Millions of people worldwide are
infected with tuberculosis, with at least 10 million new cases and 1 million
deaths reported each year. India is one of the countries with a high incidence
of this disease which is rising alarmingly with the advent of AIDS.
Drugs used in the treatment of
tuberculosis belong to two categories:
First-line drugs—These drugs combine the greatest
level ofefficacy with a relatively low level of toxicity. Examples: isoniazid,
rifampicin, ethambutol, streptomycin, and pyrazi-namide.
Second-line drugs—Microbial resistance or other
reasons(e.g. concomitant AIDS) may necessitate the addition of these drugs.
Examples: ciprofloxacin, ofloxacin, ethiona-mide, aminosalicylic acid,
cycloserine, amikacin, kana-mycin, capreomycin, and thioacetazone.
Some of these drugs have been
discussed elsewhere, and only the important examples from the remainingwill be
Isoniazid or INH represents the cornerstone of the treatment of tuberculosis, and is also the drug of choice for prophylaxis in case of positive tuberculosis skin test reaction. INH is the hydrazide of isonicotinic acid, and its isopropyl derivative iproniazid is a monoamine oxidase inhibitor used in the treat-ment of depression. INH is bactericidal for both extracellular and intracellular organisms. It is usually used with other antituberculous drugs such as rifampin and pyrazinamide. Isoniazid as sole therapy is only acceptable when used prophylactically.
Isoniazid is readily absorbed on oral or parenteral admin-istration, and diffuses easily into all body fluids and tissues. Upto 95% of the drug is excreted in the urine within 24 hours, mostly as metabolites. The main metabolic pathway involves acetylation followed by hydrolysis, the rate of acetylation being genetically and racially determined. Fast acetylation is char-acteristic of Japanese, Chinese, Eskimos, and Negroes, while slow acetylation is seen mainly among Scandinavians, Jews, and North African Caucasians. Fast acetylation is inherited as an autosomal trait. The plasma half-life is 0.7 hours in rapid acetylators and 2 to 4 hours in slow acetylators. In the presence of renal or hepatic dysfunction, slow acetylators can accumulate substantial amounts of INH in the plasma.
The principal metabolites of INH
include acetyl isoniazid, isonicotinic acid, isonicotinyl glycine, isonicotinyl
hydrazones, and traces of methylisoniazid.
The normal therapeutic dose of INH
is 5 mg/kg/day to a maximum of 300 mg/day. Up to 10 mg/kg/day (600 mg/day) is
occasionally used in severely ill patients. The incidence of adverse effects is
about 5.4%. Main features include rash, fever, jaundice, and peripheral
neuritis. Haematological effects include eosinophilia, agranulocytosis,
anaemia, and thrombocy-topenia. Vasculitis has also been reported. The
neurotoxicity of INH is due to vitamin B6 (pyridoxine) depletion. In
the normal course, pyridoxine is phosphorylated by a specific kinase in the
liver and then oxidised to pyridoxal phosphate by a flavopro-tein. The
availability of pyridoxine is affected by INH in the following ways: INH
combines directly with pyridoxine and forms an isonicotinyl-hydrazide complex
which is excreted in the urine; it forms hydrazones which inhibit pyridoxine
phosphokinase, the enzyme that converts pyridoxine to its active form; INH
hydrazides inactivate pyridoxal 5’-phosphate, rendering it
ineffective. The net effect is that there is a decrease in the availability of
gamma-aminobutyric acid (GABA) which is the main inhibitory neurotransmitter of
the CNS, since pyridoxine is necessary for the synthesis of GABA. The resultant
loss of inhibitory influence of GABA on the CNS is the presumed aetiology of
INH-induced convulsions. The hepa-totoxicity of INH is mediated directly by its
Acute INH overdose is characterised
by the clinical triad of convulsions, metabolic acidosis, and coma. Other
features include vomiting, vertigo, hyperthermia, hypotension, hyper-glycaemia,
glucosuria, and ketonuria. INH-induced convulsions are often severe and do not
respond to anticonvulsant therapy. They may develop abruptly within 30 minutes
to 3 hours after overdose. Status epilepticus may ensue with convulsions
lasting for hours and requiring aggressive treatment. Rhabdomyolysis may
develop in patients with protracted convulsions. The metabolic acidosis is
asociated with a high anion gap, and is mainly due to build-up of lactate
secondary to seizures. Severe anion gap metabolic acidosis (pH < 7.0) is
common in patients who develop convulsions after INH overdose. The acidosis is
frequently refractory to IV sodium bicarbonate therapy alone, but generally
reverses after pyridoxine therapy. Mild hepatic dysfunction has been reported
following acute overdoses of isoniazid. Clinical hepatitis with nausea,
vomiting, fatigue, fever, abdominal pain, malaise, pruritus, and elevated liver
function tests is less common, occurring in 0.3 to 1.3% of patients in most
Chronic effects include hepatitis,
peripheral neuropathy, optic neuritis, encephalopathy, psychosis, insomnia,
vertigo, arthritis, backache, anorexia, constipation, vomiting, and
haematological effects (anaemia, haemolysis, agranulocytosis, eosinophilia, and
methaemoglobinaemia). Peripheral neuritis occurs in about 20% of patients
receiving 6 mg/kg/day of INH without supplemental pyridoxine. It occurs most
often in patients who are slow acetylators, and those who are malnour-ished,
alcoholic, uraemic or diabetic. It is also dose related, occurring in 44% of
patients receiving more than 16 mg/kg/ day. A pellagra-like syndrome may also
occur with chronic INH therapy, characterised by dermatitis, diarrhoea, and dementia.
Psychosis has been reported with isoniazid therapy.
Doses as low as 1.5 grams can induce
toxicity. In relation to body weight, 10 to 30 mg/kg can cause seizures, while
doses in excess of 50 mg/kg can cause death.
Decontamination: Stomach wash can be done if the
patient is seen within 1 to 2 hours post-ingestion and is asymptom-atic. If the
patient is convulsing, seizures must be controlled and the airway secured
before gastric lavage. Activated charcoal has been shown to be beneficial and should
be administered in the usual manner.
Control of convulsions: Actively convulsing patients
should be given diazepam 5 to 10 mg IV at a rate of 5 mg/min, which can be
repeated after 10 to 20 minutes if convul- sions persist. There are however
several reported cases of INH-induced convulsions not responding to diazepam
even though it is a GABA-enhancing agent and should (theoretically) be
effective. Phenytoin has been proven to be useless in this setting and must not
be tried at all. If convul-sions are not controlled by the above measures,
consider continuous infusions of midazolam (loading
dose: 0.2 mg/ kg slow bolus; infusion:
0.75 to 10 mcg/kg/min), propofol (initial:
1 to 2 mg/kg, maintenance: 2 to 10
mg/kg/hr), or pentobarbitone (loading
dose: 10 to 15 mg/kg at a rate of 50mg/min until burst suppression, or
electrocerebral inactivity on EEG; maintenance:
0.5 to 1 mg/kg/hr). Endotracheal intubation, mechanical ventilation, and
vasopressors will be required, and consultation with a neurologist is strongly
advised. Occasionally, neuromuscular paralysis may be required to avoid
hyperthermia, severe acidosis, and rhab- domyolysis; continuous EEG monitoring
is mandatory if neuromuscular paralysis is used.
Antidote: Pyridoxine should be given to all
patients (symptomatic or asymptomatic) who are suspected to have ingested a
large amount of INH (>80 mg/kg). The recom- mended dose is 1 gram IV for
every gram of INH ingestedto a maximum of 5 grams, at a rate of 1 gram every 2
to 3minutes. If the amount of INH ingested is unknown, a doseof 5 grams may be
administered to an adult, or 70 mg/kgin a child (upto a maximum of 5 gm). This
can be repeated after 30 minutes if seizures persist. Combining pyridoxine with
diazepam is said to be synergistic and therefore recom-mended. But while
pyridoxine is a relatively safe antidote, there is some indication that it may
cause severe sensory neuropathy if given in very large doses, and so caution
should not be thrown to the winds while administering it.
Management of acidosis: If acidosis does not respond to
pyridoxine, diazepam, or IV fluids, sodium bicarbonate can be given at a dose
of 44 to 88 mEq/L by IV bolus. But care should be taken to see that it is not
mixed with pyridoxine solution.
Supportive measures : If aspiration pneumonitis
develops, endotracheal intubation must be done and intermittent positive
pressure breathing undertaken. Hypotension can be managed by IV fluids.
Elimination enhancement: INH is dialysable since it has a
low volume of distribution and is not much protein-bound. Haemodialysis is
preferable to peritoneal dialysis. In the case of the latter, pyridoxine may be
added to each litre of fluid used for dialysis. Haemoperfusion and exchange
transfusion have also been successfully employed in INH overdose.
Rifampicin is a semisynthetic
derivative of rifamycin B which is one of a group of structurally similar,
complex macrocyclic antibiotics produced by Streptomyces
mediterranei. Rifampicin and INH (given together) are the most effective
drugs avail- able for the treatment of tuberculosis. The former is also used in
the prophylaxis of meningococcal disease and H.influenzae meningitis.
A related drug, rifabutin (derived
from rifamycin S) is used in the prophylaxis of mycobacterium avium
complex-mediated infection in AIDS patients and shares some of the toxic
mani-festations of rifampicin.
Adverse effects of rifampicin
include rash, fever, nausea and vomiting, and jaundice. In some patients a
flu-like syndrome develops, characterised by fever, chills, and myalgia. There
may also be interstitial nephritis, acute tubular necrosis, and haematological
disturbances (thrombocytopenia, haemo-lytic anaemia, eosinophilia).
Rifampicin is a potent inducer of
hepatic microsomal enzymes and therefore reduces the half-life of a number of
drugs including anticoagulants, barbiturates, clofibrate, contraceptives
(oral), corticosteroids, cyclosporine, digitoxin, fluconazole, halothane,
ketoconazole, methadone, metoprolol, propranolol, quinidine, sulfonylureas,
theophylline and verapamil.
Rifampicin is a hepatotoxic poison.
Toxic hepatitis appears more frequently and with greater severity during
combination therapy with INH. This is noted most frequently in children. Apart
from liver failure, overdose of this drug produces vomiting, flushing,
angioedema, periorbital and facial oedema, mental changes, and pulmonary
oedema. Patients typically present with nausea, vomiting, mental status
changes, and reddish discolouration of the skin. Renal failure occurs less
frequently. Thrombocytopenia, haemolytic anaemia, meth-aemoglobinaemia,
hypothrombinaemia, transient leukopenia,and anaemia have been reported
following chronic ingestion of therapeutic doses. Hypersensitivity reactions
include fever, pruritus, urticaria, various skin eruptions, polyarthropathy,
and soreness of the mouth and tongue.
Overdosage can rarely result in
convulsions, arrhythmias, pulmonary oedema, and death. Ingestion of more than
14 grams is potentially lethal. Since rifampicin and its metabolites are red in
colour, overdose results in a characteristic orange-red staining of tissues,
urine, faeces, saliva, tears, and sweat (Redman
syndrome). Sclerae may also appear yellow-orange incolour. Cutaneous
staining can be partially removed by washing or scrubbing.
CBC, renal and hepatic function tests in symp-tomatic patients. Elevated total
bilirubin level is the most common finding, and may be due to interference of
rifampicin with the bilirubin assay. Liver function tests and renal tests
should be closely followed.
charcoal can be administered.
must be treated with benzodiazepines in the usual maner.
of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours
after exposure in some cases. Maintain adequate ventilation and oxygenation
with frequent monitoring of arterial blood gases and/or pulse oximetry. If a
high FIO2 is required to maintain adequate oxygenation, mechanical
ventilation and positive-end-expiratory pressure (PEEP) may be required;
ventilation with small tidal volumes (6 ml/kg) is preferred if ARDS develops.
rifampicin has an extensive volume of distribution and is significantly
protein-bound, it is not eliminated well by haemodialysis or haemoperfusion.
Ethambutol is a synthetic
bacteriostatic antituberculous drug which is effective only in actively growing
cells. Ethambutol is effective as adjunctive therapy for the treatment of
tuberculosis, but is not indicated as monotherapy for this disease. It is also
used in combination to treat other mycobacterial infections including
Mycobacterium avium-complex. It is usually given in combination with INH.
The most important adverse effects
are related to the eyes: optic neuritis (resulting in diminished visual acuity
and red-green discrimination), constriction in visual fields, and even
blindness. These effects may be unilateral or bilateral, and are usually
reversible. Optic neuritis is the principal side effect of ethambutol therapy,
but usually manifests at doses in excess of 15 mg/kg. Other effects include GI
upset, pruritis, arthralgia, vertigo, confusion, and peripheral neuritis. Gouty
arthritis has been reported after therapeutic administration of ethambutol.
Acute overdose results in nausea, vomiting, abdominal pain, fever, confusion, hallucinations, and retrobulbar neuritis (if the dose exceeds 10 gm). Acute overdose involving both ethambutol and isoniazid may result in synergistic nervous system toxicity.
Treatment involves supportive
measures. Haemodialysis or peritoneal dialysis may be beneficial. Patients
with optic neuritis can benefit from parenteral hydroxycobalamine 40 mg/day for
10 to 28 weeks followed by a reduced dose of 20 mg/day. Deaths have so far not
been reported in ethambutol overdose.
It is an analogue of nicotinamide
and is bactericidal to actively dividing tubercle bacilli. Pyrazinamide is well
absorbed orally and is widely distributed throughout the body. It is partly
hydrolysed to pyrazinoic acid and then hydroxylated to 5-hydroxypyrazinoic acid
The most serious adverse effect is
hepatitis with jaundice, and even death may occur from hepatic necrosis.
Pyrazinamide is therefore contraindicated in individuals suffering from hepatic
dysfunction or disease.
Acute overdose involving this drug
has rarely been reported.
It is a bacteriostatic anti-TB drug
which is associated with the following adverse effects: nausea, vomiting,
metallic taste, postural hypotension, mental depression, blurred vision,
head-ache, tremor, skin rashes, impotence, menorrhagia, alopecia, and
hepatitis. Concomitant administration of pyridoxine is advisable. Monitor liver
enzyme levels after significant over-dose. Monitor electrolytes in patients
with severe vomiting or diarrhoea. Monitor for evidence of encephalopathy after
significant overdose. Case reports suggest that pyridoxine, nicotinamide and
parenteral multiple vitamins may be useful in the treatment of
Use of ethionamide should be avoided
during pregnancy or in women of childbearing age, unless the benefits outweigh
its potential hazards: developmental anomalies (congenital heart disease, spina
bifida, spinal anomalies, Down’s syndrome and possible
is a broad-spectrum antibiotic elaborated by Strep. orchidaceus, which acts by interfering with bacterial cell
wall synthesis.Adverse effects include drowsiness, headache, tremor,
dysar-thria, vertigo, confusion, psychosis, and convulsions. Other effects
include megaloblastic anaemia, polyarthritis, and a pellagra-like syndrome.
Concomitant administration of pyri-doxine is advisable.
It is an antimycobacterial agent
elaborated by Strep. capreolus, and
must be given only by intramuscular or intravenous injec-tion. Capreomycin is
used concomitantly as part of a multidrug regimen to treat tuberculosis that is
resistant to other therapy. It may also be used to treat infections due to
other Mycobacterial species. Electrolyte abnormalities and metabolic alkalosis
may occur with therapeutic use. Leukocytosis, eosinophilia, and various skin
rashes may occur. Adverse effects include ototoxicity similar to streptomycin,
and renal tubular damage. Severe renal tubular dysfunction and tubular necrosis
have occurred. Loss of visual acuity has been rarely reported with capreomycin
therapy. The ototoxicity, nephro-toxicity, and neuromuscular blocking effects
of aminoglycoside antibiotics may be increased by concomitant administration of
capreomycin. Capreomycin is a possible inducer of Bartter’ssyndrome.*
There is no antidote for capreomycin
overdose. Treatment is symptomatic and supportive. Haemodialysis may be helpful
was formerly widely employed in India (in combination with INH) because of its
low cost. However it is extremely toxic, and death can result even from
therapeutic doses (150 mg). Patients with AIDS (or HIV seropositivity) are
particularly susceptible, and therefore the drug is contraindicated. When given
along with streptomycin, thioacetazone can potentiate the former’s tendency to
cause ototoxicity. Adverse effects include vomiting, anorexia, conjunctivitis,
mild to severe skin eruptions, vertigo, convulsions and cerebral oedema.