Chp. 21: Adrenergic Agents Flashcards
Sympathomimetic
Adrenergic agents that are agonists at alpha1, beta1, and beta2-adrenergic receptors because they cause stimulation or activation of the SNS.
Catecholamine (chemical structure)
A hydroxyl group is present at the C3 and C4 positions of a benzene ring
Epinephrine receptors
alpha1, alpha2, beta1, and beta2 agonist
alpha1 receptor location and effect
smooth muscle (blood vessels, bronchi, GI, uterus, urinary system)
contraction of smooth muscle, vasoconstriction
alpha2 receptor location and effect
throughout the CNS and platelets
sedation, analgesia, attenuation of sympathetically mediated responses; platelet aggregation
beta1 receptor location and effect
heart
positive inotropic and chronotropic effects
beta2 receptor location and effect
smooth muscle (blood vessels, bronchi, GI, uterus, urinary system), heart
relaxation of smooth muscle, vasodilation; positive inotropic and chronotropic effects (minor)
beta3 receptor location and effect
adipose tissue
lipolysis
What are the effects of low doses of epinephrine administered by bolus (0.01mg/kg IV)?
B1 and B2 adrenergic receptor agonist effects predominate.
B1: increased CO, myocardial oxygen consumption, coronary artery dilation, reduced arrhythmia threshold
B2: decrease in diastolic BP and PVR
What are the effects of high doses of epinephrine administered by bolus (0.1mg/kg IV)?
A1 effects predominate causing an increase in SVR
Why do epinephrine infusions cause an increase in PCV?
A1-induced splenic contraction
What anesthetic agent sensitizes the myocardium to catecholamine-induced arrhythmias?
Halothane
What are the non-primary effects of epinephrine administration?
Small increase in minute volume through bronchodilator effects (B2), increased basal metabolic rate and increased body temp, increased plasma glucose concentration, initial hyperkalemia then hypokalemia (B2), renin release, decreased renal blood flow due to regional vasoconstriction
What are the mechanisms of increased plasma glucose concentration with epinephrine administration?
1) Inhibition of insulin secretion (A2 and B2)
2) Glycogenolysis in liver and muscle (A1 and B2)
3) Lipolysis (B2 and B3)
4) Gluconeogenesis (A2 and B2)
How is epinephrine metabolized?
Rapidly by mitochondrial monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) within the liver, kidney, and circulation to inactive metabolites that are conjugated with glucuronic acid or sulfates and excreted in urine
Norepinephrine receptors
alpha1, alpha2, beta1
What effects of NE predominate at clinically used dose rates?
alpha1
What are the effects of NE at very low dose rates (0.025mcg/kg/min)?
B1 effects (increased HR and CO and decreased SVR)
What are the effects of NE at higher dose rates (0.5-1.5mcg/kg/min)?
Dose-dependent increases in SAP, DAP, and MAP, CO, and SVR and PVR
What is the effect of NE on the coronary arteries?
Vasodilation
Does NE cause excessive vasoconstriction impairing systemic circulation in isoflurane-anesthetized dogs?
No, there is no significant difference in SVR
How is NE metabolized?
Similar to epinephrine BUT 25% is extracted from the circulation as it passes through the lung, where it is deactivated by MAO and COMT in the endothelial cells of the pulmonary microvasculature.
D1 receptor location and effect
Throughout the CNS; vascular smooth muscle, kidney, sympathetic ganglia
Modulates extrapyramidal activity; vasodilation of renal and mesenteric vasculature
D2 receptor location and effect
Throughout the CNS; vascular smooth muscle, kidney, sympathetic ganglia
Inhibit further NE release
A1 receptor MOA
Excitatory GPCR linked to PLC > receptor binding activates PLC > increases intracellular IP3 > increase in intracellular [Ca2+]
A2 receptor MOA
Inhibitory GPCR linked to AC > receptor binding reduces AC activity > decrease in intracellular [cAMP]
B1 receptor MOA
Excitatory GPCR linked to AC > receptor binding activates AC > increase in intracellular [cAMP]
B2 receptor MOA
Excitatory GPCR linked to AC > receptor binding activates AC > increase in intracellular [cAMP] > cAMP activates PKA and increases Na+/K+ activity > hyperpolarization
B3 receptor MOA
Excitatory GPCR linked to AC > receptor binding activates AC > increase in intracellular [cAMP]
D1 receptor MOA
Excitatory GPCR linked to AC > receptor binding activates AC > increase in intracellular [cAMP]
D2 receptor MOA
Inhibitory GPCR linked to AC > receptor binding reduces AC activity > decrease in intracellular [cAMP]
What are the dose-dependent receptor effects of dopamine?
1-2mcg/kg/min: D1 and D2 effects
< 10mcg/kg/min: B1 effects
> 10mcg/kg/min: A1 effects
Why should dopamine infusions be stopped in a stepwise manner?
A reduction in MAP and CO generally occurs after cessation, with return to preinfusion levels after 30 minutes
What are the non-primary effects of dopamine administration?
Attenuate the response of the carotid body to hypoxemia; increase urine output due to improved hemodynamic function
What is the onset of action after the start of an infusion?
Up to 5 minutes
How is dopamine metabolized?
MAO and COMT in liver, kidney, and plasma leading to inactive compounds excreted in the urine as sulfate and glucuronide conjugates.
25% is converted to NE in sympathetic nerve terminals
Dobutamine receptors
Primarily B1 but at higher dose rates (5-10mcg/kg/min) will stimulate B2 and A1
What is the principal use of dobutamine?
To augment low CO states associated with reduced myocardial function
How is dobutamine metabolized?
Primarily COMT in the liver
Dopexamine receptors
Potent B2 stimulation with weak B1, D1, and D2 receptor effects
What is the effect of dopexamine on endogenous catecholamines?
Inhibits their neuronal uptake
What are the effects of dopexamine on the CV system?
Positive inotropic effect via cardiac B2 receptors, though systemic BP may fall due to B2-mediated vasodilation of peripheral blood vessels
What effects are high dose rates (5mcg/kg/min) of dopexamine associated with?
Tachycardia, cardiac arrhythmias, muscle twitching, and poor recoveries
Is dopexamine recommended for support of hemodynamic function in anesthetized horses?
No
What are the non-primary effects of dopexamine?
Bronchodilation via B2 receptors
How is dopexamine metabolized?
O-methylation and sulfation in the liver
Isoproterenol (isoprenaline) receptors
Potent agonist at B1 and B2 receptors
What is the use of isoproterenol under GA?
Increase HR and contractility; may also be used to promote abnormal electrical activity of the heart during electrophysiological studies
What are the effects of isoproterenol on the CV system?
B1 causes increase in HR, contractility, and CO but B2 effects reduce SVR and cause drop in MAP. Myocardial oxygen delivery is compromised due to combined effects of increased HR reducing coronary filling time, while decreased systemic BP reduces coronary perfusion.
Why was a very low-dose infusion (0.1mcg/kg/min) of isoproterenol associated with increased CO, HR, and improved myocardial blood flow?
Metabolically driven vasodilation of coronary blood vessels rather than direct stimulation of coronary vasculature B2 adrenergic receptors
What are the non-primary effects of isoproterenol?
Potent bronchodilation, increasing anatomic deadspace and V/Q mismatching; increased arousal during GA due to CNS stimulation; increased splanchnic and renal blood flow; increased BG and FFA concentration; decreased serum potassium due to intracellular shifting
How is isoproterenol metabolized?
COMT in the liver and excreted unchanged in urine. It and its metabolites may be excreted as conjugated sulfates.
Phenylephrine receptors
A1 only, referred to as a “vasopressor”
In addition to hemodynamic support, what are additional uses of PE?
Topical application to mucosal surfaces to reduce edema or hemorrhage and medical management of nephrosplenic entrapment due to reduced splenic size
What are the CV effects of PE?
Dose-dependent increase in SVR and MAP and reflex bradycardia. CO is usually minimally altered or may fall as a result of increased afterload combined with bradycardia. SVR and PVR are increased.
What deleterious effect has been reported with PE use in aged horses?
Hemorrhage, attributed to secondary hypertension caused by increased SVR
Why is PE not recommended for hypotension management in anesthetized horses?
Negative effects on CO and skeletal muscle blood flow and decreased microvascular blood flow in the GI tract
Is PE recommended during pregnancy?
No, it will reduce uterine blood flow.
How is PE metabolized?
MAO in the liver
Methoxamine receptors and effects
Direct-acting sympathomimetic amine with specific A1 agonist effects. Longer duration of action than PE. Predominantly causes vasoconstriction of arterioles with little effect at capacitance vessels. Effects on the myocardium are species-specific.
What is the role of B2 receptor agonists (clenbuterol, albuterol, terbutaline)?
Management of bronchospasm.
What are the CV effects of B2 agonists?
At high doses, can exert agonist effects at B1 receptors causing tachycardia, but at low doses, decreases in BP are noted due to B2-mediated vasodilation
Describe the arrhythmogenic effects of the B2 agonists.
Shorten the refractory period of the AV node, slow ventricular conduction, and shorten the refractory period of the ventricular myocardium. These effects are likely more pronounced with concurrent hypoxemia or hypokalemia.
What are the non-CV effects of the B2 agonists?
- Stimulate Na/K ATPase, leading to hypokalemia
- Increased BG concentration
- Relaxation of bronchial smooth muscle and reversal of hypoxic pulmonary vasoconstriction
Is clenbuterol recommended for hypoxemia in anesthetized horses?
No, associated with profuse sweating and increased oxygen consumption associated with sympathomimetic effects.
How does albuterol improve arterial oxygenation in anesthetized horses?
Predominantly through a sympathomimetic effect on hemodynamic function.
What dose of albuterol is associated with reduced bronchoconstriction in response to BAL in cats?
100mcg/kg
Ephedrine receptors
Direct and indirect sympathomimetic actions, acting as an A1, A2, B2, and B2 agonist. Inhibits action of MAO on NE.
CV effects of ephedrine
Increases CO (increased SV rather than chronotropic effect), HR, BP, coronary blood flow, and myocardial oxygen consumption
Non-CV effects of ephedrine
Bronchodilation due to B2 effects; reduces renal blood flow with decreased GFR due to A1 effects
How is ephedrine metabolized?
N-demethylation to norephedrine (also has vasopressor effects)
Why does tachyphylaxis occur with repeated ephedrine dosing?
Depletion of NE stores and reduction in magnitude of indirect sympathomimetic effects
Metaraminol
Synthetic amine with direct and indirect sympathomimetic effects. Acts predominantly on alpha receptors with some beta activity. Major CV action is to increased BP through increase in SVR.
Sympatholytics
Adrenergic receptor antagonists that prevent the actions of sympathomimetic amines on adrenergic receptors (alpha or beta)
Prazosin receptors and CV effects
- highly selective A1 antagonist
- used for management of functional urethral obstruction in dogs
- produces vasodilation of arteries and veins and reduces SVR, reducing BP (DAP most)
- recommend cessation 12-24 hours prior to anesthesia
Prazosin pharmacokinetics
Relatively low bioavailability (38%), with hepatic extraction contributing to major proportion of presystemic metabolism. Extensive tissue distribution causes rapid decrease in initial plasma concentration. Metabolism slowed with liver dysfunction.
Phentolamine
- Competitive, non-selective alpha receptor blocker with 3x greater affinity for A1 than A2
- Used in management of hypertensive crises (excessive sympathomimetics, pheochromocytomas)
- Vasodilation and hypotension
- Presynaptic A2 blockade causes NE release and tachycardia with increased CO
- Insulin secretion, precipitating hypoglycemia MONITOR BG
Phenoxybenzamine
- Long-acting, non-selective alpha receptor blocker with greater affinity for A1 than A2
- Pre-op management of pheos
- Reverse chronic vasoconstriction caused by EPI and NE secreted by tumor and expand intravascular volume
- Can result in persistent hypotension following tumor removal, so some elect to stop administration 48hr prior to GA
- Does not prevent arrhythmias
- Extensive liver metabolism, excreted in urine and bile
- Requires new alpha receptor synthesis for effects to wane
What is “intrinsic sympathomimetic activity” of beta blockers?
Results in partial agonist effect at B1, B2, or both types of adrenergic receptors.
Results in less resting bradycardia and smaller reduction in CO than observed in beta blockers without ISA.
Therapeutic usefulness of beta blockers is mediated through which receptor type?
B1 adrenergic receptors (B2 effects are undesirable)
How do beta blockers reduce HR?
Reduce automaticity in the SA node and prolong conduction time in the AV node. Reduced HR prolongs diastole and can improve coronary perfusion and increase regional myocardial O2 delivery.
How do beta blockers reduce BP?
Reduction in HR and CO and inhibition of renin-angiotensin system due to blockade of B1 receptors at the juxtaglomerular apparatus
What are the potential negative effects of beta blockers on CV function?
Prolonged systolic ejection time, dilation of ventricles, increase in coronary vascular resistance due to antagonism of coronary vasodilatory B2 receptors.
Risk factor for cardiac failure in human patients with poor LV function.
True or False: High doses of all beta blockers, irrespective of selectivity for B1, will precipitate bronchospasm via blockade of B2 receptors in bronchioles.
True
What are the effects of beta blockers on insulin?
- Increase in BG concentration through peripheral insulin resistance and decreased insulin secretion from pancreatic cells
- Decrease in BG concentration by mitigating normal increase that occurs with exercise
Atenolol
- Relatively cardioselective
- Prescribed to delay onset of adverse sequelae in HCM cats and for management of ventricular arrhythmias in dogs and cats
- Continuation generally recommended in preoperative period for patients with cardiac disease
- Has ISA
Esmolol
- Highly selective for B1
- Very lipophilic (rapid onset and offset)
- Beta blocker of choice under GA (2mcg/kg followed by 50mcg/kg/min CRI)
- Rapidly metabolized by RBC esterases
Metoprolol
- Relatively selective for B1
- Rapidly absorbed but undergoes high first-pass metabolism to oral bioavailability of 50%
Pindolol
- Non-selective beta blocker
- Has ISA
- Serotonin receptor (5-HT) antagonist
- May potentiate analgesia provided by tramadol in dogs
Propranolol
- Non-selective beta blocker
- No ISA
- S-isomer confers most cardiac effect
- Administered orally for control of HR/hypertension prior to thyroidectomy in cats or for management of pheos
- Very high first-pass metabolism
- Metabolism prolonged in hyperthyroid cats
Sotalol
- Non-selective beta blocker
- No ISA
- Potassium channel blocking effects
- Used to treat ventricular tachyarrhythmias
- Excreted unchanged in urine
- Renal impairment will reduce clearance
