Sulfonamides

BY
Jagir R. Patel
Assistant Professor
Sulfonamides
• They were the first AMAs effective against pyogenic bacterial infections

• Due to development of resistance the and availability of more safer drugs

their current utility is limited

• Except used in combination with Trimethoprim as Cotrimoxazole or

pyrimethamine
Classification
• Short acting: Sulfadiazine, sulfacetamide, Sulfadimidine, Sulfisoxazole

• Intermediate acting: Sulphamethaxazole, sulfadoxine, sulfamoxole

• Long acting: sulphamthoxypyridazine, sulfadimethoxine,

sulphamthoxypyrazine

• Special purpose: sulfacetamide, sulfadiazine, sulfasalazine

Anti Bacterial spectrum
• The sulfonamides are broad-spectrum antimicrobials
• effective against gram-positive and some gram negative organisms of
the Enterobacteriaceae.

• Good activity against Escherichia coli,

• Moderate activity against Proteus mirabilis and Enterobacter spp.
• Poor activity against in Proteus and Klebsiella spp.
• No Inhibitory activity against Pseudomonas aeruginosa and Serratia
spp. They are also effective against Chlamydia spp.,
Folate synthesis
Folate (“dihydrofolate”, “FH2”, “folic acid”, “vitamin B9”) is a cofactor (methyl-
group donor) in the synthesis of purines and pyrimidines used for DNA and RNA
synthesis

• Humans are not able to synthesize folate themselves, and exclusively rely on
absorption of folate from the GI tract

• Mammalian cells in contrast use folate receptors and folate carries in the plasma
membrane to scavenge the intact vitamin which is fundamental difference b/w
pathogen and mammalian cell which makes DHFR inhibitors an ideal target

• Folate is only active in the tetrahydrofolate (FH4) form, thus both humans and
bacteria need to activate folate to utilize it synthesis and activation of folate is
done in 3 steps
Mechanism of action
 Cont…
• Sulfonamides are synthetic structural analogues of PABA and act by displacing
PABA from its binding site on dihydropteroate synthetase, thus inhibiting bacterial
synthesis of folate this leads to an inability of the bacteria to synthesize DNA and
RNA and following inability for them to divide however, bacteria are still able to
survive without dividing, thus sulfonamides are only bacteriostatic

• Since humans do not synthesize their own folate, sulfonamides leave DNA and
RNA synthesis in human cells untouched
Resistance
• Bacteria may develop resistance to sulfonamides by plasmid transfer
and/or chromosomal mutations

• - this resistance may occur by 3 separate mechanisms

MECHANISM DESCRIPTION

DECREASED UPTAKE Due to decreased permeability of

the bacterial cell envelope to
sulfonamides

DECREASED AFFINITY Due to structural alterations

of dihydropteroate synthetase
(folate synthase enzymes)
INCREASED DISPLACEMENT Due to increased synthesis of
PABA and adopt alternative
pathway for folate synthesis
 Sulphadiazine prototype
• SULFADIAZINE, sulphadoxine, sulfomethaxazole
• General information
• Administered orally and/or IV, may cross the blood-brain barrier may
cross the placental barrier

• Medical uses
• Treatment of cystitis due to escherichia and/or proteus Infection
• Treatment of chlamydia
• Trachoma
• lymphogranuloma due to chlamydia infection
Pharmacokinetics

• Absorption: completely absorbed from G.I.T.

• Plasma protein binding about 10 to 95% more the protein binding
longer the action

• Distribution: wildly distributed plasma, CSF, and placenta

• Excretion : they are mainly excreted by the kidney through
glomerular filtration

• Both renal tubular secretion and reabsorption occurs

• The lipid soluble members are reabsorbed hence long posses long
action
Cont.…
• Side effects
• Headache, nausea and vomiting, hepatitis
• Bone marrow depression: leading to thrombocytopenia
• Granulocytopenia
• Methemoglobinemia, hemolytic anemia (if glucose-6-phosphate deficiency)
• kernicterus (in infants)
• Urolitihasis (“crystalluria”) Due to poor solubility in the low pH of the renal
tubules and following crystal formation)

• hypersensitivity reactions leading to skin rashes and/or

• Angioedema
LONG-ACTING SULFONAMIDES

• SULFAMETHOXYDIAZINE
• Side effects Same as sulfadiazine, except for urolithiasis (due to higher solubility at low
pH,

• Hypersensitivity reactions
• leading to skin rashes, angioedema and/or stevens johnson syndrome
• Drug- drug Interactions
• They inhibit the metabolism possibly display protein binding sites of phenytoin,
tolbutamide, and warfarin

• Use:
• Rarely used alone
• In chronic UTI and Gum infection
Dihydrofolate reductase inhibitors
• Dihydrofolate reductase inhibitors are structural analogues of folate and
act by competitively inhibiting dihydrofolate reductase.

• Since humans need to activate folate as well, dihydrofolate reductase

inhibitors also affect DNA and RNA synthesis in human cells (!) however,
dihydrofolate reductase inhibitors have a much stronger affinity for
bacterial dihydrofolate reductase, thus affecting human cells to a much
smaller extent

• Mechanism of resistance: due to structural alterations of dihydrofolate

reductase
Pyrimethamine

• General information
• Administered orally, may cross the blood-brain barrier
• Medical uses
• Treatment of malaria due to plasmodium falciparum and/or
• plasmodium malariae, & or plasmodium vivax, and plasmodium ovale
infection

• Treatment of malaria due to plasmodium falciparum infection then

administered in conjunction with mefloquine
• Side effects
• nausea and vomiting, folate deficiency leading to, macrocytic
hyperchromatic, anemia, leukocytopenia and/or thrombocytopenia

• Hypersensitivity reactions leading to skin rashes

Trimethoprim

• Medical uses
• Treatment of cystitis due to escherichia and/or proteus Infection
• Treatment of pneumonia due to streptococcus and/or Haemophilus
infection

• Mechanism and other side effects are same as pyrimethamine

combinations
• Pyrimethamine + Sulfadiazine

• General information this particular combination is chosen due to similar

pharmacokinetics of the 2 active compounds administered orally and/or IV
may cross the blood-brain barrier

• USE
• Toxoplasmosis due to toxoplasma infection
• Malaria due to
• plasmodium falciparum, malariae, vivax and ovale and/or with aminoquinoline
Cotrimoxazole
• The fixed dose combination (1:5 according to WHO)
• Trimethoprim + Sulamethoxazole = Cotrimoxazole

• Both drug interfere in same metabolic pathway produces sequential

blockage

• The combination produces supra-additive effect

• Sufomethaxazole inhibits folate synthetase and trimethoprim inhibits
folate reductase
Cont.…
• Both drugs match closely
• They have similar half life
• Optimum synergistic effect at (20:1 suphamethaxazole:trimethoprim) in
plasma and tissues

• Advantage of combination:
• Individually both are bacteriostatic but combination is bactericidal
• Chances of bacterial resistance are reduced
Pharmacokinetics

• Oral and parenteral use: well absorbed orally

• Widely distributed in various organs and tissues including CSF and
sputum

• Metabolized in liver excreted in urine

• Dose reduction is needed in case of renal insufficiency
Adverse effect
• Dermatologic: skin rash
• G.I.T.: nausea, vomiting
• Hematologic: megaloblastic anemia, leukopenia, thrombocytopenia
• Patients with HIV: rashes, drug induced fever, diarrhea

• Drug interactions:
• Trimethoprim + warfarin: prolonged prothrombin time
• Plasma half life of phenytoin increases
Cotrimoxazole uses

• UTI: due to grm –ve organism like E.coli , Proteus sp.

• Can be given for chronic recurrent UTI in women's
• Small doses thrice weakly for long term prophylaxis in recurrent UTI
• Male: for bacterial prostatitis as it is concentrated in prostatic tissue

• Bacterial Respiratory tract infections:

• Acute and chronic bronchitis due to H.influenza and S.Pneumoniae
Cont..

• Bacterial diarrhoeas: due to Shigella, E.coli, and salmonella sp.

• Typhoid fever: it may also be effective with fluoroquinolones

• Chancroid: caused by H. Ducreyi Cotrimoxazole is equally effective

compared to drug of choice Azithromycin