Antimycobacterial Antimycobacterial drugsdrugs

Famous AffFamous Affeected Europeanscted Europeans

Lesja Ukrainka Lesja Ukrainka

Anton TchekhovAnton Tchekhov

John KeatsJohn Keats

Frédéric ChopinFrédéric Chopin

Charlotte, Emily, and Anne Brontë Charlotte, Emily, and Anne Brontë

Franz KafkaFranz Kafka

George OrwellGeorge Orwell

Increased Risk for TBIncreased Risk for TB: : People with HIVPeople with HIV

People who smoke 20+ cigarettes People who smoke 20+ cigarettes dailydaily

Man at an increased risk for TBMan at an increased risk for TB

Mordidity on tuberculosis in Ukraine

AIDS in UkraineAIDS in Ukraine

Tuberculosis2 bln

infected

Multyresistant tuberculosis

AIDS33 mln

infected

10-15 mln co-infected

UkraineUkraine MorbidityMorbidity 10 1000/10000/1000000

populationpopulation 48,000 new cases 48,000 new cases

annuallyannually Mortality Mortality 15/100000 15/100000 Every hour 1 person Every hour 1 person

dies from tuberculosisdies from tuberculosis 8.3% of TB cases that 8.3% of TB cases that

are HIV +are HIV + 10 % of new cases are 10 % of new cases are

MDR-TBMDR-TB

2005 2006

Ukrainian PrisonsUkrainian PrisonsHigher risk for developing active TB due Higher risk for developing active TB due

to the following problems:to the following problems:

-Poor infection controlPoor infection control -Delays in diagnosis-Delays in diagnosis -Inadequate treatment-Inadequate treatment -High prevalence of HIV-High prevalence of HIV -Overcrowding and poor -Overcrowding and poor

nutritionnutrition TB is not unavoidable in prisons!TB is not unavoidable in prisons!

1993 – WHO1993 – WHO

Epidemy of tuberculosis has Epidemy of tuberculosis has started in the world, in the started in the world, in the

most countries it has spread most countries it has spread far beyond control borders far beyond control borders

and now it is a global danger and now it is a global danger for humanityfor humanity

Treatment of patients with tuberculosisTreatment of patients with tuberculosis

Chemotherapy with tuberculostaticsChemotherapy with tuberculostatics Hygiene regime Hygiene regime

DietDiet Fito therapyFito therapy

Sanatorium treatment Sanatorium treatment Collapse therapyCollapse therapy Surgical methodsSurgical methods

Other drugsOther drugs

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)

Classification of International Union of tuberculosis treatment

Antimyco-bacterial activity

Drug Moderate daily dose

High IsoniazidRifampicinRifabutin

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 ТіоаcetazonPAS-Na

0,1512,0

1st row: Isoniazid, Rifampicin, Ethambutol, Isoniazid, Rifampicin, Ethambutol,

Pirazynamid, Pirazynamid, Streptomycine Streptomycine

22ndnd row rowothers others

IsoniazideIsoniazide

Inhibits synthesis of phospholipids and Inhibits synthesis of phospholipids and damages membranes of MBT, hurts damages membranes of MBT, hurts mycolyc acidsmycolyc acids

Forms Forms compositions with two-valent ionscompositions with two-valent ions Hurts formation of RNA and DNAHurts formation of RNA and DNA Inhibits oxidative processes Inhibits oxidative processes Acts on MBT which is in state of active Acts on MBT which is in state of active

developmentdevelopment, situated int, situated intrra- and a- and extracellularly extracellularly

PPenetrates through all organs and tissuesenetrates through all organs and tissues

Metabolism in liver (acetylation)Metabolism in liver (acetylation) HINAHINA inactivators (acetylators)inactivators (acetylators)

(genetics) (genetics)SlowSlow FastFast

Since Since 6 6 h hafter test-dose after test-dose 44 mg mg//kgkg concentration in blood isconcentration in blood ismore than more than 0,8 0,8 mcg/mlmcg/ml

Intermittent administration is Intermittent administration is possiblepossible

Since Since 6 6 h hafter test-dose after test-dose 44 mg mg//kgkg concentration in blood isconcentration in blood isless than less than 0,0,22 mcg/mlmcg/ml

Hepatotoxicity increases Hepatotoxicity increases ((monoacetylhydrazine monoacetylhydrazine formationformation),),Intermittent administration Intermittent administration cannot be usedcannot be used

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, arrhythmia dyspeptic disorders, stomatitis hepatitis

Rifampicine Bactericide action, wide Bactericide action, wide spectrum of actionspectrum of action

damages synthesis of damages synthesis of proteins of MBTproteins of MBT

influences on intra- and influences on intra- and extracellular MBTextracellular MBT

penetrates through all penetrates through all organs and damaged areas organs and damaged areas (molecule in not ionized)(molecule in not ionized)

concentration concentration iin organs is n organs is 3-4 times 3-4 times highhigher than in er than in blood serumblood serum

Rifampicine

Rifampicine

Side effects of rifampicine (8-22%)

hepatotoxicity immune-allergic complications

– pseudo-flue syndrome- decreasing of platelets aggregation– haemolysis– acute hepato-renal insufficiency

induction of microsomal enzymes→ decreasing of effectiveness of oral contraceptives etc.

dyspeptic manifestations, stomatitis changes of urine, feaces, sweat, tears etc. color

into orange-red

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

Side effects of streptomycin

Allergic reactionsOtotoxic actionPeripheral neuritisNephrotoxic action

Ethambutol

Influences on atypical mycobacteriumOn intra- and extracellular MBT,

which rapidly reproduce Gets accumulated in erythrocytesPenetrates into all organs and tissues,

into caverns

Side effects of ethambutol(1-2 %)

Retro bulbar neuritis of optic nerve (disorders of color vision – green, red, inaccuracy) – shouldn’t be administered for children under the age of 12

Bronchial spasm

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

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)

Photosensitization

Ciprobai (ciprofloxacin)

Abactal (pefloxacin)

Nolicin (norfloxacin)

Other fluoroquinolones

LomefloxacinLomefloxacinLevofloxacinLevofloxacinMoxyfloxacin 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 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

Tuberculosis treatmentTuberculosis treatment

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 , at nowadays – 5-6 drugs simultaneously

ІІІ. Short lasting courses of brakeless treatment

FLUOROQUNOLONESFLUOROQUNOLONES

Classificatoin of fluoroquinolones

І generation

Ciprofloxacin * Ofloxacin * Norfloxacin * Pefloxacin * Lomefloxacin * Fleroxacin

ІІ generation

Grepafloxacin Sparfloxacin* Gatifloxacin Clinafloxacin Moxifloxacin* Trovafloxacin Levofloxacin *

Ciprolet (Ciprofloxacin)

Nolicine (Norfloxacine)

Indications for fluoroquinilones administrationIndications for fluoroquinilones administration

Drugs of І choiceDrugs of І choice

Acute attack of chronic Acute attack of chronic bronchitis bronchitis

Acute and chronic sinusitis Acute and chronic sinusitis MMaalignant otitislignant otitis Hospital pneumoniaHospital pneumonia Pneumonia and bronchitis in Pneumonia and bronchitis in

patients with tuberculosispatients with tuberculosis Pneumonia in patients with Pneumonia in patients with

mucoviscidosismucoviscidosis Cholecystitis/ cholangitisCholecystitis/ cholangitis Chronic pielonephritisChronic pielonephritis Chronic prostatitisChronic prostatitis Bacterial diarrheaBacterial diarrhea Diarrhea of travellersDiarrhea of travellers

Alternative drugs

Acute medial otitisAcute medial otitis Community-acquiredCommunity-acquired

pneumoniapneumonia SepsisSepsis Intraabdominal infectionIntraabdominal infectionss OsteomOsteomyyelitiselitis Postoperative arthritisPostoperative arthritis Gynecological infectionGynecological infectionss

MeningitisMeningitis

Side effectsSide effects of of fluoroquinilonesfluoroquinilones

– photosensitization– seizures (if combined with

metronidazole, NSAIDs)– dyspeptic disorders– changes of mood, insomnia,

depression– allergic reactions– ulcerations of cartilages in children

and teenagers

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:

phthalazole, sulgin, phthazin

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)

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 sulfonamidesSide effects of sulfonamides

Allergic reactions (rash, sometimes - Allergic reactions (rash, sometimes - multiform erythema)multiform erythema)

CrystalCrystallluriauria ( (kidney colic, anuriakidney colic, anuria)) Leukopenia, agranulocytosis, aplastic Leukopenia, agranulocytosis, aplastic

anemia, hemolytic anemia (in case of anemia, hemolytic anemia (in case of glucose-6-phosphate insufficiency of glucose-6-phosphate insufficiency of erythrocytes)erythrocytes)

Dysbacteriosis, superinfectionDysbacteriosis, superinfection

SlightSlight diuretic and hypoglycemic effects diuretic and hypoglycemic effects