Sympatholytic

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A sympatholytic (sympathoplegic) drug is a medication that opposes the downstream effects of postganglionic nerve firing in effector organs innervated by the sympathetic nervous system (SNS). [1] They are indicated for various functions; for example, they may be used as antihypertensives. They are also used to treat anxiety, such as generalized anxiety disorder, panic disorder and PTSD. In some cases, such as with guanfacine, they have also shown to be beneficial in the treatment of ADHD.

Contents

Mechanisms of action

Antiadrenergic agents inhibit the signals of epinephrine and norepinephrine. They are primarily postsynaptic adrenergic receptor antagonists (alpha and beta adrenergic receptor antagonists, or "blockers"), inhibiting the downstream cellular signaling pathways of adrenergic receptors. However, there are exceptions: clonidine is an adrenergic agonist at the α2 receptor; since this receptor is located presynaptically, agonism at this receptor inhibits the presynaptic release of adrenaline and noradrenaline, preventing postsynaptic adrenergic receptor activation and downstream signaling.

Another way to inhibit adrenergic receptor signaling is by blocking the synthesis of catecholamines. Methyltyrosine, for example, inhibits one of the key enzymes in the pathway: tyrosine hydroxylase.

For neurotransmitters to be released, they first must be stored in synaptic vesicles. Reserpine works by inhibiting VMAT, preventing the storage of neurotransmitters into synaptic vesicles. If VMAT is inhibited, neurotransmitters won't be released into the synaptic cleft, thereby inhibiting their downstream effect.

Other drugs are preferentially toxic to sympathetic neurons. One method of obtaining such specificity is to exploit drugs that are substrates for a transporter preferentially expressed on sympathetic terminals, such as the norepinephrine transporter. [2] Such transports allows the drugs to accumulate within sympathetic neurones, where they can act to inhibit sympathetic function. Such drugs include bretylium, guanethidine and 6-hydroxydopamine.

Medical uses

Hypertension

Many antiadrenergic agents used as antihypertensives include:

Anxiety

Beta blockers

There is clear evidence from many controlled trials in the past 25 years that beta blockers are effective in anxiety disorders, though the mechanism of action is not known. [3]

Some people have used beta blockers for performance type social anxiety, or "stage fright." In particular, musicians, public speakers, actors, and professional dancers, have been known to use beta blockers to avoid stage fright and tremor during public performance and especially auditions. The physiological symptoms of the fight/flight response associated with performance anxiety and panic (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand. Stutterers also use beta blockers to avoid fight/flight responses, hence reducing the tendency to stutter.

Since they promote a lower heart rate and reduce tremor, beta blockers have been used by some Olympic marksmen to enhance performance, though beta blockers are banned by the International Olympic Committee (IOC). [3] Although they have no recognizable benefit to most sports, it is acknowledged that they are beneficial to sports such as archery and shooting. A recent, high-profile transgression took place in the 2008 Summer Olympics, where 50 meter pistol silver medalist and 10 meter air pistol bronze medalist Kim Jong-su tested positive for propranolol and was stripped of his medal.

Posttraumatic stress disorder (PTSD) is theorized to be the result of neurological patterns caused by adrenaline and fear in the brain. By administering beta blockers which can cross the blood brain barrier immediately following a traumatic event, as well as over the next couple weeks, the formation of PTSD has been reduced in clinical studies. [4]

Alpha2 adrenergic agonist

Alpha2 adrenergic agonists can also be used to treat anxiety and panic, such as generalized anxiety disorder, panic disorder, or PTSD. Alpha2-adrenergic receptor agonists, such as clonidine and guanfacine, act at noradrenergic autoreceptors to inhibit the firing of cells in the locus ceruleus, effectively reducing the release of brain norepinephrine. [5] Clonidine has shown promise among patients with anxiety, panic and PTSD in clinical trials and was used to treat severely and chronically abused and neglected preschool children. It improved disturbed behavior by reducing aggression, impulsivity, emotional outbursts, and oppositionality. [6] Insomnia and nightmares were also reported to be reduced.

Kinzie and Leung prescribed the combination of clonidine and imipramine to severely traumatized Cambodian refugees with anxiety, panic and PTSD. [7] Global symptoms of PTSD were reduced among sixty-six percent and nightmares among seventy-seven percent. Guanfacine produces less sedation than clonidine and thus may be better tolerated. Guanfacine reduced the trauma-related nightmares. [8]

Alpha blockers

Prazosin is an α1-blocker that acts as an inverse agonist at α1-adrenergic receptors. [9] Raskind and colleagues studied the efficacy of prazosin for PTSD among Vietnam combat veterans in a 20-week double-blind crossover protocol with a two-week drug washout to allow for return to baseline. The CAPS and the Clinical Global Impressions-Change scale (CGI-C) were the primary outcome measures. Patients who were taking prazosin had a robust improvement in overall sleep quality (effect size, 1.6) and recurrent distressing dreams (effect size, 1.9). In each of the PTSD symptom clusters the effect size was medium to large: 0.7 for reexperiencing or intrusion, and 0.6 for avoidance and numbing, and 0.9 for hyperarousal. The reduction in CGI-C scores (overall PTSD severity and function at endpoint) also reflected a large effect size (1.4). Prazosin appears to have promise as an effective treatment for PTSD-related sleep disturbance, including trauma-related nightmares, as well as overall anxiety and PTSD symptoms. [10]

See also

Related Research Articles

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Beta blocker</span> Class of medications used to manage abnormal heart rhythms

Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.

<span class="mw-page-title-main">Propranolol</span> Beta blocker drug

Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anxiety, and essential tremors, as well to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks. It can be taken orally or by intravenous injection. The formulation that is taken orally comes in short-acting and long-acting versions. Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken orally.

<span class="mw-page-title-main">Mirtazapine</span> Antidepressant medication

Mirtazapine, sold under the brand name Remeron amongst others, is an atypical tetracyclic antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is often used in cases of depression complicated by anxiety or insomnia. The effectiveness of mirtazapine is comparable to other commonly prescribed antidepressants. It is taken by mouth.

<span class="mw-page-title-main">Clonidine</span> Medication for high blood pressure

Clonidine, sold under the brand name Catapres among others, is an α2-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal, menopausal flushing, diarrhea, spasticity, and certain pain conditions. It is used orally, by injection, or as a transdermal skin patch. Onset of action is typically within an hour with the effects on blood pressure lasting for up to eight hours.

A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs because acetylcholine (ACh) is the neurotransmitter used by the PSNS. Chemicals in this family can act either directly by stimulating the nicotinic or muscarinic receptors, or indirectly by inhibiting cholinesterase, promoting acetylcholine release, or other mechanisms. Common uses of parasympathomimetics include glaucoma, Sjögren syndrome and underactive bladder.

<span class="mw-page-title-main">Sympathomimetic drug</span> Substance that mimics effects of catecholamines

Sympathomimetic drugs are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in heart rate, force of cardiac contraction, and blood pressure. The primary endogenous agonists of the sympathetic nervous system are the catecholamines, which function as both neurotransmitters and hormones. Sympathomimetic drugs are used to treat cardiac arrest and low blood pressure, or even delay premature labor, among other things.

An adrenergic agonist is a drug that stimulates a response from the adrenergic receptors. The five main categories of adrenergic receptors are: α1, α2, β1, β2, and β3, although there are more subtypes, and agonists vary in specificity between these receptors, and may be classified respectively. However, there are also other mechanisms of adrenergic agonism. Epinephrine and norepinephrine are endogenous and broad-spectrum. More selective agonists are more useful in pharmacology.

<span class="mw-page-title-main">Prazosin</span> Antihypertensive drug

Prazosin, sold under the brand name Minipress among others, is a medication used to treat high blood pressure, symptoms of an enlarged prostate, and nightmares related to post-traumatic stress disorder (PTSD). It is an α1 blocker. It is a less preferred treatment of high blood pressure. Other uses may include heart failure and Raynaud syndrome. It is taken by mouth.

Alpha-1 blockers constitute a variety of drugs that block the effect of catecholamines on alpha-1-adrenergic receptors. They are mainly used to treat benign prostatic hyperplasia (BPH), hypertension and post-traumatic stress disorder. Alpha-1 adrenergic receptors are present in vascular smooth muscle, the central nervous system, and other tissues. When alpha blockers bind to these receptors in vascular smooth muscle, they cause vasodilation.

<span class="mw-page-title-main">Guanfacine</span> Medication

Guanfacine, sold under the brand name Tenex (immediate-release) and Intuniv (extended-release) among others, is an oral alpha-2a agonist medication used to treat attention deficit hyperactivity disorder (ADHD) and high blood pressure. Guanfacine is FDA-approved for monotherapy treatment of ADHD, as well as being used for augmentation of other treatments, such as stimulants. Guanfacine is also used off-label to treat tic disorders, anxiety disorders and PTSD.

The alpha-2 (α2) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.

<span class="mw-page-title-main">Norepinephrine</span> Catecholamine hormone and neurotransmitter

Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" is more commonly used in the United Kingdom, whereas "norepinephrine" is usually preferred in the United States. "Norepinephrine" is also the international nonproprietary name given to the drug. Regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic.

<span class="mw-page-title-main">Alpha-adrenergic agonist</span> Class of drugs

Alpha-adrenergic agonists are a class of sympathomimetic agents that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α1 and α2. Alpha 2 receptors are associated with sympatholytic properties. Alpha-adrenergic agonists have the opposite function of alpha blockers. Alpha adrenoreceptor ligands mimic the action of epinephrine and norepinephrine signaling in the heart, smooth muscle and central nervous system, with norepinephrine being the highest affinity. The activation of α1 stimulates the membrane bound enzyme phospholipase C, and activation of α2 inhibits the enzyme adenylate cyclase. Inactivation of adenylate cyclase in turn leads to the inactivation of the secondary messenger cyclic adenosine monophosphate and induces smooth muscle and blood vessel constriction.

<span class="mw-page-title-main">Adrenergic antagonist</span>

An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors. There are five adrenergic receptors, which are divided into two groups. The first group of receptors are the beta (β) adrenergic receptors. There are β1, β2, and β3 receptors. The second group contains the alpha (α) adrenoreceptors. There are only α1 and α2 receptors. Adrenergic receptors are located near the heart, kidneys, lungs, and gastrointestinal tract. There are also α-adreno receptors that are located on vascular smooth muscle.

<span class="mw-page-title-main">Alpha blocker</span> Class of pharmacological agents

Alpha-blockers, also known as α-blockers or α-adrenoreceptor antagonists, are a class of pharmacological agents that act as antagonists on α-adrenergic receptors (α-adrenoceptors).

Autonomic drugs can either inhibit or enhance the functions of the parasympathetic and sympathetic nervous systems. This type of drug can be used to treat a wide range of diseases, such as glaucoma, asthma, urinary, gastrointestinal and cardiopulmonary disorders.

Adrenergic blocking agents are a class of drugs that exhibit its pharmacological action through inhibiting the action of the sympathetic nervous system in the body. The sympathetic nervous system(SNS) is an autonomic nervous system that we cannot control by will. It triggers a series of responses after the body releases chemicals named noradrenaline and epinephrine. These chemicals will act on adrenergic receptors, with subtypes Alpha-1, Alpha-2, Beta-1, Beta-2, Beta-3, which ultimately allow the body to trigger a "fight-or-flight" response to handle external stress. These responses include vessel constriction in general vessels whereas there is vasodilation in vessels that supply skeletal muscles or in coronary vessels. Additionally, the heart rate and contractile force increase when SNS is activated, which may be harmful to cardiac function as it increases metabolic demand.

Adrenergic neurone blockers, commonly known as adrenergic antagonists, are a group of drugs that inhibit the sympathetic nervous system by blocking the activity of adrenergic neurones. They prevent the action or release of catecholamines such as norepinephrine and epinephrine. They are located throughout the body, causing various physiological reactions including bronchodilation, accelerated heartbeat, and vasoconstriction. They work by inhibiting the synthesis, release, or reuptake of the neurotransmitters or by antagonising the receptors on postsynaptic neurones. Their medical uses, mechanisms of action, adverse effects, and contraindications depend on the specific types of adrenergic blockers used, including alpha 1, alpha 2, beta 1, and beta 2.

References

  1. ↑ "Dorlands Medical Dictionary:sympatholytic".
  2. ↑ Brock, JA; Cunnane, TC (November 1988). "Studies on the mode of action of bretylium and guanethidine in post-ganglionic sympathetic nerve fibres". Naunyn-Schmiedeberg's Archives of Pharmacology. 338 (5): 504–9. doi:10.1007/bf00179321. PMID   3244392. S2CID   31949.
  3. 1 2 Tyrer, Peter (January 1992). "Anxiolytics not acting at the benzodiazepine receptor: Beta blockers". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 16 (1): 17–26. doi:10.1016/0278-5846(92)90004-X. PMID   1348368. S2CID   24742562.
  4. ↑ Burbiel, Joachim C. (2015-10-26). "Primary prevention of posttraumatic stress disorder: drugs and implications". Military Medical Research. 2: 24. doi: 10.1186/s40779-015-0053-2 . ISSN   2095-7467. PMC   4620711 . PMID   26504586.
  5. ↑ Kaplan HI, Sadock B (1998). Kaplan and Sadock's Synopsis of Psychiatry (8th ed.). Baltimore: Lippincott Williams & Wilkins.
  6. ↑ Robert J. Harmon; et al. (September 1996). "Clonidine for Posttraumatic Stress Disorder in Preschool Children". Journal of the American Academy of Child & Adolescent Psychiatry. 35 (9): 1247–1249. doi:10.1097/00004583-199609000-00022. PMID   8824068.
  7. ↑ Kinzie, J David; Leung, Paul (September 1989). "Clonidine in Cambodian Patients with Posttraumatic Stress Disorder". Journal of Nervous & Mental Disease. 177 (9): 546–550. doi:10.1097/00005053-198909000-00005. PMID   2769247. S2CID   38938044.
  8. ↑ Horrigan, Joseph P.; Barnhill, L. Jarrett (Aug 1996). "The suppression of nightmares with guanfacine". Journal of Clinical Psychiatry. 57 (8): 371. PMID   8752021.
  9. ↑ "Prazosin: Biological activity". IUPHAR. International Union of Basic and Clinical Pharmacology. Retrieved 3 June 2016.
  10. ↑ Murray A. Raskind; et al. (February 2003). "Reduction of Nightmares and Other PTSD Symptoms in Combat Veterans by Prazosin: A Placebo-Controlled Study". The American Journal of Psychiatry. 160 (2): 371–373. doi:10.1176/appi.ajp.160.2.371. PMID   12562588.
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