1. KAT G mutations-won't be able activate INH 2. InhA mutation-INH won't be able to bind to InhA to exert effects

Antituberculosis Flashcards by Lethibe Mokgwadi

TB?

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (M-TB), an acid-fast aerobic bacteria that can grow on gram stain as either gram-positive or gram-negative.

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TB treatment schedule-drugs and duration ?

Intensive Phase
-Isoniazid, Rifampicin,
Pyrazinamide,
Ethabutamol (HRZE)
-2 months

Continuation phase
-Isoniazid & Rifampicin (HR)
-4 months

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What is the most potent TB regime?

Isoniazid & Rifampicin
(HR) and hence taken throughout the course of treatment

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Ethambutol Potency?

Low potency

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Ethambutol resistance against drugs?

↓ development of drug resistance other agents

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First line of drugs for the management of TB?

RIPE

Isoniazid (INH)
Rifampicin/ Rifabutin
Ethambutol
Pyrazinamide

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Second line of drugs for the management of TB?

Group A-BLL
Bedaquiline
Linezolid
Levofloxacin/Moxifloxacin

Group B-CT
Clofazimine
Terizidone/Cycloserine

Group C-PIEDAEM
Pyrazinamide
High dose INH
Ethambutol
Delamanid
p-amino-salicylic acid
Amikacin/Streptomycin
Ethionamide
Meropenem

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Isoniazid synonyms?

H OR INH

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Isoniazid MOA and activation?

MOA:
Inhibits mycolic acid synthesis (Mycobacterial cell wall synthesis)

Activation:
Activated by Kat G (peroxidase)

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What is the most virulent component of the mycobacterium bacteria?

Mycolic acid

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Normal pathway synthesis of mycolic acid and the pharmacology pathway with INH?

Normal Pathway:

InhA →FAS-II →Mycolic → Cell wall synthesis

Pharmacotherapy-admin INH:

INH admin →INH activated by Kat G →ING inhibits InhA →Inhibits FAS-II synthesis →Inhibits Mycolic acid synthesis → Inhibits cell wall synthesis

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Isoniazid bacteria MOA, type of bacteria and onset?

Bactericidal-rapid & intermediate growing bacilli

Within 24hrs

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Isoniazid site of action and implication?

Intracellular & Extraceullar

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INH metabolism ?

First pass metabolism-Acetylation

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INH metabolism pathway?

INH →(N-actyltransferase) →Acetyl INH

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INH differing acetylates?

Slow acetylators=Neuropathy

Fast acetylators=Hepatoxic

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INH Acetyl-INH accumulation?

It is hepatotoxic

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INH Neuropathy reversal?

Pyrudoxine

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INH resistance-2?

KAT G mutations-won’t be able activate INH
InhA mutation-INH won’t be able to bind to InhA to exert effects

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INH CYP450 and antacids?

CYP450 Inhibitor
Antacids ↓ absorption

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Rifampicin CYP450?

CYP450 Inducer

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Rifampicin MOA and binding site?

Inhibits RNA synthesis

Binds to β-unit of DNA-dependent RNA polymerase

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Rifampicin resistance?

rpoβ mutations

Rifampicin & protease inhibitors and solution-substantation?

Rifampicin(CYP450) ↓ concentration of protease inhibitors(M in liver)

Replace in HIV Immunotherapy with Rifabutin since it is a less CYP450 inducer then Rifampicin

Rifampicin bacteria MOA ans site?

Bactericidal(intracelluar & extracellular)

Which antituberculosis drug is the most sterilising agent and why?

Rifampicin since it works within an hour

Rifampicin S/E?

-Red-orange discolouration of body fluids(urine, sweat, tears) -Hepatitis -Hypersensitivity

Rifabutin CYP450 intensity?

-CYP450 Inducer -Less potent inducer than Rifampicin -Less effect on protease inhibitors ∴ Preffered in TB-HIV co-infectionj

Rifabutin DOA and comparison?

Longer-acting than Rifampicin

Ethambutol & CNS?

Crosses BBB in meningitis

Ethambutol MOA?

Inhibits arabinosyl transferase (Mycobacterial cell wall component synthesis enzyme)

Ethambutol arabinosyl cell wall synthesis?

Arabinosyl transferase →Arabinogalactan synthesis → cell wall synthesis Addition of Ethambutol: Ethambutol→ ┴ Arabinosyl transferase →┴ Arabinogalactan synthesis → ┴ cell wall synthesis

Ethambutol S/E?

Eyes-Ocular toxicity(optic neuritis) Hyperuricemia & joint pain(Arthralgia)

Ethambutol S/E?

Eyes-Ocular toxicity(optic neuritis) Hyperuricemia & joint pain(Arthralgia)

Ethambutol DI?

Diuretics ( ↑ uric acid) Neurotoxic agents

Pyrazinamide and CNS?

Distributed into the meninges

Pyrazinamide pro-drug?

Pyrazinamide is the pro-drug ∴ converted into Pyrazinoic acid by mycobacterial pyrazinomidase

Pyrazinamide MOA?

Inhibits cell wall synthesis

Pyrazinamide bacteria MOA, site and pH?

Bactericidal , Intracellular & acidic medium

Pyrazinamide S/E?

-Hepatotoxicty -Hyperuricemia & joint paint

Pyrazinamide DI?

PAD -Probenecid(↑ t1/2) -Allopurinol -Diuretics

Drug-induced hepatitis and TDM?

R.I.P-toxicity ↑ RIfampicin Isoniazid Pyrazinamide monitor liver function every three days

TB Chemoprophylaxis: -Drug -Duration -Indications

Drug: Isoniazid Prevention Therapy(IPT) Duration: 6 months Indication: Children < 5yrs HIV +ve children HIV +ve & immunocompromised adults

TB-HIV Co-infection -Initiation of treatment -ART -Solution when CD4<50 -Prophylaxis -Protease Inhibitors and solution

-Initiation of treatment: TB treatment intiated first ART: ART within 8 weeks Solution when CD4<50: If CD4<50, START art WITHIN 2 weeks Prophylaxis: Co-trimoxazole prophylaxis Protease Inhibitors: Rifampicin interacts with protease inhibitors therefore use Rifabutin

TB Pregnancy -Regime -Line of drugs -Vaccine and admission -Dosage during pregnancy

-Regime: The standard daily 6-month regime -Line of drugs: 1st line drugs freely cross the placenta & excreted in breast milk -Vaccine and admission: BCG Vaccine-48hrs after completing treatment -Dosage during pregnancy: TB agents can be used during pregnancy and lactation, but maximum doses should not be exceded

Bedaquiline MOA?

Inhibits mycobacterial ATP synthetase

Bedaquiline S/E?

-QT-polongation -Hepatotoxicty -Arthralgia

Delamanid MOA and usage in children 6-12 years?

Inhibits mycolic acid synthesis Alternative in children 6-12 years

Delamanid S/E?

-QT prolongation -Peripheral neuropathyon

Levofloxacin QT effect and intensity comparison?

↓ effect on QT interval than moxifloxacin

What is the drug of choice that accomapnies Bedaquiline?

Levofloxacin

Linezolid S/E?

Myelosuppression

Clofazimine tolerance?

Well-tolerated

Clofazimine S/E?

Red-brown discolouration of skin Conjunctiva Retina Urine

Terizidone S/E?

Neurological & Psychiatric disturbances (CNS) Peripheral neuropathy

p-amino-salicylic acid?

-Hypothyroidism -Hepatitis

Ethionamide S/E?

Hepatitis Hypothrodism CNS side effects