Understanding drug pharmacology and mechanism of action helps explain therapeutic and side effects, as well as potential adverse effects when drugs are discontinued. In this four-part article series, I will provide a broad overview of the potential adverse effects associated with the discontinuation of various psychotropic drugs. The first article will focus on adrenergic, cholinergic, and histamine drugs. Because some of their pharmacological properties are shared with other psychotropic drugs, this information will be relevant for subsequent articles in this series.
The nervous system is broadly subdivided into the central nervous system (CNS), comprising the brain and spinal cord, and the peripheral nervous system (PNS) (Noback, Strominger, & Demarest, 1996). The PNS consists of nerves emerging from the CNS, either conveying information from sense organs and sensory receptors throughout the body to the CNS or sending messages from the CNS to muscles, glands, and every other organ throughout the body. Within the CNS and PNS, the somatic nervous system is responsible for transmitting and processing conscious and unconscious sensory information from the body to the CNS (i.e., vision, pain, touch, and unconscious muscle sense) and for motor control of voluntary muscles. By contrast, the autonomic nervous system serves to convey and process sensory input from visceral organs (e.g., gut, heart) and provides motor control of involuntary muscle, cardiac function, and gland secretion.
When a drug is administered, it is distributed to its site of action, where it interacts with its particular target(s), undergoes metabolism, and is then eliminated (Brunton, Lazo, Parker, Buxton, & Blumenthal, 2006). Psychotropic drug targets are enzymes, transporters, receptors, or second-messenger signal transductions systems that regulate the synthesis, recycling, and degradation of neurotransmitters and their functional activity. Drugs affect patient function through their intended therapeutic use together with unintended effects on the nervous system or other organs throughout the body. The functional consequences of taking psychotropic drugs generally encompass effects on mood (depression, mania), perception (hallucinations, delusions), arousal (sedation, anxiety, agitation), cognition (memory, concentration, attention), the neuromusculoskeletal system (gait, balance, motor coordination), vision, speech articulation, and bowel, bladder, and sexual function.
Adrenergic Receptor Drugs
The neurotransmitters epinephrine and norepinephrine bind to adrenergic receptors. The physiological effects of increased adrenergic activity include tachycardia, hypertension, and vasoconstriction, as well as increased alertness, arousal, anxiety, and motor hyperactivity (Brunton et al., 2006). The main adrenergic receptor subtypes are designated as alpha-1, alpha-2, beta-1, and beta-2. Drugs having agonist (stimulating) or antagonist (blocking) effects on adrenergic receptors are approved by the U.S. Food and Drug Administration (FDA) for various cardiovascular conditions (e.g., hypertension). Some are used for other medical conditions (e.g., migraine headache, benign prostatic hypertrophy). Several have accepted clinical applications in psychiatry.
Clonidine (Catapres®) and guanfacine (Tenex®) are presynaptic alpha-2 receptor agonist drugs. Stimulation of presynaptic alpha-2 receptors reduces the firing rate of adrenergic neurons in the brain and reduces plasma concentrations of norepinephrine. On the basis of this effect, clonidine and guanfacine have been used for treating conditions associated with increased adrenergic activity (Sadock, Sadock, & Sussman, 2006). They are effective in reducing autonomic symptoms (e.g., anxiety, hypertension, tachycardia, dilated pupils, sweating, lacrimation, rhinorrhea, diarrhea) associated with addictive drug withdrawal states (e.g., opioid, alcohol, and benzodiazepine withdrawal). They can also reduce craving, anxiety, and irritability symptoms associated with nicotine withdrawal. In Tourette syndrome and other tic disorders, they can suppress motor/vocal tics. They can improve irritability, hyperactivity, and sleep problems associated with attention-deficit/hyperactivity disorder, and guanfacine is FDA approved for this indication. In posttraumatic stress disorder (PTSD), they can reduce such autonomic symptoms as hyperarousal, exaggerated startle response, insomnia, vivid nightmares, tachycardia, agitation, and perspiration. They can be used for similar anxiety and autonomic symptoms in panic disorder and generalized anxiety disorder (GAD). After chronic use, abruptly stopping clonidine and guanfacine can cause rebound anxiety, restlessness, sweating, tremors, abdominal pain, heart palpitations, headache, and hypertension.
Prazosin (Minipress®) is a postsynaptic alpha-1 receptor antagonist drug. Blocking post-synaptic alpha-1 receptors in the CNS and PNS attenuates the effects of increased adrenergic activity throughout the body. Similar to clonidine, prazosin has been shown to be effective in reducing anxiety and autonomic symptoms associated with PTSD. Abruptly stopping prazosin after chronic use can cause rebound tachycardia and hypertension.
More than a dozen beta-adrenergic receptor antagonist drugs (beta-blockers) are currently FDA approved. Propranolol (Inderal®) and pindolol (Visken®) are the two beta-blockers used most often in psychiatry (Schatzberg, Cole, & DeBattista, 2007). Blocking postsynaptic beta-1 and beta-2 receptors in the CNS and PNS attenuates the effects of increased adrenergic activity throughout the body. Propranolol has been used to reduce anxiety and autonomic symptoms in GAD, PTSD, social anxiety disorder, and performance anxiety. Similar to clonidine, it has been used for reducing autonomic symptoms associated with addictive drug withdrawal states (especially alcohol withdrawal). Propranolol is most commonly used for treating medication-induced tremors (e.g., lithium) and antipsychotic drug-induced akathisia. Akathisia is characterized by a subjective and objective sense of restlessness, anxiety, and mild motor agitation. Propranolol (and other beta-blockers) can be effective in reducing aggressive and violent outbursts in people with impulse control disorders, brain injuries, and other degenerative neuropsychiatric conditions.
As a beta-blocker, pindolol is somewhat unusual. Under conditions of increased adrenergic activity, it blocks postsynaptic beta-1 and beta-2 receptors. However, when basal levels of adrenergic activity are lower, it has weak partial agonist (partially stimulating) effects on these receptors—referred to as intrinsic sympathomimetic activity. In addition, pindolol blocks presynaptic 5HT-1A receptors (a serotonin [5HT] receptor subtype), an effect that increases the presynaptic release of 5HT. On the basis of these unique adrenergic and 5HT effects, pindolol has been used to augment (boost) and accelerate (hasten) the therapeutic effects of antidepressant drugs. Abruptly stopping beta-blockers after prolonged use can cause rebound restlessness, sweating, tremors, tachycardia, headache, hypertension, and angina.
The neurotransmitter acetylcholine (ACh) is important for communication between neurons and muscle at the neuromuscular junction, is the main neurotransmitter in the autonomic parasympathetic nervous system, and is involved in cognitive processing, arousal, and attention (Brunton et al., 2006). Cholinergic transmission occurs through receptors throughout the CNS and PNS. Within the basal ganglia, dopamine (DA) and ACh pathways have a counter-regulatory effect on each other. For this reason, anticholinergic drugs, which block ACh receptors, are used for Parkinson’s disease and the parkinsonian effects associated with antipsychotic drugs. Anticholinergic drugs include benztropine (Cogentin®), biperiden (Akineton®), and trihexyphenidyl (Artane®). Anticholinergic adverse effects include dry mouth, constipation, blurred vision, and urinary retention.
Abruptly stopping anticholinergic drugs can lead to an anticholinergic discontinuation syndrome characterized by cholinergic rebound. These symptoms include nausea, vomiting, abdominal cramping, sweating, headache, muscle spasms, and urinary urgency. Cholinergic blockade secondarily increases DA transmission, resulting in euphoria, and stopping anticholinergic drugs after prolonged use can be associated with depression. Because chronic anticholinergic drug use can sensitize DA systems, discontinuation of these drugs is rarely associated with the development of motor dyskinesias and neuroleptic malignant syndrome (NMS), both of which are more commonly associated with antipsychotic drugs (Matsuda, Makiguchi, & Sugano, 1981; Spivak et al., 1996). Dyskinesias are characterized by abnormal, involuntary, irregular motor movements involving muscles of the head, limbs, or trunk. Symptoms of NMS include muscular rigidity, akinesia (immobility), mutism, obtundation, and agitation. Autonomic symptoms include high fever, sweating, tachycardia, and hypertension.
The effects of ACh on cholinergic transmission are terminated by the action of cholinesterase enzymes that metabolize ACh. Acetylcholinesterase inhibitor drugs block the effects of this enzyme, and they are used clinically to boost cholinergic function for the treatment of dementia. Acetylcholinesterase inhibitors include tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Reminyl®, Razadyne®). Potential adverse effects of acetylcholinesterase inhibitor drugs are due to increased cholinergic activity throughout the CNS and PNS and include nausea, vomiting, dizziness, headache, diarrhea, abdominal pain, anorexia, fatigue, sedation, muscle cramps, syncope, and bradycardia (Sadock et al., 2006). Acetylcholinesterase inhibition is reversible, so abrupt discontinuation may be associated with mild anticholinergic effects (dry mouth, constipation, blurred vision, and urinary retention).
The neurotransmitter histamine binds to H-1 and H-2 receptors in the CNS and PNS (Brunton et al., 2006). Activation of H-2 receptors in the stomach promotes acid secretion; drugs blocking this effect are used for treating acid reflux. Activation of H-1 receptors in the CNS promotes wakefulness and is involved in processes that regulate satiety (hunger) and cellular metabolism. H-1 receptor blocking drugs are associated with sedation and increased appetite.
Diphenhydramine (Benadryl®), hydroxyzine (Atarax®, Vistaril®), promethazine (Phenergan®), and cyproheptadine (Periactin®) are drugs that block H-1 receptors and have mild anticholinergic effects. Diphenhydramine is commonly used for treating insomnia, mild symptomatic anxiety, and drug-induced extrapyramidal effects. Hydroxyzine and promethazine are used primarily for insomnia and mild symptomatic anxiety. Cyproheptadine has been used for insomnia. Adverse effects of antihistamine drugs include sedation, dizziness, dry mouth, constipation, urinary retention, blurred vision, and weight gain. Abrupt discontinuation can be associated with activation, insomnia, and mild anticholinergic withdrawal symptoms such as nausea, sweating, and headache.
The pharmacology of a drug is important not only for understanding its therapeutic and side effects, but also potential adverse discontinuation effects. Adverse discontinuation effects can occur with the three classes of drugs reviewed in this article but may be potentially more serious with adrenergic receptor drugs. Tapering, rather than abruptly discontinuing, medication can avoid or minimize these effects. Nurses should be familiar with the discontinuation effects associated with these drugs. This knowledge will be important for monitoring patients during pharmacotherapy and for counseling patients and families about medication adherence. Next month’s article will focus on antidepressant drugs.
- Brunton, L.L., Lazo, J.S., Parker, K.L., Buxton, I.L.O. & Blumenthal, D. (Eds.). (2006). Goodman & Gilman’s the pharmacological basis of therapeutics (11th ed.). New York: McGraw-Hill.
- Matsuda, T.M., Makiguchi, K. & Sugano, K. (1981). Neuroleptic malignant syndrome-like state following a withdrawal of antiparkinsonian drugs. Journal of Nervous and Mental Disease, 169, 324–327. doi:10.1097/00005053-198105000-00011 [CrossRef]
- Noback, C.R., Strominger, N.L. & Demarest, R.J. (1996). The human nervous system: Structure and function (5th ed.). Philadelphia: Williams & Wilkins.
- Sadock, B.J., Sadock, V.A. & Sussman, N. (2006). Kaplan & Sadock’s pocket handbook of psychiatric drug treatment (4th ed.). Philadelphia: Lippincott Williams & Wilkins.
- Schatzberg, A.F., Cole, J.O. & DeBattista, C. (2007). Manual of clinical psychopharmacology (6th ed.). Arlington, VA: American Psychiatric Publishing.
- Spivak, B., Gonen, N., Mester, R., Averbuch, E., Adlersberg, S. & Weizman, A. (1996). Neuroleptic malignant syndrome associated with abrupt withdrawal of anticholinergic agents. International Clinical Psychopharmacology, 11, 207–209. doi:10.1097/00004850-199609000-00009 [CrossRef]