Slow-release preparations,

A number of prodrugs in clinical use are esters of fatty acids. For example, haloperidol decanoate is of interest in slow-release preparations. This compound was hydrolyzed by such hydrolases as purified carboxylesterase but was reported to be stable in human blood or plasma and in a variety of rat tissue homogenates [107], The source of this apparent lack of reactivity was competitive binding to blood and tissue proteins. In other words, protein binding sequesters this very lipophilic prodrug and prevents enzymatic hydrolysis, thereby slowing its activation and prolonging its in vivo effects. 

The solution to this problem has been the development of oral slow-release preparations - formulations of the drug in a matrix from which it slowly leaches out allowing for intestinal absorption over a period of many hours. Tmax for these preparations may be as high as 10-12 hours after ingestion. 

More hydrophilic /3-blockers, such as atenolol, bisoprolol, celiprolol, pindolol and sotalol are predominantly eliminated via the kidney. In elderly patients this may require adaptation of the dosage. Most of the shorter acting /3-blockers are available as slow release preparations. Accordingly, when used as antihypertensives /3-blockers are usually administered once daily. For other applications such as angina pectoris a twice daily dosage may be required. 

Therapy is perfectly adequate with simple iron salts (Table 2). In adults ferrous gluconate, fumarate or sulphate are all of proven equal efficiency. Approximately 50 mg of iron is present in each tablet with the remaining 300 mg made up with an inert filler. These are given on an empty stomach at least twice a day but should nausea prevail they can be taken with food. Absorption of slow release preparations is not recommended since iron is detached from the carrier beyond the main areas of absorption in the duodenum or jejunum. Stools turn black in all cases and this is a useful index of patient compliance. In 25% of individuals gastrointestinal tract side effects are encountered in the form of diarrhoea or constipation and patients will often spontaneously discontinue medication. It is therefore essential that a tablet-count be carried out on a regular basis with a substitute being provided when this first-line medication is intolerable. In children the same preparations are favoured as syrups these are given twice... 

Lithium is rapidly absorbed, reaching peak serum concentrations in 2-3 hours. It is not protein-bound and is excreted unchanged by the kidney at a rate proportional to the glomerular filtration rate. It is best given as a single daily dose around 22.00 hours and steady state serum levels are reached after 5-7 days of dosing, with the elimination half-life being around 10-24 hours for most people. Most proprietary formulations of lithium in current use are in the form of a slow-release preparation. There can be variations in kinetics between different proprietary brands and it is therefore best for individual patients to remain on the same brand. 

See Table 11-2. Resting bradycardia and a reduction in the heart rate during exercise are indicators of propranolol s 3-blocking effect, and changes in these parameters may be used as guides for regulating dosage. Propranolol can be administered twice daily, and slow-release preparations are available. 

Dosages and routes of administration Codeine is used orally in single doses of 30 to 60 mg up to a total dose of 240 mg per day for pain relief. Codeine is used in the form of different salts such as hydrochloride, phosphate and sulfate. To increase the duration of action, slow-release preparations have been developed. Codeine is often combined with other analgesics e.g. acetyl salicylic acid or paracetamol. For cough inhibition lower doses are sufficient. 

First, the protein itself can be infused directly into the cerebrospinal fluid or implanted in a biodegradable, slow-release preparation. Second, the active protein can travel across the blood-brain barrier by hiding inside a Trojan horse molecule... 

Modihed-release or slow-release preparations are designed to release the medication over a period of time. Crushing these preparations results in the whole dose being immediately available for absorption. At the least, this will cause an alteration in the patient s drug levels and at the worst it may result in an overdose. 

Opioids with long half-lives, such as pethidine, or slow-release preparations should generally be avoided, as if toxicity does ensue it will be prolonged. However, after continued unproblematic use of a regular opioid dose a slow-release preparation may be tried cautiously in patients with stable liver disease. 

Serious overdose with this xanthine bronchodilator can provoke serious hypotension, cardiac arrhythmias, and convulsions. These symptoms indicate a poor prognosis, particularly in elderly patients. Symptoms of poisoning after a high dose of a slow-release preparation can be delayed for several hours as the drug gradually accumulates to toxic concentrations. Patients with plasma concentrations greater than 60 Lig/ml may require charcoal haemo-perfusion. 

After a single oral dose of 75 mg given to 5 subjects, peak plasma concentrations of 0.10 to 0,24 pg/ml (mean 0,16) were attained in about 2 hours. Following a single oral dose of 75 mg of a slow-release preparation, average peak plasma concentrations of about 0.07 pg/ml were reported at 5 hours concentrations remained almost constant over the period 5 to 24 hours (G. P. Quinn et al., Clin. Pharmac. Ther., 1967,8, 369-373). 

The following postmortem tissue concentrations were reported in a subject who had been receiving daily oral doses of 40 mg of a slow-release preparation and who died of natural causes blood 0.9 pg/ml, bile 6.5 pg/ ml, liver 4pg/g, urine 50 pg/ml (K. Price, Bull. int. Ass.forens. Toxicol., 1974, 70(1), 12-13). 

Peretti E, Karlaganis G, Lauterburg BH. Increased urinary excretion of toxic hydrazino metabolites of isoniazid by slow acetylators. Effect of a slow-release preparation of isoniazid. Eur J Clin Pharmacol 1987 33 283-6. 

Slow release preparations Recombinant growth factors are prepared as slow-release pellets by incorporating the test molecule into an ethylene-vinyl-acetate copolymer (Elvax-40) (DuPont de... 

Pharmaceutics. It is important for any patient to adhere to the same pharmaceutical brand, as the dose of lithium ion (Li ) delivered by each tablet depends on the pharmaceutical preparation. For example, each Camcolit 250 mg tablet contains 6.8 mmol, each Liskonium 450 mg tablet contains 12.2 mmol and each Priadel 200 mg tablet contains 5.4 mmol of Li . Thus the proprietary name must be stated on the prescription. Some patients caimot tolerate slow-release preparations because release of lithium ions distally in the intestine causes diarrhoea they may be better served by the liquid preparation, lithium citrate, which is absorbed proximally. Patients who are naive to lithium should be started at the lowest dose of the preparation selected. Any change in preparation demands the same precautions as does initiation of therapy. 

Absorption of quinidine is complete and rapid. Peak serum concentrations are reached in 1.5 to 2 hours after oral intake, unless the slow-release preparation (quinidine gluconate) is used. Peak plasma concentrations are attained 4 to 5 hours after quinidine gluconate administration, and the trough concentration occurs 1 to 2 hours after the next administration. Once absorbed, quinidine is 80% protein bound. Metabolism of quinidine is by CyP 3A4. Clearance of quinidine depends on adequate hepatic and renal function. Reduction of either of these two functions results in accumulation of the drug. Renal clearance is a function of urine pH. If the urine is alkaline or if a patient has renal tubular acidosis, clearance is reduced. 

Aspirin absorption may be delayed when overdose quantities are consumed, especially of enteric-coated or slow-release preparations. This must be considered when interpreting serum salicylate values, especially for specimens obtained earlier than 6 hours after ingestion. Repeat testing within 2 to 3 hours is recommended to ensure that absorption is complete subsequent testing provides an indication of effectiveness of therapeutic intervention. Because of the aforementioned complications, proper assessment of salicylate intoxication requires sound clinical evaluation in combination with serum salicylate levels. 

At the other extreme, trazodone, nefazodone, and venlafaxine have short half-lives (about 3 to 6 hours), as does the active 4-hydroxy metabolite of venlafaxine (half-hfe of about 11 hours). The half-life of bupropion is about 14 hours. Owing to rapid aromatic hydroxylation, the half-hfe of nefazodone is very short (about 3 hours). The shorter durahon of action of these agents usually imphes the need for mulhple daily doses. Some short-achng antidepressants have been prepared in slow-release preparations (notably bupropion and venlafaxine), to ahow less frequent dosing and potentiahy to temper side effect related to agitation and GI disturbance. 

FORMULATIONS Most preparations used in the U.S. are tablets or capsules of lithium carbonate. Slow-release preparations of lithium carbonate also are available, as is a liquid preparation of lithium citrate (with 8 mEq of LF, equivalent to 300 mg of carbonate salt, per 5 mL or 1 teaspoonful of citrate liquid). The carbonate salt is favored for tablets and capsules because it is relatively less hygroscopic and less irritating to the gut than other salts, especially the chloride. 

Alternatively, if huge numbers of livestock are kept on a large area of pasture, parenteral supplementation may be preferable. For example, iodine supplementation provided by an intramuscular injection of a slow release preparation, such as iodized oil, can be sufficient for several months (Chambon and Chastin, 1993). Parenteral administration of iodine is beyond the scope of this chapter and only dietary supplementation of iodine is discussed here. 

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