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Treating anxiety with either beta blockers or antiemetic antimuscarinic drugs: a review

Mental Health in Family Medicine 2015; 11:89-99 2015 Mental Health and Family Medicine Ltd Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review Thomas P. Dooley, Ph.D.
TPD LLC, 7100 Cabin Lane, Pinson, Alabama 35126, USA; Tel: 205-222-6145; E-mail: [email protected] Beta adrenergic receptor antagonists and antiemetic scopolamine) or over-the-counter (e.g., meclizine) for the muscarinic receptor antagonists are useful for mental health treatment of non-cardiovascular symptoms that manifest in in primary care and family medicine settings, as they provide anxiety disorders. Antiemetic agents inhibit nausea, vomiting, favorable risk/benefit profiles, and especially so relative to sweating, and in some instances other psychic (CNS) symptoms. benzodiazepines. Beta blockers (e.g., propranolol) prescribed The symptoms affected by antimuscarinic agents represent the off-label have been known for decades to provide some, "inverse" of the symptoms of acute anxiety affected by beta albeit limited, anxiolytic benefit for patients affected by blockers. Thus, anxiety disorders can be treated by alternative social anxiety disorder (social phobia), including performance biochemical pathways, as well as by affecting alternative anxiety. Blockage of adrenaline's binding to cardiovascular symptoms thereof. The results of human clinical studies are beta adrenergic receptors inhibits tachycardia, reduces blood summarized for both classes of anxiolytic agents that display pressure, and thus diminishes palpitations in acute anxiety complementary pharmacologic approaches to a diverse array and panic. However, beta blockers are not effective against of symptoms.
the psychic (CNS) symptoms, such as anxiousness, fear, and avoidance. Another approach involves antiemetic muscarinic MeSH Headings/Keywords: Anxiety, Panic, Anxiolytic,
receptor antagonists that are available by prescription (e.g., Beta Adrenergic, Muscarinic, Cholinergic, Antagonist, The biochemical pathways of the beta adrenergic receptor and muscarinic receptor gene families are appropriate anxiolytic The pharmaceutical marketplace in the Western World targets for treating the symptoms of social anxiety disorder provides numerous medical treatments for anxiety disorders. (social phobia) including performance anxiety (e.g., stage fright), Two classes of medications that have demonstrated some as well as panic attack (PA), panic disorder (PD), agoraphobia, effectiveness and desirable risk/benefit profiles in the clinical generalized anxiety disorder, and post-traumatic stress disorder literature are beta blockers and antiemetic antimuscarinic drugs. (PTSD). These various anxiety Disorders are delineated within These agents have been widely used as monotherapies for a the Diagnostic and Statistical Manual of Mental Disorders least half of a century around the globe. (e.g., DSM-V). These molecular targets can be components They are appealing in large part due to historic safety profiles of the central nervous system (CNS), the peripheral nervous and because they do not exhibit the potential for chemical system, and/or of target somatic tissues (e.g., cardiovascular dependence or substance abuse. Therefore, these two classes and gastrointestinal tissues). The multiplicity of symptoms of of agents are not subject to the US Food & Drug Administration anxiety disorders are under the complex regulation of different (FDA) and Drug Enforcement Agency (DEA) as Controlled neurologic, neuroendocrine, and endocrine pathways.
Substances (i.e., "Scheduled" drugs). Furthermore, many Let us consider the multiplicity of symptoms that occur antimuscarinic drug products are sold without prescriptions, in an acute anxiety episode, of which a panic attack serves as such as over-the-counter (OTC) or in some foreign settings the foremost and severe example. Perception of a "trigger" behind-the-counter with pharmacists' assistance.
circumstance results in the autonomic release of epinephrine Beta blockers and antiemetic antimuscarinic (adrenaline), as well as cortisol and norepinephrine. This in (anticholinergic) active pharmaceutical ingredients (APIs) are turn causes multiple effects consistent with a "fight-or-flight" of particular interest for primary care physicians (PCPs), such response. Symptoms include tachycardia, palpitations (self as family practitioners, internists, and osteopaths, as well as perception of an elevated heart rate and/or of a strong heart beat), physician assistants, nurse practitioners, and dentists. There hypertension, hyperventilation with reduced blood CO and is a need to provide drugs to their affected patients with some altered pH, dyspnea, nausea, vomiting, sweating, anxiousness, anxiolytic efficacy, yet without incurring unnecessary safety fear, avoidance, trembling (tremors), headache, among others. risks. In contrast, this is problematic with the alternative, Many of the somatic and/or psychic (CNS) symptoms of panic more potent, and risk-laden options, such as benzodiazepines. attack are shared in common with other acute anxiety episodes. The more potent drugs are more likely to be prescribed by Therefore, it follows that a treatment for an array of the psychiatrists or hospitalists. Many prescribers in primary care symptoms of panic per se can also be effective against a broader settings are reluctant to prescribe the more potent drugs (e.g., list of anxiety disorders.
benzodiazepines) or are restricted from doing so. Thus, beta Some patients anticipate future episodes of panic or acute blockers and antimuscarinic agents help address this need, anxiety based upon his/her history of prior encounters with a wherein safety is the paramount decision factor.
known "trigger" circumstance. A trigger circumstance might Thomas P. Dooley
be public speaking or music performance, flying or driving, stated regarding benzodiazepines as a class of anxiolytic drugs, a crowd, decision making, an unfamiliar setting, among "Only lorazepam is currently available in a form suitable for others. Treatments may be tailored to be either prophylactic sublingual administration, which was developed in the hope or therapeutic in nature. Given the patients' anticipation of a that, by bypassing the gut, a more rapid onset could be achieved trigger leading toward likely future symptoms, p.r.n. "as needed" similar to that with intramuscular administration. However drug treatments can begin either during or immediately prior Greenblatt et al., [11] found that the sublingual formulation was to the time when symptoms would be expected to commence. absorbed at a rate that did not differ significantly from that of Alternatively prophylatics could be administered continuously regular oral administration of the standard tablets or even from over weeks or years, or within hours of the anticipated triggers.
that of sublingual administration of the standard oral tablets." In aggregate anxiety disorders are extremely common, Thus, benzodiazepines are not suitable APIs for rapid treatment affecting nearly 40 million in the US. With regard to the subset of symptoms of panic attacks or acute anxiety episodes, even experiencing the most severe episodes, the lifetime prevalence when delivered sublingually (mucosally). When "time is of the of PA is 28.3% of the adult US population [1]. The 12-month essence" for therapy, benzodiazepines are inadequate, regardless prevalence of panic disorder (PD) is estimated to be 2.7% of the of the oral or sublingual routes of administration. Perhaps the adult US population [2], with 1.2% considered as "severe" [3]. perception of benzodiazepines' fast-action is due to comparison More than half of affected adults (59.1% or 3.8 million) are with SSRIs, which require a very slow dose-escalation approach receiving treatment(s) [4]. Patients affected by PAs are often over weeks of time to produce a beneficial effect. In that context also affected by the co-morbid conditions of depression [5] as benzodiazepines are faster than SSRIs. But, in spite of FDA well as migraines and other forms of headaches [6,7].
approvals for p.r.n. use of certain benzodiazepines and their broad availability, there still remains a need for fast-acting p.r.n. The current standards-of-care for panic disorder are oral anxiolytics. In fact, an academic psychiatrist characterized this psychiatric prophylactic pharmaceuticals, including: (a) Selective need to the author as "…the Holy Grail of modern psychiatry." serotonin reuptake inhibitors (SSRIs), which are considered as the first choice medicines for PD. Examples include paroxetine Benzodiazepine and SSRI drugs can produce disabling (Paxil®), sertraline (Zoloft®), and fluoxetine (Prozac®); (b) psychic and somatic side effects, such as sedation, lethargy, Benzodiazepines, such as alprazolam (Xanax®), clonazepam chemical dependence, tolerance, impaired cognition, and sexual (Klonopin®), lorazepam (Ativan®), and diazepam (Valium®); dysfunction. As a result of these negative side effects and some and (c) Serotonin-norepinephrine reuptake inhibitors (SNRIs), potential for abuse, benzodiazepines are classified by the FDA such as duloxetine (Cymbalta®) and venlafaxine (Effexor®). as Schedule 4 (IV) Controlled Substances. Many physicians These oral therapies are taken daily for the prevention of and other prescribers are reluctant to prescribe or are restricted panic attacks. Some of these drugs are FDA approved for the from prescribing benzodiazepines. Therefore, beta blockers or prophylaxis of PD, such as paroxetine, sertraline, alprazolam, antiemetic agents that are generally perceived as historically and clonazepam. Other anxiety disorders are also treated in the safe or safer than benzodiazepines are often preferable. This same or a similar manner. For instance, social anxiety disorder, is especially true in the primary care and family practice generalized anxiety disorder, agoraphobia, and PTSD are also disciplines. Sedation and lethargy are often problems for many treated using the same or similar oral daily pharmaceutical of the oral daily anxiolytic therapies, such as benzodiazepines. regimens [8].
It is not uncommon to note a "zombie-like" state in patients taking benzodiazepines. By contrast, beta blockers are non- The pharmaceutical standards-of-care in routine psychiatric addicting and non-sedating. And, the antimuscarinic agents care of panic and anxiety disorders involve two key aspects: are non-addicting, and are non-sedating or minimally sedating (A) prophylaxis, rather than treatment of the symptoms per at appropriate antiemetic doses. However, high doses of some se; and (B) the medications are routinely given as daily oral antiemetics can produce sedation.
"maintenance" medications for persistent use (i.e., chronic prophylaxis), rather than as occasional administration p.r.n. Beta Blockers: Beta adrenergic receptor antagonists are
"as needed" at the time of episodes of symptoms (i.e., acute prescribed "off label" (i.e., without FDA approval) for anxiety disorders, and most notably for performance anxiety and social phobia. Beta adrenergic receptor antagonist agents may be Although oral benzodiazepines have been used as selected from a large group of APIs consisting of propranolol, persistent daily medications for the prophylaxis of panic and atenolol, alprenolol, acebutolol, betaxolol, bisoprolol, acute anxiety, they are not reasonable candidates for a "fast- bucindolol, celiprolol, nadolol, sotalol, esmolol, carteolol, acting" p.r.n. therapy approach. Benzodiazepines are often carvedilol, mepindolol, nebivolol, oxprenolol, penbutolol, mistakenly considered to be "fast-acting", although multiple pindolol, landiolol, metoprolol, timolol, labetolol, among clinical reports indicate otherwise. Zamorski and Albucher others. For convenient recall by prescribers the nomenclature stated, "Benzodiazepines should not be used on an as-needed for all beta blockers contains an "LOL" suffix (and not to be basis for panic disorder. None of the oral benzodiazepines confused with the abbreviation for "laughing out loud").
works quickly enough to affect any but the most prolonged panic attacks [9]." Altamura, et al. stated recently, "…it would Propranolol is the most thoroughly studied and reported in be desirable for the development of new anxiolytic drug(s) the literature of the beta blockers, having been discovered by that are more selective, fast acting and free from the unwanted Sir James Black in 1958. It serves as the prototype for this effects associated with the traditional benzodiazepines as class of drugs, having also been the most prescribed medicine tolerance or dependence [10]." Altamura and coworkers also in the world at one juncture. Propranol is a beta adrenergic Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 91 receptor antagonist that affects the autonomic nervous system and reduces cardiovascular symptoms (e.g., tachycardia and Table 1: Clinical Evidence for Beta Blockers as Anxiolytics.
hypertension) resulting from epinephrine in the circulation. Beta blockers interfere with receptor binding by catecholamines, epinephrine and norepinephrine, of which epinephrine is the principal catecholamine affecting the cardiovascular symptoms. Performance anxiety Propranolol is a lipophilic beta blocker that readily crosses the Test-taking anxiety blood-brain barrier. Therefore, it can affect both somatic and Cognitive flexibility CNS target tissues.
Propranolol is routinely delivered orally. Propranolol in Inderal® is available in oral doses ranging from 10 to 80 mg per dose for the treatment of hypertension. Multiple doses per day Cocaine withdrawal may be permitted. This drug can also be absorbed mucosally, as TSST-induced anxiety demonstrated by sublingual delivery [12], and its bioavailability CO -induced panic is higher when absorbed by this route rather than orally [13,14]. Performance anxiety Propranolol has been delivered sublingually at 10 and 40 mg Alcohol withdrawal per dose [12,13], although this can produce mouth paresthesia, Performance anxiety an undesirable effect. Also, propranolol has been delivered by Alcohol withdrawal rectal administration in mammals [15]. It does not demonstrate Alcohol withdrawal chemical dependence or sedation that are common side effects of many psychiatric medications.
Performance anxiety Propranolol is prescribed for the treatment of various cardiovascular indications with FDA approval, most notably hypertension, arrhythmia, angina, as well as prophylaxis of Performance anxiety migraines. However, there is evidence that it can have some benefit with regard to a subset of the symptoms of panic and a single dose of 40 mg of oxprenolol prior to speaking to an anxiety disorders. The drug's anxiolytic potential was recognized audience suppressed tachycardia in performance anxiety [21]. as early as 1966, "Emotions are expressed through the autonomic In contrast, in another clinical study daily oral propranolol was nervous system, and anxiety states are associated with increased not effective at treating panic disorder and agoraphobia with secretion of catecholamines. Propranolol may therefore have a panic attacks [22].
place in the treatment of anxiety, especially when the symptoms There is some evidence suggesting that propranolol might be are related to the cardiovascular system [16]." This prescient beneficial in academic test-taking among normal and anxiety- comment five decades ago was subsequently validated by prone students. Examination performance might be increased clinical studies with regard to both aspects: (a) propranolol and by pretreatment with this beta blocker [23, 24].
other beta blockers have been used "off label" in the USA for the near-term prophylaxis of performance anxiety; and (b) the To assess the clinical efficacy of an anxiolytic drug, trials pharmacologic benefits of propranolol and other beta blockers can be performed either "in life" or in a laboratory setting are restricted to the cardiovascular system's effects per se. The intended to induce anxiety. One established clinical trial design evidence is provided below. The beneficial anxiolytic effects are to provoke anxiety is the Trier Social Stress Test (TSST). This limited to blocking the pharmacologic effects of catecholamines method is used in a clinic and involves subjecting an individual upon the cardiovascular system without addressing the psychic to public speaking and mathematics questions as stressors.
(CNS) symptoms or other somatic symptoms of acute anxiety The TSST method has been used to study the effects of oral and panic, with the possible exception of tremors.
propranolol in volunteer subjects [25-28]. The assessments (Table 1) summarizes the relevant evidence from clinical of psychic anxiety can be assessed by the State-Trait Anxiety investigations in the literature regarding beta blockers used Inventory (STAI) or other similar tools [29,30]. The somatic to treat anxiety conditions. Daily oral propranolol has been and psychic effects of oral propranolol were tested using the demonstrated in one prophylactic study to suppress panic attacks TSST method in healthy adult volunteers. Propranolol (40 mg) in subjects diagnosed with panic disorder and agoraphobia one hour prior to TSST significantly reduced heart rate, reduced [17]. Tyrer and Lader demonstrated some effectiveness of systolic blood pressure, and enhanced cognitive flexibility oral propranolol in treating somatic anxiety symptoms, but during stress. In another study propranolol (80 mg) one hour not psychic (mental) anxiety [18,19]. Another daily oral prior to TSST significantly reduced heart rate, but paradoxically prophylactic study compared propranolol (3 x 80 mg/day) to increased salivary cortisol, and did not significantly affect BP oxprenolol (3 x 80 mg/day) and revealed that both beta blockers or subjective stress [25]. But, in another TSST study daily oral reduced symptoms of anxiety at one or two weeks duration [20]. propranolol (80 mg) did not affect the salivary cortisol response Both treatments reduced heart rate; propranolol by 21 - 32 bpm and oxprenolol by 16 - 23 bpm. However, propranolol An alternative clinical trial design involves the intentional was more effective at reducing palpitations when assessed on chemical provocation of a panic attack in a clinic. Several day 7 compared to oxprenolol. Another study demonstrated that methods of provocation of PA have been reported, wherein Thomas P. Dooley
atenolol has been delivered by a mucosal route in mammals Table 2: Clinical Evidence for Antimuscarinic Agents as
Another beta blocker is nadolol, which is non-selective and with a preference for beta-1 receptors. It does not pass through the blood-brain barrier. In a clinical trial with musicians, nadolol reduced pulse rate and improved one aspect of performance related to tremor [48]. A similar result was obtained for nadolol in students' singing performance [49]. In spite of being non- selective, nadolol might ironically benefit the pulmonary function in asthma patients based upon the appropriate dosage, an anti-intuitive result [50].
An alternative beta blocker is pindolol, a non-selective agent, a physician intentionally stimulates a physiologic response which can enhance the effects of co-administered antidepressants by CO inhalation [31], sodium lactate infusion [32,33], or and has some 5-HT antagonist property. Pindolol reduced cholecystokinin tetrapeptide (CCK-4) injection [32,34]. These symptoms of performance anxiety in musicians [51].
chemical exposures are used as potent tools to design controlled studies with predictable levels of PA episodes. In a study with Another example is betaxolol that can also cross the blood- healthy volunteer subjects using carbon dioxide inhalation to brain barrier. Daily oral betaxalol was delivered at 5 - 40 mg provoke panic and anxiety, propranolol significantly decreased per day in the treatment of generalized anxiety disorder and heart rate, a cardiovascular somatic symptom, but did not other anxiety-related conditions. Anxiety and panic attacks provide psychic anxiolytic benefit [35].
were reduced within several days [52]. This anxiolytic benefit is prophylactic, as the effects are observed in days, rather than Propranolol has also been investigated in patients suffering from severe posttraumatic stress disorder (PTSD). Two clinical studies of this beta blocker have shown possible benefits in the In view of the clinical studies and off-label use of various early-stage interventional prevention and subsequent therapy beta blockers, psychiatrists are aware that beta blockers can of PTSD [36,37]. Subsequent reports have also echoed that provide some symptomatic relief with regard to performance propranolol might be effective for this condition [38-40], anxiety [53]. However, beta blockers alone do not sufficiently although other reports dispute this conclusion [41,42].
address the aggregate symptoms of panic and acute anxiety episodes, and especially the psychic symptoms thereof (e.g., When considered in aggregate these clinical studies of fear, avoidance, and anxiousness).
propranolol, as the well known prototypical beta blocker, provide convincing evidence that the drug can exert somatic (i.e., Beta blockers also exhibit some benefit with regard to peripheral) effects on the cardiovascular system in the context of alcohol and drug abuse. The abuse of alcohol, prescription panic and anxiety disorders. With regard to affecting the psychic drugs, and illegal drugs (e.g., opioids, opiates, and cocaine) (CNS) symptoms, the results have been negative, inconsistent, are major mental health care concerns. The repetitive abuse of or inconclusive. That being said, there is some limited evidence these chemicals can produce physiologic dependence, tolerance, that propranolol can exert some psychic (CNS) benefits in addiction, and neurologic damage. The symptoms of sudden clinical stress trials. In a pair of clinical studies, propranolol withdrawal depend upon the abused substance, the impairment (a central and peripheral beta-blocker) significantly enhanced of neurological and neuroendocrine pathways, as well as problem solving during stress, whereas nadolol (peripheral only somatic organ impairment. The withdrawal from addictive beta-blocker) and lorezapam (benzodiazepine) did not [43, 44].
substances produces an array of symptoms, many of which Thus, propranolol enhanced cognitive flexibility ("creativity") overlap with the symptoms of panic and acute anxiety episodes. during stress. It remains unclear whether propranolol alone can Delirium tremens (DTs) occur in some alcoholics upon abrupt appreciably reduce psychic effects. In aggregate the clinical cessation of drinking. The symptoms of alcohol-related DTs are evidence does not support a benefit regarding psychic (CNS) very similar to those of panic attacks, and are in part related to anxiety symptoms.
beta adrenergic effects. The DTs can have serious and even life- threatening consequences. The standards-of-care for DTs are Numerous alternative beta blockers are available in lieu oral benzodiazepines. Withdrawal from opioid and/or opiate of propranolol. Notable among these is the common drug, addiction is physiologically distinct from alcohol withdrawal.
atenolol, that is available in oral solid dose forms ranging from 25 to 100 mg for the treatment of hypertension. Multiple doses With regard to beta blockers in substance abuse, atenolol per day may be permitted. It has been used to suppress stage has been shown in placebo-controlled trials to be beneficial fright in performers when administered orally in advance [45]. in alcohol withdrawal [54-56]. Pindolol has been used to treat Atenolol is a beta-1 selective peripheral-acting agent without alcohol withdrawal [57]. Timolol had a minimal effect on a CNS effects, which should reduce the risk for asthmatic subjects subset of symptoms of patients experiencing alcohol withdrawal [46]. Thus, atenolol might be preferred over the nonselective [58].With regard to cocaine abuse, propranolol has been used to beta blockers for patients affected by asthma or COPD [47]. treat withdrawal and overdoses [59, 60]. Note that propranolol Oral atenolol at 50 - 200 mg doses suppressed heart rate by 23 has also been shown to suppress tremors [61], consistent with - 24 beats per minute (bpm) vs. 10 bpm on placebo [46]. Also, one of the perceived benefits of beta blockers in performance anxiety in musicians (above).
Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 93 Migraine is a co-morbid condition in approximately two- mg, and a maximum daily dose of 1.2 mg [78]. Scopolamine thirds of patients suffering from panic disorder [6,62]. The can also be absorbed mucosally, as demonstrated by sublingual prevalence of migraine in the USA according to the American delivery [79,80]. It has been delivered sublingually at 0.15 mg/ Migraine Prevalence and Prevention (AMPP) study is 11.7% dose [79], intranasally at 0.4 mg [81,82], orally at 0.4 - 1.0 mg/ and probable migraine is 4.5%, for a combined total of 16.2% dose [80,83], and transdermally (Transderm Scop®) at 1.5 mg/ [63]. The rate is higher in females than in males. According dose over 3 days as antiemetic treatments or prophylactics. Oral to Smitherman and coworkers, "The first-line migraine delivery, unlike mucosal or transdermal delivery, involves first- prophylactics are not indicated for PD, and the selective pass hepatic metabolism of scopolamine, thus restricting its serotonin re-uptake inhibitors used to treat PD are not efficacious for migraine; thus, separate agents are often required to address each condition [6]." Furthermore, according to Marazziti and Antiemetic muscarinic receptor antagonist agents can be coworkers, "…the comorbidity of headache with panic disorder selected from a large group beyond scopolamine, examples of renders this condition more severe and possibly responsive to which include diphenhydramine, meclizine, buclizine, cyclizine, different treatments compared to panic disorder alone [64]." hydroxyzine, pirenzepine, benztropine (benzatropine), atropine, hyoscyamine, butylscopolamine, methylscopolamine, It is feasible that a beta blocker alone may provide therapeutic doxylamine, promethazine, trihexyphenidyl, orphenadrine and benefit for both conditions, panic and migraine. Beta-adrenergic its metabolite tofenacine. Depending on the choice of country, receptor antagonists are considered to be effective prophylactics OTC or "behind-the-counter" antiemetic antimuscarinic for chronic or episodic migraine [65-70]. Although one study agents include diphenhydramine, orphenadrine, doxylamine, reported no benefit from propranolol for treatment of acute meclizine, buclizine, cyclizine, and scopolamine. This further symptoms [71], there is some, albeit limited, evidence that underscores the perception by regulatory agencies of the safety beta adrenergic receptor antagonists, especially when delivered of antimuscarinic agents. Dryness of the mouth is a common mucosally, can also have benefit in the therapy of acute migraine side effect of antiemetic agents.
Structurally-related derivatives of scopolamine are Beta blockers may be effective as a treatment for aggression. alternative antimuscarinic APIs, such as butylscopolamine, Systemic adrenaline can produce excited, anxious, and methylscopolamine, atropine, hyoscyamine (the levo aggressive behavior in some individuals. Propranolol has been isomer of atropine), and benztropine (benzatropine). For shown to have a therapeutic effect with regard to aggressive instance, peripherally-acting butylscopolamine (scopolamine behavior [74,75].
butylbromide) is used for the treatment of abdominal spasms. Although psychiatrists (and some other physicians) are aware The butylbromide modification prevents the API from crossing of off-label use of beta blockers as prophylactics for performance the blood-brain barrier. However, direct pharmacologic action anxiety (e.g., stage fright during musical performances), the by the antimuscarinic agent upon the CNS might be preferable, current pharmaceutical standard-of-care for anxiety disorders if not necessary, for mediating psychic benefits in anxiety.
does not routinely include the use of beta blockers. But, beta In addition to the scopolamine "family" of APIs, adrenergic receptor antagonists can provide limited benefit, such there are other closely-related families of APIs exhibiting as the suppression of cardiovascular symptoms - tachycardia, antimuscarinic activities. In some cases the APIs also exhibit palpitations, and increased blood pressure, which are symptoms antihistamine properties. Examples of other "families" of of acute anxiety episodes and panic. That being stated, Zamorski antiemetic antimuscarinic agents include: (a) Ethanolamines: and Albucher concluded, "Beta blockers, once widely touted diphenhydramine (Benadryl®), doxylamine (Unisom® or as effective antipanic medications, have proven disappointing Nyquil®), orphenadrine (an OTC in Canada) and its metabolite as monotherapy in subsequent placebo-controlled trials." The tofenacine; and (b) Piperazines: meclizine (Dramamine® multiplicity, severity, and short duration of symptoms in a panic Less Drowsy Formulation or Bonine®), buclizine, cyclizine, attack make it a difficult disorder to treat by p.r.n. therapies.
hydroxyzine (Atarax® or Vistaril®), and pirenzepine. Muscarinic Receptor Antagonists: Scopolamine is the Furthermore, other types of antiemetic antimuscarinic agents
prototypical antiemetic antimuscarinic agent. It is a plant-derived are available, such as promethazine (Phenergan®) and natural product derived from the Solanaceae "nightshade" trihexyphenidyl.
family of plants (e.g., jimson weed), and is commonly used for (Table 2) summarizes the relevant evidence from clinical the treatment of motion sickness, nausea, and vomiting. It is investigations in the literature regarding antimuscarinic agents a potent nonselective muscarinic receptor antagonist that can used to treat anxiety conditions. Hydroxyzine is an FDA- inhibit all five human receptor subtypes with 0.34 - 5.3 nM Ki approved prescription medicine for the treatment of anxiety [84]. values [76]. It is lipophilic and crosses the blood-brain barrier The package insert for Atarax® (Roerig) states it is indicated to exert psychic parasympathetic (CNS) pharmacologic effects.
"for symptomatic relief of anxiety and tension associated Scopolamine is sold by prescription in the USA as a with psychoneurosis and as an adjunct in organic disease transdermal patch (Transderm Scop®) [77]. However, states in which anxiety is manifested." As a first-generation scopolamine is available without a prescription in many foreign antihistamine this drug entered the healthcare marketplace in markets, where it can be purchased OTC or behind-the-counter the mid-1950's. It displays broad receptor binding, affecting with pharmacist's assistance. For instance, in Australia it is an histamine, muscarinic, and 5-HT receptors. Placebo-controlled oral OTC product with a recommended adult dose of 0.3 or 0.6 studies with a total daily dose of 50 mg have revealed anxiolytic benefit following weeks or months of treatment in generalized Thomas P. Dooley
anxiety disorder [84-86]. This "old" drug is no longer among of pharmacologic effects can precede the zenith of plasma the frontline choices for anxiety, having been superceded levels, except for rapid intravenous administration wherein by benzodiazepines and subsequently SSRIs and SNRIs. pharmacologic effects might be concurrent or delayed slightly.
However, it has at least two beneficial properties -- an effect can be perceived faster than many other oral anxiolytics, and like The antidepressant dose via the i.v. route (4 ug/Kg) is likely other antimuscarinic agents it has a desirable risk/benefit profile to be above the blood levels attained during routine antiemetic (i.e., doesn't produce dependency). In addition to treating dosing (e.g. transdermal patches or oral dose forms), wherein generalized anxiety disorder, a few case reports suggests it sedation would be considered a significant and undesirable might be beneficial in treating panic disorder [87,88].
side effect. For comparison, sedation is generally considered in the literature to occur at 1.2 mg or higher by the oral route. Promethazine is another antimuscarinic agent with Scopolamine has been used as a safe pre-sedative, for instance antihistamine and CNS activities. Oral promethazine at 25 mg/ in pregnant women prior to delivery.
dose reaches a peak serum level (C ) in 2-3 hours, which is relatively slow for an oral drug, and can result in drowsiness In addition to scopolamine, two other muscarinic receptor within a similar time window [89]. As a premedication prior to antagonists, orphenadrine and its major metabolite, tofenacine, surgery, it produced an anxiolytic effect that was substantially have also been reported to exhibit an antidepressant effect [99- greater than placebo [90].
101]. Orphenadrine is beneficial in treating multiple symptoms of Parkinsonism. Orphenadrine administered orally (300 mg/ Although depression per se is not the focus of this review, day) for three weeks in patients afflicted by Parkinsonism was selected antimuscarinic agents can display psychic (CNS) very effective at blocking depression relative to placebo [100]. pharmacologic effects on mood, such as depression (e.g., Tofenacine at 120 – 240 mg/day for six weeks was effective major depressive disorder). Scopolamine can exhibit an in treating neurotic depression, endogenous depression, mixed antidepressant effect when administered intramuscularly [91], depression, and phobic anxiety diagnoses and within two weeks intravenously [92-94], or orally [83]. With regard to patients of initiation of therapy [101].
treated with i.v. infusions of 4 ug/Kg (e.g., 0.28 mg/70 Kg), "Significant clinical responses were observed in the evaluation Although not common knowledge among physicians at after the first scopolamine administration, 3 to 4 days after present, there is some historic evidence that scopolamine can the first treatment." And, "…those patients who observed an exert anxiolytic effect(s). Scopolamine was described a century improvement in their depression severity generally reported ago to have a "calming effect" when injected hypodermically into relief from their depressive symptoms on the first morning after patients afflicted by various psychiatric disorders (e.g., manias) scopolamine infusion (i.e., within 24 hours of drug exposure). at doses of 0.2 - 1.0 mg [102]. Coincidentally, these doses are In contrast, no improvement in mood was evident within 150 still relevant in clinical use to this day. This 1906 publication minutes of scopolamine infusion based upon the POMS" (i.e., mentioned, "…the calming effect of the medicament…The Profile of Mood States) [95]. Although i.v. administration at action of scopolamine shows itself rapid in maniacal excitement 4ug/Kg can affect depression, many patients receiving this and in acute hallucinatory delirium. The patients become calm treatment regime also experienced sedation. In addition, they gradually, and fall asleep if the dose is somewhat larger." experienced dry mouth, blurred vision, and/or lightheadedness.
A genetic study of the human M2 muscarinic receptor gene The efficacy and side effects of a drug are dependent upon (CHRM2) has revealed an association between specific genetic the dose delivered and the route of administration. It should be polymorphisms and the risk of depression in major depressive noted that the pharmacokinetic magnitude of effect and the time syndrome [103]. Consistent with these pharmacologic and to reach an effect of a "typical" API is very likely to exhibit a genetic findings in humans are laboratory studies with rodent range from intravenous > intramuscular or mucosal > oral >> models for antidepressant activity. Both pharmacologic and gene transdermal. This pattern is in fact the case for scopolamine knock-out approaches in mice revealed that the antidepressant- in humans. As an example thereof, intramuscular injection like effects of scopolamine are mediated via the M1 and/or M2 of 0.5 mg of scopolamine displayed only 57% of the absolute receptors, but not the M3, M4, and M5 receptors [76]. Thus, bioavailability relative to i.v. infusion of the same dose, and is the human M2 (and/or M1) receptor-linked second messenger subject to some delay [96]. Thus, an i.v. antidepressant dose signaling pathways in the CNS are likely to affect mood and of 0.28 mg/70 Kg of scopolamine is very likely to have an mood disorders (e.g., depression).
immediate and more profound physiologic effect relative to Alcohol dependence is comorbid with depression, and the same dose via other routes of delivery, because there are no has been genetically linked to the same human CHRM2 gene membrane and tissue barriers to entry into the circulation when encoding the M2 muscarinic receptor. Scopolamine has an injected intravenously. By contrast intranasal (mucosal) dosing M1 receptor preference over M2, but it can also bind the M2 of 0.4 mg results in a C (i.e., the peak level in the blood) after receptor [76,103]. Thus, there is a convergence between the 22 minutes [82]. Oral dosage forms of 0.6 mg displayed a peak genetic and the pharmacologic studies in both humans and plasma level at 50 minutes [97]. And, the 1.5 mg transdermal laboratory mice, thereby providing a suggested rationale for patch produces a C of 8 hours [98]. Thus, the timing to the use of scopolamine in treating alcohol addiction and/or reach peak blood levels of scopolamine by various routes of withdrawal. These findings might also apply to other antiemetic administration is or should approximate this progression: i.v. antimuscarinic agents beyond scopolamine.
at 0 min. > intranasal (mucosal) at 22+ min. > oral at 50 Scopolamine has also been shown to reduce aggressive min. >> transdermal at 8 hours. In general, the perception behavior in nonhuman primates under certain environmental Treating Anxiety with either Beta Blockers or Antiemetic Antimuscarinic Drugs: A Review 95 circumstances [104]. It is not yet clear whether this is also true antimuscarinic agent in healthy volunteers when exposed in humans. But, it can be argued that an anxiolytic calming to heat within a sauna [105]. The beta blocker was selected effect might similarly reduce aggression in some humans, which because heat induces cardiovascular stress, especially elevated is perhaps suggested by its historic effect in treating "maniacal heart rate. Scopolamine was selected as it is known to reduce excitement" [102]. sweating. The cardiovascular effects of oral atenolol (50 mg), The Future – Beyond Monotherapy: The monotherapies
oral scopolamine (0.3 mg), and coincident administration of mentioned above provide some, albeit limited, pharmacologic both drugs were monitored before, during, and after heat stress. efficacy for anxiety disorders, yet while being historically safe The coincident administration of both drugs revealed essentially approaches to therapy and/or prophylaxis in mental health. the same cardiovascular effects as atenolol alone (i.e., reduced Reaching beyond current monotherapies, another approach is heart rate and blood pressure), and either at baseline prior to combination therapies with two or more APIs. Combination heat exposure or during it. The relevant antiemetic oral dose drugs can be sold legally to patients, albeit subject to various of scopolamine alone or as an adjunct to atenolol displayed alternative regulatory oversight processes.
essentially no effect with regard to the cardiovascular symptoms, although a slight tachycardia occurred with scopolamine relative Within the USA combination drug products may be FDA to placebo. Overall, the cardiovascular effects (i.e., reduced heart approved for specific medical indications through the FDA's rate and systolic BP) were due to atenolol. Thus, scopolamine drug approval processes that can result in either approved co-adminstration did not abrogate the cardiovascular effects prescription (Rx) drugs or approved OTC drugs. Alternatively, of the beta blocker. The potential for any psychiatric and/or compounding pharmacies may formulate multiple APIs into psychic (CNS) effects of scopolamine and/or atenolol were not a compounded pharmaceutical product via either the 503A or envisioned or addressed by this study.
503B regulatory pathways. But, key parameters must be met for compounded products. For instance, several of the restrictions In view of these results [105] and given that episodes of include: (a) Each of the APIs must have been included in at least acute anxiety and panic are driven physiologically in part by one FDA-approved medication; (b) The compounded product increased epinephrine's effects on the cardiovascular system, must not be a copy of an FDA-approved combination drug; and it is appropriate to include within a combination therapy a (c) The compounded products are subject to USP 795 or USP 797 beta blocker to address the cardiovascular symptoms per se of standards and procedures during compounding or "outsource" anxiety disorders. Based upon the literature an antimuscarinic facility manufacturing, respectively. These compounded agent alone would not be anticipated to be of benefit for the products are sold by prescription only as "unapproved" cardiovascular symptoms of these psychiatric conditions. products, although subject to state boards of pharmacy and FDA Coincidentally, the antimuscarinic agent atropine is known to produce tachycardia, and scopolamine to a lesser extent. Tachycardia is antithetical to the desired outcome.
In view of the historic scientific and clinical literature mentioned above on beta blockers or antiemetic drugs as It should be emphasized that palpitations (resulting from monotherapies for anxiety disorders, the author recognized both elevated heart rate and/or blood pressure) are considered to be a need in the pharmaceutical marketplace and an opportunity to the predominant symptom that patients are aware of during panic augment the limited cardiovascular benefits of a beta blocker attacks and acute anxiety episodes. The beta blocker, within a dual with another type of API to produce a superior anxiolytic drug product, should address this primary (major) symptom of therapy for p.r.n. administration. It would be advantageous for panic and acute anxiety episodes.
the augmenting second agent: (a) to address other symptoms; Recently the author has developed novel pharmaceutical (b) to exert some psychic (CNS) pharmacologic benefits; (c) to formulations to address the augmentation of a beta blocker's effects have a rapid effect; and (d) to not be a Controlled Substance. on the cardiovascular symptoms with an antiemetic antimuscarinic Thus, the augmenting second API could not be an opiate, opioid, agent's effects on non-cardiovascular symptoms (unpublished benzodiazepine, SSRI, or cannabinoid. This led the author to an results). This new dual drug approach holds substantial promise innovative conclusion; a combination of a beta blocker plus an to address p.r.n. all or most of the symptoms of acute anxiety antiemetic antimuscarinic agent should be of substantial clinical episodes or panic, neither of which is addressed by a beta blocker benefit and reaching beyond the pharmacologic benefits of alone or an antiemetic antimuscarinic agent alone. The dual drug either class of drugs acting alone as monotherapies.
compositions provide a complementary broad coverage of the Searches of the literature did not reveal any precedents for this symptoms of acute anxiety: the beta blocker provides benefits dual drug combination therapy approach using these two classes with regard to cardiovascular symptoms (e.g., palpitations, heart of agents (i.e., beta blocker plus antimuscarinic agent) in any rate, and BP); and, the antimuscarinic agent provides benefits with medical indication in mental health or psychiatry. Secondarily, regard to non-cardiovascular symptoms (e.g., nausea, vomiting, searches did not reveal any record of both classes of APIs being sweating, anxiousness, avoidance, fear, etc.).
formulated together into a single drug formulation. Thus, this It should be noted that augmentation of a beta blocker with an dual drug approach was novel with regard to both aspects, even antimuscarinic agent, wherein the latter only affects a subset of though both classes of drugs have been in commercial use for the common symptoms of acute anxiety (i.e., nausea, vomiting, over five decades.
sweating, and/or motion sickness) per se would provide anxiolytic That being said, one relevant article addressed the superiority over a beta blocker alone or an antiemetic agent coincidental co-administration of a beta blocker with an alone. In other words, even without affecting psychic symptoms (e.g., anxiousness, fear, avoidance, etc.), the dual drug approach Thomas P. Dooley
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Address for correspondence
Thomas P. Dooley, Ph.D. TPD LLC, 7100 Cabin Lane,
Pinson, Alabama 35126, USA; Tel: 205-222-6145; E-mail: [email protected] Oct 26, 2015Accepted Nov 23, 2015

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