Tuberculosis 
An infection of Mycobacerium tuberculosum, there are other pathogenic species including a M. avium complex and M. bovis.  The drugs used to treat all these diseases are similar.
Tuberculosis (consumption) presents distinct problems in therapy, including the slow growth of the myobacterium, its dormancy, and the high rate of resistance that may develop to chemotherapy.

Drugs Used in the Treatment of Tubuculosis
Isoniazid (INH) -- Structurally similar to vitamin B₆, pyridoxine.
Mechanism of Action -- Inhibits the synthesis of mycolic acids, which are integral compenents of the cell wall of Mycobacterium.  Their absence will weaken the protective and structural functions of the cell wall.  Isoniazid will exert a bactericidal action in dividing cells and is bacteriostatic in resting or dormant cells.  Resistance to isoniazid occurs in 8-10% of patients.

Disposition -- INH is taken up by phagocytic cells, which may serve as a dormant site for the mycobacterium.  INH is metabolised by acetylation.  Therefore, fast acetylators will clear the drug relatively rapidly (requiring once a day dosing) while slow acetylators may only require weekly administration and are more prone to exhibit side effects or toxicity.

Therapeutics -- INH is used in the treatment and prevention of active tuberculosis.  (Prophylactic therapy is usually initiated in individuals who test positive for presence of the mycobacterium but may not present with classic signs of TB).

Adverse Effects -- Allergy, hepatitis (10-20%) -- Hepatic damage may be severe enough in rare cases (1%) to cause anorexia, nausea, vomiting, and jaundice.  A more common side effect is peripheral neuropathy (seen more in slow acetylators or other risk factors such as malnutrition, alcoholism, diabetes mellitus, AIDs, and uræmia).  Common practice includes the co-administration of pyridoxine, which prevents the peripheral neuropathies.  (INH competes with pyridoxine for renal reabsorption, resulting in excess loss of pyridoxine which is necessary for normal nerve function -- the lack thereof causing parasthæsias.)  CNS effects including memory loss, psychosis, and seizure may rarely occur.

 

Rifampin -- A rifamycin derivative

Mechanism of Action -- Rifampin binds to the beta subunit of bacterial DNA-dependent RNA polymerase, thus inhibiting RNA synthesis and subsequent protein synthesis.  Rifampin does not bind to human RNA polymerase.  It is bactericidal in its effects.  It is also bactericidal against Gram positive and negative cocci, enteric bacteria, and Chlamydia.

Disposition -- Rifampin penetrates most tissues and cells, providing efficacy in dormant mycobacteria.

Therapeutics -- Rifampin is used in the treatment and prevention of active TB.

Adverse Effects -- Rifampin may discolour the urine, sweat, and tears orange.  It may also cause permanent staining of soft contact lens.  Rare adverse effects include rash, thrombocytopænia, and renal and hepatic toxicity.

Drugs Interactions -- Rifampin may induce the cytochrome P₄₅₀ system, thus increasing the metabolism of any drugs metabolised by that route.

Ethambutol
Mechanism of Action -- Ethambutol inhibits the synthesis of arabinogalactan, a cell wall component of myobacteria.  It is bacteriostatic in effect.

Therapeutics -- Ethambutol is used primarily in the treatment of active TB.

Adverse Effects -- Ethambutol may cause red-green colour blindness and decreased visual acuity.  This effect is extremely rare at low doses. If the drug is withdrawn early, the visual deficits may be reversible.  However, continued administration will cause permanent colour blindness and decreased vision.  The effect may be seen in one or both eyes.
 

Pyrazinamide -- Structurally related to nicotinamide
Mechanism of Action -- The exact mechanism of action of pyrazinamide is unknown.  It may be acting as an antagonist in NADH mediated biochemical reactions.  It is bactericidal in its action.

Therapeutics -- Pyrazinamide is used primarily in combination with other anti-tuberculotics, to decrease the treatment duration (see below).

Adverse Effects -- Pyrazinamide may cause nausea, vomiting, fever, and hyperuricæmia (this is usually of no clinical concern except in patients with gouty arthritis).

Therapeutic Approaches to the Treatment of Tuberculosis -- Combination therapy is most often employed, due to resistance of the causative organism to single agents.  Resistance rarely develops to two agents.  Common combinations and their duration of therapy are provided below:
Isoniazid + Rifampin + Pyrazinamide -- 6 months therapy
Rifampin + Ethambutol + Pyrazinamide -- 6 months
Isoniazid + Rifampin -- 9 months
Rifampin + Ethambutol -- 12 months
Isoniazid + Ethambutol -- 18 months
All Other Drugs/Drug Combinations -- 24 months or longer
 

Other Drugs Effective in Tuberculosis

Streptomycin -- An aminoglycoside antibiotic.  It does not penetrate the cells to any great extent and is therefore not used for dormant tuberculosis.  Other aminoglycosides that may be used include kanamycin and amikacin.  The MOA and adverse effects of the AG will be discussed later.

Cycloserine -- An alanine analogue.
Mechanism of Action -- Cycloserine inhibits the conversion of L-alanine to D-alanine by inhibiting the enzyme alanine racemase.  This is an integral step in cell wall synthesis (to be discussed in the next section), thus inhibiting cell wall structure and function.

Therapeutics -- Cycloserine is used primarily in the treatment of resistant tuberculosis.

Adverse Effects -- CNS toxicity including headaches, tremors, psychosis, and seizures.

Para-Aminosalicylic Acid -- A para-aminobenzoic acid analogue.
Mechanism of Action -- p-Aminosalicylic Acid (PAS) acts as a folate antagonist in a mechanism similar to the sulphonamide antibacterials (to be discussed later).

Therapeutics -- PAS is used primarily in the treatment of resistant TB.

Adverse Effects -- Gastrointestinal, including gastric ulceration.

Rifabutin -- Mechanistically and structurally similar to Rifampin

Ethionamide -- Mechanistically and structurally similar to INH

Dapsone -- A sulphone
Mechanism of Action -- Dapsone inhibits folate synthesis in a manner similar to the sulphonamides.  It is bacteriostatic in effect.

Therapeutics -- Dapsone is used primarily in the treatment of Hansen's Disease.  It has also proven effective in the treatment of bites from the brown recluse spider (fiddleback), possibly reducing the ulcerative effects of the arachnotoxin.

Adverse Effects -- Dapsone may cause hæmolysis, especially in patients deficient in glucose-6-phosphate dehydrogenase.  This is not usually clinically relevant.  It may also cause a syndrome similar to erythema nodosum leprosum (a condition of leprosy characterised by skin lesions and ulceration), making it difficult to distinguish between drug effect and disease effect.  This condition may be treated with anti-inflammatory agents such as glucocorticoids and thalidomide (see below).
 
 

Clofazimine -- A phenazine dye.
Mechanism of Action -- Clofazimine binds to and inhibits DNA replication/transcription.  It is also anti-inflammatory, making it effective in the treatment of erythema nodosum leprosum.

Therapeutics -- Clofazimine is used primarily in the treatment of dapsone-resistant Hansen's disease.

Adverse Effects -- Clofazimine, as it is deposited in the skin (where it is effective against the myobacteria) may cause a discolouration (ranging from red to black) of the epidermis.

Rifampin and Ethionamide have also been used in the treatment of Hansen's Disease.

Treatment of Erythema Nodosum Leprosum (ENL)
In 1998, the FDA approved the anti-histaminic thalidomide for the treatment of this inflammatory condition associated with Hansen's disease.  Thalidomide was introduced and used in the late 1950s and early 1960s as a sedative.  It was also used as an antinauseant to reduce morning sickness in pregnancy.  Unfortunately, shortly after its introduction, numerous children were born with severe birth defects that were caused by the thalidomide.  It was removed from the market  and has only recently been investigated for use in other disease states.  It is effective in reducing aphthic ulcers in AIDS patients and has been investigated for use in Crohn's disease.  It was also found to be a very effective anti-inflammatory in Hansen's disease and will reduce the inflammation and associated skin lesions of  ENL.  It is presumably working through its anti-histaminic actions.  The S.T.E.P.S. (System for Thalidomide Education and Prescribing Safety) program was initiated which requires registration of physicians who prescribe and pharmacists who dispense thalidomide.  The program was proposed based upon similar and successful pharmacists-participating programs such as the Clozaril^R, Accutane^R, and Crixivan^R dispensing/monitoring systems.  The program is designed to ensure the education of the patients (both male and female -- since the thalidomide may be eliminated through semen and thus potentially cause the teratogenicity) on the potential harm and consequences of thalidomide use.  Patients are also extensively educated on means and importance of contraception while on thalidomide.  Note that thalidomide is also being investigated for use in cancer (multiple myeloma, brain tumours, non-small cell lung cancer, melanoma), immunological disorders (IBD, graft rejection, RA, and SLE), and dermatological conditions (Behcet's disease, lichen planus, pyoderma gangrenosum, and aphthous stomatitis).