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Transcript of Antimycobacterial drugs. 1993 – WHO Epidemy of tuberculosis has started in the world, in the most...
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Antimycobacterial drugs
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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
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UkraineUkraine 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
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Ternopil region
During 1995-2000 morbidity grew 44% higher
58 % – “fresh” patients 48 % – with comlpicated forms 25 % – people younger 30 years of
age
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Treatment of patients with tuberculosis
Chemotherapy with tuberculostatic drugs Hygiene regime Diet Fitotherapy Sanatory treatment Collaps therapy Surgical methods Other drugs
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Antimycobacterial drugs 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)
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Classification of International Union of tuberculosis treatment
Antimyco-bacterial activity
Drug Moderate daily dose
High IsoniasidRifampicinRifabutin
0,450,6
0,45
Moderate StreptomycinAmikacinKanamycinPirazynamidEtambutolOfloxacinPefloxacinCiprofloxacinetc.
1,01,01,0
1,5–2,01,2–1,60,6–0,80,4–0,8
1,0
Low ТіоацетазонПАСК-Na
0,1512,0
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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 (L-forms)
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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
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IsoniazideOrally – 0,45g 1 time/day (10mg/kg) I.v. dropply 0,15-0,18% solutionsEndobronchial, irrigation of cavities –
5-10% solutions100% bioavailability in case of oral
administration
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Metabolism in liver (acetylation) HINA inactivators (acetylators)
(genetics)Slow Fast
Since 6 hafter test-dose 4 mg/kg concentration in blood ismore than 0,8 mcg/ml
Intermittens administration is possible
Since 6 hafter test-dose 4 mg/kg concentration in blood isless than 0,2 mcg/ml
Hepatotoxicity increases (monoacetylhydrasine),Intermittens administration cannot be used
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Side effects of isoniazide (derivatives of HINA)
(5-18% of patients) CNS – 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
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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
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Rifampicine
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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
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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
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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.)
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Rifabutin
Т1/2 35-40 hoursoral administration– 0,45 g 1 time
a day
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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)
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Streptomycinwide spectrum of action influences only on MBT situated
extracellularly is not absorbed in GITconcentration in tissues is 25-40 times
lower than in blood does not penetrate in caverns, through
BBB
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Administration of streptomycin
i.m. (streptomycin sulphate) endolumbal (streptomycin-chlorcalcium
complex) into cavities, endobronchial 1 g/day – “fresh” forms of tuberculosis
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Side effects of streptomycin
Allergic reactionsOtotoxic actionPeripheral neuritisNephrotoxic action
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Ethambutol
Influences on atypical mycobacteriaOn intra- and extracellular MBT,
which rapidly reproduce Gets accumulated in erythrocytesPenetrates into all organs and tissues,
into caverns
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Ethambutol
orally 1,2-1,6 g 1 time a day
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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
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Ethionamid
Acts on resistant MBTAtypical MBTExtra- and intracellular MBTActivity grows in acid medium, of
caseous massesPenetrates into all the organs and
tissues
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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)
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Pyrasinamid
Acts on MBT, which are in condition of metabolic restmetabolic rest
On intra- and extracellular MBT Penetrates into all organs and tissues Activity grows in acid medium of caseous
masses
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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
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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
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Ciprobai (cyprofloxacin)
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Abactal (pefloxacin)
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Nolicin (norfloxacin)
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Other fluoroquinolones
LomefloxacinLomefloxacinLevofloxacinLevofloxacinMoxyfloxacin Moxyfloxacin
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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 drugs3 months – 4 drugs4-5 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
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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)
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3 main schemes of administration of anti-tuberculosis 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
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Permeability of anti-tuberculosis drugh through the BBB
Do penetrate Do not penetrate
Isoniaside Rifabutin
Rifampicin Streptomycin
Ethambutol PASA-Na
Ethionamid
Pyrasinamid
Fluoroquinolones
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FLUOROQUNOLONESFLUOROQUNOLONES
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Classificatoin of fluoroquinolones
І generation
Ciprofloxacin * Ofloxacin * Norfloxacin * Pefloxacin * Lomefloxacin * Fleroxacin
ІІ generation
Grepafloxacin Sparfloxacin Gatifloxacin Clinafloxacin Moxifloxacin* Trovafloxacin Levofloxacin *
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Ciprolet (Ciprofloxacin)
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Nolicine (Norfloxacine)
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Mechanism of actoin
penetration into microbial cell, where they inhibit DNA-gyrase
disadvantage of DNA replication performing of postantibiotic effect
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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)
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Fluoroquinolones may be used 1-2 times daily
Orally – all drugs
I.V. – ciprofloxacinum, pefloxacinum, ofloxacinum, levofloxacinum,
moxifloxacinum
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Indications for fluoroquinilones administration
Drugs of І choice
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
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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
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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
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Fluoroquinolones are contraindicated:
- for pregnant women- in lactation period - for children and
teenagers
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Sulfonamides
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Structure of sulfonamides para-Aminobenzoic acid sulfonamide
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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
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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)
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Combinated drugs of sulfonamides
1. With trimethoprim: co-trimoxazole (biseptol, groseptol, bactrim, oriprim, sumetrolin), poteseptil, sulfaton
2. With pyrimethamine: fansidar
3. With 5-aminosalycylic acid : sulfasalazine, salazo-pyridazine
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Co-trimoxazole = Bactrim (trimethoprim + sulfamethoxazole)
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Biseptol= Bactrim (trimethoprim + sulphamethoxazole)
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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.
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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)
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Co-trimoxazole
480 - for adults 960 - for adults 120 – for children 240 – for children
Orally 2 times daily
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Side effects of sulfonamides
Allergic reactions (rash, sometimes - multiform erythema)
Crystalluria (kidney colic, anuria) Leukopenia, agranulocytosis, aplastic anemia,
hemolytic anemia (in case of glucose-6-phosphate insufficiency of erythrocytes)
Dysbacteriosis, superinfection Slight diuretic and hypoglycemic effects
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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
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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
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Anti-syphilis drugsІ choice – penicillins (benzylpenicillin, procain
benzylpenicillin, benzati-benzylpenicillin)
ІІ. AlternativeІІ. Alternative::
Macrolides
Tetracyclines
ІІІ. ReserveІІІ. Reserve::
Azalides (azithromycin)
Cephalosporines (ceftriaxon)
ІІV.V. Bismuth drugs Bismuth drugs:: biochinol, bismoverol