Pharmacology of the sulphonamides and trimethoprim

Susceptible microbes require extracellular PABA in order to form DHFA, an essential step in the production of purines and the synthesis of nucleic acids. Sulphonamides are structural analogs of PABA that competitively inhibit dihyropteroate synthetase; they inhibit growth by reversibly blocking folic acid synthesis. Mammalian cells (and some bacteria) lack the enzymes required for folate synthesis and depend upon exogenous sources of folate; they are not susceptible to sulphonamide. Resistance may occur as a result of mutations that cause (a) overproduction of PABA, (b) production of a folate synthesizing enzyme that has low affinity for sulphonamides, (c) or cause a loss of permeability to the drug.

Trimethoprim inhibits bacterial DHFA reductase about 50000 times more efficiently than the same enzyme of mammalian cells. DHFA reductases convert DHFA to THFA, a step leading to the synthesis of purines and ultimately to DNA. Trimethoprim, administered with sulphonamides, produces sequential blocking in this metabolic sequence, resulting in synergism. The combination is often bactericidal, as compared to the bacteriostatic activity of a sulphonamide alone. Resistance to trimethoprim may occur from (a) reduced cell permeability), (b) overproduction of DHFA reductase, (c) or production of a reductase with reduced drug binding. Folinic acid should be given to compensate for the decrease in folate.

Sulphonamide classification:
1. Oral, absorbable - Sulphisoxazole (short-acting) ,Sulphamethoxazole (intermediate-acting), Sulphadiazine (intermediate-acting), Sulphadoxine (long-acting)
2. Oral, non-absorbable - Sulphasalazine
3. Topical use - Sulphacetamide

Absorption of the oral sulphonamides ranges from 70-100% in the small intestine, with peak blood levels occurring 2-6h after administration. They are widely distributed throughout all tissues, entering pleural, peritoneal, synovial, and ocular fluids readily. They also penetrate the CSF, and can cross the placenta to enter the foetal circulation (NB: causes kernicterus in the foetus due to haemolysis of foetal RBCs; it becomes mentally retarded). Sulphonamides are partially metabolized to inactive N-acetylated or glucuronidated metabolites in the liver, which are then excreted in the urine along with the parent drug mainly by glomerular filtration. Dosage must be reduced in renal failure.

In contrast, trimethoprim is a weak base and is eliminated and concentrated in vaginal and prostatic fluids, which are more acidic than plasma (i.e. it has more antibacterial activity in these fluids than other drugs). TMP is absorbed efficiently and widely distributed, including the CSF. It is often used in combination with sulphamethoxazole (co-trimoxazole) but may be used singly for treating acute UTIs. SMZ is chosen because it has a similar half-life to TMP. TMP is more lipid-soluble than SMZ; it has a larger volume of distribution. Dosage of TMP:SMZ is approximately 1:5.

Therapeutic uses of co-trimoxazole include complicated UTIs and prostatitis, respiratory tract infections by the Pneumococcus, Haemophilus spp., and Klebsiella spps. It is also used (in IV form) to treat Pneumocystis carinii pneumonia in AIDS patients, as well as enteric infection by Salmonella spp. and bacillary dysentery caused by Shigella spp.

Other clinical uses of the various sulphonamide combinations consist of acute toxoplasmosis (sulphadiazine + pyrimethamine) and as a second-line malarial drug (sulphadoxine + pyrimethamine; a.k.a. Fansidar).

Sulphadoxine is a long-acting sulphonamide with a half life of ~170h and is well-absorbed orally. It is excreted slowly via glomerular filtration due to its high state of plasma protein binding, and undergoes tubular reabsorption.

Sulphasalazine is used to treat inflammatory bowel disease. It is split by intestinal flora to form sulphapyridine and 5-amino salicylic acid, which is released in large amounts to produce the anti-inflammatory effect (NB: such amounts cannot be achieved with oral ingestion of salicylic acid without producing severe gastritis). Sulphapyridine is absorbable and toxic in large amounts (especially in slow acetylators).

Sulphacetamide is used as an ophthalmic solution against eye infections by susceptible bacteria, and also as adjunctive therapy for trachoma.

Adverse effects of the sulphonamides include hypersensitivity (rash may form; SJS in <1% of patients; TEN; urticaria; photodermatitis), haematological symptoms (haemolysis in G6PD-deficient patients; aplastic anaemia; myelosuppresion with reduced WBCs and platelets; FBC should be monitored), GI symptoms, crystalluria due to precipitation of acetylated metabolites in acidic or neutral urine (occurs more with sulphadiazine and less with the more water-soluble sulphonamides like sulphisoxazole; treated by alkalinizing the urine with sodium bicarbonate and increasing water intake). Neonates develop kernicterus if mothers were administered with the drug in late pregnancy.

Adverse effects of trimethoprim include megaloblastic anaemia together with leukopaenia and granulocytopaenia (due to folate deficiency). Folate supplement is given to prevent this occurrence. Note however, that in the treatment of AIDS-related PCP, folate supplementation may instead increase morbidity. It can also cause nausea and vomiting, a drug-induced fever, vasculitis, or CNS disturbances.


Pharmacology of the urinary antiseptics

Nalidixic acid inhibits bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase), which is responsible for relieving the supercoils during DNA replication. It also affects topoisomerase IV, which normally promotes the separation of DNA strands. Its spectrum of activity is limited to the Gram negative bacilli, with rapid development of bacterial drug resistance as a downside.

It has good oral bioavailability, and is metabolized to an active hydroxyl-metabolite (20%) and an inactive mono-glucuronide conjugate (80%). These are rapidly excreted in the urine (i.e. nalidixic acid is only useful for UTI treatment and not for systemic infection). In renally impaired patients, systemic toxicity may occur.

Adverse effects of nalidixic acid include GI symptoms (nausea, vomiting, diarrhoea, abdominal pain), skin effects (rash, pruritius, photosensitivity), CNS symptoms (headache, vertigo, convulsions, toxic psychosis), haematological symptoms (decreased platelet count), and musculo-skeletal symptoms (cartilage toxicity).

Nitrofurantoin damages bacterial DNA due to its highly reactive metabolites which are produced by reducing enzymes in susceptible bacteria. It has 100% bioavailability with food, and like nalidixic acid, is rapidly excreted into the urine (by glomerular filtration and tubular secretion). It colours urine brown and has a half-life of 20-60min.

It is indicated in the treatment of acute UTI due to Gram negative (E. coli and the Enterococci) and Gram positive bacteria, as well as in the suppression of chronic UTI or prevention of UTI recurrence. The duration of treatment should not exceed 14 days, and there should be rest periods between treatment courses. Its effects are greatly enhanced in acidic mediums (pH<5.0) It should not be used in renal failure or in pregnant women and children less than a year old.

Adverse effects of nitrofurantoin include GI disturbances primarily (less so with the macrocrystalline preparation, due to its slower absorption), with occasional hypersensitivity reactions (skin rash and pneumonitis, both reversible upon drug withdrawal; chronic use can cause interstitial fibrosis and the elderly and more prone to pulmonary toxicity), chills and fever, along with leukopaenia and granulocytopaenia. It also causes haemolytic anaemia in G6PD-deficient patients. Hepatocellular damage with cholestasis may lead to chronic active hepatitis, and lastly it can cause various neurological disorders (headache, vertigo, polyneuropathies).