alpha and beta antagonists – Flashcards

a peripheral efferent nervous system: innervates heart, blood vessels, visceral organs, glands and smooth muscle generally beyond conscious control

preganglionic and post ganglionic

cell body in spinal cord or brain, modulated by higher centers in brain and by spinal reflexes preganglionic axon leaves spinal cord from cranial, thoracic, lumbar or sacral region, forms synaptic connection in automatic ganglia with cell body of postganglionic autonomic nerve fiber

send their axons directly to the effector organs

modulates the ongoing activity of the involuntary visceral organs by eliciting excitatory or inhibitory responses

nonmyelinated, slower

myelinated , rapid

sympathetic and parasympathetic

cell bodies for preganglionic neurons originate in the intermediolateral cell column of the spinal cord at the thoracic and lumbar levels Relatively short preganglionic neurons leave the spinal cord at the thoracic and lumbar levels ( thoracolumbar out flow) short preganglionic axons send connections to symapthetic ganglia outside of the spinal cord 22 segmentally arranged ganglia consists of 2 chains located bilaterally with respect to the spinal cord post ganglionic neuorons cell bodies are in the paravertebral sympathetic chain - send their axons directly to effector organs

Most preganglionic sympathetic neurons synapse in the paravertebral sympathetic ganglia exception to rule : celiac, superior mesenteric, inferior mesenteric ( hypogastric ) ganglia

mediates synaptic transmission between preganglionic and postganglionic nerve fibers in the sympathetic pathway

Acetylcholine

Norepinephrine

alpha-1, alpha-2, beta-1, and beta-2:

Vasoconstriction of smooth muscle of blood vessels arterioles>veins; Also slows down motility of GI tract

Vasodilation of Arteries; Mediates synaptic transmission in the pre & postsynaptic nerve terminals (negative feedback results in decrease release of norepinephrine)

Increases HR (in SA node)also +inotropic effect by increasing contractility & automaticity in both atria & ventricles

Dilation of smooth muscle esp. tubal i.e. Bronchi & uterus (Relaxes); also increase intra- ocular pressure (Fight or Flight response)

+ inotrope = increases contractility - inotrope = decreases contractility + chronotrope = increased heart rate - chronotrope = decreased heart rate + dromotrope = increased conduction -dromotrope = decreased conduction

A sympathomimetic agent is one that elicits an autonomic sympathetic response similiar to stimulation of the receptor by a natrual catecholamine. A sympatholytic agent is one that blocks a response that would normally result from a receptor stimulation by a natrual catecholamine.

Agonist activate receptors directly. Indirect agonists activate receptors by evoking the release of an endogenous neurotransmitter.

all drugs containing the 3,4 dihydroxybenzene structure and are rapidly inactivated by the enzymes MAO or COMT. Ex: Epi, Norepi, Dopamine- natural catecholamines Isoproterenol, Dobutamine, Dopexamine- synthetic catecholamines Noncatecholamines lack the 3-hydroxyl group and are not affected by COMT and thus depend on MAO for metabolism. Metabolism is often slower. Ex: Ephedrine, Mephentermine, Amphetamine, Modafinil, Metaraminol, Phenylephrine, Methoxamine, Midodrine.

Catecholamines are metabolized by MAO - monoamine oxidase AND by COMT - catechol-O- methyltransferase. COMT exist primarily outside neuronal tissue where it catalyzes hydroxyl methylation of the central catechol group of catecholamines. MAO is present inside neurons and plasma and catalyzes the oxidative deamination of monoamines including catecholamines and serotonin. These two enzyme systems, COMT & MAO, work in combination to break down catecholamines into their metabolites (including vanillylmandelic acid) that can be eliminated via the urinary system. The lungs also function in plasma clearance of epi, norepi, and dopamine (~ 20-25%, even higher in septic patients).

Catecholamine synthesis proceeds in this order: Phenylalanine + phenylalanine hydroxylase) Tyrosine Tyrosine + tyrosine hydroxylase (enzyme) DOPA DOPA + aromatic L-amino acid decarboxylase Dopamine Dopamine + dopamine β-hydroxylase Norepinephrine Norepinephrine + phenylethanolamine N-methyltransferase Epinephrine

Epinephrine indications : Add to locals to ↓systemic absorption and ↑duration of action of anesthetic Treat allergic reactions (life threatening) Give during CPR as single most important therapeutic drug Continuous infusion to ↑myocardial contractility Contraindications: Can cause ↑in blood sugar (insulin is inhibited by α₂ mechanism) Large doses may ↑PVC's, tach or fibrillation May be exacerbated by anesthetic agents or MI Can cause hypokalemia Doses: Single-2-8micrograms Continuous infusion 1-20 mcg/min

Indications: Potent α and β agonist (not beta 2) produces intense arterial and venous vasoconstriction-but does not produce bronchodilation in the lungs Contraindications: Decreased cardiac output due to intense vasoconstriction May cause metabolic acidosis due to decreased tissue perfusion Capillary vasoconstriction and loss of protein-free fluid into the vascular space Extravasation may cause necrosis d/t vasoconstriction. Dose: Continuous-4-19mcg/min for treatment of refractory hypotension Not used as single intravenous dose

Indications: • Synthetic catecholamine • Most potent β₁ and β₂ agonist- no alpha • 2-3 times more potent than epi • 100 times more potent than norepi • Used to ↑HR in presence of heart block • Increases contractility • Increases rate and automaticityContraindications • ↑O2 demand • ↑arrhythmias Dose • Infusion 1-5mcg/min • Single dose 1-4 mcg

Indications • ↑Cardiac output • ↑myocardial contractility Contraindications: • "renal dose dopamine"contains inherent risks such as 1. Tachycardia 2. Dysrhythmias 3. Myocardial ischemia 4. Attenuation of the ventilator response to hypoxia 5. ↑intrapulmonary shunting 6. Mesenteric ischemia 7. Can exacerbate GI mucosal ischemia • Depresses ventilation-inhibits neurotransmitter at the carotid bodies • Increases intraocular pressure Dose: • Continuous infusion of 2-20mcg/kg/min • There is no bolus dose

Indications: • Synthetic catecholamine • Selective β₁ • ↑cardiac contractility • ↑Cardiac output without ↑in heart rate • Modest β₂ for periph dilation • Congestive Heart Failure patients • No peripheral vasoconstriction Contraindications: • At high doses, may cause tach or dysrhythmias >10mcg/kg/min • Improves conduction thru AV node, so may increase heart rate in AFib pts Dose: • Infusion of 2-10mcg/kg/min • No bolus dose

Dose: 50-200mcg IV; alpha adrenergic receptor activation with minimal beta activation. Produced intense peripheral vasoconstriction, increased systolic and diastolic pressures, and a reflex bradycardia that can result in decreased CO. Indications: Vasoconstrictor, treatment of hypotension, shock, supraventricular tachyarrythmias; reversal of right to left shunting, prolongation of duration of LA. Contraindications: do not use in IV regional anesthesia or local anesthesia of end organs (digits, penis, ears)

Dose: 0.25mg SQ, or by metered dose inhaler daily dose should not exceed 16-20puffs, each puff 200mcg; Beta-2 adrenergic agonist Indications: Bronchodilator, inhibition of premature labor. Contraindications: Use in caution with HTN, Ischemic heart disease, arrhythmias, DM, and those susceptible to hypokalemia

Dose: Infusion up to 350mcg/kg/min until uterine contractions are inhibited for at least 12 hours. Beta-2 adrenergic receptor agonist, increases level of cyclic AMP in uterine smooth muscle. Calcium balance is altered, resulting in relaxation. Indications: Uterine relaxation Contraindications: Use before the 20th week of pregnancy, and in those conditions in which continuation of pregnancy is hazardous to the mother or fetus, pulmonary edema is increased with concomitant administration of corticosteroids

Dose: 10-25mg IV; Synthetic indirect acting non catecholamine that stimulates alpha and beta adrenergic receptors. Act by releasing endogenous stores of norepinephrine, and stimulates adrenergic receptors. Indications: Used to increase B/P in the presence of sympathetic nervous system blockade produced by regional anesthesia or hypotension d/t inhaled or injected anesthetics, also used as chronic oral medication to treat bronchial asthma d/t bronchodilating effects. Contraindications: use cautiously in pts with HTN and CV disease, unpredictable effects in pts who are catecholamine depleted.

Dose: Antihypertensive 0.05-0.1mg 3-4x daily, hypertensive crisis 0.15-0.3mg IV over 5 min, Supplementation of anesthesia 1-2mcg/kg/hr. Selective alpha-2 adrenoceptor agonist. It inhibits central sympathetic outflow through activation of alpha-2 adrenergic receptors in the medullary vasomotor center. It decreases BP, HR, and CO, and produces a dose dependent sedation. Indications: Antihypertensive, premedications, treatment of opiod/ETOH withdrawal states, supplementation of anesthesia, prolongation of duration of Las. Contraindications: Use in caution with pts with severe coronary insufficiency, recent MI, cerebrovascular dz, chronic renal failure, Raynaud's, thromboangiitis obliterans, or a history of mental depression.

Liberated by the long postganglionic sympathetic nerves, mediates end-organ responses at the neuroeffector junction

cholinergic

adrenergic

unlike the post ganglionic sympathetic nerve terminals, releases epinephrine as the primary catecholimine

cell bodies giving rise to preganglionic parasympathetic nerves have thier origins in the brain and spinal cord they leave the brain and cord at the cranial and sacral levals " craniosacral outflow" the cranial portion of the PNS outflow innervates structures in head, neck, thorax, and abdomen Fibers travel in occulomotor ( iii) , facial ( vii) , glossopharyngeal ( ix ) , and vagal ( x ) cranial nerves sacral divisions forms the pelvic nerve and innervates the remainder of the intestines and pelvic viscera, including bladder and reproductive organs preganglionic neurons are relatively long, so the parasympathetic ganglia are located near the effector organs, post ganglionic fibers are short acetylcholine is the neurotransmitter mediating transmission in the parasympathetic ganglia as well as at postganglionic nerves innervating the effector organs

Most organs receive dual innervation consisting of SNS and PNS components Mediate opposing responses; balance exists Blockade or inhibition of one system leads to exaggeration of response by the other Some organs, such as vasculature of spleen, receive only one type of innervation—in these cases is sympathetic

One sympathetic preganglionic neuron may ramify and ultimately synapse with many postganglionic sympathetic neurons, leading to diffusion of SNS responses In contrast, parasympathetic preganglionic fibers form only single synaptic connections, resulting in more discrete and localized responses This distinction between the two systems has profound physiologic significance: Activation of SNS for fight or flight—more generalized total body response; activation of PNS associated with energy conservation and maintenance during periods of low activity. Widespread activation of PNS NOT beneficial---this is what nerve agents do to incapacitate and kill people!

Electrical impulses from the CNS result in local depolarization of the neuronal membrane as result of selective increase in the permeability of Na+ ions that flow inwardly in the direction of their electrochemical gradient Immediate repolarization follows from selective increase in permeability to K+ ions These transmembrane ion fluxes result in generation of an action potential that is propogated throughout length of axon Arrival of action potential at preganglionic or postganglionic nerve terminal triggers quantal release of neurotransmitter stored in intracellular vesicles Neurotransmitter synthesis occurs in the nerve terminal Neurotransmitter release occurs through a Ca++ dependent process called exocytosisExocytosis: storage vesicle migrates to and fuses with nerve terminal membrane—opens to extracellular space—discharges neurotransmitter into synaptic cleft Neurotransmitter diffuses across cleft and interacts with specific receptors located on cell body of postganglionic neuron or effector organ In both SNS and PNS ganglia, neurotransmitter released by preganglionic neurons is acetylcholine Activation of postjunctional membrane receptors on cell body of postganglionic neurons leads to increased ion permeability and conductance in the postganglionic neuron—an action potential is propagated When this AP reaches the postganglionic SNS and PNS nerve terminals, neurotransmitter is released Postganglionic Sympathetic neurotransmitter is norepinephrine Postganglionic Parasympathetic neurotransmitter is acetylcholine The response mediated in the effector organ subsequent to the release of neurotransmitter is dependent on the neuro-transmitter and the nature of the postjunctional receptor subtype present in the effector organAfter release, the effect of the neurotransmitter must be rapidly terminated to avoid excessive activation Most cholinergic synapses and neuroeffector junctions contain the enzyme acetylcholinesterase, which hydrolyzes AcH into acetic acid and choline—choline is taken up and reused At adrenergic neurotransmitter junctions, norepinephrine (NE) is not terminated by enzymatic deactivation—instead termination occurs by a combination of neuronal reuptake into the sympathetic nerve and by simple diffusionNE accumulated in sympathetic nerves by reuptake has two fates: 1) oxidatively deaminated by enzyme MAO in the mitichondria, or 2) sequestered in storage vesicles for subsequent release NE diffusing away from receptors is inactivated by O-methylation through the enzyme catechol-O-methyltransferase (COMT)

norepinephrine

acetylcholine

acetylcholinesterase,

1) oxidatively deaminated by enzyme MAO in the mitichondria, or 2) sequestered in storage vesicles for subsequent release NE diffusing away from receptors is inactivated by O-methylation through the enzyme catechol-O-methyltransferase (COMT)

two types of adrenergic receptors—alpha and beta Alpha and Beta receptors each have subtypesA1, A2, B1, B2, etc.

also two types of receptors—Nicotinic and Muscarinic The response of most autonomic effector cells in peripheral visceral organs is typically muscarinic. The responses in sympathetic and parasympathetic ganglia, as well as responses in skeletal muscle, are nicotinic.

heart SA node - elevated HR av node - increased conduction speed mucle fibers - increased contractility kidney - increased renin release pancreas - increased insulin secretion adipose tissue - lipolysis

skeletal muscle - relaxation lung- bronchiole muscle- relaxation secretory glands - increased secretions liver- glycogenolysis and gluconeogenesis gall bladder- relaxation bladder wall- relaxation uterus - relaxation plasma K+ - stimulate Na+-K+ pump (decreased K +)

pupil of the eye- mydriasis ( pupil dilates) arterial blood vessels - contracts other- contraction veins- contraction spleen - release RBCs stomach and intestines - relaxation pancreas - decreased insulin secreation / increased glucogon secretion uterus- contraction

On most adrenergic and cholinergic nerve terminals, the existence of prejunctional A-adrenergic receptors belonging to the A2 subtype exist Activation of receptors= decreased NE release Blockade of Alpha-2 receptors leads to increased outflow of NE Activation of prejunctional Alpha 2 receptors by norepinephrine or by exogenously administered alpha-2 adrenergic receptor agonists decreases the release of norepinephrine Presynaptic Alpha-2 receptors also exist on most cholinergic nerve terminals, and the release of acetylcholine is inhibited when these receptors are activated.

Prevent the interaction of the endogenous neurotransmitter, Norepinephrine, or sympathomimetics with the corresponding adrenergic receptor Interfere with the ability of catecholamines or other sympathomimetics to provoke alpha-responses Prevent effects of catecholamines on heart and peripheral vasculature Inhibitory action of epinephrine of insulin secretion also prevented Side effects: orthostatic hypotension, baroreceptor mediated refles tachycardia, and impotence Absence of concomitant beta-blockade permits maximum expression of cardiac stimulation from NE

Phentolamine, prazosin, and yohimbine are competitive antagonists (reversible binding with receptors) Phenoxybenzamine , in contrast, binds covalently to alpha receptors—causes irreversibe and insurmountable blockade (even massive doses or sympathomimetics ineffective until drug effect terminated by metabolism)Phentolamine and phenoxybenzamine are nonselective alpha antagonists, acting on postsynaptic alpha-1 receptors and presynaptic alpha-2 receptors Prazosin is selective for alpha-1 receptors Yohimbine is selective for alpha-2 receptors

Substituted imidazoline derivative, produces transient non-selective alpha block Causes peripheral vasodilation and decrease in BP that manifests within 2 min and lasts 10-15 min Vasodilation reflects alpha-1 blockade and direct action on vascular smooth muscle Decreased BP causes baroreceptor mediated increase in SNS activity manifesting as cardiac stimulation Alpha-2 blockade permits enhanced neural release of norepinephrine manifesting as increased HR and CO Cardiac dysrhythmias and angina may occur Clinical uses: principle use is treatment of acute hypertensive emergencies, such as with intra-op manipulation of pheochromo-cytoma or autonomic hyperreflexia 30-70 mcg/kg dose = fast decrease in BP Continuous I.V. infusion Local infiltration for treatment of extravasation of sympathomimetics

Haloalkylamine derivative Non-selective alpha antagonist—covalent bond with alpha receptors Alpha-1 blockade more intense than A-2 Slow onset (60 min to peak effect) Elimination t ½ 24 hours—cumulative effects with repeated dosesOrthostatic hypotension prominent, especially in presence of pre-existing HTN or hypovolemia Impairment of compensatory vasoconstric-tion = large BP reductions in response to blood loss or vasodilating drugs/volatiles Despite decreased BP, CO is often increased and renal blood flow is not greatly changed Cerebral and coronary vascular resistance not changed Prevents inhibitory action of epinephrine on secretion of insulin Miosis prominent r/t prevention of stimulation of radial fibers of iris Sedation Nasal congestionClinical Uses: Pre-op to control BP in Pheochromocytoma pt Excessive vasoconstriction in hemorrhagic shockExcessive vasoconstriction with associated tissue ischemia, such as accompanies hemorrhagic shock, may be reversed by phenoxybenzamine, but only after intravascular fluid volume has been replenished

Selective A-2 receptor antagonist Causes enhanced release of NE from nerves Useful in treatment of rare pt with idiopathic orthostatic hypotensionObservation that alpha-2 agonists can reduce anesthetic requirements by actions on presynaptic alpha-2 receptors in the CNS suggests a possible interaction of yohimbine with volatile anesthetics

Selective alpha-1 antagonist No effect on alpha-2 receptor activity on NE release Less likely that non-selective alpha blockers to cause reflex tachycardia Dilates both arterioles and veins

Bind selectively to Beta receptors Interfere with ability of cathecholamines or other sympathomimetics to provoke beta responses Prevent effects of catecholamines on heart and smooth muscle of airways and blood vessels Continued throughout perioperative period to avoid risk of SNS hyperactivity associated with abrupt withdrawel Propranolol is the gold standard

Mechanism of action: Exhibit selective affinity Act by competetive inhibition Reversible if sufficiently large mounts of agonist are administered Chronic administration is associated with increase in number of beta-receptors ("up-regulation")Structure activity relationships: Beta antagonists are derivatives of beta-agonist drug Isoproterenol Substituents on the benzene ring determine drug action on beta receptors as an agonist or antagonist Levorotary forms more potentClassified as non-selective and selective for beta-1 and beta-2 receptors Furthur classified as partial or pure antagonists on basis of presence or absence of intrinsic sympathomimetic activity Antagonists with intrinsic sympathomimetic activity cause less direct myocardia depression and HR slowing than drugs without this activity Partial antagonists may be better tolerated than pure antagonists by pt's with poor LV function Classification Selective antagonists include metoprolol and atenolol Beta-1 selectivity is dose dependent and is lost with large doses---Selectivity should NOT be interpreted as specificity for a specific type of beta receptor Beta blockers may produce some degree of membraneous stabilization in the heart and thus resemble quinidine---but only at plasma concentrations far greater than those needed for a clinical effect Bradycardia and diirect myocardial depression produced by beta blockers are due to removal of SNS innervation to the heart and not membrane stabilization

Non-selective beta blocker Lacks intrinsic sympathomimetic activity—a pure antagonist Blockade of Beta-1 and Beta-2 receptors is about equal Remains the standard drug to which all other beta blockers are compared Cardiac effects Most important pharm effects on the heart Beta-1 blockade—decreased HR and CO, esp during exercise or with increased SNS activity HR slowing lasts longer than negative inotropic effects, suggesting a possible subtype of receptorsConcomitant blockade of B-2 receptors by propranolol increases periph vascular resistance, including coronary resistence Prolongation of systolic ejection and dilation of cardiac ventricles increases myocardia O2 req's; however, the O2 sparing effect of decreased HR and myocardial contractility predominate As a result, propranolol may relieve myocardial ischemia even though drug-induced increases in coronary vascular resistence oppose coronary blood flow Pharmacokinetics: Rapidly, almost completely absorbed from G.I. Extensive hepatic first-pass metabolism (70 %) with oral doses Large pt variation-up to 20-fold differences in plasma concentration with oral doses Hepatic metabolism is reason oral dose must be substantially greater than I.V. dose Extensively bound to plasma proteins (90-95%) Heparin induced increases in free-fatty acids causes decreased plasma protein binding Hemodilution with cardiopulmonary bypass may alter protein binding Metabolism Hepatic metabolism Active metabolite 4-hydroxypropranol—equivalent in activity to parent drug Cardiac beta-blockade is greater after equivalent doses of oral and I.V. drug related to this metabolite Elimination t ½ 2-3 hours Metabolism greatly reduced in decreased hepatic blood flow Propranolol may decrease its owm clearance rate by decreasing CO and hepatic blood flow Renal failure does not alter elimination t 1/2., but accumulation of metabs may occur Reduces clearance of amide local anesthetics by decreasing hepatic blood flow and inhibiting metabolism in liver Bupivicaine clearance relatively insensitive to changes in hepatic blood flow; 35% decrease in clearance of this drug may reflect propranolol-induced reduction in metabolism Systemic toxicity of local anesthetics could conceivably be increased by propranolol or other beta-blockers that interference with clearance of local anesthetics Opioid Clearance: pulmonary first-pass uptake of fentanyl substantially reduced with chronic propranolol use As a result, 2-4 times as much injected fentanyl enters systemic circulation immediately after injection. This response most likely reflects the ability of one basis lipophilic amine (propranolol) to inhibit the pulmonary uptake of a second basic lipophylic amine (fentanyl

Nonselective beta blocker Long duration of action allows qd dosing Slowly and imcompletely absorbed (30%) from G.I. Tract No metabolism—75% excreted unchanged in urine, 25% in bile Elimination t ½ 20-40 hrs

Nonselective beta blocker with intrinsic sympathomimetic activity Causes minimal resting bradycardia Large doses may cause unexpected increase in BP Well absorbed from G.I. Tract Protein binding 40-60% 40-50% recovered unchanged in urine No avtive metab; elim t ½ 3-4 hours

Non-selective beta receptor antagonist Therapeutically as effective as propranolol Treatment of glaucoma Rapid and complete absorption Extensive hepatic first pass metabolism (50%) Elimination t ½ 4 hours Treatment of glaucoma: decreases IOP, presumably by reducing production of aqueous humor. Administered as eye drops in glaucoma treatment, but systemic absorption may be sufficient to cause resting bradycardia and increased airway resistance. Cases of bradycardia and hypotension that are refractory to treatment with atropine have been observed during anesthesia in pediatric and adult patients receiving topical timolol. It may also be associated with impaired control of ventillation in neonates, resulting in unexpected postoperative apnea.

Noncardioselective beta blocker No intrinsic sympathomimetic activity Unlike other beta blockers, prolongs the duration of cardiac action potentials, increases the refractory period, and prolongs the Q-T interval, which may predispose to V-Tach (Torsades)Less frequent aggravation of CHF than other beta-blockers Administered orally to treat supraventricular dysrhythmias and to patients with life-threatening ventricular dysrythmias

Selective beta-1 antagonist Prevents inotropic and chronotropic responses to beta adrenergic stimulation Selectivity is dose related—large doses likely to become non-selective Conversely, brohchodilator, vasodilator, and metabolic effects of beta-2 receptors remain intact such that metoprolol is less likely to cauuse adverse effects in pts with chronic obstructive airway disease, peripheral vascular disease, and pts vulnerable to hypoglycemia Readily absorbed Large first pass metab (40% availability) Protein binding is low (10%) No active hepatic metabolites Elimination t ½ 3-4 hours Plasma concentrations of drug do not correlate with therapeutic effect

Selective beta-1 blocker Specific usefulness in whom the continued presence of beta-2 receptor activity is desirable 50% absorbed from G.I. Tract Elimination primarily by renal excretion Elimination t ½ 6-7 hours (may increase to > 24 hours in renal failure) Selective beta-1 blocker Specific usefulness in whom the continued presence of beta-2 receptor activity is desirable 50% absorbed from G.I. Tract Elimination primarily by renal excretion Elimination t ½ 6-7 hours (may increase to > 24 hours in renal failure) Plasma concebntrations do not correlate with therapeutic effect of drug Does not enter CNS in large amount, but fatigue and mental depression still occur Unlike non-selective beta blockers, does not appear to potentiate insulin-induced hypoglycemia and can be administered with caution in pts with diabetes mellitus

Rapid onset, short-acting Beta-1 selective antagonist, administered only I.V. Full tehrapeutic effect evident within 5 min, and action ceases within 10-30 min after discontinuation Useful for preventing or tx of adverse systemic BP and HR increases that occur intraop Example: Esmolol 150 mg I.V. administered 2 minutes before direct laryngoscopy and intubation provides reliable protection vs. increases in HR and BP. ** Lidocaine or Fentanyl is effective in blunting the increase in systolic BP assoc with laryngoscopy and intubation, but HR is not influenced Has been used during resection of pheochromocytoma and may be useful in perioperative management of thyrotoxicosis, PIH, and epi- or cocaine induced cardiovascular toxicity Administration to pts chronically tx with beta blockers has not been observed to produce additional negative inotropic effects Presumed reason is that esmolol in doses used does not occupy sufficient additional beta receptors to produce detectable increases in beta blockade I.V. use only (the only other I.V. beta blockers are propranolol and metoprolol) Pain on injection (buffered to pH 4.5-5.5) Elimination t ½ is 9 minutes Rapid hydrolysis by plasma esterases, independent of renal and hepatic function Plasma esterases are distinct from plasma cholinesterase, and duration od Succinylcholine is not prolonged in pts treated with esmolol Poor lipid solubility limits crossing to CNS

Side effects similar for all beta blockers, but magnitude varies depending on their selectivity and presence or absence of intrinsic sympathomimetic activity Most prominent pharmacologic and side effects on cardiovascular system Alter airway resistance, carbohydrate and lipid metabolism, and distribution of extracellular ions Penetrate BBB and cross placenta G.I.: nausea, vomiting, diarrhea Fever, rash, myopathy, alopecia, thrombocytopenia Interactions with anesthetics Decrease plasma concentrations of high-density lipoproteins Increase triglyceride and uric acid levels Principle contraindication: preexisting AV heart block or cardiac failure not caused by tachycardia Administration to hypovolemic pts with compensatory tachycardia may cause profound hypotension Non-selective beta blockers or high doses of selective agents not recommended for COPD pts In diabetes mellitus, beta blockade may mask signs of hypoglycemia Cardiovascular System Negative inotropic and chronotropic effects Conduction speed of impulses through AV node is slowed Rate of spontaneous Phase 4 depolarization is decreased Preexisting AV heart block due to any cause may be accentuated Cardiovascular effects of beta blockade reflect removal of SNS innervation to the heart (beta-1 blockade) Non-selective beta blockers resulting in beta-2 blockade may impede LV ejection r/t unopposed alpha-adrenergic receptor mediated peripheral vasoconstriction Magnitude of CV effects greatest when pre-existing SNS activity is increased, as with exercise Administration of a beta blocker may precipitate cardiac failure in a pt who was previously compensated Resting bradycardia is minimized and cardiac failure less likely with partial beta antagonist with intrinsic sympathomimetic activity (i.e. pindolol) Influence of Beta blockers on cardiac stimulating effects of Ca++, glucagon, and digitalis is not detectable Beta blockers do not alter the response to alpha-adrenergic agonists such as epinephrine or phenylephrine Pressor effect of Epi is enhanced because nonselective beta antagonists prevent beta-2 vasodilating effect of Epi and leave unopposed its alpha-adrenergic effect The presence of unopposed alpha-adrenergic induced vasoconstriction may provoke paradoxical HTN and may precipitate cardiac failure in presence or diseased myocardium that cannot respond to SNS stimulation because of beta blockade Pt with peripheral vascular disease do not tolerate well the peripheral vasoconstriction assoc with beta-2 blockade—cold hands/feet are common side effect Principle antidysrhythmic effect is to prevent dysrhythmogenic effects of endogenous or exogenous catecholamines or sympathomimetics Treatment of excess myocardial depression: Signs: bradycardia, low CO, hypotension, cardiogenic shock Bronchospasm and ventilatory depression with beta blocker overdose Seizures and prolonged intraventricular conduction of cardiac impulses ? Result of local anesthetic properties of certain beta blockers Initial tx Atropine 7 ug.kg I.V. in incremental doses If Atropine ineffective, use drugs to produce direct positive chronotropic and inotropic effects: I.e. non-selective beta-agonist Isoproterenol 2-25 mcg/min When pure beta blocker present, pure beta agonist such as Dobutamine is recommended Atropine effective by blocking vagal effects on the heart, therefore unmasking any residual SNS innervation With pure beta blocker, pure beta agonist such as Dobutamine is recommended because isoproteronol, with beta-1 and beta-2 agonist effects, could produce vasodilation before its inotropic effects develop Glucagon 1-10 mg I.V. (stimulates adenylate cyclase and increases intracellular cAMP concentrations independent of beta receptors) Particularly effective in presence of life-threatening bradycardia and has been described as drug of choice to treat massive beta blocker overdose Transvenous cardiac pacemaker Hemodialysis Airway resistance Non-selective beta blockers such as propranolol cansistently increase airway resistance due to beta-2 receptor blockade Exaggerated in pre-existing obstructive airway disease Selective beta-1 antagonists such as metoprolol and esmolol less likely to increase airway resistance

Beta blockers alter carbohydrate and fat metabolism Tachycardia, an important warning sign of hypoglycemia in insulin dependent diabetics, is blunted by beta blockers Non-selective beta blockers are NOT recommended for administration to pts with diabetes mellitus who may be at risk for developing hypoglycemia Example: Non-selective beta blockers interfere with glycogenolysis that usually occurs in response to release of epinephrine during hypoglycemia Distribution of Extracellular K+ Stimulation of beta-2 receptors seems to facilitate movement of K+ intracellularly Beta blockade inhibits uptake of K+ into skeletal muscle, and plasma concentration of K+ may increase

Myocardial depression produced by inhaled or injected anesthetics could be additive with depression produced by beta blockers Additive CV effects greatest with enflurane, intermediate with halothane, least with isoflurane. Sevo and Des, like Forane, not associated with significant additive CV effects However, clinical experience and studies confirm that additive myocardial depression with beta blockers and anesthetics is not excessive, and therefore treatment with beta blockers may be safely administered throughout the perioperative period.An exception may be pts treated with timolol in whom profound bradycardia has been observed in the presence of inhaled anesthetics. CO and systemic BP are similar with or without beta blockade in presence of 1 or 2 MAC Isoflurane. Even acute hemorrhage doesn't alter interaction between Isoflurane and beta blockers (in contrast, cardiac depression more likely in this scenario with Enflurane) CV response to even high doses of opioids such as Fentanyl are not altered by preexisting beta blockade With anesthetic drugs that increase SNS activity (Ketamine), acute use of beta blockers may unmask direct negative inotropic effects of concominantly administered anesthetics, with resultant decrease in systemic BP and CO nervous system Beta blockers may cross BBB Fatigue and lethargy are common Vivid dreams frequent, psychotic rx rare Peripheral parasthesias described Beta blockers can cross placenta and cause bradycardia, hypotension, and hypoglycemia in newborn infants of mothers on beta blockade Breast milk likely to contain the drug withdrawl hypersensitivity Acute discontinuation: excess SNS activity that manifests in 24-48 hours Enhanced activity reflects an increase in number of beta receptors (up-regulation) during chronic therapy

Treatment of essential HTN Management of angina pectoris Treatment of post myocardial infarction pt Pre-op preparation of hyperthyroid pt Suppression of cardiac dysrhythmias Prevention of excess SNS activity Essential Hypertension Beta blockade causes gradual decrease in systemic BP Effect largely dependent on decreased CO related to decreased HR Large doses may decrease myocardial contractility as well In many pts, SVR remains unchanged Release of renin from the juxtaglomerular apparatus that occurs in response to beta -2 receptor stimulation is prevented by non-selective beta-blockers such as propranolol. This may account for a part of the anti-HTN effect, esp in pts with high circulating concentrations of renin. Because drug-induced decreases in secretion of renin will lead to decreased release of aldosterone, beta-adrenergic antagonists will also prevent the compensatory sodium and water retention that accompanies treatment with a vasodilator. management of angina pectoris Beta blockers decrease likelihood of myocardial ischemia manifesting as angina pectoris This response reflects drug-induced decreases in myocardial oxygen requirements Treatment of post- MI patients Oral treatment with beta blockers decreases CV mortality and reinfarctions, and increases chances of survival by 20-40% Instituted 5 days to 4 weeks post-MI and continued for at least 1-3 years Infusion of B-blocker within 12 hours of onset of MI may decrease infarct size and frequency of dysrhythmias Post MI patients Cardioprotective effect occurs with both selective and non-selective B-blockers Mechanism of action uncertain, but antidysrhythmic actions may be important Non-cardiac Surgery Prophylaxis Perioperative myocardial ischemia is the single most important potentially reversible risk factor for mortality and CV complications after noncardiac surgery Admin of Atenolol for 7 days before and after non-cardiac surgery in pt at risk for CAD may decrease mortality and incidence of CV complications for as long as 2 years after surgery hyperthyroid patient Thyrotoxic pts can be prepared for surgery in an emergency by IV admin of propranolol or esmolol or electively by oral admin of propranolol Advantages include rapid suppression of excessive SNS activity and elimination of need to administer iodine or antithyroid drugs suppression of Cardiac Dysrhythmias B-blockers decrease SNS activity to the heart with resulting decrease in rate of spontaneous phase 4 depolarization of ectopic cardiac pacemakers Decreased SNS activity decreases activity of SA node and slows conduction of impulses through the AV node The cardiac effects of beta blockers are responsible for the efficacy of beta blockade in suppressing intraoperative supraventricular tachydysrhythmias as well as ventricular dysrhythmias Prevention of excess SNS ACTIVITY Beta blockade associated with attenuated HR and BP changes in response to direct laryngoscopy and tracheal intubation Hypertrophic cardiomyopathies are often treated with beta blockers Tachycardia and dysrhythmias assoc with pheochromocytoma and hyperthyroidism are effectively suppressed by propranolol

Selective A-1 and non-selective B-1 and B-2 blocker effects Presynaptic A-2 receptors are spared—release of NE and continue to inhibit further release of catecholamines via the negative feedback mech resulting from stimulation of A-2 receptors Beta to alpha blocking potency is 3:1 for oral and 7:1 for IV Labetalol in humans Metabolism by conjugation of glucuronic acid, with 5% recovered unchanged in urine Elimination t ½ 5-8 hours, prolonged in presence of liver disease CV Effects: Lowers systemic BP by decreasing SVR (A-1 blockade), whereas reflex tachy triggered by vasodilation is attenuated by simultaneous B-blockade CO remains unchanged Max systemic BP lowering effect of IV dose present in 5-10 minutes Clinical uses: Treatment of HTN emergencies Tx of rebound HTN after withdrawel of clonidine therapy and HTN responses of pt with pheochromocytoma Tx of angina pectoris 0.1-0.5 mg/kg can attenuate increase in HR and BP that are assumed to result from abrupt increase in level of surgical stimulation Side Effects: Most common—Orthostatic hypotension Bronchospasm in susceptible pt CHF, bradycardia, heart block potential risks Fluid retention in chronic tx is the reason for combining this drug with a diuretic during prolonged therapy