25: Pharmacology

chapter 25 Pharmacology

A variety of drugs are available for intravenous (IV) sedation. These include a number of categories, primarily sedative-hypnotics, opioids, and anticholinergics. The drugs most commonly used in IV moderate sedation are listed in Box 25-1. Also listed in Box 25-1 are several drugs (indicated by ‡) that are not recommended for IV use by dentists who have not completed a 2-year residency in anesthesiology. These drugs are discussed briefly so that the dentist may more fully understand the rationale for their not being recommended. Other drugs, such as the barbiturates, which at one time were the drugs of choice in IV sedation, have fallen from favor as newer, safer, and more effective drugs have been introduced. Discussion of the barbiturates has been minimized. For a more in-depth discussion of these drugs, the reader is directed to previous editions of this textbook.

BENZODIAZEPINES

The benzodiazepines have become the most commonly used IV sedative drugs in both dentistry and medicine. Four benzodiazepines are discussed (Table 25-1); three of them are presently available in the United States, whereas one (flunitrazepam) is available in many other countries.

Diazepam

Diazepam was synthesized in 1959 by Sternbach and Reeder. The drug became available as Valium (Hoffmann-LaRoche) in 1963 and shortly thereafter became the most prescribed oral drug in the Western world.1 Diazepam is also available in a parenteral preparation for intramuscular (IM) (see Chapter 10) and IV use. Diazepam was originally approved by the Food and Drug Administration (FDA) in November 1963.

IV administration of diazepam appears to have begun with the work of Davidau2 in Paris in 1965. This was followed shortly thereafter by a report by Main3 in 1967, who used diazepam as an adjunct to the Jorgensen technique. In 1968, Brown reported on 40 cases in which diazepam was used alone, with the drug administered until the patient felt sleepy.4

In 1969, O’Neill and Verrill5 reported on the use of IV diazepam for sedation in minor oral surgical procedures, with good to excellent results in 51 of 52 patients treated. In 1970, O’Neill et al reported on 55 patients undergoing dental surgical procedures lasting between 20 and 45 minutes. IV diazepam provided successful sedation and cooperation in 49 patients; four others moved and spoke occasionally, but were able to be treated, and two patients required additional IV medications (methohexital) for treatment to be completed successfully.6

The dosage used in these patients was that required to produce marked ptosis (drooping of the upper eyelid; Figure 25-1). Halfway ptosis of the upper eyelid is now recognized as the Verrill sign.7 The practice of administering diazepam until the appearance of the Verrill sign produces a level of sedation (central nervous system [CNS] depression) that is considered by many to be more profound than is usually necessary and is therefore not recommended for routine use.8

Peter Foreman,9 in New Zealand, used diazepam in combination with atropine and incremental doses of methohexital. Although successful, he stated that the addition of even small amounts of methohexital greatly increased the risk of overdose. In a subsequent study, Foreman used diazepam alone for a variety of dental therapies finding that although the degree of amnesia produced by diazepam varied significantly from patient to patient, virtually all patients agreed that dental treatment had been at least tolerable rather than an ordeal. He found that IV diazepam had made it possible to treat those patients who may not have received proper treatment in the past because of fear. Foreman stated, “Diazepam has become the drug of choice for the trained general dental practitioner, as well as for the introduction of dental students to intravenous sedation.”10

With the introduction of midazolam into clinical practice, the use of IV moderate sedation with diazepam has decreased. However, as discussed in Chapter 26, there are still occasions to consider diazepam as a first-line agent for IV moderate sedation.

General Pharmacology

It is believed that emotions are largely controlled by the limbic system (i.e., the portion of the brain composed of the amygdala, hippocampus, and septal areas).12 The midbrain reticular formation, hypothalamus, and thalamus are also involved with the experience or transmission of emotions.

In very small doses, diazepam appears to act on the hippocampus, whereas other areas of the brain remain unaffected and the patient remains alert.13 Following oral administration of diazepam, this action of the drug would be appropriate; however, when diazepam is administered intravenously, a greater effect is normally desirable. Administered to the point at which sedation and ataxia (loss of muscular coordination) occur, a more generalized depression of the CNS is observed.

Research suggests that the anxiolytic properties of benzodiazepines are mediated by increased inhibitory nerve transmission.14 γ-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the brain. Glycine (aminoacetic acid), the simplest nonessential amino acid, may be the major inhibitory transmitter of the spinal cord. The anticonvulsant and sedative properties of benzodiazepines may result from a direct agonist effect on stereospecific benzodiazepine receptors, which in turn facilitate the inhibitory action of GABA on its own postsynaptic receptors.

Fate of Intravenous Diazepam

Following IV administration, diazepam reaches a peak blood level in approximately 1 to 2 minutes. The onset of clinical activity is therefore quite rapid.15 Blood levels of approximately 1.0 µg/ml may be achieved after an IV dose of 10 to 20 mg of diazepam.16 Clinically, this would equate with a deeper level of moderate sedation (not deep sedation) and a period of anterograde amnesia.

As mentioned in Chapters 7 and 10, diazepam has a plasma half-life of approximately 30+ hours.17 A commonly held misconception is that a drug with a long half-life will possess a long duration of action, whereas one with a shorter half-life will have a shorter duration of action. This is untrue, and diazepam is an excellent example of this. The β-half-life is an indicator of the rate at which a drug undergoes biotransformation (in the liver for diazepam), whereas the factor most responsible for a drug’s duration of action is its degree of receptor-site (protein) binding.

Over a period of approximately 45 minutes following titration of an appropriate dose of diazepam, the patient will remain sedated and free of anxiety. In many patients, the following distinct phases of sedation can be observed, each lasting approximately 15 minutes.

Phase 4: 46 to 60 minutes. 

At this time after receiving diazepam, virtually all patients will feel and look recovered. This is not a result of the β-half-life of the drug (30+ hours), but because of redistribution: α-half-life. The blood level of diazepam at 60 minutes after IV administration of 20 mg is 0.25 µg/ml.16 The patient is not recovered at this time. Under no circumstances should the dentist ever believe that this patient is capable of operating a car or leaving the dental or surgical office unescorted.

As redistribution of diazepam continues during this first hour after IV administration, the level of the drug increases in several storage sites including: fat, the walls of the intestines, and the gallbladder. Diazepam stored in fat will usually remain there because diazepam is quite lipid soluble and the blood supply of fat is quite poor.

A clinically significant phenomenon can arise at this point, a result of the diazepam stored in the gallbladder and intestinal walls. Known as the rebound effect or second-peak effect, it involves a recurrence of symptoms of sedation and drowsiness approximately 1 hour after the first meal taken after the patient leaves the treatment site.18 In most cases, this will occur about 4 to 6 hours following the drug’s administration (start of the procedure). After a meal, particularly one rich in lipids, the gallbladder constricts, releasing its contents of bile and unmetabolized diazepam into the small intestine, where over the next hour or so diazepam is reabsorbed back into the cardiovascular system. In some patients, the diazepam blood level may reach a level at which clinical signs and symptoms of sedation recur: The patient feels quite tired and will want to lie down for a few minutes. It becomes absolutely essential therefore that the patient receiving diazepam and his or her escort be advised of this possibility before their discharge from the dental office. The rebound effect is less likely to be observed in a patient whose gallbladder has been removed.

Because diazepam is extremely lipophilic, it cannot be excreted through the kidneys and therefore must undergo biotransformation in the liver.

Effects of Age and Disease

It is often stated that drug dosages should be decreased in very young and elderly patients in addition to patients with significant liver disease. The pharmacokinetics of diazepam have been well studied in these groups of patients.2023 The following is presented as a summary of that research:

In patients 2 years and older, diazepam is handled as in the adult. The only significant clinical advice is to adjust the dose of the drug appropriately. With titration via the IV route, clinical results are usually achieved at smaller doses than in adults (assuming a cooperative patient—not a very likely situation).

In elderly patients, the dose of diazepam by the IV (or any other) route should be decreased for several reasons. The rate at which the diazepam undergoes biotransformation is decreased in older patients. In addition, when administered orally, the drug is absorbed in the gastrointestinal tract somewhat more slowly. However, the most important reason for the apparent increased sensitivity of older patients to diazepam (and other drugs) is related primarily to protein binding. Older patients exhibit decreased protein binding of drugs.20 This means that there will be more of the free, unbound drug available within the blood to cross the blood-brain barrier and produce CNS depression. Diazepam is offered as an example: In the younger patient, diazepam is approximately 98.5% protein bound.21 Therefore the clinical effects of diazepam are produced by only 1.5% of the dosage administered: the non–protein-bound diazepam. In the older patient in whom protein binding has decreased, diazepam may be 97% protein bound, still a significant figure, but one permitting 3% (or twice as much) non–protein-bound diazepam to be available to produce CNS depression. It becomes obvious that when administered the same dose of the drug, the clinical actions on the older patient will be exaggerated. The dosages of diazepam by the oral and IM routes must be decreased in older patients. With IV administration, titration will provide effective sedation at what will likely be a smaller dose of the drug than is usually given.

Skeletal Muscle Relaxation

Diazepam and other benzodiazepines produce skeletal muscle relaxation. Research has demonstrated that the muscle-relaxant properties of benzodiazepines are caused by central rather than peripheral effects.24 Monosynaptic reflexes, such as the knee jerk, are essentially unaffected by even large doses of diazepam, whereas polysynaptic reflexes are depressed by rather small doses.

Cardiovascular System

Hemodynamic studies show that diazepam produces little effect on the cardiovascular system of healthy human subjects.28 IV diazepam, in a dose of 0.3 mg/kg, produces no clinically significant changes in either blood pressure or cardiac output.

Diazepam has been compared with thiopental as a preanesthetic induction agent in the cardiovascularly compromised patient (American Society of Anesthesiologists [ASA] 3 and 4).29 Administered intravenously in a dose of 0.2 mg/kg, less than 1% of the patients studied experienced a reduction of cardiac output of more than 15%, and none had a mean blood pressure reduction of more than 15%. In contrast, on receiving 2 mg/kg of thiopental, 85% of the patients exhibited more than a 15% reduction in cardiac output, whereas 68% demonstrated more than a 15% reduction in blood pressure. Adverse hemodynamic effects attributable to the benzodiazepines are rare in humans, even in patients with significant cardiac or pulmonary disease.30

Hepatic Disease

Agitation and combativeness are occasionally encountered in patients with liver disease. Murray-Lyon et al33 in a study of patients with severe parenchymal liver disease administered diazepam intravenously.33 Adequate sedation was achieved in all patients with no deterioration of their clinical status. Diazepam, administered with care, is an appropriate sedative for patients with impaired liver function.

Pain

In general, studies have failed to demonstrate specific analgesic properties of the benzodiazepines; however, large doses of these agents will impair motor response to painful stimulation.34 These studies show that benzodiazepines are much more capable of attenuating the emotional response to pain than of altering the actual sensation of pain.

More recent studies have demonstrated that diazepam may possess some slight analgesic properties.35 These findings do not, however, alter the fact that in clinical situations in which pain control is a factor during dental treatment, local anesthetics must still be administered in the usual manner.

Amnesia

Intravenously administered diazepam produces anterograde amnesia (i.e., a lack of recall occurring from the time of injection onward).36 Retrograde amnesia, a lack of recall of events occurring before drug administration, is quite rare. Amnesia after diazepam IM administration is uncommon and is essentially nonexistent after oral administration.

After IV diazepam administration, the duration of the amnesic period is approximately 10 minutes; however, considerable variation is noted. During this time, patients respond normally to stimulation, but at a later time (immediately postoperatively or 24 hours later), they will be unable to recall the event.

In my experience with IV diazepam sedation, amnesia developed in approximately 75% of patients in whom diazepam had been titrated to a clinically adequate level of moderate sedation. The length of amnesia has varied, but it has been limited in most persons to the first 10 to 15 minutes after diazepam administration. In fewer patients, the amnesic effect has lasted through the entire appointment.

The importance of the amnesic phase is that traumatic procedures may be completed with the patient responding normally to them; however, at the end of the procedure, the patient will have no recall of what took place. The most common procedure during this period is the administration of local anesthetic. The patient may respond to the initial administration of the local anesthetic (although administration of local anesthetic should be performed as atraumatically as possible at all times). At the end of the dental or surgical procedure, patients often question their dentist to find out how their lips or tongue became “numb” without a “shot” or “how the drug injected in their arm (diazepam/midazolam) kept them from ‘feeling’ the procedure.” Unfortunately, the amnesic period does not encompass the time period preceding the administration of the benzodiazepine (retrograde amnesia); therefore the patient will almost always recall the venipuncture attempt or attempts.

Although amnesia is usually a welcome benefit of IV moderate sedation, the absence of amnesia does not imply that the procedure was a failure. The primary goal of sedation is relaxation of the patient so that the treatment can be completed in a more ideal manner. The presence or absence of amnesia does not alter this fact. Lack of recall should be considered to be the “icing on the cake.”

Warnings

Probably the most significant side effect of intravenously administered diazepam is the occurrence of venous thrombosis, phlebitis, local irritation, or swelling. Although these complications are rare with the administration of IV diazepam as recommended in Chapter 26, a manufacturer of diazepam recommends the following as a means to minimize this possibility37:

Other warnings include the following:

The administration of IV diazepam as recommended in Chapter 26 takes into account these warnings. Titration will prevent accidental overdose in the preceding situations.

Use in Pregnancy

Any drug that crosses the blood-brain barrier also crosses the placenta, entering into the fetus. An increased risk of congenital malformation associated with the administration of benzodiazepines during the first trimester of pregnancy has been suggested in several studies.38 Because the administration of these drugs in dentistry is rarely a matter of urgency, their use at this time cannot be recommended. The possibility that a woman of childbearing potential may be pregnant at the time diazepam is used should always be considered.

Availability

Valium (Roche): 5 mg/ml in 2-ml ampules, 10-ml multiple-dose vials, and 2-ml preloaded syringe. Injectable diazepam consists of the following ingredients37:

Diazepam is classified as a Drug Enforcement Administration (DEA) Schedule IV drug. Propylene glycol and ethyl alcohol are included because diazepam is lipid soluble and relatively water insoluble; therefore it requires a nonaqueous-solvent system. Many of the complications and side effects attributed to diazepam, especially phlebitis, are in fact produced by the propylene glycol, which is closely related to ethylene glycol, a major component of antifreeze.39

The IV administration of diazepam can produce a sensation of burning in some patients. This is caused not by the diazepam, but by the propylene glycol vehicle. It is recommended that the patient be advised of this possibility as the drug is administered. The dentist will tell the patient, “There may be a feeling of warmth as the drug is administered. This is entirely normal and will pass within a few minutes.” As the drug is carried in venous blood away from the injection site, this sensation fades. Its occurrence may be minimized by opening the IV infusion to a rapid rate before injecting the diazepam. Some persons recommend the administration of 1 ml of 1% lidocaine or procaine into the IV line immediately before the administration of diazepam. The analgesic properties of lidocaine and procaine prevent the burning sensation from occurring. In my experience with diazepam, slow injection of diazepam into a rapidly running infusion prevents this sensation from arising. IV lidocaine administration is not necessary.

Dizac (Ohmeda Pharmaceutical) is diazepam in an emulsion form that does not produce the same burning sensation as is often noted with the diazepam formulation described previously. It is available as 2.5-, 5-, and 10-mg/ml injectable solutions.40

The search for a water-soluble benzodiazepine with clinical properties similar to diazepam but without its potential for venous irritation led to the development of midazolam. Diazepam was, until recently, the most commonly used IV sedative within dentistry. When used as recommended, it is safe and extremely effective in the management of severe apprehension and fear of the dental or surgical situation. IV diazepam is recognized as one of the two “basic” IV moderate sedation techniques in dentistry.

Diazepam

Proprietary name: Dizac, Valium
Classification: benzodiazepine
Availability: 5 mg/ml
Average sedative dose (IV): 10-12 mg
Maximum single dose: 20 mg
Maximum total dose: 30 mg

Diazepam

Pregnancy category D
Lactation NS
Metabolism Liver extensively; active metabolites
Excretion Urine, half-life 30-60 hr
DEA schedule IV

Midazolam

Midazolam is a 1,4-benzodiazepine compound that is similar in most pharmacologic aspects to diazepam. It possesses several attributes, however, that make it more attractive than diazepam in certain clinical situations.

Synthesized in 1975 by Walser and Fryer at Hoffmann-LaRoche, midazolam was available in many parts of the world in the early 1980s and was released for use in the United States in 1986. Midazolam first received FDA approval in December 1985. The chemical formula is 8-chloro-5(2′-fluorophenyl)-1-methyl-4H-imidazo (1,5-α)(1,4) benzodiazepine maleate. It is a colorless crystal in an aqueous solution. Each milliliter contains either 1 or 5 mg midazolam maleate buffered to a pH of 3.3.41 The acidic pH maintains the benzodiazepine ring in an open configuration, which is required for its water solubility (the diazepam ring is closed, and it is insoluble in water). Once in the body, the physiologic pH (7.4) acts to close the ring, providing the chemical structure of the drug that is required for its clinical efficacy.

Its water solubility differentiates midazolam from other parenteral benzodiazepines—diazepam, lorazepam, and chlordiazepoxide. The need for potentially irritating solvents, such as propylene glycol, is eliminated with midazolam. The water solubility of midazolam is produced by the substitution of imidazole at the 1,2 position of the 1,4-benzodiazepine ring structure and is aided because midazolam is the salt of an acid. This water solubility is responsible for the positive findings of a lack of burning sensation on injection and the absence of phlebitic sequelae at the injection site.

Pharmacokinetics and Biotransformation

Midazolam undergoes metabolism in the liver by hydroxylation into three major metabolites.42 Whereas the major metabolites of diazepam are pharmacologically active anxiolytics, the major metabolites of midazolam have no pharmacologic activity. In addition, because of its lack of active metabolites and shorter half-life, a rebound effect is not evidenced with midazolam.

The α-half-life (distribution and redistribution) of midazolam has been recorded as 4 to 18 minutes. The β-half-life (metabolism and excretion) is 1.7 to 2.4 hours. By contrast, diazepam’s β-half-life is 31.3 hours.43 The shorter half-lives of midazolam make the drug more suitable for ambulatory sedation procedures: a relatively short duration of action combined with a relatively rapid inactivation and excretion of the drug.

Midazolam is 94% protein bound, the binding occurring primarily in serum albumin. Midazolam possesses a relatively rapid onset of action, the induction of general anesthesia having ranged from 55 to 143 seconds.44

Amnesia

Midazolam, like the other parenteral benzodiazepines, has the ability to produce anterograde amnesia. Conner et al45 demonstrated the incidence of amnesia in patients receiving IV midazolam (Table 25-2).45

Table 25-2 Incidence of Amnesia in Patients Receiving Intravenous Midazolam

Time After Injection (min) Amnesic Patients (%)
2 96
30 87.5*
32 69
43 57

* Data from Fragen RJ, Caldwell NJ: Awakening characteristics following anesthesia induction with midazolam for short surgical procedures, Arzneimittelforschung 31(12a):2261-2263, 1981.

The results shown in Table 25-2 indicate that midazolam is superior to other benzodiazepines or IV drug combinations in providing anterograde amnesia. In one study, 71% of the patients did not recall being in the recovery room.45 Other studies have not demonstrated these same remarkable results, but in all cases, the degree of anterograde amnesia provided by midazolam was at least equal to that produced by diazepam.46 Retrograde amnesia is not produced by midazolam.

Since the introduction of midazolam for clinical use in the United States, I have seen the dramatic effects of midazolam-induced amnesia; most are beneficial, but some are potentially dangerous. For the typical 1-hour IV moderate sedation procedure in dental or outpatient surgical practice (e.g., colonoscopies), most patients have little recall of most or all of the procedure, and for most patients, this is quite acceptable and positive. One case, however, must be mentioned as a caution.

A young, healthy (ASA I) woman received IV midazolam and local anesthesia for the removal of three third molars. Following the 20-minute procedure, the patient appeared alert and was quite responsive to questions. Gauze packs had been placed at the sites of extraction, and the patient had been told to bite down hard on the gauze and not to swallow. She responded verbally that she would do as directed. Within 2 minutes, the patient was complaining of a lump in her throat. Observation of the mouth indicated that all gauze packs had disappeared—the patient had swallowed them. Fortunately, they were located in the esophagus and were of no great consequence. However, when questioned, the patient had absolutely no recall either of receiving the instructions given her by the dentist or of swallowing the gauze pads.47

It becomes imperative therefore for the patient to be observed much more carefully during the in-office recovery period, that special precautions be taken to prevent such events from recurring, and that postoperative instructions (verbal and written) be given to both the patient and his or her escort. The benzodiazepine antagonist flumazenil has been shown to decrease the duration of midazolam’s amnesic period.48

Cardiorespiratory Activity

Midazolam, as is typical of benzodiazepines, has minimal effect in usual doses on the cardiovascular and respiratory dynamics of the ASA 1 or 2 patient. IV doses of 0.15 mg/kg of midazolam in healthy persons have produced statistically significant, but clinically insignificant, decreases in arterial blood pressure and increases in heart rate.49 However, other researchers noted no untoward cardiovascular response with similar doses.50 Gath et al51 recommend midazolam as an induction agent for patients with ischemic heart disease because of its rapid onset of action and minimal effects on the cardiovascular system.

Diazepam and midazolam both produce the same effects on the respiratory system. Doses of 0.3 mg/kg of diazepam and 0.15 mg/kg of midazolam produced comparable depression of respiratory response to carbon dioxide (CO2) in healthy volunteers.49 It was concluded that midazolam and diazepam injected intravenously in equipotent doses depress respiration significantly and similarly. The results of the study indicate that this is mediated by direct depression of central respiratory drive rather than caused by a simultaneous depression of the muscles of respiration, although this possibility cannot be excluded. In the doses administered, equivalent to 21 mg of diazepam and 10 mg of midazolam for the typical 70-kg adult male, such a response might be expected. Since publication of this study in 1980, it has been demonstrated that equipotent doses of midazolam are approximately one fourth of the diazepam dose.

In all cases, the cardiovascular and respiratory depression noted with midazolam were typical for parenteral benzodiazepines and significantly less than those observed following equipotent doses of barbiturates (thiopental, pentobarbital). No cardiac dysrhythmias were provoked by midazolam administration.

In November 1987, Roche Laboratories, the manufacturer of midazolam, sent a warning to physicians about the use of midazolam in conscious sedation.52 It stated that the administration of midazolam had been associated with respiratory depression and respiratory arrest. Guidelines for the safe administration of this agent were offered (see Dosage and Administration). These guidelines emphasized the need for the slow titration of midazolam to all patients, especially the medically compromised.

Side Effects

The most frequently noted complaint after midazolam administration is dizziness. In the study by Conner et al,45 46% of patients mentioned experiencing dizziness. Despite this, 92% stated that they enjoyed the feeling produced by midazolam, and 100% said that they would accept the drug again if they required another operation.

Dosage and Administration

When midazolam was introduced, initial reports implied that midazolam was 1.5 times as potent as diazepam. Subsequent clinical experience with midazolam has shown it to be approximately four times as potent as diazepam. The mean effective dose for 50% of subjects (MED50) for the induction of general anesthesia is 0.2 mg/kg, although significant patient variation exists.53 Clinically adequate IV moderate sedation with midazolam should always be achieved by slow titration. In its 1987 letter, Roche recommended “an initial intravenous dose for conscious sedation as little as 1 mg, but not exceeding 2.5 mg for a normal, healthy adult.”52 Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant opioids or other CNS depressants. The initial dose and all subsequent doses should never be given as a bolus; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/ml or dilution of the 5 mg/ml formulation is recommended to facilitate slower injection.52

Doses of midazolam administered to normal, healthy (ASA 1) adult patients at the University of Southern California School of Dentistry have ranged from as little as 2 to 10 mg for an initial titrating dose. As with all drugs, there is significant patient variation in response to dosage.

Lorazepam

Lorazepam is a benzodiazepine with sedative and antianxiety effects. It may be administered either intramuscularly or intravenously. Chemically, it is 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one. Lorazepam, like diazepam, is virtually insoluble in water. Although available for IV use, lorazepam is seldom used in the outpatient ambulatory patient because of the relative inability to titrate the drug and its prolonged duration of action.54 Lorazepam was approved by the FDA in September 1977.

Lorazepam differs from most IV drugs in that its onset of clinical action is quite slow. After IV administration, lorazepam produces little or no clinical effect for about 5 minutes, with its maximum effect noted approximately 20 minutes after administration. “Average” dosages of lorazepam must be administered, a situation that takes away one of the most important safety features of the IV route of drug administration—the ability to titrate.

From personal experience with IV lorazepam, I have found that it is rather easy to oversedate the patient. Administration of 1 or 2 mg of lorazepam usually provides adequate sedation, but because of the bell-shaped curve, some patients become overly sedated at this same dose.

The duration of clinical action of lorazepam is too long for the typical dental procedure. The usual duration of sedative effects of lorazepam is 6 to 8 hours; however, some degree of unsteadiness and sensitivity to the CNS-depressant effects of other drugs (e.g., opioid analgesics prescribed for postsurgical pain control) may persist for as long as 24 hours. I recall a patient who contacted me 36 hours after receiving 2 mg of lorazepam intravenously and asked me when the effect of the drug would go away.

The introduction of flumazenil offers a means of reversing the sedative effects of lorazepam at the conclusion of the procedure. However, the clinical actions of flumazenil, especially after IV administration, are shorter than the clinical actions of lorazepam, leading to a possible recurrence of sedation after the patient is discharged from the office, a potentially dangerous situation. As discussed in the section on flumazenil, antidotal drugs and complications (see Chapter 27), consideration should be given for IM flumazenil administration whenever IV flumazenil is used.

The amnesic properties of lorazepam are impressive and include both anterograde and a degree of retrograde amnesia. Lack of recall is maximal approximately 15 to 20 minutes after IV administration and may include events occurring throughout the treatment day. This feeling of “losing a day” may not be very comfortable for the ambulatory patient. Lorazepam is more highly recommended for use in the hospitalized, monitored patient as a preoperative IM or IV drug than in the ambulatory outpatient.

Flunitrazepam

Flunitrazepam is a water-soluble benzodiazepine derivative that is chemically and pharmacologically related to diazepam and other drugs of this group. The chemical formula for flunitrazepam is 5-(o-fluorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one. The sedative, antianxiety, amnesic, and muscle-relaxing properties of flunitrazepam are similar to those of diazepam except that its sedative and sleep-inducing properties are more pronounced and longer lasting than those of diazepam.57 Foreman58 reported flunitrazepam to be approximately 15 times as potent as diazepam and suggested that the drug be diluted before administration to ensure precise titration.

Flunitrazepam is available in a 1-ml ampule containing 2 mg. The manufacturer suggests diluting the drug with 1 ml of sterile water for injection before use, providing a solution of 1 mg/ml.58 Foreman, however, suggests that further dilution is warranted, recommending the dilution of 2 mg (1 ml) of flunitrazepam in 9 ml of sterile water, providing a solution of 0.2 mg/ml.58

Flunitrazepam is known on the street as “roofies.” It is sometimes snorted to offset cocaine withdrawal. It has also acquired the title “the date-rape drug” because of its ability to induce anterograde amnesia, preventing the victim from recalling specific events while under the influence of the drug.59

Following IV administration for the induction of general anesthesia, flunitrazepam produces its clinical effects within 1 to 3 minutes, and the peak effect is noted in 5 minutes. The duration of clinical action ranged from 10 to 60 minutes, with significant variation with dosage (1 to 6 mg). The α-half-lives and β-half-lives of flunitrazepam are 19 and 34 hours.

HISTAMINE BLOCKERS (ANTIHISTAMINICS)

Promethazine, classified as a histamine blocker is, on rare occasion, employed for IV moderate sedation. The basic pharmacology of histamine-blockers has been discussed in Chapters 7 and 10. In this section, only those aspects of promethazine’s pharmacology relevant to IV administration is reviewed.

Promethazine

Promethazine is a phenothiazine derivative used primarily in pediatric dentistry as a sedative-hypnotic administered either orally or intramuscularly for the production of moderate to deep sedation. Promethazine may also be administered intravenously either as a sole agent or in combination with an opioid. Promethazine was approved by the FDA in 1951.

The clinical duration of action of promethazine following IV administration is approximately 1 to 2 hours. Clinical recovery of the patient at this time is somewhat greater than that observed after pentobarbital administration; however, it is significantly less than that seen with diazepam or midazolam. Promethazine is indicated for sedation procedures of approximately 1 hour to 2 or more hours.

The most significant adverse reaction to the administration of promethazine is the occurrence of extrapyramidal reactions. Clinical signs and symptoms of extrapyramidal reactions and their management are discussed in Chapter 7.

PROPOFOL

Propofol (2,6-diisopropylphenol) is an IV, nonbarbiturate anesthetic that is chemically unrelated to other IV anesthetics. Propofol is used to induce anesthesia that can be maintained by continuous infusion or with inhalation anesthetics. Propofol induces anesthesia as quickly as thiopental, but emergence from anesthesia is 10 times more rapid than with thiopental and is associated with minimal postoperative confusion. Propofol has no analgesic activity and causes sedation at a lower dosage than that needed for anesthesia. Unlike many other general anesthetics, propofol possesses antiemetic activity. Propofol (Diprivan) received FDA approval in October 1989. In March 1997, the FDA granted exclusivity until 2015 to Zeneca for a modified formulation that contains disodium edetate (EDTA) to retard microorganism growth. A generic formulation of propofol is available, but it contains sodium metabisulfite and not EDTA as the preservative.

Pharmacodynamics

Central Nervous System

Propofol decreases cerebral metabolism, blood flow, and intracranial pressure.64,65 However, when larger doses are administered, marked lowering of systemic arterial pressures can significantly diminish cerebral perfusion.66

Cardiovascular System

Propofol’s cardiovascular-depressant effects are more profound than those of thiopental.68 Both a direct myocardial depression and decreased systemic vascular resistance have been implicated in producing profound hypotension following large bolus doses of propofol.68,69 Age also affects cardiovascular response to propofol, and caution is mandatory when propofol is administered to elderly patients.70

Miscellaneous Effects

Propofol may have antiemetic effects. Studies have demonstrated an extremely low incidence of emetic sequelae after outpatient anesthesia with propofol.71 Propofol has a distribution half-life of 2 to 4 minutes and an elimination half-life of 1 to 3 hours.67

Like most IV anesthetics, propofol is eliminated via hepatic metabolism followed by renal excretion of the more water-soluble metabolites. There is some evidence that an extrahepatic route of elimination, such as the lungs, contributes to the clearance of propofol.67 Propofol is rapidly and extensively metabolized to inactive, water-soluble sulfate and glucuronic acid conjugates that are eliminated by the kidney.72 No changes in propofol’s pharmacokinetics have been reported to date in the presence of hepatic or renal disease.

Clinical Use

IV administration of propofol results in a rapid onset of action that is comparable with that of barbiturates.73,74 Recovery from propofol’s sedative-hypnotic effects is equally rapid.75 The duration of propofol’s central depressant effects increases in a dose-dependent fashion.76 In contrast to the barbiturates, there appears/>

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Jan 5, 2015 | Posted by in General Dentistry | Comments Off on 25: Pharmacology
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