TB

Tuberculosis (TB) is a communicable infectious disease caused by Mycobacterium tuberculosis. It can produce silent, latent infection as well as progressive, active disease (1).
Globally, 2 billion people are infected and 2 to 3 million people die from tuberculosis each year (1).
أي إن ثلث سكان الأرض تقريبا مصابون . وحسب تقدير منظمة الصحة العالمية لعام 2002 فان العراق يصنف ضمن المنطقة التي يكون معدل التدرن فيها بين 100-300 لكل مئة ألف شخص.
Pathophysiology:
TB is caused by an acid-fast bacillus, Mycobacterium tuberculosis. TB may infect any part of body, but it is usually confined to the lungs due to the high-oxygen demand of the organism and route of transmission. Transmission of M. tuberculosis consists of aerosolized droplet nuclei, which are produced when an infected person coughs, sneezes, or speaks. The droplets spread through the air and can remain airborne for long periods of time. Once inhaled, droplet nuclei are small enough that they reach the alveoli in the lungs, where the organism begins to replicate.
Active TB is caused by a patient's inability to initiate an adequate immune response. M. tuberculosis continues to multiply, resulting in an infectious state. These patients have symptoms and are considered infectious. Certain subgroups, e.g., immunocompromised patients, the elderly, and children, are at a higher risk of developing active TB compared to the general population.
In contrast, exposed patients with an adequate immune response inhibit the replication of M. tuberculosis, leading to a dormant state, referred to as latent TB. Latent TB patients are usually asymptomatic and noncontagious. However, latent TB may develop into active disease in about 10% of individuals. The highest risk for conversion is within the first two years after exposure (2).
Clinical Presentation:
Cough, with or without hemoptysis, is one of the most common symptoms of active TB. Early in the course of disease, it is often reported as a nonproductive cough. As inflammation and tissue necrosis occur, sputum is usually produced. Patients presenting with hemoptysis usually have advanced disease. Other symptoms may include fatigue, fever, weight loss, and night sweats (2).
Diagnosis:
1-The tuberculin skin test is used for detection of TB infection. After a positive tuberculin skin test result, a chest radiograph and sputum cultures are required to distinguish between active vs. latent TB. Sputum cultures are used to determine the presence of M. tuberculosis after abnormalities are identified on a chest radiograph. A patient with active TB infection usually presents with symptoms, a positive tuberculin skin test, and an abnormal chest radiograph. This patient will require isolation and pharmacologic treatment. Latent TB presents with no symptoms but with a positive tuberculin skin test and radiographic evidence of prior TB. (2).
Respiratory Isolation:

In the developed country there is a special isolation room for active or infectious TB to prevent infecting other patients and health care workers. If the patient leaves the room, or if such room is unavailable, respiratory isolation can be achieved if a surgical mask is worn over the mouth and nose. Isolation should continue until the patient is considered noninfectious or the sputum cultures are negative. A noninfectious state is classified as clinical improvement with anti-TB drugs, resulting in an asymptomatic patient(2).
وفي كل مريض يقسم الا يبصق؟؟؟؟؟؟؟
Desired Outcomes (1)

1-Rapid identification of new cases of TB
2-Isolation of the patient with active disease to prevent spread
3-Prompt resolution of signs and symptoms of disease after initiation of treat- ment
4-Achievement of a noninfectious state, thus ending isolation
5-Adherence to the treatment regimen
6-Cure as quickly as possible (generally with at least 6 months of treatment)
Treatment

General Principles (1)
1-Drug treatment is the cornerstone of TB management. A minimum of two drugs, and generally three or four drugs, must be used simultaneously.
2-Drug treatment is continued for at least 6 months and up to 2 to 3 years for some cases of multidrug-resistant TB (MDR-TB).
3-Measures to assure adherence, such as directly observed therapy (DOT), are important.
A-Treatment of latent TB
Chemoprophylaxis should be initiated in patients to reduce the risk of progression to active disease(1).
Isoniazid (INH), 300 mg daily in adults, is the primary treatment for latent TB , generally given for 9-12 months(2). Individuals likely to be noncompliant may be treated with a regimen of 15 mg/kg (to a maximum of 900 mg) twice weekly with observation (1).
If the individual has been exposed to a patient with INH-resistant M. tuberculosis or a patient who has failed chemotherapy, chemoprophylaxis with rifampin (RIF) (for 4 months) should be initiated (1)..
Pregnant women, alcoholics, and patients with poor diets who are treated with isoniazid should receive pyridoxine, 10 to 50 mg daily, to reduce the incidence of central nervous system (CNS) effects or peripheral neuropathies(1).
B-Treatment of active TB:
Treatment of active TB consists of two phases: initial and continuation.
1-The initial phase: requires a two-month duration of a three-drug to four-drug regimen, with preference for the four-drug combination. The drug regimens include the use of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) (Table 2 ).
2-Continuation phase: After completion of the initial phase, a continuation phase follows for approximately four to eight months. In the continuation phase, the drug regimen is reduced to a combination of two medications, usually consisting of rifampin and isoniazid. The current guidelines recommend daily treatment with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial phase of two months, followed by a continuation phase of isoniazid and rifampin for approximately four to five months. The newer rifamycins, rifabutin and rifapentine, may be substituted for rifampin in special situations, e.g., intolerance or serious drug interactions (2).


Second-line drugs are mainly substituted or added to preferred therapy due to intolerance or acquired drug resistance (TABLE 3). The development of acquired drug-resistant TB most commonly occurs when there is a large bacillary population, an inadequate prescribed drug regimen, or noncompliance. This type of TB requires the addition of at least two second-line medications.


.
A-Isoniazid
Isoniazid is a preferred first-line agent in the treatment of TB in the initial and continuation phase of the treatment of active and latent TB (table 2 ). Isoniazid is mainly used for its profound early bactericidal activity against actively dividing cells of M. tuberculosis. Adult daily isoniazid dosing for the initial or continuation phase consists of 5 mg/kg/day with a maximum oral dose of 300 mg. Another option for the continuation phase is a dose of 15 mg/kg with a maximum oral dose of 900 mg given once, twice, or three times a week (Table 3).
Major side effects reported from isoniazid are asymptomatic elevation of aminotransferases, hepatitis(rare) , and peripheral neurotoxicity. The elevated aminotransferases are reversible after the discontinuation of the medication.
Peripheral neurotoxicity is a dose-dependent adverse effect usually uncommon at conventional doses.The addition of pyridoxine supplement (10 to 50 mg/day) is recommended for high-risk patients to reduce risk of neuropathy (2).
B-Rifampin
Another first-line agent, rifampin, is used in the initial and continuation phase (Table 2). Rifampin possesses early bactericidal activity against active and semidormant bacterial populations, producing a sterilizing effect. Adult rifampin dosage is based on weight, with 10 mg/kg for the initial phase and a maximum of 600 mg per daily dose for the continuation phase (Table 3). Potentially dangerous side effects are transient asymptomatic hyperbilirubinemia and clinical hepatitis. Clinical hepatitis is more common with the combination of rifampin and isoniazid (2.7%) . The most frequent side effect of rifampin is the orange discoloration of bodily fluids, such as urine, sweat, tears, and sputum. Another common side effect with rifampin is pruritis with or without rash. Pruritis occurs in approximately 6% of patients but is self-limiting. Other adverse effects include flu-like syndrome, nausea, anorexia, thrombocytopenia, hemolytic anemia, and abdominal pain (2).
C-Pyrazinamide
The greatest activity against dormant or semidormant organisms is exerted by pyrazinamide, used for the initial phase of active TB (Table 2). Adult dosing for pyrazinamide is strictly based on lean body weight to minimize side effects, with a maximum dose between 2,000 and 4,000 mg, depending on the frequency given during a seven-day period (Table 4).
Major side effects are hepatoxicity and polyarthralgias. Pyrazinamide-induced hepatoxicity is usually 2% with standard dosing (Table 4), but higher rates have been reported with higher doses. Polyarthralgias occur in up to 40% of patients but are treatable with aspirin or NSAIDs. Other side effects are nausea, vomiting, acute gouty arthritis, and photosensitive dermatitis.
D-Ethambutol
Ethambutol can be used in the initial phase primarily to prevent rifampin resistance caused by M. tuberculosis. Recommended adult dosages for Ethambutol are based on 15 to 25 mg/kg, 25 to 30 mg/kg, or 50 mg/kg for daily, thrice weekly, or twice weekly, respectively.
Ethambutol dosing is based on lean body weight (Table 5). A major adverse effect of Ethambutol is a decreased visual acuity or decreased red¬green color discrimination.This effect is usually dose-related and may involve one or both eyes. Baseline visual testing is recommended; monthly retesting is advised for patients taking doses higher than the conventional dosage or if duration of therapy is more than two months. Any changes in visual acuity or color discrimination should be reported immediately, and Ethambutol should be discontinued (2).









ملاحظة : يقرا الجدول ليفهم ولا يحفظ حاليا ولكن عند الممارسة العملية لابد أن تعلم الجرع للصيدلي.

Drug Interactions: (2)

Drug interactions with anti-TB therapy can cause changes in concentrations of concomitant medications, resulting in toxicity or lack of efficacy. Rifampin is a potent enzyme inducer of the cytochrome P-450 isozymes , leading to decreased serum concentrations of medications metabolized by that isoenzyme. Dosages of affected medications may need to be increased during treatment of TB , then the dosage must be decreased within two weeks after completion of rifampin to prevent toxicity.
In contrast , The risk of toxic drug serum concentrations with anti-TB medications may result from the addition of isoniazid. Isoniazid is a potent inhibitor of the cytochrome P-450 isoenzymes. Use of isoniazid results in higher concentrations of concomitant medications due to the blockade of drug metabolism.
The inductive effect of rifampin outweighs the inhibitory effect of isoniazid; thus, the overall effect of therapy with isoniazid and rifampin results in a decrease in the concentrations of drugs.
Special Populations
1-Tuberculus Meningitis and Extrapulmonary diseases.
Extrapulmonary disease in adults can be treated in the same manner as pulmonary disease, with 6- to 9-month regimens. TB meningitis should be treated for 9-12 months(3). TB of the bone is typically treated for 9 months, occasionally with surgical debridement (1).
2-Children:
Tuberculosis in children may be treated with regimens similar to those used in adults, although some physicians still prefer to extend treatment to 9 months.
3-Pregnant Women:
Pregnant patients should not receive PZA or streptomycin, and thus a 9-month course of therapy is recommended. Pregnancy-related TB should be treated with INH, RIF, EMB, and pyridoxine for 2 months, after which the EMB can be stopped if the isolate proves to be drug sensitive(3).

Compliance :

Nonadherence to the anti-TB treatment regimen is the most common cause of treatment failure, relapse, and the emergence of drug resistance. A system called "direct observation of therapy" (DOT) was implemented as the preferred care for TB to reduce the incidence of noncompliance. DOT involves providing the anti-TB drugs directly to the patient and observing drug ingestion. DOT therapy can be managed either daily or intermittently in the hospital, office, clinic, home, or school. DOT therapy showed a statistically higher cure rate of TB compared with self-administered therapy, lower rate of relapse, failed therapy, or death from TB (2).
Pharmacist's Role:(2)

1-Pharmacists need to educate patients about side effects of the anti-TB medications and the importance of continuing medications for their full prescribed duration. Minor side effects are usually self-resolving or treatable with either dose reductions or another medication for the specific problem.

2-In addition, pharmacists need to be aware of the drug interactions with rifampin and isoniazid to prevent subtherapeutic or toxic doses of concomitant medications.

3-Pharmacists should take an active role in the improvement of compliance with anti-TB medications to prevent resistance, relapse, or death from TB.

References :
1-Joseph T. DiPiro, Robert L. Pharmacotherapy: A Pathophysiologic Approach, Sixth Edition. Copyright 2005, by The McGraw-Hill Companies, Inc.
2-Angela R. Thomason , and Emily I. Warren . Tuberculosis: A Clinical Review. US Pharm.2005;7:HS-14-HS-22
3-Cooper, Daniel H.; Krainik, Andrew J.; Lubner, Sam J.; Reno, Hilary E. L. Washington Manual of Medical Therapeutics, The, 32nd Edition. Copyright 2007 . Published by Lippincott Williams & Wilkins.