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Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
• SULFONAMIDES
• ANTIMYCOBACTERIAL DRUGS
• PRINCIPLES OF
ANTIBACTERIAL
CHEMOTHERAPY
Assoc. Prof. Iv. Lambev
E-mail: [email protected]
SULFONAMIDES
G. Domagk
(1895-1964),
bacteriologist and pathologist discovered
the first sulphonamide in
1935. Nobel prize for
Physiology and Medicine
in 1939.
Mechanism of action
•Unlike man, the most bacteria cannot
utilize external folic acid, a nutrient
which is essential for growth, and have
to synthesize it from para-aminobenzoic
acid (PABA). Sulfonamides are structurally similar to PABA and inhibit the
enzyme dihydrofolate synthetase in the
biosynthetic pathway for folic acid.
•High concentration of PABA antagonize
the effectiveness of sulfonamides.
PABA
Sulfanilamide
DHF synthetase
PABA
DHF reductase
DHFA
(-)
Sulfonamides
THFA
Purines
(-)
Trimethoprim
Dietary folate
in man
DNA
Proteins
Spectrum of activity
•Sulfonamides have a bacteriostatic action
on wide range of Gram-positive and Gramnegative microorganisms and also active
against toxoplasma, nocardia species and
chlamydia.
•Sulfonamides alone are usually reserved
for treatment of nocardiosis and
toxоplasmosis.
Resistance
•Resistance is common and due to the
production of dihydrofolate synthetase
with reduced affinity for binding of
sulfonamides, and is transmitted in
Gram-negative bacteria by plasmids.
•Resistant strains of Staphylococcus
aureus can synthesize more PABA
than normal.
Pharmacokinetics
•The most sulfonamides are well absorbed
orally although parenteral preparations of
some are available. They are widely distributed in the body and cross the BBB and
placenta.
•Sulfonamides are metabolized in the liver,
initially by acetylation which shows genetic polymorphism. The acetylated product
has no antimicrobial actions but
retains toxic potential.
Substantial amounts
of parent drugs and
N-acetyl metabolite
are excreted by the
kidney.
Unwanted effects
•Hypersensitivity reactions include rashes,
vasculitis, Stevens-Johnson syndrome.
•Haemolysis in patients with glucose-6phoshate-dehydrogenase deficiency.
•Crystalluria is a potential problem with
overdose of these drugs or with acid urine.
•Sulfonamides compete for bilirubin binding sites on albumin and can cause
kernicicterus in neonates.
Stevens–Johnson
syndrome after oral
intake of Co-trimoxazole
(Color Atlas and Synopsis
of Clinical Dermatology, 1999)
Lyell
syndrome
after oral
intake of
Co-trimoxazole
Clcr
Contraindications
•Sulfonamides should not be used in the
last trimester of pregnancy; in neonates;
during the period of lactation; in patients
with hypersensitivity reactions.
DRUG PREPARATIONS
t1/2 8–16 h:
- sulfamethoxazolе
- sulfametrolе
t1/2 > 16 h:
- sulfadimethoxinе
- sulfalen
Sulfacetamidе
•collyrium 20% 10 ml
Sulfadicramide
For local
treatment
of bacterial
conjunctivitis
Low GI resorption (30%)
- Sulfaguanidinе
in GI infections
Sulfasalazinе
®
(Salazopyrin )
• colitis ulcerosa
Sulfamethaxzole/Trimethopim
Trimethoprim inhibits dihydrofolate
reductase which converts dihydrofolate
to tetrahydrofolate:
DHF reductase
DHF synthetase
PABA
DHFA
(-)
Sulfamethoxazole
THFA
(-)
Trimethoprim
Purines
The bacterial enzyme is inhibited at 50 000
times lower concentrations than the mammalian equivalent.
The combination of trimethoprim with the
sulfonamide sulfamethoxazole (known as
co-trimoxazole – BAN) acts synergistically
to prevent folate synthesis by bacteria.
However, resistance to the sulfamethoxazole
component, and the incidence of unwanted
effects limit the value of this combination.
Thrimethoprim has a wide spectrum of
activity against Gram-positive and Gramnegative bacteria. The combination with
sulfamethoxazole is also effective against
Proteus and Pneumocystis carinii
(this is now its major indication).
Trimethoprim and sufamethoxazole are
well absorbed from the gut. Their t1/2 is
about 11 h. Trimethoprim is excreted
unchanged by the kidney. Co-trimoxazole
is availble for p.o. and i.v. use.
Co-trimoxazolе (BAN)
- tab. 480 mg
®
•Trimezol - tab. 480 mg
®
•Biseptol
Adverse effects
Sulfamethoxazole/Trimethopim
•Nausea, vomiting and
diarrhoea, which
are usually mild.
•Skin rashes.
•Folate deficiency leading to megaloblastic
changes in the bone marrow is rare except
in patients with depleted folate stores.
•Marrow depression with agranulocytoses.
ANTIMYCOBACTERIAL DRUGS
Antitubercolous drugs
•Synthetic drugs (p.o.): Isoniazid,
Ethambutol, Pyrazinamide, Ethionamide
•Antibiotics: Rifampicin (p.o.), Rifamycin
(i.v. infusion), Rifabutin; Streptomycin
Drugs for treatment of leprosy
p.o.: Rifampicin, Clofazimine, Dapsone
ANTITUBERCOLOUS DRUGS
 Isoniazid (5 mg/kg/24 h p.o. )
inhibits production of long-chain
mycolic acids which are unique to the cell
wall of mycobacteria species. It is bacteriocidal against dividing microorganisms.
Resistance is due to random mutation.
It can be troublesome in developing
countries.
Oral absorption of isoniazid is good, but
reduced by food. It diffuses well into the
body tissues, including the CSF, and penetrates into macrophages so that it is effective against intracellular tubercle bacilli.
Isoniazid undergoes genetically controlled
polymorphic acetylation in the liver. A high
percentage of fast acetylators being found
in Japanese and Eskimo populations.
In European populations 40–50% are rapid
acetylators.
Unwanted effects of isoniazid
•Nausea and vomiting.
•Peripheral neuropathy in high doses.
This can be prevented by prophylactic
oral use of pyridoxine (vitamin B6).
High risk patients are with diabetes, alcoholism, chronic renal failure, malnutrition.
•Hepatotoxicity.
•Systemic lupus erythematosus
like syndrome.
(B6)
 Ethambutol impairs synthesis of the
cell wall of mycobacteria. It is primarily
bacteriostatic. Its oral bioavailability
is 77%. Only a small amount is metabolized and most is eliminated unchanged
by the kidney.
Unwanted effects
•Headache, dizziness
•Optic neuritis
(dose-related,
but usually reversible).
 Pyrzinamide has bactericidal effect.
Adverse effects
•Hyperuricemia (it may precipitate gout)
•Hepatotoxicity
•Rashes and photosensitivity
•Sideroblastic anaemia
 Rifampicin (Rifampin) acts by
inhibition of DNA-dependent RNA
polymerase and has bactericidal effect.
It has a broad spectrum of activity
which in addition to mycobacteria
species includes brucella, legionella
and staphylococci.
•Resistance develops rapidly. It is a
one step process of mutation.
Absorption from gut is almost complete,
but is delayed by food. Peak plasma levels
reach 3 h after a single oral dose of
600 mg. The t1/2 is 3 h.
About 85-90% of the drug is protein
bound in plasma but rifampicin penetrates
well into most tissues, cavities and exudates. It is metabolized by deacetylation and
is excreted mainly in the bile. The drug
and its metabolite undergo prolonged
enterohepatic circulation.
Unwanted effects of rifampicin
•Sometimes influenza-like symtoms,
flushing and rashes.
•Hepatotoxicity, usually only producing a
transient rise in plasma of transaminases.
•Induction of drug-metabolizing enzymes
in the liver. Important interactions
include those with oral contraceptives,
phenytoin, warfarin and sulphonylureas.
•Urine and tears become pink/red which
may be a useful guide to compliance.
 Streptomycin is an aminoglycoside
antibiotic. Its antibacterial activity is due
to it binding to the 30S subunit of the
bacterial ribosome and inhibiting of protein
synthesis. It has a wide spectrum of antibacterial activity but is primarily use to
treat mycobacterial infections (i.m.).
•The main problems are eighth nerve toxicity (vestibulotoxicity more than deafness), nephrotoxicity, allergic reactions.
DRUG TREATMENT
OF TUBERCULOSIS
•Mycobacterium tuberculosis readily develops resistance to monotherapy. Three or
four drugs are used for the first 2 months,
and than the treatment is continued with
2 drugs for a further 6-9 months.
A standard regimen in the UK includes
rifampicin and isoniazid for 6 months
with ethambutol and pyrazinamide for
the first 2 months only.
PRINCIPLES OF ANTIBACTERIAL
CHEMOTHERAPY
(Adapted from Laurence et al., 1997)
The following principles, many of which
apply to drug therapy in general, are a
guide to good clinical practice
with antimicrobial agents.
•Make a diagnosis as precisely as possible:
- defining the site of action;
- defining the microorganism(s)
responsible
and their sensitivity to drugs;
- biological samples for laboratory must be
taken before treatment is begun.
•Remove barriers to cure (e.g. lack of free
drainage of abscesses, obstruction in the
urinary or respiratory tracts).
•Decide whether chemotherapy is necessary.
As a general rule, acute infections require
chemotherapy whilst chronic infections
may not. Chronic abscess or empyema
respond poorly. Even some acute infections
such as gastroenteritis are better managed
symptomatically than by antimicrobials.
•Select the best drugs. This involves
consideration of:
- specificity (the antimicrobial activity of
drug must cover the infecting organisms;
- pharmacokinetic factors (the chosen drug
must be reach the site of infection (e.g. by
crossing BBB);
- the patients (who may previously have
allergic reactions to antimicrobials or
whose routes of drug elimination my be
impaired e.g. by renal disease).
In some infections the choice of antimicrobails follows automatically from the cliniccal diagnosis because the causative organknish is always the same, and is virtually
always sensitive to the same drug, e.g.
segmental pneumonia in a young person
which is almost always caused by S. pneumonia (benzylpenicillin), some haemolytic streptococcal infections, e.g. scarlet
fever and erysipelas (benzylpenicillin),
typhus (tetracycline), leprosy, lues.
In the other cases the infecting organism is
identified by the clinical diagnosis, but no
assumption can be made as to its sensitivity
to any one antimicrobial, e.g. tuberculosis.
In the most cases the infecting organism is
not identified by the clinical diagnosis, e.g.
in urinary tract infections, meningitis etc.
In the last two categories the choice of antimicrobial drug may be guided by:
- knowledge of the like pathogens
- simple staining and sensitivity tests.
•Indications for combination therapy:
-To avoid the development of resistance
in chronic infections (tuberculosis).
- To broaden the antibacterial spectrum:
a) in a known mixed infection;
b) if the microorganism
cannot be predicted
(septicemia complicating neutropenia).
- To obtain potentation (e.g. penicillin
plus genatmicin for enterococcal
endocarditis)
•Antimicrobial therapy and pregnancy
PRC B have:
•Azithromycine
•Erythromycine
•Penicillins
•The most of
cefalosporines
•Administer the drug in optimum dose and
frequency and by the most appropriate route.
- Inadequate dose may encourage the
development of microbial resistance.
- Intermittent dosing is proffered to
continual infusion.
- Plasma concentration monitoring can be
applied to optimize therapy with aminosides, fluoroquinolones, cephalosporins
etc. in patients with kidney disease.
•Continued therapy enough until apparent
cure has been achieved.
- Most acute infections are treated for
5 to 10 days. There are many exceptions
to this, such as typhoid fever, tubercularsis and infective endocarditic, in which
relapse is possible long after apparent
clinical cure and so the drugs are
continued for a long time, determined
by experience.
•Test for cure. In some infections, microbiological proof of cure is desirable because
disappearance of symptoms and signs
occurs before the microorganisms are
eradicated, e.g. urinary tract infections
(examinations must be done after
withdrawal of chemotherapy).
•Prophylactic chemotherapy for surgical and
dental procedures should be of very limited
duration. It should be start at the time of
surgery to reduce the risk of producing
resistant microorganisms.