Antimicrobial Agents
(Sulfonamides and Quinolones)
Prof. R. K. Dixit
Pharmacology and Therapeutics
K.G.M.U. Lucknow
dixitkumarrakesh@gmail.com
Objectives
After completion of this lecture you will be able to
– Know about sulphonamides
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Types (Classification)
MOA
Combination with Trimethoprim or Pyrimethamine
Uses
ADRs, DDI, and Contraindications
Special points
– Know about Quinolones
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Types (Classification)
MOA
Uses
ADRs, DDI, and Contraindications
Special points
Suphonamides (Sulfonamides) [F=USA, Ph=UK]
 First antimicrobial agents effective against bacteria
Prontosil Red (sulfonamide chrysoidine dye) –
 by- Domagk – for – streptococcal infection.
 Broken down in body –
 into-
Sulfanilamide (Active against bacteria)
 Use increased –Overuse- Development– Resistance
 Rarely used (alone) today due to
◦ Availability of safer and effective antibiotics
◦ Resistant
Sulfonamides today used as combination
 Trimethoprim (Cotrimoxazole) as antiBacterial
Pyrimethamine (Cotrimazine) as anti-Malarial.
TB in PM
Sulfonamides (Chemistry)
• Derivatives of
• Sulfanilamide (p-Aminobenzene sulfonamide)
• Individual member differs in nature of N1substitution.
• N1substitution governs– Pharmacokinetic properties
• Free amino group at - (N4)–antibacterial activity.
DK- 41
Sulfonamides (Members)
Short Acting (4-8hrs)
•Sulfisoxazole
•Sulfadiazine•Less protein bound,
•Penetrates BBB- Meningitis
•Acetylated product is less soluble and cause for crystalluria
Intermediate acting (8-12 hrs)
•Sulfammoxazole
•Sulfamethoxazole –
•Combination with Trimethoprim, FDC ( Cotrimoxazole)
• High fraction is acetylated and may lead to Crystalluria
Long acting (> 12 hrs)
•Sulfadoxine
•Very high plasma protein binding and slow renal excretion,
•Longest acting,
•Used in malaria, Toxoplasmosis, Pneumocystis,
•In combination with Pyrimethamine,
•Sulfamethoxypyrazine
Special purpose Sulfonamides
Sulfacetamide•Ocular drops
Mafenide –
•Active in presence of
•Pus and Pseudomonas
•Produces severe burning
•Have Carbonic Anhydrase Inhibitor activity
•Can alkalinize urine,
•Produce Acidosis, & Hyperventilation
Silver sulfadiazine –
• Releases silver ions (antimicrobial ),
• Burn dressing,
• May be absorbed
Sulfasalazine – (Sulfapyridine + 5-ASA)
• Used in
• Rheumatoid arthritis
• Ulcerative colitis and
Triple Sulfa =
•Sulfamethazine
•Sulfadiazine
•Sulfamerazine
MetDiaMerza
Sulphasalazine
=
•5Amino Salicylic Acid
(Used for Ulcerative Colitis)
+
•Sulphapyridine
(Used for Rheumatoid Arthritis)
Sulfasalazine
Sulfapyridine
Absorbed, Useful in
RA, Produces ADR
5-Amino Salicylic Acid
Not absorbed, Anti-inflammatory in
GIT, Useful in IBD
(UC, and Crohn’s disease),
Suphonamides (MOA)
• Bacteria synthesize folic acid from PABA
• Sulfonamide is
– Structural analogue of PABA and
– Inhibit Dihydrofolic Acid Synthetase
• Dihydrofolic acid by Dihydrofolic acid synthetase.
• Tetrahydrofolic acid by Dihydrofolic acid reductase
• Tetrahydrofolic acid for synthesis of RNA,
DNA
• PABA antagonizes action of Sulfonamides
• Pus is rich in PABA, (Purines, Pyrimidines).
• Procaine local anesthetic releases
PABA and reduces Sulfonamides
action
• Human cells
–Utilize preformed Folic Acid and
–Enzymes less affinity for Sulphonamides.
Sulfonamides (MOA)
PABA
+
Dihydropteridine
Dihydropteroic acid Synthetase
Static
Sulfonamides (PABA analogues)
Sulfomethoxazole (Bacterial)
Sulfadiazine (Bacterial)
Sulfodoxine (Malarial)
Dihydropteroic acid
Glutamate
+
Cotrimoxazole
Dihydrofolate Reductase
Folic
Acid
Cidal
Dihydrofolic Acid
Dihydrofolate
Reductase
(Mammalian)
Cotrimazine
Timethoprim (Bacterial) /
Pyrimethamine (Malarial)
Static
Tetrahydrofolic Acid
RNA
DNA
Proteins
Nucleic Bases
Amino Acids
Suphonamides
Resistance is due to
•Increased production of PABA
•Folate synthetase affinity Less
•Adoption of alternate pathway
in folate metabolism
Spectrum
•Primarily bacteriostatic
•Both Gram positive and gram negative
Pharmacokinetics•Orally absorbed
•PPB is variable (10-95%)
•Cross Placenta
•Metabolized by Acetylation
•By microsomal acetyl transferase
•Acetylated metabolites inactive but
•Produce Crystalluria
Adverse effects
•Crystalluria
•Dose related Tt. Fluid, Alkalizers
•Fixed Drug Reaction, Hypersensitivity
•Stevens-Johnson syndrome,
•Photosensitization,
•Hepatitis
•Contact Dermatitis
•Haemolysis in G-6-P-D deficiency
•Kernicterus•Premature new born, Bilirubin in brain
Sulphur Containing Drugs (Diuretics, COX-2 inhibitors, Protease inhibitors, Antileprotics)
•Dapsone
•Sulfonylurea (Antidiabetic)
•Protease inhibitors (Anti HIV)
•Carbonic Anhydrase inhibitors,,
•Celecoxib, Valdecoxib (COX-2)
•Loop diuretics,
•Thiazides
D
S
P
Caught
Lootera
Thief
Fixed Drug Reactions
• Fixed drug reactions are so named because they
recur at the same site with each exposure
• Drugs causing fixed drug eruptions:
– Trimethoprim, Sulfonamides , Cotrimoxazole
– Fluconazole, Ciprofloxacin, Doxycycline,
Clarithromycin, NSAIDs, Phenytoin, Cetirizine,
Pseudoephedrine
Fixed Drug Reactions
• Usually develop within 30 minutes to 8 hours of
taking the drug.
• They are sometimes solitary at first, but with
repeated attacks new lesions may appear and
existing ones may increase in size.
• Involves limbs, around mouth, eyes, genitalia and
perianal areas
• As healing occurs, crusting and scaling followed
by brown colour at the site.
Stevens–Johnson syndrome,
• A form of toxic epidermal necrolysis (TEN)
• Life-threatening skin condition,
• Cell death causes the epidermis to separate from
the dermis.
• The syndrome is thought to be a hypersensitivity complex
that affects the skin and the mucous membranes.
• Begins with fever, sore throat, and fatigue, and commonly
misdiagnosed
• Ulcers and other lesions begin to appear in the mucous
membranes, almost always in the mouth and lips, but also
in the genital and anal regions.
• Conjunctivitis of the eyes occurs in about 30%
• Characterized by confluent epidermal necrosis with
minimal associated inflammation.
• An idiosyncratic, delayed-hypersensitivity reaction.
• Slow acetylators, Immunocompromised, and patients with
brain tumors undergoing radiotherapy with concomitant
antiepileptics are among those at most risk.
• Patients with sulfonamide-induced toxic epidermal
necrolysis have been shown to have a slow acetylator
genotype that results in increased production of
sulfonamide hydroxylamine .
• These drug metabolites may have direct toxic effects or
may act as haptens that interact with host tissues,
rendering them antigenic.
• Causes
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Disorder of the immune system.
The immune reaction can be triggered by drugs or infections.
Genetic factors are associated with a predisposition to SJS
The cause of SJS is unknown in one-quarter to one-half of cases.
May be after viral infections, malignancies, medications.
No reliable test to establish a link between a particular drug and SJS
• A leading cause sulfa drugs.
• Other drugs
– Allopurinol, Barbiturates,Carbazepine,Valproate, Ethosuximide,
Valdecoxib, Phenytoin, Lamotrigine,
– Levofloxacin, Diclofenac,, Isotretinoin, Fluconazole, , sitagliptin, ,
Vancomycin, Pyrimethamine, Cefixime,
Drug Interactions
•Inhibit Metabolism &
•Displace from protein binding site
Increased Concentration of Other Drugs
(Phenytoin, Tolbutamide, Warfarin, Methotrexate etc.)
Uses
•Rarely used alone
•Some times for chronic UTI
•Topical for conjunctivitis, Burn
Cotrimoxazole
Fixed Dose Combination (FDC) of
Trimethoprim (Diaminopyridine)
+
Sulfamethoxazole (Sulfonamide)
Preparation ratio 1:5
Ratio at site of action 1:20
Produce Sequential block
•Combination is Cidal
(Individual component static)
• Why Sulfamethoxazole?
– because of similar t1/2 ( half life 10 hrs)
• Why Ration of 1:5?
– Trimethoprim has large volume of distribution.
– Optimum synergism at ratio 1: 20 at site of action.
• Why not harming human cells?
Trimethoprim is
50,000 times active against bacterial DHFRase
Mammalian cells use preformed folic acid
Spectrum
•Gram Positive
•Gram negative
Resistance
•Acquire DHFRase of lower affinity
Adverse effects
Drugs having Anti-folate actions
•Pralatrexate
•Pemetrexed
•Proguanil
•Pyrimethamine
•Methotrexate
•Trimethoprim
•Same as sulfonamides
•Renal toxicity
•Teratogenicity
•Trimethoprim, an antifolate enhance teratogenic effect
•Bone marrow suppression ( in elderly)
Drug Interactions
•Same as sulfonamide
•Cotrimoxazole + Diuretics – Chance of thrombocytopenia
Uses of Sulphonamides and Cotrimoxazole
•Faciomaxillary infections
•RTI
•UTI
•Prostatitis
•Typhoid
•Bacterial diarrhea and dysentery
•Pneumocystis infection in AIDS
•Chancroid
•Burn dressing
Cotrimoxazole
• Drug of Choice
– Pneumocystis pneumonia
– Nocardia
– Yersinia enterocolitica
• As Alternative
– Salmonella typhi
– Shigella, E.coli
– Vibrio cholerae
– Brucella
– Atypical mycobacterium
Thanks