Anti-tuberculosis

Dr. Muhammad Sarfraz

College of Pharmacy Al-Ain University
Al Ain, UAE.
 Tuberclosis (TB)
Mycobacteria are rod-shaped aerobic bacilli.
It multiply slowly, every 18 to 24 hours in vitro.
Mycobacterial infections classically result in the formation of slow-growing and
granulomatous lesions.
The lesion can be in the lungs and other major organs.
The diseases include:
Mycobacterium tuberculosis causes the disease known as tuberculosis (TB):
Pulmonary TB
Extra-pulmonary TB
Leprosy
Non-Tuberculous Pathogenic Mycobacteria

The Major Pathogens

Mycobacterium tuberculosis, (TB)
Mycobacterium leprae, (leprosy)
Mycobacterium bovis
Mycobacteria
The Principle of Therapy:

 Interrupt tuberculosis transmission

- To make the patient non-infectious
 To cure patient (curative) and eradicate the pathogens
- To reduce morbidity and death
 To prevent relapse and emergence of Multidrug-resistant TB (MDR-TB)
 To achieve the therapeutic objectives
- Combination drug therapy is required
 - Two-Phase Multi-Drug treatment is mandatory
Antimycobacterials
TB Treatment
 1st Line Drugs
 Refer to the main combination of drugs for TB therapy
 Isoniazid, INH (H), Rifampicin (R), Pyrazinamide (Z) , Ethambutol (E),
Streptomycin (S)

 2nd Line Drugs

 Typically less effective, more toxic, and less extensively studied
 Used for patients who cannot tolerate the 1st line drug or who are
infected with resistant TB
TB Treatment

• Monotherapy with any single drug is unsatisfactory and

resistance develops.
• Multi-Drug Therapy must be followed (Combination).
• Long duration of treatment for cure – at least 6 months to 12-24
months

Drug combination is given by TWO PHASES

• Initial / Intensive Phase (Bactericidal)
• Continuation / Maintenance Phase (Sterilizing)
 Multi-Drugs & Two Phases of anti TB treatment

Maintenance/Continuation
Intensive Phase
Phase

Isoniazid

Rifampicin
Pyrazinamide

Ethambutol

Month 0 1 2 3 4 5 6
TB Treatment: NEW CASES

 6-month regimen consisting of:

 2 months of EHRZ (2-EHRZ) followed by
 4 months of HR (4-HR) is recommended for newly-
diagnosed PTB.
 Pyridoxine 10-50 mg daily needs to be added if isoniazid is
prescribed.
 Daily treatment is the preferred regimen.

 Adopted from WHO. Treatment of Tuberculosis Guidelines (4th

Ed.), 2010
ISONIAZID, INH (isonicotinic acid hydrazide)
 Antibacterial effect limited to mycobacteria
 Bacteriostatic on resting and bactericidal on growing bacteria
 MOA:
 Activated inside bacillus by KatG to an isonicotinoyl radical,
 Eventually inhibits synthesis of mycolic acid, essential component in cell
wall, leading to cell death.
 PK:
 F=1, rapid absorption
 Enters CNS and casseous focus, metabolized by NAT2,
 Excreted in urine within 24 hr.

•Resistance to isoniazid is associated with mutations resulting in overexpression

of inhA , which encodes an NADH- dependent acyl carrier protein reductase
•mutation or deletion of the katG gene and mutations in kasA

KatG = multifunctional catalase-peroxidase

Isoniazid
• Adverse Reactions
• Fever, skin rashes, Drug-induced systemic lupus erythematosus.
• Isoniazid-induced hepatitis is the most common major toxic effect.
• Peripheral neuropathy
• Isoniazid promotes excretion of pyridoxine, and this toxicity is readily
reversed by administration of pyridoxine in a dosage as low as 10
mg/d.
• Hematologic abnormalities
• reduces metabolism of phenytoin, increasing its blood level and toxicity
 RIFAMPIN
• Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by
Streptomyces mediterranei.
• MOA: Rifampin binds to the β subunit of bacterial DNA-dependent RNA polymerase
(rpoB) and thereby inhibits RNA synthesis.  bactericidal (kills intracellular bacteria)
• Resistance results- point mutations in rpoB , the gene for the β subunit of RNA
polymerase.
• P.K:
• PO well absorbed; food may delay or slightly reduce peak
• Peak plasma time: PO, 2-4 hr
• Highly lipophilic; crosses blood-brain barrier well, into CSF Protein bound: 80%
• Metabolized by liver; undergoes enterohepatic recirculation
• Half-life: 3-4 hr (prolonged in hepatic impairment); in end-stage renal disease, 1.8-
11 hr
• Excretion: Feces and urine.
MOA of Rifampicin
RIFAMPICIN BINDS TO THE BACTERIAL DNA DEPENDENT RNA
POLYMERASE ENZYME.

INHIBIT RNA SYNTHESIS (m-RNA, r-RNA, t-RNA).

NO PROTEIN SYNTHESIS.

NO GROWTH AND MULTIPLICATION OF BACTERIA.

RIFAMPICIN IS BACTERIOSTATIC.

Animal also have DNA dependent RNA polymerase enzyme but Rifampicin
does not bind with that.
• Uses: Rifampin, 600 mg daily or twice weekly for 6 months, also is effective in
combination with other agents in some atypical mycobacterial infections and in
leprosy.
• Rifampin, 600 mg daily for 4 months as a single drug, is an alternative to isoniazid
for patients with latent tuberculosis
• unable to take isoniazid or who have had exposure to a case of active
tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain.
Adverse reactions
• harmless orange color to urine, sweat, and tears
• rashes, thrombocytopenia, nephritis.
• cholestatic jaundice and hepatitis,
• cause a flu-like syndrome characterized by fever, chills, myalgias, anemia, and
thrombocytopenia.
• Rifampin strongly induces most cytochrome P450 isoforms (1A2, 2C9, 2C19,
2D6, and 3A4), which increases the elimination of anticoagulants some
anticonvulsants.
 ETHAMBUTOL
 MOA:
 Ethambutol inhibits arabinosyl transferase III, thereby disrupts the assembly
of mycobacterial cell wall.
 No activity against other genus.
 Resistance to ethambutol is due to mutations resulting in
overexpression of emb gene products or within the embB structural
gene (arabinosyl transferase).
 PK:
 Bioavailability ~80% after oral administration
 Widely distributed, not metabolized
 >80% excreted unchanged in urine.
 Adverse Effects:
 Optic neuritis (decreased visual acuity and inability to differentiate
red/green), 1% - 15%, depends on dose/duration & reversible.
 Rash, drug fever, GI upset, peripheral neuritis, hyperuricemia, headache,
confusion, pruritus and joint pain.
ETHAMBUTOL
 PYRAZINAMIDE (analog of nicotinamide)
 MOA:
 Activated inside Mycobacteria to pyrazinoic acid (POA− ) & POAH which acidify
extracellular milieu.
 Subsequent accumulation of POAH acidifies the intracellular milieu and inhibits
enzyme function and collapses the transmembrane proton motive force, thereby
killing the bacteria.
 Also inhibit cell membrane synthesis.
 Resistance may be due to impaired uptake of pyrazinamide or mutations in
pncA that impair conversion of pyrazinamide to its active form.
 PK:
 Well absorbed (F >0.9), wide distribution, concentrated in lung (20x),
 Excreted by the kidney.
 Adverse effects:
 Hepatitis (jaundice 2-3%, death),
 Hyperuricaemia (gout),
 Arthralgia,
 GI: Nausea, Vomiting, diarrhea
 Second – line drugs

(1) in case of resistance to first-line agents

(2) in case of failure of clinical response to conventional

therapy;

(3) in case of serious treatment-limiting adverse drug

reactions
Second Line Anti-TB Drugs

Aminoglycosides: Amikacin, Kanamycin

 MOA:
 Inhibits protein synthesis by binding with 30S ribosomal subunit and
causing misreading of the genetic code during translation.
 PK:
 Water soluble, highly polar (ionized), poor GI absorption.
 Need to be given paranterally. Low passage across cell membranes.
 Excreted in urine
 Adverse Effects:
 Ototoxic - vertigo, deafness,
 Nephrotoxic - renal damage
 CI: Pregnancy (deafness in infant)
 Second Line Anti-TB Drugs
Capreomycin
• Peptide protein synthesis inhibitor, given by injection.
• ADR: nephrotoxic and ototoxic
Cycloserine
• Inhibits cell wall synthesis
• ADR: peripheral neuropathy, depression, psychosis.
Pyridoxine should be given.
PAS (Para-Amino Salicylic acid)
• Folate synthesis antagonist, similar structure to PABA & sulfonamides.
Bacteriostatic.
Active exclusively against M. tuberculosis.
• Good absorption and rapid excretion in urine
• Toxicity: GI upset (give with meals or antacid),
Allergy-fever, joint pain, skin rash, hepatitis, jaundice
 Second Line Anti-TB Drugs

Quinolones: moxifloxacin, levofloxacin, gatifloxacin

• Both more active against M. tuberculosis than ciprofloxacin (which is
more active against atypical mycobacteria) (bactericidal)
• Inhibit DNA synthesis and supercoiling by binding with topoisomerase
Linezolid
• Good intracellular concentration. Used for MDR TB. Limited by bone
marrow suppression, irreversible peripheral & optic neuropathy.
Clofazimine
• MOA: Possibly membrane disruption, inhibition of phospholipase A2,
K+ transport, electron transport chain, or efflux pump; generation of
hydrogen peroxide.
ADR: GI disturgance ~50%, skin and body secretion discoloration
OVERVIEW: Mechanisms of action of anti-TB drugs
Mechanisms of Drug Resistance in TB
Anti-Tuberculosis Drugs