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Aminoglycosides, Sulfonamides and TrimethoprimAminoglycosides Synergism with Beta Lactam AntibioticsIt is believed that by giving Gentamicin together with Penicillin G may produce synergism. This is because Penicillin acts by inhibiting the cross linking of peptidoglycan on the bacterial cell wall. This inhibition may lead to altered cell wall permeability and makes Gentamicin easier to cross the cell wallDrugs/InfoPharmacokineticsMechanism of ActionSpectrum of ActivityAdverse EffectsAgents Streptomycin Gentamycin Neomycin Amikacin Can be either Natural products Semisynthetic compounds All of them generally produced from derivative compounds produced by soil Actinomycetes spp. Nomenclature Aminoglycosides with suffix “mycin” at the end Produced by Streptomyces spp. ExampleStreptomycin Aminoglycosides with suffix “micin” at the end Produced by Micromonospora spp. Example Gentamicin Absorption Generally hydrophilic in nature Therefore very poorly absorbed orally Administered only parenterally Distribution Poor tissue penetration Cant pass BBB Doesn’t bind to plasma protein Vd is equal to that of plasmaMetabolism Doesn’t undergo metabolism Excretion Eliminated unchaged via urine It needs to enter the bacterial cell through an active transport It binds to the 30S Ribosomal Subunit of bacteriaThis will interfere protein synthesis through Block the formation of the initiation complex Inhibit the translocation of tRNA Premature chain termination Misreading of codon on mRNA templateIncorporate wrong amino acids All of these will to production of non-functional protein Selective Toxicity Humans are Eukaryote by which they have 80S Ribosomal subunit consisting of 60S40STherefore, Aminoglycosides wont be able to cause toxicity to human’s genetic translation Aerobic Gram Negative Bacilli Pseudomonas aeruginosa Enterobacteriociae spp.Ototoxicity Accumulation in the endolymph and perilymph Leads to destrcution of Cochlear apparatus Vestibular apparatus The damage is irreversible Characterized byTinnitus Hearing lossHeadache Vertigo Nausea vomiting Nephrotoxicity Due to its active metabolite being excreted via urine, it may lead to Destruction of tubular cells Glomerular dysfunction Need renal close monitoring for pts taking more than 10days Neuromuscular block Occurs when given with Neuromuscular blockers Leads to inhibition the release of Ach Treated by Calcium AchE inhibitors Clinical UsesUTI Tuberculosis Bacterial Endocarditis Plague Ear and eye infection DosingIt has a longer post-antibiotic effects (PAE) In order to have a prolong PAE, the initial dose should be high enough But if the dose is low, the dosing should be repeated to have the PAERepeated dose my lead to significant continuous side effects; hence a large single daily dose is advised SulfonamidesAdministration of Procaine with Sulfonamides Procaine, an ester anesthetic, is metabolized in the plasma by the enzyme pseudocholinesterase through hydrolysis into para-amino benzoic acid (PABA)Sulfonamide on the other hand inhibits the conversion of PABA to Dihydrofolate though competitively inhibit the Dihydropteroate Synthase Procaine may increase the level of PABA and this will reduce the possibility of Sulfonamide to inhibit the action of Dihydropteroate Synthase Drugs/InfoPharmacokineticsMechanism of ActionSpectrum of ActivityAdverse EffectsClassifications Orally Absorbable Short acting (t1/2 = 6-8 hrs)Sulfadiazine Intermediate acting (t1/2 = 10-12 hrs)Sulfamethoxazole Long acting (t1/2 = 7-8 days)Sulfadoxine Orally Non-absorbable Sulfadiazine Topical Silver Sulfadiazine Absorption Oral absorption depends on the type of Sulfonamides Distribution Wide tissue distribution including the CSFExtensive plasma protein bound May displace Warfarin from AlbuminMetabolism Hepatic metabolism (some)Excretion Excreted via urine Highly soluble in alkaline urine Hence acidic urine such as in Gouty Arthritis may percipitate Sulfonamides and form Crystalluria Can be avoided by giving Urine Alkalinizer Certain microbes require p-aminobenzoic acid (PABA) in order to synthesize dihydrofolic acid which is required to produce purines and ultimately nucleic acidsSulfonamides,chemical analogs of PABA, are competitive inhibitors of dihydropteroate synthetaseSulfonamides therefore are reversible inhibitors of folic acid synthesis and bacterostatic not bacteriocidalSulfonamides should not be given to patient with lesion with massive tissue destruction and pus without removing them, this is because Tissue destrustion may release all folic acid derivatives and compound for folic acid synthesisThese compounds may compete with Sulfonamides for the same enzyme, therefore reducing the effectiveness of Sulfonamides Active against Pneumocystis jeroveci Toxoplasma gondii Chlamydia trachomatis Nocardia spp. Resistance in Most Gram Positive cocci and bacilli Crystalluria Renal toxicity Steven Johnson Syndrome Hemolytic Anemia Contraindication Neonates, lactating mother and last trimester pregnant women May cause Kernicterus due to displacement of Bilirubin from Albumin G6PD Deficiency May cause Hemolytic Anemia Clinical Uses**very few being as a single agent Trachoma Topical Sulfacetamide Burn Topical Silver Sulfadiazine Ulcerative Colitis Sulfasalazine TrimethoxybenzylpyrimidineDrugs/InfoPharmacokineticsMechanism of ActionSpectrum of ActivityAdverse EffectsTrimethoprimTrimethoprim is highly lipid soluble, by which it can be easily, distributed across body compartments including the prostate and vaginal. This is why trimethoprim has more antibacterial action in prostate and vaginal fluid This is also because, Trimethoprim is a weak base, therefore it will remain accumulated in the vaginal and prostate fluid which much acidic in natureAbsorption Efficient oral absorption Distribution Highly lipid soluble Tissue distribution is higher compared to Sulfonamides High Vd Metabolism Hepatic metabolism Excretion Excreted via urine Trimethoprim acts by interfering with the action of bacterial dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acidTetrahydrofolic acid is an essential precursor in the de novo synthesis of the intermediate Thymidine monophosphate (dTMP), precursor of DNA metabolite Thymidine triphosphateEffective against Gram Positive Bacteria Gram Negative Bacteria Nevertheless resistance develops very quickly if being used alone Thrombocytopenia Megaloblastic anemia Due to lowering of Folic Acid level Can be counter act by giving Folinic Acid (Leucovorin)Hyperkaleamia Antagonises the epithelial sodium channel (ENaC) in the distal tubuleClinical UsesVery rarely used in monotherapy CombinationDrugs/InfoPharmacokineticsMechanism of ActionClinical UsesAdverse EffectsCo-Trimexazole (Bactrim?)Sulfamethoxazole Trimethoprim Sulfamethxazole was choosen to combine with Trimethoprim because both have the same intermediate half life The ratio is 1 part Trimethoprim with 5 part of Sulfamethoxazole (1:5)This is because Trimethoprime is more lipophilic compared to Sulfamethoxazole This makes Trimethoprime having higher Vd and less concentrated inside the serum compared to latter drugAbsorption Very well absorb orally Distribution Trimethoprim is much more distributed across body compartments compared to Sulfamethoxazole This will give rise to 1:20 plasma concentration after admin between Trimethoprim and Sulfamethoxazole Metabolism Hepatic metabolism Excretion Excreted via urine Urinary Tract Infections (very effective)Acute noncomplicated UTI Complicated UTI Pneumocystis jeroveci pneumonia Nocardiosis STD Syphilis Lymphogranuloma Gonorrhea Respiratory Tract Infections Prostitis Combination side effects of both Sulfamethoxazole and Trimethoprim ................
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