Sulfonamides

BY
Jagir R. Patel
Anand pharmacy college

Jagir R. Patel, Assistant Professor, Dept

Pharmacology, APC
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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

Classification

• Short acting: Sulfadiazine, sulfacetamide,

Sulfadimidine, Sulfisoxazole
• Intermediate acting: Sulphamethaxazole, sulfadoxine,
sulfamoxole
• Long acting: sulphamthoxypyridazine, sulfadimethoxine,
sulphamthoxypyrazine
• Special purpose: sulfacetamide, sulfadiazine,
sulfasalazine

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC
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.,

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

Mechanism of action

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

 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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

General toxicity of sulphonamides
• Toxicity

• Skin rash due to hypersensitivity is the most common adverse effect.

• These can also cause granulocytopenia, thrombocytopenia and aplastic

anemia (more common in HIV infected patients).

• Sulfonamides can cause acute hemolysis in patients with G-6 PD deficiency.

• These can precipitate in the urine at acidic pH and may result in crystalluria
and hematuria.

• These can displace bilirubin from plasma protein binding sites and may
result in kernicterus in the new born (if given in third trimester of pregnancy).

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

Uses of sulphonamides
• Sulfacetamide is used for ocular infections whereas mafenide and silver
sulfadiazine are used in burn patients as topical agents.

• Sulfadiazine can be used for nocardiosis and sulfisoxazole for urinary tract
infections.

• Sulfasalazine and olsalazine are used for the treatment of ulcerative colitis.

• Sulfadoxine + pyrimethamine is used for malaria.

• Sulfadiazine and pyrimethamine combination can be used for the treatment

of toxoplasmosis and prophylaxis of Pneumocystis jiroveci pneumonia in
AIDS patients

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

 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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

 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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

Stevens Johnson syndrome

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

 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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

Jagir R. Patel, Assistant Professor, Dept
Pharmacology, APC
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
• PK
• 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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

 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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

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
• 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

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

mnemonics

Jagir R. Patel, Assistant Professor, Dept Pharmacology, APC

Jagir R. Patel, Assistant Professor, Dept
Pharmacology, APC