunodeficiency Virus (HIV) facts

A
  • Lentivirus (HIV-1 and HIV-2)
  • Retrovirus family - +ssRNA virus
  • Fast replication cycle and multiple infection
  • Reverse transcriptase - error prone - drug resistance
  • Latent ability (hides out in cells, gets expressed later) - viral integrase enzyme
  • Acquired immune deficiency (AIDs)
  • Blood/fluid transfer
  • Pandemic
  • 25 million killed
  • 0.6% infected
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12
Q

Describe how HIV works

A
  • Invades helper T cells (CD4 +)
  • Also macrophages and dendritic cells
  • Targets CD4 receptors and chemokine co-receptors (CCR5 and CCR4)
  • Loss of CD4+ cells
  • Cell-mediated immunity lost
  • 90% progress to AIDs within 10-15 years
  • Drug therapy raised survival 3 to 5-fold
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13
Q

Origin of HIV:
“USA first” model
Probability = ?

A

0.01%

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14
Q

Origin of HIV:
“Haiti first” model
Probability = ?

A

99.8%

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15
Q

Treatment options for HIV

A
  • No cure
  • Post-exposure prophylaxis
  • Highly active anti-retroviral therapy (HAART)
  • 3 drugs belonging to at least 2 classes
  • Newer integrase and entry inhibitors can now be added
  • Aggressive treatment in children
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16
Q

NRTI

A

Nucleoside/nucleotide reverse transcriptase inhibitors

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17
Q

Describe NRTIs

A
  • Analogs of native ribosomes - lack 3’ hydroxyl
  • Phosphorylated to triphosphate by host enzymes
  • Incorporated in viral DNA
  • Lack of 3’-hydroxyl leads to DNA chain termination
  • Drug affinity > HIV reverse transcriptase
  • Toxicity due to inhibition of mitochondrial (mt) DNA polymerase
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18
Q

Describe the NRTI - Zidovudine (AZT)

A
  • First drug approved
  • FDA-approved March 20th 1987
  • Twice daily 300 mg as part of HAART
  • GSK patent expired 2005
  • Pyrimidine analog
  • Converted to triphosphate by cellular enzymes
  • Oral delivery; good penetration across BBB
  • T1/2 3 hour
  • Toxic to bone marrow (mitochondria do not have full copies of their own DNA - leads to many problems and damage of cells, specifically bone marrow)
  • Inhibits DNA pol-gamma in mitochondria
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19
Q

Describe the NRTI - Abacavir

A
  • guanosine analogue
  • unaffected by food
  • t1/2 = 1.5 hours
  • not to be taken with alcohol
  • resistance develops slowly
  • hypersensitivity reactions can be severe
  • higher risk of myocardial infarction
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20
Q

Describe the NRTI - Lamivudine

A
  • cytosine analogue
  • good bioavailability
  • unaffected by food
  • t1/2 = 2.5 hours
  • recommended in pregnant women
  • inhibits RT in HIV and HBV
  • does not inhibit mtDNA or bone marrow
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21
Q

Describe the NRTI - Emtricitabine

A
  • fluor-derivative of lamivudine
  • inhibits RT in HIV and HBV
  • long intracellular half-life of 39 hour makes once a day treatment feasible
  • good bioavailability and unaffected by food
  • oral formulation contraindicated in young children, pregnant women and renal hepatic failure
22
Q

Describe the NRTI - Tenofovir

A
  • acyclic analogue of adenosine
  • long half-life allows once a day dosing
  • GI complaints and renal dysfunction contraindicated
23
Q

NNRTI

A

Non-Nucleoside/nucleotide reverse transcriptase inhibitors

24
Q

Describe NNRTIs

A
  • non-competitive inhibitors of HIV-1 reverse transcriptase
  • no activation required
  • no effect on bone marrow or mitochondrial DNA polymerase
25
Q

Describe the NNRTI - Efavirenz

A
  • once daily treatment on an empty stomach
  • metabolized by CYP3A4 and CYP2B6.
  • CNS side effects
  • Some severe (ex. psychosis, skin rash, avoid in pregnant women, induces CYP3A4)
26
Q

Describe the NNRTI - Nevirapine

A
  • good oral bioavailability
  • not food dependent
  • metabolized by CYP3A isoforms
  • Recommended in pregnant women
  • Severe rash can occur
  • Liver toxicity
  • Can induce CYP3A system
27
Q

HIV protease inhibitors

A
  • introduced 1995
  • reversible inhibitors of HIV aspartyl protease
  • prevents proteolysis of viral polyprotein
  • 1000 fold higher affinity for HIV protease
  • prevents maturation of viral particles
  • non-infectious virus produced
  • used in HAART
28
Q

Pharmacokinetics of HIV protease inhibitors

A
  • poor oral bioavailability
  • substrates for CYP3A4 isozyme of cyt P450
  • substrates for P-glycoprotein multi drug efflux pump in endothelial cells of brain - restricts access to CNS
  • bind to plasma proteins - alpha 1 acid - glycoprotein
29
Q

Adverse effects of HIV protease inhibitors

A
  • parasthesia, nausea, vomiting, diarrhea
  • Diabetes phenotype
  • Fat redistribution
30
Q

Resistance of HIV protease inhibitors

A

Mutations of HIV protease gene

31
Q

Major toxicities and concerns with the HIV protease inhibitor - Lopinavir

A

GI adverse effects are the most common

32
Q

Major toxicities and concerns with the HIV protease inhibitor
- Ritonavir

A

Diarrhea, nausea, taste perversion, vomiting, anemia, increased hepatic enzymes, increased triglycerides

Requires refrigeration; take with meals; chocolate milk improves the taste

33
Q

What drug classes should not be administer with any protease inhibitor

A

Antiarrhythmics, ergot derivatives, antimycobacterial drugs, benzodiazepines, barbiturates, anticoagulants, herbal supplements

**linked to inhibition of CYP isozymes

34
Q

Describe HIV integrase inhibitors - mechanism of action

A

Integrase binds to viral DNA & catalytically processes 3’ ends.

Integrase joins viral and cellular DNA.

Raltegravir blocks strand transfer.

Degradation or recombination and repair.

35
Q

Describe the HIV integrase strand transfer inhibitor - Dolutegravir

A
  • metabolized by UGT1A1 and CYP3A
  • inhibits renal transporter OCT2 and so contraindicated with dofetilide and metformin
  • rash and hypersensitivity can occur
36
Q

Describe the HIV integrase strand transfer inhibitor - Elvitegravir

A
  • requires boosting

ex. cobicistat (inhibitor of CYP3A4)

37
Q

Describe the HIV integrase strand transfer inhibitor -

Raltegravir

A
  • metabolized by UGT1A1
  • Does not interact with Cyt p450 system
  • Antacids should be used with caution
  • Severe hypersensitivity and rash can occur
38
Q

Describe viral fusion inhibitor

A
  • new class
  • Enfuvirtide
  • HIV protein gp41 mediates cell fusion
  • 36 amino acid peptide binds to gp41
  • given subcutaneously
  • expensive - 25,000 p.a.
  • salvage therapy - for multi drug resistant HIV
39
Q

Describe the co-receptor inhibitor: Maraviroc

A
  • specifically binds to host CCR5 (V3 loop) - thus only effective against HIV-1 tropic for CCR5.
  • contraindicated in renal impairment
  • caution required with hepatic problems
  • substrate for CYP3A4
  • resistance linked to mutations in gp120 protein
40
Q

Describe the influenza virus

A
  • Flu A and B most common
  • Flu A carried in aquatic birds - domestic birds
  • Flu A most severe
  • No RNA proof-reading - drug resistance
  • Spanish flu (type A) pandemic 1918-1919 - 40-100 million died
41
Q

Describe the key proteins of the influenza virus

A
  • (-)ssRNA virus
  • aerosol passage
  • attack epithelial cells
  • Hemagglutinin (Hag) binds to silica acid sugars on cells
  • Neuraminidase cleaves sailic residues to release virus
  • M2 ion channel - proton channel that modulates pH
42
Q

Influenza virus life cycle

A
  • Hag binds to cell surface
  • Mediates endocytosis of particle
  • M2 regulates uncoating
  • M2 also controls Hag processing
  • Release of particles from buds requires neuraminidase
43
Q

Describe neuraminidase inhibitors

A
  • viral neuraminidase - glycoside hydrolase enzyme
  • cleave glycosidic linkages on neuraminic (sailic) acid
  • permits release of viral particle from host cell
  • Zanamivir (inhale); Oseltamivir (oral) - effective prophylaxis and against spread of infection in flu A and B
  • Problem - needs to be taken within 6-12 hours**
44
Q

List 2 inhibitors of viral uncoating

A

Amantadine

Rimantadine

45
Q

Describe Amantadine and Rimantadine (inhibitors of viral uncoating)

A
  • Block M2 channel
  • Prevent acidification of viral particle
  • Stop release of viral genome and uncoating
  • Early therapy effective against influenza A
46
Q

Describe Hepatitis B Virus (HBV)

A
  • most common form (of hepatitis?)
  • hepatitis, cirrhosis, carcinoma
  • dsDNA virus (but uses reverse transcriptase)
  • blood-blood transfer
  • 2 billion people infected (type B)
  • acute liver damage
  • vaccination possible
  • persistent infection - cccDNA (covalently closed circular)
47
Q

Describe hepatitis C virus

A
  • (-)ssRNA virus
  • Difficult to detect symptoms
  • blood-blood transmission
  • 200 million infected
  • treatment in patients likely to exhibit cirrhosis
48
Q

Describe interferon treatment

A
  • chronic infection only
  • interferon alpha 2a/2b
  • raises cell resistance - antiviral state
  • innate induction of interferon by high levels of dsRNA or foreign RNA
  • elevates MHC1 - presentation to cytotoxic CD8 T cells
  • Increases p53 - apoptosis
  • Subcutaneous injection: 4-6 months
49
Q

Describe anti-HBV drugs

A
  • use of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
  • DNA chain termination
  • Lamivudine
  • Tenofovir
  • Combined with interferon
50
Q

Ribavirin is an anti-HCV drug

A
  • guanosine analogue
  • inhibits capping of viral mRNA and viral RNA-dependent RNA polymerase - also inhibits influenza/HIV-1
  • hemolytic anemia and range of other side effects
  • contraindicated in pregnancy, kidney disease and vascular disease

*Standard therapy now ribavirin plus peg interferon alfa

51
Q

Describe the protease inhibitors that work as anti-HCV drugs

A
  • inhibit NS3/4A protease that cleavers HCV-encoded poly-proteins
  • numerous side effects and drug: drug interactions
  • CYP3A interactions
  • Contraindicated with statins and rifampin

ex. Boceprevir - combined with ribavirin and peginterferon
ex. Telaprevir
ex. Sofosbuvir - inhibits HCV NS5B RNA-dependent RNA polymerase
- combined with ribavirin and peg interferon alfa
- very expensive

52
Q

____ and ____ use reverse transcriptase (RT)

A

HIV

HBV

Pharmacology (21 decks)

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