Anti-tuberculosis agents

Question 1

What are the first line drugs against tuberculosis? How are they administered?

Answer 1

(RIPES)
Rifampicin (PO)
Isoniazid (PO)
Pyrazinamide (PO)
Ethambutol (PO)
Streptomycin (IM injection)

Question 2

What bacterium causes Tuberculosis?

Answer 2

Mycobacterium tuberculosis

Question 3

What are the Principles of tuberculosis treatment?

Answer 3

1. Treatment of tuberculosis needs to be prolonged to ensure the killing of these slowly growing / semi dormant organisms which, if not fully eradicated, may cause relapse.
2. Giving a single drug will select for a population that is resistant to this drug after a period. Hence monotherapy must be avoided in active TB.
3. Before starting tuberculosis treatment,
   - assess liver enzyme for pyrazinamide
   - assess visual acuity and colour vision for ethambutol
4. Treatment for TB is initiated if sputum obtained for Ziehl-Neelsen stain for AFB is positive

Question 4

Which of the 4 standard first line anti-tuberculosis drugs must be avoided or used with caution if the patient suffers from liver disease?? ( also, which of these are excreted by kidney?)

Answer 4

Rifampicin
Isoniazid
Pyrazinamide (excreted by kidney)

Hepatic toxicity: P (highest) , I, R (lowest)

Question 5

What is the mechanism of action of rifampicin?

Answer 5

Rifampicin is a bactericidal drug that kills growing, metabolically active bacilli as well as bacilli in the stationary phase, during which metabolism is reduced

Rifampicin inhibits gene transcription of mycobacteria by blocking the DNA-dependent RNA polymerase, which prevents the bacillus from synthesizing messenger RNA and protein, causing cell death.

Question 6

State 2 clinical indications for rifampicin.

Answer 6

1. Latent / Active tuberculosis
2. Leprosy, against Mycobacterium leprae

Question 7

Which of the 4 standard first line anti-tuberculosis drugs are safe for use in patients with kidney failure? ( excreted by hepatic means)

Answer 7

Rifampicin (undergoes hepatic metabolism) and Isoniazid

Question 8

Name 3 adverse effects associated with rifampicin

Answer 8

1. Hepatitis
2. Cutaneous reactions
3. Gastrointestinal symptoms
   Could have orange discoloration of bodily fluid too

Question 9

Is rifampicin an CYP Inducer/inhibitor?

Answer 9

CYP inducer. Note DDI: increased metabolism of certain drug by CYP450 eg. warfarin, corticosteroids, hormonal contraceptive and HIC protease inhibitors

Question 10

What is the mechanism of action of isoniazid?

Answer 10

Isoniazid has a bactericidal effect on rapidly growing bacilli, with limited effect on slow growing bacilli.

Isoniazid is activated by the catalase-peroxidase enzyme of M. tuberculosis. The activation of isoniazid produces oxygen-derived free radicals that can inhibit the formation of mycolic acids of the bacterial cell wall, cause DNA damage and, subsequently, the death of the bacillus.

Question 11

Which enzyme is involved in the metabolism of isoniazid, and presents with wide variation in activity in the community due to genetic polymorphisms?

Answer 11

N-acetyl transferase (rapid acetylator vs slow acetylator phenotypes are found in the population due to the genetic polymorphism

Question 12

State 2 adverse effects related to isoniazid

Answer 12

1. Peripheral Neuropathy
2. Hepatitis

Question 13

Patients on isoniazid are often co-administered _________ to help overcome ________ deficiency to avoid peripheral ________ .

Answer 13

pyridoxine (vit B6), vitamin B6, neuropathy

Question 14

What food – food interactions must patients taking isoniazid be aware for?

Answer 14

They should avoid food rich in tyramine and histamine (certain types of fish, cheese and red wine).

Question 15

Is isoniazid an CYP Inducer/inhibitor?

Answer 15

Inhibitor; this can increase plasma concentration of anticonvulsants such as oral anticoagulants

Question 16

What is the mechanism of action of pyrazinamide?

Answer 16

Pyrazinamide is the most effective drug in eliminating persistent bacilli which are responsible for bacteriological relapse.

Pyrazinamide is converted to its active form, pyrazinoic acid, by the microbial enzymes. The accumulation of pyrazinoic acid decreases the intracellular pH to levels that cause the inactivation of critical pathways necessary for the survival of the bacteria.

Question 17

Which of the first line anti-tuberculosis drugs is highly effective against the persistent bacilli

Answer 17

Pyrazinamide

Question 18

State 1 clinical indications for pyrazinamide.

Answer 18

Only active tuberculosis.

Question 19

How is pyrazinamide excreted?

Answer 19

Kidney

Question 20

Which of the 4 standard first line anti-tuberculosis drugs (R.I.P.E) is/are highly associated with causing gout like symptoms?

Answer 20

1. Pyrazinamide (More common with pyrazinamide then ethambutol)
2. Ethambutol

Question 21

Which of the 4 standard first line anti-tuberculosis drugs must be avoided or used with caution if the patient suffers from kidney impairment? (excreted by kidney)

Answer 21

1. Pyrazinamide (inhibit renal tubular secretion of uric acid)
2. Ethambutol

Question 22

What is the mechanism of action ethambutol?

Answer 22

Ethambutol inhibits the arabinosyltransferase enzyme and interferes with the polymerization of arabinose into arabinogalactan, the principal polysaccharide on the mycobacterial cell wall.

Question 23

Which of the 4 standard first line anti-tuberculosis drugs (R.I.P.E) is/are highly associated with causing visual toxicity?

Answer 23

Ethambutol

Question 24

Which class of antibiotics does streptomycin belong to? What can it replace in our first line anti TB drug?

Answer 24

Aminoglycoside. Ethambutol.

Question 25

In which groups of individuals would physicians have a high index of suspicion for multi drug-resistant tuberculosis?

Answer 25

Individuals

1. who were previously treated for TB,
2. who have failed TB treatment,
3. who are known contacts of patients with MDR-TB, or
4. who come from countries with high prevalence of drug resistant tuberculosis

Question 26

What is considered a cure of TB?

Answer 26

Demonstration of negative sputum smear or culture in the last month of treatment and on at least one previous occasion

Question 27

What are some adverse effect of streptomysin?

Answer 27

Ototoxicity: hearing loss, tinnitus, vertigo
Neurotoxicity
Nephrotoxicity