Category:Sympathomimetics

A sympathomimetic is a medicine that produces effects similar to those of activation of the sympathetic nervous system, by direct agonism at adrenergic receptors, by indirect release of endogenous catecholamines from nerve terminals, by inhibition of catecholamine reuptake, or by combinations of these. The category is mechanistically broad and clinically spans an unusual range of indications: anaphylaxis and severe asthma exacerbation, the vasopressor support of shock, bronchodilation in asthma and COPD, the attention deficit hyperactivity disorder medicines, nasal decongestion, the relief of urinary stress incontinence (limited use), heart-failure inotropic support, and the older psychostimulant uses.

The history of the category begins with adrenaline. The Japanese-American chemist Jokichi Takamine, working at Parke-Davis in New York City in 1900, was the first to isolate a pure crystalline preparation of epinephrine from the adrenal medulla of cattle.^[1] The compound was the first hormone to be isolated in pure form, predating insulin by twenty-one years. Adrenaline's clinical use began immediately, as a topical haemostatic for ophthalmic and surgical bleeding and as an injectable medicine for acute asthmatic attack; the original 1900 preparation, mixed with cocaine, formed the basis of the local-anaesthetic-with-vasoconstrictor combination still used today in dental and minor-surgical anaesthesia. The 1948 demonstration by the American pharmacologist Raymond Ahlquist that the multiple effects of catecholamines were mediated by two receptor types, which he termed alpha and beta, provided the framework that organises the entire category.^[2] Subsequent work distinguished beta-1 (cardiac), beta-2 (smooth muscle and metabolic), and beta-3 (adipose, bladder) subtypes, and alpha-1 (post-junctional vasoconstrictor) from alpha-2 (presynaptic feedback inhibition and central sedation) subtypes.

The therapeutic pharmacopoeia of the sympathomimetics follows the receptor-subtype map. The non-selective catecholamines epinephrine (adrenaline) and norepinephrine activate alpha and beta receptors in different relative balance: epinephrine is alpha-1 = beta-1 ≈ beta-2; norepinephrine is alpha-1 > beta-1, with negligible beta-2. Their clinical uses follow: epinephrine for anaphylaxis (1:1000 intramuscular for the alpha-1 vasoconstriction, the beta-2 bronchodilation, and the cardiac beta-1 inotropy), for cardiac arrest (1:10,000 intravenous), and as a local-anaesthetic adjunct; norepinephrine as the first-line vasopressor in septic shock, where alpha-1-mediated vasoconstriction is the desired effect. Dopamine, the immediate precursor of norepinephrine, is dose-dependent: low-dose ("renal-dose") activates dopaminergic D1 receptors but the resulting natriuresis has no demonstrated clinical benefit; mid-dose activates beta-1 inotropy; high-dose activates alpha-1 vasoconstriction.

The selective sympathomimetics achieve specific receptor subtype effects. The beta-1 selective agonist dobutamine (Eli Lilly, 1975) provides inotropic support in acute decompensated heart failure and cardiogenic shock without the marked tachycardia and arrhythmia of isoproterenol. The beta-2 selective agonists (albuterol, salmeterol, formoterol, indacaterol; described under bronchodilators) provide bronchodilation with reduced cardiac effect. The beta-3 selective agonists mirabegron and vibegron relax detrusor smooth muscle for overactive bladder. The alpha-1 selective agonist phenylephrine is used intravenously as a vasopressor (particularly in anaesthesia-induced hypotension) and as a topical or oral decongestant (the latter with limited evidence of efficacy at the oral 10 mg dose). The alpha-2 selective agonists clonidine, guanfacine, and dexmedetomidine activate presynaptic and central alpha-2 receptors, reducing sympathetic outflow; they are used in hypertension, in ADHD (clonidine and guanfacine extended-release), in opioid and alcohol withdrawal, and (dexmedetomidine) as a sedative in intensive-care settings.

The indirect-acting sympathomimetics displace endogenous catecholamines from storage vesicles or inhibit their reuptake. Ephedrine, extracted from Ephedra sinica in 1885 and isolated as a pure compound by Nagai in 1887, releases stored noradrenaline and was the first orally bioavailable sympathomimetic. Pseudoephedrine, the related stereoisomer, has been used as a nasal decongestant since the 1950s; its over-the-counter availability has been progressively restricted because of methamphetamine-precursor diversion. The psychostimulants amphetamine (synthesised by Lazăr Edeleanu in 1887, brought to clinical use by Smith Kline French as Benzedrine in 1933 for narcolepsy) and methylphenidate (Ciba, 1944, refined to its current dextro-only Focalin formulation) are mixed-mechanism sympathomimetics combining noradrenaline-release with dopamine-reuptake inhibition; their pharmacology is described in detail under their individual medicine pages and under the controlled-substance categories.

The clinical use of a sympathomimetic carries a corresponding profile of adverse effects. Tachycardia and palpitations are characteristic of beta-1 activation; tremor and hypokalemia of beta-2 activation; sympathetic vasoconstriction-induced hypertension, headache, and rare extremity ischaemia of alpha-1 activation; sedation, dry mouth, and rebound hypertension on withdrawal of alpha-2 agonists. The use of any sympathomimetic in a patient on a monoamine oxidase inhibitor produces a hypertensive crisis that is among the most predictable medicine interactions in pharmacology and is the basis of the food-restriction requirements on the older MAOIs. The use of vasopressor sympathomimetics extravasated into peripheral tissue produces ischemic necrosis; central-venous administration is required for prolonged or high-dose infusion of norepinephrine, dopamine, or epinephrine.

By receptor selectivity:

• Non-selective catecholamines:
  • Epinephrine (adrenaline): anaphylaxis, cardiac arrest, local-anaesthetic adjunct, severe asthma, refractory hypotension
  • Norepinephrine: first-line vasopressor in septic shock and other distributive shock
  • Dopamine: dose-dependent (D1, beta-1, alpha-1), now less commonly used than norepinephrine
• Beta-1 selective (inotropic): dobutamine
• Beta-2 selective (bronchodilator, also indexed under bronchodilators and beta-2 agonists): albuterol, levalbuterol, terbutaline, salmeterol, formoterol, indacaterol, olodaterol, vilanterol, ritodrine (uterine relaxant)
• Beta-3 selective (overactive bladder; cross-indexed under OAB medicines): mirabegron, vibegron
• Alpha-1 selective:
  • Phenylephrine (intravenous vasopressor, oral and topical decongestant)
  • Midodrine (oral, orthostatic hypotension)
  • Topical decongestants oxymetazoline, xylometazoline, naphazoline
• Alpha-2 selective (sympathoinhibitory, central):
  • Clonidine (hypertension, ADHD, opioid withdrawal, restless legs)
  • Guanfacine (ADHD extended-release, hypertension)
  • Dexmedetomidine (ICU sedation, procedural sedation)
  • Alpha-methyldopa (hypertension; selected use in pregnancy hypertension)
• Indirect-acting:
  • Ephedrine (releases stored noradrenaline; intravenous for anaesthesia-induced hypotension, oral as nasal decongestant)
  • Pseudoephedrine (oral decongestant)
  • Phenylpropanolamine (withdrawn for stroke risk in 2000)
• Mixed-mechanism (release + reuptake inhibition) (cross-indexed under psychostimulants):
  • Amphetamine and its derivatives (mixed amphetamine salts as Adderall, dextroamphetamine, lisdexamfetamine, methamphetamine)
  • Methylphenidate and dexmethylphenidate

The boundary of this category is "medicine whose principal action is agonism of adrenergic receptors, directly or indirectly." The non-catecholamine medicines that block these receptors (the beta-blockers, the alpha-1 blockers) are the opposite of sympathomimetics and are collected under their own categories. The serotonin- and noradrenaline-reuptake inhibitors used as antidepressants (venlafaxine, duloxetine) and the noradrenaline-reuptake-inhibitor ADHD medicine atomoxetine have indirect sympathomimetic properties but are classified by their psychiatric indication. The opioid agonist meperidine has weak amphetamine-like central psychostimulant properties on its normeperidine metabolite but is not a sympathomimetic in any clinically meaningful sense. The triptans act on 5-HT1B/1D receptors of cranial vasculature and are sometimes mistakenly described as sympathomimetic; they are not, and are collected under triptans.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.