Dr Rupa Arun Korde

Associate professor
Dept of Pharmacology
SDMCMS&H
SULFONAMIDES
 Structural analogue of p-amino benzoic acid (PABA)

 First AMA’s

 Prontosil, a azo dye, used by Domagk to cure his

daughter of streptococcal septicemia in 1932

 Resistance, availability of safer & effective

antibiotics has limited its usage

 Except in combination with Trimethoprim or

Pyrimethamine (for malaria)
 Orally absorbable sulfonamides
 Short acting
sulfacytine, sulfadiazine, sulfisoxazole, sulfamethizole- t½- 6-9 hrs
 Intermediate acting
sulfamethoxazole, sulfamoxole– t½ - 10-12 hrs
 Long acting
sulfamethopyrazine, Sulfadoxine-- t½ - 7-8 days
 Orally non absorbable
Sulfasalazine, olsalazine. Balsalazine
 Topical agents
Silver sulfadiazine, mafenide, sulfacetamide
 CHEMISTRY OF SULFONAMIDE
 Prontosil breaks down to form sulfanilamide.
 Sulfanilamide is similar in shape to PABA (para-
aminobenzoic acid)
 PABA is part of folic acid
 Sulfanilamide is a competitive inhibitor of enzyme
that incorporates PABA into folic acid
 Result: folic acid synthesis stops
 Sulfonamides are synthetic derivatives of
sulfanilamide
 FOLIC ACID BIOSYNTHESIS
DIHYDROPTERIDINE

2 ATP

PYROPHOSPHATE
DERIVATIVE
PABA
Dihydropteroate
2HN COOH
Synthetase

sulfonamide

2HN SO2NH2
DIHYDROPTEROIC ACID

Glutamic Acid

DIHYDROFOLIC ACID
ANTIMICROBIAL ACTIVITY-SULFONAMIDES
 Spectrum of activity: broad-spectrum

 Primarily bacteriostatic ; but bactericidal conc. in urine.

 G+ve bacteria: group A Streptococcus pyogenes and

Streptococcus pneumoniae

 G-ve bacteria: meningococcus, gonococcus, Escherichia coli,

shigella, etc

 Others: bacillus anthracis, Nocardia actinomyces, Chlamydia

trachomatis, LGV, inclusion conjunctivitis and some protozoa
 RESISTANCE
 Prominent - gonococci, pneumococci, Staph, meningococci,
E.coli, Shigella

 Produce increased PABA

 Low affinity for folate synthetase

 Adopt alternative pathway in folate metabolism.

 Limited its usefulness

 No cross resistance with other AMA’s

 PHARMACOKINETICS
 Rapidly & nearly completely absorbed

 Highly protein bound

 Widely distributed- serous cavity, CSF, crosses placenta

 Metabolism by acetylation (acetylated derivative precipitates

crystalluria)

 Excreted mainly by the kidneys

PREPARATION
 Sulfadiazine - prototype, short acting, was
preferred in meningitis.
 Sulfamethoxazole - combined with
Trimethoprim in Cotrimoxazole.
 Sulfadoxine
 ultralong acting (t1/2 5-9 days)
 used in combination with Pyrimethamine in Rx of malaria, pneumocystis
carinii pneumonia in AIDS, toxoplasmosis.

 Sulfacetamide - used topically in the eye for

ophthalmia neonatorum (caused by chlamydia)
 Sulfasalazine - ulcerative colitis & rheumatoid
arthritis
 PREPARATION
 Mafenide
 Atypical sulfonamide
 Active in presence of pus
 Used topically for burn dressing

 Silver sulfadiazine
 Active topically
 Active against even pseudomonas (other sulfo. Resistant)
 Silver actions responsible for efficacy
 Burns & chronic ulcers
 ADVERSE EFFECTS
 Nausea, vomiting & abdominal discomfort
 Hypersensitivity- exfoliative dermatitis, SJS,
photosensitivity, serum sickness, polyarteritis nodosa
 Hepatitis – focal or diffused
 Contact sensitization
 Haemolysis in G6PD deficiency
 Interactions with phenytoin, tolbutamide, warfarin &
methotrexate.
 Crystalluria
 Seen with acidic urine
 Acetylated form of the drug may be precipitated, mainly in
collecting tubules & the calyces- leads to urinary obstruction
& renal colic, crystalluria, albuminuria & hematuria
 Minimized by
 Adequate fluid intake to maintain urine output of 1200ml
 Making urine alkaline
 Use of sulfonamide with acetylated metabolites soluble in acid
urine e.g. sulfisoxazole.
KERNICTERUS IN THE NEWBORN
 Results from displacement of bilirubin from plasma protein binding sites.

 Free bilirubin goes into the CNS.

 High concentrations in the brain cause kernicterus in the newborn.

 USES
 Systemic use of sulfonamides ALONE is rare now.
 Sulfamethoxazole combined with Trimethoprim as
COTRIMOXAZOLE for many bacterial infections, P. carinii,
& nocardiasis.
 Sulfonamides combined with Pyrimethamine for Rx of
malaria & toxoplasmosis.
 Sulfasalazine used for ulcerative colitis & rheumatoid
arthritis
 used topically – sulfactemide sodium- chlamydial eye
infections
 Silver sulphadiazine or mafenide- porphylaxis or treatment
of infections in burns
CO-TRIMOXAZOLE
 COTRIMOXAZOLE
 FDC of TMP (80mg) & sulfamethoxazole (400mg)
 TMP related to antimalarial drug Pyrimethamine
 TMP selectively inhibits DHFR.
 Individually both sulfonamide & TMP are bacteriostatic, but
combination is cidal (Synergism).
 Both have nearly same t1/2.
 Dose ratio 5:1 because TMP enters many tissues, has larger
Vd, rapidly absorbed & has 40% PPB.
 Additional organisms covered - S.typhi, Serratia, Kleb, P.carinii
& many sulfonamide resistant strains.
Synergism
 PABA + Pteridine

Dihydropteroic Synthetase SULFONAMIDE

DIHYDROPTEROIC ACID

Dihydrofolate Synthetase

DIHYROFOLIC ACID
Dihydrofolate Reductase
TRIMETHOPRIM
TETRAHYDROFOLIC ACID
 Hypersensitivity reaction
 Allergic rashes
 Photosensitivity
 Drug fever
 Stevens-Johnson syndrome
HEMATOLOGICAL EFFECTS
 Leukopenia, thrombocytopenia and megaloblastosis.

 Most likely in patients with preexisting folate deficiency or in patients taking

prolonged therapy.

 CI during pregnancy
 50 % incidence of fever, rash, bone marrow hypoplasia in AIDS pts
 Elderly - bone marrow toxicity
 Urinary tract infection (UTI)-
 Uncomplicated lower urinary tract infection- E.coli
 2single strength (SS) tablet twice daily for 5 to 10 days
 Prophylaxis single dose – 4tablets – acute cystitis

 GIT infection- travellers diarrhoea – E. coli, shigellosis,

campylobacter jejuni & y. enterocolitica- less effective for
diarrhoea due to cholera
 Pneumocystis jirovecii ( carinii) pneumonia
 Drug of choice ( 1DS tab 4-6 times a day)& prophylaxis-
(1 DS tab daily) Continued for 2-3 wks or more depending on
the response & toxicity
 Respiratory infection– gram –positive cocci( streptococcus
pneumonia & Haemophilus influenzae- URTI & LRTI
including otitis media & chronic bronchitis
 Typhoid- strains are sensitive
 Staphylococcus aureus infection including MRSA– some
cases
 Miscellaneous infections ( as alternative)
 Chancroid (H. ducreyi)-(800+160mg)BD x14 days
 Nocardosis- AIDs
 Plague- 1-2 wks course
 Brucellosis
 Granuloma inguinale
 Listeriosis
 Gram –ve septicaemia
 1st choice of drug in pseudomonas & xanthomonas
 Useful in whipples disease & intestinal infection due to
intestinal parasites
 Alternative for Enterobacter, citrobacer, serratia
PNEUMOCYSTIS PNEUMONIA (PCP)
www.learningradiology.com/
PNEUMO CYSTIS PNEUMONIA (PCP)
 The most common opportunistic infection in advanced AIDS (80% of AIDS
patients have at least one episode).

 Now considered a fungus (P.jurovecii).

 Multiple infections are often present simultaneously with the PCP.

PROPHYLAXIS

 Routine prophylaxis has been successful in improving survival.

 PCP prophylaxis is indicated if the patient has a CD4 T lymphocyte count lower
than 200 cells/mm3, or has oral candidiasis regardless of the CD4 count.

 (1 DS tab daily) Continued for 2-3 wks or more depending on the response &
toxicity
TREATMENT OF PCP

 Early therapy is essential as success of therapy is related to severity of the

disease at the time of initiation of therapy.
 1DS tab 4-6 times a day . Continued for 2-3 wks or more depending on the
response & toxicity
 This is a case report of a 32-year-old woman who came to our hospital with complaints
of nonproductive cough for 2 months, respiratory distress, and low-grade fever. For
the past 4 months, she has been on antiretroviral therapy of tenofovir, lamivudine, and
efavirenz for her HIV-positive diagnosis. Her vitals were: blood pressure 100/60 mm
Hg, pulse rate 60 beats/minute, respiratory rate 18 breaths/min, oxygen saturation
(SpO2 ) 90% in room air, and body temperature 38°C. There was no rash,
lymphadenopathy, or any bleeding manifestations. On further examination, there
were chest rales with normal heart sounds. No additional sounds or murmurs were
heard. Neurological examination revealed no motor, sensory, or autonomic deficits.
 A chest X-ray showed features of bilateral, diffuse pulmonary infiltrates .
High-resolution computerized tomography thorax showed consolidated airspaces
bilaterally with ground-glass opacities.
 A raised serum lactate dehydrogenase (LDH): 629 (normal range: 119–229 U/L), a
raised serum C-reactive protein: 12.8 mg/dl CD4 + lymphocyte level of 110 cells/µl
were other significant findings
 A fiberoptic bronchoscopy revealed a typical endobronchial system and
bronchoalveolar lavage was obtained from the left lobe which was then stained by
Giemsa stain, and it revealed cysts of P. jirovecii
 Diagnosis of P. jirovecii pneumonia was further confirmed by elevated serum
(1-3)-β-D glucan level (40.2 pg/ml; normal level:
 How to treat this patient?
 The patient was then started on a regimen of SMX-TMP 1600 mg and 320 mg 8
hourly.
 Methylprednisolone [1000 mg] pulse therapy for 3 days was started followed by
prednisolone 1 mg/kg/day.
 Her respiratory distress started subsiding 7th day onward.
 She was discharged after 9 days of hospitalization on SMX-TMP for pneumonia and
a 21-day prednisone taper for inflammation
 SULFONAMIDE SUMMARY
SULFONAMIDE THERAPEUTIC USE ADVERSE REACTIONS

Sulfisoxazole UTI’s GI, Hypersensitivity

Sulf-acetamide Opthalmic Infs. reactions, crystalluria
Silver Burn therapy
sulfadiazine

TMP+SMX PCP, Respiratory Hypersensitivity

Infs., UTI’s reactions, Hematologic
effects
THANKYOU