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Pharmacology > Anti-viralAgents →↑↓ > Flashcards

Anti-viralAgents →↑↓ Flashcards

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1
Q

**Life cycle of Virus

A

Viruses Hijack Our Cells

Viruses are intracellular parasites

Live and replicate inside other living cells

Depends on the synthetic processes of the host cells

Different virus have different host cells

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2
Q

Influenza Viruses
HSV
HIV virus

A

Influenza virus
Hemagglutinin HA
Neuraminidase NA

HA promotes binding and entry
NA allows budding and release

HSV
Glycoprotein gB gC
Cell surface proteoglycans (Heparan sulfate)
Glycoproteins gD of HSV bind to TNF NGF family protein receptor
MEmbrane fusion and viral penetration

HIV
CD4 receptor binding
co-receptor binding
Conformational change in gp120 Gp41 can initiate fusion

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3
Q

Replication of genetic materials& integration to the host genome

A

DNAvirus→enter cell as viral RNA → Viral DNA → integrated viral DNA between target site duplication

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4
Q

Budding

A

Release
Budding out (host cells intact
lysis of host cell

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5
Q

Types of Herpes Virus Infections-life long infection

A

Cytomegalovirus Disease and Retinitis
caused by
cytomegalovirus

Genital herpes infection
caused by herpes simplex virus

Herpes zoster
caused by varicella-zoster virus

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6
Q

Herpes zoster infection

A

caused by varicella-zoster virus

Highlycontagious

Most children are infected by early age

First exposure: Chickenpox

Latent infections: nerve cells(dorsal ganglion)

Reactivation: Shingles

Vaccine is available (MMRV)

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7
Q

Drugs for Herpes Virus Infection (Nucleoside analogs)

A

Inhibiting DNA/RNA Synthesis

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8
Q

Mechanism, Route of Acyclovir

A

is a guanine analog

Mechanism of actions:

  1. Competitive substrate for DNA polymerase.
  2. Leads to chain termination

Acyclovir has to be activated by thymidine kinase (only in infected cell) to form acyclovir triphosphate.

Intravenous (IV) preparation
Used for treatment of serious infections.

Oral preparation –Effective in treating primary infections. Less effective in treating recurrences.

Topical preparation –Keep an outbreak contained to a small area. (Treatment for cold sore on mouth)

Long term prophylaxis –Decreases the frequency of recurrences of genital herpes. (can be re-activated by strong sunlight, stress….etc.)

Toxicity: (oral) GI distress, headache.

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9
Q

Acyclovir and its derivatives

A 
Valacyclovir
Famciclovir
Canciclovir
Valganiclovir
Trifluridine
Idoxuridine
Vidarabine
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10
Q

Drugs for Herpes virus infections (Inhibiting viral entry)

A

Docosanol

Prevents vira lentry, inhibits fusion between HSV envelop and plasma membranes.

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11
Q

Structure and classification Influenza (Flu)

A

Caused by enveloped RNA viruses.

  1. Influenza A
  2. Influenza B
  3. Influenza C

Classified based on NP, M1 and M2 proteins

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12
Q

Nomenclature of Influenza A

A

Divided into 18 H (H1-H18) and 11 N (N1-N11) subtypes.
Potentially 198 different subtypes of influenza A viruses.

Only viruses of the H1N1, H1N2, H3N2, H5N1, H7N3, H7N7, H9N2 have expanded their host to humans.

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13
Q

Reason Emergence of new strains

A

Natural Reservoir –large variety of species (chickens, birds, ducks, pigs and humans).

Animal to human transmission.

Re-assortment of the segmented genome of 2 parent viruses.

Mutation occurs at high rate (especially on the surface glycoproteins).

New variant is able to escape the host defense (vaccinated or not vaccinated).

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14
Q

Influenza B and C

A

Influenza B

Not divided into subtypes.

Type B flu is found only in humans and seals.

This limited host limits the generation of new strains by re-assortment.

Mutate at a rate 2 to 3 times lower than A viruses.

Do not cause pandemics.

Influenza C

Found in humans

People generally do not become very ill from the influenza type C viruses

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15
Q

Transmission and symptoms of Influenza

A

Nasal secretions

Aerosols containing the virus

Direct contact with bird droppings

Contact with contaminated surfaces

Usually recover in 2-7 days

Causes serious respiratory illness (hospitalization and death) in weak/frail or elderly people

Flu can be distinguished by a high fever with a sudden onset and extreme fatigue (usually more severe)

Antiviral drugs are effective in treating influenza
Only if given at early stage of infection

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16
Q

Mechanism of Entry of Influenza cells

A

Hemagglutinin (HA) –involved in the binding of the virus to host cell receptors

Neuraminidase–concerned with release of progeny virions from the cell surface.

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17
Q

Drugs for Influenza Virus Infection (Amantadine / Rimantadine)

A

Amantadine / Rimantadine
Prevention or treatment of influenza A infection only
Should be given within 48 hrs after contact.

  1. Block pore formation by M2 proteins of influenza A only
  2. Prevents H+ions from entering the virus.
  3. Prevents acidification of the virus core, which is required to active viral RNA transcriptase.

Toxic effects: GI irritation, dizziness, ataxia, slurred speech.

18
Q

Oseltamivir(Tamiflu) / Zanamivir

A

Effective for influenza A or B infection

Resistance are increasing

More effective if used within 24 hrs(Five-day therapy)

MoA

  1. Binds to Influenza neuraminidase
  2. Prevents the cleavage of sialic acid residues
  3. Inability to release progeny virions

Prevent the spread of virus after it reproduces !

19
Q

Peramivir

A

First FDA-approved IV drug of influenza in Dec 2014

Neuraminidase inhibitor

Effective against both influenza A and B viruses.

Administrated intravenously

Intended to be given in a single dose.

For patients who have difficulty with inhaled or oral medicines.

Common side effects:
Diarrhea, in less than 2% of patients.

Rare side effects:
Stevens-Johnson syndrome
and erythema multiforme

20
Q

Baloxavir (Xofluza; PA endonuclease inhibitor):

A

Effective against influenza A & B virus

Administered in a single dose

Significantly shorten the duration of flu symptoms

Inhibits polymerase acidic endonuclease, thus impairs mRNA synthesis and prevents virus to reproduce

21
Q

Structure and Types and Properties of Human Immunodeficiency Virus (HIV)

A

Is a retrovirus

HIV-1 (America)
HIV-2 (Africa)

HIV Latency: Many years before causing any symptoms.

  • transmit it to others through their blood and bodily fluids
  • develop into AIDS
  • eventually weakens the immune system, that the patient may die of rare infections that would never be a problem for a healthy person

HIV virus is designed for fast evolution because it makes a lot of mutations when copying its own genome to make new virus particles (No proof read mechanism)

Thus, the viruses in an infected person’s body are constantly changing, which helps HIV become resistant both to the immune system and to the drugs that are used to treat it.

HIV infections must always be treated with a combination of drugs, so that if a virus arises that is resistant to one drug, it is most likely still susceptible to the other drugs in the treatment regimen

Combinations of drugs is the cocktail treatment
Highly active anti-retroviral therapy (HAART)

22
Q

MoA of HIV Infection

A

Mostly infectsCD4+cells (alsocalled T-lymphocytes).

Destruction of CD4+cells impairs the immune system resulting in an increase risk of opportunistic infections.

23
Q

Progression of HIV infection to acquired immunodeficiency syndrome(AIDS) occur in four phases:

A

Influenza-like symptoms
Virus undergoes rapid replication
Dramatic decline of CD4+ in viral replication
Immune system is damaged Viral production increase.

24
Q

Drug for Attachment inhibitor of HIV:

A

Rukobia (Fostemsavir)

Phosphonooxymethylprodrug of temsavir
Temsavir binds and inhibits the activity of gp120, a subunit within the HIV-1 gp160 envelope glycoprotein that facilitates the attachment of HIV-1 to host cell CD4 receptors

Side effect: May induce ALT and AST levels in patients with Hep B or C, Nausea.

25
Q

Drug of Entry/ Fusion inhibitor of HIV 1

A

Maraviroc
Attachment of HIV also involves transmembrane chemokine receptor CCR5.
Maraviroc blocks CCR5 and hence reduces viral attachment.
Adverse effects: Cough, diarrhea, muscle, joint pain

26
Q

Drug of Entry/ Fusion inhibitor 2

A

Enfuvirtide
A synthetic 36amino-acidpeptide.

Binds to the gp41 subunit of the viral envelope glycoprotein

Prevents conformational changes needed for the fusion of the membranes.

Administrated subcutaneously.

27
Q

HIV as an RNA virus

A

Once HIV infected CD4+ lymphocytes, it replicates its genetic materials by converting RNA genome into DNA using its own reverse transcriptase so that its proteins can be expressed by the cell.

Many anti-HIV drugs target this HIV specific reverse transcriptase.

28
Q

Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

A

Inhibiting DNA Synthesis

Structurally similar to natural occurring specific nucleosides/nucleotides

Act as terminators via their insertion into the growing DNA chain.

Lacks a 3’hydroxyl group on the ribose ring, attachment of the next nucleotide is impossible.

29
Q

Nucleoside analogs of HIV

A 
Zidovudine
Abacavir 
Diadanosine 
Lamivudine 
Emtricitabine
 Stavudine 
Zalcitabine
30
Q

Nucleotide analog of HIV

A

Tenofovir
Newer drug
Used for salvage therapy for multiple drug failures

31
Q

Non-nucleoside Reverse Transcriptase Inhibitors

A

Another specific class of reverse transcriptase inhibitors.

They are not competitive substrates of reverse transcriptase.

But directly binds to reverse transcriptase and changes its structure so that the active site is disrupted.

32
Q

Name of Non-nucleoside Reverse Transcriptase Inhibitors

A

Efavirenz Nevirapine

Effective in preventing HIV
vertical transmission

Given as single doses to mothers at the onset of labor and to the neonate

33
Q

MoA of Integrase Inhibitors

A

Virus must incorporate its genome into the host cell genome so the viral genetic material can be replicated.

The integration is accompanied by an HIV enzyme called integrase.

Raltegravir inhibits integrase

34
Q

Moa of Protease inhibitors

A

HIV synthesizes all of its important proteins, including reverse transcriptase, integrase …etc.

As one large polypeptide chain with multiple proteins connected together.

In order for these proteins to work and form a mature viral particle, it must first be cut apart from each other using the HIV protease (also known as aspartate protease).

No new viral particle can be generated

35
Q

Name of Protease inhibitors (PI)

A 
Lopinavir (The oldest protease inhibitors)
Atazanavir
Indinavir 
Saquinavir
Ritonavir
Nelfinavir 
Amprenavir 
Fosamprenavir D
arunavir 
Saquinavir 
Tipranavir

Ritonavir is administrated concurrently to boost the bioavailiabity of another PI

36
Q

Drawbacks of proteases inhibitors

A

Many drug-drug interactions

Disorders in carbohydrate & lipid metabolism
Insulin resistance, hyperglycemia, hyperlipidemia

Buffalo Bumps Gynecomastia

37
Q

Adverse effects of Protease inhibitors

A

GI disorders

Hepatoxicity

Increase bleeding risk in hemophiliacs

Kidney stone

38
Q

Regimen

A

2NRTIs and a protease inhibitor

2NRTIs and 1NNRTI ( most commonly efavirenz) or

3NRTIs (one should be abacavir

Therapy with a single anti-HIV medication should never be used, except with possible exception of pregnancy to reduce perinatal transmission.

39
Q

Monoclonal Antibody Ibalizumab for Multidrug-Resistant HIV-1

A

This is a new class of antiviral medication specifically for adultsliving with HIV who have tried multiple HIV medications and whose HIV has been resistant to current available therapies.

A humanized IgG4 monoclonal antibody

Binds to extracellular domain 2 of the CD4 receptors to prevent post-attachment conformational changes in the CD4-HIV envelope gp-120 complex and block viral entry into the host CD4 cell.

Blocks your body’s HIV infected cells from spreading the virus into those which are uninfected

It is administered by IV every two weeks&raquo_space; combine use with other antiviral agents

40
Q

Adverse effect of Ibalizumab

A

No reported drug–drug interactions

Most common adverse effects are diarrhea, dizziness, nausea, and rash.

41
Q

Names highlighted in summary drugs name

A

Nucleoside reverse transcriptase inhibitors NRTIs
Zidovudine

Nucleotide reverse transcriptase inhibitors
Tenofovir

Non-nucleoside reverse transcriptase inhibitors
Efavirenz

42
Q

Names highlighted in summary drugs name

A

Nucleoside reverse transcriptase inhibitors NRTIs
Zidovudine

Nucleotide reverse transcriptase inhibitors
Tenofovir

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz

Entry inhbitors
Maraviroc

Integrase inhbitiors
Raltegravir

Attachment inhibitors
Fostemsavir

Protease inhbiitors
Indinavir

Monoclonal Antibody
Ibalizumab

Pharmacology (30 decks)

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