 |
|
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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 alpha1 .
Pre-synaptic receptors
alpha2 .
alpha2 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 alpha2 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 alpha1 receptors.
Multiple forms of both alpha1 and alpha2 receptors have been identified.
Following exposure to catecholamines, there is a progressive loss of the ability of the target site to respond to catecholamines. This phenomenon is termed tachyphylaxis, desensitization or refractoriness.
Regulation of catecholamine responsiveness occurs at several levels:
|
Receptors |
G proteins |
Adenyl cyclase |
Cyclic nucleotide phosphodiesterase |
Stimulation of ß-adrenergic receptors rapidly causes receptor phosphorylation and decreased responsiveness. The phosphorylated receptor exhibits:
decreased coupling to Gs and
decreased stimulation of adenylyl cyclase.
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.
|
Monoamine Oxidase (MAO) |
Catechol-O-Methyl Transferase (COMT) |
Inhibitors of MAO, such as cordially, 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 (minimal dobutamine extraction
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
Alpha Adrenergic Agonists
Alpha1-selective agonists--uses:
Nasal congestion
Hypotension
Paroxysmal atrial tachycardia
Mydriasis
Vasoconstriction with local anesthetics
Alpha2-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
Clinical Use: a-adrenoceptor antagonists
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 alpha receptor blockers: pheochromocytoma (alpha-receptor antagonists prevent hypertensive responses caused by catecholamines secreted by the tumor
"Catecholamine-secreting pheochromocytoma of adrenal medulla gross. 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. For more information concerning endocrine pathology http://www.kumc.edu/instruction/medicine/pathology/ed/ch_21/ch_21_f.html
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)
a1-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
increase myocardial contractility
Vasopressors
increase systemic blood-pressure after sympathetic nervous system blockade following regional anesthesia
During restoration of intravascular fluid volume
Prolonged sympathomimetic administration to support blood-pressure is not recommended
Disadvantages associated with using sympathomimetics without significant ß1 -- adrenergic effects:
Intense vasoconstriction
Hypertensive responses promoting reflex-mediated bradycardia
Treatment of bronchospasm impatient with asthma
Addition to local anesthetic solutions -- reducing systemic local anesthetic absorption
Management of severe allergic (hypersensitivity) reactions
Alpha 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 (alpha 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 a1 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 b1 and b2 adrenoceptor subtypes.
Result: positive inotropic action mediated by beta receptor activation
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.
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 may be an indication of inadequate renal perfusion.
Fenoldopam and dopexamine: newer drugs
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.
The organic nitrates and nitrites are denitrated to produce nitric oxide (NO) which:
activates guanylyl cyclase.
Activation of cyclase results in increased concentrations of cyclic guanosine 3',5'-monophosphate (cyclic GMP) which results in vasodilation by increasing the rate of light-chain myosin dephosphorylation.
Nitric oxide synthetase produces endogenous nitrates by action on L-arginine.
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.
Overview: Amrinone and milrinone
Amrinone and milrinone are bipyridine derivatives that are relatively selective inhibitors of cGMP-inhbited, cyclic AMP phosphodiesterase (type III).
These agents cause vasodilation (decreased afterload) and increase myocardial contractility.
Milrinone is the agent of choice among the phosphodiesterase inhibitors for short-term parenteral support in severe heart failure patients.
Oral formulations are not used due to intolerable side-effects including increases in mortality.
Amrinone has been associated with a reversible thrombocytopenia
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 a2 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 a and ß adrenergic receptors increase diastolic pressures improving coronary perfusion.
Termination of paroxysmal supraventricular tachycardia may be accomplished by increased vagal (cholinergic) reflex tone following alpha adrenergic receptor agonist administration. Other drugs (e.g. adenosine, Ca2+ channel blockers) are more commonly used.
Vascular Effects: alpha Adrenergic Agonists
Epinephrine: Vasoconstriction-reduced bleeding in surgical procedures nose and throat surgical procedures
alpha adrenergic agonists may be injected into the penis for treatment of priapism.
Sinus surgery: local application of phenylephrine (Neo-Synephrine) or oxymetazoline (Afrin) for vasoconstriction.
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.
alpha 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 a1 adrenergic receptor constricting 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.
a 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 hypotensive shock.
Mechanism: ß adrenergic receptor activation may suppress 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
Classified as an indirect-acting synthetic non-catecholamine
Resistant to MAO metabolism in the gastrointestinal tract
Routes of administration: oral, IV, intramuscular
Pharmacological actions due to both direct in indirect components:
direct action on adrenergic receptors
promotes endogenous norepinephrine release (indirect)
Pharmacokinetics:
40% of ephedrine does excreted unchanged in urine
Hepatic deamination (hepatic MAO); conjugation
Generally slow inactivation-- accounting for prolonged duration of action
Pharmacodynamics:
Cardiovascular Effects:
Similar to epinephrine; less pressor effect; longer lasting
IV ephedrine:
increased systolic & diastolic blood pressure, heart rate, cardiac output, coronary blood flow, skeletal muscle blood flow
decreased renal blood flow, splanchnic blood flow
Primary mechanism for cardiovascular effects: activation of cardiac ß1 receptors
A second ephedrine dose: reduced blood-pressure response: tachyphylaxis --mechanisms:
depletion of norepinephrine storage sites
prolonged ephedrine-adrenergic receptor occupancy
Clinical Use
Ephedrine by IV administration:frequently selected sympathomimetic to increase systemic blood pressure following sympathetic blockade secondary to:
Regional anesthetia
Hypotension due to injected/inhaled anesthetics
Chronic, oral administration to manage bronchial asthma
Antiemetic activity (similar to droperidol (Inapsine)) but with diminished sedation when administered in conjunction with general anesthesia for outpatient laproscopy
Mephentermine (Wyamine)
Indirect-acting synthetic, non-catecholamine sympathomimetic
Structurally similar to methylamphetamine, but limited CNS-stimulation
Activates a & b -adrenergic receptors
IV administration: ephedrine-like cardiovascular effects.
Metaraminol (Aramine)
Overview:
Indirect & indirect acting, synthetic, none-catecholamine sympathomimetic
Activates alpha & beta -adrenergic receptors
Uptake into post-ganglionic sympathetic nerve terminals; displace his norepinephrine; behaves as a weak, false transmitter
Not a substrate for MAO or COMT enzymatic degradation
Pharmacodynamics:
Cardiovascular Effects:
Significant, peripheral vasoconstriction
Less positive inotropic action compared to ephedrine
Following IV administration, sustained increased in both systolic and diastolic blood pressure reflecting alpha-adrenergic receptor activation (peripheral vasoconstriction)
Reflex bradycardia
decreased cardiac output
Renal Effects: decreased blood flow
Cerebral effects: decreased blood flow
Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp. 271-272
Adverse Effects: beta-Adrenoceptor Antagonists
Rebound hypertension and tachycardia upon abrupt discontinuation (receptor "up-regulation" with chronic use)
Hypoglycemic episodes in insulin-dependent diabetics
Increase plasma triglycerides (VLDL); Decrease plasma high-density lipoproteins (HDL)
Non-selective Adrenergic Antagonists (blockers) adverse effects:
Bronchoconstriction, due to ß2-antagonism (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)
alpha-Adrenergic Antagonists (Blockers)
alpha-adrenergic receptor activation is responsible for many actions of both endogenous catecholamine and drugs.
alpha1-adrenergic receptor activation results in:
contraction of arterial and venular smooth muscle
alpha2-adrenergic receptor activation:
decreased sympathetic outflow
increased vagal tone
increased platelet aggregation
decreased release of the transmitters acetylcholine and norepinephrine (presynptic inhibitory effect)
metabolic regulation
decreased insulin release
decreased lipolysis
increases vascular tone in some vascular beds
alpha-adrenergic receptor antagonists:
phentolamine (Regitine): comparable potency α1 and α2-adrenergic receptors
prazosin (Minipress): more potent at α1 compared to α2-adrenergic receptors
yohimbine (Yocon): more potent at α2 compared to α1-adrenergic receptors
alpha1-adrenergic receptor antagonists- Cardiovascular Effects
alpha1-adrenergic receptor blockade inhibits vasoconstriction caused by endogenous catecholamines.
alpha1-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 alpha1 and alpha2 adrenergic receptors, then the a2 presynaptic effect serves to increase norepinephrine release further increasing heart rate through ß1 cardiac stimulation.
alpha1-adrenergic antagonists block effects of sympathomimetic amines. For example:
pure a-adrenergic agonist effects (phenylephrine (Neo-Synephrine)) are nearly completely blocked
norepinephrine alpha-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-ß2 receptor-mediated relaxation of vascular smooth muscle may be due to cAMP-dependent kinase phosphorylation of myosin light chain kinase (producing an inactive form)
alpha2-adrenergic receptor antagonists
α2-adrenergic antagonists increase norepinephrine release from nerve endings.
Activation of central nervous system (CNS) a2-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.
smooth muscle relaxation by a2-adrenergic receptor activation may be mediated by nitric oxide (NO).
Phenoxybenzamine (Dibenzyline)
Phenoxybenzamine blocks both a1 and a2 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: Secondary to a Adrenergic Blockade
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 alpha-adrenergic blocking drugs
treatment of 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): used to control blood pressure prior to definitive surgical treatment.
useful in controlling autonomic hyperreflexia in patients with spinal injury.
Effective in treating benign prostatic hypertrophy
Major adverse effects of alpha adrenergic blockade:
Hypotension
Orthostatic hypotension
Reflex tachycardia
Inhibition of ejaculation
Phentolamine (Regitine) and Tolazoline (Priscoline)
Competitive antagonist at both alpha1 and alpha2 adrenergic receptor
Phentolamine also blocks 5-HT (serotonin) receptors.
Phentolamine causes mast cell histamine release.
Tolazoline less potent, but otherwise similar to phentolamine.
Phentolamine: clinical use
short-term management of pheochromocytoma
counteracts dermal necrosis following extravasation of vasoconstrictive, alpha adrenergic receptor agonists
Major adverse effects
Prazosin (Minipress) and Terazosin (Hytrin)
Prazosin and terazosin are selective a1 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.
Therapeutic Uses: 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: alpha1 adrenergic receptor blockade reduces bladder and urethral trigone muscle tone.
Other alpha adrenergic receptor blockers
yohimbine (Yocon) a2 adrenergic receptor blocker
labetalol (Trandate, Normodyne) (a 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 beta-adrenoceptor antagonists
Non-selective (blocks both beta1 and beta2 type beta receptors
hypertension
angina
arrhythmias
glaucoma
migraine
Beta1-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
ß receptor blockers reduce blood pressure in patients with hypertension (not in normal subjects)
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 ß receptor blockers. (mechanism for reduction in peripheral resistance is unknown)
Some antihypertensive ß receptor blockers also exhibit a -receptor blocking properties, e.g. labetalol. In this case reduction in peripheral resistance is explained by a -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 interfer 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): lipophillic 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, may occur during anesthesia in pediatric and adult patients receiving topical timolol (Blocadren).
may impair neonatal ventilation -- an unexpected postoperative apnea may ensue (blood-brain barrier immaturity in the neonate may facilitate CNS access and promote this effect)
contraindicated in patients
with congestive heart failure
cardiac conduction abnormalities (partial heart block)
asthma
Labetalol (Trandate, Normodyne) a1and ß1 adrenergic receptor antagonist
decreases blood pressure in hypertensive patients
a1blocking action decreases vascular smooth muscle tone
ß1 adrenergic receptor antagonism reduces heart rate
ß2 adrenergic receptor agonist property also promotes vascular relaxation.
may be used to reduce heart rate & blood-pressure increases in anesthetized patients who are responding to a rapid increase in the level of surgical stimulation
Interaction of beta-adrenergic receptor antagonists with anesthetics:
Myocardial depression: 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 {decreasing systemic blood-pressure & cardiac output}
Selective-ß1 adrenergic receptor antagonists
Metoprolol (Lopressor)
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)
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 -- 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) have reduced positive chronotropic effects and reduced duration of electrically-induced seizures
Other esmolol (Brevibloc) uses the:
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 reduces 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 beta 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)
glaucoma (timolol)
essential tremor
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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
