Beta-adrenergic Blocking Agents and Dental Vasoconstrictors

A clinically significant interaction between epinephrine or levonordefrin with nonselective beta-adrenergic blocking agents, although apparently rare in the dental setting, is potentially serious and can lead to significant hypertension with a concomitant reflex bradycardia. Based on the results of epinephrine infusion studies, the severity of the interaction seems dose related; small epinephrine doses cause less of a pressor response than larger doses. The interaction can be seen after intraoral submucosal injections but is generally of a smaller magnitude, at least with only 1 or 2 cartridges of lidocaine plus 1:100,000 epinephrine. However as demonstrated by 1 case report, some individuals are hypersensitive to this interaction. Inadvertent intravascular injections of local anesthetic plus vasoconstrictor and the use of high doses of vasoconstrictor are likely to result in a more pronounced response. Patients with significant cardiovascular disease may be especially vulnerable to the most serious sequelae resulting from the pressor reactions of the drug combination.

Adverse drug interactions involving dental vasoconstrictors have been the focus of several reviews and commentaries within the dental literature. Considering the many millions of dental local anesthetic cartridges containing epinephrine administered to patients in any given year, reports of serious drug interactions with these agents in the outpatient dental setting have been exceedingly rare. However, based on a case series describing severe hypertensive events in plastic surgery patients who were on chronic propranolol for the treatment of hypertension or migraine headaches and received what was typically high therapeutic dosages of lidocaine with epinephrine, and because this pressor effect has been reproduced in the clinical research setting in patients taking propranolol and other nonselective beta-adrenergic blocking agents when administered epinephrine infusions or submucosal dental injections, the potential exists for a similar adverse drug interaction in dental patients.

Epinephrine pharmacology and safety

One reason for the relative safety of vasoconstrictors in the current practice of dentistry is that epinephrine is by far the most widely used vasoconstrictive agent. Although epinephrine has α 1 adrenergic effects on some vascular beds, most notably under the skin and mucous membranes leading to vasoconstriction, it also has vasodilatory effects on other vascular beds that contain predominantly β 2 adrenergic receptors, such as those in skeletal muscle resulting in vasodilation ( Table 1 ). This opposing vasodilatory property of epinephrine limits the potential pressor effects of the drug compared with levonordefrin and norepinephrine, which in the case of levonordefrin has approximately 50% less, and in the case of norepinephrine almost no β 2 adrenergic activity. Norepinephrine is no longer available in dental cartridges because clinical research and case reports revealed a significant pressor effect following dental injections with even low therapeutic doses of the drug. Levonordefrin is found only in the 2% mepivacaine formulation whose current use dwarfs that of lidocaine, articaine, bupivacaine, and prilocaine formulations, which contain various concentrations of epinephrine.

Table 1
Some physiologic actions of epinephrine at various receptors
Receptor Response
α 1 adrenergic Constriction of blood vessels in skin and mucous membranes
β 1 adrenergic Increased heart rate
Increased contraction force
β 2 adrenergic Dilation of bronchial smooth muscle
Dilation of blood vessels in skeletal muscle and certain internal organs (brain)

Typically most systemic effects of epinephrine, whether they involve myocardial stimulation caused by β 1 adrenergic receptor activation or changes in vascular tone, are short-lived, usually of only 10 to 20 minutes duration, because of the drug’s short half-life in the blood stream. For example, in a recent study in normal healthy volunteers, the intraoral injection of 7 cartridges (11.9 mL) of 4% articaine with 1:100,000 epinephrine (0.119 mg epinephrine total), which represented the maximum recommended dose of articaine in individuals weighing 68 kg or more, produced only small but significant ( P <.05) increases in heart rate (9 beats per minute) and systolic blood pressure (6 mm Hg) that completely dissipated within 13 minutes of the final injection. In addition, the β 2 adrenergic effects of epinephrine were demonstrated in this study by small decreases in diastolic blood pressure and total peripheral resistance.

Another factor adding to the safety of epinephrine in dental practice is that for most dental procedures, adequate pain control and/or hemostasis usually requires far less local anesthetic and vasoconstrictor than used in the study by Hersh and colleagues. The few deaths attributed to vasoconstrictor use in the dental office have involved excessive doses of epinephrine, typically in patients with significant cardiovascular disease. A case report describing a fatality in a 58-year-old dental patient with symptomatic angina, 2 previous myocardial infarctions, type 2 diabetes, and a continuing smoking history after the injection of 5 cartridges of 2% lidocaine plus 1:50,000 epinephrine (0.18 mg epinephrine total), clearly supports this assumption. In contrast to this tragic outcome, geriatric patients with a mean age of 70 years on various cardiovascular medications and cardiac arrhythmias confirmed by electrocardiography experienced no adverse sequelae during minor oral surgical procedures when the mean dose of epinephrine was limited to only 0.04 mg. So in reality most serious adverse events reported with epinephrine administration probably involve excessive dosing and/or poor aspirating technique in cardiovascularly compromised individuals, not adverse drug interactions.

Clinical pharmacology of beta-adrenergic blocking agents

Beta-adrenergic blocking agents are classified as either being nonselective, meaning they block both β 1 receptors on the heart and β 2 receptors on the bronchial and the vasculature smooth muscle almost equally well; or they are cardioselective, that is they preferentially block β 1 receptors. Table 2 classifies some of the more commonly prescribed β-blockers into these categories. Both classes of beta-adrenergic blocking agents are commonly used in the treatment of hypertension, angina, and cardiac arrhythmias, although the cardioselective β-blockers have become more popular in these patient populations because β 2 blockade produced by drugs such as propranolol can lead to bronchoconstriction in sensitive individuals, a potentially lethal event in asthmatic patients and in those with other bronchospastic disorders. However, in individuals who have migraine headache the older nonselective β-blockers are frequently used as prophylactic agents for this condition, because of their ability to block β 2 receptors on the cerebral vasculature, possibly limiting vasospasm, which is associated with some migraine headaches.

Table 2
Classification of some beta-adrenergic blocking drugs with common trade names in parentheses
Nonselective Beta-adrenergic Blockers Cardioselective Beta-adrenergic Blockers
Propranolol (Inderal) Acebutolol (Sectral)
Nadolol (Corgard) Atenolol (Tenormin)
Timolol (Blocadren) Metoprolol (Lopressor)
Sotalol (Betapace) Bextalol (Kerlone)
Pindolol (Visken) Bisprolol (Zebeta)

Clinical pharmacology of beta-adrenergic blocking agents

Beta-adrenergic blocking agents are classified as either being nonselective, meaning they block both β 1 receptors on the heart and β 2 receptors on the bronchial and the vasculature smooth muscle almost equally well; or they are cardioselective, that is they preferentially block β 1 receptors. Table 2 classifies some of the more commonly prescribed β-blockers into these categories. Both classes of beta-adrenergic blocking agents are commonly used in the treatment of hypertension, angina, and cardiac arrhythmias, although the cardioselective β-blockers have become more popular in these patient populations because β 2 blockade produced by drugs such as propranolol can lead to bronchoconstriction in sensitive individuals, a potentially lethal event in asthmatic patients and in those with other bronchospastic disorders. However, in individuals who have migraine headache the older nonselective β-blockers are frequently used as prophylactic agents for this condition, because of their ability to block β 2 receptors on the cerebral vasculature, possibly limiting vasospasm, which is associated with some migraine headaches.

Table 2
Classification of some beta-adrenergic blocking drugs with common trade names in parentheses
Nonselective Beta-adrenergic Blockers Cardioselective Beta-adrenergic Blockers
Propranolol (Inderal) Acebutolol (Sectral)
Nadolol (Corgard) Atenolol (Tenormin)
Timolol (Blocadren) Metoprolol (Lopressor)
Sotalol (Betapace) Bextalol (Kerlone)
Pindolol (Visken) Bisprolol (Zebeta)

Theoretic basis for the interaction

As previously discussed, when epinephrine is absorbed systemically it is not a pure vasoconstrictor because it activates both α 1 and β 2 adrenergic receptors (see Table 1 ). However, if a nonselective β-blocker such as propranolol is used and significant systemic absorption of epinephrine occurs, the β 2 vasodilatory effects (and the β 1 cardiac stimulatory effects) of epinephrine will be blocked, allowing the α vasoconstrictive effects to function unopposed. The actions of epinephrine throughout the body would now resemble that of an almost pure vasoconstrictor like norepinephrine, theoretically resulting in an increase in systolic and diastolic blood pressure, and a compensatory reflex bradycardia. These types of events in a patient with significant cardiovascular disease could increase the risk of myocardial ischemia and stroke.

Case reports supporting the interaction

Dramatic increases in systolic and diastolic blood pressures have been reported in plastic surgery patients on propranolol for hypertension or migraine prophylaxis who received facial injections of lidocaine with epinephrine. Table 3 summarizes this case series. All patients were middle aged, were taking chronic propranolol, and had normal blood pressures after preoperative sedation and pain control regimens that included opioids, benzodiazepines (in all cases intravenous diazepam was titrated to effect), and in some cases barbiturates, neuroleptics, and the antihistamine hydroxyzine. Cases 1 and 2 showed significant hypertensive responses with a severe reflex bradycardia after the lidocaine with epinephrine injections. They had received the equivalent epinephrine dose of 5.5 to 6.5 dental cartridges of 2% lidocaine with 1:100,000 epinephrine. Blood pressures returned to normal in these patients within 15 to 60 minutes with no intervention. Case 3, for which preoperative blood pressure and pulse were unknown, experienced a severe hypertensive response and cardiac arrest that was successfully defibrillated when the amount of epinephrine contained in 3.5 dental cartridges was administered. Cases 4 and 5 were administered amounts of epinephrine that would be considered absolute maximum recommended dosages in healthy adult dental patients and certainly not in dental patients with significant cardiovascular disease. The patient described in case 4 was also taking a thiazide/potassium–sparing diuretic combination (Dyazide) as well as propranolol. Both patients exhibited dramatic increases in blood pressure. The pulse rate, instead of decreasing, significantly increased in case 4, probably the result of that patient being pretreated with atropine before the procedure, which blocked the compensatory reflex vagal effect of the hypertensive response. In case 5,hydralazine (a vasodilator) was administered intravenously to reduce the severe increase in blood pressure. Case 6 received a relatively small amount of epinephrine approximately equal to the amount found in 2 dental cartridges containing a 1:100,000 solution. As in case 4, a combination thiazides/potassium–sparing diuretic was also being used to control blood pressure. After the injection, blood pressure rose to 260/150 and intravenous hydralazine was used to normalize the blood pressure. Although these cases tend to implicate the presence of the nonselective beta-adrenergic blocking agent propranolol as the culprit in these hypertensive events, as pointed out by other investigators, these patients were taking multiple preoperative drugs and 2 were also taking diuretics, both of which may have played some role in the ultimate course of the adverse interactions.

Oct 29, 2016 | Posted by in General Dentistry | Comments Off on Beta-adrenergic Blocking Agents and Dental Vasoconstrictors
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