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Midazolam

A Review of its Pharmacological Properties and Therapeutic Use

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Summary

Synopsis: Midazolam1 is a short-acting water-soluble benzodiazepine (at pH < 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.

Pharmacodynamic Studies: Midazolam, in common with other benzodiazepines, is an anxiolytic and sedative with about twice the sedative potency of diazepam. It also has anticonvulsant, sleep inducing, and muscle relaxant properties and powerful anterograde amnestic action similar to that of diazepam but not that of lorazepam, whose amnestic action is slow and prolonged. Seven to 9 hours following midazolam, patients feel more awake and have better psychomotor performance than after an equivalent dose of diazepam or lorazepam. When used in higher dosage for induction of anaesthesia, there is considerable interindividual variation in response, especially in the young. Variations in binding to protein and to benzodiazepine receptor sites may be partially responsible for this.

Midazolam causes minimal changes in cardiorespiratory function. A small increase in heart rate and a decrease in systemic vascular resistance seen especially in people with high vascular tone (hypertensive, hypovolaemic and emotionally stressed) are usually apparent. The reduction in preload and afterload may improve performance in the failing heart. In therapeutic doses a change occurs in respiratory pattern, with a decrease in tidal volume and increase in frequency. The abdominal contribution to respiration is depressed with preservation of the thoracic component.

Midazolam reduces the adrenergic but not the cortisol or renin response to surgical stress. Blood flow to the liver and kidneys decreases but flow to brain and myocardium is preserved with no changes in myocardial or cerebral oxygen consumption.

Pharmacokinetic Studies: Following intravenous administration of midazolam the drug is rapidly distributed (t1/2α = 15 min). After single oral doses of midazolam 10 to 40mg peak plasma concentrations are usually attained within 30 minutes. Systemic availability averages 44% after a 15mg dose, this low value being explained by first-pass hepatic extraction. Midazolam is 80 to 100% absorbed after intramuscular injection.

The volume of distribution (0.8 to 1.5 L/kg) is higher in women than in men, in the obese than in non-obese and in elderly than in young subjects. Midazolam is extensively bound to plasma proteins (about 96%) and factors influencing binding alter the free fraction. Midazolam, a high-clearance drug whose elimination is partly dependent on hepatic perfusion, is eliminated almost exclusively by biotransformation, and the principal metabolite (α-hydroxymidazolam) is rapidly conjugated to a glucuronide. Total body clearance is much greater than that of diazepam, and elimination half-life is generally 1.5 to 3.5 hours.

Therapeutic Trials: Midazolam has been studied mostly as an intravenous sedative-hypnotic for use with local anaesthesia and in higher dosages as an induction agent for general anaesthesia. It has also been studied as an hypnotic when administered orally or as a preanaesthetic medication when given intramuscularly.

In comparative studies, midazolam 0.05 to 0.12 mg/kg was as useful as diazepam 0.057 to 0.2 mg/kg in producing satisfactory sedation and operating conditions in patients undergoing gastroscopy, cystoscopy, cardiac catheterisation and spinal anaesthesia. The onset of effect was usually more rapid with midazolam and the degree of amnesia greater with midazolam than with diazepam, but the onset of effect with midazolam in unpremedicated patients varies between individuals. Verbal contact was not lost and recovery time was generally similar with both drugs but fewer patients experienced injection pain with midazolam.

Many investigators have compared midazolam and thiopentone for the induction of general anaesthesia but their opinions of its usefulness have varied. Induction time has invariably been greater with midazolam than with thiopentone, and the interindividual variation in induction time has also been greater with midazolam, particularly in unpremedicated patients. However, when preceded by narcotic premedication, especially fentanyl, midazolam becomes a more predictable induction agent. Apnoea has generally occurred less frequently with midazolam than with thiopentone in lightly premedicated patients; cardiovascular changes tended to be fewer with midazolam. However, recovery time has usually been greater with midazolam. Although the level of sedation with midazolam was variable, patients accepted inhalation agents readily and the transition was smooth. Excitatory induction complications seldom occurred. Some investigators thus considered that midazolam 0.15 to 0.36 mg/kg compared favourably with thiopentone 3 to 6.4 mg/kg, provided the delayed induction was acceptable, while others considered that it was not sufficiently reliable for use as a routine induction agent, but useful in elderly and ‘poor risk patients’ and for cardiac operations because of its minimal cardiorespiratory depression.

As midazolam, unlike diazepam, is well absorbed following intramuscular administration it has been studied as a preanaesthetic medication when given by this route. Midazolam 0.07 and 0.08 mg/kg has generally produced better quality sedation, more amnesia, a more marked antianxiety effect and caused less injection pain than hydroxyzine 1 to 1.5 mg/kg.

Side Effects: Side effects with midazolam are usually confined to occasional reports of nausea after intramuscular or intravenous administration and slight changes in arterial blood pressure, heart rate and respiration. Rapid intravenous administration of doses used to induce anaesthesia generally produce apnoea of short duration in fewer patients than does thiopentone. Local effects on veins are infrequent, although pain on injection and thrombophlebitis occur occasionally.

Dosage and Administration: Dosage should be titrated according to patient response, but as a guide, midazolam 0.07 to 0.1 mg/kg is usually given for intravenous sedation and 0.15 to 0.3 mg/kg for induction of anaesthesia; 0.07 to 0.08 mg/kg is used for intramuscular preoperative sedation.

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Authors and Affiliations

  1. Department of Anaesthetics, The Queen’s University of Belfast, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland

    J. W. Dundee, N. J. Halliday, K. W. Harper & R. N. Brogden

  2. ADIS Drug Information Services, Auckland, New Zealand

    J. W. Dundee, N. J. Halliday, K. W. Harper & R. N. Brogden

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  1. J. W. Dundee
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Various sections of the manuscript reviewed by: M.E.Crawford, Department of Anesthesiology, Kobenhavns Amts Sygenhus I Herler, Denmark; M.J. Eadie, Department of Medicine, University of Queensland, Royal Brisbane Hospital, Brisbane, Australia; R.J. Fragen, Department of Anesthesia, Northwestern University, Chicago, Illinois, USA; D.J. Greenblatt, Division of Clinical Pharmacology, Tufts-New England Medical Center, Boston, Massachusetts, USA; I Hindmarch, Human Psychopharmacology Research Unit, The University of Leeds, England; C. McK. Holmes, Department of Anaesthesia, Medical School, University of Otago, Dunedin, New Zealand; S. Jensen, Department of Anaesthesia, Arhus Kommunehospital, Arhus, Denmark; A. Kales, Department of Psychiatry and Sleep Research and Treatment Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; J. Kanto, Department of Anaesthesiology, Turku University Central Hospital, Turku, Finland; U. Klotz, Dr Margarete Fischer-Bosch-Institut, Stuttgart, West Germany; J.G. Reves, Department of Anesthesiology, University of Alabama in Birmingham, Alabama, USA; S. Sjövall, Department of Anaesthesiology, Turku University Central Hospital, Turku, Finland; M.T. Smith, Department of Medicine, University of Queensland, Royal Brisbane Hospital, Brisbane, Queensland, Australia; CR. Soldatos, Department of Psychiatry and Sleep Research Unit, Athens University Medical School, Athens, Greece.

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Dundee, J.W., Halliday, N.J., Harper, K.W. et al. Midazolam. Drugs 28, 519–543 (1984). https://doi.org/10.2165/00003495-198428060-00002

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