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RS Pharmacology Antituberculosis Yusr Batch

Tuberculosis
Tuberculosis (TB) is caused by Mycobacterium tuberculosis, which can produce
either a silent, latent infection or a progressive, active disease.

 Mycobacteria are rod-shaped aerobic bacilli that multiply slowly, every 18 to 24

hours in vitro.
 Their cell walls contain mycolic acids, which give the genus its name.
 Some nontuberculous mycobacteria such as:
• Mycobacterium kansasii,
• Mycobacterium fortuitum,
• Mycobacterium avium complex (MAC) (very small, has common features
with viral infections due to intracellular infection so can sometimes be very
difficult to treat)
cause infections in patients with other medical problems, especially the
acquired immunodeficiency syndrome (AIDS).
(Considered to be one of the most difficult infections to treat because of its cell wall, has
mycolic acid (very fatty) so some of the drugs cant penetrate. They also have slow
dividing time so it can develop mechanism for drug resistance. Need longer time for
treatment, at least 6 months and in turn low compliance from patients to take 4 different
dugs for 6 months. Could develop Extended resistance (to two medications of first line
and one medication of 2nd line). So length of treatment extends to 2 years.)

Clinical Presentation of Tuberculosis

(Presents most in the elderly, immunocompromised , pregnancy). Geographically, Low

prevalence in Jordan.

Signs and Symptoms

• Patients typically present with weight loss(loss of appetite), fatigue, a

productive cough, fever, and night sweats.
• hemoptysis (cough with sputum and blood)
Sometimes patient test positive for TB but has no symptoms (Latent).

Diagnose using laboratory tests.

Laboratory Tests

• Moderate elevations in the white blood cell (WBC) count with a lymphocyte
predominance. (tuberculin skin test)

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Chest Radiograph

• Patchy or nodular infiltrates in the apical areas of the upper lobes or the
superior segment of the lower lobes.
• Cavitation that may show air-fluid levels as the infection progresses.

Desired Outcomes • The desired outcomes for the treatment of

tuberculosis are:
 Initiation of specific antituberculosis treatment ( the earlier treatment starts the
less chance the TB will develop resistance and develop from pulmonary to extra
pulmonary. Start early even if suspected ( latent ); at least one drug for 9-month
duration)
 Prompt resolution of the signs and symptoms of disease
 Achievement of a noninfectious state in the patient, thus ending isolation
 Adherence to the treatment regimen by the patient (Adherence to treatment
could be enhanced by monitoring side effects)
 Cure of the patient as quickly as possible (generally at least 6 months of
treatment)

Chemotherapy for Tuberculosis

• first-Iine agents for antituberculosis therapy

– Ethambutol, Isoniazid, Pyrazinamide, Rifamycins

• Treatment : combination of 3-4 drugs for 6 months -2 years

(Usually take all 4 for the first 2 months and then only Rifamycins and Isoniazids only
for the remaining 4 months)(Every 2 months, diagnostic tests are needed to check out
the response to treatment)

• Second-Iine medications • either less effective, more toxic, or have not been studied

as extensively.

• useful in patients who cannot tolerate the first-Iine drugs or resistant to the firstIine
agents.

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(not recommended to add more than one drug

because of overlapping toxicity. Aminoglycoside can
cause nephrotoxicity and ototoxicity; can’t be paired
with capreomycin since they are similar. Cycloserine is
very effective but can cause nephrotoxicity.
Fluoroquinolones and macrolides are safe but not as
effective)

Isoniazid (Isonicotinic acid) (INH) (similar to B6)

• synthetic analog of pyridoxine.

• MOA: Block production of mycolic acids (Mycolic acid is b-hydroxylated fatty
acids found in mycobacterial cell walls) Mycolic acid is a lipid, makes waxy layer
around cell wall so drugs find it hard to penetrate waxy layer

• most potent of the antitubercular drugs

– never given as a single

– prodrug that is activated by a mycobacterial catalase- peroxidase (KatG)

• Antibacterial spectrum: Narrow spectrum

– Isoniazid is bacteriostatic, but for rapidly dividing organisms, it is bactericidal.

Isoniazid is a prodrug for bacteria.

It can’t be given alone ; infection will develop resistance within two weeks. Combination
of drugs not only for synergism effect but also to prevent extended resistance , so we
don’t have to use second line drugs as they have serious side-effects.

Isoniazid - PK

• Absorption

– Orally administered isoniazid is readily absorbed on empty stomach.

– Absorption is impaired if isoniazid is taken with food, particularly carbohydrates, or

with aluminum-containing antacids

• Distributed equally

– Easily penetrates cells, even into CNS

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• Undergoes N-acetylation

• Isoniazid undergoes N-acetylation and hydrolysis, resulting in inactive products.

[Note: Isoniazid acetylation is genetically regulated, with the fast acetylators exhibiting a
90-minute serum half-life(medication everyday), as compared to 3 to 4 hours for slow
acetylators(medication taken every other day)]

• Metabolites – in the urine

Isoniazid – side effects

Peripheral neuropathy (more common in slow acetylators)

• paresthesias of the hands and feet due to a relative pyridoxine (B6) deficiency??

B6 responsible for neuropathy(All vitamin B group is responsible but B12 + B6 are the
most)

• Mostly corrected by supplementation of 25 to 50 mg per day of pyridoxine

• Excreted into breast milk it can cause B6 deficiency in children

• Patients with pyridoxine deficiency, such as pregnant women, alcoholics, children, and the
malnourished, are at increased risk. ( as well as the elderly )

– Hepatitis and (hepatotoxicity→ more common in fast acetylators)

caused by a toxic metabolite of monoacetylhydrazine

Monoacetylhyrazine: inactive metabolite and very toxic to the liver

• The incidence increases with age (greater than 35 years old), among patients who
also take rifampin, or among those who drink alcohol daily.

– Hypersensitivity

• Interactions: CYP450 inhibitors

• Inhibits metabolism of phenytoin – CNS toxicity

• Isoniazid may inhibit the metabolism of carbamazepine(cause CNS toxicity), and
warfarin(cause bleeding → reduce warfarin dose)

Rifamycins: Rifampin (inducer for isoniazid), rifabutin and rifapentine

(With Rifampin, be careful with drug-drug interaction)

• MOA: Blocks mycobacterial DNA-dependent RNA polymerase.

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- inhibits mRNA synthesis.

• Broad spectrum: Bactericidal

(Combination with Isoniazid very effective ; rifampin is bactericidal and isoniazid is

bacteriostatic)

Unlike isoniazid , it has broad spectrum : works on G+ve, G-ve and TB.

Penetrates CNS as well.

– Rifampin is bactericidal for both intracellular and extracellular mycobacteria,

including M. tuberculosis, and atypical mycobacteria, such as M. kansasii

– G+ and G- : meningococci, H. influenzae

• Absorbed well after oral. administration.

• Good distribution

– adequate levels in CSF even in the absence of inflammation.

• The drug is taken up by the liver and undergoes enterohepatic cycling

RIFAMPIN

• Rifampin usually is given orally, but it also can be given as a 30-minute

intravenous infusion.
• Oral doses are best given on an empty stomach.
• Rifampin generally is given at 600 mg daily or intermittently

• Rafapentine – long t1/2 – once weekly dosage possible

RIFAMPIN– side effects

• Side effect
• Elevations in hepatic enzymes
• hepatotoxicity occurring in less than1%.
• Urine, tears and feces have an orange-red color;
• Tears may permanently stain soft contact lenses orange-red
• Allergic reactions to rifampin have been reported
• These reactions may take the form of a flu-like syndrome with development of fever,
chills, headache, arthralgias, and, rarely, hypotension

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• Alternatively, hemolytic anemia or acute renal failure may occur, requiring permanent
discontinuation.

RIFAMPIN

• Metabolism:

 Rifampin's potent induction of hepatic enzymes, especially cytochrome P450

3A4, may enhance the elimination of many other drugs

 it shortens its half-life (i.e. autoinduction) → tolerance occurs with time

(concentration in the blood decreases
 women who use oral contraceptives must use another form of contraception
during therapy because increased clearance of the hormones may lead to
unexpected pregnancies.
(Rifampin could be given IV in case of flaring because its autoinduction activity,
tolerance occurs)

Pyrazinamide

(also prodrug for bacteria)

• Pyrazinamide is a synthetic orally effective, bactericidal

• antitubercular agent used in combination with isoniazid, rifampin, and ethambutol.

• mechanism – unknown

– The enzyme Pyrazinamidase hydrolyzed it to pyrazinoic acid – the active form of the
drug

– Some resistant strains lack the pyrazinamidase

• Lipophilic

– Penetrates well including CNS

– It undergoes extensive metabolism.

• S/E

– Rash

– hepatotoxicity

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– Urate retention can also occur and may precipitate a gouty attack →increase
uric acid level (hyperuricemia), so if the patient has gout, it’s not recommended to
use this drug

(Very important monitoring parameter: Liver enzyme) If the patient takes 3 drugs
instead of 4, he must increase the duration of treatment to 9 months instead of 6
months (4 drugs for 6 months)

Ethambutol

• Bacteriostatic (Synergism effect with isoniazid

– specific for most strains of M. tuberculosis and M. kansasii

• MOA: inhibits arabinosyl transferase enzyme important in the synthesis of the
mycobacterial cell wall

• Oral

• Distribution:

– CNS – useful in tuberculosis meningitis.

– parent drug and metabolites are excreted by glomerular filtration and tubular
secretion.

• Side effects:

– optic neuritis

• results in diminished visual acuity and loss of ability to discriminate between red and
green.

• Visual acuity should be periodically examined.

– gout may be exacerbated

• urate excretion is decreased by the drug;

ETHAMBUTOL

• Ethambutol is active against most mycobacteria, including M. tuberculosis and M.

avium, but it is generally bacteriostatic.
• Ethambutol should not be given with antacids.
• For patients with renal failure, the ethambutol dose should be reduced to three
times per week.

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• Visual test should be monitored monthly + kidney function test before starting the
medication + monitoring kidney function monthly

(Ethambutol with isoniazid has synergism effect)

• Second line – anti-TBC

• Ethionamide: (used if treatment with isoniazid failed)

• This is a structural analog of isoniazid that also disrupts mycolic acid synthesis.

• Ethionamide is widely distributed throughout the body, including the CSF.

• Metabolism is extensive, most likely in the liver, to active and inactive metabolites.
• Adverse effects : hepatotoxicity. Hypothyroidism)‫(قصور الغده الدرقية‬, gynecomastia)‫(تثدي‬,
alopecia)‫(ثعلبه‬, impotence)‫(ضعف جنس‬, and CNS effects also have been reported

Second line – anti-TBC

• Less active, more toxic or more active against atypical strains of mycobacteria

• streptomycin – see aminoglycosides (toxic; most effective 2nd-line but only

used if there is resistance after 6-9 months because it is only give iv and causes
oto & nephro-toxicity, given for two weeks iv in hospital)

– streptomycin-resistant organisms may be treated with kanamycin or amikacin

• fluoroquinolones ( not very effective)

– moxifloxacin and levofloxacin,

– treatment of multidrug- resistant tuberculosis →If R.I.P.E. are used but there is resistance,
we use fluoroquinolones.

• cycloserine (toxic)

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– Inhibits cell-wall synthesis – s/e: seizures, neuropathies

• capreomycin (toxic)
– Parenterally - reserved for multidrug-resistant tuberculosis. – monitoring - nephrotoxicity
and ototoxicity.

• Macrolides ( least effective)

– Azithromycin and clarithromycin – for M. avium

– General Approaches to Treatment

• Monotherapy can be used only for infected patients who do not have active
TB (latent infection, as shown by a positive skin test).
• Once active disease is present, a minimum of two drugs, and generally three
or four drugs, must be used simultaneously.
• The duration of treatment depends on the condition of the host, extent of
disease, presence of drug resistance, and tolerance of medications.
• The shortest duration of treatment generally is 6 months, and 2 to 3 years of
treatment may be necessary for cases of multidrug- resistant TB (MDR-TB).
• Because the duration of treatment is so long and because many patients feel
better after a few weeks of treatment, careful follow- up is required.

Treating Latent Infection (We don’t need combination)

• Isoniazid is the preferred drug for treating latent TB infection.

• Generally, isoniazid alone is given for 9 months.
• The treatment of latent TB infection (LTBI) reduces a person's lifetime risk of active
TB from approximately 10% to approximately 1%
• The treatment of LTBI has been called prophylaxis, chemoprophylaxis, or preventive
treatment.

Treating Active Disease

• The treatment of active TB requires the use of multiple drugs.

There are two primary antituberculosis drugs: isoniazid and rifampin, with the rest of
the drugs having specific roles.
• The standard TB treatment regimen is:
isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by
isoniazid and rifampin for 4 months, a total of 6 months of treatment.

‫( طريقة حفظ من الدكتورة‬r.i.p.e. in first four months)

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• Without pyrazinamide, a total of 9 months of isoniazid and rifampin treatment is

required
Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by
DrugSusceptible Organisms

Monitoring Tests for patients with

TB: Liver enzyme, kidney function,
optic visual acuity, uric acid level
test for gout.

Drug resistance should be suspected in the following situations:

• Patients who have received prior therapy for TB

• Patients from areas with a high prevalence of resistance (South Africa, Mexico,
Southeast Asia, the Baltic countries, and the former Soviet states)
• Patients who are homeless, institutionalized, intravenous drug abusers, or infected with
HIV
• Patients who still have acid-fast bacilli-positive sputum smears after 1 to 2 months of
therapy
• Patients who still have positive cultures after 2 to 4 months of therapy
• Patients who fail treatment or relapse after treatment
• Patients known to be exposed to MDR-TB cases
Drug resistance

Empirical therapy with four or more drugs may be needed for acutely ill patients.
• A new term in use, XDR-TB, refers to “extensively drug- resistant TB.” Such organisms
are resistant to at least isoniazid, rifampin, a fluoroquinolone and one second- line
injectable drug (amikacin,capreomycin, or kanamycin).

If someone got infected by TB before, and got infected again, we don’t use the R.I.P.E.
course, instead, we replace one of them with one of the second line drugs.

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Special Populations

1. Tuberculous Meningitis and Extrapulmonary Disease

• Patients with CNS tuberculosis usually are treated for longer periods (9 to 12
months instead of 6 months)
 isoniazid, pyrazinamide ,ethionamide , and cycloserine penetrate the
cerebrospinal fluid readily, but rifampin, ethambutol, and streptomycin have
variable CNS penetration.
 Of the quinolones: levofloxacin may be preferred based on current data.
• Extrapulmonary TB of the soft tissues can be treated with conventional
regimens.
• TB of the bone typically is treated for 9 months
2. Children
• TB in children may be treated with regimens similar to those used in adults, although
some physicians still prefer to extend treatment to 9 months.
• Pediatric doses of isoniazid and rifampin on a milligram-per-kilogram basis are
higher than those used in adults
3. Pregnancy
• Women with TB should be cautioned against becoming pregnant because the
disease poses a risk to the fetus and to the mother.
• If already pregnant, the usual treatment is isoniazid, rifampin, and ethambutol for
9 months (or until she gives birth then change line of treatment)
• Isoniazid or ethambutol are relatively safe for use in pregnant women.
• B vitamins are particularly important during pregnancy and should be provided to
women being treated for TB.
• Pyrazinamide has not been studied in large numbers of pregnant women, but
anecdotal data suggest that it may be safe. → so it’s preferred to use R.I.E. with out
P.

Pregnancy C/I

• Streptomycin use during pregnancy may lead to hearing loss in the newborn,
including complete deafness.
• Ethionamide may cause premature delivery and congenital deformities when used
during pregnancy.
• cycloserine generally cannot be recommended during pregnancy.

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• Ciprofloxacin, levofloxacin, moxifloxacin, and the other quinolones are

associated with permanent damage to cartilage

• Pregnant women with LTBI are not at the same level of risk compared with those
with active disease. Therapy with isoniazid for LTBI may be delayed until after
pregnancy
• Although most antituberculosis drugs are excreted in breast milk, the amount of drug
received by the infant through nursing is insufficient to cause toxicity. Quinolones
should be avoided in nursing mothers, if possible.
4. Renal Failure
• Pyrazinamide and ethambutol typically require a reduction in dosing frequency
from daily to three times weekly
• Serum concentration monitoring must be performed for cycloserine to avoid
doserelated toxicities in renal failure patients
• For nearly all patients, isoniazid and rifampin do not require dose modification in
renal failure. They are eliminated primarily by the liver.

.‫ اللهم إنا نستودعك غزه وأهلها وأرضها ومن عليها يا رب العالمين‬.‫اللهم احفظ غزه بعينك التي ال تنام‬

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