Sulphonamides (Antimetabolites) Lecture Notes PDF

**SULPHONAMIDES (ANTIMETABOLITES)** **INTRODUCTION:** The antimetabolites inhibit DNA, RNA and protein synthesis by blocking the folate pathway. *[Tetrahydrofolate donates one single carbon molecules]* to the synthesis of purines, pyrimidines and some amino acids (methionine, formyl-methionine and...

**SULPHONAMIDES (ANTIMETABOLITES)** **INTRODUCTION:** The antimetabolites inhibit DNA, RNA and protein synthesis by blocking the folate pathway. *[Tetrahydrofolate donates one single carbon molecules]* to the synthesis of purines, pyrimidines and some amino acids (methionine, formyl-methionine and serine). Being structurally related to Para-amino benzoic acid ( PABA), the sulfonamides compete with PABA and prevent it being incorporated into folate pathway. On the other spectrum, Trimethoprim prevents reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) by binding to and inhibiting dihydrofolate reductase. Because Trimethoprim has very low affinity for human dihydrofolate reductase, the human cells are virtually spared from this reaction. **This is selective toxicity.** **SULFONAMIDES** **INTRODUCTION** These are synthetic antimicrobial agents whose use in recent practice of chemotherapy has been limited due to availability and use of more potent antimicrobial agents. However, they remain a valuable group of drugs in chemotherapy. **CHEMISTRY OF SULFONAMIDES** The basic structure of sulfonamides is that of **sulphanilamide** and the majority of congeners or derivatives (analogues) are known to have substitutions on the amino group which may result in the loss of bacteriostatic properties. PABA (p-Aminobenzoic Acid) Sulphanilamide Group COOH SO~2~NH~2~ NH~2~ NH~2~ **SITES OF ANTIMETABOLITE ACTION** Dihydropterotate synthetase Enzyme Blocked by Sulfonamides (Reference: Katzung textbook of Pharmacology). **PHARMACODYNAMICS** **Mode of action** Having a structural similarity to PABA, the sulfonamides compete with this substrate, (PABA) for the enzyme dihydropterotate synthetase. This form of competitive antagonism prevents the synthesis of bacterial folic acid and formation of it\'s one-carbon carrying co-factor(THF). This deprives the cell of the essential cofactors for purines, pyramides and amino acid synthesis. **Antimicrobial action** Sulfonamides are therefore bacteriostatic and are known to be toxic to cells/organisms that synthesize their own folic acid. **Selective toxicity** Sulfonamides do not interfere with I.e. have limited or no action on any organism that makes use of preformed folic acid. Example, man, **Further on the MOA & Antimierobial Activity Sulphonamides** Unlike mammals, organisms that are susceptible to Sulfonamide cannot use (preformed) exogenous folic acid but must synthesize theirs from PABA. The pathway shown above is thus essential for production of purines, pyrimidines and nucleic acid synthesis for such organisms. Being structural analogs of PABA, sulfonamides inhibit the enzyme dihydropteroate synthase and hence, folate production. **Spectrum of activity** The specific action of most sulphonamides against most bacteria vary/differ very little. With a *[wide spectrum]* of antibiotic activity, they are effective against both gram positive and gram negative bacteria, Chlamydia trachomatis, Nocardia species, even some protozoas. Also included in the list of organisms Sulphonamides can inhibit are some enteric bacteria such as Escherichia coli, Salmonella, Shigella, Klebsiella pneumoniae, and Enterobacter species which are also inhibited. -Only few indications of these drugs as first line drugs abound in simple urinary tract infection (UTT) in our environment. **Exceptions:** Rickettsiae species and pseudomonas aeruginosa. **Interestingly, Rickettsiae species are not inhibited by sulfonamides but are instead stimulated in their growth.** The antimicrobial activity of sulphonamides is poor against most anaerobes. **NOTE:** Pseudomonas aeruginosa is intrinsically resistant to sulfonamide antibiotics (accesspharmacy,mhnmedical.com\> content). **PHARMACOKINETICS OF SULFONAMIDES** The major difference between the sulfonamides is in their pharmacokinetics parameters as well as their dosage schedules. **Administration**: can be administered orally, parenterally, topically and suppository. So they have three (3) main divisible groups; 1\. Oral, absorbable. 2\. Oral, non-absorbable. 3 Topical. Also; 4\. Parenteral and 5\. Suppository. **Absorption**: Most of the sulfonamides are well absorbed from the gastrointestinal tract (GI). Those that are poorly absorbed have a restricted clinical usage only for GIT infections. However, most sulfonamides are orally active therefore, they are systemically active. The parenteral injection of this class of drugs is normally better especially for infections that are limited within the walls of the GIT and not in the lumen. Topical (rare) formulation are also available though their usage are limited by sensitization risks. Suppository formulations are also available. **Distribution**: they are well distributed throughout the body water including the CSF. **Bio-availability**: Protein binding varies from 20% to over 90% with extent of protein binding dependent on the particular agent. **Metabolism**: A portion of an absorbed drug is acetylated or glucuronidated in the liver. **Excretion**: The drug and the inactive metabolites are then excreted into the urine. The dose of drug must be reduced in significant renal failure and interval between doses prolonged. **CLINICAL USES.** Their clinical uses are better studied using the different type of routes of drug administration. 1. Topical route: -Sodium sulfacetamide(sulfacetamide sod.) is an ophthalmic solution or ointment is an effective *[treatment for bacterial conjunctivitis]* and as an adjunct for *[treatment of trachoma]*. -Silver sulfadiazine is a much less toxic topical sulfonamide and is preferred to mefenide acetate for prevention of wound infection. -Mafenide acetate is used topically also to prevent bacterial colonization of wounds. Generally, the application of sulfonamides to the skin wounds or mucous membrane is some what undesirable (unwanted) because of their low activity and high risk or allergic sensitization, few exception are as above stated. 2\. Oral Route - The highly soluble and rapidly excreted agents are commonly employed here. \(a) In previously untreated infections of the urinary tract e.g. -sulfisoxazole, -Tripple sulfonamide and -sulfamethoxazole. \(b) In chlamydial infections; E.gs are the chlamydial infections of the genital tract, the eye (trachoma) and the respiratory tract are normally effectively treated with oral sulphonamides though tetracyclines and Erythromycin may be drugs of choice. ( c) In some bacterial infections: sulphadiazine as well as sulfisoxazole is the treatment of choice. In other bacterial infection including haemolytic streptococci, meningococci and shigella, sulfonamides were formally drugs of choice; but due to wide spread sulfonamide resistance among those organisms, better drugs are now employed. Owing to sulphonamide low cost and their antibacterial action, they still are widely used for the following conditions I. Respiratory tract infection II. Bronchitis III. Bacillary dysentery IV. Otitis media and V. Pneumonia 3. Intravenous route: the sodium salt of many sulfonamides are available for parenteral administration. Because of their alkaline nature, they are normally given intravenously and not intramuscularly and normally in 5% dextrose water(ie. 50% dextrose in 100ml water). Intravenous sulfonamides are generally reserved *[for comatose patients]*. Most commonly are patients with *[meningitis]* or *[those unable to tolerate the oral route]*. Some sulfonamides are used for other purposes other than anti-bacterial actions eg. 1. Oral hypoglycemic agents: The sulfonyl ureas ;Tolbutamide, Chloropropramide are used. 2. Used as diureties: Some aromatic and heterocyclic sulfonamides e.g. Acetazolamide and Dichlorphenamide are potent inhibitors of Carbonic anhydrase (used as diureties). **TOXIC EFFECTS** Their wide range of side effects can be divided in to two (2) 1\. Those due to allergy and 2\. Those resulting from local (direct) toxicity. The commonest side effects include the following. \(I) Fever (drug induced). \(II) Skin rashes. (I11) Photosensilivity. \(IV) Urticaria(an itchy skin eruption characterized by weals with pale interiors and well-defined red margins). \(V) Gastrointestinal adverse effect like; Nausea, Vomiting, Diarrhoea **OTHERS ARE:** i. Conjunctivitis. ii. Arthritis iii. Haematopoietic disturbances. iv. Hepatitis. v. Dermatitis. vi. Psychosis has been reported. vii. Other toxicities are urinary tract disturbances. Most sulfonamides many precipitate in the urine especially in **neutral or acidic pH producing** crystalluria which eventually leads to; \>\>Nephrotoxicity. \>\>Haematuria or \>\>Obstructions. This is normally best treated using newer soluble sulfonamides e.g sulphisoxazole an sulfamethoxazole or keeping the urine pH alkaline or by forcing fluids and performing urine analysis every week. Crystalluria is more with older agents like sulfadiazine. Sulfonamides are implicated in various types of Nephritis (Nephropathy, Nephrotic syndrome, degeneration of renal tubular epithelium) as well as in allergic nephritis. viii. **Kernicterus**; occurs in fetuses or new born because sulfas displaces bilirubin from their binding sites on serum albumin. The unbound bilirubin is then able to pass into the brain causing Kirnicterus.(an abnormal accumulation of bile pigment in the brain and other nerve tissue; causes yellow staining and tissue damage) ix. Haematopoietic Disturbances; They induce anemia whether Haemolytic or aplastic. They also produce Granulocytopenia, Thrombocytopenia or even Leukaemoid reactions. **So to prevent the above, it is important to be checking every 3-5 days the white cell count and haemoglobin levels of patients on these drugs.\[and those of their breastfeeding neonate\]** x. In patients with G6PD deficiency, erythrocytes are known to have haemolytic reactions. **CONTRAINDICATIONS** They are c/i in new born, infants less than 2months old as well as pregnant women at term (last month of pregnancy) due to the dangers of Kernicterus. **INTERACTION:** Sulfas inhibits the metabolism of phenytoin, tolbutamide and watfrine and thus enhances their action. **RESISTANCE TO SULFONAMIDES** Bacterial resistance to sulfonamides can arise from plasmid transfer or random mutations. The resistance is generally irreversible and may be any of the following: 1\. Altered enzyme- Bacteral dehydropteroate synthetase can undergo mutation or be transferred via plasmid leading to decreased affinity for sulfas. The drug then becomes least active against such resistant microbial agents. 2\. Decreased uptake- Permeability to sulfas may be reduced in some resistance strains. 3\. Increased PABA synthesis: Enhanced production of the neutral PABA by the microorganisms through mutation or other processes can overcome inhibition of dihydropteroate synthetase by sulfas. **NOTE: Organisms resistance to one member of this drug (sulfas) family are resistance to all, but may be susceptible to Cotrimoxazole.**