Nursing Pharmacology: Autonomic Pharmacology Adrenergic Drugs
Clinical Use: Sympathomimetic Agents: Brief Summary
α Adrenergic Agonists
Paroxysmal atrial tachycardia
Vasoconstriction with local anesthetics
Central antihypertensives: never injected intravenously to lower blood pressure due to vasoconstrictive effects via vascular, nonjunctional alpha2-adrenoceptors
α1-selective agonists (adverse effects)
α2-selective agonists (adverse effects)
α1-selective antagonists: management of hypertension
α2-selective antagonists: treatment for impotence
Adverse Effects caused by alpha receptor antagonists (blockers) limit use.
orthostatic (postural) hypotension
Non-selective α receptor blockers: pheochromocytoma (α-receptor antagonists prevent hypertensive responses caused by catecholamines secreted by the tumor)
Pheochromocytoma of adrenal medulla
"Catecholamine-secreting pheochromocytoma of adrenal medulla gross specimen.
Note spherical enlargement of the adrenal medulla in this cross section of adrenal."
1999 KUMC Pathology and the University of Kansas, used with permission.
courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.
Non-selective Adrenergic agonists
Epinephrine (α & ß agonist effects)
Bronchodilator activity: limited by cardiovascular effects
Cardiac function improvement
Added to local anesthetic solutions (epinephrine promotes vasoconstriction which reduces the rate at which local anesthetics diffuses away from the site of action)
Usefulness for bronchodilation limited by adverse cardiac and vascular effects
ß1-adrenergic receptor selective agonists
Short term treatment of cardiac decompensation acts primarily to increase cardiac output with minor effects on heart rate (may be related to slight alpha1-agonist activity)
α1-agonist activity tends to increase total peripheral resistance and blood pressure at high doses
ß2-selective agonists (various drugs)
treatment of asthma
relief of bronchospasm
for uterine relaxation in premature labor
Overview-- Varied Clinical Uses of Adrenergic Drugs
Positive inotropic agent
As positive inotropic agents, these drugs increase myocardial contractility
The vasopressor properties of these drugs increase systemic blood-pressure. For example, after sympathetic nervous system blockade following regional anesthesia, vasopressors may elevate blood pressure towards the normal range.
During restoration of intravascular fluid volume, vasopressor administration helps to support blood pressure and hence tissue perfusion.
Prolonged sympathomimetic administration to support blood-pressure is not recommended
Disadvantages associated with using sympathomimetics without significant ß1 receptors adrenergic effects:
Intense vasoconstriction may occur due to α-receptor mediated vascular smooth muscle contraction.
Hypertensive responses caused by vasopressors then induce a reflex-mediated bradycardia
Treatment of bronchospasm in asthmatic patients.
Addition of sympathetic drugs (e.g. epinephrine) to local anesthetic solutions reduce systemic local anesthetic absorption due to localized vasoconstriction.
Management of severe allergic (hypersensitivity) reactions
α receptor agonists: increase peripheral vascular resistance which may be valuable in managing hypotensive states associated with shock
Norepinephrine, phenylephrine (Neo-Synephrine), metaraminol (Aramine), mephentermine (Wyamine) and methoxamine (Vasoxyl) may be used to maintain blood pressure in severe hypotension.
The objective is to ensure adequate CNS perfusion
The use of these agents may be indicated if the hypotensive state is due to sympathetic failure, such as possibly occurring following spinal anesthesia or injury
In shock due to other causes, reflex vasoconstriction is typically intense; adding a agonists may be harmful by further compromising organ (e.g. renal) perfusion.
Increasing heart rate and contractility by isoproterenol (Isuprel), epinephrine or norepinephrine (Levophed) may adversely affect cardiac performance in damaged myocardium
These agents increase myocardial oxygen requirements and may induce arrhythmias
Norepinephrine (Levophed) by increasing afterload (α-adrenergic receptor activation) may worsen myocardial performance
Dopamine and Dobutamine
At low doses, dopamine (Intropin) interactions with D1 receptor subtype results in renal, mesenteric and coronary vasodilation.
This effect is mediated by an increase in intracellular cyclic AMP
Low doses result in enhancing glomerular filtration rates (GFR), renal blood flow, and sodium excretion.
At higher doses, dopamine (Intropin) increase myocardial contractility through activation of ß1 adrenergic receptors
Dopamine (Intropin) also promotes release of myocardial norepinephrine.
Dopamine (Intropin) at these higher dosages causes an increase in systolic blood and pulse pressure with little effect on diastolic pressures.
At high doses dopamine causes vasoconstriction by activating α1 adrenergic receptors.
Dopamine (Intropin) and dobutamine (Dobutrex) are used for short-term inotropic support of the failing heart.
Dobutamine (Dobutrex) is less arrhythmogenic and produces less tachycardia compared to endogenous catecholamines or isoproterenol.
Dobutamine (Dobutrex) is a racemate that binds to and activates β1 and β2 adrenoceptor subtypes.
Dobutamine-mediated β receptor activation causes a positive inotropic effect (increased force of cardiac contraction, i.e. increased contractility).
Dobutamine (Dobutrex) does not activate dopamine receptors and therefore does not increase renal blood flow.
Because of its vasodilator properties, dobutamine's positive inotropism is accompanied by a decrease in afterload (resistance against which the heart must pump).
For this reason dobutamine is favored over dopamine for most advanced heart failure patients who have not improved with digoxin, diuretics, and vasodilator therapy.
Dopamine (Intropin) may produce tachycardia which may increase left ventricular work.
Dopamine-induced vasodilation is mediated by direct stimulation of D1 and D2 post-synaptic dopamine receptors.
Vasodilation of renal vasculature is noteworthy and may benefit patients with marginal GFR due to poor renal perfusion.Dopamine, (Intropin)at low concentrations, acts at D1 receptors and improve myocardial contractility (positive inotropism).
Dopamine (Intropin)produces less of an increase in heart rate compared to isoproterenol and dopamine dilates renal arteries, promoting better kidney perfusion.
Dobutamine (Dobutrex), through complex actions mediated by a and ß receptors enhances contractility without substantially increasing either heart rate or peripheral resistance.
Therapeutic Uses for Dopamine & Dobutamine: Summary
Treatment of cardiogenic and hypovolemic shock by enhancing renal perfusion despite low cardiac output.
Oligouria (low urine output) may be an indication of inadequate renal perfusion.
Fenoldopam and dopexamine are newer drugs that may be useful in treating heart failure by improving myocardial contractility.
Dopamine (Intropin) at higher doses increases myocardial contractility by ß1 - adrenergic receptor activation.
Drugs in Cardiogenic Shock: Nitrates, Adrenergic Agonists, Amrinone (Inocor) and Milrinone (Primacor)
In cardiogenic shock precipitated by acute myocardial infarction, salvage of reversibly damaged myocardial may be accomplished by:
I.V. nitroglycerin (decreasing preload)
Sublingual nitroglycerin is used to relieve symptoms of angina or as a prophylactic before exertional activities that would otherwise cause angina.
Angina pectoris caused by temporary myocardial ischemia is responsive to treatment by organic nitrates.
These agents act primarily by vasodilation (especially venodilation) which reduces myocardial preload and therefore myocardial oxygen demand.
Nitrates also promote redistribution of blood flow to relative ischemic areas.
Some arteriolar dilation,evidenced by flushing and dilation of meningeal arterial vessels, is responsible for headache associated with nitroglycerin use.
Intra-aortic balloon pump (reducing afterload)
Surgery to repair valve pathologies or to revascularize
Cardiogenic Shock may be caused myocardial stunning due to prolonged cardiopulmonary bypass
In cardiogenic shock dopamine (Intropin) and Dobutamine (Dobutrex) may be useful as positive inotropic agents
Dobutamine (Dobutrex) may be preferable because of a decreased likelihood of increasing heart rate and peripheral resistance (increasing afterload increases myocardial work).
Amrinone (Inocor) and milrinone (Primacor) (phosphodiesterase inhibitors) have positive inotropic effects that may be useful if other agents are ineffective.
Antihypertensive Effects of some adrenergic receptor agonists
Centrally-acting sympathomimetics, such as clonidine (Catapres) or methyldopa (Aldomet), are effective antihypertensive drugs.
For clonidine (Catapres), the mechanism of action is activation of α2 adrenergic receptors which then reduce sympathetic outflow.
Adrenergic Agonists in Treating some Cardiac Arrhythmias
In cardiac arrest, epinephrine may be beneficial.
Epinephrine may help initiate a rhythm by increasing myocardial automaticity
During external cardiac massage a agonists may improve cerebral perfusion by shunting blood to the brain (cerebral vessels are thought to be relatively insensitive to vasoconstricting effects of these drugs).
Epinephrine by activating both α and ß adrenergic receptors increases diastolic pressures improving coronary perfusion.
Termination of paroxysmal supraventricular tachycardia may be accomplished by increased vagal (cholinergic) reflex tone following α adrenergic receptor agonist administration.
Other drugs (e.g. adenosine, Ca2+ channel blockers) are more commonly used.
Epinephrine-mediated vasoconstriction results in reduced bleeding in nose and throat surgical procedures
α-adrenergic agonists may be injected into the penis for treatment of priapism.
In sinus surgery, local application of phenylephrine (Neo-Synephrine) or oxymetazoline (Afrin) is useful, because of vasoconstrictive drug effects, for control of bleeding.
ß adrenergic receptor agonists have had limited use in chronic management of congestive heart failure
In congestive failure, a significant loss of ß1 receptors (50%) occurs. Loss of receptor number and desensitization limit ß adrenergic receptor agonist efficacy.
ß adrenergic receptor agonists have a prominent role in chronic and acute management of asthma.
ß2 selective adrenergic receptor agonists, mediating bronchodilation, are preferable.
Clinical management of asthma is discussed in more detail elsewhere.
α-adrenergic agonists are effective decongestants. (allergic, acute or chronic rhinitis).
These agents increase airflow by decreasing nasal mucosal volume.
Nasal mucosal volume is decreased by α1 adrenergic receptor vasoconstricting effects on nasal venous capacitance vessels.
Chronic use or upon discontinuation, a "rebound" hyperemia worsens congestion.
This rebound effect and loss of efficacy with chronic use limits clinical efficacy.
α-adrenergic agonists, such as phenylephrine, should be used with caution in hypertensive patients or those using a monoamine oxidase inhibitor (MAO).
Preparations are available for both oral and topical use.
Oral use is associated with increased systemic effects.
Epinephrine is the agent of choice in emergency management of acute hypersensitivity reactions (reaction to food, insect bites, drug allergy)
Subcutaneous epinephrine administration alleviate symptoms rapidly and may be lifesaving when airway is compromised or in cases of hypotensive shock.
The mechanism of action in this setting is ß adrenergic receptor activation which suppresses mast release of histamine and leukotriene mediators.
Glucocorticoids and antihistamines are also used in management of severe hypersensitivity reactions.
Hollenberg, S.M. and Parrillo, J.E., Shock, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 215-222
Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.222-224.
Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p.259.