Antituberculosis drugs are subdivided on basic and reserve.
The basic drugs (first line drugs):
- Isoniazid (H),
- Rifampicin (R),
- Pyrazinamide (Z),
- Streptomycin (S),
- Ethambutol (E),
- Thioacetazone (T)
they are prescribed separately or in combined forms.
Reserve drugs (second line drugs):
- protionamid (Pt) (этионамид- Et),
- kanamicin (K),
- amikacin (A),
- kapreomicn (Cap),
- cycloserin (Cs),
- rifabutin (Rb),
- PAS,
- phtorchonolones (Fq).
The second line drugs are applied under supervision of antituberculosis establishment, in which the centralized quality surveillance microbiological diagnostics and treatment of tuberculosis are carried out.
Isoniazid.
Isoniazid is derivative of the izonicotinic acid. To drugs of this group refer metazid, ftivazid, calusid.
Mechanism of action.
Isoniazid is rapidly transported into actively growing MBT in a cyanide – inhibitable oxygen-dependent process. Once inside , isoniazid interacts with the catG gene product [the catalase-peroxidase enzyme] and forms the active moiety. The activated drug binds and inhibits the inhA gene encoded enoy1 reductase. Isoniazid inhibits mycolic acid syntesis in MBT by a specific inhibitory effect on the syntesis of saturated fatty acids greater than 26 carbons, implicating elongation of fatty acids as a target for its action. As isoniazid is also a potent inhibitor of the mycobacterial catalase-peroxidase, it may inhance the susceptibility of the bacteria to reactive oxygen species generated in the macrophage phagosomal compartments. It also acts as antinicotinamide adenine dinucleotide [NAD] metabolite and may also react with mycobacterial protein. Proteins coding inhA in MBT concentrate or activate isoniazid.
Isoniazid is well absorbed from the gastrointestinal tract and readily distributes in all body fluids. It is metabolized by acetilation in the liver and is mainly excreted by the kidneys. Based on the rate of acetylation, the population can be divided in “fast” or “slow” acetylators. Its half-life varies from one to three hours. The acetylator status however, does not interfere with the antituberculosis effect or the incidence of hepatotoxicity.
Isoniazid is generally well tolerated but the adverse effects observed are isoniazid-induced hepatotoxicity and peripheral neuritis. Hypersensitivity reactions like rashes, arthralgia and rheumatoid syndrome are uncommon and neurological disturbances are only seen in toxic concentrations. Peripheral neuritis caused by isoniazid is due to perydoxine deficiency and is most often seen in patients who are predisposed to neuritis e.g., malnourished individuals, alcoholics , patients with diabeted mellitus and pregnant women. The advantages of isoniazid are that it is a very powerful (bactericidal) drug. It has very few adverse effects. It is very cheap. Because it is so powerful, the dose is small.
Isoniazid is normally given by mouth. In special circumstances it can be given intravenously and intrathecally. Highly effective concentrations of the drug are obtained in all tissues and the CSF. There is no cross-resistance with other drugs. The rate of conversion of isoniazid to an inactive form (acetilation) varies in different races but is of no practical importance in standard treatment. However slow inactivators are more likely to get the complication (peripheral neuropathy).
Preparation and standard doses.
- Daily: 300 mg (children 5 mg/kg) in a single dose
- Intermittent (x 2/week): 15 mg/kg plus pyridoxine (Vit. B6) 10 mg with each dose: maximum 750 mg. (x 3/week): 10 mg/kg.
- Miliary or meningeal tuberculosis: 5-10 mg/kg.
- Chemoprophylaxis: 5 mg/kg.
- Intravenously: 200-300 mg (adults) 100-200 mg (children)
Isoniazid is supplied as tablets of isoniazid alone or combined with other drugs.
Metazidum, dose 20 mg/kg and phthivazidumdose 30-40 mg/kg per day in tablets 0,5 gг. Saluzidum solubile 5%, introduce intra mascular, intra vein intra lumbar, endobronchal. Adverse effects. Adverse effects of isoniazid are uncommon. Generalised skin rashes rarely occur. Peripheral neuropathy (tingling and numbness of the hands and feet) is the main adverse effect. It is commoner in malnourished patients and with high doses. It can be treated by giving 100-200 mg pyridoxine daily. It can be prevented by giving 10 mg piridoxine daily. It is worth giving routine pyridoxine with high dosage isoniazid (for instance in twice weekly treatment).
Hepatitis may also occur especially in patients more than 35 years old. Isoniazid interacts with drugs given for epilepsy (anti-convulsants) and dosages of these drugs may need to be reduced during chemotherapy.
Rifampicin.
Rifampicin is a semi-synthetic derivative from rifamycin B produced by Amycolatopsis mediterranei. It is bactericidal for MBT.
Mechanism of action.
Rifampicin acts by binding to the beta-subunit of mybacterial DNA-dependent RNA-polymerase and prevents initiation of transcription. It is active against both extrcellular and intrcellular organisms, and has a particularly rapid action against slow growing bacilli in the caseous material where pH is neutral but oxygenation is poor. Rifampicin is well-absorbed from the gastrointestinal tract and freely distributes to the lungs, liver, bone, urine and saliva. Approximately four per cent of plasma concentration is found in CSF of patients with inflamed meninges. Rifampicin is deacetulated in the liver to an equally active metabolite and both excreted in bile. The biliary rifampicin is reabsorbed from the gut and enterohepatic circulation is established. Approximately 70% of the dose is excreted in faeces, and the remainder in urine. Rifampicin is always given per os in a single dose, but there is form for intravenous introduction. There is no cross-resistance to other anti-tuberculosis drugs. Highly effective concentrations obtained in all tissues and moderate levels in the CSF. Although the cost is higher than most other usual drugs, the results are so good that chemotherapy may be cheaper per cured case.
Preparation and dose.
Daily, depending on body weight:
- 55 kg body-weight and over 600 mg
- Under 55 kg: 450 mg (10 mg/kg, maximum)
- children 10 mg/kg (maximum 450 mg)
Intermittent:
450 mg twice or thrice weekly.
It should be taken half an hour before breakfast.
Preparation.
It is supplied as capsules or tablets, ampoules (syrup is also available) either alone or combined with other drugs. All patients should be warning that rifampicin colors the urine, sweat and tears pink.
Adverse reactions.
The main side-effects when the drug is given daily are gastro-intestinal: nausea, anorexia and mild abdominal pain, diarrhea occurring less frequently.
Cutaneous reactions in the form of mild flushing and itchiness of the skin, and occasionally a rash, occur very infrequently.
Hepatitis is extremely uncommon unless the patient has a history of liver disease or alcoholism. It is wise to estimate liver function from time to time in such patients. A significant rise in billirubin may occur in patients with congestive cardiac failure.
The following patterns of adverse effects (syndromes) occur mostly in patients having intermittent treatment.
- Influenza like syndrome, shiveriness, malaise, and headache and bone pain.
- Thrombocytopenia and purpura: platelets fall to a very low level and hemorrhages occur. It is essential to stop treatment immediately.
- Respiratory and shock syndrome: shortness of breath, wheeziness, fall in blood pressure, collapse.
- Acute hemolytic anemia and renal failure.
Rifampicin should never be given again if the shock syndrome, acute hemolytic anemia or acute renal failure has occurred.
Rifampicin and other drugs. Rifampicin stimulates liver enzymes which may break down other drugs more rapidly than normal. This includes the estrogens in the contraceptive pill, oral coumarin anticoagulants, oral diabetic drugs, digoxin, methadone, morphine, phenobarbitone and others.
Streptomycin.
Streptomycin is produced by Streptomyces griseus. It is a member of the aminoglycoside-aminocyclitol group of antibiotics and is bactericidal against wide veriety of gram-negative and gram-positive bacteria.
Mechanism of Action.
Streptomycin acts by inhibiting bacterial protein synthesis. The 30s ribosomal subunit seems to be the primary intracellular site of action of streptomycin and other aminoglycosides. The 30s ribosomal subunit consists of 21 proteins and a single 16s molecule of ribonucleic acid [RNA}, of which at least three proteins and perhaps the 16s ribosomal subunit contribute to the streptomycin-binding site. This binding blocks the initiation of protein synthesis, leading to accumulation of abnormal initiation complexes of “streptomycin monosomes”. The aminoglycosides also cause misreading of the mRHA template and incorporation of incorrect amino acids in the growing polypeptide chain. MBT rapidly becomes resistant when this agent is used alone. However, when used in combination with other drugs such as isoniazid and rifampicin, streptomycin is bactericidal and prevents the emergence of resistant strains. It is mainly active against bacterial populations in cavities where the pH is low. Streptomycin is not absorbed from the intestine so it should be administered by intramuscular injection. It diffuses readily into most body tissues. The concentrations are very low in normal CSF (cerebrospinal fluid) but the levels are higher if there is meningitis. It does however cross the placenta. As it is excreted almost entirely through the kidney the dosage has to be lowered in patients with poor renal function and in older age groups.
Preparation.
Streptomycin sulphate for intramuscular injection is supplied as a powder in vials. It is made into a solution by adding distilled water. Ideally, solutions should be prepared immediately before administration. Make sure the nurse gives the injection into a different site each day. Daily injections into the same site are very painful. Because it is painful, only give streptomycin to children if it is essential.
HIV can be spread by infected needles. If you cannot use a new needle for every patient, or if you cannot be sure that sterilisation is absolutely reliable, you should substitute ethambutol for streptomycin. This is particularly important if you are working in an area which has a high prevalence of AIDS.
Adverse effects.
The main adverse effects are cutaneous hypersensitivity and ototoxicity (damage to eighth cranial nerve). From other side effects practical importance have: Quincke’s edema; eosinophilia; serum sickness. Hemolytic anemia, agranulocytosis, thrombocytopenia appear more rare.
Skin reactions — rash and fever — usually occur in the second and third weeks.
Vestibular and auditory (ototoxicity) toxicity. The signs of vestibular (balancing) apparatus damage are shown by giddiness. It may start suddenly and, if acute, there may be vomiting. Unsteadiness is more marked in darkness. Examination of the eyes may show nystagmus. It is more likely to occur in older patients: attention to dosage is very important. If the signs of vestibular and ototoxicity toxicity appear treatment with streptomycin must stopped immediately. The damage to the nerve may be permanent if the drug is not stopped when the symptoms start. If the drug stopped immediately, symptoms usually clear over weeks. Deafness occurs extremely rarely.
Anaphylaxis:
injection may be followed by tingling around the mouth, nausea and occasionally by sudden collapse.
Streptomycin should be avoided, if at all possible, in pregnancy because it may cause deafness in the child.
Ethambutol.
Etambutol is a synthetic agent, which is only active against MBT. Though it has been classified as a bacteriostatic drug, recent studies show that is has a bactericidal action also. Ethambutol is a bacteriostatic drug. It is mainly used to prevent the emergence of drug resistance to the main bactericidal drugs (isoniazid, rifampicin and streptomycin). It is given orally.
Mechanism of action.
Ethambutol is rapidly taken up into MBT where it acts by interfering with the synthesis of the outer envelope of the MBT wall. Mycolic acids are attached to the 5’-hydroxyl groups of the terminal D-arabinose residues of the arabino-galactan synthesis by either inhibition of arabinnnosyl transferase or some enzyme involved in the synthesis of the arabinose receptor. The major intermediate in the biosynthesis of arabinogalactan, beta-D-arabinofurasil-1-monophosphodecaprenol, rapidly accumulated incide the cell within minutes of etambutol administration in vitro. Etambutol is a specific inhibitor of spermidine synthase and thus interferes with polyamine function. Ethambutol also decreses the rate of emergence of resistant strains. It is well-absorbed after oral administration and is widely distributed in the body. Less than 10% of plasma concentrations are achieved in CSF even when the meninges are inflamed. Ethambutol is partly metabolized by oxidation in the liver and 50% of the dose is excreted unchanged in urine. The half-life may be prolonged in patients with hepatic or renal disfunction.
Ways of administration and dosage. Because of the risk of blindness large doses are no longer given. You must make sure not to give more than the recommended dose. Never give ethambutol to young children who are unlikely to tell you they are losing their sight.
Contrandications: optic [retrobulbar] neuritis; diabetic retinopathy; pregnancy.
Adverse reactions. The main and possibly very serious, adverse reaction is progressive loss of vision caused by retrobulbar neuritis. Limitations of the field of vision; green and red colour-blindness. When you start the patient on treatment warn him about possible decrease in vision. The patient will notice failing eyesight even before anything shows in the eye when at examination of it with the ophthalmoscope. At this situation the drug must be withdrawn immediately. If it is done there is every chance that he will recover his sight. If a patient continues the treatment he may become completely blind. Eye damage is much more common if the patient has renal failure.
But do not use ethambutol in young children: they may not tell you if they are losing vision.
Hepatotoxicity may be discovered only on carrying out routine biochemical tests. Anorexia, mild fever, tender enlargement of liver and spleen may be followed by jaundice. If severe hepatitis occurs do not give the Ethambutol again.
Arthralgia is quite common and is often mild. The pain affects both large and small joints – shoulders, knees and fingers especially. The level of uric acid is increased and gout may occur. Simple treatment with aspirin is often sufficient.
Other side effects: neural disorders (headache, epileptiform fit), anaphylactic reactions, bronchospasmodic reaction.
Pyrazinamide.
Pyrazinamide is a synthetic pyrazine analogue of nicotinamide. Pyrazinamide is a front-line bactericidal drug which is an essential component of the standard regimen for tuberculosis in the initial two monts of therapy.
Mechanism of Action.
The exact mechanism of action of pyrazinamide is not known. It is transported or diffuses across the mycobacterial cell wall and is converted into its active form pyrazanoic acid by a specific amidase enzyme. The specific target of pyrazanoic acid is unknown but it could interfere with pyridine nucleitide synthesis and turnover. Pyrazinamide is particularly active against the semi-dormant extracellular and intracellular populations of MBT in an acidic environment in the inflamed tissue. Pyrazinemide is also active against organisms inside the macrophages. Pyrazynamide is well-absorbed after oral administration and readily diffuses into all body fluids and tissues. Because CSF concentrations are equal to those in plasma, pyrazynamide is particularly valuable in the treatment of tuberculosis meningitis. Pyrazinamide is metabolized in the liver to an active metabolite, pyrasanoic acid and it is primarily excreted by the kidneys.
Treatment and dosage.
It is administered by mouth: each tablet contains 400 or 500 mg pyrazinamide: it should be taken in a single dose.
Side effects.
The most common side-effect observed with pyrasinamide is hepatotoxixity. As pyrazanoic acid inhibits uric acid excretion, transient hyperuricaemia may be observed. The resulting arthralgia is related to serum uric acid levels and is usually self-limited and subsides within a few weeks of continued medication. Pyrazinamide does not cause gout in patients who are not genetically predisposed.
Thioacetazone.
Thiacetozone is a thiosemicarbazone derivative with bacteriostatic action on MBT. It is primarly used to prevent the development of resistance to more potent antituberculosis drugs such as isoniazid.
Mechanism of Action.
The exact mechanism of action of thiacetozone is unknown. Current evidence suggests thqt thiacetozone might inhibit mycoloc acid biocyntesis. It is well absorbed orally and peak plasma concentrations are reached four to five hours. The plasma half-life is 12 hours and 20% of the drug is excreted unchanged in urine. Thioacetazone is a weak drug but is very valuable as a companion drug in preventing the development of isoniazid resistance.
Means of introduction and dosage.
Thioacetazone is administerd in a single dose daily. Make sure you give exactly the right dose. Too small a dose will fail to prevent resistance. It is unsuitable for intermittent use.
Adverse effects.
The main adverse effects are generalized cutaneous reactions and gastro-intestinal symptoms. These are very common in patients with HIV infection and may be very severe. Fever and rash are sometimes severe and exfoliation of skin may occur. Gastro-intestinal symptoms include nausea, abdominal discomfort and vomiting. Thioacetazone is poorly tolerated by the Chinese population of Hong Kong and Singapore, by Europeans and surprisingly well tolerated in East African countries and in South America. However, severe reactions may occur in patients with HIV infection.
Contrandications: disease of liver, kidney, hematosis organs, diabetes mellitus.
Dosage:
0,05 g. x 3 times a day, per os, with glass of water. The day dose – 2-2,5 mg/kg. Is inexpedient to combine thioacetazone administration with ethionamid and protionamid because of cross drug resistance.
Combined first-line antituberculosis drugs are used in all stages of controlled treatment.
Myrin (3 components preparation) 1 tablet contains: isoniazidm75 mg + rifampicin 150 mg + ethambutol 300 mg.
Myrin-II (4 components preparation) 1 tablet contains: isoniazid 60 mg + rifampicin 120 mg + ethambutol 250 mg +pyrazinamid 225 mg.
Rifater (3 components preparation) 1 tablet contains: isoniazid 50 mg + rifampicin 120 mg + pyrazinamid 225 mg.
Rifinah ((2 components preparation) 1 tablet contains: isoniazid 100 mg + rifampicin 150 mg.
Second-line anti-tuberculous drugs.
These drugs are used for patients whose bacilli have been proved to be resistant to all the five standard drugs. They are very difficult to use. They have many side-effects. They are less effective and very expensive. An experienced specialist has to work out the best drug combinations for each patient. World Health Organization recommends that the drugs should only be used in specialist centres.
The following drugs have been used for this purpose. The names are only given here for reference.
Ethionamide, Capreomycin, Prothionamide, Kanamycin, Sodium para-aminosalicylate (PAS), Viomycin Cycloserine Amikacin, Ofloxacin, Ciprofloxacin.
It is necessary to remember, that in the various countries many other preparations are authorized for treatment of the tuberculosis. In this connection it is important to know what specific anti-tuberculous preparations are authorized for application by local bodies of public health services.