Transcript Side effects

Kharkiv National Medical University
Department of Pharmacology and Medical Prescription
assistant Gordiychuk D.
“Antibiotics Part II.
Antimycobacteria agents.”
Plan of lecture:
Pharmacology of Tetracyclines,
Aminoglycosides, Macrolides and Azalides,
Chloramphenicoles, Rifampicine,
Lincosamides.
 Pharmacology of Antimycobacterial agents.
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Antibiotics ("Anti" – against, "bios" - life)
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Antibiotics - a substance produced by microorganisms, or
produced from vegetable and animal tissues, and their semisynthetic and synthetic analogs selectively inhibit the viability of
microorganisms sensitive to them.
Importance of Antibiotics:
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The elimination of the global crisis of infectious diseases (cholera, plague,
dysentery).
Effective at the dangerous diseases (sepsis, meningitis, peritonitis,
pneumonia).
≈ 20 million people die each year from infectious diseases.
1/3 of all hospital patients are treated with antibiotics.
Over the past 20 years there were 20 new infectious diseases (Legionnaires'
disease, hairycell leukemia, hemorrhagic fever and others).
Unconventional use of antibiotics: peptic ulcer, asthma, myocardial
infarction, atherosclerosis.
In breadth of application group of antibiotics ranked the first place in the
world.
Today, there is no person at least who did not use antibiotics.
There is no country that doesn’t threat of epidemics and pandemics.
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Bacterial cell
Cytoplasmic membrane
Cell wall
Nuclear apparatus
Ribosomes
Violation
of the cell wall
synthesis.
B-lactams
Glycopeptide
Violation
of cytoplasmic
membranes
permeability.
Polymyxins
Gramicidin
Antifungal
Violation
of RNA
synthesis
Rifampicin
Violation
of protein
synthesis at the
level of
ribosomes.
Tetracyclines
Chloramphenicols
Lincosamides
Macrolides
Azalides
Aminoglycosides
Fuzidinum
Antimicrobial drugs have also been
classified broadly into:
1. bacteriostatic, i.e. those that act primarily
by arresting bacterial multiplication, such as
tetracyclines, chloramphenicol, macrolides,
lincosamides.
2. bacteriocidal, i.e. those which act primarily
by killing bacteria, such as penicillins,
monobactams, carbapenems,
cephalosporins, aminoglycosides,
rifampicin etc.
Aminoglycosides (Classification)
1 GENERATION
 Neomycin
 Streptomycin
 Kanamycin
 Monomycin
2 GENERATION
 Gentamycin
 Tobramycin
 Netilmycin
3 GENERATION
 Amikacin
Mechanism of Aminoglycosides
action
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Aminoglycosides are bactericidal antibiotics.
The antibacterial properties of aminoglycosides is a result of
inhibition of bacterial protein synthesis through
irreversible binding to the 30S-bacterial ribosome.
However other antibiotics that inhibit the synthesis of proteins
(such as tetracycline) are not bactericidal.
Recent experimental studies show that the initial site of action
is the outer bacterial membrane. The cationic antibiotic
molecules create fissures in the outer cell membrane, resulting
in leakage of intracellular contents, enhanced antibiotic uptake
and creation of defective bacterial proteins.
This rapid action at the outer membrane is responsible for the
bactericidal activity.
Energy is needed for aminoglycoside uptake into the bacterial
cell. Anaerobes have less energy available for this uptake, so
aminoglycosides are less active against anaerobes.
Spectrum of aminoglycosides
Staphylococci,
 Streptococci,
 Escerichia,
 Salmonella,
 Shigella,
 Vibrio cholerae,
 Klebsiella
pneumonica
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Aerobacter,
 Neiseria,
 Brucella,
 Proteus,
 Yersinia pestis,
 Serratia,
 Pseudomonos
aeruginosa.
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Spectrum of aminoglycosides
Some of the drugs are effective against
Mycobacteria tuberculosis (Streptomycin,
Kanamycin, and Amikacin).
 Aminoglycosides are effective only against
aerobic organisms, since anaerobes lack the
oxygen-requiring transport system.
 Drugs II and III generation potentiate the action
of penicillins and cephalosporins.
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Clinical uses of
AMINOGLYCOSIDES
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Respiratory infections,
Subacute bacterial endocarditis,
Plague
Tularemia
Meningitis (Gentamycin)
Urinary tract infections
Osteomyelitis
Lung abcesses
Septic processes caused by Pseudomonas
aeruginosa
Tuberculosis (Streptomycin, Kanamycin, and
Amikacin).
Side effects of
AMINOGLYCOSIDES
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Ototoxicity
Vestibulotoxicity (nausea,vomiting,vertigo, nistagmus)
Nephrotoxicity
Neuromuscular blockade (reduction of Ca2+ and Ach
release, especially neomycin and streptomycin)
Allergic reactions
Superinfection
Imunosupression
- Contraindicated introduction of aminoglycosides
in the same syringe with penicillins, polymyxin B,
cephalosporins - possible physical and chemical
incompatibility!!!
Tetracyclines
Natural
Tetracycline
Semisynthetic
Methacycline
Doxacycline (Vibramycine)
Tetracyclines are also classified as:
(1) short-acting (chlortetracycline, tetracycline,
oxytetracycline) based on plasma t1/2 of 6–8 h;
(2) intermediate acting (demeclocycline and
methacycline) – t1/2 12 h;
(3) long-acting (doxycycline and minocycline)
with plasma t1/2 16–18 h.
The almost complete absorption and slow
excretion of DOXYCYCLINE AND MINOCYCLINE
ALLOW FOR ONCE-DAILY DOSING.
Mechanism of TETRACYCLINE
action
Penetration of antibiotic into susceptible
microorganisms is mediated by transport
protein;
 On penetration the drug is binding to the 30 S
subunit of the bacterial ribosome;
 It results in inhibition of bacterial protein
synthesis.
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Spectrum of Tetracyclines
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Cocci;
Gram-positive bacilli:
Clostridia,
listeria,
corynebacteria,
B. anthracis;
Gram-negative bacilli:
H. ducreyi
Vibrio cholerae,
Yersinia pestis,
Y. enterocolitica,
Campylobacter,
H. pylori
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Brucella
Pasterella multocida,
F. tularensis
anaerobes;
spirochetes, T. pallidum
and Borrelia;
rickettsiae (typhus etc.)
chlamydiae.
Moderately sensitive:
Actinomyces.
Entomoeba histolitica (at
high concentrations),
Malarial Plasmodium
Exclusion of spectrum
Tetracyclines do not inhibit:
 Pseudomonas aeruginosa and Mycobacterium
tuberculosis.
 Many staphylococci, steptococci, enterococci
and enterobacteria are now resistant to these
antibiotics!!!
Resistance
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Because many strains of the following groups of Gr+
microorganisms [Streptococcus pyogenes, Streptococcus
pneumoniae, Enterococcus group (Streptococcus faecalis and
Streptococcus faecium), Alpha-hemolytic Streptococci (viridans
group); other microorganisms Chlamydia psittaci] have been
shown to be resistant to Tetracycline, culture and
susceptibility testing are recommended.
Up to 44 % of strains of Streptococcus pyogenes and 74 % of
Streptococcus faecalis are resistant to Tetracycline drugs.
Therefore, Tetracyclines should not be used for streptococcal
disease unless the organisms have been demonstrated to be
susceptible.
Because of resistance to Tetracyclines, testing of
susceptibility is recommended in infections caused by:
Escherichia coli, Klebsiella species, Enterobacter aerogenes,
Shigella species.
Clinical uses of TETRACYCLINES
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Empirical therapy
Chlamydial urethritis and endocervicites
Atypical pneumonia caused by Mycoplasma
Cholera
Brucellosis
Plauge
Relapsing fever
Rickettsial infections
Clinical uses of
TETRACYCLINES
(second choice)
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Tetanus
Antrax
Actinomycosis
Tularemia
Syphilis
Amebiasis
Chloroquin resistant malarial P. Falciparum
Acne vulgaris
Legionnaires' disease
Side effects of TETRACYCLINES
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GIT: anorexia, nausea, epigastric distress, vomiting, diarrhea,
glossitis, hypertrophy of tongue papillae (black hairy tongue),
dysphagia, enterocolitis, pancreatitis, dysbacteriosis;
Hepatotoxicity, steatosis;
Teeth: disturbances of teeth growth, discoloration of teeth,
enamel hypoplasia;
Disturbances of bones growth;
Pseudotumor syndrome (rare): severe headache and vision
problems due to dangerous secondary intracranial
hypertension;
Vertigo;
Phototoxicity (risk of sunburn);
Catabolic effect.
Side effects of tetracyclines
(cont.)
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Skin: maculopapular and erythematous rashes.
Exfoliative dermatitis has been reported but is
uncommon.
Onycholysis and discoloration of the nails have
been reported rarely.
They may increase muscle weakness in myasthenia
gravis and exacerbate systemic lupus erythematosus.
Other: bulging fontanels in infants;
Blood: hemolytic anemia, thrombocytopenia,
thrombocytopenic purpura, neutropenia and
eosinophilia have been reported;
Superinfection, candidiasis, vitamin B deficiency,
hyperbilirubinemia.
Tetracycline teeth
Phototoxic Sunburn after Doxycycline intake
Contraindications
Pregnancy or lactation,
 Children before 8 years old,
 Hepatic insufficiency,
 Renal insufficiency,
 Hypersensitivity to
tetracyclines.
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MACROLIDES and AZALIDES
CLASSIFICATION
I GENERATION
II GENERATION
III GENERATION
(AZALIDES)
The combination of
macrolides with
tetracyclines and
other drugs.
1.Erithromycin
2. Spiramycin
3. Josamycin
4. Midecamycin
5. Roxithromycin
6. Clarithromycin
7. Flurithromycin
8. Dirithromycin
9. Azithromycin
(Summamed)
10. Oletetrine
11. Zinerite
MACROLIDES
mechanism of
action:
Binds with 5OSsubunit of microbial
ribosomes and
inhibit RNA and
protein synthesis in
the bacterial cell.
MACROLIDES SPECTRUM
WIDE SPECTRUM: GR + and GR- cocci, bacillus, intra-cellular
organisms.
•Staphylococci,
•Streptococci,
•Gonococci,
•Anaerobic cocci,
• Enterobacteriaceae
•Strains of Pseudomonas, H. influenzae,
Campylobacter, Helicobacter, Chlamydia,
Ligionella, Bordetella, M. pneumonia,
P. carinii, T. gondii, M. avium complex.
Resistant to MACROLIDES ARE MOST OF Grbacterias!!!
Indications for MACROLIDES
• Infection of the upper and lower respiratory tract
(acute bronchitis, exacerbation of chronic bronchitis,
acquired pneumonia).
• ENT infections (acute otitis, tonsillitis,
tonzilofaringit).
•Gynecological infections.
• Skin and soft tissue infection (pyoderma, boils).
• Toxoplasmosis, mycobacteriosis of HIV infected.
• Ophthalmic infections,
• Diphtheria,
•Leprosy,
•Cystic fibrosis.
•Syphilis, prostatitis, urethritis, chlamydia, etc.
FEATURES of MACROLIDES
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Bacteriostatic effect mainly against GR+ bacteria
(streptococci, staphylococci).
Activity against intracellular bacteria (chlamydia,
mycoplasma, legionella).
One of the least toxic antibiotics.
Well absorbed from the gastrointestinal tract,
acidstable, are able to consentrate in the
inflammation area.
Bioavailability greater than that of tetracyclines
(well penetrate into tissues and cells with creation of
high concentration).
Inductors of microsomal liver enzymes.
Adverse reactions of MACROLIDES.
Cross-sensitivity,
 Dyspeptic disorders,
 Cholestasis,
 Reversible ototoxicity,
 Ventricular tachycardia,
 Cross-resistance,
 Embryonic and foetotoxic effects
(clarithromycin).
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Lincosamides
Natural
Lincomycin
Semisynthetic
Clindamycin (Dalacin C)
•Mechanism of action: Inhibition of microbial cell
proteins synthesis (similar to macrolides).
•Mostly bacteriostatic action type (high conc.bactericidal).
•The narrow spectrum: mostly Gr + cocci.
•Able to accumulate in bone and joints!!!
•Rapid development of resistance.
•No cross-sensitivity with β-lactams.
Lincosamides
Indications:
•As a reserve antistaphylococcal drugs in
tonzillofaringitis, pneumonia, infections of
the skin, soft tissues, bones, joints.
Side effects:
•Severe pseudomembranous colitis
(ulceration, perforation of the intestine,
peritonitis).
•Treatment of colitis - vancomycin or
metronidazole, detoxification therapy!!!!
Chloramphenicol (Levomycetin)
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Chloramphenicol palmitate
Chloramphenicol succinate
Spectrum is very broad, much resembling that
of tetracycline, like the last it is not active
against Pseudomonas aeruginosa.
 But in contrast to tetracyclines it does not act
on Chlamydiae or Enterobacter species.
 Chloramphenicol is the most toxic
antibiotic!!!
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Mechanism of
CHLORAMPHENICOL action
Chloramphenicol binds to a ribosome on the
50S subunit, which is responsible for
catalyzing the formation of bonds between
amino acids, preventing the bacteria from
linking amino acids together.
 Chloramphenicol is able to halt the
production of bacterial proteins, which keeps
the bacteria from replicating and growing. This
brings about bacteriostatic effect.
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Indications for CHLORAMPHENICOL
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Meningitis:!!!Drug is excellent BBB penetrating!!!
Staphylococcal brain abscesses (the first choice).
Typhoid fever, formerly chloramphenicol was the drug of first
choice for typhoid, but now it is seldom used because of
multiple drug-resistance of Salmonella typhi.
Anaerobic infections (Bact. fragilis).
Chloramphenicol may be used
as a second choice agent
in the treatment :
 Cholera (tetracycline-resistant),
 Brucellosis,
 Rickettsial infections.
Indications
Because of its excellent BBB penetration (far
superior to any of the cephalosporins),
chloramphenicol remains the first choice
treatment for staphylococcal brain
abscesses.
 It is also useful in the treatment of brain
abscesses due to mixed organisms or when
the causative organism is not known.
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Indications.
Chloramphenicol is active against the three
main bacterial causes of meningitis:
Neisseria meningitidis, Streptococcus
pneumoniae and Haemophilus influenzae. In
the West, chloramphenicol remains the drug of
choice in the treatment of meningitis in
patients with severe penicillin or
cephalosporin and GPs allergy are
recommended to carry intravenous
chloramphenicol in their bag.
 In low income countries, the WHO recommend
that oily chloramphenicol be used first-line to
treat meningitis.
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Chloramphenicol side effects.
Aplastic anaemia is the most serious side
effect of chloramphenicol, it is rare and is
generally fatal. It usually occurs weeks or
months after chloramphenicol treatment has
been stopped.
 Bone marrow suppression, as a direct toxic
effect of Chloramphenicol on human
mitochondria. It manifests first as a fall in
hemoglobin levels; this anaemia is fully
reversible once the drug is stopped and does
not predict future development of aplastic
anaemia.
 Increased risk of childhood leukemia.
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Chloramphenicol side effects.
Gray baby syndrome in
intravenous use of
chloramphenicol.
 This causes several
adverse effects, including
hypotension and
cyanosis. The condition
can be prevented by
using the drug at the
recommended doses, and
monitoring blood levels.
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CHLORAMPHENICOL side effects.
• Newborn infants lack an effective glucuronic acid
conjugation mechanism for the degradation and
detoxification of chloramphenicol.
•Consequently, when infants are given dosages above
50 mg/kg/d, the drug may accumulate, resulting in the
gray baby syndrome, with vomiting, flaccidity,
hypothermia, gray color, shock, and collapse.
•To avoid this toxic effect, chloramphenicol should
be used with caution in infants and the dosage
limited to 50 mg/kg/d or less (during the first week
of life) in full-term infants.
•Chloramphenicol
inhibits hepatic
microsomal
enzymes that
metabolize
phenytoin and
warfarin.
NB!
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Chloramphenicol
should not be
used for
infections
treatable by other
safer
antimicrobials!!!!
Rifampicin.
Rifamycin
 Rifampicin
 Rifabutin
 Rifaximin
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Mechanism of action: incorporation into DNA spiral, inhibition of
DNA-dependent RNA-polymerase → inhibition of replication and
transcription in microorganisms.
Spectrum of action: wide, Mycobacterium tuberculosis, leprosy.
Bactericidal.
Indications: tuberculosis, leprosy, infections caused by multidrugresistant pathogens.
Side effects: allergic reactions of heavy genesis, manifested by
liver damage; flu-like syndrome, hemolytic anemia.
Antitubercular drugs.
TUBERCULOSIS
(TB)
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It is an infectious disease
caused by various strains of
mycobacteria, usually
Mycobacterium
tuberculosis.
Typical localization - the
lungs, but disease can also
affect other parts of the
body.
It is spread through the air
when people who have an
active TB infection cough,
sneeze, or otherwise
transmit respiratory fluids
through the air.
TUBERCULOSIS (TB)
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The classic symptoms of active TB infection are:
a chronic cough with blood-tinged sputum,
fever, chills,
night sweats,
loss of appetite, weight loss, fatigue.
Diagnosis of active TB relies on radiology (commonly
chest X-rays), as well as microscopic examination and
microbiological culture of body fluids.
Diagnosis of latent TB relies on the tuberculin skin test
(TST) and/or blood tests.
Spread of tuberculosis in the
world
In 2003 tuberculosis, affected 8.7 million
people. Most of these people lived in Asia and
Africa, a small proportion were in Europe and in
America.
 In India near 2 million people develop active
form of disease.
 About 0,5 million die of TB every year in this
country.
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Spread of tuberculosis in the
world
Mycobacterium tuberculosis
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Mycobacteria are slowly growing microorganism and thus
relatively resistant to chemotherapeutic agents.
Some of mycobacterium cells can be dormant and completely
resistant to many drugs.
Mycobacterial cell wall is impermeable to many agents.
Mycobacteria may reside inside the macrophages, being
inaccessible to the drugs poorly penetrating into
macrophages.
Mycobacteria is highly resistant in environment.
Mycobacteria are capable of developing resistance to any
single drug.
To delay the development of resistance combination of
several drugs are used in the treatment of tuberculosis.
The response of mycobacterial infection to chemotherapy is
slow, the treatment is long lasting.
Classification of anti-TB drugs
(according to antitubercular efficacy)
A. (The most effective)  Ethionamide (ET)
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Cycloserine (C)
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Isoniazid (INH)
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Capreomycin
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Rifampicin ( R)
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Levofloxacin
B. (Effective)
C. (Less Effective)
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Streptomycin (S)
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Paraaminosalicylic
Acid ( PAS)
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Pyrazinamide (Z)
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Thiacetazone (T)
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Ethambutol (E)
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Kanamycin (K)
Classification of anti-TB drugs
(according to clinical uses)
A drug may be considered as second-line
instead of first-line for one of three possible
reasons: it may be less effective than the firstline drugs (e.g., p-aminosalicylic acid); or it
may have toxic side-effects (e.g., cycloserine);
or it may be effective, but unavailable in many
developing countries (e.g., fluoroquinolones)
 The third line drugs include drugs that may be
useful, but have doubtful or unproven efficacy.
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Classification of anti-TB drugs
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First line drugs for
tuberculosis
Isoniazid,
Rifampicin,
Ethambutol
Pyrizanamide.
Streptomycin.
Second line drugs
Amikacin, Kanamycin.
Capreomycin.
Ciprofloxacin, Levofloxacin,
Moxifloxacin
Ethionamide, Prothionamide
 Cycloserine
 Para aminosalicylic acid
Third line drugs for
tuberculosis
 Rifabutin
 Macrolides like
clarythromycin
 Linezolid
 Thioacetazone
 Vitamin D
 Thioridazine
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Isoniazid
Isoniazid is the hydralazide of isonicotinic acid.
 It inhibits synthesis of mycolic acids, which
are essential components of mycobacterial cell
wall.
 Effect tuberculocidal.
 It acts on extracellular as well as on the
intracelular mycobacteria.
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Pharmacokinetics of isoniazid
Isoniazid is rapidly and almost completely
absorbed, and peak blood levels are reached
in about 1 to 2 hours.
 Bioavailability is reduced when isoniazid is
administered with food.
 It diffuses readily into all body fluids
(including cerebrospinal, pleural, and ascitic),
tissues, organs, and excreta (saliva, sputum
and feces).
 The drug also passes through the placental
barrier and into milk in concentrations
comparable to those in the plasma.
 Isoniazid is <10% bound to plasma proteins.
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Pharmacokinetics of isoniazid
Isoniazid is metabolized by the liver mainly
by acetylation and dehydrazination.
 The N-acetylhydrazine metabolite is
responsible for the hepatotoxic effects seen
in patients treated with isoniazid.
 The rate of acetylation is genetically
determined.
 Slow acetylation may lead to higher blood
concentrations with chronic administration of
the drug, with an increased risk of toxicity.
 Isoniazid and its metabolites are excreted in
the urine with 75 to 95% of the dose excreted
in 24 hours.
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Clinical use
Used in conjunction with other
antituberculosis agents in the treatment of
pulmonary and extrapulmonary tuberculosis.
 Used alone in the prophylaxis of
tuberculosis.
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Side effects of Isoniazid
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Peripheral neuropathy (occurs frequently )
Hepatitis has been reported in less than 5% of
patients. Jaundice have rarely been reported.
Hypersensitivity
Isoniazid-induced lupus-like reactions
Psychosis, depression, and aggression have been
rarely reported with isoniazid therapy.
Exacerbations of preexisting schizophrenia.
G.I.T. side effects include nausea, vomiting, and
epigastric distress. A few cases of pancreatitis have
been reported.
Pharmacokinetics of RIFAMPICIN
It is easily absorbed from the GIT
 Distribution of the drug is high throughout the
body. It reaches effective concentrations in
many organs and body fluids, including the
CSF.
 About 60% to 90% of the drug is bound to
plasma proteins.
 It is metabolized by deacetylation, but
metabolite is active antimicrobial.
 It is eliminated with urine (30%) and about
60% to 65% is excreted through the feces.
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Rifampicin (side effects)
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Hepatotoxic - hepatitis, liver failure in severe cases.
Respiratory – breathlessness.
Cutaneous - flushing, pruritus, rash, redness and
watering of eyes.
Abdominal - nausea, vomiting, abdominal cramps
with or without diarrhea.
Flu-like symptoms - chills, fever, headache.
Arthralgia, and malaise.
Rifampin has good penetration into the brain, this
may directly explain some malaise and dysphoria in a
minority of users.
Red staining of urine and other body fluids.
Pyrazinamide
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Pyrazinamide is derivative of INH like isoniazid. It is
more active in acidic medium.
More tuberculocidal to intracellularly located
mycobacteria.
It is well absorbed from the GIT.
It is widely distributed in body tissues and fluids
including the liver, lungs and cerebrospinal fluid (CSF).
It is hydrolyzed in the liver to its major active
metabolite, pyrazinoic acid.
Pyrazinamide may be bacteriostatic or bactericidal
against Mycobacterium tuberculosis depending on
the concentration of the drug attained at the site of
infection.
Pyrazinamide
Indications: Pyrazinamide is indicated for the
initial treatment of active tuberculosis in adults
and children.
 It should only be used in conjunction with
other effective antituberculous agents.
 Side effects:
 Hyperuricemia,
 acute gouty arthritis,
 fever,
 loss of appetite, nausea and vomiting,
 yellowish discoloration of the skin and eyes.
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Ethionamide
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Minimum inhibitory concentration (MIC)
against M.tuberculosis (H37Rv): 0.25 microgram/ml.
Ethionamide may be bacteriostatic or bactericidal in
action, depending on the concentration of the drug
attained at the site of infection and the susceptibility of the
infecting organism.
The exact MECHANISM OF ACTION of ETHIONAMIDE
has not been fully elucidated, but the drug appears to
inhibit peptide synthesis in susceptible organisms.
Antimicrobial spectrum of Ethionamide comprises M.
tuberculosis, M. bovis and M. Segmatis.
Ethionamide is structurally similar to methimazole, has
been shown to inhibit thyroid hormone synthesis, and
was reported to cause hypothyroidism in several TB
patients.
Ethambutol

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An antitubercular agent that inhibits the transfer of
mycolic acids into the cell wall of the tubercle
bacillus.
It may also inhibit the synthesis of spermidine in
mycobacteria.
The action is usually bactericidal, and the drug can
penetrate human cell membranes to exert its lethal
effect.
Ethambutol
About 75% to 80% of an orally administered
dose of ethambutol is absorbed from the
gastrointestinal tract.
 The most commonly recognized toxic effect of
ethambutol is optic neuropathy, which
generally is considered uncommon and
reversible in medical literature.
 Other side effects: are pruritus, joint pain,
gastrointestinal upset, abdominal pain, malaise,
headache, dizziness, mental confusion,
disorientation, and possible hallucinations.

Para-Aminosalicylic Acid

Aminosalicylic acid is an
anti-mycobacterial agent
used with other antituberculosis drugs (most
often isoniazid) for the
treatment of all forms of
active tuberculosis due
to susceptible strains of
tubercle bacilli.
Para-Aminosalicylic Acid





There are two mechanisms responsible for aminosalicylic acid's
bacteriostatic action against Mycobacterium tuberculosis.
Firstly, aminosalicylic acid inhibits folic acid synthesis
(without potentiation with antifolic compounds). The binding of
para-aminobenzoic acid to pteridine synthetase acts as the
first step in folic acid synthesis.
Aminosalicylic acid binds pteridine synthetase with greater
affinity than para-aminobenzoic acid, effectively inhibiting the
synthesis of folic acid.
As bacteria are unable to use external sources of folic acid,
cell growth and multiplication slows.
Secondly, aminosalicylic acid may inhibit the synthesis of
the cell wall component, mycobactin, thus reducing iron
uptake by M. tuberculosis.
Para-Aminosalicylic Acid



The most common side
effects: gastrointestinal intolerance manifested by
nausea, vomiting, diarrhea, and abdominal pain.
Hypersensitivity reactions: Fever, skin eruptions of
various types, exfoliative dermatitis, lymphoma-like
syndrome, leucopenia, agranulocytosis,
thrombocytopenia, Coombs' positive hemolytic
anemia, jaundice, hepatitis, pericarditis, hypoglycemia,
optic neuritis, encephalopathy, Leoffler's syndrome,
and vasculitis and a reduction in prothrombin.
Crystalluria may be prevented by the maintenance
of urine at a neutral or an alkaline pH!!!
Thank you!!!!