Page 468 - Basic _ Clinical Pharmacology ( PDFDrive )

454 SECTION V Drugs That Act in the Central Nervous System

Clinical Uses & Dosage a ceiling effect for benzodiazepine-induced decreases in CMRO 2 as
evidenced by midazolam’s inability to produce an isoelectric EEG.
The principal clinical use of thiopental (3–5 mg/kg IV) or metho- Patients with decreased intracranial compliance demonstrate little or
hexital (1–1.5 mg/kg IV) is for induction of anesthesia (uncon- no change in ICP after the administration of midazolam. Although
sciousness), which usually occurs in less than 30 seconds. Patients neuroprotective properties have not been shown for benzodiaze-
may experience a garlic or onion taste after administration. Solu- pines, these drugs are potent anticonvulsants used in the treatment of
tions of thiopental sodium for intravenous injection have a pH status epilepticus, alcohol withdrawal, and local anesthetic-induced
range of 10–11 to maintain stability. Rapid co-injection with seizures. The CNS effects of benzodiazepines can be promptly
depolarizing and nondepolarizing muscle relaxants, which have terminated by administration of the selective benzodiazepine antago-
much lower pH, may cause precipitation of insoluble thiopentone nist flumazenil, which improves their safety profile.
acid. Barbiturates such as methohexital (20–30 mg/kg) may be
administered per rectum to facilitate induction of anesthesia in B. Cardiovascular Effects
mentally challenged patients and uncooperative pediatric patients.
When a barbiturate is administered with the goal of neuroprotec- If used for the induction of anesthesia, midazolam produces a
tion, an isoelectric EEG indicating maximal reduction of CMRO greater decrease in systemic blood pressure than comparable doses
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has traditionally been used as the end point. More recent data of diazepam. These changes are most likely due to peripheral
demonstrating equal protection after smaller doses have chal- vasodilation inasmuch as cardiac output is not changed. Similar
lenged this practice. The use of smaller doses is less frequently to other intravenous induction agents, midazolam’s effect on sys-
associated with hypotension, thus making it easier to maintain temic blood pressure is exaggerated in hypovolemic patients.
adequate cerebral perfusion pressure, especially in the setting of
increased ICP. C. Respiratory Effects
Benzodiazepines produce minimal depression of ventilation,
although transient apnea may follow rapid intravenous admin-
BENZODIAZEPINES istration of midazolam for induction of anesthesia, especially in
the presence of opioid premedication. Benzodiazepines decrease
Benzodiazepines commonly used in the perioperative period the ventilatory response to carbon dioxide, but this effect is
include midazolam, lorazepam, and less frequently, diazepam. not usually significant if they are administered alone. More
Benzodiazepines are unique among the group of intravenous severe respiratory depression can occur when benzodiazepines are
anesthetics in that their action can readily be terminated by administered together with opioids. Another problem affecting
administration of their selective antagonist, flumazenil. Their ventilation is airway obstruction induced by the hypnotic effects
most desired effects are anxiolysis and anterograde amnesia, which of benzodiazepines.
are extremely useful for premedication.
The chemical structure and pharmacodynamics of the benzo- D. Other Effects
diazepines are discussed in detail in Chapter 22. Pain during intravenous and intramuscular injection and subse-
quent thrombophlebitis are most pronounced with diazepam and
Pharmacokinetics in the Anesthesia reflect the poor water solubility of this benzodiazepine, which
Setting requires an organic solvent in the formulation. Despite its bet-
ter solubility (which eliminates the need for an organic solvent),
The highly lipid-soluble benzodiazepines rapidly enter the CNS, midazolam may also produce pain on injection. Allergic reactions
which accounts for their rapid onset of action, followed by redis- to benzodiazepines are rare to nonexistent.
tribution to inactive tissue sites and subsequent termination of the
drug effect. Additional information regarding the pharmacokinet- Clinical Uses & Dosage
ics of the benzodiazepines may be found in Chapter 22.
Despite its prompt passage into the brain, midazolam is con- Benzodiazepines are most commonly used for preoperative medi-
sidered to have a slower effect-site equilibration time than propo- cation, intravenous sedation, and suppression of seizure activity.
fol and thiopental. In this regard, intravenous doses of midazolam Less frequently, midazolam and diazepam may also be used to
should be sufficiently spaced to permit the peak clinical effect to induce general anesthesia. The slow onset and prolonged dura-
be recognized before a repeat dose is considered. Midazolam has tion of action of lorazepam limit its usefulness for preoperative
the shortest context-sensitive half-time, which makes it the only medication or induction of anesthesia, especially when rapid and
one of the three benzodiazepine drugs suitable for continuous sustained awakening at the end of surgery is desirable. Although
infusion (Figure 25–8). flumazenil (8–15 mcg/kg IV) may be useful for treating patients
experiencing delayed awakening, its duration of action is brief
Organ System Effects (about 20 minutes) and resedation may occur.
The amnestic, anxiolytic, and sedative effects of benzodi-
A. CNS Effects azepines make this class of drugs the most popular choice for
Benzodiazepines decrease CMRO and cerebral blood flow but to a preoperative medication. Midazolam (1–2 mg IV) is effective
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smaller extent than propofol or the barbiturates. There appears to be for premedication, sedation during regional anesthesia, and brief