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.