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anti-microbials > Drugs for HIV & Related Opportunistic Infections > Flashcards

Drugs for HIV & Related Opportunistic Infections Flashcards

1
Q

Classes of anti-HIV drugs & examples

A
  1. Nucleoside reverse transcriptase inhibitors (NRTIs) (Zidovudine, Lamivudine)
  2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (Efavirenz, Nevirapine)
  3. Protease Inhibitors (Lopinavir, Ritonavir, Atazanavir, Darunavir)
  4. Entry/fusion Inhibitors (Maraviroc)
  5. Integrase Inhibitors (Raltegravir)
  6. DNA polymerase inhibitors (Acyclovir/Valacyclovir, Ganciclovir/Valganciclovir)
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2
Q

Aim of anti-HIV therapy

A
  1. Reduce viral load
  2. Modify progression of disease

Once initiated, is lifelong

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3
Q

Mechanism of zidovudine (ZDV)

A
  1. ZDV is a thymidine analogue
  2. Phosphorylated by host cell enzymes - forms 5’ triphosphate
  3. Competes with naturally occurring nucleotides for the active centre of reverse transcriptase - proviral DNA strand formation cannot occur with these faulty nucleotides
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4
Q

Mechanism of lamivudine (LVD)

A
  1. LVD is a cytidine analogue

2. Competes with cellular nucleotides for forming of proviral DNA by HIV RT

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5
Q

Toxicity of nRTIs (4+3)

A

ZDV

  1. GIT
  2. Myelosuppression - severe anemia, neutropenia
  3. CNS
  4. Lactic acidosis + fatty degeneration of liver (steatosis)

LVD

  1. GIT
  2. CNS
  3. Risk of lactic acidosis when combined with another nRTI in pregnancy
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6
Q

Drug interactions of nRTIs (2+1)

A
  1. Isoniazid decreases hepatic metab of ZDV - increases blood ZDV levels
  2. Probenecid decreases renal clearance of ZDV - increases blood ZDV levels
  3. Elevated when co-administered with cotrimoxazole
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7
Q

Mechanism of action of nnRTIs

A

Binds non-competitively to catalytic site of action of viral RT - inhibits DNA strand formation

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8
Q

PK of nnRTIs

A

Efavirenz

  • orally, on empty stomach (high fat meal increases plasma levels)
  • does not cross BBB readily as it is highly protein bound

Nevirapine

  • orally, good bioavailability with or without food
  • very lipid soluble, enters CSF more readily, crosses placenta, secreted in breast milk
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9
Q

Toxicity of nnRTIs (4+3)

A

Efavirenz

  1. CNS
  2. Skin rash
  3. Raised liver enzymes
  4. Potential teratogenicity

Nevirapine

  1. Rash
  2. Fever, nausea, headache, somnolence
  3. Severe hepatitis - liver failure
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10
Q

Precautions & Drug interactions of nnRTIs (3+4)

A
  1. Monitor hepatic transaminase
  2. Minimise freq of rash - gradual dose esclation
  3. Avoid in pregnant patients
  4. Efavirenz induces its own metab & that of other drugs eg warfarin, phenytoin
  5. Nevirapine induces its own metab by CYP3A4 enzymes and increases metab of coadministered PIs
  6. Enzyme inducers eg rifampicin decrease blood levels of nevirapine
  7. Enzyme inhibitors eg St John’s wort increases blood levels of nevirapine
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11
Q

Mechanism of action of protease inhibitors

A
  1. Bind to active site of HIV proteases - blocks its cleaving action on the polypeptides
  2. Normal fn of protease - cleaves bonds in nascent polypeptide - release specific HIV structural & functional proteins/enzymes for virions
  • Boost w ritonavir - at low doses, no significant anti-protease activity, set plasma levels at therapeutic levels
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12
Q

Toxicity of protease inhibitors (6)

A
  1. Hyperglycemia/diabetes
  2. Maldistribution of fat
  3. Hyperlipidemia
  4. Reduce bone mineral density (osteomalacia) due to accelerated bone loss (minimize by giving Vit D & calcium supplements)
  5. Hepatic injury w hyperbilirubinemia & elevated transaminases
  6. Increased risk of bleeding
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13
Q

Drawbacks & drug interactions of protease inhibitors (3+1)

A
  1. Drug resistance if used singly - usually used w 2 RTIs
  2. Poor patient compliance (pill burden)
  3. ADR & interactions w other drugs
  4. Inhibits CYP450 enzymes & interacts w CYP40
    - inhibition - clarithromycin, grapefruit
    - inducers - rifampicin, phenytoin
    - substrates - lovastatin, sildenafil
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14
Q

Mechanism of action of maraviroc

A
  1. CCR5 receptor antagonist

2. Blocks CCR5 - HIV is unable to bind via gp120 protein to CCR5 receptor to enter T cells - unable to enter & infect

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15
Q

Uses of maraviroc

A
  1. In HIV strains using CCR5 receptor

2. Used in combination with other anti-HIV drugs

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16
Q

Toxicity of maraviroc (3)

A
  1. Allergic rash
  2. Hepatotoxicity
  3. Cardiotoxicity
17
Q

Mechanism of action of raltegravir

A

Inhibits integrase - unable to integrate viral fenetic material into DNA of infected Th cell

18
Q

Toxicity of raltegravir (2)

A

Liver glucuronidation

  1. Allergic reaction with rash & hepatitis
  2. Muscle pain - rhabdomyolysis
19
Q

Highly Active Anti Retroviral Therapy (HAART)

A
  • nnRTI used in combination with 1-2 nRTIs to avoid development of resistance which occurs when used singly
  • PIs reduce viral load to undetectable levels - delay/prevent onset of symptoms/progression to AIDS - prolong survival
20
Q

Mechanism of action of viral DNA polymerase inhibitors

A

Acyclovir - acyclic derivative of guanosine
Ganciclovir - acyclic analog of guanosine
Valacyclobir/valganciclovir - prodrugs

  1. Drug (acyclovir/ganciclovir) converted to Drug-GTP form via viral thymidine kinase & host kinases
  2. Competes with naturally occurring nucleotide-GTP for incorporation into growing strand of viral DNA - blocks further strand growth

Resistance: gene mutation in thymidine kinase/DNA polymerase

21
Q

PK of viral DNA polymerase inhibitors

A 
Acyclovir
- oral, topical - eyedrops/cream, IV
- 20% oral bioavailability 
Valacyclovir 
- higher bioavailability 55%, oral, rapidly converted after absorption
  • well distributed into tissues & body fluid, CSF penetration ~50%
  • metabolised by cellular phosphatases, excreted by kidneys
22
Q

Uses of acyclovir (3)

A
  1. HSV infection (mucocutaneous, genitalia, encephalitis)
  2. VZV infection (orally for immunocompetent, IV for immunocompromised - to reduce incidence of dissemination of VZV)
  3. Prophylaxis (A) on immunosuppressants & undergoing transplant/radiation therapy w risk of infection/reactivation (B) with frequent recurrence of genital HSV infection

Susceptibility: HSV>VZV>EBV>CMV

23
Q

Uses of ganciclovir (3)

A
  1. IV - systemic CMV infection in immunocompromised
  2. Oral - maintenance therapy for CMV retinitis in immunocompetent
  3. Valganciclovir - reduces transmission of genital HSV

Susceptibility: CMV>HSV>VZV>EBV

24
Q

Toxicity of acyclovir (4)

A
  1. GIT related
  2. Renal dysfunction from IV administration (deposition of drug in renal tubules)
  3. CNS related (headache, encephalopathy)
  4. Hematologic (A) Thrombotic thrombocytopenia purpura (B) Hemolytic uremic syndrome (immunocompromised)
25
Q

Toxicity of ganciclovir (6)

A

More toxic

  1. Bone marrow suppression - neutropenia
  2. GIT related
  3. Irreversible aspermatogenesis
  4. Potential mutagenicity & carcinogenesis
  5. Teratogenicity & possible embryotoxicity
  6. CNS related, headache

anti-microbials (6 decks)

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