Protamine Sulfate, USP. Protamine sulfate has an anticoagulant effect, but if used in the proper amount, it counteracts the action of heparin and is used as an antidote for the latter in cases of overdosage. It is administered intravenously in a dose that depends on the circumstances.
Dicumarol, USP. Dicumarol, 3,3'-methylenebis[4-hy-droxycoumarin], is a white or creamy white crystalline powder with a faint, pleasant odor and a slightly bitter taste. It is practically insoluble in water or alcohol, slightly soluble in chloroform, and dissolved readily by solutions of fixed alkalies. The effects after administration require 12 to 72 hours to develop and persist for 24 to 96 hours after discontinuance.
Dicumarol is used alone or as an adjunct to heparin in the prophylaxis and treatment of intravascular clotting. It is used in postoperative thrombophlebitis, pulmonary embolus, acute embolic and thrombotic occlusion of peripheral arteries, and recurrent idiopathic thrombophlebitis. It has no effect on an already-formed embolus but may prevent further intravascular clotting. Because the outcome of acute coronary thrombosis depends largely on extension of the clot and formation of mural thrombi in the heart chambers, with subsequent em-bolization, dicumarol has been used in this condition. It has also been administered to arrest impending gangrene after frostbite. The dose, after determination of the prothrombin clotting time, is 25 to 200 mg, depending on the size and the condition of the patient. The drug is given orally in the form of capsules or tablets. On the second day and thereafter, it may be given in amounts sufficient to maintain the prothrom-bin clotting time at about 30 seconds. If hemorrhages should occur, a dosage of 50 to 100 mg of menadione sodium bisulfite is injected, supplemented by a blood transfusion.
Warfarin Sodium, USP. Warfarin sodium, 3-(a-acetonylbenzyl)-4-hydroxycoumarin sodium salt (Coumadin, Panwarfin), is a white, odorless, crystalline powder, with a slightly bitter taste; it is slightly soluble in chloroform and soluble in alcohol or water. A 1% solution has a pH of 7.2 to 8.5.
By virtue of its great potency, warfarin sodium at first was considered unsafe for use in humans and was used very effectively as a rodenticide, especially against rats. At the proper dosage level, however, it can be used in humans, especially through the intravenous route.
Warfarin Potassium, USP. Warfarin potassium, 3-(a-acetonylbenzyl)-4-hydroxycoumarin potassium salt (Athrombin-K), is readily absorbed after oral administration, and a therapeutic hypoprothrombinemia is produced within 12 to 24 hours after administration of 40 to 60 mg. This salt is therapeutically interchangeable with warfarin sodium.
Anisindione, USP. Anisindione, 2-(p-methoxyphenyl)-1,3-indandione, 2-(p-anisyl)-1,3-indandione (Miradon), is a p-methoxy congener of phenindione. It is a white, crystalline powder, slightly soluble in water, tasteless, and absorbed well after oral administration.
In instances when the urine may be alkaline, an orange color may be detected. This is caused by metabolic products of anisindione and is not hematuria.
Eculizumab. Eculizumab (Soliris) is a monoclonal antibody that binds to the terminal complement protein C5 in RBCs. This blocks the cleavage of C5 and halts the process of complement-mediated cell destruction of the RBCs. Eculizumab has been shown to be effective in treating PNH and in March 2007 was approved by the FDA for treating PNH.77
o SYNTHETIC HYPOGLYCEMIC AGENTS
The discovery that certain organic compounds will lower the blood sugar level is not recent. In 1918, guanidine was shown to lower the blood sugar level. The discovery that certain trypanosomes need much glucose and will die in its absence was followed by the discovery that galegine lowered the blood sugar level and was weakly trypanocidal. This led to the development of several very active trypanocidal agents, such as the bisamidines, diisothioureas, bisguani-dines, and others. Synthalin (trypanocidal at 1:250 million) and pentamidine are outstanding examples of very active trypanocidal agents. Synthalin lowers the blood sugar level in normal, depancreatized, and completely alloxanized animals. This may be caused by reduced oxidative activity of mitochondria, resulting from inhibition of the mechanisms that simultaneously promote phosphorylation of ADP and stimulate oxidation by nicotinamide adenine dinucleotide (NAD) in the citric acid cycle. Hydroxystilbamidine isethionate, USP, is used as an antiprotozoan agent.
In 1942, p-aminobenzenesulfonamidoisopropylthiadia-zole (an antibacterial sulfonamide) was found to produce hypoglycemia. This result stimulated research for the development of synthetic hypoglycemic agents, several of which are in use today.
Sulfonylureas became widely available in 1955 for the treatment of non-ketosis-prone mild diabetes and are still the drugs of choice. A second class of compounds, the biguanides, in the form of a single drug, phenformin, has been used since 1957. Phenformin was withdrawn from the U.S. market, however, because it causes lactic acidosis, from which fatalities have been reported.
The sulfonylureas may be represented by the following general structure:
These are urea derivatives with an arylsulfonyl group in the 1-position and an aliphatic group at the 3-position. The aliphatic group, R', confers lipophilic properties to the molecule. Maximal activity results when R' consists of three to six carbon atoms, as in chlorpropamide, tolbutamide, and acetohexamide. Aryl groups at R' generally give toxic compounds. The R group on the aromatic ring primarily influences the duration of action of the compound. Tolbutamide disappears quite rapidly from the bloodstream by being metabolized to the inactive carboxy compound, which is excreted rapidly. Chlorpropamide, however, is metabolized more slowly and persists in the blood much longer.
The mechanism of action of the sulfonylureas is to stimulate the release of insulin from the functioning jS-cells of the intact pancreas. In the absence of the pancreas, they have no significant effect on blood glucose. The sulfonylureas may have other actions, such as inhibition of secretion of glucagon and action at postreceptor intracellular sites to increase insulin activity.
For a time, tolbutamide, chlorpropamide, and acetohexamide were the only oral hypoglycemic agents. Subsequently, a second generation of these drugs became available. Although they did not present a new method of lowering blood glucose levels, they were more potent than the existing drugs. Glipizide and glyburide are the second-generation oral hypoglycemic agents.
Whether they are first- or second-generation oral hypo-glycemic drugs, this group of agents remains a valuable ad junct to therapy in adult-onset diabetes patients. Accordingly, the sulfonylureas are not indicated in juvenile-onset diabetes.
Tolbutamide, USP. Tolbutamide, 1-butyl-3-(p-tolylsul-fonyl)urea (Orinase), occurs as a white, crystalline powder that is insoluble in water and soluble in alcohol or aqueous alkali. It is stable in air.
Tolbutamide is absorbed rapidly in responsive diabetic patients. The blood sugar level reaches a minimum after 5 to 8 hours. It is oxidized rapidly in vivo to 1-butyl-3-(p-car-boxyphenyl)sulfonylurea, which is inactive. The metabolite is freely soluble at urinary pH; if the urine is strongly acidified, however, as in the use of sulfosalicylic acid as a protein precipitant, a white precipitate of the free acid may be formed.
Tolbutamide should be used only when the diabetic patient is an adult or shows adult-onset diabetes, and the patient should adhere to dietary restrictions.
Tolbutamide Sodium, USP. Tolbutamide sodium, 1-butyl-3-(p-tolylsulfonyl)urea monosodium salt (Orinase Diagnostic), is a white, crystalline powder, freely soluble in water, soluble in alcohol and chloroform, and very slightly soluble in ether.
This water-soluble salt of tolbutamide is used intravenously for the diagnosis of mild diabetes mellitus and of functioning pancreatic islet cell adenomas. The sterile dry powder is dissolved in sterile water for injection to make a clear solution, which then should be administered within 1 hour. The main route of breakdown is to butylamine and sodium p-toluene sulfonamide.
Chlorpropamide, USP. Chlorpropamide, 1-[(p-chloro-phenyl)-sulfonyl]-3-propylurea (Diabinese), is a white, crys-
talline powder, practically insoluble in water, soluble in alcohol, and sparingly soluble in chloroform. It will form water-soluble salts in basic solutions. This drug is more resistant to conversion to inactive metabolites than is tolbutamide and, as a result, has a much longer duration of action. One study showed that about half of the drug is excreted as metabolites, with the principal one being hydroxylated in the 2-position of the propyl side chain.78 After control of the blood sugar level, the maintenance dose is usually on a once-a-day schedule.
Acetohexamide, USP. Acetohexamide, 1-[(p-acetyl-phenyl)sulfonyl]-3-cyclohexylurea (Dymelor), is related chemically and pharmacologically to tolbutamide and chlor-propamide. Like the other sulfonylureas, acetohexamide lowers the blood sugar level, primarily by stimulating the release of endogenous insulin.
Tolazamide, USP. Tolazamide, 1-(hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea (Tolinase), is an analog of tolbutamide and is reported to be effective, in general, under the same circumstances in which tolbutamide is useful. Tolazamide, however, appears to be more potent than tolbu-tamide and is nearly equal in potency to chlorpropamide. In studies with radioactive tolazamide, investigators found that 85% of an oral dose appeared in the urine as metabolites that were more soluble than tolazamide itself.
Acetohexamide is metabolized in the liver to a reduced form, the a-hydroxyethyl derivative. This metabolite, the main one in humans, possesses hypoglycemic activity. Acetohexamide is intermediate between tolbutamide and chlorpropamide in potency and duration of effect on blood sugar levels.
Glipizide. Structurally, glipizide, 1-cyclohexyl-3-[[p-[2(methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea (Glucotrol), is a cyclohexylsulfonylurea analog similar to acetohexamide and glyburide. The drug is absorbed rapidly on oral administration. Its serum half-life is 2 to 4 hours, and it has a hypoglycemic effect that ranges from 12 to 24 hours.
Glyburide. Similar to glipizide, glyburide, 1-[[p-[2-(5-chloro-o-anisamido)ethyl]-phenyl]sulfonyl]-3-cyclohexyl-urea (DiaBeta, Micronase, Glynase), is a second-generation oral hypoglycemic agent. The drug has a half-life elimination of 10 hours, but its hypoglycemic effect remains for up to 24 hours.
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...