antitubercular drugs
TRANSCRIPT
Antitubercular drugs
Dr. Yahya Ibn Ilias
Tuberculosis remains the most important communicable disease in the world.
The World Health organization (WHO) estimates that one-third of the world’s population is infected with Mycobacterium tuberculosis.
The mycobacteria are slow growing intracellular organisms that require the administration of a combination of drugs for extended periods to achieve effective therapy and to prevent the emergence of resistance.
The risk of adverse reactions therefore must be a major consideration in drug selection.
All Mycobacterium species share a characteristic cell wall, thicker than in many other bacteria, which is hydrophobic, waxy, and rich in mycolic acids / mycolates.
The cell wall consists of the hydrophobic mycolate layer and a peptidoglycan layer held together by a polysaccharide, arabinogalactan.
The biosynthetic pathways of cell wall components are potential targets for new drugs for tuberculosis.
The three basic concepts in tuberculosis treatment are as follows:
(1) Regimens must contain multiple drugs to which the organism is susceptible.
(2) Drugs must be taken regularly.
(3) Drug therapy must continue for a sufficient time.
Traditionally,antituberculosis drugs that are classified as first-line drugs are superior in efficacy and possess an acceptable degree of toxicity.
Most patients with tuberculosis can be treated successfully with these drugs.
Second-line drugs are more toxic and less effective, and they are indicated only when the M.tuberculosis organisms are resistant to the first-line agents.
Therapy with second-line agents may have to be prolonged beyond the standard period of treatment, depending on the clinical, radiographic, and microbiological response to therapy
Classification
First-line drugs: good efficacy, less toxicity and being well tolerated for patients
Ethambutol EMB or E,
Isoniazid INH or H,
Pyrazinamide PZA or Z,
Rifampicin RMP or R,
Streptomycin STM or S.
Second-line drugs: when drug resistance occurs:
Ethionamide Ciprofloxacin/Ofloxacin Cycloserine Kanamycin Para-aminosalicylic acid. Amikacin Clarithromycin Azithromycin
FIRST-LINE ANTITUBERCULARDRUGS
Isoniazid
Mechanism of Action
Isoniazid is active against susceptible bacteria only when they are undergoing cell division.
Susceptible bacteria may continue to undergo one or two divisions before multiplication is arrested.
Isoniazid can inhibit the synthesis of mycolic acids,which are essential components of mycobacterial cell walls.
The mycobacterial enzyme catalase–peroxidase activates the administered isoniazid to its biologically active form.
Antimicrobial Activity
Isoniazid is bacteriostatic for “resting” bacilli but bactericidal for dividing microorganisms.
The minimal tuberculostatic inhibitory concentration (MIC) of isoniazid is 0.025 to 0.05 µ g/mL.
BACTERIAL RESISTANCE
Isoniazid resistance most commonly results from mutations in catalase-peroxidase KatG that decrease its activity, preventing conversion of the prodrug isoniazid to its active metabolite.
Mutations in genes involved in mycolic acid biosynthesis also cause resistance.
Clinical Uses
Isoniazid is among the safest and most active mycobactericidal agents.
It is considered the primary drug for use in all therapeutic and prophylactic regimens for susceptible tuberculosis infections.
It is also included in the first-line drug combinations for use in all types of tuberculous infections.
Isoniazid is preferred as a single agent in the treatment of latent tuberculosis infections in high-risk persons having a positive tuberculin skin reaction with no radiological or other clinical evidence of tuberculosis.
Mycobacterium kansasii is usually susceptible to isoniazid.
Pharmacokinetics
Absorption: Well absorbed following PO/IM administration.
Distribution: Widely distributed; readily crosses the blood-brain barrier. Crosses the placenta; enters breast milk in concentrations equal to plasma.
Metabolism/Excretion: 50% metabolized by the liver 50% excreted unchanged by the kidneys.
Liver: CYP450: 3A4 inhibitor
Half-life: 1–4 hr.
Adverse Effects
Isoniazid-induced Hepatitis and Peripheral neuropathy are two major untoward effects.
Patients with underlying chronic disorders e.g alcoholism, malnutrition, diabetes, and AIDS are at particular risk for neurotoxicity.
Isoniazid promotes renal excretion of pyridoxine, resulting in a relative deficiency and neuropathy.
The neurotoxic effects are reversed without altering the antimycobacterial action by the administration of 10 to 50 mg/day of pyridoxine.
CNS toxicity may range from excitability and seizures to psychosis.
Other adverse reactions include gastrointestinal (GI) intolerance, anemia, rash, tinnitus, and urinary retention.
Drug Interactions
High Isoniazid plasma levels inhibit phenytoin metabolism and potentiate phenytoin toxicity when the two drugs are coadministered.
• Aluminum-containing antacids may decrease absorption .
Contraind./Precautions
Contraindicated in: • Hypersensitivity. • Acute liver disease. • Previous hepatitis from isoniazid.
Use Cautiously in:
• History of liver damage or chronic alcohol ingestion.
• Severe renal impairment (dosage reduction may be necessary)
• Malnourished patients, patients with diabetes, or chronic alcoholics (increased risk of neuropathy) .
• Pregnancy and lactation (although safety is not established, isoniazid has been used with ethambutol to treat tuberculosis in pregnant women without harm to the fetus).
Patient/Family Teaching
• If a dose is missed, take as soon as possible unless almost time for next dose; do not double up on missed doses.
• Advise patient to notify health care professional promptly if signs and symptoms of hepatitis (yellow eyes and skin, nausea, vomiting, anorexia, dark urine, unusual tiredness, or weakness) or peripheral neuritis (numbness, tingling, paresthesia) occur Pyridoxine may be used concurrently to prevent neuropathy.
Any changes in visual acuity, eye pain, or blurred vision should also be reported immediately.
• Caution patient to avoid the use of alcohol during this therapy, as this may increase the risk of hepatotoxicity
• Emphasize the importance of regular follow-up physical and ophthalmologic exams to monitor progress and to check for side effects.
Rifampin/Rifampicin
Mechanism of Action
Rifampin is a semisynthetic macrocyclic antibiotic produced from Streptomyces mediterranei.
It is a large lipid soluble molecule that is bactericidal for both intracellular and extracellular microorganisms.
Rifampin binds strongly to the β -subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis.
Rifampin does not affect mammalian polymerases.
Therapeutic Effects:
• Bactericidal action against susceptible organisms.
Spectrum:
• Broad spectrum activity against :- Mycobacterium sp. Staphylococcus aureus. H. influenzae. Legionella pneumophila. Neisseria meningitidis.
Pharmacokinetics
Absorption: Well absorbed following oral administration.
Distribution: Widely distributed; enters CSF. Crosses placenta; enters breast m
ilk.
Metabolism/Excretion: Mostly metabolized by the liver; 60% eliminated in feces via biliary elimination.
Half-life: 3 hr.
Clinical Uses
Rifampin is a first-line antitubercular drug used in the treatment of all forms of pulmonary and extrapulmonary tuberculosis.
Rifampin is an alternative to isoniazid in the treatment of latent tuberculosis infection.
Rifampin also may be combined with an antileprosy agent for the treatment of leprosy.
Rifampin is also used in methicillin-resistant staphylococcal infections, such as osteomyelitis and prosthetic valve endocarditis
Adverse Reactions
The most commonly observed side effects are GI disturbances and nervous system symptoms, such as nausea, vomiting, headache, dizziness, and fatigue.
Hepatitis is a major adverse effect, and the risk is highest in patients with underlying liver diseases, the rate of hepatotoxicity is increased if isoniazid and rifampin are combined.
Rifampin imparts a harmless red-orange color to urine, feces, saliva, sweat, tears.
Patients should be advised of such discoloration of body fluids.
Use Cautiously in:
• History of liver disease.
• Concurrent use of other hepatotoxic agents.
• Pregnancy or lactation.
Patient/Family Teaching
• Advise patient not to skip doses or double up on missed doses.
• Advise patient to notify health care professional promptly if signs and symptoms of hepatitis (yellow eyes and skin, nausea, vomiting, anorexia, unusual tiredness, weakness) or of thrombocytopenia (unusual bleeding or bruising) occur.
• Inform patient that saliva, sputum, sweat, tears, urine, and feces may become red-orange to red-brown and that soft contact lenses may become permanently discolored.
• Advise patient that this medication has teratogenic properties and may decrease the effectiveness of oral contraceptives. Counsel patient to use a nonhormonal form of contraception throughout therapy.
Pyrazinamide
Mechanism of Action : - is a Prodrug.
Its exact mechanism of action is not known, although its target appears to be the mycobacterial fatty acid synthetase involved in mycolic acid biosynthesis.
M. tuberculosis has the enzyme pyrazinamidase which is only active in acidic conditions.
Pyrazinamidase converts Pyrazinamide to the active form, Pyrazinoic acid which accumulates in the bacilli.
Pyrazinoic acid inhibit the enzyme fatty acid synthetase (FAS), which is required by the bacterium to synthesis fatty acids .
It was also suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection.
Resistance
A mutation in the gene (pncA) that encodes pyrazinamidase is responsible for drug resistance.
Resistance can be delayed through the use of drug combination therapy.
Pharmacokinetics
Absorption: Well absorbed after oral administration.
Distribution: Widely distributed. Reaches high concentrations in the CNS (same as plasma). Excreted in breast milk.
Metabolism/Excretion: Mostly metabolized by the liver. 3–4% excreted unchanged by the kidneys.
Half-life: Pyrazinamide — 9.5 hr. Pyrazinoic acid — 12 hr. Both are prolonged in renal impairment.
Clinical Uses
Pyrazinamide is an important component of short-term (6-month) multiple-drug therapy of tuberculosis.
In combination with isoniazid and rifampin, it is active against the intracellular organisms that may cause relapse.
Note : four-drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol), pyrazinamide is the most common cause of drug-induced hepatitis.
Adverse Reactions
Hepatotoxicity is the major concern in 15% of pyrazinamide recipients.
It also can inhibit excretion of urates, resulting in hyperuricemia.
Nearly all patients taking pyrazinamide develop hyperuricemia and possibly acute gouty arthritis.
Other adverse effects include nausea, vomiting, anorexia ,drug fever, and malaise.
Pyrazinamide is not recommended for use during pregnancy.
Spectrum: • Active against mycobacteria only.
Classifications Antituberculars
Ethambutol
MOA :
Ethambutol is a water-soluble, heat-stable compound that acts by inhibition of arabinosyl transferase enzymes that are involved in cell wall biosynthesis.
Nearly all strains of M. tuberculosis and M. kansasii and most strains of Mycobacterium avium-intracellulare are sensitive to Ethambutol.
Ethambutol has no effect on other bacteria.
Drug resistance
Drug resistance relates to point mutations in the gene (EmbB) that encodes the arabinosyl transferases that are involved in mycobacterial cell wall synthesis.
Pharmacokinetics
Absorption: Rapidly and well absorbed (80%) from the GI tract.
Distribution: Widely distributed; crosses blood-brain barrier in small amounts; crosses placenta and enters breast milk.
Metabolism/Excretion: 50% metabolized by the liver, 50% eliminated unchanged by the kidneys.
Half-life: 3 hr (increased in renal or hepatic impairment).
Time/Action Profile (blood levels)
ROUTE ONSET PEAK DURATION PO rapid 2–4 hr 24 hr
Indications
• Active tuberculosis or other mycobacterial diseases (with at least one other drug).
Adverse Reactions
The major toxicity associated with Ethambutol use is retrobulbar neuritis impairing visual acuity and red-green color discrimination.
This side effect is dose related and reverses slowly once the drug is discontinued.
Mild GI intolerance, allergic reaction, fever, dizziness, and mental confusion are also possible.
Hyperuricemia is associated with ethambutol use due to a decreased renal excretion of urates; gouty arthritis may result.
Therapeutic Effects:
• Tuberculostatic effect against susceptible organisms.
Classifications antituberculars
Patient/Family Teaching
Take missed doses as soon as possible unless almost time for next dose; do not double up on missed doses
Health care professional should also be notified if unexpected weight gain or decreased urine output occurs.
Emphasize the importance of routine exams to evaluate progress and ophthalmic examinations if signs of optic neuritis occur.
Streptomycin
Streptomycin, an aminoglycoside antibiotic was the first drug shown to reduce tuberculosis mortality.
Streptomycin is bactericidal against M. tuberculosis in vitro but is inactive against intracellular organisms.
Most M. tuberculosis strains and nontuberculosis species, such as M. kansasii and M. avium intracellulare, are sensitive.
About 80% of strains that are resistant to isoniazid and rifampin are also resistant to streptomycin.
Multi drug resistance (MDR-TB)
Isoniazid : REZ for 9 – 12 months
Rifampicin : HE for 18 months
If both HR : EZ +quinolone for 9 -12 months +inj. Streptomycin or amikacin for first 4 – 6 months
H – Isoniazide R – Rifampicin S – Streptomycin Z – Pyrazinamide E – Ethambutol
Tuberculosis in pregnant women
H,R and Z
2 HRZ + 4 HR for 6 month
E can be added during late but not early pregnancy.
S is contraindicated
DOTS
DOTS (directly observed treatment, short-course), is the name given to the tuberculosis control strategy recommended by the World Health Organization.
According to WHO, “The most cost-effective way to stop the spread of TB in communities with a high incidence is by curing it.
DOTS has five main components:
Political commitment with increased and sustained financing
Case detection through quality-assured bacteriology
- Bacteriology remains the recommended method of TB case detection, first using sputum smear microscopy and then culture and drug susceptibility testing (DST)
Standardized treatment regimen directly of six to eight months observed by a healthcare worker or community health worker for at least the first two months.
A regular, uninterrupted drug supply.
A standardized recording and reporting system that allows assessment of treatment results.