The complex drug therapy of tuberculosis products is dominated by chemotherapeutic
agents. These include the following drugs:
A. Synthetic funds
I series (basic)
II series (back-up)
isoniazid Ethionamide
pyrazinamide
ethambutol Prothionamide
Sodium p-aminosalicylate
thioacetazone
(PAS).
Bepask
B. Antibiotics
I series (basic)
II series (back-up)
rifampicin Cycloserine
Streptomycin sulfate,
kanamycin sulfate
Streptomycin sulfate,
florimitsin
calcium chloride complex
On Antimicrobial spectrum of these groups means differ
significantly. Synthetic agents act only on Mycobacterium
tuberculosis (individual compounds are effective against
Mycobacterium and leprosy). On the other they do not affect
the microorganisms. At the same time, the antibiotics used in
the treatment of tuberculosis, characterized by a wide
spectrum of antimicrobial action.
Anti-TB drugs have mainly bacteriostatic effect. However,
some drugs cause certain concentrations and bactericidal
effect (isoniazid, rifampicin, streptomycin). The mechanism
of action of TB drugs has not been studied.
Taking into account the duration of the treatment of tuberculosis (12-18
months or more) of particular importance is the problem of drug
resistance. In principle, the stability of Mycobacterium tuberculosis
develops all drugs, but to the one it occurs quickly (rifampicin,
streptomycin), the other - relatively slowly (eg, sodium paraaminosalicylate). To reduce the rate of development of resistance
usually 2-3 kombi¬niruyut drug. At the beginning of the simultaneous
use of a number of treatment antitubercular agents also makes sense
because of the sensitivity of the pathogen in a patient known to certain
drugs, and can be established only after a few weeks. However, the
sooner treatment is started, the more successful it is. Therefore,
chemotherapy is started without waiting for the results of
bacteriological studies. Typically, this provides the desired therapeutic
effect, since strains of Mycobacterium tuberculosis that are resistant to
both drugs 2-3, are relatively rare.
Recently proposed the following classification n / TB
means:
I group - the most effective drugs: isoniazid and
rifampicin
Group II - preparations average efficiency:
ethambutol, streptomycin, ethionamide,
pyrazinamide, kanamycin, cycloserine, florimitsin;
Group III - drugs with moderate efficiency: Pasco,
tioatsetazon.
The search for new anti-TB drugs are ongoing. The
challenge is to create a high-level and low-toxic
drugs devoid of side effects. It is important that
resistance to them Mycobacterium tuberculosis may
develop more slowly. Should take into account the
economic side. Such drugs should be available for
widespread use in medical practice, especially since
the treatment of very long.
Anti-TB drugs in group I
a) Synthetic means
The main representative of the group of isonicotinic acid hydrazide (Ginko)
is isoniazid (tubazid, izonitsid). He is highly active against Mycobacterium
tuberculosis (superior streptomycin). Unlike streptomycin affects both
intracellularly located Mycobacterium tuberculosis. Has an inhibitory effect
on the causative agent of leprosy. Other microorganisms to isoniazid
insensitive.
On Mycobacterium tuberculosis isoniazid has a bacteriostatic or bactericidal
effect, the mechanism of which has not yet been elucidated. There is
evidence that isoniazid inhibits the synthesis micole acids is an important
structural component of the cell wall of Mycobacterium tuberculosis. With
this tie and high selectivity of isoniazid on Mycobacterium hook in host
tissue, as well as from other microorganisms micole acids not. It is not
excluded that a certain value is inhibition of nucleic acid synthesis.
Stability of Mycobacterium tuberculosis to isoniazid develops much more
slowly than to streptomycin and rifampicin.
Isoniazid is well absorbed from the gastrointestinal tract. After 1-2 hours,
it accumulates in the maximum blood plasma concentrations. The drug is
easily penetrates through tissue barriers and relatively evenly distributed
throughout all tissues. Found in bacteriostatic concentrations in the
cerebrospinal fluid and serous cavities. Most of isoniazid undergoes
chemical reactions with the formation of metabolites and conjugates. One
of the important ways of inactivation of isoniazid in the body is
acetylation. Found that the rate of this process is genetically determined.
In some individuals there is a slow inactivation of isoniazid, while its
concentration in the body decreases more gradually than in the case of
rapid inactivation of the drug. Rate of decline in plasma INH 50% of these
groups can vary by 2.5 times. It is natural that these features should be
considered when dosing of isoniazid, as it affects not only the maintenance
of bacteriostatic concentrations of the substance, but also the development
of side effects.
The basic amount of isoniazid and its conversion products released during
the 1st day. They are derived mainly kidneys.
Isoniazid is used in all forms of tuberculosis. Enter drug usually on the
inside, sometimes rectally. If necessary, it can be administered
intravenously (it is well soluble), intramuscular injection. Isoniazid
solutions used for washing also serous cavities and sinus tracts.
Isoniazid may be accompanied by various side effects. The main negative
feature of isoniazid is its neurotoxicity. It is manifested mainly neuritis,
including sometimes marked optic nerve damage. Possible adverse effects
of the central nervous system (insomnia, seizures, mental disorders,
memory disorders, impaired balance). In some patients the dryness of the
mouth cavity, nausea, vomiting, constipation, mild anemia. Allergic
reactions are rare relative-enforcement. In some cases there are skin
reactions, fever, eosinophilia.
Many of the side effects associated with inhibition of isoniazid formation
process pyridoxal phosphate, which is a coenzyme necessary for the
various reactions of amino acids.
In this connection, to prevent side effects (e.g., neurite
outgrowth) administered simultaneously with isoniazid,
pyridoxine (vitamin B6).
Allergic reactions eliminate anti-allergic agents.
The derivatives of isonicotinic acid hydrazide are also
ftivazid, metazid, salyuzid soluble. All of them are less
active than isoniazid, and there are no advantages in
comparison with it are not. Use them rarely, usually
isoniazid intolerance.
b) Antibiotics
Rifamycin group
Rifampicin (rifotsin) is an antibiotic produced by Sterptomyces
mediterranei. It represents the structure of the macrocyclic complex. This
group is a semi-synthetic drug rifampicin (rifampin, rifadin, rimaktan).
Both compounds have a pronounced effect on Mycobacterium leprae and
tuberkuse and Gram-positive bacteria. In high concentration active against
Gram-negative organisms (Escherichia, capsular bacteria, some strains of
Pseudomonas aeruginosa, Shigella, Salmonella) and some species of
Proteus.
The mechanism of antimicrobial action of the rifamycin group of
antibiotics is associated with inhibition of RNA synthesis (probably due to
inhibition of DNA-dependent RNA polymerase). They exert bacteriostatic
and bactericidal effect higher concentrations.
Especially interesting rifampicin, which when administered in activity
approaching isoniazid. Rifampicin is well absorbed from the
gastrointestinal tract. Its maximum concentration in the blood is
determined after 2-4 hours. It is readily penetrate through tissue barriers
including the blood brain barrier. The therapeutic effect lasts up to 8-12
hours. Provided the drug in the bile, partly in the urine, and bronchial tear
glands.
The main application - the treatment of all forms of tuberculosis.
However, rifampicin fairly quickly develop resistance of
Mycobacterium tuberculosis, and therefore it is advisable to
combine with other anti-TB agents. Rifampicin is used also in cases
when other drugs are ineffective.
Rifampicin appointed interior and a / c, rifampicin - intramuscularly,
intravenously and topically.
Preparations of rifamycin may have a negative effect on liver
function (especially against the background of existing disease or
long use of drugs). Leucopenia. A number of patients, there
diarrheal disorders. Sometimes there allergic reactions. It is not
recommended to use these antibiotics in the first 3 months of
pregnancy (not eliminate the adverse effects on the fetus). Keep in
mind that rifampicin stains urine, sputum and tear fluid in red. One
of the drawbacks of rifampicin is its high cost.
Antituberculosis drugs group II
a) Synthetic means
TB is characterized by high activity of ethambutol (diambutol, miambutol). The
experimental data, when given enterally ethambutol isoniazid is similar in activity. On the
other microorganisms are not affected. The mechanism of action of ethambutol is
associated with inhibition of cell wall synthesis. Stability of mycobacteria to ethambutol
develops relatively slowly.
From the gastrointestinal tract the drug is not fully absorbed (about 3/4), but sufficient to
provide an amount of a bacteriostatic effect. Maximum plasma concentrations are 2-4
hours; reduction of 50% occurs after about 8 hours.
Provided mainly kidneys for 1 nights stay. Found in the urine unchanged ethambutol
(90%) and its metabolites. A small portion of the intestine is displayed (about 20%).
Ethambutol prescribed for different forms of tuberculosis, usually in combination other
drugs (eg, rifampicin + ethambutol + isoniazid, rifampicin + ethambutol, isoniazid +
ethambutol).
Of the side effects of ethambutol for the most typical visual impairment (including color
perception disorder, especially the ability to distinguish green and red colors). If there is
optic neuritis, this complication takes a severe course. Impairment typically occur 2-6
months after the beginning of treatment and ethambutol dose dependent substance.
With timely elimination of the drug eyesight gradually restored. Because of the possibility
of such a side effect of ethambutol treatment is performed under systematic control of
visual function. Allergic reactions ethambutol is rare.
The spectrum of action of ethionamide (tionid, trekator) includes the
causative agent Mycobacterium tuberculosis and leprosy. Getting used to it
Mycobacterium tuberculosis occurs quickly, so it is always used in
combination with other drugs.
From the gastrointestinal tract is absorbed well. At the maximum
concentration in the plasma accumulated in about 3 hours. Ethionamide
penetrates quite well through the blood brain barrier. Rapidly inactivated in
the liver and excreted in the urine primarily as metabolites.
Enter product inside and rectally. For intravenous use ethionamide
hydrochloride.
Ethionamide often causes side effects. Most expressed his irritating. Thus,
arising from the ingestion of dyspeptic symptoms (sometimes difficult runs)
are observed in approximately 50% of patients. To reduce them appoint
nicotinamide. There are also allergic reactions. Sometimes develop hepatitis,
orthostatic collapse, disorders of the central and peripheral nervous systems,
and many other side effects.
Similarly, the drug is prothionamide (treventiks). There is evidence that it is
somewhat less toxic than ethionamide.
Pyrazinamide for tuberculostatic activity exceeds the PAS, but inferior to
isoniazid, rifampicin and streptomycin. On the other organisms are not
affected. When applying only pyrazinamide it quickly develops resistance of
Mycobacterium tuberculosis.
Is well absorbed from the gastrointestinal tract and accumulated in maximal
concentrations in plasma after 1-3 hours. Penetrates the blood-brain barrier.
The basic amount of pyrazinamide and its metabolites are excreted by the
kidneys.
Used in combination with other drugs. Pyrazinamide administered enterally
3-4 times a day.
Of the side effects is the most serious hepatotoxicity. In this regard, the use of
pyrazinamide requires systematic monitoring of liver function. Abnormal
liver function is the basis for the abolition of the drug. A number of patients
are also observed dyspeptic symptoms, delay in the body of uric acid under
the influence of pyrazinamide sometimes leads to gout attacks. There may be
allergic reactions (fever, dermatitis, eosinophilia, and others.).
B) Antibiothics
Group streptomycin
Other antibiotics
Cycloserine produced a variety of actinomycetes: Actinomyces orchidaceus,
Actinomyces gryphalus, Actinomyces lavendulae. Also obtained synthetically. As a
medicine used D-isomer of cycloserine.
It has a wide spectrum of action. The most effective against extracellular and
intracellular Mycobacterium tuberculosis (inferior to the activity of isoniazid,
rifampicin, streptomycin). In other microorganisms affects only at high
concentrations.
Cycloserine bactericidal effect by disrupting cell wall synthesis. This is due to the fact
that they possess chemical similarity to D-alanine, cycloserine on competitive
principle able to inhibit the activity of enzymes D-alanine racemase and Dalaninsintetazy. As a result, the formation is broken dipeptide D-alanyl-D-alanine
required to construct a number of bacterial cell wall.
Stability of Mycobacterium tuberculosis to cycloserine develops relatively slowly.
From the gastrointestinal tract cycloserine absorbed well. 2-4 hours in plasma
determined by the maximum concentration of the drug. The plasma protein does not
bind cycloserine. It penetrates into the cerebrospinal fluid, where its concentration
similar to those in plasma.
1/3 entered cycloserine subjected to chemical transformations, the drug is released by
the kidneys (in the 1st day of about 50%).
Indications for cycloserine is intolerance or ineffectiveness of other antiTB drugs. The best results were observed in the combined use with other
drugs cycloserine group I or II. Putting it inside.
When using cycloserine frequently observed side effects. Basically it is
the neuro-psychiatric disorders: headache, dizziness, tremors,
convulsions, anxiety or depression, psychosis. Sometimes there
dyspepsia. Allergic reactions are rare.
For correction of changes in the CNS administered pyridoxine, glutamic
acid, ATP preparations.
Kanamycin is a producer Streptomyces kanamyceticus. Kanamycin has a
wide range of actions, including Mycobacterium tuberculosis, many
Gram-positive and Gram-negative bacteria. To him insensitive
streptococci (except enterococci), pneumococci. It has no effect on
Pseudomonas aeruginosa, anaerobes, spirochetes, pathogenic fungi and
viruses true.
Its mechanism of antimicrobial action associated with inhibition of
protein synthesis in bacteria. Kanamycin has both bacteriostatic
and bactericidal action.
Addictive bacterial kanamycin developing quite rapidly. From the
gastrointestinal tract the drug is absorbed to a small extent. For
resorptive action, he was appointed by intramuscular injection.
When this route of administration the maximum concentration in
the plasma determined kanamycin approximately in 1 hour. The
antibacterial effect is kept to 6-12 hours. After the blood-brain
barrier kanamycin hardly penetrates. Excreted by the kidneys.
In medical practice, use of kanamycin as a Group II anti-TB drug,
as well as infection with Gram-negative organisms (Escherichia
coli, bacteria capsular et al.), Proteus, Staphylococcus aureus, and
other agents that are sensitive to kanamycin. The basis for the use
of kanamycin is the inefficiency of other antibiotics.
In addition to intramuscular injection formulation may be introduced into
the body cavity. In addition, it is sometimes appointed interior (for
suppression of intestinal microflora).
Kanamycin is highly toxic. Thus, it has a higher ototoxicity than
gentamicin and streptomycin (but less than neomycin).
The appearance of tinnitus is a reason to remove the drug, as it may cause
damage as a result of the auditory nerve irreversible hearing loss up to a
full hearing. Ototoxic effect of kanamycin is especially dangerous during
long-term use of antibiotics (to treat tuberculosis). Vestibular disorders
occur relatively rarely. Kanamycin and has distinct nephrotoxicity. In this
regard, the treatment must be monitored not only hearing condition, but
also the function of the kidneys. Furthermore, it is possible negative effect
on the liver. Sometimes there allergic reactions. Contraindications and
precautions are the same as in the application of neomycin and
gentamicin.
To the anti-media group II from the antibiotics also include capreomycin
sulfate and florimitsina (viomycin).
Group III anti-TB drugs
a) Synthetic means
This group of reserve antituberculosis drugs represented compounds of
different chemical structure. These include PAS and tioatsetazon. Each of
these substances is used in combination with drugs dru¬gimi.
Sodium p-aminosalicylate (PAS) has a bacteriostatic effect on Mycobacterium
tuberculosis. Its mechanism of action is due to the competitive relationship
with para-amino benzoic acid, essential for the growth and multiplication of
Mycobacterium tuberculosis. On the other it does not affect microorganisms.
Activity sodium para-aminosalicylate low. In this regard, it is used only in
combination with other, more active agents. As already noted, the stability of
PAS develops slowly.
Sodium para-aminosaliiilat well absorbed from the digestive tract. The
maximum concentration in plasma determined after 1-2 h. A large part of the
drug (about 50%) bound to plasma proteins. In serous cavities accumulate in
sufficient quantities. Penetrates the blood-brain barrier to a small extent.
After 6h plasma levels found in low concentrations. Derived from the
organism in unchanged form by the kidneys, as well as metabolites and
conjugates (mainly acetylated derivative para-aminosalicylic acid). Within 6
hours, about 60% is released and after 24 hours - about 90% of the
administered dose.
Used in all forms of tuberculosis. Usually appointed inside, sometimes resort
to intravenous administration.
Of the side effects are most frequent dyspepsia, svyazan¬nye with irritating
drug. In this case, there are nausea, vomiting, diarrhea, abdominal pain,
disturbed appetite. Rarely occur agranulocytosis, hepatitis, crystalluria. A
number of patients indicated the development of goiter with symptoms of
hypothyroidism. Possible complications of allergic origin, which manifest
skin reactions, fever, arthritis, eosinophilia, and others.
Spectrum antimicrobial action thioacetazone (tibon, konteben)
ogra¬nichivaetsya pathogen Mycobacterium tuberculosis and leprosy. By TB
activity tioatsetazon inferior drugs groups I and II. Stability of
Mycobacterium tuberculosis to thioacetazone develops relatively slowly.
The drug is well absorbed from the gastrointestinal tract. Partially inactivated
in the liver. Excreted from the body during the 1st day. Most of the drug is
excreted by the kidneys.
Thioacetazone used inside mainly forms with extrapulmonary tuberculosis
(tuberculosis serous and mucous membranes, lymph nodes, etc.). In some
cases tioatsetazon prescribed in leprosy.
Thioacetazone has significant toxicity. It is relatively often
causes severe complications of the blood (anemia,
leukopenia, agranulocytosis), kidney (albuminuria,
cylindruria) and liver (up to yellow atrophy of the liver).
Furthermore, when using observed dyspeptic disorders,
allergic reactions and other side effects.
The use of thioacetazone requires continuous monitoring of
the blood, liver and kidneys.
Antisyphyllitic drugs
The main place in the treatment of syphilis take drugs benzylpenicillin. For this
purpose, as a short-range (benzylpenicillin sodium or potassium salt) and longacting (procaine penicillin G, Bitsillin) drugs. Penicillin has a rapid and
pronounced treponemotsidnoe action. To become drug resistant Treponema
pallidum were observed. Penicillin drugs are effective in syphilis at all its stages.
Assign their courses, the duration of which is determined by the form and stage of
disease.
When hypersensitive benzylpenicillin (e.g., in connection with allergic reactions)
for the treatment of syphilis can be used other antibiotics - tetracyclines and
erythromycin, azithromycin, ceftriaxone. However, they are inferior to the
effectiveness of penicillin drugs.
In addition to antibiotics in the treatment of syphilis using bismuth drugs. These
include biyohinol (8% slurry yodovismutata quinine neutralised peach oil) and
bismoverol (suspension of basic bismuth salts monovismutvinnoy acid neutralized
peach oil). Unlike antibiotics spectrum of action of drugs bismuth limited syphilis.
On the activity they are inferior to benzylpenicillin. Treponemostaticheskoe their
action is associated with inhibition of enzymes containing sulfhydryl groups.