L72: Drugs For Treatment Of TB And Influenza Flashcards
Isoniazid
Mechanism:
- isoniazid (prodrug) converted to active form by catalase peroxidase
- inhibit enoyl-acyl carrier protein reductase (InhA)
- enzyme component of fatty acid synthase II (FAS-II) complex
- stop synthesis of ***LONG chain mycolic acid (cell wall)
- Oral/IV
- acetylated in liver by N-acetyltransferase —> acetyl-isoniazid (inactive)
- Slow acetylators: toxic concentration
- Fast acetylators: require higher dose
- kills intracellular + extracellular
- inhibit growth of dormant organism in macrophage
SE:
- diarrhoea
- upset stomach
- liver injury
- ***peripheral neuropathy (pyridoxine B6)
Rifampicin
Mechanism:
- bind to beta-subunit of RNA polymerase
- inhibit transcription of mRNA
- inhibit ***protein synthesis
- Oral/IV
- kill intracellular + extracellular
SE
- ***red-orange discolouration of secretions
- ***Enzyme inducer
- GI upset
- skin rashes
Rifabutin
- derivative of Rifampicin
- long half life
- less enzyme inducer
- same efficiency as Rifampicin, less drug reaction with anti-HIV drug
Ethambutol
Mechanism:
- inhibit arabinose transferase (EmbB)
- stop synthesis of ***arabinogalactan (cell wall component)
SE:
- ***Optic neuritis (not recommended under 5)
- decreased visual acuity and red-green blindness
Pyrazinamide
Mechanism
- pro-drug converted to pyrazinoic acid by pyrazinamidase
- inhibit fatty acid synthase I (FAS-I)
- inhibit synthesis of ***SHORT chain mycolic acid (cell wall component)
- weak extracellular bactericidal activity
- Potent intracellular activity
SE:
- GI upset
- ***Hepatotoxicity
Streptomycin
Mechanism:
- bind to 30S ribosomal subunit
- interfere with mRNA translation
- facilitate codon misreading
- inhibit ***protein synthesis
- IM injection
- Only extracellular (do not penetrate macrophage / TB lesion)
SE:
- ***Affect hearing
Commons regime of anti-TB drugs
3 drug regime:
- Rifater (Isoniazid + Rifampin + Pyrazinamide): 6 months
—> 3 drug 2 months (Isoniazid + Rifampin + Pyrazinamide)
—> 2 drug 4 months (Isoniazid + Rifampin)
2 drug regime:
Rifamate (Isoniazid + Rifampicin): 9 months
MDR-TB:
- 5/ 6 drug regime
- individualised with at least 4 drugs susceptible
- 1-2 years
- expensive
- daily administration and strict compliance
Improvement within 2-3 weeks
Influenza A vs B vs C
Influenza A:
- large natural reservoir
- animal to human transmission
- allow emergence of new strains (genetic reassortment + mutation)
- cause pandemics
Influenza B:
- limited host —> limit new strain generation
- do not cause pandemics
Influenza C:
- only in humans
- not very ill
Influenza virus survival
Survive in low temperature:
Up to 4 days at 22oC
More than 30 days at 0oC
Killed by heat and common disinfectant (formalin, iodine compounds)
Influenza replication cycle
- Attachment + internalisation
- Fusion + uncoating
- Transcription + translation
- Assembly + packaging
- Budding + dispersal
Function of Haemagglutinin and Neuraminidase
Haemagglutinin: bind to host cell receptors
Neuraminidase: cleave sialic acid residue —> release of progeny virions
Drugs used in influenza
- Amantadine / Rimantadine (for influenza A only, with 48 hours):
MOA: inhibit uncoating of influenza A
- block M2 pore function
- prevent H+ ion entering virus
- prevent acidification of virus core —> prevent activation of viral RNA transcriptase
- inhibit viral replication
SE: GI irritation, dizziness, ataxia - Oseltamivir / Zanamivir (for influenza A/B, within 24 hours, OD for 5 days)
MOA:
- bind to Neuraminidase
- inhibit cleavage of sialic acid residues
- prevent release of progeny virions
Peramivir (for influenza A/B):
- Neuraminidase inhibitor
- IV single dose
- SE: diarrhoea, SJS
- Baloxavir / Xofluza (for influenza A/B):
- single dose
MOA:
- inhibit polymerase acidic endonuclease
- impair mRNA synthesis
***Summary of anti-TB drugs + influenza drugs
- Isoniazid (prodrug: inhibit InhA —> inhibit FAS-II —> inhibit ***long chain mycolic acid synthesis)
- Rifampicin/Rifabutin (bind beta-subunit of RNA polymerase —> inhibit mRNA transcription —> inhibit ***protein synthesis)
- Ethambutol (inhibit arabinose transferase —> inhibit ***arabinogalactan synthesis)
- Pyrazinamide (prodrug: inhibit FAS-I —> inhibit ***short chain mycolic acid synthesis)
- Streptomycin (bind to 30S —> inhibit mRNA translation —> inhibit ***protein synthesis)
Extracellular + intracellular: Isoniazid + Rifampicin
Intracellular only: Pyrazinamide
Extracellular only: Streptomycin
***Summary of influenza drugs
- Amantadine/Rimantadine (A only: block M2 protein channel —> prevent acidification of virus core —> prevent activation of RNA transcriptase —> prevent uncoating)
- Oseltamivir/Zanamivir/Peramivir (A/B: bind to neuraminidase —> prevent cleavage of sialic acid residue —> prevent release of progeny virions)
- Baloxivir (A/B: inhibit polymerase acidic endonuclease —> inhibit mRNA synthesis)
