First line anti tb

1. Anti TB
RASHED ALOTAIBI
MEDICAL RESIDENT
KFGH

2. Objectives
 History of TB
 First line Anti TB.
 Pharmacology.
 Side effects.
 Management of common side effect.

3. 150 millions yrs
ago
>>
Mycobacterium
ulcerans
2400 BC
Egyptian mummies >>
characteristic Pott's
lesions
Hippocrates
(400BC)
>>Phthisis
(shrunken) >>
PTB
12, 13th century >>
king’s evil
(TB lymphadenitis)
>>
curable by the
touch of royalty
1882, Dr. Robert
Koch, discovery
of Mycobacterium
tuberculosis,

4. First line
1. INH (isonicotinylhydrazide)
2. Rifampicin.
3. Pyrazinamide.
4. Ethambutol.

5. INH
(isonicotinylhydrazide)
• Interactions: inhibit the cytochrome
(CYP): phenytoin, theophylline, carba
mazepine, primidone, and warfarin.
• No renal adjustment.
• NB with hepatic dysfunction.
• Safe in pregnancy.
• Milk excretion is minimal.
• MOA: Inhibit mycolic acid
synthesis (long fatty acid in cell
wall).
• Metabolism: acetylation (variant).
• Elimination: 75 -96 % kidney.
• Dose: 5 mg/kg orally once daily.
• 1-2 hours after meals

6. INH
(isonicotinylhydrazide)
Adverse reaction:
• Neurological reactions.
• Hepatotoxicity.
• Poisoning.
• Drug-induced lupus syndrome.
• Dermatologic (urticarial rash).
• Gastrointestinal (abdominal pain, nausea,
vomiting).
• Hematologic abnormalities.

7. Neurological reactions:
Competes with vitamin B6
(pyridoxine) in its action as a
cofactor in the synthesis of synaptic
neurotransmitters.
peripheral neuropathy, ataxia, and
paresthesia
Risk factor:
• Elderly.
• Pregnant.
• Children.
• Malnourishment.
• alcoholics,.
• CLD.
• CKD.
• DM
Prevention:
• Pyridoxine 10 mg/day.
• Risk factors: 25-50 mg/day.
Treatment:
• 100 – 200 mg/day

8. Hepatotoxicity
Mild hepatotoxicity:
- AST, ALT <100.
- 20% of the
patients.
- Self limited.
- Not related to
metabolism rate or
dose
- observation.
INH hepatitis:
- symptomatic.
- 0.5-1%.
- Fatality 0.05 – 0.1%.
- Start 2-3 months.
Risk factors:
- elderly.
- Alcoholics.
- CLD.
- CYP meds.
- Drug abuse.
- Female.
- Rapid
acetylators.
- Immunosuppress
ed
• fatigue, malaise, anorexia.
• N/V.
• flu-like symptoms.
• RUQ pain.
• Jaundice 10 %.
• Acute liver failure 1-3%.
• Encephalopathy, ascites,
edema.
• Diagnosis: work
up for high LFT

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13. INH Poisoning:
 Altered or depressed mental status or
seizures, including status epilepticus.
 Higher ingestion doses (≥20 mg/kg).
 BG, ASA level, acetaminophen level.
 ECG (QTC by other medications).
 Rx: seizure >> benzodiazepines,
pyridoxine.
 pyridoxine : 1 g intravenously for every
gram of INH ingested, rate 0.5 g/min.
 Lorazepam: repeated doses: 2 mg IV
every 5 minutes until seizures are
controlled.

14. RIFAMPIN (Rifampicin)
• Interactions: rifampin to induce
cytochrome P450 CYP3A
• No renal adjustment.
• NB with hepatic dysfunction.
• Safe in pregnancy (animal
teratogenicity)
• MOA: inhibit bacterial DNA-
dependent RNA polymerase
• Metabolism: hepatic, half-life of three
hours. < 30 % eliminated unchanged.
• Elimination: 75 -96 % kidney.
• Dose: 10 mg/kg (maximum 600 mg daily) given daily
• oral dose is taken on an empty stomach

15. Medication affected
- oral or other hormonal contraceptives.
- Glucocorticoids.
- Cyclosporine.
- HMG-CoA reductase inhibitors ("statins").
- macrolide antibiotics.
- Tacrolimus.
- Warfarin.
- direct oral anticoagulants (eg, dabigatran).
- Phenytoin.
- Levothyroxine.
- azole antifungal agents.
- oral sulfonylurea hypoglycemics.
- antimalarials, quinidine.
- Verapamil.
- Methadone.
- beta-blockers.
- antiretrovirals (most notably protease
inhibitors, select nonnucleoside reverse-
transcriptase inhibitors
[eg, etravirine and rilpivirine) and integrase
inhibitors (eg, raltegravir, dolutegravir,
and elvitegravir).

16. RIFAMPIN (Rifampicin)
 Orange or red-orange discoloration of body fluids.
 GI upset.
 CNS(headache, fever).
 Dermatologic (rash, itching, flushing).
 Hematologic (thrombocytopenia, neutropenia, and
acute hemolytic anemia).
 Pruritus (with or without rash).
 Hepatitis.
 Flu like syndrome (1-2 hs after dose, more with
intermittent doses)

17. RIFAMPIN (Rifampicin)
When to stop medications:
 Anaphylaxis.
 Cutaneous vasculitis.
 Red cell aplasia.
 Leukopenia.
 Agranulocytosis.
 Thrombocytopenia.
 DIC.
 Hemolytic anemia.
 Pulmonary infiltrates (pneumonitis)
 Lupoid reactions.
 AKI

18. Ethambutol
• Renal dose adjustment.
• HD: dose after dialysis.
• Safe in pregnancy.
• MOA: not fully known, inhibition of
arabinosyl transferase, an enzyme that
polymerizes arabinose into arabinan and
then arabinogalactan, a mycobacterial cell
wall constituent.
• Metabolism: partially by liver, 50-80%
eliminated unchanged.
• Dose:
• 40 to 55 kg >>800 mg (14.5 to 20 mg/kg)
• 56 to 75 kg >> 1200 mg (16 to 21.4
mg/kg)
• 76 to 90kg >> 1600 mg† (17.8 to 21.1
mg/kg)
• Elimination: 75 -96 % kidney.

19. Ethambutol
Adverse reaction: dose related
 Visual changes Optic neuritis:
 Change in visual acuity.
 Red-green color blindness.
 Reversible in most patients.
 baseline visual acuity, (Snellen test) and
color discrimination tests.
 EMB should be discontinued
immediately and permanently if there
are any signs of visual toxicity.
 If vision does not improve stop INH.
 Risk factors include age, hypertension,
renal failure and HIV.
 Neutropenia, thrombocytopenia.
 nausea, vomiting, abdominal pain.
 Hepatotoxicity
 CNS (headache, dizziness,
confusion).
 Cutaneous reactions

20. Pyrazinamide
• Renal dose adjustment, daily
dose to 3 times a week
• HD: dose after dialysis.
• Pregnancy: Category C risk
(Risk not ruled out ).
• MOA: enters the bacterium passively and
is metabolized via pyrazinamidase within
the cytoplasm to pyrazinoic
acid;(unknown), PZA and its analog, 5-
chloro-PZA, may inhibit the fatty acid
synthetase I (FASI) enzyme of M.
tuberculosis .
• Metabolism & Elimination: primary by
liver, but its metabolites are excreted in
the urine and may accumulate in patients
with renal insufficiency.
• Dose:
• 40 to 55 kg >>1000 mg (18.2 to 25
mg/kg).
• 56 to 75 kg >> 1500 mg (20 to 26.8
mg/kg).
• 76 to 90kg >> 2000 mg(22.2 to 26.3
mg/kg)

21. Pyrazinamide
Adverse reaction:
 Hepatotoxicity.
 Gastrointestinal symptoms (nausea, vomiting).
 Non-gouty polyarthralgia: 40% of patients, no need to stop, respond to
NSAIDS.
 Asymptomatic hyperuricemia: assist in patient adherence.
 Acute gouty arthritis: rare.
 Transient morbilliform rash: This usually is self-limited, with continuation of
the drug.
 Dermatitis: PZA may cause cutaneous adverse drug reactions as well as
photosensitive dermatitis

22. Hyperuricemia:
More than 2 hours of research UpToDate, PubMed
Reviewed more than 20 articles.

23. But, what I have noted
 Most of the studies before 2000.
 Rifampicin decrease the incidence of arthralgia caused by PZN.
 One small double blinded study: ASA better than allopurinol in PZN
induced arthralgia due to hyperuricemia + allopurinol have deleterious
effect on UA level.
Horsfall, P., Plummer, J., Allan, W., Girling, D., Nunn, A. and Fox, W. (1979). Double blind controlled comparison of aspirin, allopurinol
and placebo in the management of arthralgia during pyrazinamide administration. Tubercle, 60(1), pp.13-24.

24. Double blind controlled comparison of aspirin, allopurinol and placebo in the management of
arthralgia during pyrazinamide administration.
Tubercle. 1979 Mar;60(1):13-24.
Horsfall PA, Plummer J, Allan WG, Girling DJ, Nunn AJ, Fox W.

26. Other adverse effects:
 Flushing, itching >> antihistamine.
 Hives, moderate to severe allergy >> stop all anti TB till symptoms resolve
>> desensitization-rechallenge, except in:DIHS , SJS.
 N/V: rule out other causes >>
 Often resolve within 1-2 wks.
 Take medication that cause nausea at night.
 Metoclopramide then ondansetron then promethazine.
 3rd: decrease the dose.

27. Sources
 UpToDate.
 Official American Thoracic Society/Centers for Disease Control and
Prevention/Infectious Diseases Society of America Clinical Practice
Guidelines: Treatment of Drug-Susceptible Tuberculosis.
 Guidelines for the Management of Adverse Drug Effects of
Antimycobacterial Agents.