Transcript Document 7146292

Sulphonamides.
Antimycobacterial agents
1993 – WHO
Epidemy of tuberculosis has
started in the world, in the
most countries it has spread
far beyond control borders
and now it is a global danger
for humanity
Ukraine
 During
1995-2000 tuberculosis morbidity
grew 30 % higher and equals to 42/10000
of population
 Totally – 640 000 sick people, 30 000 of
whіch are with open form
 mortality also increases and equals to
14/10 000
 Every hour 1 patient with tuberculosis dies
Ternopil region
During
1995-2000 morbidity grew
44% higher
58 % – “fresh” patients
48 % – with comlpicated forms
25 % – people younger 30 years of
age
Treatment of patients with
tuberculosis
 Chemotherapy
with tuberculostatic drugs
 Hygiene regime
 Diet
 Fitotherapy
 Sanatory treatment
 Collaps therapy
 Surgical methods
 Other drugs
Antimycobacterial drugs
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Derivatives of HINA: isoniazid, ftivazid etc.
Antibiotics: rifampicin, rifabutin, strepromycin, kanamycin,
florimycin, capreomycin, cycloserine
Derivatives of pyrazin-carbonic acid: pyrazinamide
Ethambutol
Tiourens: tioacetazone (tibon), salutizone
Derivatives of tiamide-α-ethylizonicotinic acid:
ethionamide, protionamide
Salts of PASA: PASA-Na etc.
Combinated tuberculostatics:
inabutol (isoniazid + ethambutol)
infiricine (rifampicine + isoniazide)
rifater (isoniazide + rifampicine + pyrazinamide)
Classification of International Union of
tuberculosis treatment
Antimycobacterial activity
Drug
Moderate daily dose
High
Isoniasid
Rifampicin
Rifabutin
Moderate
Streptomycin
Amikacin
Kanamycin
Pirazynamid
Etambutol
Ofloxacin
Pefloxacin
Ciprofloxacin
etc.
1,0
1,0
1,0
1,5–2,0
1,2–1,6
0,6–0,8
0,4–0,8
1,0
Low
Тіоацетазон
ПАСК-Na
0,15
12,0
0,45
0,6
0,45
Properties of antimycobacterial drug confidence in high effective treatment:
 Good
permeability in all organs and
tissues, including BBB
 Influence on mycobacteria, situated
intracellulary
 Influence on atypical forms of
mycobacteria
 Influence on mycobacteria which stay
in latent phase of development (Lforms)
Isoniazide
Inhibits synthesis of phospholipids and damages
membranes of MBT
 Forms compositions with two-valent cations
 Hurts formation of RNA and DNA
 Inhibits oxydating processes
 Acts on MBT which is in state of active
development, situated intra- and extracellularly
 Penetrates through all organs and tissues

Isoniazide
– 0,45g 1 time/day (10mg/kg)
 I.v. dropply 0,15-0,18% solutions
 Endobronchial, irrigation of cavities –
5-10% solutions
 100% bioavailability in case of oral
administration
 Orally
Metabolism in liver (acetylation)
HINA inactivators (acetylators)
(genetics)
Slow
Fast
Since 6 h
after test-dose 4 mg/kg
concentration in blood is
more than 0,8 mcg/ml
Since 6 h
after test-dose 4 mg/kg
concentration in blood is
less than 0,2 mcg/ml
Intermittens administration is
possible
Hepatotoxicity increases
(monoacetylhydrasine),
Intermittens administration
cannot be used
Side effects of isoniazide (derivatives of HINA)
(5-18% of patients)
– headache, euforia, insomnia,
dizzyness
 peripheral neuritis (derivatives of HINA –
antivitamins В6), prophylaxis – 50 mg Vit В6
daily
 allergy (treatment – antihistamine)
 heart – tachycardia, arythmia
 dispeptic disorders, stomatitis
 hepatitis
 CNS
Rifampicine
 Bactericide
action, wide spectrum of
action
 damages synthesis of proteins of MBT
 influences on intra- and extracellular
MBT
 penetrates through all organs and
damaged areas (molecule in not ionized)
 concentration in organs is 3-4 times
larger than in blood serum
Rifampicine
Rifampicine
 0,6
g 1 time daily with empty stomach
 entero-hepatic recirculation
 Increases the activity of microsomal
enzyme system of liver →
autoinduction → increasing of
rifampicine metabolism
Side effects of rifampicine
(8-22%)
hepatotoxicity
 immune-allergic complications
– pseudo-flue syndrome
- decreasing of platelets aggregation
– haemolysis
– acute hepato-renal insufficiency
 induction og microsomal enzymes→ decreasing
of effectiveness of oral contraceptives etc.
 dyspeptic manifestations, stomatitis
 change of urine, feaces, sweat, tears etc. color
into orange-red

Rifabutin (mycobutin)
 wide
spectrum of action
 it is 10 times more effective than rifampicine
 influences on intra- and extracellular MBT
 concentration in organs is 5-10 times higher
than in plasma, in neutrophiles - 9 times
higher, in monocytes - 15 times higher
 influences on atypical forms of mycobacteria
(M. avium complex etc.)
Rifabutin
Т1/2
35-40 hours
oral administration– 0,45 g 1 time
a day
Side effects of rifabutin
 dyspeptic
disorders, hepatitis, jaundice,
 leuco-, thrombocytopenia, anemia (especially
if combined with isoniazide)
 artralgy, mialgy
 allergic reactions (rarely including
anaphylactic shock)
 reverse uveitis (damage of eye retina)
Streptomycin
 wide
spectrum of action
 influences only on MBT situated
extracellularly
 is not absorbed in GIT
 concentration in tissues is 25-40 times
lower than in blood
 does not penetrate in caverns, through
BBB
Administration of streptomycin
 i.m.
(streptomycin sulphate)
 endolumbal (streptomycin-chlorcalcium
complex)
 into cavities, endobronchial
 1 g/day – “fresh” forms of tuberculosis
Side effects of streptomycin
 Allergic
reactions
 Ototoxic action
 Peripheral neuritis
 Nephrotoxic action
Ethambutol
 Influences
on atypical mycobacteria
 On intra- and extracellular MBT,
which rapidly reproduce
 Gets accumulated in erythrocytes
 Penetrates into all organs and tissues,
into caverns
Ethambutol
orally 1,2-1,6 g 1 time a day
Side effects of ethambutol
(1-2 %)
Retrobulbar
neuritis of optic
nerve (disorders of color vision –
green, red, inaccuracy) –
shouldn’t be administered for
children under the age of 12
Bronchial spasm
Ethionamid
 Acts
on resistant MBT
 Atypical MBT
 Extra- and intracellular MBT
 Activity grows in acid medium, of
caseous masses
 Penetrates into all the organs and
tissues
Ethionamid
perorally 0,5 –0,75 g/day
Side effects
 Allergic
reactions
 Disturbances of GI tract
 Toxic hepatitis
 Neurotoxicity
(CNS, peripheral neurites)
 Endocrine disorders (gynecomastia,
menorrhagia, impotence, hypoglycemia)
Pyrasinamid
 Acts
on MBT, which are in condition of
metabolic rest
 On intra- and extracellular MBT
 Penetrates into all organs and tissues
 Activity grows in acid medium of caseous
masses
Pyrasinamid
 1,5-2,0
g orally
 Especially in a case of torpid current
of tuberculosis, in case of heavy
achievable and caseous sources,
during the period of finishing
treatment
Side effects of pyrasinamid
 hepatotoxicity
–
–
early – 7th day
late – after 6-8 months
 dyspeptic
disorders
 arthralgia (retains uric acid in the
organism – pyrasine-carbon acid is its
antagonist)
 Photosensibilization
Ciprobai (cyprofloxacin)
Abactal (pefloxacin)
Nolicin (norfloxacin)
Other fluoroquinolones
Lomefloxacin
Levofloxacin
Moxyfloxacin
Standard regimes of anti-tuberculosis
treatment according to WHO
Category of patients
Treatment scheme
Basic duration of
treatment
(months)
Primarily diagnosed tuberculosis
(МBT+), heavy spread forms (MBT–)
2-3 months – 4 drugs,
4-5 months – 2 drugs
6–8
Patients with relapse of tuberculosis
and non-effectively treated primarily
diagnosed patients (MBT + in sputum
smear)
2 months – 5 drugs
3 months – 4 drugs
4-5 months – 3 drugs
6–8
Primarily diagnosed tuberculosis
(MBT–)
At first – 3,
after – 2 drugs
6
Chronic forms of tuberculosis
Individual regimes
(depending on sensitivity of
MBT) of 5-6 drugs
12
Principles of rational
chemotherapy of tuberculosis
Appropriate in time administration of
chemical drugs
 Administration of combinations of drugs
 Long-lasting treatment
 Brakeless treatment
 Administration of optimal doses
 Choice of way of introduction (orally, i.v.
dropply or bolus, i.m., endolymphatically, by
inhalations, endotracheally, endopleurally,
intracavernously)

3 main schemes of administration of antituberculosis drugs
 І.
Traditional long lasting (brakeless) treatment
 ІІ. Intermitting chemotherapy
3
times a week
 1 time a week (HINA in slow acetylators)
 mixed chemotherapy (interchange of one drug in a
certain combination - 3-4 drugs daily from 5-6 of the
administered) – 1-3 times a week the combination is
changed
 ІІІ.
Short lasting courses of brakeless treatment
Permeability of anti-tuberculosis drugh
through the BBB
Do penetrate
Do not penetrate
Isoniaside
Rifabutin
Rifampicin
Streptomycin
Ethambutol
PASA-Na
Ethionamid
Pyrasinamid
Fluoroquinolones
FLUOROQUNOLONES
Classificatoin of
fluoroquinolones
ІІ generation
І generation
Ciprofloxacin *
 Ofloxacin *
 Norfloxacin *
 Pefloxacin *
 Lomefloxacin *
 Fleroxacin

Grepafloxacin
 Sparfloxacin
 Gatifloxacin
 Clinafloxacin
 Moxifloxacin*
 Trovafloxacin
 Levofloxacin *

Ciprolet (Ciprofloxacin)
Nolicine (Norfloxacine)
Mechanism of actoin
 penetration
into microbial cell, where they
inhibit DNA-gyrase
 disadvantage of DNA replication
 performing of postantibiotic effect
Fluoroquinolones get accumulated
in macrophages and neutrophiles in
concentrations which overcome
concentration in blood serum
4-8 times, they penetrate in all
organs and tissues well (low level
of molecular ionisation)
Fluoroquinolones may be used 1-2 times daily
Orally – all drugs
I.V. – ciprofloxacinum, pefloxacinum,
ofloxacinum, levofloxacinum,
moxifloxacinum
Indications for fluoroquinilones administration
 Drugs of І choice
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
Acute attack of chronic
bronchitis
Acute and chronic sinusitis
Malignant otitis
Hospital pneumonia
Pneumonia and bronchitis in
patients with tuberculosis
Pneumonia in patients with
mucoviscidosis
Cholecystitis/ cholangitis
Chronic pielonephritis
Chronic prostatitis
Bacterial diarrhea
Diarrhea of travellers
 Alternative drugs

Acute medial otitis
Community-acquired
pneumonia
Sepsis
Intraabdominal infections
Osteomyelitis
Postoperative arthritis
Gynecological infections

Meningitis






Side effects of fluoroquinilones
–
–
–
–
–
–
photosensibilization
seizures (if combined with metronidazole,
NSAIDs)
dyspeptic disorders
changes of mood, insomnia, depression
allergic reactions
ulcerations of cartilages in children and
teenagers
Interaction
 pefloxacin,
grepafloxacin inhibit
metabolism of euphyllin, manifestation of
intoxication
 Zn2+, Ca2+, Mg2+, Al3+ (antacids etc.),
bismuthi salts, iron drugs, sukralfat depress
absorption of fluoroquinolones in
gastrointestinal tract
Fluoroquinolones are
contraindicated:
- for pregnant women
- in lactation period
- for children and
teenagers
Sulfonamides
Structure of sulfonamides
para-Aminobenzoic acid
sulfonamide
Classification of sulfonamides
(according to level of absorbtion in gastro-intestinal
tract and systemic action)
Drugs of resorbtive action: most of
sulfonamides
Drugs which act in intestinal cavity:
ftalazole, sulgin, ftazin
Drugs for local administration:
sulfacyl-sodium, silver sulfazine, mafenide
Classification of sulfonamides
(accordingly to duration of action)
Short action: streptocid, sulfadimezine, aethazole,
norsulfazole, urosulfan, sulfizoxazole, sulfacyl-sodium
 Medium duration of action: sulfamethoxazole (is a part
of co-trimoxazole)
 Longlasting action: sulfadimethoxyn, sulfapirydazin,
sulfamonomethoxyn
 Super longlasting action: sulfalen, sulfadoxyn (is a part
of fansidar)

Combinated drugs of
sulfonamides
With trimethoprim: co-trimoxazole
(biseptol, groseptol, bactrim, oriprim,
sumetrolin), poteseptil, sulfaton
2. With pyrimethamine: fansidar
3. With 5-aminosalycylic acid : sulfasalazine,
salazo-pyridazine
1.
Co-trimoxazole = Bactrim (trimethoprim +
sulfamethoxazole)
Biseptol= Bactrim
(trimethoprim + sulphamethoxazole)
Indication for sulfonamides administration
Local


1. eye infections – trachoma, blennorrhea (sulfacyl-Na)
2. burns, wounds (silver salts, mafenide)
Orally






1. intestinal contamination (ftalazole 8-15g/daily 4-6 days)
2. chronic inflammatory diseases of intestines (salazo-substances)
3. nocardiosis (pneumonia, brain abscess), malaria (fansidar)
4. infections of urinary tracts – their primary treatment, chlamidia
infections
5. rarely – infections of respiratory tracts, LOR-infections, dysentery
6. herpetiform dermatitis of During (sulfapyridine)
Parenteral

Sulfacyl-Na i.v.
Indications for co-trimoxazole administration
Pneumcystic pneumonia (children, patients with
AIDS)
 Pneumonia caused by Н. Influenzae, S.
pneumoniae, Legionella pneumophila
 Gonococcal
urethritis,
prostatitis,
oropharyngeal gonorrhea
 Urological and genital infections caused by
sensitive E. coli, Proteus mirabilis, Salmonella
typhi, Shigella
 Gastro-intestinal
infections
(shigellosis,
salmonellosis, hostage of Salmonella typhi)

Co-trimoxazole
 480
- for adults
 960 - for adults
 120 – for children
 240 – for children
Orally 2 times daily
Side effects of sulfonamides
 Allergic
reactions (rash, sometimes multiform erythema)
 Crystalluria (kidney colic, anuria)
 Leukopenia, agranulocytosis, aplastic anemia,
hemolytic anemia (in case of glucose-6phosphate insufficiency of erythrocytes)
 Dysbacteriosis, superinfection
 Slight diuretic and hypoglycemic effects
Causes and prophylaxis of crystaluria
 Acetyl
derivatives of sulfonamides get
crystalized in kidney canalicules
 Risk increases when:
– acidic reaction of urine (inflammatory
process, nutrients – lemons, grape juice,
sorrel)
– decreasing of urine quantity
– big dose (drugs of short action)
 Prophylaxis: 2 l of alkaline drink/day
Sulfonamides
should not be combined:
 1)
with drugs that inhibit blood formation
(butadion, analgin, laevomycetin etc.)
 2) with peroral hypoglycemic drugs
(derivatives of sufanyl-urea) and diuretcis
 3) with derivatives of PABA (novocain),
PASA, folic acid
 4) with α- and β- adrenomimetics, difenine,
methotrexat
Anti-syphilis drugs
І choice – penicillins (benzylpenicillin, procain
benzylpenicillin, benzati-benzylpenicillin)
ІІ. Alternative:
Macrolides
Tetracyclines
ІІІ. Reserve:
Azalides (azithromycin)
Cephalosporines (ceftriaxon)
ІV. Bismuth drugs: biochinol, bismoverol