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worldwide from a single infectious disease agent. Indeed up to 1/2 of the world's population is infected with TB. The registered number of new cases of TB worldwide roughly correlates with economic conditions: the highest incidences are seen in those countries of Africa, Asia, and Latin America with the lowest gross national products. WHO estimates that eight million people get TB every year, of whom 95% live in developing countries. An estimated 2 million people die from TB every year.
billion people will be newly infected, 200 million people will get sick, and 35 million will die from TB - if control is not further strengthened. The mechanisms, pathogenesis, and prophylaxis knowledge is minimal. After a century of decline TB is increasing and there are strains emerging which are resistant to antibiotics. This excess of cases is attributable to the changes in the social structure in cities, the human immunodeficiency virus epidemic, and failure of most cities to improve public health programs, and the economic cost of treating.
Mycobacterium tuberculosis. It has been known since 1000 B.C., so it not a new disease. Since TB is a disease of respiratory transmission, optimal conditions for transmission include:
overcrowding poor personal hygiene
population (3.1 billion) is infected with Mycobacterium tuberculosis. Mycobacterium avium complex is associated with AIDS related TB.
Transmission
Pulmonary tuberculosis is a disease of respiratory
transmission, Patients with the active disease (bacilli) expel them into the air by:
coughing, sneezing, shouting, or any other way that will expel bacilli into the air
bacilli multiply 4 -6 weeks and spreads throughout the body. The bacilli implant in areas of high partial pressure of oxygen:
lung
renal cortex reticuloendothelial system
heal and a scar will appear in the infected loci. There will also be a few viable bacilli/spores may remain in these areas (particularly in the lung). The bacteria at this time goes into a dormant state, as long as the person's immune system remains active and functions normally this person isn't bothered by the dormant bacillus.
When a person's immune system is depressed., a
secondary reactivation occurs. 85-90% of the cases seen which are of secondary reactivation type occurs in the lungs.
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Classification of Drugs
3 Groups depending upon the degree of
Isoniazid
Considered the drug of choice for the chemotherapy of TB.
Mechanism of action
Unknown, but the hypothesis include effects on lipids,
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Resistance
Organism eventually develops resistance.
failure of the drug to penetrate or be taken up by the micro-organism (by active transport system),
Remember treatment is up to 2 years.
Pharmacokinetics
Absorption: INH rapidly absorbed either oral or
Excretion
75-95% of a dose excreted in the urine in 24 hr.
- Mostly as a metabolite.
- The main excretory product- acetylisoniazid.
This is a result of enzymatic acetylation, Very important in terms of metabolism, Isoniazid is under genetic control, There are 2 groups of people. Fast and slow acetylators
Excretion cont.
Those that have slow acetyl transferase activity are
slow acetylators Average t1/2, is less than 90 minutes, in the slow acetylators, t1/2 will be about 3 hours.
Ethnicity- Eskimos,Native American Indians, and
Adverse Effects
Induced Hepatitis (2% of Population) due to the
buildup of toxic metabolic products of acetylisoniazid --> acetylhydrazine. This is more frequent in slow acetylators.
Hepatic reactions to Isoniazid are also age
dependent
There is a 250X increase in the incidence of hepatitis
over age. More frequent in the fast acetylators when measured intragroup, (Compare elderly fast acetylators patients with elderly slow patients,) Ranges from mild hepatitis to serious tissue necrosis.
Age dependency
% incidence 0.13 .59 age 25 35
1.09
1.75
45
55
2.5
>60
Drug Interaction
Competition between Isoniazid and Phenytoin
(anticonvulsant). They both compete for drug metabolism enzymes. Phenytoin interferes with metabolism of isoniazid by reduction in excretion or enhancement of effect of isoniazid
Rifampin
Mechanism of Action
Rifampin inhibits DNA dependent RNA polymerase of the
bacilli.
Resistance:
Due to alteration of the target (DNA dependent RNA
polymerase) of the drug, prevents further initiation but not elongation. The micro-organism can change the structure of the enzyme so that the drug no longer has an effect.
Pharmacokinetics
Absorption
Distribution:
has an orange red color in body excretions, This color will be imparted to all body fluids.
Adverse Effects:
Does not cause many side effects in any great frequency. G.I. reactions: Anorexia, Nausea ,Vomiting Mild
abdominal pain, Hepatic Reactions in children, pregnant women and alcoholics, can result in minor elevations in serum transaminase as some jaundice
Allergic Reactions
Fever Skin Eruptions Rash Pruritis
metabolizing enzymes. This will decrease the half-life of some other drugs. (ie. phenytoin, digitoxin)
WARNING!
Rifampin and Isoniazid are the most effective drugs for the treatment of TB, The drug enjoys high patient compliance and acceptability. But these 2 drugs should never be given alone! They are always used in combination because resistance occurs to one drug alone very rapidly. They are used in combination with each other initially as well as other drugs. Bacilli must become resistant to two drugs in order to remain viable. Statistically, the chances are verv small of the bacilli becoming resistant to both. . Prophylaxis is with one drug usually isoniazid.
the fidelity mRNA and garbles the message, leads to nonsense proteins.
Streptomycin only binds to the 30s subunit.
Adverse Effects:
day. 80% of the drug is excreted in the urine and 50% of that is as an acetylated metabolite which is insoluble. You must make sure the patient's urine is normal or alkaline.
Adverse effects
GI irritation due to the amount of drug given
(high doses) nausea, vomiting, bleeding, occurs in 30-40% of the patients. be careful with those who have peptic ulcers
hepatotoxicity
Hypersensitivity reactions Rash, Fever some All will disappear when the drug is stopped
compliance:
1st and 2nd line drugs; these drugs are also used in combination.
Aminoglycosides Capreomycin - Viomycin - Kanamycin
Adverse effects
These drugs are: Nephrotoxic - will cause Proteinuria,
Hematuria, Nitrogen metabolism, and Electrolyte disturbances However effect is reversible when drug is stopped.
vestibular function, leads to cranial nerve 8 damage. The nerve damage is permanent.
Capreomycin has replaced viomycin because of less
toxic effects, but all three drugs have the same effects.
Cycloserine
can cause CNS disturbances Therapeutic States
Cycloserine should be used when re-treatment is necessary or when the micro-organism is resistant to the other drugs.
It must be given in combination with other anti-
tuberculosis drugs.
Mechanism of Action:
occurs in 3-4 hours Distributed throughout all body fluids, including CSF About 50% is excreted in unchanged form in the urine during the first 12 hours. Only about 35% of the drug metabolized This drug can accumulate to toxic conc in patients with renal insufficiency
Toxicity:
Confusion, Nervousness, Psychotic states with suicidal tendencies , Paranoid reactions, Catatonic and depressed reactions
Chemoprophylaxis of TB
Used only in high risk groups
Household members and other close contacts of a patient
isoniazid. Prophylaxis uses only one drug. In patients who are HIV+ and TB+ and have the disease; they are treated for a minimum of 9 months, The first 2 months using isoniazid and rifampin and for the next 7 months or longer, use only 2 or 3 of the 2nd/3rd line drugs and Isoniazid/Rifampin.
Chemotherapy of TB
Most patients are treated in an ambulatory setting -
admitted to the hospital - diagnosis is established initiate and stabilize therapy - send patient home , usually after 2 or 3 weeks
First and second line agents are usually given orally.
Treatment
Isoniazid, Ethambutol, & Rifampin are given for 2
months.
Isoniazid & Rifampin are given for 4 months.
Ethambutol, Rifampin & Parazinamide. Incidence of drug resistance is 2-5% in the U.S.
Prolonged bed rest is not necessary or helpful in
obtaining a speedy recovery. The patient must be seen at regular and frequent intervals to follow the course of the disease and treatment. Look for toxic effects
Antitubercular Agents
Tuberculosis, TB
Mycobacterium Infections
Common Infection Sites
lung (primary site)
brain bone liver kidney
Mycobacterium Infections
Aerobic bacillus
Birds (avian)
Mycobacterium Infections
Tubercle bacilli are conveyed by droplets. Droplets are expelled by coughing or sneezing,
Antitubercular Agents
Primary Agents isoniazid* Secondary Agents capreomycin
ethambutol
pyrazinamide (PZA) rifampin streptomycin
*most frequently used
cycloserine
ethionamide kanamycin para-aminosalicyclic acid (PSA)
isoniazid
Other mechanisms of action
Antitubercular Therapy
Effectiveness depends upon:
Type of infection Adequate dosing Sufficient duration of treatment Drug compliance Selection of an effective drug combination
who are to receive isoniazid or rifampin (especially in elderly patients or those who use alcohol daily).
Assess for contraindications to the various agents,
the initial period of their illnessinstruct in proper hygiene and prevention of the spread of infected droplets.
Emphasize to patients to take care of themselves,
medications nor take other medications, including OTC, unless they check with their physician.
Diabetic patients taking INH should monitor their
urine, stool, saliva, sputum, sweat, or tears may become reddish-orange; even contact lenses may be stained.
Vitamin B6 may is needed to combat peripheral neuritis
and fever
Lab studies (culture and sensitivity tests)