SULPHONAMIDES AND CO TRIMOXAZOLE : A BRIEF OUTLOOKBY : VISHNU. R. NAIRTHIRD YEAR PHARM.DNATIONAL COLLEGE OF PHARMACYKERALA UNIVERSITY OF HEALTH SCIENCES (KUHS), KERALA STATE

SULPHONAMIDES

A. GENERAL FEATURES:•Defined as “SULFA-related group of antibiotics, that are derived

from sulphanilamide, which are able to prevent the multiplication of some pathogenic bacteria”……………………..

•Mainly, they are derivatives of PRONTOSIL RED (A dye)

• Inactive in nature

• Becomes active in-vivo……………………..

B. CLASSIFICATION OF SULPHONAMIDES:• BASED ON SITE OF ACTION:

1. For general infections:

- Sulphanilamide - Sulphadiazine - Sulphamethoxazole

- Sulphadoxine - Sulphapyridine - Sulphamethocine

- Sulphathiazole

2. For intestinal infections:

- Pthalyl Sulphathiazole

- Succinyl Sulphathiazole

- Sulphasalazine

3. For Dermatitis:

- Dapsone - Solapsone

CONTINUED…………………………….4. For local infections:

- Sulphacetamide sodium

- Mafenide sodium

- Silver Sulphadiazine

5. For UTI (Urinary Tract Infections):

- Sulphadiazine

- Sulphacetamide sodium

• BASED ON PHARMACOKINETIC PROPERTIES:

1. Poorly acting Sulphonamides :

- Sulphasalazine

- Pthalyl sulphathiazole

CONTINUED……………………………..2. Rapidly absorbed and excreted Sulphonamides ( Systemic Sulphonamides):

- Sulphamethoxazole

- Sulphisoxazole (Sulphafurazole)

3. Topically used sulphonamides:

- Mafenide sodium

- Sulphacetamide sodium

- Silver Sulphadiazine

• BASED ON CHEMISTRY:

1. N4-substituted sulphonamides (PRO-DRUGS):

- Prontosil dye

- sulphaguanidine

CONTINUED……………………………..2. N1-substituted sulphonamides:

- Sulphadiazine

- Sulphacetamide

- Sulphadimidine

3. Both N1 and N4 substituted sulphonamides:

- Succinyl Sulphathiazole

- Pthalyl Sulphathiazole

4. Non-aniline sulphonamides:

- Mafenide sodium

CONTINUED………………………………• BASED ON PHARMACOLOGICAL ACTIVITY:

1. Anti-bacterial agents:

- Sulphasalazine

- Sulphisoxazole, etc.

2. Oral hypoglycemic agents:

- Tolbutamide

3. Diuretics:

- Furosemide - Bumetanide - Chlorthalidone

4. For Dermatitis:

- Dapsone - Solapsone

CONTINUED………………………………….• BASED ON DURATION OF ACTION:

1. Ultra-long acting ones (half-life : >50 hours) :

- Sulphasalazine - Sulphacetamide sodium - Sulphalene

- Sulphadoxine

2. Long-acting ones (half-life >24 hours):

- Sulphadimethoxine

3. Intermediate acting ones: (half-life : 10-24 hours):

- Sulphamethoxazole

4. Short acting ones (half-life < 10 hours):

- Sulphamethizole - Sulphisoxazole……………………………..

C. STRUCTURE-ACTIVITY RELATIONSHIP OF SULPHONAMIDES (SAR):• Sulphonamides are considered to be the derivatives of SULPHANILAMIDES (para-amino benzene

sulphonamide)

• Individual compounds of sulpha drugs differ on the basis of N1-substitution, which imparts solubility and potency to the drug

• Free amino (NH2-) group is essential for anti-bacterial activity

• Sulphanilamide skeleton is the minimum structure required for anti-bacterial activity

• Sulphur atom should be directly linked to the benzene ring

• Amino and sulphonyl radicals should be at 1,4- position

• 1,2 and 1,3 isomers are less active

• Any substitution on aromatic ring/ replacement of benzene ring by other ring decreased/ abolished activity of the drug

CONTINUED……………………………..• Substitution of heterocyclic aromatic nucleus in N1-position yields highly potent

compounds

• N1-disubstitution renders compound ineffective (since at least 1 hydrogen is necessary for ionization, to show anti-bacterial activity)

• pKa value should be in between 6.6-7.4 for exhibiting anti-bacterial activity

• Lipid solubility is proportional to the pharmacokinetic and anti-bacterial activity of the drug

• Lipid solubility is directly proportional to half life of the drug…………………

D. MECHANISM OF ACTION OF SULPHONAMIDES:•UNDER NORMAL CONDITIONS (IN BACTERIA):

PTERIDINE combines with PABA (PARA-AMINO BENZOIC ACID) in the presence of enzyme DIHYDROPTEROATE SYNTHETASE Forms DIHYDROPTEROIC ACID (a) GLUTAMATE gets added to (a) forms DHFA (DIHYDRO FOLIC ACID) DHFA, in the presence of DIHYDROFOLATE REDUCTASE enzyme gets converted to THFA (TETRAHYDROFOLIC ACID) THFA forms THYMIDYLIC ACID DNA and genetic bases (purine, pyrimidine, thymidine etc. ) formed…………………….

SULPHONAMIDES block the enzyme DIHYDROPTEROATE SYNTHETASE thus PTERIDINE cannot combine with PABA Thus Dihydropteroic acid is not formed……………..

CONTINUED………………………………..• Sulphonamides are bacteriostatic in nature

• Thus, their anti-bacterial efficacy is just 20-30%

• Thus, they are used in combination with TRIMETHOPRIM (Di-amino pyrimidine) as COTRIMOXAZOLE (SULPHAMETHOXAZOLE+TRIMETHOPRIM COMBINATION)…………………………………………………

E. ANTI-BACTERIAL SPECTRUM OF SULPHONAMIDES:• Sulphonamides are primarily BACTERIOSTATIC against Gram positive and Gram negative

organisms

• Organisms that are sensitive to sulphonamides include:

- Streptococcus pyogenes - Calymmobacterium granulomatis

- Haemophilus influenzae - Vibrio cholera

- Staphylococcus aureus - Meningococci

- E.coli - Toxoplasma

- Shigella

- Actinomyces………………………………….

VI. SULPHONAMIDE RESISTANCE:• Organisms that are resistant to sulphonamides include:

- Staphylococcus aureus - E.Coli

- Meningococci - Streptococcus viridans

- Gonococci - Anaerobes

• Mechanisms of resistance include:

1. Production of increased amounts of PABA

2. Mutants contain folate synthase enzyme shows less affinity for sulphonamides

3. Bacteria adopt alternative pathway for folate metabolism

* Usually CROSS RESISTANCE is observed for microbes within sulphonamides…………….

VII. PHARMACOKINETICS:• Rapidly and completely absorbed from GIT

• Extent of protein binding : 10-95%

• Widely distributed in body

• Enters serous cavities easily

• Cross placenta easily

• Metabolized in liver by non-microsomal acetyl transferase

• Excreted by kidney (via GLOMERULAR FILTRATION)………………………..

VIII. ADVERSE DRUG REACTIONS OF SULPHONAMIDES:• Nausea

• Vomiting

• Epigastric pain

• Crystalluria

• Hypersensitivity reactions:

- Urticaria

- Drug fever

- Rashes

• Photosensitivity

• Stevens-Johnson syndrome

• Kernicterus………………………………….

IX. DRUG INTERACTIONS OF SULPHONAMIDES:1. SULPHONAMIDES + WARFARIN Decreased metabolism of WARFARIN

2. SULPHONAMIDES + PHENYTOIN Increased levels of PHENYTOIN

3. SULPHONAMIDES + METHOTREXATE Increased levels of METHOTREXATE METHOTREXATE TOXICITY

4. SULPHONAMIDES + KETOROLAC Increased toxicity of each other life-threatening condition may occur

5. SULPHASALAZINE + AMILORIDE Increased Serum potassium levels HYPERKALEMIA Serious interaction………………………..

X. CONTRAINDICATIONS FOR SULPHONAMIDES:• Blood dyscrasias

• Don’t use in Glucose-6-phosphate dehydrogenase individuals hemolysis can occur

• Hypersensitivity

• Intestinal or urinary tract obstruction

• Porphyrias

• Vitamin.K deficiency

• Thyrotoxicosis ……………………………..

XI. INDIVIDUAL COMPOUNDS:•SULPHADIAZINE:- Protein binding capacity : 50%

- Acetylated derivative of drug less soluble in urine Crystalluria can occur

- Drug cross BBB easily thus used for MENINGITIS (previously)

- Dose : 0.5 g BID…………….

CONTINUED………………………………….•SULPHADOXINE, SULPHAMETHOPYRAZINE:- Ultra-long acting compounds (Due to increased plasma protein binding, and slow renal

excretion)

- Half-life: 5-9 days

- Uses:

a. Above drugs + PYRIMETHAMINE treatment of PLASMODIUM FALCIPARUM associated malaria

b. PNEUMOCYSTIS JIROVECI PNEUMONIA in AIDS patients

c. TOXOPLASMOSIS

- ADRs: serious cutaneous reactions thus not much used……………………….

CONTINUED………………………………•SULPHAMETHOXAZOLE:- Slow oral absorption

- Slow urinary excretion

- Preferred compound to be combined with TRIMETHOPRIM, since both have similar half-lives (10 hours)

- ADR: Crystalluria

- Dose:

1 g BID for 2 days then 0.5 g BID………………………..

CONTINUED…………………………………….•SULPHACETAMIDE SODIUM:- Mainly used in the treatment of CHLAMYDIAL INFECTIONS ….example OPHTHALMIA

NEONATORUM caused by CHLAMYDIA OCULOGENITALIS

- ADR: Sensitivity reactions

- DOSE: 10%. 20% 30% eye drops…………………….

CONTINUED………………………………………..•MAFENIDE SODIUM:- Mainly used topically

- Inhibits Gram positive and Gram negative bacteriae

- Mainly active in the pus presence (contrary to normal sulphonamides, which becomes inactive in the presence of pus), and against PSEUDOMONAS and CLOSTRIDIA, that are not inhibited by normal sulphonamides

- ADR:

1. Burning sensation and severe pain at raw site 3. Hyperventilation

2. Acidosis 4. Rashes

- DOSE: 1% Topical cream……………………………..

CONTINUED……………………………………•SILVER SULPHADIAZINE:- Active against most bacteria and fungi

- Anti-microbial action is attributed to slow release of SILVER ions…

- USES:

1. Preventing infection of burnt surfaces

2. Chronic ulcers

- ADR:

1. Itching

2. Burning sensation

- DOSE: 1% cream……………………………….

CONTINUED…………………………………•SULPHASALAZINE:- USES:

1. Ulcerative colitis

2. Rheumatoid arthritis

- DOSE: 1-2 g QID

- ADRs:

1. Anorexia

2. Headache……………………………………………

CONTINUED………………………………………•DDS (DAPSONE, DIAMINO-DIPHENYL SULFONE):- USES:

1. Leprosy

2. Nocardiosis

- DOSE: 100 mg daily

- ADRs:

1. Peripheral neuropathy

2. Anemia…………………………

CO-TRIMOXAZOLE

A. GENERAL FEATURES:• It is a combination of TRIMETHOPRIM (1 part) + SULPHAMETHOXAZOLE ( 5 parts)

• SULPHAMETHOXAZOLE is selected for combination with TRIMETHOPRIM, since both possess nearly the same half-life (10 hours)

• SULPHAMETHOXAZOLE Possesses poor volume of distribution compared to TRIMETHOPRIM thus we use 5 times volume of SULPHAMETHOXAZOLE compared to TRIMETHOPRIM

• Individually SULPHAMETHOXAZOLE acts as BACTERIOSTATIC when combined with TRIMETHOPRIM becomes BACTERICIDAL

• TRIMETHOPRIM is not a sulfa drug, but it possess a DIAMINO-PYRIMIDINE ring in its structure, which is closely related to the anti-malarial drug PYRIMETHAMINE

• TRIMETHOPRIM blocks DIHYDROFOLATE REDUCTASE enzyme favors SULPHAMETHOXAZOLE to become BACTERICIDAL………………………….

B. SPECTRUM OF ACTIVITY OF CO-TRIMOXAZOLE:• Organisms covered include:

1. Salmonella typhi

2. Enterobacter

3. Klebsiella species

4. Staphylococcus aureus

5. Streptococcus pyogenes

6. Shigella

7. E.Coli

8. Pneumocystis jiroveci

9. Haemophilus influenzae……………………

C. RESISTANCE TO CO- TRIMOXAZOLE:• Organisms develop resistance to CO-TRIMOAZOLE mainly through:

1. Plasmid-mediated acquisition of DHFRase (DIHYDROFOLATE REDUCTASE) Possess lower affinity for inhibitor

* Mainly such kind of resistance is observed in widespread use…………………………

D. ADR OF CO- TRIMOXAZOLE:• Nausea

• Vomiting

• Rashes

• Megaloblastic anemia (in folate deficient patients)

• Headache

• Toxic epidermal necrolysis

• Erythema multiforme

• Peripheral neuritis

• Stevens- Johnson syndrome

• Hyperkalemia …………………………………………….

E. CONTRAINDICATIONS OF CO- TRIMOXAZOLE:• Documented hypersensitivity

• Pregnancy: May cause NEONATAL HEMOLYSIS and METHAEMOGLOBINEMIA

• Elderly: May increase risk of BONE MARROW TOXICITY

• Patients with renal disease: Increased risk of HYPERKALEMIA and UREMIA can occur

• Increased dose given to AIDS patients with PNEUMOCYSTIS JIROVECI infection can cause BONE MARROW HYPERPLASIA

• In MEGALOBLASTIC ANEMIA patients

• In patients with significant degree of HEPATIC IMPAIRMENT…………..

F. DRUG INTERACTION OF CO-TRIMOXAZOLE:• CO- TRIMOXAZOLE + DIURETICS THROMBOCYTOPENIA risk

• CO-TRIMOXAZOLE + AMIODARONE increased QT-interval High life-threatening risk

• CO- TRIMOXAZOLE + BIVALIRUDIN Increased levels of BIVALIRUDIN

• CO-TRIMOXAZOLE + CYCLOSPORINE Increased risk of NEPHROTOXICITY

• CO –TRIMOXAZOLE + ARGATROBAN Increased levels of ARGATROBAN…………………………..

G. DOSE OF CO- TRIMOXAZOLE:

•20 mg (TRIMETHOPRIM) + 100 mg (SULPHAMETHOXAZOLE) : PAEDIATRIC TABLET

•160 mg (TRIMETHOPRIM) + 800 mg (SULPHAMETHOXAZOLE): For ADULTS, BID………………………….

H. USES OF CO- TRIMOXAZOLE:• In UTI (URINARY TRACT INFECTION):

- For CHRONIC CYSTITIS

- For CHRONIC PROSTATIS

• In RESPIRATORY TRACT INFECTIONS:

- For FACIO-MAXILLARY INFECTIONS

- For OTITIS MEDIA

- For CHRONIC BRONCHITIS

• In BACTERIAL DIARRHOEAS and DYSENTRY

• In PNEUMOCYSTIS JIROVECI associated PNEUMONIA:

- Both PROPHYLACTIC and THERAPEUTIC value in AIDS patients

CONTINUED……………………….• In CHANCROID:

- 3rd line drug of choice

- Less expensive

- Alternative to CEFTRIAXONE, AZITHROMYCIN or CIPROFLOXACIN

• To protect AGRANULOCYTOSIS patients from RESPIRATORY TRACT INFECTIONS

• In SEPTICAEMIAS ( Intensive parenteral therapy)…………………………………

COTRIMAZINE (GENERAL INFO. ONLY):

• Combination of TRIMETHOPRIM and SULPHADIAZINE• Have similar properties and uses as that of CO-TRIMOXAZOLE• DOSE:- 90 mg (TRIMETHOPRIM) + 450 mg (SULPHADIAZINE) tablet- 180 mg (TRIMETHOPRIM) + 820 mg (SULPHADIAZINE)

tablet…………………

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