Authors:Bhurgri Ghulam Rasool,Momina Taki Muhammad,Shamim-Ur-Rehman,ShahMurad,RajKumar Chohan,DahriGhulam Mustafa, Shaikh zulfikar,
Tuberculosis, one of the oldest diseases known to affect human, is caused by bacteria belonging to mycobacterium tuberculosis complex. The disease usually affects the lungs, although in up to one third of cases other organs are involved. If properly treated, tuberculosis caused by drug susceptible strains is curable in virtually all cases. If untreated, the disease may be fatal within 5 years in more than half of cases. Transmission usually takes place through airborne spread of droplet nuclei produced by patients with infectious pulmonary tuberculosis (Mario C Raviglione, Richard JO Brein, 2003).
Tuberculosis is a disease of great antiquity. Today, tuberculosis gas become the most important communicable disease in the world, with over 8 millions cases of pulmonary tuberculosis occurring each year 95% which are in developing countries (A Gordon Leitch, 2000).
Tuberculosis is chronic granulomatous disease of human and other mammals caused by a group of closely related obligate pathogens, the mycobacterium tuberculosis complex, and comprising M. tuberculosis. The human tubercle bacillus - M. bovis - the bovine tubercle bacillus, -agricanum - a heterogeneous type found principally in effuational Africa with properties intermediate between the former two species and M-microti-a rare cause of disease involves and other small mammals but attenuated for humans. (PDO D awis et al, 2003).
Annual risk of infection
Middle income Latin America
Middle income East and South
(A Gordon Leitch, 2000)
In 1994 World Health Organization (WHO) declared that tuberculosis (TB) constituted a global emergency. It developed a five point strategy known as direct observe treatment strategy (DOTS) in order to combat the increasing incidence of the disease. The main aim was to detect 70% of smear positive tuberculosis (TB) cases and to treat85% of smear positive new cases successfully. This strategy has improved worldwide cure rates. Tuberculosis is an increasingly important cause of morbidity and mortality in refugees and displaced populations, particularly during the post acute phase of complex emergencies (Alison H Rodger et al., 2002).
In Pakistan, only limited data is available, however, the prevalence of tuberculosis is estimated to be as high as 250,000 cases annually. According to official estimates, the rate of open bacillary cases among adult population (15 years and above), was 17% and among children 5 to 9 years of age, 13% were infected with tuberculosis. It is thought to be the fourth major cause of all deaths in Pakistan (Shamim A Qazi et al., 1998).
PATHOLOGY OF TUBERCULOSIS:
CASE WITH INFECTOUS TUBERCULOSIS
Cough and generate droplet nuclei which are ingaled by a contact
Onset of CMI response
Bacillimia Apical Implant
Sterilization of the primary complex
Multiple of tubercle bacilli
Restoration of CMI
Caseation of necrosis
Figure: Schematic representation of the basic events in the pathogenesis of tuberculosis.
CMI: Cell mediated immune.
(VB Balasurbramanian et al., 1994).
DRUG TREATMENT OF TUBERCULOSIS
Tuberculosis is among the top ten cause of global mortality and affects low icome countries in particular. The treatment of smear positive tuberculosis using World Health Organizzation (WHO) directly observed treatment, short course, Direct observe treatment strategy (DOTS) has far highest impact while BC immunization recuces childhood tuberculosis mortality (Martien W Borgdorff et al.m 2002).
Drugs used in the treatment of tuberculosis can be divided into two major categories. First line after combined the greatest level of efficacy with unacceptable degree of toxicity. These include isoniazid, rifampin, ethambutol, streptomycin and pyrazinamide. Excellent results for patients with non drug resistant tuberculosis can be treated with 6 month course of treatment, for the first 2 months, isoniazid, rifampin and pyrazinamide are given, followed by isoniazid and rifampin for remaining 4 months (William A Petri Jr, 2001).
Rifampin is a semisynthetic broad spectrum bactericidal antibiotic derived from streptomyces mediaterani.The introduction of this antibiotic that permitted the development of the first effective short course of 9 month chemotherapy for tuberculosis.
It is an addition of antituberculosis activity, it has wide range of activity against other bacteria including staphylococcus, Streptococcus, Clostridium, Coliforms, Pseudomonas, Proteus,Shigella and Legionella. Rifampin is almost completely absorbed from gastrointestinal tract after an oral dose. When it is taken is an empty stomach the plasma levels of 6-7 ug/ml are reached at 3 hours and its half-life of about 5 hours (A Gordon Leitch, 2000).
Rifampin dependent antibodies are considered responsible for most of immunological side effects in which hepatotoxicity, thrombocytopenia and allergic reactions are important (Mehta YS et al., 1996). Rifampin causes anorexia, nausea, vomiting, diarrhea, fever, dizziness, bone pain, shortness of breath, urine and saliva are colored orange red (Cheema MA, 2000).
Since its introduction in 1952 isoniazid has been widely recognized as a safe and effective chemotherapeutic agent against tuberculosis. Numerous studies of isoniazid in combination with other tuberculous drugs have repeatedly demonstrated its therapeutic efficacy (Richard et al.,1972).
Isoniazid is the most widely used antituberculosis agent. It is an ideal in many aspects, being bactericidal, relatively non-toxic easily administered and inexpensive. It is readily absorbed from the gastrointestinal tract, with peak concentration of approximately 5ug/ml occurring about 2 hour after administration. It penetrates to all tissues including cerebrospinal fluids (C.S.F.) some part of drug excreted in urine in unchanged form but proportion is acetylated by hepatic acetyl transferase to an inactive form. Drug is usually given orally with combination of rifampin and pyrazinamide are available (A Gordon Leitch, 2000). Isoniazid is still most important drug world wide for the treatment of all types of tuberculosis. The commonly usual dose is 10-50 mg/kg/day with maximum of 300 mg (William A Petri Jr, 2001).
The incidence of adverse effects of isoniazid are skin rash, fever , jaundice hypersensitivity to isoniazid may result in fever, various skin eruption occurs (William A Petri Jr, 2001).
Isoniazid preventive therapy is contraindicated in persons with chronic active hepatitis should be given caution to person who consumes alcohol daily (M Suess, 1994).
Ethambutol is a synthetic, water soluble, heat stable compound. Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are inhibited in vitro by ethambutol. Ethambutol is an ingibitor of mycobacterial arabinosyl transferases, which are encoded by the embCAB operon. Arabinosy1 transferases are involved in the polymerization reaction of arbinoglycan, an essential component of the mycobacterial cell wall (Henry FC, 2001). It is rapidly absorbed from intestine. It is excreted in urine. It should not be given in renal disease (MA Cheema, 2000). The most important side effect is optic neuritis, resulting decrease of visual acuity and loss of ability to differentiate red from green (William A Petri Jr, 2001).
Hypersensitivity to ethambutol is rare. The most common serious adverse event is retrobulbar neuritis causing loss of visual acuity and red green color blindness. The dose related side effect is more likely to occur at a dosage of 25 mg/kg/day continued for several months. The peripheral neuropathy owing to demyelinization. Other less common adverse effects include gastrointestinal intolerance, hyperurecemia, and hypersensitivity reactions including rash, and rarely thrombocytopenia. It is safe during pregnancy with no known teratological effects (Edwards D,Chan,2003).
Pyrazinamide is bactericidal in an acid environment and as sterilizing effect on intracellular mycobacteria. It is well absorbed from gastrointestinal tract, with peak concentration of about 50ug/mloccurring 1.5-2 gour after ingestion. It penetrates well into tissues including cerebrospinal fluid (A Gordon Leitch, 2000).
Pyrazinamide is synthetic orally effective bactericidal ant tubercular agent used along with isoniazid and rifampin (William A Petri Jr, 2001).
The reasons for this increased incidence of hepatotoxicity reactions in developing countries are unclear, Perhaps poor nutrition, increased age, wide spread parasitism, chronic infections, indiscriminate use of various drugs without prescription may play a role individually or collectively (H Turktas et al.,1994).
Gastrointestinal reactions, cutaneous reactions, sidiroblastic anemia (A Harries, 2003). Moreover pyrazinamide is considered to be significantly less hepatotoxic than isoniazid and rifampin. Less common adverse reactions to pyrazinamide include rhabdomyolysis with myoglobinuric renal failure, gouty arthritis, photosensitivity, maculopapular raxh, thrombocytopenia, increased serum iron, urticaria, and other hypersinsitivity reactions (Edward DE Ehan et al., 2004).
Streptomycin is tuberculocidal, but less effective than isoniazid or rifampin, acts only on extracellular bacilli (because of poor penetration into cells). Thus, host defense mechanisms are needed to eradicate the disease. It penetrates tubercular cavities, but does not cross to the cerebrospinal fluid (CSF), and has poor action in acidic medium. Resistance developed rapidly when streptomycin was used alone in tuberculosis most patients had a relapse (Tripathi, 2003). Streptomycin is bactericidal for tubercle bacillus in vitro. Concentration as low as 0.4 mg/ml may inhibit the growth. Vast majority of strains of mycobacterium tuberculosis are sensitive to 10mg/ml (William A Petri Jr, 2001)
Untoward effects include rash and fever, auditory and vestibular function of eighth cranial nerve is affected (William A Petri Jr, 2001).
Unfortunately, the protective efficacy of BCG, the most widely used vaccine against pulmonary tuberculosis varies from 0% to 80%. BCG gives good protection (75-80%) against disseminated tuberculosis includes tuberculous meningitis, in childhood, BCG is given at birth or as soon as possible, therefore after and although the duration of protection is uncertain, it may not be longer than 15 years, this limiting protection against infectious pulmonary tuberculosis, which may occur mainly in adults (Martein W Borgdorff et al., 2002).
Today over, 70 years of BCG development, it is still the only tuberculosis vaccine availed, and the achievements of tuberculosis vaccine research have been largely operational, such as expanding delivery of BCG through the expanded programe on immunization and holding field trials in different geographical locations (Ann M Ginberg,2002).
MATERIAL AND METHODS
This study was carried out in the department of Pharmacology and Therapeutics, Basic Medical Sciences Institute (BMSI), Jinnah Postgraduate Medical Centre, Karachi, from January 2005 to June 2005.
The 100 newly diagnosed patients of pulmonary tuberculosis, enrolled is this study after taking informed and written consent.
The patients were selected as diagnosed cases of pulmonary tuberculosis from medical chest OPD and chest ward of Jinnah Postgraduate Medical Center, Karachi. Out of these 97 patients were associated through out the study period. Out of remaining three have not come for follow up.
All patients, in this study, were selected according to following criteria:
- Diagnosed cases of pulmonary tuberculosis.
- Age between 2o to 70 years.
- Sex either male or female.
- Patients suffering from liver disease.
- Patients suffering from cardiac disease.
- Patients suffering from renal disease.
- Patients suffering from diabetes mellitus.
- Patients suffering from other respiratory disease.
- Patients suffering from HIV infections.
- Pregnant or nursing women.
- Patients with previous multiple drug resistance.
The study period extended up to 24 weeks and 12 follow up visits of patients were taken. The required information such as name, age, sex, occupation, address, details of follow up visits and laboratory investigations etc, of each patients were recorded on proforma especially designed for this study.
The selected patients were divided according to untoward effects of drugs during study period.
Group1: In this group those patients were included who manifested the hepatitis in different age groups
Group2: In this group those patients were included who manifested the peripheral neuropathy inh defferent age groups
Group3: In this group those patients were included who manifested the skin rashes in different age groups
Group4: In this group those patients were included who manifested the joint pain in different age group
Group5: In this group those patients were included who manifested the optic neuritis in different age group
Group6: In this group those patients were included who manifested the thrombocytopenia in different age group
Group7: In this group those patients were included who manifested the nephrotoxicity in different age group
Group 8: In this group those patients were included who manifested the ototoxicity in different age group
- Isoniazid—adult 5 mg/kg -maximum 300 mg
- Rifampin—-adult 10 mg/kg -maximum 450 mg
- pyrazinamide 15-30 mg/kg
- Ethambutol 15-25 mg/kg-maximum 300 mg
- Streptomycin — 15 mg/kg - maximum 1 gm
- Disposable syringes.
- C.P. bottles.
- Kits for the liver function test, measurement of urea, creatinine
Ninety seven patients were studied after medications with anti tuberculosis therapy and divided in eight groups after the manifestation of untoward effects of therapy.
The observations of all the treatment groups were recorded on day 0, day 30 and day 80.
Table 1 and figure 1 show hepatitis after taking the anti tuberculosis drugs. The hepatitis was manifested more in combined therapy during medication of pulmonary tuberculosis. The hepatitis found significant different with p < 0.01 among anti tuberculosis therapy. Out of 97 patients, there were 15 patients were affected by this untoward effect. The highest proportion of hepatitis in isoniazid (10.3%) followed by pyrazinamide (3.1%) and rifampin (2.1%
The hepatitis in different age groups. The decade between 20-29 of age has shown maximum number of hepatitis (5.1 & followed by the extreme age 60-69 years (P<0.05), keeping the high proportion of isoniazid as compared to pyrazinamice (1.03%) and rifampin (2.06%) in different age groups. Isoniazid manifested 4 cases of hepatitis in age group 20-29 years, pyrazinamide 1 respectively. Four patients produced hepatitis in age between 60 to 69. Pyrazinamide produced hepatitis in age between 60 to 69. Pyrazinamide produced hepatitis (2.66%). INH and rifampin affected with equal percentage (1.03%). Two patients were produced hepatitis in age between 30-39 years. The INH and rifampin affected with equal (1.03%) in this age group respectively. It was non significant statistically. One patient was affected by isoniazid in the age group of 50-59 years. It was non significant statistically
The peripheral neuropathy in 25 patients out of 97 patients. The isoniazid produced more peripheral neuropathy than other causative drugs. The isoniazid affected 11.3% patients. The pyrazinamide and ethambutol produced the peripheral neuropathy in same percentage (7.2%). It was non significant statistically.
The peripheral neuropathy in different age groups. The age between 60 and above was more affected than other age groups. Isoniazid produced 602% peripheral neuropathy in this age group. Ethambutol produced 1.03% peripheral neuropathy. The age group between 20-29 developed peripheral neuropathy by isoniazid 301%, pyrazinamide 2.01% and ethambutol 1.03% respectively. The total patients were 6 with this age group. The age between 30-39 manifested peripheral neuropathy by isoniazid 1.03% and ethambutol 1.03% respectively. The age between 40-49 was affected by peripheral neuropathy by pyrazinamide 3.1% and ethambutol 3.1%
Therapy produced, 3 patients, thrombocytopenia. The rifampin produced thrombocytopenia in 3.1% males.
Thrombocytopenia according to age groups. The combined therapy affected in age between 40-49, 1.03%, 50-59, 1.03% and 60 and above 1.03% respectively. The rifampin produced this side effects with same percentages i.e. 1.03% in age groups 40-49, 50-59 and above.
Table 10 and figure 10 show the joint pain as an adverse effect of anti tuberculosis drugs. The combined therapy affected 8 patients out of 97. pyrazinamide produced joint pain in 8.24% patients.
Table 12 and figure 12 show the joint pain according to age groups. The pyrazinamide affected 3.09% in age between 60 and above, 2.06% in age between 20-29 and 1.03% in further age groups respectively.
The optic neuritis. The combined therapy produced optic neuritis in 7 patients out of 97. ethambutol produced 7.2% optic neuritis
The optic neuritis according to age groups. The combined therapy produced the optic neuritis in 3 in 6o to69, 2 in 50-59 and one in 30-39 and 40-49 years respectively. The ethambutol produced the optic neuritis in 3.09 in age between 60-69, 2.06% in 50-59 and 1.03% in 40-49 and 30-39 tears.
Skin rashes as an adverse effect of anti tuberculosis drugs. The skin rashes found significant (P<0.01) by combined therapy. The combined therapy produced skin rashes in 6 patients out of 91 patients. The pyrazinamide produced skin rashes (4.12%) and rifampin produced 2.1% respectively.
Skin rashes in age groups. The combined therapy produced skin rashes in 2 from 20-29 years age group, 1 from 40-49 years, 1 from 60-69 respectively. The pyrazinamide produced skin rashes 2.06% in age between 20-29 years, 1.03% in 50-59 years, 1.03% in 60-69 years age group, 1.03% in 50-59 years respective
Nephrotoicity as an adverse effect. Streptocomycin was main drug to manifest the nephrotoxicity in combined therapy during treatment of pulmonary tuberculosis in combined therapy during treatment of pulmonary tuberculosis patients. Out 97 patients, there were 3 reactions documented in this study. Nephrotoxicity in gender after taking the anti tuberculosis drugs. Two males and one female was affected during the study
The nephrotoxicity in different age group. In the age group 30-39 1, 40-49 1, and 50-59 1 reaction was documented in this study.
The ototoxicity after taking anti tuberculosis drugs. There were 2 reactions recorded in this study.
Table show overall side effects of ATT in this study.
Overall Frequency of Adverse Effect
This study observed the untoward the untoward effects of antituberculous drugs in pulmonary tuberculosis patients. The selected patients were divided into two groups according to the age and sex. In this study the following reaction i.e., hepatitis, peripheral neuropathy, thrombocytopenia, joint pain, optic neuritis, ototoxicity and nephrotoxicity were recorded in the first line antituberculous drugs used in pulmonary tuberculosis patients.
The adverse effects of antituberculous drugs i.e., isoniazid (INH), pyrazinamide, rifampin, ethambutol and streptomycin were observed during this study, discussed here.
Isoniazid (INH) 300 mg per day was started in selected 97 tuberculosis patients. The major side effects were recorded after two weeks of medication, which included hepatitis and peripheral neuropathy.
Hepatitis – there were 10 reactions of hepatitis were documented in this study. In a group of gender, there were 7 reactions in male and 3 reactions in female. According to age group between 20-29, the isoniazid produced 4 reactions, 3 reactions in 40-49, 1 reaction in other age groups. Isoniazid was stopped but remaining other drugs rifampin, pyrazinamide, ethambutol and streptomycin were continued in these patients.
After the stoppage of isoniazid, the liver function test was normal in 6 cases, isoniazid was reintroduced after 2-3 weeks with dose of 50 mg per day and was increased subsequently to 300 mg per day. There were 4 cases referred to the Medical Outpatient Department (OPD) for management of liver disease.
Peripheral neuropathy – isoniazid produced 11 reactions of peripheral neuropathy out of 25 reactions in this study. According to gender, 4 reactions were produced in male and 7 reactions in female. According to age group the peripheral neuropathy produced in age group 30-39 and 40-49 respectively. This showed the higher side effect of isoniazid in older age group.
Pyrazinamide (1-2 g/day) – the major side effect of this drug were produced after 3-4 weeks of medication. The hepatitis 3, peripheral neuropathy 7, joint pain 8, and skin rashes were documented in this study.
Hepatitis – the pyrazinamide produced 3 reactions of hepatitis in this study. According to gender, 1 male and 2 female reactions were recorded in this study. According to age, pyrazinamide produced 2 reactions in age group of 60-69 and 1 reaction 20-29 of age group. The 1 reaction of pyrazinamide was subsided when drug was stopped. But 2 reactions in older age group, the liver function test did improved and they were referred to the Medical Outpatient Department (OPD) for the management of liver disease.
Peripheral neuropathy – there were 7 reactions caused by pyrazinamide were documented in this study, according to gender, 2 reactions in male and 5 reactions in female according to age group, age between 50-59 3 reactions and 1 reaction in age group 20-29 and 40-49 respectively. These reactions were reversible after decreasing dose of pyrazinamide.
Skin rashes – the pyrazinamide produced 4 reactions out of 6 reactions of antituberculous drugs in this study. According to gender, in female 3 reactions and 1 reaction in male were recorded in this study. According to age group, 2 reactions were recorded in age group of 20-29 and 1 reaction in 50-59, 60-69 respectively. Skin rashes were subsided after stoppage of pyrazinamide for 3 weeks.
Joint Pain – there were 8 reactions of joint pain documented in this study. This study showed that pyrazinamide was only causative drug for joint involvement, the uric acid level was done before and after the start of drug. A remarkable increase level of uric acid was noted after the pyrazinamide treatment. Thus the drug was stopped in these 8 patients and later the level of uric acid significantly decreased and joint involvement clinically improve.
Ethambutol was administered at dose of 15-30 mg/Kg/Day. The side effects of this drug were manifested after 2-3 weeks of treatment. The peripheral neuropathy and optic neuritis were recorded as main side effects.
Peripheral neuropathy – there were 7 reactions of peripheral neuropathy recorded in this study. The ethambutol produced these reactions in 2-4 weeks after starting of treatment. According to gender, 5 in female and 2 reactions in male, were observed in this study. According to age group, 3 reactions in 50-59 and 1 reaction in each age group respectively. These reactions were reversible after stoppage of the drug.
Optic neuritis – the ethambutol produced the 7 side effects of optic neuritis in this study. According to gender, male manifested 4 and female 3 reactions of optic neuritis in this study. According to age group 3 reactions in 60-69 age group and 2 in 50-59 group and 1 reaction in 50-59, 30-39 age group respectively in this study. Drug was discontinued in these 7 cases of optic neuritis but the remaining four other drugs were continued. They were referred to Eye Outpatient Department for the management of optic neuritis. Only in two patients drug was reintroduced with low dose 15-20 mg/Kg/Day.
Rifampin (450 mg/day) – after 2-3 weeks of starting with combined therapy, the major side effects were manifested. When this drug was hold, the hepatitis 2 and skin rashes 3 were improved and reactions of thrombocytopenia were documented in this study.
Hepatitis – according to gender, 1 reaction of hepatitis in male and 1 in female produced by rifampin. According to age group, 1 reaction in 30-39 and 60-69 were produced by rifampin. One side effect of hepatitis was improved when drug was stopped after one week and other patient was referred to Medical out patient department for further management.
Skin Rashes – the rifampin developed the skin rashes in two patients; one in male and one in female in this study. According to age group, 1 adverse effect in 40-49 and 50-59 were observed respectively. These skin rashes were reversible after stoppage of drug.
Thrombocytopenia – after 5-11 weeks of treatment of tuberculosis patients, the level of platelets were decreased and clinically the patients were complaint epistaxis, bruises, and petechial rashes. Rifampin was stopped in 3 patients but the remaining other four drugs were continued.
Streptomycin (1 g per day) – it was started with other drugs. After 3-7 weeks of medication, 3 patients complaint of oliguria and 2 patients presented during follow up with hearing deficit. These reactions proved clinically and laboratory investigations.
Nephrotoxicity was recorded in these patients two in male and 1 in female. According to age group 1 in 30-39, 2 40-49 and 1 50-59 side effects were documented in this study. Drug was stopped for 3 weeks and found that blood urea nitrogen and creatinine levels were decreased, therefore this drug was permanently stopped and the remaining four drugs were continued.
The proximal renal tubule cells may accumulate aminoglycoside, accounting for nephrotoxicity associated with aminoglycosides. The mechanism of renal toxicity is hypothesized to by the inhibition of intracellular phospholipase in the proximal tubule. The renal insufficiency is typically characterized by the nonoligouric decrease in glomerular filtrate rate occurring after at least taking a week therapy. Baseline and periodic surveillance of analysis blood urea nitrogen levels, creatinine values is indicated (Edward et al., 2004).
Streptomycin is nephrotoxic and should used with caution in patients with renal impairment. If reaction is trouble some which is an infrequent occurrence, the dose may be reduced (NCG,2002).
Ototoxicity – there were 2 reactions recorded in this study. According to gender, 1reaction was in male and 1 in female was documented in this study. Side effects of streptomycin were recorded. One in age group 20-29 and one in 40-49. The drug was a stopped and patients were advised to consult in Ear Nose and Throat OPD. Remaining other drugs were continued.
Interestingly, the damage may be fairly isolated to either the choclear or vestibular component, or rarely both. The mechanism for the cochlear toxicity is unclear, although the target site is considered to the outer hair cells of the organ of corti.
Aminoglycoside induced cochlear dysfunction is generally considered to be irreversible. Injury to the hair cells of the ampullar cristae by aminoglycosides is the mechanism of the vestibular toxicity. Sign and symptoms of vestibular toxicity include nausea, vomiting, vertigo and nystagmus (Edward et al., 2004).
Our study matches with study of Menzies et al (2005), who observed the side effects of antituberculous therapy. They reported that at least monthly a nurse, a case manager, a treating physician saw the 430 test patients who had active tuberculosis therapy . At the time of their visit patients were questioned specifically about the occurrence of common side effects of their tuberculosis drugs. Liver enzyme levels were checked routinely in all patients after one month of treatment. Patients were encouraged to return at any time if symptoms or problems arose during therapy.
The striking observation is that pyrazinamide was association with rate of toxicity that was threefold higher than isoniazid and rifampin and 20-fold higher than ethambutol. The rate of toxicity with pyrazinamide was 1.5 per 100 person – months compared with 0.5 per 100 person – months for isoniazid. Pyrazinamide rashes attributed to pyrazinamide may have led to in appropriate drug discontinuation. It seems that pyrazinamide-related rashes usually resolve spontaneously and not considered a reason to stop therapy. While in this study the rate of toxicity of pyrazinamide was higher than isoniazid and rifampin. Therefore, causative drugs like pyrazinamide, isoniazid and rifampin was stopped, because they induced hepatitis, which increase risk of liver damage. However, ethambutol and streptomycin were continued in this study.
In case of skin rashes, pyrazinamide was responsible drug but it was discontinued from therapy, skin rashes were improved after three weeks.
There was a difference between this study and Menzies study may be due to short duration of study period, difference in number of patients studied. Moreover, his study conducted in United States of America. In this study there was a short duration of study and small selected number of patient and many environmental factors were involved. The patients selected in this study belong to poor socioeconomic class and they could not repeatedly visit Doctors for their checkup the occurrence of side effects of antituberculous drugs.
The British Thoracic Society (1998) guides that if the aspartate aminotransferase and alanine transferase are two or more times normal, liver function should be monitored for two weeds, then two weekly until normal. If the aspartate aminotransferase and alanine transferase under two times normal, liver function should be repeated at two weeks. If the aspartate aminotransferase and alanine transferase level rises to five times normal or bilirubin level rises, rifampin, isoniazid and pyrazinamide should be stopped. Alternative treatment will need to be considered if the patient is unwell or is smear positive and within two weeks of starting treatment.
Reactions most frequently observed with intermittent regimens of rifampin are cutaneous syndrome consisting of flushing and/or pruritus, with or without rash, involving particular face, and scalp, often with redness and watering of eye (Fried et al., 2004). Pyrazinamide produce GIT reactions, cutaneous reactions and sidero blastic anaema (Harries, 2004).
The results of this study matches with the study of Pelletier et al (2003), who observed the side effect of antituberculous drugs in 4.30 patients between 1990-99. They stated that the major adverse reaction of first line antituberculous drug, which results in discontinuation of that drug, has severely implication. They may be considerable morbidity even mortality particular may drug-induced hepatitis. Alternative agents may gave greater problems with toxicity and often less effective so that treatment must be prolonged, with attendant challenged to ensure complains as a risk of treatment failure and relapse are higher. In their results, only 37 patients had major side effects on six occasions. Severe hepatitis resulted in discontinuation of the isoniazid and pyrazinamide and neither were restarted. In three instances (two of rash and one of the severe gastrointestinal intolerance). Rifampin and pyrazinamide were stopped not rechallenged. They observed the rifampin did not commonly cause the drug-induced hepatitis. The drug mostly responsible for occurrence of hepatitis or rash during therapy of antituberculosis in tuberculosis hepatitis or rash during therapy of antituberculosis in tuberculosis patients was pyrazinamide.
In this study, pyrazinamide manifested more side effects than other antituberculous drugs were documented according to age and gender. But incidence of drug-induced hepatitis was observed more in isoniazid than other antituberculous drugs. The rifampin had shown less side effects than other antituberculous drugs.
The occurrence of side effects in the present study was noted to be much higher than the study done by Pelletier and colleagues. In this study there is a short duration of study and small selected number of patient and many environmental factors were involved. The patients selected in this study belong to poor socio-economical class and they could not repeatedly visit Doctors for their checkup the occurrence of side effects of antituberculous drugs.
Hepatotoxicity is one of the most serious adverse effects of anti tuberculosis drugs (ATD). Although many risk factors gave been associated with antituberculosis drugs induced hepatotoxicity, their influence on hepatitis severity has not been studied systematically. This study evaluated whether the presence of hepatotoxicity risk factors (advanced age, chronic liver diseases, abuse of alcohol or other drugs or malnutrition) influences the severity of ATD induced hepatotoxicity (Villar et al., 2004).
The results of present study match with the study of Fernanoted it al (2004). Their prospective cohort study of 471 active tuberculosis diseased patients treated with isoniazid, rifampicin and pyrazinamide were followed in tuberculosis clinic between January 1998 and July 2002. The incidence of antituberculous drug induced hepatitis was 18.2% patients in a risk group and 5.8% patients in non-risk group. Antituberculous drug-induced hepatitis is a significant and more severe in patients with risk factors. Our study correlates with this study because our big part of population live in a risk factor i.e., poverty, malnutrition, lack of clean water, combine family structure, high prevalence of viral hepatitis. So in our study there were more cases of hepatitis due to pyrazinamide, isonaizid and rifampin gave been responsible for drug-induced hepatitis.
Manifestations of hepatotoxicity include a symptomatic elevation in serum aminotransferase, jaundice and liver tenderness. One recommendation for monitoring for rifampin and pyrazinamide induced hepatitis is to determine the levels of aminotransferase at baseline and at 2, 4 and 6 weeks of treatment and to discontinue rifampin/pyrazinamide when there is (a) serum aminotransferase level that exceeds five times the upper limit of normal in an a symptomatic individual (b) any elevation of serum aminotransferase that accompanied by symptoms of hepatitis (c) any elevation in serum bilirubin (Edward et al., 2004).
The results of this study also match with the results of study carried out by Dossing et al (1996). They observed 61 patients out of 127 patients had elevated aspartate aminiotranferase after the treatment of antituberculous drug. Most of these were men with daily alcohol consumption of 60 g. Hepatitis were confirmed by challenged with pyrazinamide 7 and isoniazid 6 cases.
In the present study, we monitored that occurrence of untoward effects of antituberculous drugs. There was a difference between two studies due to short duration of study and small selected patients. In this study, the cases of hepatitis were recorded more than the study done my Dossing et al.
This study also matched with the study of Ferner (1990). He observed that ethambutol dose related toxicity. He reported sub clinically impairment of color discrimination relatively common in 54 patients received about 15 mg/Kg/Day of ethambutol as a part of antituberculous therapy. In the present study, the ethambutol produced the opticneurites in high percentage than the Ferner’s study. But similar results were observed in old age patients group who were affected more in both studies. The peripheral neuropathy has been reported in 3 tubercular patients who had receiving the athambutol by 13 to 50 mg/Kg/day.
Peripheral neuropathy was manifested by ethambutol in our study. There were 7 reactions of peripheral neuropathy produced by ethambutol but these reactions were reversible after stoppage of ethambutol.
In patients prescribed ethambutol it is recommended that after obtaining baseline visual acuity and color perception tests, these tests be repeated every 4 to 6 weeks, especially with new visual symptoms (Chan et, 2004).
Zinc is found in high concentration in choroids, retina, and ganglion cells and is used by retinal dehydrogenase for transformation of retinal. This last step is important for color vision. Most case of color toxicity are bilateral and result from a dose related retro bulbar optic neuritis that can either axial or peripheral. Axial neuritis involves the papillomacular bundle. It reduces visual acuity and causes central scotomas and color vision deficits. The peripheral visual field deficits but stable visual acuity and color vision (DorothyNahm Friedberg et al.,2004).
Ellard et al (1976) in their study observed the occurrence of joint pain on a reduction of renal elimination of urate in man caused by administration of pyrazinamide.
The urinary excretion of pyrazinamide, pyrazinoic acid, 5-hydroxypyrazinoic acid and uric were determined in healthy subjects after giving single or multiple doses of pyrazinamide or its metabolites pyrazinoic acid. The results obtained demonstrated that 5-hydroxypyrazinoic acid is major metabolite of pyrazinoic acid in man and supported previous evidence under that retention of uric acid caused by the administration of pyrazinamide is mediated by pyrazinoic acid. After giving 3 g pyrazinamide the urinary excretion of uric acid was maximally suppressed for 24 hours. Prolonged exposure to pyrazinoic acid resulted in a net reduction in the urinary excretion of uric acid. The finding suggested that the degree of uric acid retention in patients treated with pyrazinamide containing regimens could be reduced by giving pyrazinamide intermittently (Ellard et al., 1976).
This study matched with study conducted by Ellard and coworkers. Pyrazinamide was responsible for joint pain for different age group and gender in the present study. The old age group was commonly affected by pyrazinamide.
In a study of Hussain et al (2003), ocular reaction and toxic neuropathy were produced by ethambutol in patient’s age between 11 to 80 years. The defected color vision was fouced in 76% of eyes and 27% of eyes had defect in color vision inspite having visual acuity of 6/9 or 6/6. Dilated fundus examination revealed normal optic disc in 66 (67%) of eyes, disc pallor in 27 (28%) of eyes and 4 (4%) eyes had swollen by hyperemic disc.
The results of present study matched with the results of study conducted by Hussain and coworkers because the ethambutol was effected in the same pathogeneses in old age group.
Ethambutol is an effective treatment for tuberculosis. It can cause a multitude of dose and time dependent ocular side effects including color changes, visual field defects, and either unilateral or bilateral optic neuritis. Gradual decreases in central visual acuity and green red color vision problem (or less commonly blue yellow color vision defects) have been reported. These defects continue to progress for 1 to 2 months after drug is discontinued (Katherine, 2002).
This study was also correlated with the study of Mehta (1996). He observed thrombocytopenia in three patients of pulmonary tuberculosis during therapy. Rifampicin was causative drug. The immunological studies in all three patients showed the presence of antiplatelets antibodies reaction resulting in thrombocytopenia.
Moreover, binding of these antibodies to platelet membrane was more avid in presence of rifampicin. In present study, thrombocytopenia was major side effect of rifampin in different age and gender groups. These three patients were separated on the bases of blood complete picture and clinically showed bleeding from nose, petechial rashes and bruises. The pyrazinamide was stopped and it did not reintroduced in these cases.
Tuberculosis is a granulomatous disease, caused by mycobacterium tuberculosis. As world Health Organization estimates more than 300,000 new cases of tuberculosis develop in Pakistan every year. Cure of infectious cases of tuberculosis is the key to effective control of the disease. Treatment of tuberculosis patients reduces suffering and, if adequately, prevents death from tuberculosis. The first tine of drugs used in the treatment of tuberculosis consists of isoniazid, pyrazinamide, rifampin, streptomycin, and ethambutol. The major side effects are those giving rise to serious health hazards, and require discontinuation of the drug and referral to chest physician. Minor side effects cause relatively little discomfort; they often respond to symptomatic or simple treatment but occasionally persist for the duration of drug treatment. Chemotherapy should be stopped or temporarily interrupted only of severe drug intolerance or toxicity occurs. In fact tuberculosis drugs are relatively toxic and mild side effects are not uncommon but most do not warrant drug withdrawal.
A Harries. What are the most common adverse drug events to first line tuberculosis drugs, and what is procedure for reintroduction of drugs. Bulletin of WHO 2004; 154-158.
AD Harries, NJ Hargreaves, F Gause, JH Kwanjama and FM Salaniponi. “Preventing tuberculosis among health workers in Malawi”. Bulletin of WHO 2002; 526.
Afficial Ammerican Statement. American thoracic society. Treatment of TB and TB infection in adults and children. Am Jr Respiratory Int Car Med 1994; 1359-1374.
Agordon Leitch. “Management of Tuberculosis”, Crofton and Douglas’s Respiratory Disease 5th edition 2000; 444-564.
Agordon Leitch. “Tuberculosis”, Crofton and Douglas’s Respiratory Disease 5th edition, 2000; 476-505.
Alison J Rodger Mice Toole, Babyinuntlvangi, Vmuana and Peter Duts Schmann. “Dots-based tuberculosis treatment and control during civil conflict and HIV epidemic. Church and Pur District, India WHO Bullin 2002; 451-456.
Ann M Ginsberg. What new in TB vaccine? Bulletin of WHO 2002; pp. 483-488.
Arther C Guyton, John D. Pulmonary ventilation In: “Hall Medical Physiology” 10th edition Philadelphia WB Saunder Company 2000; pp.432.
Balasubramanian V CH, Weigeshaus BT Taylor and Smith DW. Pathogeneses of tuberculosis pathway to apical localization. Tubercle and Lung Disease 1994; 75:168-178.
BTS “Adverse reactions to tuberculosis therapy”. Joint Tuberculosis Committee of British Thoracic Society. Thorax 1998; 3:536-548.
Chan KL, Chan HS, Lui SF, Lai KN. Recurrent acute pancreatitis induced by isoniazid. Tubercle and Lung Disease 1994; 75:383-385.
Cheema MA. “Anti Tubercular drugs” Multi author test book of pharmacology and therapeutics” Vol. II, Lahore, National Medical Publication, 2000; pp. 368-370.
Czent. Study of the effect of concomitant food on the bioavability of rifampin. Tubercle and Lung Disease 1995; 76:109-113.
D Marsh, B Hashim, F Hassany and L Hussain. Front line management of pulmonary tuberculosis: analysis of tuberculosis and treatment practices in urban Sindh, Pakistan. Tubercle and Lung Disease 1996; 77:86-92.
David Guwatudde, Sarah Zalwango, Mosses R Kamya, Sara M Debanne, Mireyal J Diaz, Alphonse Okqera, Roy D Muqerova, Charles King and Christopher C Whaten. Burden of tuberculosis in Kampla Uganda. Bulletin of WHO 2003; 799-805.
Dick Menzies. Respiratory epidemiology unit, side effects of common anti-tuberculosis drugs. Am J resp Crit Care Med 2003.
Dorthy Nahm, Friedberg it al. Ocular complications of ethambutol In: Tuberculosis. 2nd Edition. Philadelphia Lipincott William and Wilkins 2004.
Edward D Chan, Celphi Chaterjee, Michael D Iseman. Pyrazinamide, ethambutol, Aminoglycosides 2nd edition, Philadelphia, Lippincott William and Wilkins 2004; 573-589.
Fernandez villar A, Sopina, B Fernandez villar, Luro. Influence of rixk factors on the severity of anti tuberculosis and induced hepatotoxicity. International J Tuber Dis 2004; 8(12):499-505.
Frieden and M Espinal What is the therapeutic effect and what is the toxicity of antituberculosid drug? Toman’s Tuberculosis WHO 2004; 110-121.
GA Ellard and Ruth M hastam. Observation on the reduction of the renal elimination of urate in man caused by the administration of pyrazinamide. Tubercle Lung Dis 1976;57:97-103..
H Turktas, M Unsal, N Tuled, O Uruc. Hepatotoxicity of antituberculous therapy (rifampin, isonizid and pyrazinamide) or viral hepatitis. Tubercle and Lung Disease 1994; 75:58-60.
Henry F, Chambers. “Antimycobacterial drugs”. In: Basic and Clinical Pharmacology, eight edition ,edited by Bertram G Katzung International edition Lame Medical books New York 2001; pp. 803-8114.
Intizar Hussain, Kamran Khalid, M Tayy B. Ocular manifestation of ethambutol toxic optic neuropathy in patients with pulmonary tuberculosis. Pak Postgrad Med J 2003; 14.
M Dossing, JTR Wilikes, DS Askgard, B Liver infury during anti tuberculosis treatment : an 11 year study. Tubercle Lung Dis 1996; 77:335-340.
M Suess. Tuberculosis preventive therapy in HIV infected individuals. Division of communicable disease. Bulletin WHO 1211 Geneva 27, Switzerland 1994.
Martein W Borgdorf. “ Annual risk of tuberculosis infection time for an up date” . Bullentin of WHO 2002; 501-503.
MD isman. What’s in aname… TB or not TB? Tubercle and Lubh Disease 1996; 77:102.
Megan Muray and Edward Nardell. Global epidemiology of tuberculosis: achievements and challenge to current knowledge. Crofton and Douglas’s Respiratory Disease 5th edition, 2004; 80(6):477-483.
Mario C, Raviglione/Richard O’Brain, “Tuberculosis” In: Harrison’s Principles of Internal Medicine, Stephen L, Hauser Dan L. Longo et al . 15th edition vol I, New York MC Graw hill Medical publication division 2001; pp. 1024-35.
Nizami SQ. Childhood TB. J Pak Med Assoc 1998;48:88.
Ormerod IP and Horfield. N. “Frequency and type of reactions to antituberculosis drugs: observations in routine treatment. Tubercle and Lung Disease 1996; 77:37-42.
Perveen Kumar. Tuberculosis. In: Clinical Medicine 5th edition, Edinburg, WB saunder 2002; pp. 892-897.
PaulNunn, Anthony Harries, PeterGodfrey, Rajgupta, Dermot Maher, Masio Raviglone. The research agenda for improving health, systems performance, and service delivery for tuberculosis control. A WHO perspective World Health Organization 2002; 471-476.
PDO Dawis, DJ uirling and JM Grange. Pulmonary disease IN: Infectious desease 6th edition, Lippincott Williams and Wilkins, Philadelphia 2003; pp. 1644-657.
Pelletier, Yee et al. Incidence of serious side effects from first line antituberculosis drugs among patients treated for active tuberculosis. AJP and Crit care Med 2003.
Philip C Hopwell. Tuberculosis control how the world has changed since 1990. Bulletin of WHO 2002; 427-728.
R Ferner. P. “Ethambutol” New castle upon tyne. Peer Review Strasbourg, France, April 1990.
Richard A Garibaldo, Ronald #E and H Febrebee. Isoniazid associated hepatitis. Am Rev Resp Dis 1972; 1-6:356-367.
Shamim A Qazi, A. KIhan, m. Ak Khan “Epidemiology of childhood of tuberculosis in hospital setting”. J Pak Med Assoc 48:1998.
Tripathi KD. “Antitubercular drugs” In: Essentials of Medical Pharmacology 5th edition, New Dehli, Japee Brothers 2003; pp.698-708.
W Levinson. “Mycobacteria” IN: Medical Microbiology and Immunology. Examination and Board Review 5th edition, New York, Lous Medical Books 200; p.157.
William AP Jr. “Anticicrobial agents” Goodman and Gilmans the Pharmacological bases of therapeutics 10th edition, (Joe1 G Hardman, Ph.D. Lee E. Limbird et a1). McGraw Hill Medical Publishing Division, New York 2001, pp.1273-1295.
YS Mehta EE Jinina, SS Badakere, D M obanty. Rifampin induced ummune thrombocytopenia. Tubercle and lung Disease 1996; 77:558-562.