Midazolam is a short-acting water-soluble benzodiazepine (at pH less than 4), a member of a new class of imidazobenzodiazepine derivatives. At physiological pH the drug becomes much more lipid soluble. Water solubility minimises pain on injection and venous thrombosis compared with diazepam administered in organic solvent. Midazolam is a hypnotic-sedative drug with anxiolytic and marked amnestic properties. To date it has been used mostly by the intravenous route, for sedation in dentistry and endoscopic procedures and as an adjunct to local anaesthetic techniques. It has proved less reliable than thiopentone, but preferable to diazepam, as an intravenous induction agent and is unlikely to replace the other well established drugs. However, due to the cardiorespiratory stability following its administration, midazolam is useful for anaesthetic induction in poor-risk, elderly and cardiac patients. The short elimination half-life (1.5-3.5h) and the absence of clinically important long acting metabolites make midazolam suitable for long term infusion as a sedative and amnestic for intensive care, but clinical trials have yet to be completed. Thus, a combination of properties make midazolam a useful addition to the benzodiazepine group.

Midazolam. A review of its pharmacological properties and therapeutic use

Midazolam is a 1,4-benzodiazepine derivative with a unique chemical structure: depending on environmental pH, the drug can produce highly water-soluble salts (pH less than 4) or exist in lipophilic diazepine ring-closed form (pH greater than 4). This characteristic contributes to rapid onset of action and to good local tolerance after parenteral administration. After both oral and parenteral administration, midazolam has a fast absorption rate and is rapidly excreted, with a half-life of only about 2 hours. A reasonably good correlation has been found between plasma levels and clinical effects, indicating a fast but brief response. As a hypnotic, midazolam is mainly indicated in insomniac patients with difficulties in falling asleep or having a pathologic sleep pattern during the first half of the night. No marked hangover effects are present the next morning. In anesthesiology, midazolam appears to be a useful, short-acting, sedative-anxiolytic and amnesic premedicant after both oral and parenteral administration. In minor surgery, however, the slow, unpredictable onset and variable duration of action, as compared with thiopental, may inhibit its routine use as an induction agent, especially in young patients, without heavy premedication. In major surgery, midazolam is an alternative to thiopental for induction of anesthesia in spite of its slow, variable induction time. Its advantages include good cardiovascular stability, transient and mild respiratory depression, low frequency of venous irritation, production of anterograde amnesia and short duration of action in comparison with other benzodiazepines.

https://accpjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/j.1875-9114.1985.tb03411.x

Midazolam: The First Water-soluble Benzodiazepine; Pharmacology, Pharmacokinetics and Efficacy in Insomnia and Anesthesia

Background: Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine. Objectives: The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport. Methods: A search of the National Library of Medicine PubMed was done with terms such as chronic renal failure, cytochrome P450 [CYP], liver metabolism, efflux drug transport and uptake transport, including relevant articles back to 1969. Results: Animal studies in CRF have shown a significant downregulation (40 – 85%) of hepatic and intestinal CYP metabolism. High levels of parathyroid hormone, cytokines and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein and organic anion transporting polypeptide are also affected. Conclusion: CRF alters intestinal, renal and hepatic drug metabolism and t...

The effect of chronic renal failure on drug metabolism and transport

Critically ill patients exhibit a range of organ dysfunctions and often require treatment with a variety of drugs including sedatives, analgesics, neuromuscular blockers, antimicrobials, inotropes and gastric acid suppressants. Understanding how organ dysfunction can alter the pharmacokinetics of drugs is a vital aspect of therapy in this patient group. Many drugs will need to be given intravenously because of gastrointestinal failure. For those occasions on which the oral route is possible, bioavailability may be altered by hypomotility, changes in gastrointestinal pH and enteral feeding. Hepatic and renal dysfunction are the primary determinants of drug clearance, and hence of steady-state drug concentrations, and of efficacy and toxicity in the individual patient. Oxidative metabolism is the main clearance mechanism for many drugs and there is increasing recognition of the importance of decreased activity of the hepatic cytochrome P450 system in critically ill patients. Renal failure is equally important with both filtration and secretion clearance mechanisms being required for the removal of parent drugs and their active metabolites. Changes in the steady-state volume of distribution are often secondary to renal failure and may lower the effective drug concentrations in the body. Failure of the central nervous system, muscle, the endothelial system and endocrine system may also affect the pharmacokinetics of specific drugs. Time-dependency of alterations in pharmacokinetic parameters is well documented for some drugs. Understanding the underlying pathophysiology in the critically ill and applying pharmacokinetic principles in selection of drug and dose regimen is, therefore, crucial to optimising the pharmacodynamic response and outcome.

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Pharmacokinetics of Drugs Used in Critically Ill Adults

The pharmacokinetics of midazolam and its metabolite, 1-OH midazolam, were studied in six critically ill patients during and after a continuous intravenous infusion of midazolam. Four patients had an increased elimination half-life of midazolam; two were associated with a reduction in plasma clearance with low plasma concentrations of the metabolite, and two with normal metabolite levels and increased volume of distribution. The two patients with reduced clearance suffered from septic shock and were studied over a longer period. Their altered clearance was due to a reduced capability to form the 1-OH metabolite. As their condition improved, plasma concentrations of 1-OH midazolam increased and midazolam clearance returned towards normal. The impaired ability of critically ill patients with septic shock to metabolise midazolam, may be due to reduced organ perfusion and may lead to cumulation of midazolam in these patients.

Failure of critically ill patients to metabolise midazolam.

Fifteen patients with chronic renal failure (CRF) were given midazolam 02 mg/kg iv over 15 s All but one lost consciousness in a time ranging from 22-100 s (mean +/- SD was 55 +/- 26 s) after drug administration Patients regained consciousness from 6-105 min (mean 53 +/- 32) after drug administration The calculated mean plasma level of midazolam at arousal was 81 +/- 47 ng/ml Pharmacokinetics parameters were determined from midazolam plasma levels measured in 16 consecutive venous blood samples The pharmacokinetic parameters in CRF patients were compared with those of healthy volunteers matched for age, sex, and body size with the CRF patients Protein binding was determined by equilibrium dialysis CRF patients had a significantly higher (P less than 0005) plasma-free drug fraction (65% +/- 07) compared with the control patients (39% +/- 01) Total (bound plus unbound) kinetics differed in the two groups: volume of distribution 38 +/- 3 1/kg in CRF patients versus 22 +/- 2 1/kg in controls (P less than 0001), and clearance 114 +/- 16 ml X min-1 X kg-1 in CRF patients versus 67 +/- 09 ml X min-1 X kg-1 in controls (P less than 002) When kinetic parameters were corrected for protein binding, CRF patients unbound volume of distribution (635 +/- 68 1/kg) and free drug clearance (189 +/- 29 ml X min-1 X kg-1) were not different from the control group's volume of distribution (556 +/- 57 1/kg) and free drug clearance (176 +/- 24 ml X min-1 X kg-1)(ABSTRACT TRUNCATED AT 250 WORDS)

J G Reves

Papers

The pharmacokinetics of midazolam in chronic renal failure patients.