Alpha + Beta Antagonistsjeg

Alpha & Beta AntagonistsAlpha & Beta Antagonists

Juan E Gonzalez, MS, CRNAJuan E Gonzalez, MS, CRNA

OverviewOverview

• IntroductionIntroduction• Mechanism of ActionMechanism of Action• Specific drugsSpecific drugs• Clinical UsesClinical Uses• PharmacokineticsPharmacokinetics• Side EffectsSide Effects• Combined alpha & beta adrenergic Combined alpha & beta adrenergic

receptor antagonistreceptor antagonist

IntroductionIntroduction

• Alpha & Beta adrenergic receptor Alpha & Beta adrenergic receptor antagonists prevent the interaction of the antagonists prevent the interaction of the endogenous endogenous neurotransmitterneurotransmitter norepinephrine (N.E) or norepinephrine (N.E) or sympathomimetics (endogenous or sympathomimetics (endogenous or synthetic catecholamines, synthetic synthetic catecholamines, synthetic noncatecholamines) with the noncatecholamines) with the corresponding adrenergic receptorcorresponding adrenergic receptor

• Such interference attenuates SNS Such interference attenuates SNS homeostatic mechanisms & evokes homeostatic mechanisms & evokes predictable pharmacologic responsespredictable pharmacologic responses

Nervous SystemNervous System

The Nervous System is divided into the

•Peripheral Nervous System (PNS)

•Central Nervous System (CNS)

•Spinal Cord

•Brain

ANS ANS

• Controls visceral functionsControls visceral functions• Exerts PARTIAL control ofExerts PARTIAL control of

– BPBP– G.I. motility & secretionG.I. motility & secretion– Urinary bladder emptyingUrinary bladder emptying– SweatingSweating– Body temperature Body temperature

• ANS activation via centers in ANS activation via centers in hypothalamus, brainstem, spinal cordhypothalamus, brainstem, spinal cord

The ANS regulates:The ANS regulates: • Muscles Muscles

– in the skin (around hair follicles; smooth muscle) in the skin (around hair follicles; smooth muscle) – around blood vessels (smooth muscle) around blood vessels (smooth muscle) – in the eye (the iris; smooth muscle) in the eye (the iris; smooth muscle) – in the stomach, intestines and bladder (smooth muscle) in the stomach, intestines and bladder (smooth muscle) – of the heart (cardiac muscle) of the heart (cardiac muscle)

• Glands Glands • The ANS is divided into three parts:The ANS is divided into three parts:

– sympathetic nervous systemsympathetic nervous system– parasympathetic nervous systemparasympathetic nervous system – enteric nervous systementeric nervous system

ANSANS

The autonomic nervous system is always working. It is NOT only active during "fight or flight" or "rest and digest" situations. Rather, the autonomic nervous system acts to maintain normal internal functions and works with the somatic nervous system.

The enteric nervous system is a third division of the autonomic nervous system that you do not hear much about. The enteric nervous system is a meshwork of nerve fibers that innervate the viscera (gastrointestinal tract, pancreas, and gall bladder).

ANSANS

TERMINOLOGYTERMINOLOGY

• CholinergicCholinergic– Effects of Effects of

AcetylAcetylcholinecholine• Parasymp NS Parasymp NS (parasymp ganglia, (parasymp ganglia,

effector cells) effector cells) • Parts of Symp NSParts of Symp NS (symp ganglia, adrenal (symp ganglia, adrenal

medulla, sweat glands)medulla, sweat glands)• Some CNS neuronSome CNS neuron• Somatic nerves Somatic nerves

innervating skeletal innervating skeletal musclemuscle

• AdrenergicAdrenergic– Effects ofEffects of

NorNoradrenalineadrenaline

(Norepinephrine)(Norepinephrine)• Postganglionic Postganglionic

symp fibers at end symp fibers at end organ tissuesorgan tissues

Cholinergic ReceptorsCholinergic Receptors

• NicotinicNicotinic– GangliaGanglia

• AutonomicAutonomic• SympSymp• ParasymParasym

– Skeletal muscleSkeletal muscle

• MuscarinicMuscarinic– GlandsGlands

• LacrimalLacrimal• Salivary Salivary • Gastric Gastric

– Smooth muscleSmooth muscle• BronchialBronchial• GIGI• BladderBladder• Blood vesselsBlood vessels

– HeartHeart• SA nodeSA node• AV nodeAV node

Nerve ConductionNerve Conduction

NMJ Neuron NMJ Neuron

Alpha1 receptor stimulation Alpha1 receptor stimulation (postsynaptic)(postsynaptic)

• Mydriasis (pupillary dilation d/t Mydriasis (pupillary dilation d/t contraction of radial eye muscles)contraction of radial eye muscles)

• BronchoconstrictionBronchoconstriction• VasoconstrictionVasoconstriction• Uterine contractureUterine contracture• Contraction of sphincters of GI/GU tractContraction of sphincters of GI/GU tract• Insulin/lipolysisInsulin/lipolysis

Alpha2 receptor stimulation Alpha2 receptor stimulation (presynaptic)(presynaptic)

• N.E. releaseN.E. release• Some vasoconstriction of vascular Some vasoconstriction of vascular

smooth musclesmooth muscle• SedationSedation• Sympathetic outflowSympathetic outflow

– Peripheral vasodilationPeripheral vasodilation– Lowers BPLowers BP

Beta1 receptor stimulation Beta1 receptor stimulation (cardiac)(cardiac)

• + Chronotropic effect ( HR)+ Chronotropic effect ( HR)• + Dromotropic effect ( conduction)+ Dromotropic effect ( conduction)• + Inotropic ( contractility)+ Inotropic ( contractility)

Beta2 receptor stimulation Beta2 receptor stimulation (non-cardiac)(non-cardiac)

• Relaxes smooth muscleRelaxes smooth muscle– BronchodilationBronchodilation– VasodilationVasodilation– Relax uterus/bladder/gutRelax uterus/bladder/gut

• Glycogenolysis, lipolysis, gluconeogenesis Glycogenolysis, lipolysis, gluconeogenesis (making glucose from aminoacids & from (making glucose from aminoacids & from the glycerol portion of fat), insulinthe glycerol portion of fat), insulin hypoglycemiahypoglycemiagluconeogenesis). gluconeogenesis).

• Activation of Na/K pump Activation of Na/K pump – K goes in (can produce hypoK & dysrhythmia)K goes in (can produce hypoK & dysrhythmia)

Sympathetic NS (fight Sympathetic NS (fight or flight)or flight)

Sympathetic nerve fibers arise from Throraco lumbar (T1-L2) segments of spinal cord (preganglionic, mostly myelinated, slow-conducting B fibers, ACH) and pass to paravertebral SNS chains and from the chain (postganglionic, mostly unmyelinated, C fibers, N.E. adrenergic) to tissue & organs.

Sweat glands & some blood vessels are innervated by postganglionic SNS fibers that secrete ACH

Parasympathetic NSParasympathetic NS(rest & digest)(rest & digest)

CranioSacral

(CN III, V, VII, IX, X and sacral region, S2, S3 and sometimes S1 & S4 in addition). In contrast to the SNS, preganglionic fibers (ACHcholinergic) of PNS pass uninterrupted to ganglia near or in the innervated organ. Very short postganglionic fibers (ACHcholinergic)

Structure Sympathetic Stimulation Parasympathetic Stimulation

Iris (eye muscle) Pupil Dilation Pupil Constriction

Salivary Glands Saliva production reduced Saliva production increased Oral/Nasal mucosa Reduced Mucus production Mucus production increased

Heart Inc Heart rate and force Heart rate and force decreased

Lung Bronchial muscle relaxed Bronchial muscle contracted

Stomach Peristalsis reduced Gastric juice secreted; inc motility

S Intestine Motility reduced Digestion increased

L Intestine Motility reduced Inc secretions and motility

LiverInc glycogen to glucose conversion

Kidney Decreased urine secretion Inc urine secretion

Adrenal medullaNorepinephrine andepinephrine secreted

Bladder Wall relaxed, Sphinct closed Wall contracted, Sphinct relaxed

Ratio of Epi vs. N.E.Ratio of Epi vs. N.E.

• Cells in the adrenal medulla synthesize and Cells in the adrenal medulla synthesize and secrete norepinephrine and epinephrine.secrete norepinephrine and epinephrine. The ratio The ratio of these two catecholamines differs considerably among of these two catecholamines differs considerably among species:species:– humans humans 80%80% – cats cats 60%60%– chicken chicken 30%30% of the catecholamine output is of the catecholamine output is

epinephrineepinephrine– Following release into blood, these hormones Following release into blood, these hormones

bind adrenergic receptors on target cells, bind adrenergic receptors on target cells, where they induce essentially the same effects where they induce essentially the same effects as direct sympathetic nervous stimulation.as direct sympathetic nervous stimulation.

Making N.E. & EpiMaking N.E. & Epi

20% 80%

Inactivation of Inactivation of Neurotransmitter Neurotransmitter

Diffusion Diffusion (N.E.)(N.E.) ReuptakeReuptake (N.E., dopa, (N.E., dopa,

serotonin) serotonin)

Inactivation of Inactivation of NeurotransmitterNeurotransmitter

Enzymatic Metabolism by Enzymatic Metabolism by

Degradation enzymes MAO & Degradation enzymes MAO & COMTCOMT

Alpha Blockers Alpha Blockers

• Bind selectively to alpha receptorsBind selectively to alpha receptors• Interfere with ability of catecholamines or other Interfere with ability of catecholamines or other

sympathomimetics to provoke alpha responses on sympathomimetics to provoke alpha responses on the heart & peripheral vasculaturethe heart & peripheral vasculature

• Inhibitory action of epinephrine on insulin Inhibitory action of epinephrine on insulin secretion is prevented too (insulin production is secretion is prevented too (insulin production is not reduced)not reduced)

• Side effects: orthostatic hypotension, Side effects: orthostatic hypotension, baroreceptor-mediated reflex tachycardia, baroreceptor-mediated reflex tachycardia, impotenceimpotence

• Absence of Beta blockade allows maximum Absence of Beta blockade allows maximum expression of cardiac stimulation from N.E.expression of cardiac stimulation from N.E.

Mechanism of Action Mechanism of Action (alpha blockade)(alpha blockade)

• Competitive Inhibition Competitive Inhibition (reversible binding with (reversible binding with receptors)receptors)

– PhentolaminePhentolamine– PrazosinPrazosin– YohimbineYohimbine

• Covalent Bond Covalent Bond (irreversible & insurmountable (irreversible & insurmountable blockade)blockade)– PhenoxybenzaminePhenoxybenzamine

(once blockade in effect, even massive doses of (once blockade in effect, even massive doses of sympathomimetics are ineffective sympathomimetics are ineffective

UNTIL METABOLISM OF Phenoxybenzamine takes placeUNTIL METABOLISM OF Phenoxybenzamine takes place

Mechanism of Action Mechanism of Action (alpha blockade)(alpha blockade)

What specific alpha receptors are blocked??What specific alpha receptors are blocked??

- Phentolamine & Phenoxybenzamine - Phentolamine & Phenoxybenzamine

(postsynaptic alpha-1, presynaptic alpha-2)(postsynaptic alpha-1, presynaptic alpha-2)

- Prazosin- Prazosin

(alpha-1)(alpha-1)

- Yohimbine- Yohimbine

(alpha-2)(alpha-2)

Phentolamine (REGITINE)Phentolamine (REGITINE)

• Transient (10-15min) nonselective alpha Transient (10-15min) nonselective alpha blockadeblockade

• Peripheral vasodilation (alpha-1 block) & Peripheral vasodilation (alpha-1 block) & decreased BP within 2 min (lasts 10-15 min) decreased BP within 2 min (lasts 10-15 min) elicit baroreceptor- mediated cardiac elicit baroreceptor- mediated cardiac stimulation reflexstimulation reflex

• Enhanced neural release of N.E. (alpha-2 block) Enhanced neural release of N.E. (alpha-2 block) HR/CO, angina, dysrhythmias HR/CO, angina, dysrhythmias

• Parasympathetic “override”: hyperistalsis, Parasympathetic “override”: hyperistalsis, abdominal pain, diarrheaabdominal pain, diarrhea

Phentolamine Phentolamine ( (Clinical Uses)Clinical Uses)

• Acute HTN emergenciesAcute HTN emergencies– Intraop manipulation of PHEOCRHOMOCYTOMAIntraop manipulation of PHEOCRHOMOCYTOMA– Autonomic NS HyperreflexiaAutonomic NS Hyperreflexia

• 30 to 70 mcg/kg IV (prompt/transient dec in BP)30 to 70 mcg/kg IV (prompt/transient dec in BP)• Drip may be desirable to maintain steady stateDrip may be desirable to maintain steady state

• Accidental extravascular injection of Accidental extravascular injection of sympathomimetic drugsympathomimetic drug– Local infiltration of phentolamine-containing Local infiltration of phentolamine-containing

solution (2.5 to 5mg in 10ml)solution (2.5 to 5mg in 10ml)

PhenoxybenzaminePhenoxybenzamine(Dibenzyline) (Dibenzyline)

• Non-selective (alpha-1 & alpha-2 Non-selective (alpha-1 & alpha-2 blocker) covalent bondblocker) covalent bond

• Alpha-1 block > Alpha-2 blockAlpha-1 block > Alpha-2 block• Slow onset (up to 60 min to reach peak) Slow onset (up to 60 min to reach peak)

IV or PO. Long time required for IV or PO. Long time required for structural change of the molecule structural change of the molecule needed to render drug activeneeded to render drug active

• Elimination half-time: 24 hr (cumulative Elimination half-time: 24 hr (cumulative effect with repeated doses)effect with repeated doses)

PhenoxybenzaminePhenoxybenzamine

• Cardiac EffectsCardiac Effects– Orthostatic hypotension (if HTN or Orthostatic hypotension (if HTN or

hypovolemia)hypovolemia)– Impairement of compensatory Impairement of compensatory

vasoconstriction vasoconstriction exaggerated drop in BP exaggerated drop in BP in response to blood loss or vasodilating in response to blood loss or vasodilating drugs (eg,VAA)drugs (eg,VAA)

– CO, renal blood flow unchanged (unless CO, renal blood flow unchanged (unless preexisting renal vasoconstriction)preexisting renal vasoconstriction)

– Cerebral/coronary vascular resistances Cerebral/coronary vascular resistances don’t changedon’t change

PhenoxybenzaminePhenoxybenzamine

• Non-Cardiac effectsNon-Cardiac effects– Prevents inhibitory action of epi on the Prevents inhibitory action of epi on the

secretion of insulin (more insulin secreted)secretion of insulin (more insulin secreted)– Catecholamine-induced Glycogenolysis in Catecholamine-induced Glycogenolysis in

skeletal muscle or lipolysis not alteredskeletal muscle or lipolysis not altered– Stimulation of radial fibers of the iris is Stimulation of radial fibers of the iris is

prevented prevented miosis (pupillary constriction miosis (pupillary constriction near vision) near vision)

– SedationSedation– Nasal stuffiness (unopposed alpha blockade Nasal stuffiness (unopposed alpha blockade

vasodilation in mucous membranes) vasodilation in mucous membranes)

PhenoxybenzaminePhenoxybenzamine

• Clinical UsesClinical Uses– Preoperative treatment of HTN of pt with Preoperative treatment of HTN of pt with

PHEOCHROMOCYTOMA (0.5-1 mg/kg PO)PHEOCHROMOCYTOMA (0.5-1 mg/kg PO)• With chronic alpha blockadeWith chronic alpha blockaderelieving intense relieving intense

peripheral vasoconstriction, allows expansion of IV peripheral vasoconstriction, allows expansion of IV volume as reflected by a drop in Hctvolume as reflected by a drop in Hct

– Given to Pt with excessive vasoconstriction with Given to Pt with excessive vasoconstriction with associated tissue ischemia (eg. hemorrhagic associated tissue ischemia (eg. hemorrhagic shock) but only after IV fluid volume is replenishedshock) but only after IV fluid volume is replenished

– Dz’s with a large component of vasoconstriction Dz’s with a large component of vasoconstriction (Raynaud’s syndrome)(Raynaud’s syndrome)

YOHIMBINE (Procomil)YOHIMBINE (Procomil)

An alkaloid derived from the bark of the tree An alkaloid derived from the bark of the tree Corynanthe yohimbi.Corynanthe yohimbi.It is an alpha-It is an alpha-adrenergic blocking agent that in excess causes antidiuresis, increased blood adrenergic blocking agent that in excess causes antidiuresis, increased blood pressure, tachycardia, irritability, tremor, sweating, dizziness, nausea, and vomiting. pressure, tachycardia, irritability, tremor, sweating, dizziness, nausea, and vomiting. It is used therapeutically to treat erectile dysfunction.It is used therapeutically to treat erectile dysfunction.

• Blocks presynaptic alpha-2 receptors Blocks presynaptic alpha-2 receptors enhanced release of N.E. from nerve enhanced release of N.E. from nerve endingsendings

• Tx of:Tx of:– Idiopathic orthostatic hypotension (rare)Idiopathic orthostatic hypotension (rare)– ImpotenceImpotence– Crosses BBB, may cause muscle activity & Crosses BBB, may cause muscle activity &

tremortremor– OverdoseOverdosetachy, HTN, paresthesiatachy, HTN, paresthesia

PrazosinPrazosin

• Selective postsynaptic alpha-1 blockerSelective postsynaptic alpha-1 blocker• Leaves intact the inhibiting effect of Leaves intact the inhibiting effect of

alpha-2 receptor activity on N.E. release alpha-2 receptor activity on N.E. release from nerve endings from nerve endings less likely than less likely than nonselective alpha blockers to cause nonselective alpha blockers to cause reflex tachycardiareflex tachycardia

• Dilates both arterioles and veinsDilates both arterioles and veins

PrazosinPrazosin

• Clinical UseClinical Use– Preoperative treatment of HTN of pt Preoperative treatment of HTN of pt

with PHEOCHROMOCYTOMA (0.5-1 with PHEOCHROMOCYTOMA (0.5-1 mg/kg PO)mg/kg PO)

Beta BlockersBeta Blockers

• Bind to Beta adrenergic receptors and Bind to Beta adrenergic receptors and block effects of catecholamines & block effects of catecholamines & sympathomimetics on the heart & sympathomimetics on the heart & smooth muscles of the airways & blood smooth muscles of the airways & blood vesselsvessels

• Beta blockers should continue during Beta blockers should continue during periop period to avoid reflex SNS periop period to avoid reflex SNS hyperactivityhyperactivity

Beta BlockersBeta Blockers

• Selective Affinity for Beta-adrenergic Selective Affinity for Beta-adrenergic receptorsreceptors

• Competitive inhibitionCompetitive inhibition• Beta blockade can be reversed by Beta Beta blockade can be reversed by Beta

agonist by displacement from occupied agonist by displacement from occupied receptors if large amount of agonist is receptors if large amount of agonist is givengiven

• Chronic Beta Blocker use = increased Chronic Beta Blocker use = increased number of beta-adrenergic receptors number of beta-adrenergic receptors (upregulation)(upregulation)

Structure Activity Structure Activity RelationshipsRelationships• Beta Blockers: derived from isoproterenol Beta Blockers: derived from isoproterenol

(beta agonist)(beta agonist)• Substitutions on the benzene ring Substitutions on the benzene ring

determine if drug is antagonist or agonistdetermine if drug is antagonist or agonist• Levorotatory forms of beta Levorotatory forms of beta

agonists/antagonists more potent than agonists/antagonists more potent than Dextrorotatory forms (Lefties Rock!!)Dextrorotatory forms (Lefties Rock!!)

• Example: Dextrorotatory isomer of Example: Dextrorotatory isomer of Propanolol has <1% of the potency of the Propanolol has <1% of the potency of the Levorotatory form (Lefties Rock!!)Levorotatory form (Lefties Rock!!)

ClassificationClassification

• Nonselective for beta1 & beta2 Nonselective for beta1 & beta2 receptors (propanolol, nadalol, timolol, receptors (propanolol, nadalol, timolol, pindolol)pindolol)

• Cardioselective for beta1 receptors Cardioselective for beta1 receptors (esmolol, metoprolol, atenolol, (esmolol, metoprolol, atenolol, acebutolol, betaxolol)acebutolol, betaxolol)

• Beta receptor selectivity is dose-Beta receptor selectivity is dose-dependentdependent

• Beta receptor selectivity is lost when Beta receptor selectivity is lost when large doses of antagonist is givenlarge doses of antagonist is given

More on ClassificationMore on Classification

• PurePure antagonists: absent intrinsic antagonists: absent intrinsic sympathomimetic activity (metoprolol, atenolol, sympathomimetic activity (metoprolol, atenolol, propanolol, nadalol)propanolol, nadalol)

• PartialPartial antagonists: present intrinsic antagonists: present intrinsic sympathomimetic activity (timolol, pindolol, sympathomimetic activity (timolol, pindolol, acebutolol, betaxolol)acebutolol, betaxolol)

• Partial antagonists cause less direct myocardial Partial antagonists cause less direct myocardial depression and less heart rate slowing than pure depression and less heart rate slowing than pure antagonistsantagonists

• PartialPartial antagonists may be antagonists may be betterbetter tolerated than tolerated than pure antagonists by pts with pure antagonists by pts with poor left ventriculat poor left ventriculat functionfunction

Propanolol (aka Inderal)Propanolol (aka Inderal)

• First Beta antagonist introduced First Beta antagonist introduced clinicallyclinically

• Standard drug to which all Beta Blockers Standard drug to which all Beta Blockers are compared toare compared to

• Nonselective for beta1 & beta2 Nonselective for beta1 & beta2 receptors (equal antagonism)receptors (equal antagonism)

• Pure antagonist (lacks sympathomimetic Pure antagonist (lacks sympathomimetic intrinsic activity)intrinsic activity)

• Optimal plasma concentration attained Optimal plasma concentration attained when resting HR=55 to 60bpmwhen resting HR=55 to 60bpm

Propanolol Propanolol Cardiac EffectsCardiac Effects

• Decreased HR, decreased myocardial Decreased HR, decreased myocardial contractility, decreased C.O. (Beta1)contractility, decreased C.O. (Beta1)

• Increased Peripheral Vascular Resistance, Increased Peripheral Vascular Resistance, increased coronary vascular resistance increased coronary vascular resistance (Beta2)(Beta2)

• Although prolongation of systolic ejection Although prolongation of systolic ejection and dilatation of cardiac ventricles and dilatation of cardiac ventricles increase Myocardial O2 requirements, increase Myocardial O2 requirements, the the O2-sparing effects of decreased HR & O2-sparing effects of decreased HR & contractility predominate (compensate)contractility predominate (compensate)

PropanololPropanololPharmacokineticsPharmacokinetics• Rapid GI absorptionRapid GI absorption• Systemic availability limited by Systemic availability limited by extensive extensive

hepatic first-pass metabolismhepatic first-pass metabolism (95% of drug (95% of drug absorbed via first-pass)absorbed via first-pass)

• Huge individual variation in hepatic first-Huge individual variation in hepatic first-pass metabolism (up to 20-fold difference in pass metabolism (up to 20-fold difference in plasma concentration in similarly dosed pts)plasma concentration in similarly dosed pts)

• PO dose 40-800mg/day is much higher than PO dose 40-800mg/day is much higher than IV dose (0.05mg/kg in increments of 0.5mg-IV dose (0.05mg/kg in increments of 0.5mg-1mg q5min)1mg q5min)

PropanololPropanololMetabolismMetabolism

• Clearance from plasma: hepaticClearance from plasma: hepatic• Elimination half-time: 2-3hrsElimination half-time: 2-3hrs• Elimination is decreased when hepatic Elimination is decreased when hepatic

blood flow decreases. May decrease its blood flow decreases. May decrease its own clearance rate by decreasing C.O. own clearance rate by decreasing C.O. and hepatic blood flowand hepatic blood flow

• Renal failure does not alter elimination Renal failure does not alter elimination half-life BUT accumulation of half-life BUT accumulation of metabolites takes placemetabolites takes place

Propanolol & Local Propanolol & Local AnestheticsAnesthetics

• Decreases clearance of AMIDE L.A. by Decreases clearance of AMIDE L.A. by dec hepatic blood flow & inhibition of dec hepatic blood flow & inhibition of liver metabolismliver metabolism

• Bupivacaine clearance is decreased Bupivacaine clearance is decreased 35%35%

• Higher Chance of Systemic toxicity of Higher Chance of Systemic toxicity of bupivacaine and other amide L.A. bupivacaine and other amide L.A.

Propanolol & OpioidsPropanolol & Opioids

• Pulmonary first-pass uptake of Fentanyl is Pulmonary first-pass uptake of Fentanyl is HIGHLY DECREASED in pts taking HIGHLY DECREASED in pts taking propanololpropanolol

• 2-4 times as much injected Fentanyl enters 2-4 times as much injected Fentanyl enters systemetic circulation right after injection systemetic circulation right after injection (more chance of overdosing with Fentanyl (more chance of overdosing with Fentanyl in pt wo takes Propanolol)in pt wo takes Propanolol)

• This response reflects ability of one basic This response reflects ability of one basic lipophilic amine (propanolol) to inhibit lipophilic amine (propanolol) to inhibit pulmonary uptake of another basic pulmonary uptake of another basic lipophilic amine (fentanyl) lipophilic amine (fentanyl)

Metoprolol (Lopressor)Metoprolol (Lopressor)

• Beta1 blocker, prevents inotropic & Beta1 blocker, prevents inotropic & chronotropic responses to beta chronotropic responses to beta stimulationstimulation

• OK to use in COPD/PVD pts since NO OK to use in COPD/PVD pts since NO Beta2 blocking properties at normal Beta2 blocking properties at normal dose (2-15mg IV). Becomes dose (2-15mg IV). Becomes nonselective at high dosesnonselective at high doses

Metoprolol Metoprolol PharmacokineticsPharmacokinetics

• High hepatic first-pass metabolism High hepatic first-pass metabolism (only 40% reaches systemic (only 40% reaches systemic circulation)circulation)

• Low protein binding (10% bound)Low protein binding (10% bound)• Elimination half-life 3-4hrsElimination half-life 3-4hrs

Atenolol (Tenormin)Atenolol (Tenormin)

• Most selective Beta1 BlockerMost selective Beta1 Blocker• Periop Tx will decrease incidence of post Periop Tx will decrease incidence of post

MI in CAD ptsMI in CAD pts• Enters CNS in very small amounts BUT Enters CNS in very small amounts BUT

fatigue/depression still occursfatigue/depression still occurs• Can be used with caution in IDDM pts Can be used with caution in IDDM pts

whose HTN is not controlled with other whose HTN is not controlled with other antiHTN (antiHTN (does notdoes not potentiate Insulin- potentiate Insulin-Induced Induced HypoglycemiaHypoglycemia seen with seen with nonselective Beta blockersnonselective Beta blockers))

Atenolol PharmacokineticsAtenolol Pharmacokinetics

• 50% of PO dose (50-100mg/day) 50% of PO dose (50-100mg/day) absorbed by GIabsorbed by GI

• Little/no hepatic metabolismLittle/no hepatic metabolism• Renal excretionRenal excretion• Elimination half-life 6-8hrs (more than Elimination half-life 6-8hrs (more than

24 hrs in renal failure)24 hrs in renal failure)• IV dose for acute MI (5mg over 5min IV dose for acute MI (5mg over 5min

followed by another 5mg 10min later)followed by another 5mg 10min later)

Esmolol (Brevibloc)Esmolol (Brevibloc)• Rapid onset, short acting Beta1 blocker given Rapid onset, short acting Beta1 blocker given

ONLY IV (0.5mg/kg)ONLY IV (0.5mg/kg)• Useful to Tx HTN/Tachy in response to intraop Useful to Tx HTN/Tachy in response to intraop

noxious stimulation & intubation (lido/fentanyl noxious stimulation & intubation (lido/fentanyl blunt inc BP but not HR) (eg 150mg IV 2min blunt inc BP but not HR) (eg 150mg IV 2min before Laryngoscopy)before Laryngoscopy)

• Used prior to ECT (attenuation of HR increase & Used prior to ECT (attenuation of HR increase & decrease length of seizure)decrease length of seizure)

• Used in Pheochromocytoma, thyrotoxicosis, Used in Pheochromocytoma, thyrotoxicosis, PIH, epinephrine- or cocaine-induced PIH, epinephrine- or cocaine-induced cardiovascular toxicity cardiovascular toxicity

Esmolol Esmolol PharmacokineticsPharmacokinetics• pH 4.5-5.5 (pain on injection?)pH 4.5-5.5 (pain on injection?)• T1/2T1/29min (rapid hydrolysis in blood by 9min (rapid hydrolysis in blood by

plasma esterases, plasma esterases, independentindependent of liver, of liver, renal, hepatic function)renal, hepatic function)

• Plasma esterases that hydrolyze Esmolol Plasma esterases that hydrolyze Esmolol are different than Plasma Cholinesteraseare different than Plasma Cholinesterase

• Dose: 0.5mg/kg (peaks 5min). Return Dose: 0.5mg/kg (peaks 5min). Return of HR to predrug level within 10-30minof HR to predrug level within 10-30min

• Poor lipid solubility limits crossing into Poor lipid solubility limits crossing into CNS/placenta CNS/placenta But still crossesBut still crosses

Beta BlockersBeta BlockersSide EffectsSide Effects

• Similar Side Effects. Magnitude depends Similar Side Effects. Magnitude depends on Selectivity and Presence/Absence of on Selectivity and Presence/Absence of Intrinsic Sympathomimetic ActivityIntrinsic Sympathomimetic Activity

• May alter airway resistance, May alter airway resistance, carbohydrate/lipid metabolism, carbohydrate/lipid metabolism, distribution of extracellular ionsdistribution of extracellular ions

• Cross CNS/placentaCross CNS/placenta• GI: N/V/DGI: N/V/D• Fever, rash, myopathy, alopecia, Fever, rash, myopathy, alopecia,

thrombocytopenia with chronic usethrombocytopenia with chronic use

Beta BlockersBeta BlockersContraindicationsContraindications

• DO NOT use in pts with AV Block or h/o heart DO NOT use in pts with AV Block or h/o heart failure not caused by tachycardiafailure not caused by tachycardia

• Be cautious Be cautious Hypovolemic/tachyHypovolemic/tachy pt since Beta pt since Beta Blockade may cause profound hypotensionBlockade may cause profound hypotension

• Nonselective Beta Blockers or high dose of Nonselective Beta Blockers or high dose of Selective Beta Blockers ARE NOT Selective Beta Blockers ARE NOT RECOMMENDED for pts with RECOMMENDED for pts with COPDCOPD (can cause (can cause broncoconstriction), broncoconstriction), PVDPVD (can cause peripheral (can cause peripheral vasoconstriction), vasoconstriction), DiabetesDiabetes (hypoglycemia may (hypoglycemia may be masked be masked no increase in HR) no increase in HR)

Combined Alpha & BetaCombined Alpha & BetaLabetalol (Trandate)Labetalol (Trandate)

• Selective Alpha1 and Nonselective Beta BlockerSelective Alpha1 and Nonselective Beta Blocker• Labetalol is thought to have Labetalol is thought to have selective beta-2 selective beta-2 partialpartial

agonistagonist (go figure!!) and nonselective beta (go figure!!) and nonselective beta antagonist actionantagonist action

• Presynaptic Alpha2 receptors are spared Presynaptic Alpha2 receptors are spared released N.E. continues to inhibit further release of released N.E. continues to inhibit further release of catecholaminescatecholamines

• Labetalol is 1/5-1/10 as potent as Phenatolamine Labetalol is 1/5-1/10 as potent as Phenatolamine (alpha blockade)(alpha blockade)

• Labetalol is 1/3-1/4 as potent as Propanolol (Beta Labetalol is 1/3-1/4 as potent as Propanolol (Beta Blockade)Blockade)

• Beta to Alpha potency ratio 7:1 (IV) and 3:1 (PO)Beta to Alpha potency ratio 7:1 (IV) and 3:1 (PO)

LabetalolLabetalolPharmacokineticsPharmacokinetics

• Metabolism: Conjugation of Metabolism: Conjugation of glucuronic acidglucuronic acid

• 5% unchanged drug recovered in 5% unchanged drug recovered in urineurine

• T1/2 = 5-8hrs, prolonged in liver T1/2 = 5-8hrs, prolonged in liver dz, unchanged renal dzdz, unchanged renal dz

LabetalolLabetalolCV ProfileCV Profile

• Dec BP by dec SVR (alpha1)Dec BP by dec SVR (alpha1)• Vasodilation via alpha1 BLOCKADE & Vasodilation via alpha1 BLOCKADE & partial beta2 partial beta2

AGONIST activityAGONIST activity((http://lysine.pharm.utah.edu/netpharm/netpharm_0http://lysine.pharm.utah.edu/netpharm/netpharm_00/druglist/labetalol.htm0/druglist/labetalol.htm))

& Stoelting page 300& Stoelting page 300• Dec HR by attenuating reflex tachy via Beta Dec HR by attenuating reflex tachy via Beta

BlockadeBlockade• Unchanged C.O.Unchanged C.O.• BP should be lowered within 5-10min of BP should be lowered within 5-10min of

0.1-0.5mg/kg IV dose0.1-0.5mg/kg IV dose

LabetalolLabetalolClinical UsesClinical Uses

• HTN emergencies (eg HTN emergencies (eg epi overdose from local)epi overdose from local)

• 20-80mg IV q10min20-80mg IV q10min• Pheo pts with rebound HTN after Pheo pts with rebound HTN after

withdrawal of Clonidinewithdrawal of Clonidine• Tx angina pectorisTx angina pectoris• Used in surgeries where “Controlled Used in surgeries where “Controlled

Hypotension” needed (10mg intermittently Hypotension” needed (10mg intermittently prn)prn)

LabetalolLabetalolSide EffectsSide Effects

• Orthostatic hypotension (most common)Orthostatic hypotension (most common)• Bronchospasm (susceptible pts)Bronchospasm (susceptible pts)• Other Beta Blockade S.E.Other Beta Blockade S.E.

– CHFCHF– BradyBrady– Heart BlockHeart Block– Incomplete Alpha blockade in the presence Incomplete Alpha blockade in the presence

of more complete Beta Blockade of more complete Beta Blockade excessive alpha stimulationexcessive alpha stimulation

ReferencesReferences

• Pharmacology & Physiology in Pharmacology & Physiology in anesthesia practice. Stoelting, 3anesthesia practice. Stoelting, 3rdrd edition, p 288-301edition, p 288-301

• Clinical Anesthesiology. Morgan & Clinical Anesthesiology. Morgan & Mikhail, 3Mikhail, 3rdrd edition, p 212-223 edition, p 212-223

• http://lysine.pharm.utah.edu/http://lysine.pharm.utah.edu/netpharm/netpharm_00/druglist/netpharm/netpharm_00/druglist/labetalol.htmlabetalol.htm