SULFONAMIDESSULFONAMIDES

First effective chemotherapeutic First effective chemotherapeutic agentagent

ChemistryChemistry

Structural analogue of Structural analogue of PABAPABA.. Sulfonamides are with diff. chemical, physical, Sulfonamides are with diff. chemical, physical,

pharmacological and anti bacterial properties. pharmacological and anti bacterial properties. Produced by substitutions at gp (-SOProduced by substitutions at gp (-SO22 –NH –R) –NH –R)

or the amide group (-NH2) of sulfanilamide or the amide group (-NH2) of sulfanilamide nucleus. nucleus.

Sulfanilamide is Sulfanilamide is para-aminobenzenesulfonamidepara-aminobenzenesulfonamide

CLASSIFICATIONCLASSIFICATIONI.I. Well absorbed by Mouth and Rapidly eliminated Well absorbed by Mouth and Rapidly eliminated

(short Acting)(short Acting)

a.a. General PurposeGeneral Purpose SulfadiazineSulfadiazine

b.b. Mainly for UTIMainly for UTI SulfisoxazoleSulfisoxazole SulphamethizoleSulphamethizole SulfamethoxazoleSulfamethoxazole

II.II. Well absorbed by GIT and Slowly eliminated (Long Well absorbed by GIT and Slowly eliminated (Long Acting)Acting)

SulphadoxineSulphadoxine SulphamethoxypyridazineSulphamethoxypyridazine Sulphadimethoxine Sulphadimethoxine Sulphaphenazole Sulphaphenazole

III.III. Poorly absorbed by GITPoorly absorbed by GIT Sulfasalazine Sulfasalazine

IV.IV. For Topical ApplicationFor Topical Application SulfacetamideSulfacetamide Silver SulfadiazineSilver Sulfadiazine Mafenide Mafenide

V.V. Miscellaneous GroupMiscellaneous Group

SulfapyridineSulfapyridine

VI.VI. Sulfonamide CombinationSulfonamide Combination CotrimoxazoleCotrimoxazole (Sulfamethoxazole & trimethoprim) (Sulfamethoxazole & trimethoprim) FansidarFansidar (Sulfadoxine & Pyrimethamine) (Sulfadoxine & Pyrimethamine)

Mostly well absorbed after oral adm. Divided into three major Mostly well absorbed after oral adm. Divided into three major

groups.groups.

1.1. Oral absorbable Oral absorbable

2.2. Oral non absorbable Oral non absorbable

3.3. Topical Topical

PHARMACOKINETICSPHARMACOKINETICS

Oral absorbableOral absorbable

absorption – stomach and intestine absorption – stomach and intestine Distribution – Widely distributed Distribution – Widely distributed

CNS, CSF, placenta and fetusCNS, CSF, placenta and fetusPPB 20 – 90 % to serum albumin PPB 20 – 90 % to serum albumin PPL 2 – 6 hrs PPL 2 – 6 hrs Metabolism – Liver Metabolism – Liver Excretion – Urine , feces, bile, milk and other Excretion – Urine , feces, bile, milk and other secretionssecretions

MetabolismMetabolism

A portion of the absorbed drug is acetylated or A portion of the absorbed drug is acetylated or glucronidated in the liver.glucronidated in the liver.

Dosage reduction is required in renal failure.Dosage reduction is required in renal failure.

MOAMOAThey are bacteriostatic They are bacteriostatic

PABA

Dihydrofolic Acid (Folate)

Tetrahydrofolic Acid

Purines

DNA

Dihydropteroate Synthase

Dihydrofolate Reductase

SulfonamidesX

X Trimethoprim

Sulfonamides susceptible organisms, unlike Sulfonamides susceptible organisms, unlike mammals, cannot use exogenous folate but mammals, cannot use exogenous folate but must synthesize it from PABA. must synthesize it from PABA.

ANTIBACTERIAL SPECTRUM ANTIBACTERIAL SPECTRUM

Exert bacteriostatic effectExert bacteriostatic effect Gram +ve and Gram -ve bacteriaGram +ve and Gram -ve bacteria Some enteric bacteria like Some enteric bacteria like

E. Coli, Shigella, Salmonella, Klebsiella.E. Coli, Shigella, Salmonella, Klebsiella. Nocardia, Chlamydia trachomatis and some Nocardia, Chlamydia trachomatis and some

protozoa.protozoa.

ResistanceResistance

Mammalian cells lack the enzymes required Mammalian cells lack the enzymes required for folate synthesis from PABA and depend on for folate synthesis from PABA and depend on exogenous source of folate, so they are not exogenous source of folate, so they are not susceptible to sulfonamides.susceptible to sulfonamides.

Resistance in bacteriaResistance in bacteria Sulfonamides resistance may occur as a result of Sulfonamides resistance may occur as a result of

mutations.mutations. A- Overproduction of PABAA- Overproduction of PABA B- Production of a folic acid synthesizing B- Production of a folic acid synthesizing

enzyme that has low affinity for sulfonamides.enzyme that has low affinity for sulfonamides. C- Impair permeability to the sulfonamide or C- Impair permeability to the sulfonamide or

active effluxactive efflux An alternative metabolic pathway for synthesis An alternative metabolic pathway for synthesis

of essential metaboliteof essential metabolite

Therapeutic UsesTherapeutic Uses

A- Oral Absorbable AgentsA- Oral Absorbable Agents

Urinary Tract InfectionsUrinary Tract Infections

Not therapy of first choiceNot therapy of first choice

Sulfadiazine with pyrimeythamine---acute Sulfadiazine with pyrimeythamine---acute toxoplasmosistoxoplasmosis

B- Oral Nonabsorbable AgentsB- Oral Nonabsorbable Agents

Sulfasalazine is used in ulcerative collitis, Sulfasalazine is used in ulcerative collitis, enteritis and other inflammatory bowl disease.enteritis and other inflammatory bowl disease.

C- Topical AgentsC- Topical Agents

Sodium sulfacetamide ophthalmic Sodium sulfacetamide ophthalmic solution or ointment is used for solution or ointment is used for

Bacterial conjunctivitisBacterial conjunctivitis

TrachomaTrachoma

Silver sulfadiazine used for prevention of Silver sulfadiazine used for prevention of infection of burn wounds.infection of burn wounds.

Nocardiosis:Nocardiosis:

Sulfisoxazole or sulfadiazineSulfisoxazole or sulfadiazine

Used in combination Used in combination • Pneumocystis Carinii – sulfamethoxazole Pneumocystis Carinii – sulfamethoxazole

combined with trimethoprim (Co-trimoxazole)combined with trimethoprim (Co-trimoxazole)

• Resistant Malaria (Sulfadoxine + Resistant Malaria (Sulfadoxine + Pyrimethamine – Fansidar)Pyrimethamine – Fansidar)

• Acute toxoplasmosis – (Sulfadiazine + Acute toxoplasmosis – (Sulfadiazine + Pyrimethamine)Pyrimethamine)

ADVERSE EFFECTSADVERSE EFFECTS

A.A. Hypersensitivity Reactions:- Hypersensitivity Reactions:-

1. Fever, Skin rashes, exfoliative dermatitis, photosensitivity, 1. Fever, Skin rashes, exfoliative dermatitis, photosensitivity,

urticaria, N, V, D Angioedema & Steven – Johnson syndromeurticaria, N, V, D Angioedema & Steven – Johnson syndrome

Stomatitis, conjunctivitis, arthritis and hepatitis. Stomatitis, conjunctivitis, arthritis and hepatitis.

2.Hematopoietic Disturbances :- Hemolytic or Aplastic anemia, 2.Hematopoietic Disturbances :- Hemolytic or Aplastic anemia,

Granulocytopenia, Thrombocytopenia, Leukemoid reactionsGranulocytopenia, Thrombocytopenia, Leukemoid reactions

Can provoke hemolytic reactions in patients Can provoke hemolytic reactions in patients with glucose-6-with glucose-6-

phosphate dehydrogenase deficiency.phosphate dehydrogenase deficiency.

Urinary Tract DisturbancesUrinary Tract Disturbances:- Sulfonamides :- Sulfonamides may precipitate in urine, especially at neutral may precipitate in urine, especially at neutral or acid pH producing crystalluria, Hematuria or acid pH producing crystalluria, Hematuria or even obstruction and nephritisor even obstruction and nephritis

Less with sulfisoxazole.Less with sulfisoxazole. Treatment Treatment

Sodium bicarbonate and adequate Sodium bicarbonate and adequate hydration.hydration.

CONTRAINDICATIONSCONTRAINDICATIONS

Premature babies, newborns & infants less Premature babies, newborns & infants less than 2 monthsthan 2 months

Pregnant woman at term – KernicterusPregnant woman at term – Kernicterus Displacement of bilirubin from plasma Displacement of bilirubin from plasma

albumin. albumin. Deposition of bilirubin in basal ganglia and Deposition of bilirubin in basal ganglia and

sub thalamic nuclei of brain.sub thalamic nuclei of brain.

Drug interactionsDrug interactions

Oral anticoagulantsOral anticoagulants Sulfonylurea Sulfonylurea Hydantoin anticonvulsantsHydantoin anticonvulsants Potentiate the effect of these drugsPotentiate the effect of these drugs Inhibition of metabolism or displacement from Inhibition of metabolism or displacement from

albuminalbumin

TRIMETHOPRIMTRIMETHOPRIM

ChemistryChemistry::

Trimethoxybenzyl PyrimidineTrimethoxybenzyl Pyrimidine

Chemically Related to anti malarial drug pyrimethamine Chemically Related to anti malarial drug pyrimethamine

both are folate antagonists. both are folate antagonists.

PABA

Dihydrofolic Acid (Folate)

Tetrahydrofolic Acid

Purines

DNA

Dihydropteroate Synthetase

Dihydrofolate Reductase

SulfonamidesX

X Trimethoprim

MOAMOA

PharmacokineticsPharmacokinetics

Given orally fully absorbed from GIT.Given orally fully absorbed from GIT.

Distribution:- Widely distributed, in body fluids and Distribution:- Widely distributed, in body fluids and

tissues, including CSF concentrates in acidic media of tissues, including CSF concentrates in acidic media of

prostatic and vaginal fluid.prostatic and vaginal fluid.

PPB: 65 – 70 %PPB: 65 – 70 %

Excretion : in urine within 24 hrs.Excretion : in urine within 24 hrs.

ResistanceResistance

Reduced cell permeability.Reduced cell permeability. Overproduction of dihydrofolate reductase.Overproduction of dihydrofolate reductase. Production of altered reductase with reduced Production of altered reductase with reduced

drug binding.drug binding.

Resistance is plasmid encoded.Resistance is plasmid encoded.

Clinical UsesClinical Uses Acute UTI: 100 mg – B.d.Acute UTI: 100 mg – B.d. Bacterial Prostatitis (Fluroquinolones are Bacterial Prostatitis (Fluroquinolones are

preferred )preferred )

CO-TRIMOXAZOLECO-TRIMOXAZOLE

Combination of trimethoprim with Combination of trimethoprim with

sulfamethoxazole.sulfamethoxazole.

Sulfamethoxazole – 400 mg. Ratio 1:5Sulfamethoxazole – 400 mg. Ratio 1:5

Trimethoprim – 80 mg.Trimethoprim – 80 mg.

One double strength tablet trimethoprim 160 One double strength tablet trimethoprim 160

mgmg

Sulfamethoxazole 800 mg Sulfamethoxazole 800 mg

Advantages of Using Co-TrimoxazoleAdvantages of Using Co-Trimoxazole

1.1.Bactericidal. (Individual drugs are bacteriostatic) Bactericidal. (Individual drugs are bacteriostatic)

2.2.Wide antibacterial spectrum.Wide antibacterial spectrum.

3.3.More efficacy.More efficacy.

4.4.Less dose of each drug.Less dose of each drug.

5.5.Less incidence of toxicity.Less incidence of toxicity.

PHARMACOKINETICSPHARMACOKINETICS

Can be given orally or I/VCan be given orally or I/V

MOAMOAPABA

Dihydrofolic Acid (Folate)

Tetrahydrofolic Acid

Purines

DNA

Dihydropteroate Synthetase

Dihydrofolate Reductase

SulfonamidesX

X Trimethoprim

Antibacterial spectrumAntibacterial spectrum

Gram +ve and gram –ve organisms (resistant Gram +ve and gram –ve organisms (resistant to individual drugs)to individual drugs)

Chlamydia diphtheriaeChlamydia diphtheriae and and N meningitidisN meningitidis.. E. coli, Proteus mirabilis, Proteus marginii, E. coli, Proteus mirabilis, Proteus marginii,

Enterobacter spp, Salmonella, Shigella, Enterobacter spp, Salmonella, Shigella, PseudomonasPseudomonas and and SerratiaSerratia are inhibited. are inhibited.

Klebsiella, Brucella, Pasteuralia, Yersinia Klebsiella, Brucella, Pasteuralia, Yersinia andand Nocardia asteroids.Nocardia asteroids.

Bacterial ResistanceBacterial Resistance

Plasmid mediated that codes for an altered Plasmid mediated that codes for an altered dihydrofolate reductase.dihydrofolate reductase.

Pharmacokinetics Pharmacokinetics

Pharmacokinetic profiles of sulfamethoxazole Pharmacokinetic profiles of sulfamethoxazole and trimethoprim are closely matched to and trimethoprim are closely matched to achieve a constant ratio of 20: 1 in their achieve a constant ratio of 20: 1 in their concentrations in blood and tissues.concentrations in blood and tissues.

Readily enters CSF and sputum.Readily enters CSF and sputum. Excreted through kidneys.Excreted through kidneys.

1.1. Respiratory infections:Respiratory infections:Pneumocystis jiroveci Pneumocystis jiroveci Pneumonia in AIDS patientPneumonia in AIDS patientHemophilis influenzae Hemophilis influenzae Streptococcus pneumoniae Streptococcus pneumoniae Moraxella catarrhalis Moraxella catarrhalis Klebsiella pneumoniaeKlebsiella pneumoniaeI/V use is for moderate to severe pneumocystis I/V use is for moderate to severe pneumocystis

pneumonia, gram-negative bacterial sepsis pneumonia, gram-negative bacterial sepsis Caused by multidrug-resistant species.Caused by multidrug-resistant species.

CLINICAL USESCLINICAL USES

Acute otitis media in childrenAcute otitis media in children Acute maxillary sinusitis in adults.Acute maxillary sinusitis in adults.

2.2. GIT Infections:GIT Infections:ShigellosisShigellosisSystemic Systemic SalmonellaSalmonella infection (Typhoid Fever) infection (Typhoid Fever)

3. UTI uncomplicated, complicated and recurrent.3. UTI uncomplicated, complicated and recurrent.4. Prostatitis 4. Prostatitis 5. Acute Gonococcal Urethritis 5. Acute Gonococcal Urethritis 6. Non tuberculous mycobacterial infections 6. Non tuberculous mycobacterial infections

Prophylaxis in Neutropenic patientsProphylaxis in Neutropenic patients

Low dose therapy Low dose therapy

Emergence of resistant bacteria limit its Emergence of resistant bacteria limit its use.use.

Useful in carriers of Useful in carriers of Salmonella typhi Salmonella typhi

Adverse effectsAdverse effects

Folate deficient cells Folate deficient cells Megaloblastic anemia Megaloblastic anemia Leukopenia Leukopenia ThrombocytopeniaThrombocytopenia 75% of untoward effects involve skin 75% of untoward effects involve skin Nausea, vomiting, drug fever, vasculitis, renal Nausea, vomiting, drug fever, vasculitis, renal

damage, CNS disturbances.damage, CNS disturbances.

Pyrimethamine and sulfonamidePyrimethamine and sulfonamide

Pyrimethamine + sulfadiazine used for Pyrimethamine + sulfadiazine used for treatment of leishmaniasis and toxoplasmosis.treatment of leishmaniasis and toxoplasmosis.

Pyrimethamine + sulfadoxine used for Pyrimethamine + sulfadoxine used for Falciparum malaria. Falciparum malaria.

Adverse EffectsAdverse Effects

1.1. Hematological Hematological

Trimethoprim – Megaloblastic Anemia, Leukopenia, Trimethoprim – Megaloblastic Anemia, Leukopenia,

Granulocytopenia Granulocytopenia

Prevented by simultaneous administrations of folinic acid Prevented by simultaneous administrations of folinic acid

6 – 8 mg/D which does not enter bacteria.6 – 8 mg/D which does not enter bacteria.

2.2. Rashes, Fever, Vasculitis Rashes, Fever, Vasculitis

2.2. GIT dist. – Nausea, vomiting, Glossitis & GIT dist. – Nausea, vomiting, Glossitis &

stomatitis.stomatitis.

3.3. HIV patients with pneumocystis pneumonia HIV patients with pneumocystis pneumonia

shows fever, rashes, leukopenia, diarrhea, shows fever, rashes, leukopenia, diarrhea,

elevation of hepatic aminotransferases, elevation of hepatic aminotransferases,

hyperkalemia, hypernatremia. hyperkalemia, hypernatremia.

That’s all for todayThat’s all for today