Upload
elvin-edwards
View
276
Download
4
Tags:
Embed Size (px)
Citation preview
Sulfonamides
(Antimetabolites)
Classes of Sulfonamides
3
I. Systemic Sulfonamides According to their duration of action they are
divided to:
Short-acting Sulfonamides
Intermediate-acting sulfonamides
Long-acting sulfonamides
4
A( Short-acting Sulfonamides
They are rapidly absorbed and rapidly excreted. Their half lives from 4-7 hours and they are administered every 4 to 8 hours.
HN
S
O
O
H2N
Sulfaisoxazole
NO
CH3
CH3
4-amino-N-(3,4-dimethylisoxazol-5-yl)benzenesulfonamide
HN
S
O
O
H2N
Sulfamethizole
S
NN
CH3
4-amino-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide
HN
S
O
O
H2N
N
4-amino-N-(pyridin-2-yl)benzenesulfonamide
Sulfapyridine
Sulfadimidine or sulfamethazine
S
O
O HN
N
N CH3
CH3
H2N
4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide
S
O
O HN N
N
CH3
H2N
4-amino-N-(4-methylpyrimidin-2-yl)benzenesulfonamide
Sulfamerazine
5
B( Intermediate-acting sulfonamides
They are absorbed and excreted more slowly than short-acting. Their half lives range from 10 to 12 hours so they are given twice
daily.
S
O
O HN N
N
H2N
4-amino-N-pyrimidin- 2-yl-benzenesulfonamide
SulfadiazineSulfamethoxazole
S
O
O HN
ON
CH3
H2N
4-amino-N-(5-methylisoxazol-3-yl)-benzenesulfonamide
C( Long-acting sulfonamides
They are rapidly absorbed but slowly excreted their half lives are 35 to 40 hours.
S
O
O HN
N N
OCH3
OCH3
H2N
Sulfadimethoxine
S
O
O HN
N N
OCH3
H2N
Sulfadoxine
OCH3
7
II. Intestinal sulfonamides Water soluble latent forms which are poorly absorbed from the
GIT (5%) and thus reach a high concentration in the colon lumen,
By means of either bacterial or enzymatic hydrolysis releases the parent sulfonamide.
Examples: sulfasalazine, phthalylsulfathiazole and succinylsulfathiazole (Prodrugs).
Phthalylsulfathiazole
O
OH
O
NH
S
O
O
HN S
N
O
HONH
S
O
O HN
S
N
O
Succinylsulfathiazole
NNH
S
O
O
HN N
O
O
HO
Sulfasalazine Sulfasalazine is mainly used for treatment of inflammatory bowel disease,
including ulcerative colitis and Crohn's disease. It is also effective in several types of arthritis, particularly rheumatoid arthritis
Reductive metabolism by means of azoreductase enzyme converts the drug to sulfapyridine and 5-aminosalicylic acid (anti-inflammatory) both components are active
Intestinal sulfonamides )cont.(
NNH
S
O
O
HN N
O
O
HO
Azoreductase
H2N
S
O
O
HN N
Sulfapyridine
NH2
HO
O
HO
5-aminosalicylic acid
9
Ophthalmic sulfonamides They are used in treatment of conjunctivitis and
other superficial ocular infections.
CH3
O
NaN
S
O
O
H2N
Sulfacetamide Sodium
CH3
O
HN
S
O
O
H2N
Sulfacetamide
IV. Sulfonamides for burn therapy
Mafenide is not a true sulfonilamide, it is not effective systemically, but is particularly effective topically in the treatment of burns or for healing infected wounds.
S
O
ONH2
H2N
4-(aminomethyl)benzenesulfonamide
Mafenide
Sulfonamides for burn therapy )cont.(
Silver sulfadiazine is used as effective topical antimicrobial agents, especially against Pseudomonas s. in burn therapy, where treatment failure with other drugs may occur.
Ag+
N- N
N
S
O
O
H2N
Silver sulfadiazine
Mixtures of sulfonamides
1.Sulfonamides aloneThe main purpose is to reduce the risk of crystalluria
a(Trisulfapyrimidine Each drug is administered in one third of the total dose, they behave independently concerning solubility but their therapeutic effects are additive.
OS
HN
N
N
H2N
O
Sulfadiazine
OS
HN
N
N
H2N
O
Sulfamerazine
CH3 OS
HN
N
N
H2N
O
Sulfamethazine
CH3
CH3
b. Multiple )or Triple( sulfas They are a 1:1:1 combination of sulfabenzamide,
sulfacetamide, and sulfathiazole. The combination is primarily used as topical cream for Gardnerella vaginalis in vaginal infections
S
O
O HN
H2N
sulfabenzamide
S
O
O HN
S
N
H2N
Sulfathiazole
CH3
O
HN
S
O
O
H2N
Sulfacetamide
2( Mixtures of sulfonamides with other drugs
Sulfamethoxazole and Trimethoprim There is a synergistic effect obtained from such combination. It is usually given orally and I.V. administration. When taken orally the tablet has a standard ratio of
5 : 1 40 mg of the sulfa and 8 mg trimethoprim. Both drugs are excreted in urine their half lives are about 8-10
hours
N
NH2N
NH2
OCH3
OCH3
OCH3
TrimethoprimSulfamethoxazole
S
O
O HN
ON
CH3
H2N
Trimethoprim is often given in conjunction with the sulfonamide sulfamethoxazole.
The latter inhibits the incorporation of PABA into folic acid, while the former inhibits dihydrofolate reductase.
Therefore, two enzymes in the one biosynthetic route are inhibited.
This is a very effective method of inhibiting a biosynthetic route and has the advantage that the doses of both drugs can be kept down to safe levels. To get the same level of inhibition using a single drug, the dose level of that drug would have to be much higher, leading to possible side-effects.
This approach has been described as
'sequential blocking'.
H2N COOH FOLIC ACID TETRAHYDROFOLATE
Dihydropteroate Synthetase
dihydrofolate reductase
SULFAMETHOXAZOLE TRIMETHOPRIM
Pharmacokinetic factors of the combination
Pairing these two particular antibacterial agents was based upon pharmacokinetic factors and convenient availability.
For such a combination to be useful in vivo the two agents must arrive at the necessary infected tissues at the correct time and in the right ratio.
It is used for oral treatment of urinary tract infections, shigellosis, otitis media, traveler's diarrhea and bronchitis.
Selectivity of Trimethoprim
There is a significant differences between the bacterial and the mammalian dihydrofolate reductases away from the active site.
The bacterial enzyme is sensitive to inhibition by trimethoprim by up to 100,000 times lower concentrations than is the mouse enzyme. This difference explains the useful selective toxicity of trimethoprim.
18
Advantages of this combination
The combination of sulfamethoxazole-trimethoprim is not only
synergistic in vitro but is less likely to induce bacterial resistance than
either agent alone.
Thus, these agents block sequentially at two different steps in the same
essential pathway, and this combination is extremely difficult for a naive
microorganism to survive.
It is also comparatively uncommon that a microorganism will
successfully mutate to resistance at both enzymes during the course of
therapy.
It is useful and comparatively nontoxic for AIDS patients who are
infected with the pneumonia causing opportunistic pathogen
Pneumotystis carinii.
19
Thank for your Attention