Sulphonamides

Dr.K.Sreedhar R.Pai
Professor and Head
Department of Pharmacology
Manipal College of Pharmaceutical Sciences,
Manipal-576104
ksr.pai@manipal.edu
Gerhard Domagk
Sulphonamides- History
 Prontosil protected mice from
streptococcal infection (Domagk 1935)
 Nobel Prize in medicine 1938
 Cure of staphylococcal septicaemia in
an infant (Foerster, 1933) by prontosil
 Sulphanilamide, active metabolite of
prontosil (Colebrook and Kenny, 1936)
Prontosil
 Sulphonamides- Chemistry
 Derivatives of p-aminobenzene
sulphonamide

H 2N SO2NHR
 Classification
 Rapidly absorbed and excreted
 Sulphisoxazole, Sulphadiazine, (Short acting 4-8 hrs)
 Sulphamethoxazole (Intermediate acting 8-12 hrs)
 Long acting (> 7 days)
 Sulphadoxine, Sulphamethoxypyridazine
 Poorly absorbed
 Sulphasalazine
 Topical use

Sulphacetamide, Silver sulphadiazine
Antibacterial Spectrum
 Active against Gram +ve and –ve
bacteria
 Susceptible organisms include
 Strep. Pyogenes (septic infections)
 Strep. pneumoniae (pneumonia)
 Haemophilus influenzae (meningitis)
 Haemophilus ducreyi (chancroid)
Antibacterial Spectrum (Cont)
 Susceptible species
 Nocardia (lung disease)
 Actinomyces (abscesses)
 Chlamydia trachomatis (trachoma)
 Minimum inhibitory concentration (MIC)
 0.1 µg/ml for C. trachomatis
 4 to 64 µg/ml for E. coli
Antimicrobial action-Mechanism
 Pteridine + PABA
 Inhibited by sulphonamides

 Dihydropteroic acid
 + Glutamic acid
 Dyhydrofolic acid
 Inhibited by trimethoprim

 Tetrahydrofolic acid
Pharmacokinetics
 70-100% absorption orally
 Cmax in 2-6h
 Protein bound, widely distributed
 Major metabolite –N4 acetylated product
(no antibacterial action, but toxicity
retained)
 Excreted mainly via urine
Sulphonamides - Uses
 Urinary tract infections (sulphisoxazole)
 Nocardiosis (Sulphadiazine)
 Toxoplasmosis (Sulphadiazine
+Pyrimethamine)
 Prophylactic use: Streptococcal
infections
Special purpose :
 Sulfacetamide (eye) ? As eye drops &
ointment
a) High aqueous solubility

b) Neutral pH and non-irritant nature of the

drug
c) Good penetrability on topical administration

d) Low incidence of hypersensitivity reactions

e) Low cost
Special purpose :
 Silver Sulfadiazine  topical for preventing
infections of burn wounds. Silver slowly
release silver ions which are toxic to
microorganism, not effective in the presence
of pus and tissue fluids

 Sulfasalazine  colon (ulcerative colitis)

 Sulfadoxine  resistant falciparum (with

pyrimethamine)
Adverse effects
 Urinary tract disturbances
 Crystalluria, haematuria, obstruction
 Haematopoietic disturbances
 Anaemia, Granulocytopenia etc (G6PDD)?
 Fever, skin rashes, dermatitis,
photosensitivity, urticaria, nausea,
vomiting, diarrhoea
Pharmacogenitic Variation in
Drug response due to enzyme
deficiency
 Glucose -6-phosphate dehydrogenase deficiency
 African Americans, Mediterranes Jews, Middle
East and South East races – deficient in G6PD
 Responsible for supply of NADP ---acts as
cofactor for glutathion reductase
 NADP---oxidised glutathion to reduced
gutathion-------convertes Fe+++ to Fe++ in
hemoglobin---also stability to RBC
 Oxidising drugs Primaquine, Sulfone,
nitrofurantoin----hemolytic anaemia
 Adverse effect of
Sulfanamides (ABC of Rash)
A- Aplastic anemia
B- Bilirubin displacement (Kernicterus)
C- Crystalluria

R-Rash
A-Acetylation
S-SLE
H-Hemolysis of G-6-PD deficiency
Drug interactions
 Potentiate the action of
 Sulphonylureas
 Oral anticoagulants
 Hydantoins
 By inhibition of metabolism and/OR
 Displacement from protein binding
Co-trimoxazole
 Combination of sulphonamide with
trimethoprim (5:1 gives 20:1 Cp)
 Trimethoprim + (Sulphamethoxazole)?
 Similar t1/2 (11 and 10h)
 Sequential inhibition of enzymatic
pathway Synergistic combination
 Sequential Blockade

Pteridine Dihydropteroic acid (Inhibited

by sulphonamide)

Dihydrofolic acid Tetrahydrofolic

acid (Inhibited by trimethoprim)

Bacteriostatic effect to bactericidal

Antibacterial spectrum
 Wide antibacterial spectrum
 Chlamydia diphtheriae, Neisseria
meningitidis, S. pneumoniae
 Staph, E coli, Proteus, Salmonella,
Shigella, Klebsiella, Brucella
 Maximum synergism when microbes are
sensitive to both drugs
Resistance
 Reduced cell permeability
 Overproduction of DHFR or altered
reductases
 By mutation or plasmid encoded
Uses
 Pneumonia (P. jiroveci)
 Shigellosis
 Systemic salmonella infections
 Urinary tract infections
 Prostatitis
 Respiratory tract infections (alternative
to β-lactam drugs)
Uses (cont)
 IV co-trimoxazole?
 Solution of 80mg trimethoprim +
400mg sulphamethoxazole per 5ml
diluted in 125 ml of 5% dextrose (60-90
min infusion)
 Agent of choice in pneumocystis
pneumonia, G-ve sepsis, shigellosis,
typhoid
Adverse effects
 Megaloblastic anaemia
 Leukopenia, Granulocytopenia
 Drug fever, nausea, vomiting
 Renal damage, vasculitis
 Occasional CNS disturbances
 Note
 Other DHFRase inhibitors are
pyrimethamine, methotrexate, proguanil and
pentamidine
 All DHFRase inhibitors can cause
megaloblastic anemia
 Assignments
 Outline the MoA of sulfa drugs
 How does resistance develop to sulfa
 Classify sulfa drugs in AMA with examples & application
 Discuss the therapeutic applications of Sulfa drugs
 Explain the special use of sulfacetamide, sulfadoxine,
silver sulfadiazine
 Discuss the ADRs of sulfa drugs
 Compare and contrast sulfa drugs with co trimoxazole
 Explain the logic of combining TMP with SMX
 Cotrimoxazole can cause megaloblastic anemia but not
sulfadiazine. Why?
 Sulfa are is inactive in presence of Pus , Procaine?