SULFONAMIDES - Classification, MOA, ADR and Use

 

SULFONAMIDES

The first antimicrobials effective against Pyogenic Bacterial infections.

Derivatives of Sulfanilamide containing a “sufonamido “ring (SO2NH2).

Structurally and chemically related to p-aminobenzoic acid (PABA).

Structurally similar to many drugs – thiazides, acetazolamide, dapsone and sulfonylureas etc.

Physically – available as white powder, mildly acidic and form water soluble salts with bases.

However, indications and practical uses are very few these days.

Sulfonamides – Classification

Short acting: Sulfadiazine, Sulfadimidine, Sulfacetamide

Intermediate acting: Sulfamethoxazole

Long acting: Sulfadoxine, Sulfamethoxypyrazine, Sulfadimethoxine etc.

Topically used: Mafenide, Silver sulfadiazine and Sulfacetamide

Ulcerative colitis: Sulfasalazine

Sulfonamides – Antibacterial Property

Bacteriostatic against gm +ve and gm –ve bacteria

Bactericidal in urine

Susceptible organisms: Str. pyogens, H. influenzae, H. ducreyi, Callymatobacterium grannulomatosis, V. cholerae, Chlamydia, Actinomyces etc.

Few strains of Staph aureus, gonococci, meningococci, pneumococci, E. coli and Shigella

Chlamydiae: trachoma, lymphogrnuloma venereum. Inclusion conjunctivitis. Also Actinomyces and Nocardia

Protozoa:

Plasmodium (Sulfadoxine + Pyrimethamine)

Toxoplasmosis (Sulfadiazine + Pyrimethamine)

PCP (Sulfamethoxazole + Trimethoprim = SXT)

Sulfonamides – MOA

                             

Sulfonamides – Resistance

Many strains – S. aureaus, pneumococci, gonococci, meningococci, Strep. Pyogens, E. coli and Shigella

Mechanism:

1.       Production of increased amounts of PABA (Staph,  Neisseria)

2.       Folate synthase enzyme has low affinity to sulfonamides.

3.       Adopt alternative pathway of folate synthesis – structural  changes in folate synthase (E coli) – encoded  chromosomally and plasmid mediated

Resistant to one sulfonamide – resistant to all

No cross resistance

Sulfonamides – Kinetics

Rapidly and completely absorbed from GIT

Extend of plasma protein binding differs (10 –95%)

Longer acting ones are highly plasma protein bound

Widely distributed – enters in serous cavity easily

Metabolized by non-microsomal acetyl transferase in liver – slow and fast acetylators

Acetylated product – inactive excreted in urine (but, more toxic than parent) – crystalluria

Acetylated form accumulates in blood – toxic in renal faiure

Reabsorbed in tubule

Sulfonamides – ADRs

Nausea, vomiting and epigastric pain

Crystalluria – alkanization of urine

Hypersensitivity (2 – 5%) – rashes, urticaria, drug fever. Exfoliative dermatitis, SJ syndrome (long acting ones)

Hepatitis

Haemolysis – G-6-PD deficiency

Kernicterus – displacement of bilirubin

Individual Sulfonamides

Sulfadiazine: General purpose use – absorbed orally and rapidly excreted. More crystalluria. Preferred in meningitis.

Sulfamethoxazole: slower absorption and lower excretion. 10 Hrs.  Half-life. Combination with Trimethop

Sulfadoxine: Ultra-long acting >1 week. High protein bound – long excretion. Not suitable for pyogenic infections – low plasma conc.  Used in Malaria, Pneumocystis jiroveci and toxoplasmosis

Sulfacetamide: Ophthalmic use – infections by bacteria, chlamydia, ophthalmia neonatorum etc

Mafendie: Atypical sulfonamide. Local application – inhibits variety of bacteria – active in presence of pus – pseudomonas and clostridia

Silver sulfadiazine: Bacteria, fungi, Pseudomonas. In burn cases

Sulfonamides – Uses

Rarely used now a days systemically

UTI: caused by E. coli and P. mirabilis: Sulfisoxazole – 1 gm 4 times daily

Malaria: sulfadoxine and pyrimethamine combination

Toxoplasmosis: sulfadiazine + pyrimethamine

In Combination with Trimethoprim: Cotrimoxazole

Ulcerative colitis: Sulfasalazine – 1-4 gm initially and 500 mg 6 Hrly.

Locally:

Sodium sulfacetamide: 10-30% ophthalmic solution in bacterialconjunctivitis, trachoma etc.

Mafenide acetate (1% cream) and Silver sulfadiazine 1% cream):  Burn dressing and chronic ulcers

Trimethoprim

Trimethoprim (trimethyl benzyl pyrimidine) is a diaminopyrimidine, chemically related to Pyrimethamine

Do not confuse: Clotrimazole (antiungal) - Cotrimoxazole is TMP – SMZ, but Sulfadoxine + Pyrimethamine is antimalarial

MOA: Sequential block of folate metabolism

Trimethoprim is 50,000 or more times more active against bacterial DHFRase enzyme than mammalian

So, no harm to human folate metabolism

MOA OF TRIMETHOPRIM-SULFAMETHOXAZOLE

Cotrimoxazole – general points

Individually, both are bacteriostatic, but combination is – bactericidal

Both drugs have almost similar half-lives (10 Hrs)

Maximum synergism if the organism is sensitive to both the agents.

Optimal synergism is obtained at 20 (S): 1 (T) concentration (MIC of both is reduced by 3 - 6 times)

1.       This ratio is obtained at 5:1 dose ratio (e.g. 800 mg: 160 mg)

2.       Because TMP has large Vd and enters many tissues – plasma conc. is low

But, TMP crosses BBB and placenta and SMZ not

TMP is more rapidly absorbed than SMZ

TMP is 45% plasma protein bound but SMZ is 65% bound

TMP is partly metabolized in liver

Cotrimoxazole – antibacterial spectrum

Similar to sulfonamides

Additional benefits: Salmonella typhi, Serratia, Klebsiella Enterobacter, Yersinia and Pneumocystis jiroveci

– Sulfonamides resistance strains of S. aureus, E. coli, gonococci, meningococci and H influenza

RESISTANCE: Slow to develop

– By mutational changes or plasmid mediated acquisition of a DHFRase enzyme having lower affinity for the inhibitior.

Cotrimoxazole – ADRs

All adverse effects of sulfonamides – nausea, vomiting,stomatitis,rash etc

Folate deficiency (megaloblastic anaemia) – patients with marginal folate levels

Blood dyscrasias

Pregnancy: teratogenic risk, Neonatal haemolysis and methaemoglobinaemia

Patients with renal disease may develop uremia

Fever, rash and bone marrow hyperplasia

Elderly – risk of bone marrow toxicity from cotrimoxazole

Diuretics given with cotrimoxazole have produced a higher incidence of thrombocytopenia

Bone marrow hypoplasia among AIDS patients with Pneumocystis jiroveci infection

Cotrimoxazole – Uses

Uncomplicated infection of the lower urinary tract infection

– Cystitis (5 tablet dose)

– Chronic and recurrent urinary tract infections (including enterobacteriaceae) – 3-10 days

Respiratory tract infection – lower and upper, chronic bronchitis, facio-maxillary infections, otitis media due to gm+ve cocci and H influenzae etc

Typhoid

Bacterial diarrhoeas & dysentery: due to campylobacter, E coli, Shigella etc.

Pneumocystis jiroveci: Severe pneumonia - Prophylactic use in AIDS patients with neutropenia. Dose – DS tablet 4-6 times 2-3 weeks

Chancroid – H. ducreyi

Alternative to penicillin in agrannulocytosis patients, scepticaemia etc.