Antimycobacterial drugs

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

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

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 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 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

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)

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

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

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

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

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 hoursoral 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)

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

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 reactionsOtotoxic actionPeripheral neuritisNephrotoxic action

Ethambutol

Influences on atypical mycobacteriaOn intra- and extracellular MBT,

which rapidly reproduce Gets accumulated in erythrocytesPenetrates 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 MBTAtypical MBTExtra- and intracellular MBTActivity grows in acid medium, of

caseous massesPenetrates 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 restmetabolic 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

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

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 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

Permeability of anti-tuberculosis drugh through the BBB

Do penetrate Do not penetrate

Isoniaside Rifabutin

Rifampicin Streptomycin

Ethambutol PASA-Na

Ethionamid

Pyrasinamid

Fluoroquinolones

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)

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

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

1. With trimethoprim: co-trimoxazole (biseptol, groseptol, bactrim, oriprim, sumetrolin), poteseptil, sulfaton

2. With pyrimethamine: fansidar

3. With 5-aminosalycylic acid : sulfasalazine, salazo-pyridazine

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-6-phosphate 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 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