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Order of agonist potency
Isoproterenol > epinephrine > norepinephrine
ß-receptors are divided into two major categories: ß1 and ß2.
ß1 receptors are associated with the myocardium.
ß2 receptors are associated with smooth muscle and most other sites.
The subdivision of beta receptors followed from the observation that in the heart norepinephrine and epinephrine were equipotent, whereas epinephrine was many fold (10 - 50) more potent at smooth muscle.
Order of agonist potency
epinephrine > norepinephrine
>> isoproterenol
Multiple alpha receptor subtypes have been identified.
Multiple forms were suggested when, after administration of an alpha-receptor antagonist, repetitive nerve stimulation resulted in increasing amount of norepinephrine release. This findings suggested a presynaptic alpha-receptor binding site.
Post-synaptic receptors are classified as α1 .
Pre-synaptic receptors → α2 .
α2 receptors are also present post-synaptically.
This site is involved in the action of some centrally-acting antihypertensive agents, e.g. clonidine.
Some drugs, such as clonidine are more active at α2 receptors.
Clonidine (Catapres)
Clonidine acts in the brain at post-synaptic alpha2 receptors, inhibiting adrenergic outflow from the brainstem. Inhibition of sympathetic outflow results in a decrease in blood pressure.
Clonidine reduces cardiac output (by reducing both stroke volume and heart rate) and peripheral resistance. Reduction in stoke volume occurs due to increased venous pooling (decreased preload).
Clonidine does not interfere with cardiovascular responses to exercise.
Renal blood flow and function is maintained during clonidine treatment.
Clonidine has minimal or no effect on plasma lipids.
Some drugs such as methoxamine (Vasoxyl) or phenylephrine (Neo-Synephrine) are more active at α1 receptors.
Multiple forms of both α1 and α2 receptors have been identified.
Following exposure to catecholamines, there is a progressive loss of the ability of the target site to respond to catecholamines.
For example, stimulation of ß-adrenergic receptors rapidly causes receptor phosphorylation and decreased responsiveness.
This phenomenon is termed tachyphylaxis, desensitization or refractoriness.
Regulation of catecholamine responsiveness occurs at several levels:
Receptors
G-proteins
Adenyl cyclase
Cyclic nucleotide phosphodiesterases
Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, 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.112-137.
Besides reuptake and diffusion away from receptor sites, catecholamine action can end due to metabolic transformation.
Two primary catecholamine degrading enzymes:
Monoamine Oxidase (MAO)
Catechol-O-Methyl Transferase (COMT)
Inhibitors of MAO, such as phenelzine (Nardil), and tranylcypromine (Parnate) increase norepinephrine, dopamine, and serotonin (5-HT) brain concentrations. These concentration increases may be responsible for antidepressant action of MAO inhibitors.
About 25% of circulating norepinephrine is extracted during a single passage through the lungs.
About 20% of clinical dopamine doses are cleared by the lung, although there is minimal dobutamine extraction, an exception.
Epinephrine is not extracted -- same concentration arterial & venous blood
Inhaled anesthetics may interfere with the pulmonary amine transport system required for norepinephrine transport into pulmonary cells.
Clinical Use: Sympathomimetic Agents: Brief Summary
α Adrenergic Agonists
α1-selective agonists--uses:
Nasal congestion
Hypotension
Paroxysmal atrial tachycardia
Mydriasis
Vasoconstriction with local anesthetics
α2-selective agonists--uses:
Central antihypertensives: never injected intravenously to lower blood pressure due to vasoconstrictive effects via vascular, nonjunctional alpha2-adrenoceptors
Adverse effects of
alpha-adrenoceptor agonists:
α1-selective agonists (adverse effects)
Hypertension
Headache
Excitability
Restlessness
α2-selective agonists (adverse effects)
Xerostomia
Sedation
Constipation
Dizziness
Headache
Profound hypotension
α1-selective antagonists: management of hypertension
α2-selective antagonists: treatment for impotence
Adverse Effects caused by alpha receptor antagonists (blockers) limit use.
excessive tachycardia
orthostatic (postural) hypotension
headache, dizziness
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 (alpha & 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)
Isoproterenol (ß1,2)
Usefulness for bronchodilation limited by adverse cardiac and vascular effects
ß1-adrenergic receptor selective agonists
Dopamine (Intropin)
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)
Clinical Uses
treatment of asthma
relief of bronchospasm
emphysema
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
Vasopressors
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.
ß- agonists: increase heart rate and contractility
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
Vasodilation Effects
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.
Positive inotropism:
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.
Vasopressor:
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
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)
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:
supplemental oxygen
i.v. nitroglycerin (decreasing preload)
Nitroglycerin
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.
Vascular Effects: α Adrenergic Agonists
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.
Therapeutic uses of indirect-acting adrenoceptor agonists
Ephedrine is classified as an indirect-acting synthetic non-catecholamine
This drug is resistant to MAO metabolism in the gastrointestinal tract.
Routes of administration include oral, IV, and intramuscular.
Pharmacological actions due to both direct and indirect components:
Direct action is mediated by activation of adrenergic receptors.
Indirect action is based on drug-induced endogenous norepinephrine release.
Pharmacokinetics:
40% of ephedrine does excreted unchanged in urine
Hepatic deamination (hepatic MAO) and conjugation reactions are important drug metabolizing pathways for ephedrine.
Ephedrine's prolonged duration of action results from slow inactivation.
Pharmacodynamics:
Cardiovascular Effects:
Ephedrine's cardiovascular activity is similar to epinephrine but shows a reduced pressor effect and is longer lasting.
IV ephedrine:
IV ephedrine administration results in increased systolic & diastolic blood pressure, heart rate, cardiac output, coronary blood flow, skeletal muscle blood flow.
IV ephedrine, by contrast, causes a reduction in both renal and splanchnic blood flow.
Primary mechanism for cardiovascular effects is activation of cardiac ß1 receptors.
A second ephedrine dose causes a lesser blood-pressure response, which is an example of "tachyphylaxis."
The reduced response following a second dose is due to, in part, depletion of norepinephrine storage sites.
Clinical Use
Ephedrine by IV administration may be used to increase systemic blood pressure following sympathetic blockade during regional anesthesia or to reverse a hypotensive response due to injected or inhaled anesthetics.
Chronic, oral ephedrine administration may be helpful in bronchial asthma management.
Mephentermine (Wyamine)
This drug is classified as an indirect-acting synthetic, non-catecholamine sympathomimetic agent.
Mephentermine is similar in chemical structure to methylamphetamine, but with reduced CNS-stimulation.
Mephentermine activates α and β-adrenergic receptors and following IV administration results in ephedrine-like cardiovascular effects.
Metaraminol (Aramine)
Overview:
Metaraminol is classified as a direct and indirect acting, synthetic, non-catecholamine sympathomimetic
This agent activates α and β-adrenergic receptors
Upon uptake into post-ganglionic sympathetic nerve terminals, metaraminol displaces norepinephrine and acts as a weak, false transmitter (i.e. not the normal norepinephrine neurotransmitter).
Metaraminol is not a. substrate for MAO or COMT enzymatic degradation.
Pharmacodynamics:
Cardiovascular Effects:
Metaraminol administration causes significant, peripheral vasoconstriction but exhibits less positive inotropic action compared to ephedrine. (A positive inotropic effect is an increase in force of cardiac contraction; a positive chronotropic effect is an increase in heart rate.)
Following IV administration, metaraminol increases both systolic and diastolic blood pressure as a result of α-adrenergic receptor activation which in turn causes peripheral vasoconstriction.
The increase in blood pressure after metaraminol then activates an autonomic nervous system reflex which compensates for the increase in blood pressure by slowing the heart rate, i.e. , reflex bradycardia
Bradycardia is associated with a reduction in cardiac output.
Renal effects of metaraminol include a decrease in blood flow; moreover, reduction is cerebral blood flow is also noted.
Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp. 271-272
Adverse Effects:
β-Adrenoceptor Antagonists
Rebound hypertension and tachycardia upon abrupt drug discontinuation (receptor "up-regulation" with chronic use).
Hypoglycemic episodes in insulin-dependent diabetics.
Increased plasma triglycerides (VLDL); Decreased plasma high-density lipoproteins (HDL)
Non-selective
adrenergic antagonists (blockers) adverse effects:
Bronchoconstriction, due to ß2-antagonism therefore use should be limited to non-asthmatics.
Decreased myocardial contractility.
Decreased heart rate (cardiac output).
ß1-selective Adrenergic
Antagonists (blockers) adverse effects:
Careful use in asthmatics because selectivity for ß1- vs. ß2- is limited.
Decreased myocardial contractility.
Decreased heart rate (cardiac output).
α-Adrenergic Antagonists (Blockers)
α-adrenergic receptor activation is responsible for many actions of both endogenous catecholamine and drugs.
α1-adrenergic receptor activation results in contraction of arterial and venular smooth muscle.
α-adrenergic receptor activation causes:
decreased sympathetic outflow.
increased vagal tone.
increased platelet aggregation.
decreased release of the transmitters acetylcholine and norepinephrine (presynptic inhibitory effect).
metabolic regulation effects, e.g.:
decreased insulin release
decreased lipolysis
α-adrenergic receptor antagonists:
phentolamine (Regitine) exhibits comparable potency at α1 and α2-adrenergic receptors
prazosin (Minipress) is more potent at α1 compared to α2-adrenergic receptors
yohimbine (Yocon) is more potent at α2 compared to α1-adrenergic receptors
α1-adrenergic receptor antagonists- Cardiovascular Effects
α1-adrenergic receptor blockade inhibits vasoconstriction caused by endogenous catecholamines.
α1-adrenergic receptor blockers cause an arteriolar and venular vasodilation (a reduction in peripheral resistance) that decreases blood pressure. (BP = Cardiac Output x Total Peripheral Resistance)
Hypotensive responses trigger baroreceptor reflexes that act to increase
heart rate
cardac output
fluid retention
If the drug blocks both α1 and α2 adrenergic receptors, then the α2 presynaptic effect serves to increase norepinephrine release further increasing heart rate through ß1 cardiac stimulation.
α1-adrenergic antagonists block effects of sympathomimetic amines. For example:
pure α-adrenergic agonist effects (phenylephrine (Neo-Synephrine)) are nearly completely blocked
norepinephrine α-receptor mediated effects are blocked but ß1 effects remain.
"Epinephrine reversal": epinephrine blood pressure increases (pressor effects) are converted to vasodepressor effects due to a receptor blockade in the presence of continued ß2 receptor activation.
Recall that ß2 receptor activation causes vasodilation by meanse of ß2 receptor activation that leads to relaxation of vascular smooth muscle.
α2-adrenergic receptor antagonists
α2-adrenergic antagonists increase norepinephrine release from nerve endings.
Activation of central nervous system (CNS) α2-adrenergic receptors cause a decrease in sympathetic outflow and consequently a decrease in blood pressure.
α2-adrenergic antagonists such as yohimbine (Yocon) increase sympathetic outflow and increase blood pressure.
Activation of a2-adrenergic receptors can result in smooth muscle contraction or relaxation, depending on vascular beds.
Phenoxybenzamine (Dibenzyline)
Phenoxybenzamine blocks both α1 and α2 adrenergic receptors.
Phenoxybenzamine reacts with a adrenergic receptors to form a covalent bond.
Receptor blockade is "irreversible" (covalent) and reactivation of receptor function requires de novo receptor synthesis
Pharmacological effects are secondary to α adrenergic blockade. Such effects include:
a decrease in peripheral resistance
reflex cardiac stimulation
impaired response to hypovolemia and anesthetic-induced vasodilation
impaired response to exogenous pressors
orthostatic hypotension
Therapeutic Uses for α-adrenergic blocking drugs
Treatment of elevated and fluctuating blood pressure due to pheochromocytoma.
Pheochromocytomas are adrenal medullary tumors secreting into the circulation large amounts of catecholamines.
High blood catecholamine levels cause severe hypertension.
Phenoxybenzamine (Dibenzyline) or phentolamine (Regitine) are used to control blood pressure prior to definitive surgical treatment.
Drugs in this category are useful in controlling autonomic hyperreflexia in patients with spinal injury.
Some α adrenergic antagonists (blockers) are effective in treating benign prostatic hypertrophy by relaxing smooth muscle that otherwise would impede urine flow.
Major
adverse effects of α-adrenergic blockade:
Hypotension
Orthostatic hypotension
Reflex tachycardia
Inhibition of ejaculation
Phentolamine (Regitine) and Tolazoline (Priscoline)
Competitive antagonist at both α1 and α2 adrenergic receptor
Phentolamine also blocks 5-HT (serotonin) receptors.
Phentolamine causes mast cell histamine release.
Tolazoline is less potent, but otherwise similar to phentolamine.
Some clinical uses for phentolamine:
short-term management of pheochromocytoma
counteracts dermal necrosis following extravasation of vasoconstrictive, α-adrenergic receptor agonists
Major
adverse effects
Prazosin (Minipress) and Terazosin (Hytrin)
Prazosin and terazosin are selective α1 adrenergic receptor blockers.
Both cause a significant reduction in peripheral vascular resistance and venous return, a combination which reduces reflex tachycardia.
Prazosin and trazosin decrease preload: no significant increase cardiac output or heart rate.
Possible CNS effect: suppression of sympathetic outflow.
Significant orthostatic hypotension
following first-dose.
Some therapeutic uses for prazosin/terazosin:
Essential hypertension.
Congestive heart failure (arteriolar and venular dilatation)
Reduction in preload and afterload improves cardiac output
Reduction in pulmonary congestion
Prazosin has not been shown to improve longevity (by contrast to treatment with an angiotensin converting enzyme (ACE) inhibitor or by a combination of the vasodilator hydralazine and an organic nitrate.
Benign prostatic hypertrophy
Mechanism is: α1-adrenergic receptor blockade reduces bladder and urethral trigone muscle tone.
Other alpha adrenergic receptor blockers
Yohimbine (Yocon) α2 adrenergic receptor blocker
Labetalol (Trandate, Normodyne) (α and ß receptor blocker)
Ketanserin (5-HT [serotonin] and alpha-adrenergic receptor blocker)
Some antipsychotic drugs (e.g. haloperidol (Haldol), chlorpromazine (Thorazine))
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.225-232.
Clinical uses for β-adrenoceptor antagonists
Non-selective (blocks both β1 and β2 type beta receptors).
hypertension
angina
arrhythmias
glaucoma
migraine
β1-Selective
arrhythmias
hypertension
ß-Adrenergic Antagonists are clinically important drugs, used in treatment of hypertension, coronary vascular disease and arrhythmias.
Propranolol is an example of a non-selective ß-adrenergic receptor blocker, i.e. capable of blocking both ß1 and ß2 receptor subtypes.
Metoprolol (Lopressor) and atenolol (Tenormin) are examples of ß1 selective drugs, having a greater affinity for ß1 compared to ß2 receptor subtypes.
The selectivity is not absolute in that a "ß1 selective" drug will interact with ß2 sites.
ß1 selective antagonists are cardioselective.
ß receptor blockers exert most of their therapeutic actions on the cardiovascular system.
ß receptor blockers: Effects on the heart:
decrease heart rate
reduce contractility
decrease conduction velocity in atria and AV node
decrease phase 4 depolarization
reduce myocardial oxygen demand
increased refractory period of the AV node
ß receptor blockers: Antihypertensive Effects:
β- receptor blockers reduce blood pressure in patients with hypertension (not in normal subjects)
β-receptor blockers are effective in reducing blood pressure in both "high-renin" and "low-renin" patients.
Renin release in response to sympathetic stimulation is blocked by ß receptor blockers.
A long-term reduction in peripheral resistance, in addition to a reduction in cardiac output, contributes to the antihypertensive effects of β receptor blockers. (mechanism for reduction in peripheral resistance is unknown)
Some antihypertensive ß receptor blockers also exhibit α -receptor blocking properties, e.g. labetalol. In this case reduction in peripheral resistance is explained by α -receptor blocking properties
In asthmatic patients or patients
with COPD (chronic obstructive pulmonary disease)
ß receptor blockers cause dangerous
bronchiolar constriction.
This effect is particularly prominent with nonselective ß receptor blockers, such as propranolol.
ß adrenergic receptor antagonists influence carbohydrate and lipid metabolism.
Catecholamines increase glycogenolysis and glucose availability in hypoglycemia: this response is reduced by ß adrenergic receptor antagonists.
In insulin-dependent diabetes, adrenergic receptor antagonists impede recovery from hypoglycemia.
Adrenergic receptor antagonists may mask symptoms of hypoglycemia.
This property interfers with the patients ability to anticipate
a hypoglycemic episode.
Circulating free fatty acids are utilized by exercising muscle.
Increasing availability of free fatty acids may be mediated by ß3 adrenergic receptor subtypes. ß adrenergic receptor antagonists interfere with this metabolic response.
ß adrenergic receptor agonists decrease plasma K+ concentration by promoting transport into cells, primarily muscle.
In exercise, serum K+ increases.
Catecholamines are involved in regulating serum levels.
ß adrenergic receptor antagonists interfere with this K+ regulation mechanism.
Other Effects
ß adrenergic receptor antagonists block catecholamine-induced tremor and mast-cell degranulation.
Nonselective-ß adrenergic receptor antagonists
Propranolol (Inderal) is a nonselective ß adrenergic receptor antagonist.
Effective in treating
essential hypertension
angina
certain arrhythmias
Propranolol (Inderal) decreases amide local anesthetic clearance by:
decreasing hepatic blood flow
inhibiting hepatic metabolism
Bupivacaine (Marcaine): 35% decrease in clearance -- probably due to metabolic effects since bupivacaine is a low extraction drug (not sensitive to hepatic blood flow changes)
Possible increases in systemic toxicity of bupivacaine (Marcaine) (and other amide local anesthetics) when the anesthetics are administered concurrently with propranolol (Inderal).
Propranolol (Inderal) (after chronic administration) reduces pulmonary first-pass uptake of fentanyl (Sublimaze).
As a consequence: immediately after fentanyl (Sublimaze) administration, 2X to 4X more injected Fentanyl (Sublimaze) into the systemic circulation
possible mechanism: propranolol (a basic, lipophilic amine) inhibits the pulmonary uptake of a second basic lipophilic amine (fentanyl)
Nadolol (Corgard): nonselective ß adrenergic receptor antagonist
Long half-life
May accumulate in patient with renal dysfunction
Timolol (Blocadren): nonselective ß adrenergic receptor antagonist
ocular use: treatment of glaucoma
systemic effects common after ocular application
Bradycardia and hypotension refractory to atropine effects may occur during anesthesia in pediatric and adult patients receiving topical timolol (Blocadren).
Timolol may impair neonatal ventilation resulting in an unexpected postoperative apnea. (Blood-brain barrier immaturity in the neonate may faciliate the drug's access to the brain, promoting this effect.)
Contraindicated in
patients
with congestive heart failure.
cardiac conduction abnormalities (partial heart block)
asthma
Labetalol (Trandate, Normodyne) α1 AND ß1 adrenergic receptor antagonist.
This drug decreases blood pressure in hypertensive patients.
α1 blocking action decreases vascular smooth muscle tone.
ß1 adrenergic receptor antagonism reduces heart rate.
ß2 adrenergic receptor agonist property also promotes vascular relaxation.
Labetalol may be used to reduce heart rate and blood-pressure increases in anesthetized patients, who are reacting to a rapid increase in the level of painful surgical stimulation.
Interaction of beta-adrenergic receptor antagonists with anesthetics:
Additive myocardial depression between anesthetics and beta-adrenergic antagonist is not excessive; beta-adrenergic treatment may be maintained, safely, throughout the perioperative period.
Exception:
timolol (Blocadren)
Substantial bradycardia observed in presence of inhaled anesthetics
Additive cardiovascular effects with inhaled anesthetics with beta-adrenergic receptor blockade drugs:
Greatest: enflurane (Ethrane)
Intermediate: halothane (Fluothane)
Least: isoflurane (Forane) (also, sevoflurane (Sevorane, Ultane) and desflurane (Suprane))
When using anesthetic drugs such as ketamine (Ketalar) that increase sympathetic nervous system activity or when excessive sympathetic activities is present (e.g.hypercarbia), beta-receptor blockade may unmask the drug's negative inotropic property, thereby decreasing systemic blood-pressure and cardiac output.
Selective-ß1 adrenergic receptor antagonists
Metoprolol (Lopressor)
Metoprolol is a cardioselective ß1 adrenergic receptor antagonist.
Effective in treating essential hypertension
Effective in treating symptoms of coronary artery disease
Contraindicated in
management of acute myocardial infarction
if heart rates are < 45 bpm.
Esmolol (Brevibloc)
Esmolol is also a cardioselective ß1 adrenergic receptor antagonist.
Very short duration of
action
i.v. administration
Effective in rapid termination of paroxymal supraventricular arrhythmias
Short
duration of action (plasma esterases, not
plasma cholinesterases) is beneficial in
management of intraoperative adverse
BP/heart rate increases associated with
noxious stimulation (e.g. during tracheal intubation)
IV esmolol administration before direct laryngoscopy in tracheal intubation protects against heart rate in systolic blood pressure increases which is typically associated with tracheal intubation.
Perioperative hypertension and tachycardia may also be generally prevented by esmolol (Brevibloc) administration over a 15 second period before anesthesia induction.
Esmolol (Brevibloc) , IV, administered to patients undergoing electroconvulsive treatment and anesthetized with methohexital (Brevital) and succinylcholine (Anectine) is associated with reduced positive chronotropic effects and reduced duration of electrically-induced seizures
Other esmolol (Brevibloc) uses:
Reduced catecholamine release during anesthesia in patients with hypertrophic obstructive cardiomyopathy.
Reduced catecholamine release in patients experiencing hypercyanotic spells (associated with tetralogy of Fallot)
Esmolol (Brevibloc) reduces plasma propofol concentration needed to prevent patient movement upon surgical skin incision-- unknown mechanism
Atenolol (Tenormin)
Most cardioselective ß1 adrenergic receptor antagonist
Used in treating hypertension
Somewhat longer action compared to metoprolol
Atenolol may have special benefit for patients undergoing noncardiac surgery but having significant underlying coronary artery disease:
Preoperative IV atenolol (Tenormin) , postoperative IV atenolol (Tenormin) , and oral therapy during hospitalization reduce mortality and incidence of cardiovascular complications.
Perioperative atenolol (Tenormin) for high-risk patients (CHD): reduces postoperative myocardial ischemia incidence.
Adverse Effects of ß
adrenergic
receptor antagonists
Cardiovascular
congestive heart failure (due to negative chronotropic/inotropic effects)
bradycardia
abrupt discontinuation may cause angina and increases the risk of sudden death
Pulmonary
bronchoconstriction due to blockade of ß2 adrenergic receptors
ß adrenergic receptor antagonist contraindicated in asthma
CNS
fatigue
sleep disturbances
depression
Metabolic Effects
delays recovery from insulin-induced hypoglycemia
decreases awareness of onset of hypoglycemic symptoms.
increases blood lipid levels
Therapeutic Uses for β-adrenergic receptor antagonists (Blockers)
Hypertension
Supraventricular arrhythmias
Ventricular arrhythmias
Myocardial infarction (decreases myocardial oxygen demand)
Acute dissecting aortic aneurysm (reduced inotropism)
Hypertrophic obstructive cardiomyopathy
symptoms of hyperthyroidism
Prophylaxis of migraine (propranolol, metoprolol, timolol)
Acute panic disorder
Stage fright (performance anxiety)
Gaucoma (timolol)
Essential tremor
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) The McGraw-Hill Companies, Inc.,1996, pp.232-242.
Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp. 293-301
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