Sulphonamides and diamino-pyrimidines Flashcards
Sulphonamides in general
-One of the oldest groups of antimicrobial compounds.
-Widely used in food prod. animals because of their low cost & ease of adm.
-Use: widespread, particularly as mass medicines for the control of diseases in food processing species.
-Marketed rarely alone, frequently in combination with diaminopyrimidines &/or antibiotics.
-Medicated premix, or oral, topical, intrauterine pessaries & injectable preparations.
-Broad spectrum of bacteriostatic activity, affecting Gr+, Gr- & many protozoan organisms.
-Bacteriostatic diaminopyrimidines are currently used in veterinary medicines only in combination with sulphonamides (alone resistance develops rapidly).
-Structure:
o Sulphonamides: Bad solubility in acidic environment. Na-salt is used, highly alkaline.
o 2,4-diaminopyrimidines e.g. trimethoprim: Weak base, poorly soluble in water
Active substances – sulphonamides
•Local:
o Sulfacetamide
o Mafenide
o Silver sulfadiazine (used as ointments, especially good for burning injuries)
•Intestinal disinfectant: Sulfaguanidine (stays in GI-tract, but not dissinfectant)
•Systemic:
o Short (given b.i.d. orally)
Sulfadimidine
Sulfadiazine
Sulfamethoxazole
Sulfachlorpyridazine
Sulfadoxine
Sulfquinoxaline (most toxic) –>
Sulfachlorpyrazine –> these two used against Cocidia!
Sulfasalazine (Salazopyrin) – used in chronic colititis, idiopathic colitis
o Long (given every 2nd day) – sulfadimethoxine
Active substances – 2,4-diaminopyrimidines
•Trimethoprim – short •Diaveridine •Poromethapim •Ormethoprim •Long: o Aditoprim o Baquiloprim
Mechanism of action
- Inhibition of folid acid synthesis, on two steps (sulphonamides+diaminopyrimidines) (Folic acid is used in DNA synthesis – will be inhibited).
- Sulphonamides compete with PABA for the enzyme dihydropteroate synthetase, preventing incorporation of PABA into the folic acid (pteroylglutamate)
- Diaminopyrimidines inhibit THF synthesis from DHF by combining with the enzyme dihydrofolate reductase
- Selective toxicity: greater affinity for the bacterial enzyme than the mammalian - susceptible microorganisms must synthesise folic acid, whereas mammalian cells use preformed folic acid
Mode of action
• If we use them alone they are bacteriostatic, if we combine them they are bacteriocidal.
Antimicrobial activity of Sulphonamides
•Mode of action: bacteriostatic
•Wide antibacterial spectrum:
o Gr+/- bacteria
o Aerobic & several anaerobic bacteria
o Chlamydia spp, Bordetella bronchiseptica
o Nocardia ssp. – very sensitive – SA are excellent - 1st choice! (usually found on skin surface, but can enter thoracic cavity – life threathening!)
•Antiprotozoal effect:
o Coccidian! (Eimeria spp., Isospora spp)
o Toxoplasma spp (1st choice is Clindamycin)
Resistance of sulphonamides
•Very frequent among sulphonamides
•Mycoplasma and Pseudomonas aeruginosa
•Chromosomal mutation (develops slowly & gradually)
•Plasmid & integrin-mediated resistance
•Cross-resistance among the sulphonamides is complete!
•Mechanisms:
o Decreased penetration
o PABA-specific dihydropteroate-synthetase enzyme
o Overproducing of PABA (purulent tissue debris)
Antimicrobial activity of diaminopyrimidines
- Mode of action: bacteriostatic
- Wide antibacterial spectrum
- Gr +/- aerobic bacteria
- Negligible activity against: anaerobes, Chlamydia spp., Mycbacterium spp., Mycoplasma spp., Leptospira spp.
- Anti-protozoal effect
Resistance of diaminopyrimidines
- Plasmid & integrin-mediated resistance (at least 20 different resistance genes)
- Plasmid or chromosomal synthesis of a resistance dihydrofolate reductase enzyme
- Commonly multiple resistance, including sulphonamide resistance
Advantages of the combination
•Synergistic interactions – potentiated sulphonamides
o 2 bacteriostatic agents –> bactericidal effect
o 10-fold increased activity of the diaminopyrimidines component, 100-fold of the sulphonamides
o Broadened spectrum
o Resistance less frequent
- Antimicrobial activity of combinations:
•Mode of action: bactericidal
•Wide antibacterial spectrum
o Gr +/- bacteria (see under the individual components)
o Anti-protozoal effect (Toxoplasma, coccidia)
o Further sensitive parasites: Pneumocystis spp., some malarias
•Not active against: Mycoplasma, mycobacteria, rickettsia, Spirochaetes, Leptospira spp., Pseudomonas aeruginosa
•In vivo they are not active against anaerobes.
Pharmacokinetic properties of sulphonamides
•Absorption: moderate or good abs. after PO adm. (except sulfaguanidine)
•Distribution: good to tissues, EC fluid, purulent material, tissue debris!, meningitis: good penetration across BBB, also to prostata.
•Metabolism:
o Liver:
Acetylation of badly soluble metabolites (Cats, Hu, less in dog!) to acetyl-sulphonamide
Glucuronidation - glucuronic acid soluble molecules, quick excretion
o Precipitation in urine with acidic pH: acetyl sulphonamides will cause acetyl-sulpha crystals! - bad solubility (Cat, dogs (less of these metabolites), Hu, not Herb.) - Can be avoided by drinking a lot, but not in dehydrated animals or acidified urin (vit.C and methionin).
•Elimination: kidney (active + metabolites) – less bile, milk, glomerular filtration, active tubular secretion & tubular reabsorption
Pharmacokinetic properties of diaminopyrimidines
- Absorption: well absorbed PO
- Distribution: excellent, high Vd, good penetration through special barriers; liquor, prostate, milk
- Metabolism & elimination: partly metabolised in liver, elimination via kidney in an active form, TMP half-life: notable difference from humans (shorter!)
Pharmacokinetic properties of combinations
o Sulphonamides: worse penetration to tissues
o Diaminopyrimidines: quickly enters to tissues, shorter half-life of TMP (except humans!)
o Ormethoprim, aditoprim, baquiloprim: longer half-life, less frequent dosing (dog 48h)
o SC administration of combinations is not preferred in cows (TMP deposit - low concentration), may in other species as well.
Side effects of sulphonamides
•Wide therapeutic index (s.e. mainly caused by sulphonamide-compoenents)
•Nephrotoxicity, crystalluria (acidic urine, acetyl metabolite), haematuria
•Rarely idiosyncratic drug reactions (immune mediated toxicity)
•Allergy (in Doberman Pinschers more frequent)
•Keratoconjunctivitis sicca (frequently in small dogs) – not first week, but check every week if longer with Schirmer test – lacrimal gland can be irreversible damaged
•Relatively to large doses? Irreversible!
•Dysimbiosis: vit.K deficiency in poultry (causes bleedings, provide extra vit.K)
•Haematological deviations
o Sulphmethaemoglobinaemia
o Sulfaquinoxaline: vit K antagonism in different species leads to haemorrhagic diathesis!
•Hypothyroidism
Side effects of diaminopyrimidines
- They are relatively nontoxic drugs
- Folic acid deficiency at high doses
- Aditoprim & baquiloprim are hepatotoxic
