Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Drug Information, Professional
Figure 1: A rough sketch of isoniazid metabolism leading to drug toxicity. Among the metabolites of . Chloramphenicol, Methadone. Cimetidine, Phenytoin. Structure for Ethambutol (DB) . In patients with normal renal function, 3 to 4 hours. In patients with impaired renal function, up to 8 hours. Methadone, Ethambutol may decrease the excretion rate of Methadone which could result in. Structure-activity Relationship. An extensive number of analogs of ethambutol have been prepared, but none have proven to be superior to ethambutol itself.
This autoinduction partly explains the decreased drug efficacy in some tuberculosis patients that had lead to the failure of treatment.
UGT1A UDP- glucoronosyltransferase 1A is an important phase 2 enzyme that transfers glucoronic acid to a number of xenobiotcs or its metabolites and endogenous substrates resulting their elimination from the body either through renal or biliary routes, depending on molecular weight.
This enzyme is also induced by rifampicin via the PXR receptor. Enzyme induction leads to increased clearance steroids, heme, environmental toxins and drugs. In addition to the above mechanisms for drug interactions with rifampicin, there are some drug interactions that cannot be solely explained by the induction of cytochrome P enzymes.
Design, Synthesis and Evaluation of Novel Ethambutol Analogues
For instance, the interaction with digoxin, which can instead be explained by the increased level of intestinal p-glycoprotein. P-glycoprotein is a plasma membrane bound efflux transporter present in various drug eliminating organs like the liver, brain, and intestinal lumen. Rifampicin also induces p-glycoprotein and its level is increased 3. The induction is thought to be mediated by activation of PXR by rifampicin.
Researchers have shown that rifampicin induced duodenal MRP2 mRNA in 14 out of 16 individuals after nine days of oral treatment with mg daily rifampin [ 23 ]. The same study has also found that MRP2 protein, which is expressed in the apical membrane of enterocytes,was significantly induced by the same treatment.
Complex drug interactions with rifampicin can occasionally complicate the therapy, especially when the patient has HIV infection or any other concomitant diseases.
Ethambutol - DrugBank
For instance, a cyclosporine dose has to be increased about 3-fold to maintain therapeutic plasma level when co administered with rifampicin [ 24 ].
Concomitant administration of rifampicin and simvastatin can lead to greatly reduced cholesterol lowering efficiency of the latter [ 24 ]. Warfarin clearance increases in presence of rifampicin and thus requires a higher dose to achieve the same therapeutic outcome. Thus, rifampicin controls efficacy and toxicity of various lifesaving drugs. Ethambutol EMB Ethambutol is another important first-line of drug against tuberculosis. Ethambutol is thought to inhibit a number of metabolites essential for the survival of the bacteria.
It mainly inhibits the synthesis of arabinogalacton - an important component of the mycobacterial cell wall. The metabolism of the drug is depicted below: The L configuration of ethambutol is found to be the more toxic isomer [ 25 ]. Several animal studies have isolated both the metabolites from the urine.
Optical toxicity is predominant with ethambutol. Optic neuritis is a rare but detrimental side effect. It manifests primarily as retrotubular neuritis with the involvement of either axial fibres or, less commonly, periaxial fibres Figure 4. Ethambutol can chelate various cations such as zinc, and copper.
Several enzymes important for maintaining normal body functions require copper and zinc as cofactors. Depleted levels of these cations during ethambutol treatment would therefore affect the normal function of various enzymes.
Current Overview of Anti-Tuberculosis Drugs: Metabolism and Toxicities
A rough sketch of ethambutol metabolism. Zinc which influences cell metabolism through a variety of mechanisms, appears to play an integral role in maintaining normal ocular function. Zinc is present in high concentrations in ocular tissue, particularly in the retina and choroid. Zinc deficiency has been shown in a number of species to result in a variety of gross, ultrastructural and electrophysiologic ocular manifestations.
- Design, Synthesis and Evaluation of Novel Ethambutol Analogues
- Rifampin, Isoniazid, Pyrazinamide, and Ethambutol (Systemic)
Extensive studies have been carried out for understanding the role of zinc in the visual system of different species. The physiological functions for zinc have been studied predominantly in retina and retinal pigment epithelium where zinc is believed to interact with taurine and vitamin A, modify photoreceptor plasma membranes, regulate the light-rhodopsin reaction, modulate synaptic transmission and serve as an antioxidant [ 26 ]. Earlier studies have established that ethylene diamine and its substituted derivatives can form stable complexes with Zinc and many other cations [ 27 ].
Studies have shown that treatment with ethambutol in dogs and rhesus monkeys can produce the metabolite Ethambutol [ d -2,2'- ethylenediimino di-l-butanol], a substituted ethylene diamine, which results in a significant decrease in ocular zinc concentrations [ 28 ]. The same study has shown that depleted copper levels are responsible for cardiac toxicity in dogs, likely due to the malfunction of cytochrome C oxidase, a copper requiring enzyme.
In fact, alcohol dehydrogenase ADHwhich is also involved in ethambutol metabolism, is itself a zinc requiring enzyme. Ethambutol increases the ability of ADH to oxidize ethanol in yeast and it does so by influencing the depolymerisation of the enzyme [ 29 ].
Other side effects of ethambutol, though rare, include peripheral neuropathy, cutaneous reaction and hepatitis. Due to severe optical toxicity ethambutol is not administered in pediatric patients.
Conclusion Hepatotoxicity is the major side effect for almost all first-line antituberculosis drugs with exception of ethambutol. The exact mechanism of liver toxicity is difficult to predict for each individual drug as they are almost always co-administered with each other. Only exception is perhaps isoniazid that is used as monotherapy in latent tuberculosis.
Ethambutol diffuses into actively growing M. Rifampin diffuses well to most body tissues and fluids, including the cerebrospinal fluid CSFwhere concentrations are increased if the meninges are inflamed; concentrations in the liver, gallbladder, bile, and urine are higher than those found in the blood. Because it is lipid-soluble, rifampin may reach and kill susceptible intracellular, as well as extracellular, bacteria and Mycobacteria species.
Isoniazid is widely distributed to all fluids and tissues, including CSF, pleural and ascitic fluids, skin, sputum, saliva, lungs, and muscle. Pyrazinamide is widely distributed to most fluids and tissues, including liver, lungs, kidneys, and bile. Ethambutol is distributed to most tissues and body fluids, except CSF. Hepatic; rifampin is rapidly deacetylated by auto-induced microsomal oxidative enzymes to the active metabolite O-desacetylrifampin.
Time to peak serum concentration Rifampin—1. Peak serum concentration Rifampin: Children 6 to 58 months of age: In dialysis— Significant amounts of isoniazid are removed from the blood by hemodialysis. Tuberculosis during pregnancy should be managed on a case-by-case basis because of the complexity of management decisions. It has rarely caused postnatal hemorrhages in the mother and infant when administered during the last few weeks of pregnancy; vitamin K may be indicated.
Imperfect osteogenesis and embryotoxicity were reported in rabbits given up to 20 times the usual daily human dose. Isoniazid Isoniazid crosses the placenta, resulting in fetal serum concentrations that may exceed maternal serum concentrations.SAR of Parasympatholytic agents/ antimuscarinic agents/ anticholinergic agents
Studies in rats and rabbits have shown that isoniazid may be embryocidal. Pyrazinamide Adequate and well-controlled studies in humans have not been done; the risk of teratogenicity has not been determined. Studies in mice given high doses of ethambutol have shown that ethambutol causes a low incidence of cleft palate, exencephaly, and vertebral column abnormalities.