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Pharmacology > Antivirals and Antiretrovirals > Flashcards

Antivirals and Antiretrovirals Flashcards

1
Q

Antivirals for treating HSV 1 and 2 and Varicella Zoster Virus

A 
Systemic
• Acyclovir - comes topically 
• Valacyclovir
• Famciclovir
Topical
• Penciclovir; Docosanol
• Trifluridine
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2
Q

Antivirals for treating CMV in immunosuppressant or transplant patients

A 
Ganciclovir 
Valganciclovir
Foscarnet
Cidofovir
Letermovir
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3
Q

Acyclovir

A

Oral, IV, topical - low bioavailability with wide distribution

If therapy is initiated during prodromal phase then healing time may be shortened

Causes inhitibition of Viral Thymidine Kinase - eventual stopping of viral DNA synthesis and chain termination

For Rx Hsv1/2, VZV requires higher dose because acyclovir is less potent against Vericella

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4
Q

What are the resistance mechanisms drugs have against antivirals for HSV and VZV?

A

mutations in viral thymidine kinase or viral DNA polymerase, absent or def. viral thymidine kinase or altered substrate specificty

There is low degree of resistance to Acyclovir / Valcyclovir; but resistant virus are cross-resistant to penciclovir

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5
Q

Valacyclovir

A

Oral prodrug - hydrolysis to acyiclivr bioavil 55% with wide distribution

therapy can shorten healing time of HSV or VZV infections

Inhibits Viral thymidine kinase -> inhibition of viral synthesis and chain termination

HSV-1, HSV-2, VZV - provides higher systemic levels of drug than acyclovir

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6
Q

Famciclovir

A

Oral prodrug or Penciclovir bioavailability ~75%

Initiate during prodromal stage ⇒ may shorten healing time, duration of pain, and period of viral shedding

Inhibits viral thymidine kinase - inhibits viral DNA synthesis and inserts self into DNA causing chain termination

RX – HSV-1, HSV-2, VZV, EBV, HBV

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7
Q

Acyclovir, Valacyclovir, Famciclovir Adverse Effects

A

In the Rx of HSV, VZV, CMV the drugs can cause adverse effect with high IV or oral doses — normally safe and well tolerated

cystalline nephropathy

CNS - delirium, seizures, tremors, EPS, myoclonus

thrombocytopenia

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8
Q

Topical Rx for HSV infection

A

frequent application

Acyclovir, penciclovir and docossanol all come in topical cream version

Trifluidine is for ophthalmic solutions in Rx of Primary keratoconjunctivitis and Recurrent epithelial keratitis

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9
Q

Ganciclovir

A

Valganciclovir is prodrug

deoxy-guanosine analog

Active against all herpes viruses but especially effective against CMV

preferrentially inhibits viral dna polymerases

uses - CMV retinitis, acute herpetic keritiits

valgan - oral for CMV retinitis and propholaxis of CMV infection

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10
Q

Ganciclovir / Valganciclovir - Toxicities and Contraindications

A

Toxicities include myelosuppression, (dose-limiting: Neutropenia, thrombocytopenia), Gi effects and CNS effects

Contraindication - teratogenic, embryotoxic, inhibits spermatogensis

Blocks renal tubular secretion

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11
Q

Foscarnet

A

pyrophosphate analog

given IV, treatment of CMV retinitis

Reversible noncompetitive block of pyrophosphate binding site of viral polymerase

AEs – nephrotoxicity is the major dose-limiting effect, hypocalcemia

mutatgenic so caution with pregnancy

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12
Q

Cidofovir

A

Cytidine Analog -

  1. Inhibits viral DNA synthesis,
  2. Incorporation into DNA causes chain termination

cross-resistance with ganciclovir

THERAPEUTIC USE – IV, Treatment of CMV retinitis

Cautions - can cause proximal tubule injury leading to metabolic acidosis – administer with probenecid and saline

probenecid inhibits OAT which slows the tubular secretion of the drug

embryotoxic, mutagenic, gonadotoxic

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13
Q

Letermovir

A

CMV DNA terminase complex

Given oral and IV, low bioavialbiltiy but greatly increases w/ cyclosporine

high plasma protein binding, Substrate of P-glycoprotein, OATP1B1/1B3, glucuronidation with fecal excretion

Letermovir blocks the pUL56 in CMV DNA terminase complex&raquo_space;> eventual alteration in genome length

used for the prophylaxis of CMV infection and disease, given to adult seropositive recipents of allogeneic bone marrow transplant

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14
Q

Letermovir - Drug Interactions and Adverse Effects

A

CYP3A4, P-gp, OATP inhibitor
CYP2C9, 2C19 inducer

CONTRAINDICATED drug
combinations
• pimozide
• ergot alkaloids
• simvastatin
• pitavistatin

Nausea, vomiting, diarrhea, abdominal pain, headache, fatigue, peripheral edema, tachycardia, decrease platelet count and hemoglogin

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15
Q

Standard of care for HIV infection

A

2 NRTIs + an INSTI, or an NNRTI, or a boosted PI

Outcome of initial therapy - undetectable viral load and a CD4 count increase of 50-150 cells in he first year

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16
Q

Name some general adverse effects on antiretroviral therapy?

A

Immune reconstitution inflammatory syndrome

lipodystrophy syndrome

drug interaction - with inhibitors or inducers of metabolic enzymes

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17
Q

What are the NRTI’s - Nucleoside/tide Reverse Transcriptase Inhibitors

A

activity against HIV-1 and HIV-2, some have activity against HBV

zidovudine (ZDV)*
stavudine (d4T)
zalcitabine (ddC)
lamivudine (3TC)*
emtricitabine (FTC)*
abacavir (ABC)*
didanosine (ddi) 
tenofovir (TFV)*
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18
Q

Viral Resistance to NRTIs - single amino acid substitution: M184V/I

A

lamivudine and emtricitabine

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19
Q

Mitochondrial Toxicity - antivirals

A

NRTIs - Zalcitabine, didanosine, stavudine, zidovudine

associated with DNA polymerase-γ inhibition

common effects - myopathy, lipoatrophy, hepatic steatosis and lactic acidosis

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20
Q

antiviral therapy should be discontinued when which mitochondrial toxic effects occur?

A

(NRTIs)

inc ALT/AST, progressive hepatomegaly, metabolic acidosis with unknown origin, peripheral neuropathy or pancreatitis

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21
Q

NRTI Drug Interactions

A

Renal OAT inhibition - causes decreased renal clearance of one or both drugs
-effects probenecid, acyclovor, other anti-herpes drugs, and anti-HBV drugs

mechanisms of DI’s through competition at active site and additive toxicities

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22
Q

why is zidovudine + stavudine a bad combination for antiviral drugs

A

they are both thymidine analogs which have antagonistic effects

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23
Q

why are the antiviral drugs Didanosine + Stavudine a bad combination?

A

fatal lactic acidosis

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24
Q

Didanosine + Zalcitabine = bad effects, why?

A

Additive peripheral neuropathy

25
Q

Didanosine + Tenofovir — why are these drugs contraindicated?

A

They are both adenosine analogs that compete at the site of function and lead to virologic failure

26
Q

Lamivudine + Zalcitadine = bad effects, why?

A

They are both cytidine analogs and are antagonist to each others efficacy - inhibit the intracellular phosphrylation of one another

27
Q

Lamivudine + Emtricitabine —- contraindicated together for what reason?

A

they are analogs leading to enhanced toxicity

28
Q

Zidovudine

A

NRTIs - Alternative agent for antiretroviral therapy - thymidine analog

HIV-1, HIV-2, and human T-cell lymphotrophic viruses (HTLV) I and II

Used IV for prevention of mother-to-child HIV transmission

exhibits mitochondrial toxicity

29
Q

Lamivudine

A

NRTI - cytidine analog in antiretroviral: at a higher dose once daily dosing and lower doses twice daily dosing.

Used for HIV-1, HIV-2, HBV

Rebound HBV infection can happen in patients if lamivudine is d/c and replaced with a drug not also effective against HBV

30
Q

Emtricitabine

A

NRTI - cytidine analog. Fluorinated version of lamivudine. Antiretroviral Rx

daily dose

used for HIV1, HIV2, HBV- supresses not approved for treatment of HBV
-rebound HBV infection when d/c

hyperpigmentation of palms or soles

31
Q

Abacavir

A

antiretroviral treatment, NRTI- guanosine analog, used for both HIV-1 and HIV-2

Associated with a gene - HLA-B 5701 that causes hypersensitivity syndrome

metabolized by alcohol dehydrogenase - alcohol increases abacavir levels

32
Q

Tenofovir

A

antiretroviral - NRTI, adenosine analog

used for HIV1 and HIV2, HBV

rebound HBV

fanconi syndrome and decreased bone marrow density

33
Q

NNRTI’s - Non-nucleoside Reverse Transcriptase Inhibitors

A

highly effective HIV infection when used with 2 NRTIs

They bind to allosteric site on reverse transcriptase

Efavirenz*
Nevirapine* 
Etraverine* 
Rilpivirine*
Delavirdine
34
Q

Viral Resistance to NNRTIs

A

Efavirenz, nevirapine, delavirdine, and rilpivirine

Resistance is seen to these drugs with a single point mutation in the HIV virus

Nervirapine can induce resistance with just a single dose

cross-resistance is seen K103N and Y181C

Etravirine - 2 mutation, cross resistance with rilpivirine

35
Q

NNRTI Class Toxicities

A

antiretroviral drugs NNRTI toxicities are

rashes - usually in the first 4 weeks of treatment, usually mild and self-limited with rare SJS/TEN

long term use causes fat redistribution

Nevirapine - fatal hepatitis

NNRTI’s have high potential for drug interactions

36
Q

Efavirenz

A

Antiretroviral, alternate with 2 NRTIs

tolerable and potent

displays CNS symptoms - impaired concentration, dysphoria, vivid or disturbing dreams, insomnia and psychosis

1teratogenic - causes neural tube and CNS defects

Efravirenz is a inducer of CYP2B6 and CYP3A4 and inhbitor of CYP2C9/19

37
Q

Nevirapine

A

NNRTI, antiretroviral, used for initial therapy in HIV, salvage therapy and in neonates

adverse effect is hepatitis, considered safe during pregnancy
-risk factor is pregnant women with CD4 counts greater than 250 cells

Nevirapine is autometabolic inducer at CYP3A4, also induces CYP2B6

38
Q

Rilpivirine

A

NNRTI, antiretroviral

HIV treatment in naive adults (ones who have not been treated yet)

virologic failure is common in patients with a high baseline plasma viral load

adverse effects - CNS effects, QT interval prolongation

no evidence of fetal harm in animal studies

substrate of CYP3A4

39
Q

Etravirine

A

NNRTI, antiretroviral

Treatment in experienced HIV infected adults only

no evidence of harm during pregnancy

can be used in pediatric patients

Etravirine - inducer of CYP3A4 and UGTs (maraviroc dose should be doubled in concurrent therapy) and inhibitors of CYP2C9/19

40
Q

NNRTI Drug Interactions

A

Efavirens/Nevirapine cannot be used with Tenofovir and Didanosine

Efravirenz is a inducer of CYP2B6 and CYP3A4 and inhbitor of CYP2C9/19

Nevirapine is autometabolic inducer at CYP3A4, also induces CYP2B6

Etravirine - inducer of CYP3A4 and UGTs (maraviroc dose should be doubled in concurrent therapy) and inhibitors of CYP2C9/19

Rilpivirine is a substrate of CYP3A4

41
Q

HIV Protease Inhibitors

A

Activity against HIV-1 and HIV-2

subtrates of P-glycoprotein, cleared by CYP3A4

Fosamprenavir

Lopinavir-Ritonavir

Atazanavir

Darunavir

Prevent proteolytic cleavage of HIV gag and pol proteins

42
Q

what is the purpose of ritonavir and cobicistat with protease inhibitors?

A

potent CYP3A4 / P-glycoprotein inhibitors

↑concentrations, ↑duration of action and improve virologic activity of the protease inhibitor

all PI’s are given with these except Nelfinavir

43
Q

What are the mechanisms of resistance against PI’s?

A

acculmulation of at least 4 or 5 codon substitutions

primary mutations in enzymatic active site causes a 3 to 5x decreased sensitivity

Cross-resistance to other PIs due to 2° mutations

44
Q

Effects Protease Inhibitors on HIV

A

Favorable long-term suppression of viremia

↑ CD4 lymphocyte counts

Reduce disease progression

Improve long-term survival

must be balanced against short- and long-term toxicities, including the risk of insulin resistance and lipodystrophy

45
Q

HIV PIs Class Toxicities

A

Nausea, vomiting, diarrhea

Cushingoid appearance, e.g. central obesity, buffalo hump, Triglyceride and LDL increased levels, and hyperglycemia

skin rashes, SJS, TEN

Peripheral neuropathy, myalgia

Cardiac conduction abnormalities

46
Q

Protease Inhibitor Drug Interactions

A

CYP3A4 inhibition → drugs with narrow TI, increase statin levels and muscle toxicity, increase digitoxin, decreased oral contraceptive efficacy and decreases methadone levels

47
Q

Ritonavir

A 
Pharmacokinetic enhancer (low doses)
(antiretroviral effects at higher doses)
• dose-dependent GI toxicities
• Paresthesias, metabolic toxicities

adverse effects - paresthesia, asthenia, hepatitis, PR interval prolongation

48
Q

Fosamprenavir

A

Prodrug, protease inhibitor

dephosphorylated to amprenavir in the intestinal mucosa, better tolerated than amprenavir

GI effects common

fatigue, depression, rash

49
Q

Lopinavir/r

A

protease inhibitor

adverse effects - GI and metabolic effects are common, cardiotoxicity, lactic acidosis, CNS depression, respiratory complications, acute renal failure and death

toxic to neonates

50
Q

Atazanavir

A

protease inhibitor, formulated with cobicstat

Lowest pill burden of PIs (once daily)

Can cause unconjugated bilirubinemia through UGT inhibition

Also causes pancreatitis, asthenia, increase in transaminases, PR or QT prolongation

interacts with tenofovir increases the levels, and PPIs and H2 inhibitors

51
Q

Darunavir

A

protease inhibitor, formulated with cobicstat

Use: Treatment-naïve and treatment-experienced patients

has sulfonamide moiety - rash in up to 10% of patients

Causes hepatitis and elevations in serum transaminases

52
Q

HIV Integrase Strand Transfer Inhibitors

A

Raltegravir
Elvitegravir / cobicistat
Dolutegravir
Bictegravir

Activity against HIV-1 and HIV-2

block HIV-encoded integrase prevents integration of virus DNA into the host chromosome

53
Q

Raltegravir

A

used in treatment-naive and experienced patients, safe in children

Metabolized UGT1A1 and excreted in the feces and urine, taken orally

Resistance is through integrase gene mutations

well tolerated but adverse effects possible are myopathy and hypersensitivity reactions

54
Q

Entry Inhibitors

A

Enfuvirtide
Maraviroc
Ibalizumab-uiyk

55
Q

Enfuvirtide - MOA and Uses

A

Entry Inhibitors - Synthetic peptide, binds to a hydrophobic groove of the gp41 subunit

SubQ; Metabolized by proteolytic hydrolysis

Treatment-experienced: Adults and children ≥ 6 years old, not effective as monotherapy - needs to be given with 2 other antiretroviral drugs

56
Q

Enfuvirtide - Adverse Effects and Resistance

A

Injection site reactions; Hypersensitivity reactions, and Pneumonia

resistance - mutations in the codon which binds domain gp41, increased with more changes

57
Q

Maraviroc

A

HIV Entry Inhibitor

oral, variable bioavailability, CYP3A4, fecal and urine excretion

Mechanism: Maraviroc blocks gp120 to CCR5 receptor

resistance through changing tropism to CXCR4

Used for CCR5 HIV virus infected patients older than 16, in combination with other agents

Prior to therapy, tropism testing should be performed

58
Q

Maraviroc Cautions

A 
Adverse effects:
• Dizziness; depression; paresthesias
• Hepatotoxicity with allergic features
• Hypersensitivity reaction
• Orthostatic hypotension
• Bacterial respiratory infection / Herpes

Drug interactions:
• Strong CYP3A4 inducers and inhibitors

59
Q

Ibalizumab-uiyk

A

HIV Entry Inhibitor

IV every 14 days, blocks CD4 2nd extracellular domain away from MHC2

prevents HIV attachment and entrance

preserves normal immune function

Used for therapeutic experienced patients

Pharmacology (23 decks)

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