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Since the 1999 Institute of Medicine (IOM) report, “To Err Is Human: Building a Safer Health System,” asserted that up to 98,000 US patients die each year as a result of preventable medical errors, a renewed vigilance in all areas of medicine with respect to patient safety has transpired.1 While this landmark publication brought the issue of patient safety into the public consciousness, a follow-up study by the IOM, “Crossing the Quality Chasm: A New Health System for the 21st Century,” made four major points: errors are common and costly, systems cause errors, errors can be prevented and safety improved, and medication-related adverse events are the single leading cause of injury.2 In 2006 the IOM recommended to increase the use of technology to reduce the risk for medication errors, but the advent of electronic health records and computerized prescriber order entry are only part of the solution in addressing this ongoing problem.3 This issue takes on even more importance as healthcare delivery systems become more complex and specialized. Hospitalized patients may receive medications that interact with those taken as outpatients, and there is a greater likelihood that patients will continue to be taking an increased number of medications in the ambulatory setting such as the dental office.4-7
Prescribing medication is a key component in patient care, regardless of the setting. The privilege to write prescriptions is one of the most significant responsibilities that dentists acquire upon their licensures.8 To ensure that medications are prescribed and administered safely, an accurate and complete medication history of the patient is needed, and this information must be validated routinely.9,10 Incomplete or inaccurate medication histories can lead to drug interactions, unexpected adverse drug reactions, unintentional discontinuation of medications, or failure to detect drug-related problems, all of which can result in a medical emergency.10,11 According to a study performed by Malamed,12 in a survey of 2704 dentists throughout North America, 13,836 emergencies occurred within a 10-year period. Though none of these were truly dental emergencies, they were potentially life-threatening medical problems that patients developed while in dental offices. Medical emergencies can and do happen in the practice of dentistry, many of which are the result of adverse drug reactions.13
This article will review six specific pharmacological reversal agents as they relate to the practice of dentistry: naloxone, flumazenil, epinephrine, diphenhydramine, phentolamine, and atropine (Table 1). In general, these antagonists were developed for administration as reversal agents in emergency situations in which a patient had an untoward effect, typically caused by too much medication. Some newer agents being developed are now being considered for more routine use to reverse the effects of an agonist medication once the dental procedure is complete and the effects of the agonist medication are no longer required.
Pharmacodynamics and Pharmacokinetics
The fundamental relationship between the pharmacodynamics (ie, what the drug does to the body) of a drug and its pharmacokinetics (ie, what the body does to the drug) is expressed in the following equation14: effect = affinity for site of action × drug level × biological variance.
Pharmacodynamics defines what the drug is capable of doing and is often referred to as the “lock and key hypothesis,” in which the drug represents the “key” and the receptor to which it attaches is considered to be the “lock.” The interaction between this key and lock results in the drug’s effect(s). For example, any drug that can stimulate the gamma-aminobutyric butyric acid (GABA) receptor in the central nervous system (CNS) can cause anxiolysis or sedation.15-17 However, a sufficient amount of the drug must reach that target to have a physiologically meaningful effect. In other words, enough “keys” have to engage enough “locks” before a clinically noticeable effect is elicited. The pharmacokinetics of a drug determines whether that amount is achieved.18,19
For most medications, this is not an all-or-none effect. A threshold amount of target site occupation is needed to elicit a response. Below this level, the receptors will not be sufficiently engaged to have a physiologically meaningful effect, also termed subtherapeutic. Conversely, occupation above a specific upper limit will be associated with an increased likelihood of adverse effects. This fact is fundamental to understanding the potential benefit of therapeutic drug monitoring, which is a means to determine the second variable in the above equation. Levels of drug in the body are determined by dosing rate and clearance, as expressed by this second equation14: drug level = dosing rate/clearance.
Population pharmacokinetic studies help determine standard doses of medications needed to achieve the optimal drug level in the average person. The concept of the “average person” is critical because patients are not created equally, especially in how they respond to medications. This is the reason for the third variable in the first equation: biological differences among patients can shift their individual dose-response curves, either reducing or enhancing the magnitude of the drug response. This biological heterogeneity can be the result of differences in diagnosis, genetics, gender, age, organ function, or the internal environment of the body. Biological variance also includes the presence of other medications and, therefore, highlights the important role drug interactions play in the ultimate effect medications may have in a patient.14
Agonists and Antagonists
An agonist is a drug that binds to a receptor and triggers a response; it often mimics the action of a naturally occurring substance. Benzodiazepines, such as diazepam, were developed based on this premise, as they augment the effects of the naturally occurring neurotransmitter, GABA.
While a receptor agonist produces an action, an antagonist is a type of drug that does not provoke a biological response upon binding to a receptor, but instead blocks or reverses agonist-mediated responses. The development of antihistamines such as diphenhydramine, for example, will ameliorate the histaminic response of an allergic reaction by antagonizing the effects of the naturally occurring neurotransmitter, histamine. Antagonists have affinity for their target receptors but no efficacy; binding disrupts the interaction of an agonist currently attached to the receptor and inhibits the function primarily through receptor occupancy. Antagonist activity can be reversible or irreversible depending on the permanence of the antagonist-receptor complex (ie, the half-life of the antagonist medication). Figure 1 gives examples of some common agonists and antagonists.
In general, antagonists were developed for administration as reversal agents in emergency situations in which a patient had an untoward effect typically caused by too much agonist medication. Most drug antagonists achieve their effects by competing with agonists at binding sites or receptors.20 Some of the agents now being developed are being considered for more routine use to reverse the effects of an agonist medication once the dental procedure is complete and the effects of the agonist medication are no longer required.
Pharmacological Reversal Agents in Dental Practice
Opioid antagonists are used clinically to reverse respiratory depression in patients who breathe inadequately after opioid overdose or the use of opioid anesthesia. In addition, opioid antagonists can reduce or reverse opioid-induced nausea and vomiting, pruritus, urinary retention, rigidity, and biliary spasm associated with numerous therapies using opioids.
Although naloxone is generally considered to be a pure opioid receptor antagonist, it can delay gastric emptying similar to morphine.21 Furthermore, high-dose naloxone possesses partial agonistic activity on µ- and κ-opioid receptors in cultured cells.22 In other trials, morphine requirements were significantly less in patients receiving naloxone, thus suggesting that naloxone enhances the analgesic effect.23 Possible mechanisms postulated for this apparent paradoxical outcome of naloxone include opioid receptor upregulation and enhanced release of endogenous opioids.
Introduced into clinical practice in the late 1960s, the recommended dosage range for naloxone is from 0.4 mg to 0.8 mg. The onset of action of intravenous naloxone is rapid (<2 minutes), and its half-life and duration of effect are short, 30 and 60 minutes respectively.24 If intravenous access is not available, naloxone in doses similar to those given intravenously is effectively absorbed after subcutaneous, intramuscular, and intratracheal administration.24 Because respiratory depression from opioids may outlast the effects of naloxone boluses or short infusions, continuous infusion of naloxone may be required to maintain reversal of respiratory depression.25 Renarcotization occurs more frequently after the use of naloxone to reverse longer-acting opioids such as morphine. Use of naloxone has also been reported to reverse the effects of alcohol, barbiturates, and benzodiazepines, although this has not been borne out in large, controlled clinical trials.26 While it is not advisable to reverse the effects of a benzodiazepine overdose with naloxone, naloxone may be appropriate to consider if flumazenil has no effect, as patients do not always reveal narcotic use to oral healthcare providers and the combination of these drugs can be synergistic.27
Other opioid antagonists include naltrexone, nalmefene, and methylnaltrexone, although naloxone continues to be the preferred agent over some of these newer reversal agents. Naltrexone is longer acting than naloxone (plasma half-life of 8 to 12 hours versus 0.5 to 1.5 hours) and is active when taken orally. Findings from a double-blind, placebo-controlled study of patients undergoing cesarean section indicated naltrexone 6 mg was an effective prophylactic against the pruritus and vomiting associated with intrathecal morphine but was linked with a shorter duration of analgesia.28 Nalmefene is equipotent to naloxone but is longer acting after oral (0.5 mg/kg to 3 mg/kg) and parenteral (0.2 mg/kg to 2 mg/kg) administration.29 In one study, prophylactic administration of nalmefene significantly decreased the need for antiemetics and antipruritic medications in patients receiving intravenous morphine.30 Methylnaltrexone is the first quaternary ammonium opioid receptor antagonist and, therefore, does not cross the blood–brain barrier, which separates circulating blood from the brain’s extracellular fluid in the central nervous system. Methylnaltrexone can reverse the adverse effects of opioid medications mediated by peripheral opioid receptors, whereas the opioid effects mediated by opioid receptors in the CNS, such as analgesia, are not affected. Because methylnaltrexone does not cross the dura (the outermost membrane surrounding the brain and spinal cord), it might be able to reverse the peripherally mediated side effects of epidural opioids (ie, constipation, nausea, vomiting).31
Flumazenil is an antagonist selective for benzodiazepines. As a competitive antagonist, it binds with a very strong affinity at the benzodiazepine binding site of the GABA receptor complex in the CNS.32 Flumazenil is indicated for mitigating the adverse clinical effects of a benzodiazepine overdose, most notably unconsciousness, and cardiovascular and respiratory depression.33 In the emergency department, its use can quickly confirm a clinical diagnosis of a benzodiazepine overdose, thereby obviating the need for other time-consuming and expensive interventions. In the dental office, with patients undergoing minimal or moderate sedation with benzodiazepines, it speeds return-to-baseline alertness in emergency situations, especially when the patient proceeds into a deeper level of sedation than intended.
According to the product monograph, an intravenously titrated dose of up to 1 mg administered over 1 to 3 minutes will usually reverse the sedative effects of benzodiazepines.34 An initial adult dose of 0.2 mg is given intravenously over 30 seconds; a second dose of 0.2 mg may be given, followed by 0.2-mg doses at 30-second intervals. Most patients will respond to less than 1 mg. In children, the initial dose is 0.01 mg/kg. Because the duration of action of flumazenil is short (0.7 to 1.3 hours), re-sedation occurs in up to 65% of patients and requires either re-dosing or continuous infusion (0.25 mg/hr to 1 mg/hr).34
Flumazenil is indicated for intravenous use. Studies of orally administered flumazenil show that even though it is rapidly absorbed, less than 25% of the drug reaches the systemic circulation because of extensive hepatic first-pass metabolism.35 This low bioavailability nullifies the oral route of flumazenil administration as clinically appropriate for reversing benzodiazepine-induced oversedation. The efficacy and onset latency for flumazenil administered via the intravenous (IV), intramuscular (IM), sublingual (injection under the tongue), and rectal routes of administration have been evaluated in canine models of benzodiazepine-induced respiratory depression with all four routes of administration resulting in a reversal of respiratory depression.35-37 In human trials performed at the University of Washington, subjects were administered flumazenil 0.2 mg by IV, IM, or oral subcutaneous injection and all participants had a marked improvement in their observer’s visual assessment scores, bispectral index scores, and digit symbol substitution test (DSST) scores, regardless of the route of administration.38 (Note: The DSST is a component of the Wechsler adult intelligence test and is often used for assessing drug-induced cognitive and psychomotor impairment.) Flumazenil has also been effective when administered intranasally, obviating the need for any injection.39,40
The results of these studies and earlier work indicate that flumazenil administered via routes other than the IV can effectively reverse the CNS depression produced by benzodiazepines, as well as the cognitive and psychomotor impairments.41 The dentist must not solely rely on sedative antagonist therapy, however, as basic life support skills, airway support, and rescue ventilation will be needed before flumazenil begins to take effect due to the drug’s latency.
Flumazenil is not recommended for routine reversal because seizures and cardiac dysrhythmias can occur with its administration, and although most of these effects are well tolerated, fatalities have been reported.34 Coingestion of drugs with proconvulsant properties is associated with an increased risk for seizures, presumably due to loss of the benzodiazepine’s protective anticonvulsant effect when the antagonist is administered. According to the literature, combined overdose (intentional) of benzodiazepines with tricyclic antidepressants accounts for 50% of these documented seizures.34 Coingestants possessing prodysrhythmic properties, such as carbamazepine or chloral hydrate, may increase the likelihood of cardiac effects by a similar mechanism.34
Dental practitioners must reserve the use of flumazenil for emergency use only. The employment of the drug should be considered only when the patient’s level of sedation is determined to be deeper than intended, the patient is nonresponsive to verbal commands, or a precipitous change in vital signs is noted. The drug should not be used for routine reversal following an uneventful or normal sedation procedure. Dental patients should be allowed to recover normally following enteral sedation and should satisfy all discharge criteria without the aid of flumazenil prior to being released. The Academy of General Dentistry recommends in its white paper on enteral sedation that any patient who has received flumazenil should be kept in the office for at least 2 hours for monitoring before discharge.42 Because flumazenil has a short duration of action (approximately 45 minutes), if a patient is monitored for an additional 2 hours after flumazenil administration, the practitioner can verify that the patient is acceptable for discharge and recovering without needing the confounder of flumazenil antagonism.
Epinephrine is the single most important injectable drug in the emergency kit.43 It is an endogenous catecholamine that stimulates both alpha (α)- and beta (β)-adrenergic receptors and is the drug of choice for treating cardiovascular and respiratory manifestations of acute allergic reactions. When administered in resuscitative dosages, epinephrine causes bronchodilation and increased systemic vascular resistance, heart rate, arterial blood pressure, myocardial contractility, and myocardial and cerebral blood flow.44 Epinephrine also nonspecifically antagonizes histamine to further enhance these distinct effects; however, unlike antihistamines, this type of antagonism is sometimes referred to as physiologic rather than direct.45 This distinction is important in understanding why a physiologic antagonist such as epinephrine is a more effective agent than an antihistamine in treating systemic histamine toxicity.46
For treatment of life-threatening signs and symptoms of an acute allergic reaction, the clinician must administer epinephrine immediately, injecting the drug subcutaneously (0.3 mg to 0.5 mg of a 1:1,000 solution) or intramuscularly for a more serious emergency (0.4 mg to 0.6 mg of the epinephrine same solution). Epinephrine is available in ampules and in preloaded syringes or autoinjectors for immediate use.45 Caution should be exercised with autoinjectors however, because of a growing body of evidence indicating that the currently supplied needle length may be too short to be effective in larger patients.47,48 Epinephrine is also indicated for the treatment of acute asthmatic attacks that are unrelieved by the use of β2-adrenergic receptor agonists such as albuterol.49
Antihistamines or histamine H1-antagonists do not alter the formation, release, or degradation of histamine, but competitively antagonize it at receptor sites. Diphenhydramine is the most common representative of this general drug class, although diphenhydramine belongs to seven distinct chemical subgroups, specifically ethanolamines. These agents can inhibit the contraction of gastrointestinal and bronchial smooth muscles, the increase in capillary permeability, and the flare-and-itch components of the typical mild or delayed-onset allergic reaction. Antihistamines antagonize the effects of histamine by inhibiting further action, but they have no directly opposing actions of their own. In essence, these medications have a high affinity for histamine receptors but on their own, they lack efficacy.46 The basic mechanism of action can be explained in terms of a competitive blockade of receptors; antihistamines interact with histamine receptors on the target cell resulting in decreased availability of these receptors for histamine. Diphenhydramine is typically administered as a 50-mg IM injection followed by 25 mg to 50 mg orally every 3 to 4 hours for up to 3 days following a reaction.43
H1-antihistamines exert various effects that are of additional value in the dental realm. While they do not block histamine-induced gastric secretion (this is the result of H2-antihistamines such as ranitidine and famotidine), they do antagonize the increased secretions of the salivary glands and the increased release of epinephrine from the adrenal medulla stimulated by histamine.46 This first antisialogogue effect is of benefit in helping to keep the field dry while the latter effect manifests as anxiolysis, lassitude, and drowsiness. This mechanism for CNS depression is further enhanced by direct blockade of the histamine neurotransmitter in the brain,50 and many of the first-generation H1-antihistamines have been used as sedative agents in their own right to reduce procedural anxiety associated with dental appointments.51
Another clinically useful effect of the first-generation H1-antihistamines is inhibition of nausea and vomiting. As a consequence of dental surgery, because blood can be emetogenic when swallowed, these agents offer some excellent prophylactic measures against potential emesis.
Most antihistamines also have some degree of local anesthetic activity. This property is most notable in diphenhydramine, promethazine, pyrilamine, and tripelennamine and has been used clinically in dentistry.52 In fact, diphenhydramine’s use as an anesthetic agent in medicine for minor laceration repair has shown it was either less effective or equivalent to the use of a lidocaine solution.53-58 Studies in the dental literature have also found the administration of diphenhydramine to be a viable option for inferior alveolar nerve blocks.59
Patients often report that persistent local anesthetic effects long after the dental appointment concludes interferes with normal activities such as eating, speaking, and drinking, and may even cause drooling.60 Many have the perception of an altered appearance and would prefer to avoid prolonged perioral anesthesia. Phentolamine is a newly introduced, local anesthetic antagonist that effectively reverses the influence of vasopressors on submucosal vessels.61 It is an α receptor blocker formulated in dental cartridges, and when it is injected into the same site where anesthetic was administered, vessels dilate, leading to enhanced absorption of local anesthetic. This shortens the duration of anesthesia.62
Because of its expense, phentolamine may have a limited role, and in many cases sustained anesthesia is preferred during the postoperative period for pain management. Phentolamine may be of greatest value in the management of small children or patients with special needs who may be prone to self-inflected injury (eg, inadvertent biting of the lips, tongue, and/or cheek,) while tissues remain numb. Aadditional subpopulation may be elderly or fragile patients with diabetes for whom adequate nutritional intake may be hindered by prolonged numbness. The use of phentolamine has also been suggested for busy patients who must return to work and communicate effectively.63
While primarily known as a medication for advanced cardiac life support, atropine has been added to the list of drugs as part of the minimum dental emergency kit in California, and other boards are considering its inclusion.64 Atropine is administered intravenously or intramuscularly for clinically significant bradycardia at doses of 0.5 mg every 3 to 5 minutes, not to exceed 3 mg, or 0.04 mg/kg. Similar to epinephrine, autoinjectors are available for IM administration although this formulation is used primarily by the US Department of Defense in severe and life-threatening organophosphate or carbamate insecticide or nerve-agent poisonings.
Atropine antagonizes the action of acetylcholine at parasympathetic sites in smooth muscles, secretory glands, and the CNS. These actions increase cardiac output and dry secretions. Atropine has no effect on the nicotinic receptors responsible for muscle weakness, fasciculation, and paralysis. The onset of action is rapid and the elimination half-life is 2 to 3 hours. While some oral healthcare practitioners have used atropine to inhibit salivation and secretions prior to procedures, doses less than 0.5 mg have been associated with paradoxical bradycardia.65 For this indication, doses of 0.6 mg 30 to 60 minutes preoperatively either intramuscularly, intravenously, or subcutaneously can be given and repeated every 4 to 6 hours as needed. California is one of the few states in which the dental board requires dentists to have an anticholinergic as part of their emergency kits, and this is typically atropine.
Medical emergencies can and do happen in the practice of dentistry, with some of which the result of adverse drug reactions. Pharmacological antagonists have been developed for administration as reversal agents in emergency situations in which a patient had an untoward effect, typically caused by too much medication. This article reviewed six specific reversal agents as they relate to the practice of dentistry: naloxone, flumazenil, epinephrine, diphenhydramine, phentolamine, and atropine. Agents being developed are now being considered for more routine use to reverse the effects of an agonist medication once the dental procedure is complete and the effects of the agonist medication are no longer required.ABOUT THE AUTHORS
Mark Donaldson, BSP, ACPR, PharmD
Director of Clinical Pharmacy
Vizient Advisory Services
School of Pharmacy
University of Montana
Clinical Assistant Professor
School of Dentistry
Oregon Health & Sciences University
Jason H. Goodchild, DMD
Clinical Associate Professor
Department of Oral Medicine
University of Pennsylvania School of Dental Medicine
Associate Professor and Chairman
Department of Diagnostic Sciences
Creighton University School of Dentistry
Queries to the authors regarding this course may be submitted to firstname.lastname@example.org.
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