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Pharmacology > Antiretroviral Drugs > Flashcards

Antiretroviral Drugs Flashcards

1
Q

Which of the following conditions increase urgency to initiate HAART

A
  • Pregnancy
  • AIDS-defining conditions
  • Acute opportunistic infections
  • Lower CD4 counts
  • HIV-associated nephropathy
  • Acute/early infection
  • HIV/hepatitis B or C coinfection
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2
Q

How long until HAART shows efficacy?

Predictors of virological success?

A

After initiation of HAART, viral load reduction to below limits of assay detection usually occurs within
the first 12 to 24 weeks of therapy.

Predictors of virologic success include the following:
• low baseline viremia,
• high potency of the ARV regimen,
• tolerability of the regimen,
• convenience of the regimen, and
• excellent adherence to the regimen
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3
Q

List current HIV Drug Classes?

A 
• Nucleoside/-tide Reverse Transcriptase Inhibitors
(NRTIs)
• Nonnucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
• Protease Inhibitors (PIs)
• Entry/fusion Inhibitors
• Integrase Inhibitors (INSTIs)
• Pharmacokinetic Enhancers
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4
Q

Name two Pharmacokinetic enhancers and MOA?

A

Currently two commonly used:
• Ritonavir (protease inhibitor)
• Cobicistat

MOA
• Potent inhibitors of CYP 3A4
• Increase plasma concentrations of ARV allowing for lower and/or less frequent dosing
• Improve tolerability of ARV

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5
Q

Characteristic of Ritonavir dosing regimen?

A

• Used in combination with most protease inhibitors
(not nelfinavir)
• Never used alone

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6
Q

Combinations of cobicistat?

A

• Used commonly in combination with the INSTI
elvitegravir
• Also found in combination with darunavir and
atazanavir

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7
Q

List the nucleoside/tide reverse transcriptase inhibitors(NRTIs)?

A
  • Abacavir
  • Didanosine
  • Emtricitabine
  • Lamivudine
  • Stavudine
  • Tenofovir
  • Zidovudine
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8
Q

MOA of NRTIs?

A

• Analogs of native ribosides (lack 3’OH)
• Phosphorylated by cellular enzymes and incorporated into viral DNA by reverse transcriptase
• Lack of 3’OH terminates DNA elongation
ie. they are competitive inhibitors of reverse
transcriptase
• Most have activity against HIV-2 as well as HIV-1

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9
Q

NRTIs resistance and PK?

A
  • Emerges rapidly if used alone

* Cross-resistance between agents of same analog class can occur

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10
Q

NRTIs AE?

A

• If more than one NRTI given toxicities may overlap
• AE mainly due to inhibition of mitochondrial DNA
polymerase: peripheral neuropathy, myopathy,
lipoatrophy & lactic acidosis
• Pancreatitis, myelosuppression & cardiomyopathy can
also occur
• Liver toxicity is rare but fatal (lactic acidosis,
hepatomegaly with steatosis).
• Zidovudine & stavudine may be particularly associated
with dyslipidemia & insulin resistance

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11
Q

NRTIs drug interactions?

A

• Didanosine & tenofovir
Tenofovir increases plasma didanosine levels ~60%.
Doses of didanosine have to be reduced.
• NRTIs are not generally metabolized by cytochrome
enzymes

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12
Q

Zidovudine abbreviation, analog, AE, recommendation?

A

Abbreviation: ZDV, AZT
Nucleoside Analog
Thymidine

Adverse effects
• Bone marrow suppression (neutropenia, anemia)
• GI intolerance, headaches, insomnia

  • Zidovudine is no longer recommended in current
    guidelines due to unacceptable toxicity
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13
Q

Stavudine moa, abbreviation, analog, AE, recommendation?

A

Strong inhibitor of b and g DNA polymerases (high
affinity for mitochondrial DNA polymerase, which can lead to toxicity)

Abbreviation: d4T

Nucleoside Analog
Thymidine

Adverse Effects
• Peripheral neuropathy, lactic acidosis
• Hyperlipidemia, neuromuscular weakness
* Stavudine is no longer recommended in current
guidelines due to unacceptable toxicity
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14
Q

Didanosine abbreviation, analog, AE, recommendation?

A

Abbreviation DDL

Nucleoside Analog
Adenosine

Adverse Effects
High affinity for mitochondrial DNA polymerase
• Pancreatitis (esp. alcoholics and patients with hypertriglyceridemia)
• Peripheral neuropathy, diarrhea, hepatic dysfunction, CNS effects

  • Didanosine is no longer recommended in current
    guidelines due to unacceptable toxicity
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15
Q

Tenofovir AE, analog, and recommendation?

A

One of preferred NRTIs in currently recommended
regimens

Abbreviation: TDF

Nucleotide Analog (only NRTI that is nucleoTIDE)
Adenosine

Adverse Effects
• GI (nausea, diarrhea, vomiting, flatulence)

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16
Q

Tenofovir contraindications?

A

• Serum creatinine monitored with renal insufficiency
• Only NRTI with sig. drug interactions (increases
didanosine concentrations and dosage reductions are
usually required)
• Decreases concentrations of atazanavir. Atazanavir
can be ‘boosted’ with ritonavir

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17
Q

Lamivudine Abbreviation, analog, resistance, AE, and effect?

A

DOES NOT affect mitochondrial DNA synthesis or bone marrow precursor cells

Abbreviation: 3TC

Nucleoside Analog
Cytosine

Resistance
• High level resistance occurs with single amino acid substitutions

Adverse effects
• Few significant (headache, dry mouth)

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18
Q

Emtricitabine abbreviation, structure, analog, AE, recommendation?

A

Abbreviation: FTC

Structural relative of lamivudine

One of preferred NRTIs in currently recommended
regimens

Nucleoside Analog
Cytosine

Adverse effects
• Hyperpigmentation of palms and soles (occurs most frequently in dark-skinned people)

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19
Q

Abacavir abbreviation, analog, clinical use, and resistance?

A

Abbreviation: ABC

Nucleoside Analog
Guanosine

Clinical Uses
• Contraindicated if patient has HLA-B*5701 mutation

Resistance
• HIV resistance requires several mutations and tends to develop slowly.

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20
Q

Abacavir AE?

A

Adverse Effects
• GI, headache, dizziness
• 5% - ‘hypersensitivity’ reaction (one or more of rash, GI, malaise, respiratory distress).
Contraindicated if patient has HLA-B*5701 mutation
• Sensitized individuals should NEVER be re-challenged
(can be genetically screened)

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21
Q

List 3 Non-nucleoside reverse transcriptase inhibitors(NNRTIs)

A
  • Efavirenz
  • Nevirapine
  • Rilpivirine
22
Q

NNRTIs MOA?

A

• Highly selective, noncompetitive inhibitors of HIV-1 RT
• Bind at a distinct site away from active site (NNRTI
pocket)
• All NNRTI’s bind within the same pocket
• All result in inhibition of RNA- and DNA-dependent
DNA polymerase
• DO NOT REQUIRE PHOSPHORYLATION BY
CELLULAR ENZYMES
• Lack in vitro activity against HIV-2

23
Q

Advantages and disadvantages of NNRTIs?

A

Advantages
• Lack of effect on host blood-forming elements
• Lack of cross resistance with NRTIs (binding sites are
distinct)

Disadvantages
• Cross-resistance with NNRTIs
• Drug interactions
• High incidence of hypersensitivity reactions (eg, rash)

24
Q

NNRTIs AE

A

• Skin rash (including Stevens-Johnson syndrome)
• GI intolerance
• All are CYP3A4 substrates and can act as inducers,
inhibitors or both of CYPs

25
Q

Nevirapine abbreviation, PK, AE. and Contraindications?

A

Abbreviation: NVP

Pharmacokinetics
• Excreted mainly in urine as metabolites (CYP 3A4 & CYP
2B6)

Adverse Effects
• Potential severe hepatotoxicity (don’t use in women with CD4+ counts >250 cells/mm3 & men >400 cells/mm3)
• Rash (16%), dermatologic effects (Stevens-Johnson
syndrome & toxic epidermal necrolysis)
• 14 day titration period at ½ dose is mandatory to
reduce risk of serious epidermal reactions

Contraindications
• Inducer of CYP 3A4

26
Q

Efavirenz clinical applications, AE?

A

Clinical Applications
• Not a first-line agent in current guidelines

Adverse Effects
• High rate of CNS toxicities (50%) (dizziness, headache,
vivid dreams, loss of concentration) – possible association with suicidality
• Rash (25%)
• Increased triglycerides, HDL and total cholesterol
(lipid levels must be monitored at beginning of and during therapy)

27
Q

Rilpivirine AE?

A
  • Rash
  • Insomnia, depression
  • Increased liver enzymes
28
Q

List 5 Protease inhibitors(PIs)

A
  • Atazanavir
  • Darunavir
  • Indinavir
  • Lopinavir
  • Nelfinavir
29
Q

Protease Inhibitor moa?

A

MOA
• Reversible inhibitors of HIV aspartyl protease (enzyme
responsible for cleavage of viral polyprotein into RT,
protease & integrase)
• Protease inhibition prevents virus maturation & results in
production of non-infectious virions
• DO NOT REQUIRE INTRACELLULAR ACTIVATION
• Active against both HIV-1 and HIV-2

30
Q

Protease Inhibitor PK?

A

• Poor oral bioavailability
• High-fat meals can increase (nelfinavir) or decrease
(indinavir) bioavailability
• Substrates for CYP 3A4 (most require enhancing with
a PK enhancer)
• Substrates for P-glycoprotein pump

31
Q

PI AE?

A

Adverse Effects
• Parathesias, nausea, vomiting, diarrhea
• Disturbances in lipid metabolism (diabetes,
hypertriglyceridemia, hypercholesterolemia)
• Chronic admin → fat redistribution & accumulation
resulting in central obesity, dorsocervical fat enlargement,
peripheral & facial wasting, breast enlargement and a
cushingoid appearance(buffalo hump)

32
Q

Protease Inhibitors(PIs) drug interactions and resistance?

A

Drug Interactions
• Potent inhibitors and substrates of CYP isoforms,
therefore have high potential for drug interactions.

Resistance
• Accumulation of stepwise mutations of protease gene.
Can lead to high levels of resistance.

33
Q

Atazanavir clinical application, pk, contraindications, and special AE?

A

Clinical application:
Given with RTV

PK
Structurally unrelated to other PIs
Well absorbed with food
Highly protein bound

Contraindications:
Metabolized by & inhibits CYP3A4
Proton-pump inhibitor
Admin. must be > 12h apart from H2 - blockers & antacids

Special AE
PR interval prolongation,
benign hyperbilirubinemia, rash, nephrolithiasis

34
Q

Darunavir clinical application, pk, contraindications, and special AE?

A

Clinical application: Inhibits HIV protease resistant to
other PIs

PK: Well absorbed with food

Contraindications: Metabolized and inhibits CYP3A4

Special AE:
Rash, avoid in patients with sulfur allergy

35
Q

Indinavir (IDV) clinical application, pk, contraindications, and special AE?
*no longer
recommended

A

Clinical Application
Given with RTV

PK
Least protein bound (60%)
Absorption decreased
when taken with meals

Contraindications
Dosage should be reduced with hepatic insufficiency

Specific Adverse Effects
Rash, blurred vision,
nephrolithiasis & hyperbilirubinemia
(adequate hydration important)

36
Q

Lopinavir(LPVr) clinical application, pk, contraindications, and special AE?

A

Clinical application: One of
preferred PIs.
Given with RTV

PK
Poor intrinsic bioavailability

Contraindications:
Enzyme inducers(St Johns Wort) should be avoided.  Oral solution contains EtOH(avoid disulfiram or metronidazole)

Special AE:
Generally well tolerated, diarrhea, nausea and flatulence are common

37
Q 
Nelfinavir (NFV) Clinical
Application,PK ,Contraindications Specific
Adverse Effect
*no longer
recommended
A

Clinical Application
Cannot be boosted by RTV

PK
Metabolized by several CYPs
Major metabolite (CYP2C19) has antiviral activity equal to parent compound

Contraindications
Numerous (due to
inhibition of CYP)

Specific Adverse Effect
Diarrhea (controlled by
loperamide),
nausea, flatulence

38
Q

Fusion inhibitor?

Entry Inhibitor?

A

Fusion Inhibitor
• Enfuvirtide
Entry Inhibitor
• Maraviroc

39
Q

Enfuvirtide(T-20) clinical use and MOA?

A
  • First approved drug that inhibits viral fusion
  • Approved for use in treatment-experienced adults with evidence of HIV replication
  • No activity against HIV-2

MOA
• Structurally similar to gp41 (HIV protein mediates
membrane fusion)
• Binds to gp41 subunit of the viral envelope glycoprotein,
preventing ability of virion to fuse cell membrane

40
Q

Enfuvirtide PK, AE, and abbreviation?

A

Pharmacokinetics
• Parenteral admin. only
Adverse Effects
• Injection-related (3% discontinue)
• Hypersensitivity reactions & eosinophilia rarely
• No drug interactions with other antiretrovirals have
been noted

Abbreviation: T-20

41
Q

Maraviroc MOA, PK, and AE?

A

MOA
• Binds specifically and selectively to CCR5 (one of two coreceptors necessary for entrance of HIV into CD4+
cells)
• Result in blocking HIV entry (only CCR5-tropic virus can
be treated with maraviroc)

Pharmacokinetics
• Metabolized by CYP 3A4 (reduce dose when given with
PIs)

Adverse Effects
• Well tolerated, risk of hepatotoxicity

42
Q

Integrase strand transfer inhibitors(INSTI’s) clinical applications?

A

Clinical Applications
• In combination with other antiretrovirals, INSTI’s are
approved for treatment-experienced and treatmentnaive patients with evidence of viral replication
• Currently most popular antiretroviral class due to good side-effect profile and favorable effects on lipid
metabolism

43
Q

INSTI’s MOA and AE?

A

MOA
• Bind integrase (enzyme essential to the replication of
both HIV-1 and HIV-2)
• Lead to specific inhibition of the final step in
integration of viral DNA into host cell DNA

Adverse Effects
• Generally well tolerated (rash, nausea, headache,
diarrhea, insomnia)
• Rare and severe effects: increases in creatine
phosphokinases, myopathy, rhabdomyolysis and
hypersensitivity

44
Q

List 4 INSTIs?

A

Bicetegravir
Dolutegravir
Elvitegravir
Raltegravir

45
Q

Bicetegrair PK, AE, and Drug Interactions?

A

PK: UGT1A1 and CYP3A4
substrate

AE: Diarrhea, headache,
nausea

Drug Interactions: some CYP interactions

46
Q

Dolutegravir PK, AE, drug interactions, and contraindications?

A

PK:
UGT1A1 and CYP3A4 substrate
AE”
Diarrhea, headache, nausea

Drug Interactions:
Some CYP interactions

Contraindications:
Pregnancy (due to neural tube defects)

47
Q

Elvitegravir PK, AE, drug interactions, and contraindications?

A

Pharmacokinetics
Primarily CYP3A4 substrate.
Requires ‘PK enhancing’ with cobicistat

Adverse Effects
Diarrhea, headache, nausea

Drug Interactions
CYP interactions likely

48
Q

Raltegravir PK, AE, and drug interactions?

A

Pharmacokinetics
Primarily UGT1A1 substrate

AE
Diarrhea, headache, nausea. Slight increases in creatine
phosphokinases

Drug Interactions:
Rifampin, tipranavir and
efavirenz may decrease concentration.
PPI’s may increase
concentration
49
Q

Current recommendations for Treatment- Naive Patients?

A

Consist of two NRTI’s plus a third drug from one of the other classes, preferably an INSTI
Current Preferred Regimens:
(1) Bictegravir + tenofovir + emtricitabine
(2) Dolutegravir + abacavir + lamivudine*
(3) Dolutegravir + tenofovir + emtricitabine
(4) Raltegravir + tenofovir + emtricitabine
* Only for patients who are HLA-B*5701 negative

50
Q

Current recommendations for infant born to HIV infected Mother?

A

In addition to maternal HIV therapy, the WHO recommends
that all newborn infants receive post-exposure prophylaxis
from exposure to HIV during delivery through 4-6 weeks of
life.
The recommended regimen for high-risk infants is:

Nevirapine + Zidovudine

51
Q

HIV prophylaxis following a needle stick?

A

Upon exposure to HIV, healthcare personnel should
immediately receive a post-exposure prophylaxis
regimen containing at least 3 antiretroviral drugs
Preferred regimens:

Raltegravir + tenofovir + emtricitabine
Dolutegravir + tenofovir + emtricitabine*

Regimen is given for 28 days and can be stopped if
source is shown to be HIV-negative.
* Not in pregnant patients

Pharmacology (49 decks)

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