Upload
raj-kumar
View
2.925
Download
1
Tags:
Embed Size (px)
Citation preview
Tuberculosis
www.freelivedoctor.com
Tuberculosis (TB) remains the leading cause of death 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.
www.freelivedoctor.com
It is estimated that between 2000 and 2020, nearly one 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.
www.freelivedoctor.com
TB is an ancient infectious disease caused by 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 poor public hygiene
www.freelivedoctor.com
With the increased incidence of AIDS, TB has become more a problem in the U.S., and the world.It is currently estimated that 1/2 of the world's population (3.1 billion) is infected with Mycobacterium tuberculosis. Mycobacterium avium complex is associated with AIDS related TB.
www.freelivedoctor.com
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
www.freelivedoctor.com
Once inhaled by a tuberculin free person, the 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
www.freelivedoctor.com
This is known as the primary infection. The patient will 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.
www.freelivedoctor.com
www.freelivedoctor.com
Classification of Drugs 3 Groups depending upon the degree of effectiveness and potential side effects First Line: (Primary agents)
are the most effective and have lowest toxicity. Isoniazid Rifampin
Second Line: Less effective and more toxic effects include (in no particular order): p-amino
salicylic acid, Streptomycin, Ethambutol Third Line
are least effective and most toxic. Amikacin, Kanamycin, Capreomycin, Viomycin, Kanamycin, Cycloserine
www.freelivedoctor.com
Isoniazid
Considered the drug of choice for the chemotherapy of TB. discovered in 1945 a hydrazide of isonicotonic acid is bacteriostatic for resting bacilli, bactericidal for growing bacilli.
www.freelivedoctor.com
Mechanism of action
Unknown, but the hypothesis include effects on lipids, nucleic acid and biosynthesis. Primary action seems to inhibit the biosynthesis of mycolic acids which are part of cell wall structure.
www.freelivedoctor.com
www.freelivedoctor.com
Resistance
Organism eventually develops resistance. The mechanism of resistance is related to the 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.
www.freelivedoctor.com
Pharmacokinetics
Absorption: INH rapidly absorbed either oral or parenteral route. Peak [plasma] of 3-5 micrograms/milliliter after oral administration. Distribution: Diffuses readily into all bodily fluids
does not bind to plasma proteins In the CSF the [conc] is about 20% of
[plasma], t1/2 =1-3 hrs.
www.freelivedoctor.com
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
www.freelivedoctor.com
Excretion cont.
Those that have slow acetyl transferase activity are slow acetylators, may produce more of the toxic intermediate.This is an inherited trait ==> Autosomal DominantThe average [plasma] will be (1/3) to (1/2) of the 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 Asians are fast aceytlators,
www.freelivedoctor.com
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.
www.freelivedoctor.com
Age dependency
% incidence age
0.13 25
.59 35
1.09 45
1.75 55
2.5 >60
www.freelivedoctor.com
Patients with renal failure, the normal dose can be given, because it is secreted in the inactive form.Patients with hepatic insufficiency - give a reduced dose of the drug.ETOH causes induction of drug metabolizing enzymes, Isoniazid is broken down faster. Leads to lsoniazid hepatotoxicity.Glucose 6- Phosphate deficiency. People with a deficiency of Glucose-6-phosphate cannot adequately process the drug.
www.freelivedoctor.com
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
www.freelivedoctor.com
Rifampin
Mechanism of ActionRifampin inhibits DNA dependent RNA polymerase of the bacilli.
www.freelivedoctor.com
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.
www.freelivedoctor.com
PharmacokineticsAbsorption
peak levels reached 2-4 hrs. after oral doserapidly eliminated in the bile and reabsorbed (enterohepatic circulation) It can be delayed with use of aminosalicylic acid.during this time there is a progressive deacylation of the drug;the metabolites maintain full effectHalf life is 6 hours.
www.freelivedoctor.com
Distribution:Throughout the total body waterPresent in effective concentrations in many organs and body fluids including CSF,With Rifampin you must warn patients: The drug has an orange red color in body excretions, This color will be imparted to all body fluids.
www.freelivedoctor.com
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
www.freelivedoctor.com
Allergic Reactions FeverSkin EruptionsRashPruritisRifampin does induce microsomal drug metabolizing enzymes. This will decrease the half-life of some other drugs. (ie. phenytoin, digitoxin)
www.freelivedoctor.com
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.
www.freelivedoctor.com
2nd Line Drugs: Not as effective
and have more toxicity
Streptomycin The first drug used clinically for treatment of TB 1947-1952; was the only drug available at that time.is an aminoglycoside antibioticacts by protein synthesis inhibitor and decreases the fidelity mRNA and garbles the message, leads to nonsense proteins.Streptomycin only binds to the 30s subunit.
www.freelivedoctor.com
Adverse Effects: affects C. Nerve 8: auditory and vestibular functions. - this drug is now 2nd 'line because of its toxicity.
www.freelivedoctor.com
para- Aminosalicylic Acid
a structural analog of PABA (p-aminobenzoic acid) is bacteriostatic inhibits de novo folate synthesishalf life = 1 hour after 4 g. doseyou can give this drug up to 12 grams per 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.
www.freelivedoctor.com
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 ulcersHypersensitivity reactions Rash, Fever some hepatotoxicityAll will disappear when the drug is stoppedThis drug has poor patient acceptability and compliance:
www.freelivedoctor.com
Third Line Drugs - least effective and most toxic
Third line drugs are used when resistance is developed to 1st and 2nd line drugs; these drugs are also used in combination.Aminoglycosides Capreomycin - Viomycin - Kanamycin
www.freelivedoctor.com
Adverse effects
These drugs are: Nephrotoxic - will cause Proteinuria, Hematuria, Nitrogen metabolism, and Electrolyte disturbances However effect is reversible when drug is stopped.
www.freelivedoctor.com
Ototoxic will result in deafness and some loss of 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.
www.freelivedoctor.com
Cycloserinecan 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: An analog of D-alanine synthetase, will block bacterial cell wall synthesis.
www.freelivedoctor.com
Pharmacokinetics: Rapidly absorbed Peak [plasma] 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
www.freelivedoctor.com
Toxicity: Most common in the CNS: Headache, Tremor, Vertigo, Confusion, Nervousness, Psychotic states with suicidal tendencies , Paranoid reactions, Catatonic and depressed reactions
www.freelivedoctor.com
Chemoprophylaxis of TBUsed only in high risk groups
Household members and other close contacts of a patient with active TB.A positive skin test in persons less than 35 years.A positive skin test reactive in the immunosuppressed, persons with leukemia, and Hodgkin's Disease,HIV + patients with a positive TB test,
www.freelivedoctor.com
The drug of choice for chemoprophylaxis is 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.
www.freelivedoctor.com
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 weeksFirst and second line agents are usually given orally. Third line drugs are given parenterally.
www.freelivedoctor.com
Treatment
Isoniazid, Ethambutol, & Rifampin are given for 2 months.Isoniazid & Rifampin are given for 4 months.If you suspect resistance to isoniazid use Isoniazid, 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
www.freelivedoctor.com
Antitubercular Agents
Tuberculosis, “TB”Caused by Mycobacterium tuberculosisAntitubercular agents treat all forms of mycobacterium
Mycobacterium Infections
Common Infection Siteslung (primary site)brainboneliverkidney
Mycobacterium Infections
Aerobic bacillusPassed from infected: Humans Cows (bovine) Birds (avian)
Mycobacterium Infections
Tubercle bacilli are conveyed by droplets.Droplets are expelled by coughing or sneezing, then gain entry into the body by inhalation.Tubercle bacilli then spread to other body organs via blood and lymphatic systems.Tubercle bacilli may become dormant, or walled off by calcified or fibrous tissue.
Antitubercular Agents
Primary Agents Secondary Agents
isoniazid* capreomycinethambutol cycloserinepyrazinamide (PZA) ethionamiderifampin kanamycinstreptomycin para-aminosalicyclic
acid (PSA)*most frequently used
Antitubercular Agents: Mechanism of Action
Three GroupsProtein wall synthesis inhibitors streptomycin,
kanamycin, capreomycin, rifampin, rifabutinCell wall synthesis inhibitors cycloserine,
ethionamide, isoniazidOther mechanisms of action
Antitubercular Agents:Mechanism of Action isoniazid (INH)
Drug of choice for TBResistant strains of mycobacterium emergingMetabolized in the liver through acetylation—watch for “slow acetylators”
Used for the prophylaxisor treatment of TB
Antitubercular Agents:Therapeutic Uses
Antitubercular Therapy
Effectiveness depends upon:Type of infectionAdequate dosingSufficient duration of treatmentDrug complianceSelection of an effective drug combination
Antitubercular Agents: Side Effects
INHperipheral neuritis, hepatotoxicityethambutolretrobulbar neuritis, blindnessrifampinhepatitis, discoloration of urine, stools
Antitubercular Agents: Nursing Implications
Obtain a thorough medical history and assessment.Perform liver function studies in patients who are to receive isoniazid or rifampin (especially in elderly patients or those who use alcohol daily).Assess for contraindications to the various agents, conditions for cautious use, and potential drug interactions.
Antitubercular Agents: Nursing Implications
Patient education is CRITICAL:Therapy may last for up to 24 months.Take medications exactly as ordered,
at the same time every day.Emphasize the importance of strict compliance
to regimen for improvement of condition or cure.
Antitubercular Agents: Nursing Implications
Patient education is CRITICAL:Remind patients that they are contagious
during the initial period of their illness—instruct in proper hygiene and prevention of the spread of infected droplets.
Emphasize to patients to take care of themselves, including adequate nutrition and rest.
Antitubercular Agents: Nursing Implications
Patients should not consume alcohol while on these medications nor take other medications, including OTC, unless they check with their physician.Diabetic patients taking INH should monitor their blood glucose levels because hyperglycemia may occur.INH and rifampin cause oral contraceptives to become ineffective; another form of birth control will be needed.
Antitubercular Agents: Nursing Implications
Patients who are taking rifampin should be told that 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 associated with INH therapy.
Antitubercular Agents:Nursing Implications
Monitor for side effectsInstruct patients on the side effects that
should be reported to the physician immediately.
These include fatigue, nausea, vomiting, numbness and tingling of the extremities, fever, loss of appetite, depression, jaundice.
Antitubercular Agents:Nursing Implications
Monitor for therapeutic effects:Decrease in symptoms of TB, such as cough
and feverLab studies (culture and sensitivity tests)
and CXR should confirm clinical findingsWatch for lack of clinical response to therapy,
indicating possible drug resistance