Pharmacology

All benzodiazepines have hypnotic, sedative, anxiolytic, amnesic, anticonvulsant, and centrally produced muscle relaxant properties. The drugs differ in their potency and efficacy with regard to each of the pharmacodynamic actions. The chemical structure of each drug dictates its particular physicochemical properties and pharmacokinetics, as well as its receptor binding characteristics. Binding of benzodiazepines to their respective receptors is of high affinity and is stereospecific and saturable; the order of receptor affinity (and thus potency) of the three agonists is lorazepam > midazolam > diazepam. Midazolam is approximately 3 to 6 times ^[40] and lorazepam 5 to 10 times as potent as diazepam.

The mechanism of action of benzodiazepines is reasonably well understood.^{[371] [372] [373]} The interaction of ligands with the benzodiazepine receptor represents one of the few examples in which the complex systems of biochemistry, molecular pharmacology, genetic mutations, and clinical behavioral patterns can be explained. More is understood about the mechanism of action of benzodiazepines than about the mechanism of many other general anesthetics. Through recent genetic studies the GABA_A subtypes have been found to mediate the different effects (amnesic, anticonvulsant, anxiolytic, and sleep).^[373] Sedation, anterograde amnesia, and anticonvulsant properties are mediated through α₁ -receptors, ^[373] and anxiolysis and muscle relaxation are mediated by the α₂ GABA_A receptor.^[373] Drug effect is a function of the blood level. By using plasma concentration data and pharmacokinetic simulations, it has been estimated that a benzodiazepine receptor occupancy rate of less than 20% may be sufficient to produce the anxiolytic effect, sedation is observed with 30% to 50% receptor occupancy, and unconsciousness requires 60% or higher occupation of benzodiazepine agonist receptors.^[374]

It is agreed that benzodiazepines exert their general effects by occupying the benzodiazepine receptor that modulates GABA, the major inhibitory neurotransmitter in the brain. GABA-adrenergic neurotransmission counter-balances the influence of excitatory neurotransmitters. Benzodiazepine receptors are found in highest density in the olfactory bulb, cerebral cortex, cerebellum, hippocampus, substantia nigra, and inferior colliculus, but lower densities are found in the striatum, lower portion of the brainstem, and spinal cord. Although there are two GABA receptors, the benzodiazepine receptor is part of the GABA_A receptor complex on the subsynaptic membrane of the effector neuron. This receptor complex is made up of three protein subunits—α, β, and γ—arranged as a pentameric glycoprotein complex ( Fig. 10-14 ). These proteins contain the various ligand binding sites of the GABA_A receptor, such as the benzodizepine, GABA, and barbiturate binding sites. The benzodiazepine binding

Figure 10-14 Model of the γ-aminobutyric acid (GABA)-benzodiazepine receptor complex. Current data suggest a pentameric protein composed of α-, β-, and γ-subunits; the proposed arrangement of subunits is arbitrary. There are two sites for GABA binding (on the β-subunits) and a single site for benzodiazepine (BDZ) binding (depicted on the γ₂ -subunit). Homology between the GABA_α receptor and the nicotinic acetylcholine receptor suggests that the chloride ion channel is formed by contributions from each subunit. (Redrawn with modification from Zorumski CF, Isenberg KE: Insights into the structure and function of GABA-benzodiazepine receptors: Ion channels and psychiatry. Am J Psychiatry 148:162, 1991.)

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A fascinating and therapeutically significant discovery regarding the benzodiazepine receptor is that the pharmacologic spectrum of ligands includes three different types or classes^[371] that have been termed agonists, antagonists, and inverse agonists ( Fig. 10-15 ), names that connote their actions. Agonists (e.g., midazolam) alter the conformation of the GABA_A receptor complex so that binding affinity for GABA is increased, with resultant opening of the chloride channel. Agonists and antagonists bind to a common (or at least overlapping) area of the receptor by forming differing reversible bonds with the receptor.^[377] The well-known effects of an agonist then occur (anxiolysis, hypnosis, and anticonvulsant action). Antagonists (e.g., flumazenil) occupy the benzodiazepine receptor, but they produce no activity and therefore block the actions of both agonists and inverse agonists. Inverse agonists reduce the efficiency of GABA-adrenergic synaptic transmission, and because GABA is inhibitory, the result of decreased GABA is CNS stimulation. The potency of

Figure 10-15 Spectrum of the intrinsic activities of benzodiazepine receptor ligands, which range from agonists to inverse agonists. Structures of agonist, partial agonist, antagonist, partial inverse agonist, and inverse agonist compounds are shown. Intrinsic activity is greatest among agonists and is least among inverse agonists. Intrinsic activities are schematically indicated as positive by a plus sign and as negative by a minus sign, with 0 indicating a lack of intrinsic activity. (Redrawn with modification from Mohler H, Richards JG: The benzodiazepine receptor: A pharmacological control element of brain function. Eur J Anaesthesiol Suppl 2:15–24, 1988.)

Long-term administration of benzodiazepines produces tolerance, which is defined as a decrease in efficacy of the drug over time.^[378] Although the mechanism of chronic tolerance is not fully understood, it appears that long-term exposure to benzodiazepines causes decreased receptor binding and function (i.e., downregulation of the benzodiazepine-GABA_A receptor complex). This decrease would explain the increased dose requirements of benzodiazepines for anesthesia in patients who take them on a long-term basis. Interestingly, it appears that after the cessation of long-term use of benzodiazepines, the receptor complex becomes upregulated,^[378] which could mean an increased susceptibility to benzodiazepines during a period after recent use.

The onset and duration of action of a bolus intravenous dose of a benzodiazepine depend on the lipid solubility of the drug, a finding that probably explains the differences in onset and duration of action of the three benzodiazepines used in clinical practice in the United States. Midazolam and diazepam have a more rapid onset of action (usually within 30 to 60 seconds) than lorazepam does (60 to 120 seconds). The half-life of equilibrium between the plasma concentration and the EEG effect of midazolam is approximately 2 to 3 minutes and is not affected by age.^[379] This half-life is about two times longer than that of diazepam, but when compared with diazepam, midazolam has sixfold greater intrinsic potency.^[40] Similar data

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Effects on the Central Nervous System (see Chapter 21 )

The benzodiazepines reduce CMRO₂ and CBF in a dose-related manner. Midazolam and diazepam maintain a relatively normal ratio of CBF to CMRO₂ . In healthy human volunteers, midazolam, 0.15 mg/kg, induces sleep and reduces CBF by 34% despite a slight increase in PaCO₂ from 34 to 39 mm Hg.^[381] Brown and colleagues ^[382] studied EEG tracings after 10 mg intravenous midazolam and showed the appearance of rhythmic beta activity at 22 Hz within 15 to 30 seconds of administration in healthy volunteers. Within 60 seconds, a second beta rhythm occurred at 15 Hz. Alpha rhythm started to reappear at 30 minutes; however, after 60 minutes, resistant rhythmic beta activity was noted at 15- to 20-µV amplitude. The EEG changes were similar to the EEG effects with diazepam and were not typical of light sleep, although the patients were clinically asleep. The best method of monitoring depth with midazolam is use of the EEG BIS index.^[383]

Midazolam, diazepam, and lorazepam all increase the seizure initiation threshold of local anesthetics and lower the mortality rate in mice exposed to lethal doses of local anesthetics.^[384] Midazolam and diazepam induce a dose-related protective effect against cerebral hypoxia, which was demonstrated by extension of mouse survival time when mice were placed in 5% oxygen. The protection afforded by midazolam is superior to that of diazepam but less than that of pentobarbital.^[384] Antiemetic effects are not a prominent action of the benzodiazepines.

Effects on the Respiratory System

Benzodiazepines, like most intravenous anesthetics, produce dose-related central respiratory system depression. The respiratory depression may be greater with midazolam than with diazepam and lorazepam, although comparative studies of the three do not exist. Lorazepam (2.5 mg intravenously [IV]) produces a similar, but shorter-lasting decrease in tidal volume and minute ventilation than diazepam (10 mg IV) does in patients with lung disease.^[385] The peak decrease in minute ventilation after midazolam (0.15 mg/kg) is almost identical to that produced in healthy patients given diazepam (0.3 mg/kg), as determined by carbon dioxide response data.^[386] The slopes of the ventilatory response curves to carbon dioxide are flatter than normal (control) but not shifted to the right, as with opioids. Judging from the plasma level and steepness of the dose-response effect on PaCO₂ curves ( Fig. 10-16 ),^[387] midazolam is about five to nine times as potent as diazepam. The peak onset of ventilatory depression with midazolam (0.13 to 0.2 mg/kg) is rapid (about 3 minutes), and significant depression remains for about 60 to 120 minutes.^{[348] [388]} The rate of midazolam administration affects the time of onset of peak ventilatory depression; the faster the drug is given, the more quickly this peak depression occurs.^[388] The respiratory depression associated with midazolam is more pronounced and of longer duration in patients with chronic obstructive pulmonary disease, and the duration of ventilatory depression is longer with midazolam (0.19 mg/kg) than with thiopental (3.3 mg/kg).^[348] Lorazepam (0.05 mg/kg) alone does not depress the carbon dioxide response, but when lorazepam is combined with meperidine, predictable respiratory depression occurs.^[389] It is probable that benzodiazepines and opioids produce additive or supra-additive (synergistic) respiratory depression, even though they act at different receptors.

Figure 10-16 A, Increase in PaCO₂ from baseline versus plasma concentration after three intravenous bolus doses of diazepam (0.15 mg/kg) given at 20-minute intervals. B, Increase in PaCO₂ from baseline versus the midazolam plasma concentration after three intravenous bolus doses of midazolam (0.05 mg/kg) given at 20-minute intervals. The solid line represents a best-fit model of the data from the three injections. Mean values are represented as plus or minus standard error of the mean. (Redrawn from Sunzel M, Paalzow L, Berggren L, Eriksson I: Respiratory and cardiovascular effects in relation to plasma levels of midazolam and diazepam. Br J Clin Pharmacol 25:561–569, 1988.)

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Apnea occurs with the benzodiazepines. The incidence of apnea after induction of anesthesia with thiopental or midazolam is similar. Apnea occurred in 20% of 1130 patients given midazolam for induction and 27% of 580 patients given thiopental in clinical trials with midazolam.^[359] Apnea is related to the dose of the benzodiazepine and is more likely to occur in the presence of opioids. Old age, debilitating disease, and other respiratory depressant drugs probably also increase the incidence and degree of respiratory depression and apnea with benzodiazepines.

Effects on the Cardiovascular System

Used alone, the benzodiazepines have modest hemodynamic effects. The hemodynamic changes reported with anesthetic induction doses of diazepam, midazolam, and lorazepam are shown in Table 10-2 . These values represent the peak hemodynamic effect in the first 10 minutes after administration and are derived from studies of both healthy subjects and patients with ischemic and valvular heart disease.^{[169] [170] [184] [331] [390]} The predominant hemodynamic change is a slight reduction in arterial blood pressure that results from a decrease in systemic vascular resistance. The mechanism by which benzodiazepines maintain relatively stable hemodynamics involves the preservation of homeostatic reflex mechanisms,^[341] but some evidence indicates that the baroreflex is impaired by both midazolam and diazepam. ^[391] Midazolam causes a slightly greater decrease in arterial blood pressure than the other benzodiazepines do, but the hypotensive effect is minimal and about the same as seen with thiopental.^[185] Despite the hypotension, midazolam, even in doses as high as 0.2 mg/kg, is safe and effective for induction of anesthesia even in patients with severe aortic stenosis. The hemodynamic effects of midazolam and diazepam are dose related: the higher the plasma level, the greater the decrease in systemic blood pressure^[387] ; however, there is a plateau plasma drug effect above which little change in arterial blood pressure occurs. The plateau plasma level for midazolam is 100 ng/mL, and that for diazepam is about 900 ng/mL.^[387] Heart rate, ventricular filling pressure, and cardiac output are maintained after induction of anesthesia with the benzodiazepines. In patients with elevated left ventricular filling pressure, diazepam and midazolam produce a "nitroglycerin-like" effect by low-ering the filling pressure and increasing cardiac output.

The stresses of endotracheal intubation and surgery are not blocked by midazolam.^[169] Thus, adjuvant anesthetics,

TABLE 10-9 -- Uses and doses of intravenous benzodiazepines

	Midazolam	Diazepam	Lorazepam
Induction	0.05–0.15 mg/kg	0.3–0.5 mg/kg	0.1 mg/kg
Maintenance	0.05 mg/kg prn	0.1 mg/kg prn	0.02 mg/kg prn
	1.0 µg/kg/min
Sedation *	0.5–1.0 mg repeated	2 mg repeated	0.25 mg repeated
	0.07 mg/kg IM
prn, as required to keep the patient hypnotic and amnestic.

*Incremental doses are given until the desired degree of sedation is obtained.