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5. HDS Neuro Psych > HIV Medications > Flashcards

HIV Medications Flashcards

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1
Q

HIV Antivirals

Drug Classes

A
  • Fusion inhibitors
  • Co-receptor Antagonists
  • Reverse Transcriptase Inhibitors
    • Nucleoside analogues (NRTI)
    • Nucleotide analogues (NRTI)
    • Non-nucleoside (NNRTI)
  • Integrase Inhibitor
  • Protease Inhibitors
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2
Q

Fusion Inhibitors

Drugs & MOA

A

Enfuvirtide (Fuzeon/T-20)

Binds gp41 ⇒ ⊗ entry of HIV into host cell

Not yet part of a recommended regimen

Reserved for patients resistant to other drugs

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3
Q

Enfuvirtide (Fuzeon)

Adverse Effects

A

Subcutaneous injection BID

Side effects are local injection site reaction, increased rate of bacterial pneumonia, and hypersensitivity

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4
Q

Co-Receptor Blockers

Drugs & MOA

A

Maraviroc (Selzentry)

CCR5 Antagonist

  • Maraviroc blocks CCR5 co-receptor ⇒ ⊗ viral entry
  • Only effective for CCR5-tropic HIV ⇒ susceptibility tests
  • Not yet part of a recommended regimen
  • Reserved for pts resistant to other drugs
    • ~ 55% of pts who fail two antiviral regimens infected w/ CCR5-tropic virus
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5
Q

Maraviroc (Selzentry)

Adverse Effects

A
  • Cough, fever, rash, URI, MSK symptoms, abdominal pain, and postural dizziness
  • Black box warning for hepatoxicity
  • Cardiovascular events ⇒ poss. ↑ in MI
  • Metabolized by cytochrome p450 ⇒ ∆ by enzyme inducers and inhibitors
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6
Q

Reverse Transcriptase (RT)

DNA Synthesis

A

Makes dsDNA from viral RNA

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7
Q

Nucleoside Analogues

(NRTI)

A

Part of the first line therapy for AIDS

  • Zidovudine (AZT) ⇒ 1st drug in this class but now not as widely used
  • Lamivudine (3TC)
  • Emtricitabine (Emtriva)
  • Abacavir (ABC)
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8
Q

Nucleoside Reverse Transcriptase Inhibitors (NRTI)

MOA

A
  • 2’3’ dideoxyanalogues phosphorylated to triphosphates by host cellular kinases
  • Integrated by RT in growing DNA chain
    • Reverse transcriptase more susceptible vs mammalian DNA polymerase
  • Causes chain termination of RNA → DNA
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9
Q

Nucleoside Analogues

Class Specific Adverse Effects

A
  • Mitochondrial toxicity
    • ⊗ of mitochondrial DNA polymerase 𝛾
      • ⊗ DNA replication
      • Impaired synthesis of mitochondrial enzymes
      • Abnormal oxidative phosphorylation
      • Tissue sensitivity ∝ cellular mitochondrial content
    • Rare especially w/ agents selected for current use
    • Can lead to lactic acidosis, pancreatitis, peripheral neuropathy, myopathy, cardiomyopathy, hepatic steatosis, and lipid dystrophy
    • Lactic acidemia ass. w/ common NRTI side effects
      • N/V, headache, abd pain, fatigue, weight loss
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10
Q

Zidovudine (AZT)

Adverse Effects

A

frAnemia and neutropenia

May also be related to mitochondrial toxicity

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11
Q

Abacavir (ABC)

Adverse Effects

A
  • Causes a hypersensitivity reaction
    • Not related to mitochondrial toxicity
  • Can be fatal
  • Occurs in 6% of the population
  • Related to HLA-B*5701 variant
  • Fever, rash, nausea, malaise, respiratory sx
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12
Q

Nucleoside Analogues

Pharmacokinetics

A

All of the NRTI’s are excreted in the kidney

Require dosage adjustment in renal insufficiency

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13
Q

Nucleoside Analogues

Drug Interactions

A
  • Inhibitors of cytochrome p450 (ex. Cimetidine) ⇒ ↑ level of some drugs in this class including AZT
    • Probenecid can also increase the levels
  • Inducers of cytochrome p450 (Ex. Rifampin) ⇒ ↓ levels
  • Overlapping toxicity
    • Avoid drugs with similar adverse effects
  • Competition for activation
    • Drugs should not be activated by the same kinase
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14
Q

Nucleotide Reverse Transcriptase Inhibitor (NRTI)

Drugs & MOA

A

Tenofovir (Vemlidy, Viread)

  • Same as nucleoside analogue but does not need to be phosphorylated
    • Administered as a prodrug - Tenofovir alafenamide
    • Causes DNA chain termination of RT
  • Used in combo w/ a nucleoside analogue
  • Used alone as pre-exposure prophylaxis and for Hep B treatment
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15
Q

Nucleotide Analogues

Adverse Effects

A

Weakness, headache, diarrhea

No reported mitochondrial toxicity

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16
Q

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

Drugs & MOA

A

Efavirenz (Sustiva) / Nevirapine

⊗ Reverse Transcriptase @ allosteric site

  • Different mech. than nucleoside/nucleotide inhibitors
    • Used in combo w/ them
  • Do not require phosphorylation
17
Q

NNRTI

Class Specific Side Effects

A
  • CNS adverse effects
    • Dizziness: initially dose @ bedtime
    • Vivid dreams
    • Depression
  • Rash
  • Steven-Johnson syndrome
  • Hepatitis esp. w/ nevirapine
    • Usually occur early in therapy
  • Teratogenic in animals
    • Not used during pregnancy
18
Q

NNRTI

Drug Interactions

A

Drugs in this class are substrates for cytochrome P450 system and inducers (cyp450 3A4)

19
Q

Integrase Inhibitors

Drugs

A
  • Dolutegravir
  • Elvitegravir
    • CYP3A4 metabolized
    • Ritonavir boosts bioavailability
  • Raltegravir
    • Glucuronidated
    • No ritonavir boosting
20
Q

Integrase Inhibitors

MOA

A

Target the viral integrase

  • Used in combo w/ two nucleoside/nucleotides as part of a standard regimen
  • Dolutegravir/lamivudine recommended as initial treatment for pts w/ a viral load < 500k
  • Integrase inhibitor-based combinations are the recommended initial treatment for HIV infection
21
Q

Integrase Inhibitors

Adverse Effects

A
  • Hypersensitivity reactions
  • Serious dermatological reactions
  • Rhabdomyolysis
  • Diarrhea
  • Nausea
  • Headache
22
Q

Integrase Inhibitors

Drug Interactions

A
  • Rifampin ⇒ ↑ glucuronidation ⇒ ↑ elimination
  • Divalent cations (ex. Antacids) may bind raltegravir ⇒ ⊗ action
  • Elvitegravir is marketed w/ cobistat which ⊗ cytochrome P450 3A ⇒ prolonged action
23
Q

Protease Inhibitors

Drugs & MOA

A

Darunavir (Prezista) & Ritonavir (Norvir)

  • Viral proteases ⇒ cleave proteins used in viral assembly ⇒ vital for viral production
  • HIV viral aspartate protease (pol gene encoded) that contains a dipeptide structure not seen in mammalian proteins
  • Protease inhibitors target this dipeptide region
24
Q

Protease Inhibitors (PI)

Class Specific Adverse Effects

A
  • Most can cause nausea, vomiting and diarrhea
  • Hyperglycemia
    • Insulin resistance
    • ↓ glucose tolerance
  • New-onset DM / DKA
  • Lipodystrophy ⇒ changes in body fat distribution
    • Central obesity and peripheral fat wasting
    • Pts may have Cushingoid appearance
    • Fat atrophy may be due to mitochondrial toxicity of NRTI
    • Fat accumulation may be due to HLD and insulin resistance caused by PIs
  • Hyperlipidemia ⇒ ↑ triglycerides and/or cholesterol
    • Ritonavir has the largest effect
    • Long- term effects are not clear but ↑ lipids could lead to cardiovascular events or pancreatitis
    • Evaluate lipids and fhx of cardiac disease
  • Hepatotoxicity ⇒ ± ↑ transaminase levels w/ or w/o clinical hepatitis
    • Most cases are asymptomatic
    • Can occur at any point during therapy
25
Q

PI Boosting

A

Ritonavir causes a profound ⊗ cytochrome p450

Low concentrations used to prolong actions of other HAARTs ⇒ “PI boosting”

Possible effects of PI boosting:

  • ↑ Absorption & ↓ first-pass metabolism ⇒ ∆ Cmax
    • ⊗ cyp450 in wall of GI tract that normally metabolizes drug
    • ⊗ P-gp that normally transports drug out of endothelial cells
    • More drug cross GI into blood
  • ↓ Liver metabolism ⇒ ∆ T½
26
Q

Long-term Antiretroviral Therapy

Metabolic Effects

A
27
Q

HIV Lipodystrophy

A
28
Q

Combination Therapy

Justification

A
  • Greater efficacy & dec. toxicity
    • Lower dosing of each drug in combo
  • Mutation conferring resistance to one drug do not necessarily confer resistance to other drugs
  • Integrase inhibitor-based combos are currently preferred
29
Q

Integrase Inhibitor-Based Regimen

A

Recommended initial treatment for HIV infection

  • Dolutegravir + abacavir/lamivudine (test for HLA-B*5701) ⇒ first choice
  • Dolutegravir + tenofovir/emtricitabine
  • Elvitegravir-combistat (booster) + tenofovir/emtricitabine
  • Raltegravir + tenofovir/emtricitabine
30
Q

PI-Based Regimen

A

Darunavir/ritonavir + tenofovir/emtricitabine

(PI + NRTI)

31
Q

NNRTI based regimen

A

Efavirenz + tenofovir/emtricitabine marketed as Atripla

No longer recommended

CNS effects

Possible association w/ suicidality

32
Q

Truvada

A

Tenofovir/emtricitabine marketed as Truvada

Taken prophylactically ↓ infection rate by almost 70%

33
Q

HIV

Genotyping

A

Important in new pts or those who failed therapy d/t resistance

34
Q

Post-Exposure Prophylaxis

A

Exposure to HIV ⇒ immediate tx w/ combo therapy used in pts w/ advanced disease

Raltegravir + Tenofovir/Emtricitabine

35
Q

HIV Antivirals

Summary

A
  • Fusion inhibitors
    • Enfuvirtide
    • Nevirapine
  • Co-receptor Antagonists
    • Maraviroc
  • Reverse Transcriptase Inhibitors
    • Nucleoside (NRTI)
      • Zidovudine
      • Lamivudine
      • Emtricitabine
      • Abacavir
    • Nucleotide (NRTI)
      • Tenofovir
    • Non-Nucleoside (NNRTI)
      • Efavirenz
  • Integrase Inhibitor
    • Raltegravir
    • Dolutegravir
    • Elvitegravir
  • Protease Inhibitors
    • Darunavir
    • Ritonavir

5. HDS Neuro Psych (46 decks)

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