Pharmacology

Epinephrine Hydrochloride (Adrenalin)

1. Action: a. Alpha/ beta agonist i. Vasoconstriction >vasodilation ii. Increase HR, conduction iii. Increase contractility iv. Bronchodilation v. High doses: 1. Vasoconstriction via alpha stim vi. Low doses 1. Vasodilation via B2 stim 2. Indications: a. Inotropic support b. Bronchial asthma c. Anaphylactic shock d. Adjunct to local anesthesia e. Cardiopulmonary arrest (CPA) f. Asystole g. V-fib h. Pulseless VT i. PEA a. Infusion: 1-4 mg/250ml b. Initial rate: 1-5 mcg/min c. Maintenance: d. IVP: 1mg every 3-5min o An endogenous catecholamine synthesized in the adrenal medulla. § Direct stimulation of B1-receptors of the myocardium raises BP, CO, and myocardial O2 demand by increasing contractility and HR (increased rate of spontaneous phase IV depolarization) § Alpha1-stimulation decreases splanchnic and renal blood flow but increases coronary perfusion pressure by increasing aortic diastolic pressure. § Systolic BP rises, although B2-mediated vasodilation in skeletal muscle may lower diastolic pressure. B2-stimulation also relaxes bronchial smooth muscle. o Dosing: § Low doses: (<0.02mcg/kg/min), stimulation of B2 § Moderate doses: (0.008-0.06mcg/kg/min), B1 stimulation. § High doses: (>2mcg/min), alpha1 stimulation vasoconstriction o Uses: Epinephrine is the principal pharmacologic treatment for anaphylaxis and can be used to treat VF or cardiac arrest (ability to enhance automaticity). Often used as an inotrope to improve cardiac function and enhance stroke volume; as an adrenergic agonist and vasopressors for refractory hypotension; or as a positive chronotropic agent to increase HR in bradycardia. o Complications: cerebral hemorrhage, coronary ischemia, and ventricular dysrhythmias (B1-stimulation). § Volatile anesthetics, particularly halothane, potentiate the dysrhythmics effects. o SE: § Hyperglycemia: attributable to increased gluconeogenesis and the stress response to epinephrine administration. Typically occurs in pt's that received epinephrine within first 6-8 hours post-op and disappears within a few hours after discontinuation. (Insulin gtt) § Metabolic acidosis: may occur secondary to the inadequate metabolism and lactate buildup that occurs in response to B1 stimulation- it is not related to hypoperfusion. o Nurse: Monitor for dysrhythmias and myocardial ischemia; monitor BS closely if pt on insulin gtt and if epinephrine is titrated down; vasodilators may be necessary if pt becomes hypertensive and medication being used more for inotropic properties. Adrenergic agonists cause vasoconstriction- significant tissue damage can occur if extravasation of these agents into subcutaneous tissue occurs immediate treatment with phentolamine (Regitine 10-15ml)- non-selective alpha-antagonist.

Beta3- Receptors:

o Are found in the gallbladder and brain adipose tissue. Their role in gallbladder physiology is unknown, but they are thought to play a role in lipolysis and thermogenesis in brown fat.

Diltiazem (Cardizem)

1. Action: a. Ca+ channel blocker (prevents Ca++ influx) b. Decerases coronary vascular tone c. Decreases force of myocardial contraction d. Dilates coronary arteries 2. Indications: a. To control ventricular rate in A-fib and AF b. Treat coronary artery spasm c. Treat chronic stable angina d. Treat HTN e. Treat A-tachycardia

Atropine Sulfate

1. Action: a. Parasympatholytic/ anticholinergic i. Increase HR by blocking acetylcholine/vagal stim to heart ii. Increase CO iii. Decrease bronchial and gastric secretions b. Indications: i. DoC for symptomatic sinus bradycardia ii. Organophosphate poisoning (extremely large doses may be needed) c. Dose: i. IVP 0.5mg

Nipride (Nitroprusside Sodium)

1. Action: a. Vasodilation (anterior>venous) 2. Indications: a. Hypertensive emergencies b. Afterload reduction 3. Dose: a. Maintenance: 0.3-10mcg/kg/min b. Onset 1-2 min

Levophed (Norepinephrine)

1. Action: a. Alpha>beta agonist i. vasoconstriction ii. Increase HR, conduction iii. Increase contractility 2. Indications: a. Inotropic support b. Circulatory support (decreased peripheral resistance) 3. Dose: a. Initial rate: 8-12mcg/min b. Maintenance rate: 2-4 mcg/min c. Onset: 1-2 min o Direct alpha1-stimulation with little B2-activity induces intense vasoconstriction of arterial and venous vessels. Increased myocardial contractility from B1-effects, along with peripheral vasoconstriction, contributes to a rise in BP. § Both systolic and diastolic BP usually rise, but increased afterload and reflex bradycardia prevent any elevation in CO. § Decreased renal and splanchnic blood flow and increased myocardial O2 requirements limit the outcome benefits of norepinephrine in management of refractory shock. § Norepinephrine has been used with an alpha-blocker (e.g. phentolamine) in an attempt to take advantage of its B-activity without the profound vasoconstriction cause by alpha-stimulation. § Most common treatment for vasodilatory hypotension/shock associated with CPB o IV bolus dose: (0.1mcg/kg) or continuous infusion dose: (2-20mcg/min). o SE: Increase in myocardial workload and oxygen consumption; end-organ damage (kidneys and mesentery); may exacerbate hyperglycemia and metabolic acidosis (d/t increased lactate production). o Nurses: Can lead to decreased perfusion and tissue necrosis and limb loss (close monitoring of peripheral perfusion); pt's should receive adequate volume resuscitation prior to administration.

Dobutamine Hydrochloride (Dobutrex)

1. Action: a. Beta agonist (B1) b. Increase contractility (increase CO) without increasing heart rate c. Vasodilation 2. Indications: a. Inotropic support b. HF/pulmonary edema c. Cardiomyopathy 3. Dose: a. Infusion: 500mg in 500ml D5W/NS b. Intial rate: 1-5mcg/kg/min c. 2.5-10mcg/kg/min o A synthetic catecholamine and positive inotrope that acts on both B1 and B2-receptors. § B1-receptor: has higher affinity towards; rise in CO d/t increased myocardial contractility and HR. § B2-receptor: activation leads to a decline in peripheral vascular resistance, which usually prevents rise in BP Decreases SVR o Left ventricular pressure decreases and coronary blood flow increases. § Favorable effects on myocardial oxygen balance= good choice for CHF and CAD pt's (may be detrimental in pt's with ischemia). · Useful in pt's with low CO and high SVR or PVR and cannot tolerate vasodilators to decrease afterload. § Useful in pt's with high pulmonary pressures (mitral valve replacement), with or without a history of pulmonary HTN, and low HR because dobutamine is associated with a decrease in pulmonary artery pressure, left ventricular stroke work index, CI, PAOP, and SVR. o IV dose: (2-20mcg/kg/min) o SE: Observe for HOTN, dysrhythmias, and myocardial ischemia. Also, angina, dyspnea, HTN, and headache. (Dobutamine less likely to cause dysrhythmias than other inotropes). o Nurses: Ensure pt is volume resuscitated prior to initiation; monitor vitals and electrolytes.

Dopamine Hydrochloride (Intropin)

1. Action: Indications: a. Dopaminergic: (1-5 mcg/kg/min) ->renal perfusion b. Beta: (5-10 mcg/kg/min) ->inotropic support i. Increase HR, conduction ii. Increase contractility c. Alpha: (>10 mcg/kg/min) ->circulatory support i. Vasoconstriction 2. Dose: a. Concentration: 800mg/500ml b. Maintenance rate: 2.5-50mcg/kg/min i. 1-5 mcg/kg/min (renal-mesenteric vasodilation) ii. 5-10 mcg/kg/min (increase contractility, vasoconstriction) iii. 10 mcg/kg/min & > (vasoconstriction, increase preload, SVR) iv. 20 mcg/kg/min & > (severe vasoconstriction) o An endogenous nonselective direct and indirect adrenergic and dopaminergic agonist. § Low dose (0.5-3mcg/kg/min): primarily activates dopaminergic receptors (D1) vasodilates the renal vasculature and promotes diuresis and natriuresis (does not impart any beneficial effect on renal function). § Moderate dose (3-10mcg/kg/min): B1-stimulation increases myocardial contractility, HR, SBP, and CO. (Myocardial O2 demand typically increases more than supply). § High dose: (10-20mcg/kg/min): alpha1-effects cause an increase in peripheral vascular resistance and a fall in renal blood flow § The indirect effects of DA are d/t release of norepinephrine from presynaptic sympathetic nerve ganglion. o Uses: Commonly used in treatment of shock to improve cardiac output, support BP, and maintain renal function. Often used in combination with a vasodilator, which reduces afterload and further improves CO. The positive chronotropic and proarrhythmic effects of DA limit its usefulness is some pt's. o SE: CP, HTN, palpitations, tachyarrhythmias, headache, anxiety, dyspnea, oliguria, nausea, and vomiting. o Nurses: Systolic pressures are often elevated with DA, making it a poor choice for pt's with pulmonary HTN; contraindicated in pt's with tachyarrhythmias; caution should be used in pt's with angina, hypovolemia, or ventricular dysrhythmias. Tissue extravasation can lead to tissue necrosis- Regitine.

Amiodarone Hydrochloride (Cordarone)

1. Actions: a. Antiarrhythmic b. Potent Vasodilator c. Does not significantly alter myocardial membrane potential d. Suppresses automaticity of both SA and AV nodes directly as well as His-Purkinje system and accessory pathways e. Alpha and beta-blocking as well as vagolytic and sodium, potassium and calcium channel blocking f. Highly lipid soluble 2. Indications: a. A-fib b. A-flutter c. PSVT d. V-Fib e. V-tachycardia f. Wolff-Parkinson-White syndrome 3. Dose: a. Infusion 450mg-250ml b. Loading: 150mg over 10 min i. Then 1mg/min x 6hrs ii. Then 0.5mg/min x c. IVP: 300mg i. 2nd dose 150mg

Neo-Synephrine (Phenylephrine Hydrochloride)

1. Actions: Powerful alpha agonist a. Vasoconstriction 2. Indications: circulatory support (decreased peripheral resistance) 3. Dose: a. Infusion: 10-40 mg in 250 ml D5W or NS (up to 100mg/250ml) b. Initial: 10-40 mcg/min c. Maintenance: 10-20 mcg/min d. IVP: 500 mcg bolus- increased 100-200mcg up to 1mg o A non-catecholamine with predominantly selective alpha1-agonist activity. o Effect: § Peripheral vasoconstriction with a concomitant rise in systemic vascular resistance and BP. (Useful in pt's with high CI who are profoundly vasodilated) § Reflex bradycardia mediated by the vagus nerve can reduce cardiac output. § Also used topically as a decongestant and mydriatic agent. o Small IV boluses 50-100 ug (0.5-1mcg/kg). Duration of action: ~15min o Tachyphylaxis occurs with Phenylephrine infusions requiring upward titration. o Phenylephrine must be diluted from 1% solution (10mg/1ml ampule), usually to 100mcg/ml solution. § Mix 0.1mg in 100ml bag (100mcg/ml); or 0.1mg in 50ml bag (200mcg/ml) o SE: Phenylephrine can cause hypoperfusion to tissues and end-organs d/t vasoconstriction, which can lead to visceral and renal ischemia; also causes increase in myocardial O2 consumption and may exacerbate metabolic acidosis. HTN, MI, tachyarrhythmias, pulmonary edema. o Nurses: Pt should receive adequate volume resuscitation prior to initiation; is contraindicated in pt's with severe HTN and tachycardia; caution should be used for pt's with bronchial asthma, diabetes, or HTN.

Vasopressin (Pitressin)

1. Classification: a. Exogenous parenteral form of ADH b. Stimulates contraction of vascular smooth muscle c. Prominent effect in capillaries, small arterioles d. Neither adrenergic agent nor vascular denervation prevents direct effect on smooth muscle contractile elements 2. Action: a. Promotes re-absorption of water b. Can stimulate contraction of vascular smooth muscle and smooth muscle of the GI tract 3. Indications: a. Alternative presser to epinephrine to treat refractory v-fib b. Hemodynamically support of septic shock 4. Dose: a. IVP: 40 units x1 Tx of V-fib 5. Precautions: a. Increases SVR b. Not recommended for responsive patient with CAD o The nonpeptide is stored primarily in granules in the posterior pituitary gland and is released after increased plasma osmolality or hypotension, as well as pain, nausea, and hypoxia. § Vasopressin is synthesized to a lesser degree by the heart in response to elevated cardiac wall stress and by the adrenal gland in response to increased catecholamine secretion. § It exerts its circulatory effects through: · V1a (vascular smooth muscle): stimulation mediates constriction of vascular smooth muscle. · V2 (renal collecting duct system): stimulation mediates water reabsorption by enhancing renal collecting duct permeability. · Vasopressin increases secretion of corticotropin (hormone produced by anterior pituitary) that stimulates the adrenal cortex to produce cortisol- a major hormone responsible for blood pressure regulation. § Vasopressin causes less direct coronary and cerebral vasoconstriction than catecholamines and has a neutral or inhibitory impact on CO. The vasopressor effects are relatively preserved during hypoxic and acidotic conditions, which often develop in shock. o CPB frequently causes the release of vasopressin (ADH) that may contribute to post-bypass vasoconstriction. Data indicate vasopressin levels diminish as hypotension continues, therefore, the body may have a limited supply of vasopressin that is exhausted with the initial bout of hypotension. § Vasodilatory shock: decreased MAP, organ hypoperfusion, lactic acidosis, decreased SVR, and maldistribution of blood volume end-organ failure. o Indications: vasodilatory shock following CPB (MAP<70) despite fluid resuscitation, inotropic therapy, and norepinephrine administration § Post-op CPB pt's who have protracted HOTN demonstrate poor vascular smooth muscle response to catecholamines. § It is believed some pt's may have low vasopressin concentrations- may need exogenous supply. Also, it is very helpful for pt's with low EF who take ACE inhibitors. § Indicated for cardiac arrest as an early substitute for epinephrine. § Vasopressin may be effective in Milrinone-related HOTN. o Infusion dosage: (0.01-0.1 units/min) o SE: end-organ damage from vasoconstriction, leading to hypoperfusion, hyponatremia, and increased SVR- all occur secondary to vasoconstriction. o Nurses: Caution of vascular disease; monitor for decrease CO, CP, myocardial ischemia (coronary vasoconstriction), dysrhythmias, bronchoconstriction, metabolic acidosis, tremors, GI infarction, abdominal cramping, and water intoxication.

Etomidate:

Non-Barbiturates: § hypnotic agent with no analgesic effects. · Considered agent of choice in pt's with cardiovascular instability Less likely to see HOTN; HR, contractility, and CO remain stable · SE: Post-op nausea and vomiting (PONV), hiccoughs, involuntary tremors, or suppressed adrenal function.

Milrinone:

Phosphodiesterase Inhibitors:] o Phosphodiesterase 3 is an intracellular enzyme associated with the sarcoplasmic reticulum in cardiac myocytes and vascular smooth muscle that breaks down cAMP into AMP. PDI's increase the level of cAMP by inhibiting its breakdown by phosphodiesterase within the cell, which leads to an increase in the amount of calcium that moves into the cells through ion channels increased myocardial contractility. (Potent inotrope) o Potent vasodilator of vascular smooth muscle by decreasing intracellular calcium concentration this effect causes relaxation of the vasculature and ventricles, thereby increasing SV and CO/CI and lowering afterload. § Milrinone promotes myocardial (diastolic) relaxation and improves coronary, skeletal muscle, and mesenteric blood flow § Decreases coronary vascular resistance- has highly favorable effect on myocardial oxygen consumption. · Minimally affects myocardial O2 demand o Reduces preload and afterload, and increases contractility. o Indications: Right HF and pulmonary vasoconstriction; ventricular failure. o Loading dose: (50-75mcg/kg); continuous infusion dose: (0.25-0.75mcg/kg/min). Has rapid onset of action, and effects last 2-4hrs following titration or discontinuation; half-life: 36min, which is shorter than inamrinone (Amrinone). o SE: VT or SVT- proarrhythmic properties; HOTN should be anticipated. o Nurses: Pt may also require vasopressor; aggressive replacement of electrolytes- arrhythmias more likely to occur if electrolyte imbalance. § This drug is particularly useful if adrenergic receptors are down-regulated or desensitized in the setting of chronic HF, or after chronic B-agonist administration. § Inamrinone is used less often because of its side effect of dose-related thrombocytopenia.

· Gabapentin (Neurontin):

o An anticonvulsant and GABA neurotransmitter analog; however, does not interact with GABA receptors, and it does not inhibit GABA uptake or degradation. MOA is unknown. o Used to treat peripheral neuropathies and seizures.

Nicardipine:

[Calcium-channel Antagonists:] § Acts directly on arterioles to cause peripheral vascular and coronary vasodilation and lower BP. § Has little effect on contractility or AV node conduction § Indicated: post-op HTN § Dose: (3-15mg/hr) § SE: headache, hypotension, N/V, edema, dizziness, tachycardia, angina, MI. § Nurses: contraindicated in pt's with advanced AS. Use caution if also giving B-blocker.

Metoprolol:

o A cardioselective B1-antagonsit with no intrinsic sympathomimetic activity (ISA). Class II antiarrhythmic § Decreases tissue response to catecholamines (especially epinephrine and norepinephrine)- it has negative inotropic effect and decreases HR, contractility, CO, and BP. o Indications: used to decrease workload of the heart by decreasing HR and prophylactially to prevent AF and a-flutter after cardiac surgery. In addition to rate control for AF, it may be used for rhythm conversion. o Currently recommended as first-line therapy for AF. Treatment with a beta-blocker has the efficacy rate of 52-65% in reducing the frequency of AF. o IV dose: (5-15mg q5-7.5min). Also available in oral dose. o SE: bradycardia, AV block, HF symptoms, widening QRS complexes, HOTN, bronchospasm. o Nurses: § Valve replacement surgeries make pt's prone to heart block- metoprolol is contraindicated in these cases; should be used with caution in pt's with COPD, asthma, and pump dysfunction. § Metoprolol may mask signs of hypoglycemia. § If pt's do not convert to NSR or become unstable, SCV may be performed once rate control is achieved (SCV will typically not be effective until rate control is achieved, as intense adrenergic activity is occurring). Pt's should be considered for anticoagulation if AF persists >48hrs. § Black box warning: abrupt withdrawal may result in angina pectoris, the occurrence of MI, and ventricular arrhythmias.

Carvedilol (Coreg):

o A non-cardioselective mixed beta and alpha-blocker used in management of CHF secondary to cardiomyopathy, left ventricular dysfunction following acute MI, and HTN. May be more effective than metoprolol in preventing post-op AF in cardiac surgery pt's (non-FDA labeled indication). § B-blockade: decreases HR, BP, contractility, and CO § Alpha-blockade: causes vasodilation. o Dosage: HTN: (6.25mg BID); HF: (3.125mg daily)

Ephedrine:

o A non-catecholamine sympathomimetic, whose cardiovascular effects are similar to epinephrine: increased BP, HR, contractility, CO, and bronchodilator. § Ephedrine has a longer duration of action, is much less potent, has indirect and direct actions, and stimulates the CNS (its raises MAC). · Indirect agonist properties may be due to peripheral post-synaptic norepinephrine release, or by inhibition of norepinephrine reuptake. o Common vasopressor used in anesthesia § Believed not to decrease uterine blood flow, and thus was commonly used in OB cases (however, Phenylephrine has been argued to be more effective- d/t faster onset, shorter duration of action, and better titratability and maintenance of fetal pH). § Also believed to have antiemetic properties, particularly in association with hypotension following spinal anesthesia. Clonidine premedication augments the effects of ephedrine. o Adults: IV bolus dose: (2.5-10mg); Children: IV bolus dose: (0.1mg/kg). Subsequent doses are increased to offset the development of tachyphylaxis, which is probably d/t depletion of norepinephrine

Isoproterenol (Isuprel):

o A pure B-agonist § B1-effects: increased HR, contractility, and CO. SBP may be increased or remain unchanged. § B2-effects: decreases peripheral vascular resistance and DBP § Myocardial O2 demand increases, while oxygen supply falls, which makes it a poor inotropic choice.

· Aminocaproic acid (Amicar):

o An anti-fibrinolytic agent- it works by preventing plasminogen from binding to fibrin, thereby stopping the activation of plasmin and preventing clot breakdown. o Indications: post-op bleeding pt that occurs secondary to fibrinolysis. o Dosage: (5mg bolus over 1hr, followed by infusion at 1mg/hr for 8hrs or until bleeding stopped). o SE: Thrombocytopenia, dysrhythmias, and thrombosis formation. Serious: bradyarrhythmias, HOTN, renal failure, and rhabdomyolysis. o Nurses: Contraindicated in pt's with coagulopathies. Use with caution in pt's with cardiac, hepatic, or renal insufficiency.

Naloxone (Narcan):

o An opioid antagonist, which has the greatest affinity for the mu receptor, but competes for the mu, kappa, and sigma opiate receptor sites in the CNS. o Indications: hypoventilation following narcotic administration- small doses should be enough to stimulate respiration. o IV Dosage: (0.4-2mg, may be repeated q2-3min as needed). o SE: cardiac dysrhythmias, HTN, HOTN, VF, pulmonary edema, and hepatotoxicity. o Nurses: Continue to watch for hypoventilation d/t short half-life of Narcan as compared to narcotics.

Diltiazem:

o Blocks calcium ion influx during depolarization of cardiac and vascular smooth muscle. § Decreases vascular resistance and causes relaxation of the vascular smooth muscle decreased BP. § A negative inotropic effects occurs as well, as contractile strength is regulated by calcium ions flowing in and out of cell. o Indications: Used to lower ventricular response in AF, a-flutter, and SVT; may also be used for rhythm conversion (class IV antiarrhythmic); may be used to prevent vasospasm of IMA grafts by relaxing vascular smooth muscle and stabilizing vessel. o IV bolus dose: (0.25mg/kg, followed by infusion at 5-15mg/hr) § Primarily used for rate control rather than rhythm conversion. o SE: AV blocks (more often in valve operations- particularly mitral), bradycardias, HF, edema, dizziness, and headache. o Nurses: Can safely be given to pt's with marginal BP if given slowly; it may increase effects of anesthetics- pt may take longer to wake up.

· Dexamethasone (Decadron):

o CPB stimulates a SIRS, with the associated release of pro-inflammatory mediators and subsequent hemodynamic instability. The use of steroids in cardiac surgery remains controversial; however, some research has indicated that pt's receiving pre and post-operative steroid doses experience less systemic inflammation. o Any post-op pt exhibiting protracted vasodilatory shock should be suspected of having adrenal insufficiency. In stressed pt's (cardiac surgery pt's) a low or normal cortisol level can be assumed to be associated with adrenal insufficiency. § Adrenal insufficiency responds to steroids, which raise cortisol levels. Cortisol plays a vital role in regulating blood pressure by increasing the sensitivity of the vasculature to endogenous epinephrine and norepinephrine. In the absence of normal cortisol levels, widespread vasodilation occurs secondary to the effects of pro-inflammatory mediators. A cosyntropin stimulation test can be performed for diagnosis of adrenal insufficiency. o MOA: steroids decrease inflammation by suppressing neutrophil migration, decreasing production of pro-inflammatory mediators, and reversing the increase in capillary permeability. o Indications: post-op hemodynamic instability associated with a CPB-induced inflammatory response. o Dosage: treatment of shock (4-10mg). For shock unresponsive to steroids (1-6mg/kg or up to a maximum of 40mg). o SE: dysrhythmias, cardiac arrest, HF, circulatory collapse, edema, myocardial rupture (if administered after MI), increased ICP seizure, adrenal suppression, DM, hyperglycemia, GI bleed and perforation. o Nurses: Monitor potassium, CBC, glucose, occult stool; Ca-channel blockers decrease steroid metabolism; caution with diabetics (hyperglycemia), GI disease (bowel perforation), renal disease (fluid retention), history of seizures; steroids should be gradually tapered.

[Antiarrhythmics:] · Categories of Antiarrhythmics:

o Class 1: Sodium-channel blockers o Class 2: Beta-blockers o Class 3: Potassium-channel blockers o Class 4: Calcium-channel blockers

· Protamine Sulfate:

o Combines with heparin to form an inactive salt, which has no anticoagulation activity. o Indications: post-op coagulopathy that is d/t inadequate heparin reversal. o Dosage: (1mg of Protamine sulfate for every 100 units of heparin that needs to be reversed, up to a maximum dose of 50mg). Dose is administered over 10min- heparin is neutralized within 5min and the effect last 2hrs. o SE: HOTN, elevated PAP, bradycardia, and non-cardiogenic pulmonary edema. § Type I reaction: If the medication is administered too quickly HOTN develops as a result of histamine release, with resultant decreases in SVR and PVR effects can be reversed with alpha-agonist. § Type II reaction: either an anaphylactic or anaphylactoid reaction with associated HOTN, tachycardia, bronchospasm, flushing, and pulmonary edema · Reaction is often related to immunoglobulin E or G causing release of histamine, leukotrienes, and kinins. The release of these substances results in capillary leak, HOTN, and pulmonary edema. · May occur within the first 10-20min or more. § Type III reaction: causes catastrophic pulmonary vasoconstriction, with associated increase in PAP, HOTN (secondary to peripheral vasodilation), decreased left atrial depression, right ventricular dilation, and myocardial depression. · Believed to result from activation of various mediators of the inflammatory response. Complement activation leads to leukocyte aggregation, which causes pulmonary edema; the arachidonic acid pathway stimulates production of thromboxane, which causes constriction of pulmonary vasculature (the latter effect subsides in ~10min). o Nurses: Pt's with allergies to fish have high risk of anaphylactoid type of Protamine reaction, as Protamine is made of a protein found in fish sperm. Caution when administering Protamine to men who are infertile or who have undergone vasectomy, as anti-protamine antibodies may be present in these individuals. There is also a 30-to-50-fold increased risk of protamine reaction in pt's who take NPH insulin § If reaction occurs, administer alpha-agonist to increase SVR, 500mg of calcium chloride to increase SVR and promote contractility, an inotropic agent to decrease PVR, a vasodilator to decrease preload and PVR, aminophylline to control wheezing, and heparin to reverse a protamine reaction.

Dopaminergic Receptors:

o Group of adrenergic receptors that are activated by dopamine o D1-Receptors: § Activation mediates vasodilation in the kidney, intestine, and heart o D2-Receptors: § Are believed to play role in the antiemetic action of droperidol.

· Nonsteroidal Antiinflammatory Drug (NSAID):

o Inhibit cyclooxygenase (COX) isoenzyme. § COX-1: maintains gastric mucosa and stimulates platelet aggregation § COX-2: is expressed during inflammation; spare both the gastric mucosa and platelet function. However, their use is associated with an increased risk for cardiovascular thromboembolic events. Because nonspecific NSAID's, such as ketorolac also inhibits COX-2, their use following CABG is contraindicated.

Methylene Blue (Urolene Blue):

o Inhibits nitric oxide, which is released in large quantities in pt's following CPB. Nitric oxide produces profound vasodilation and vasoplegia (HOTN with normal or high CO2, low CVP, low PAOP, and low SVR). o Indicated for vasodilatory shock in the immediate post-op CPB period. o IV dose: (1-2mg/kg over 20min). o SE: HTN and a brief period of factitious low oxygen saturation on pulse oximetry (lasts <10min, results from interference with light absorption). Also, HOTN, abdominal pain, dizziness, headache, confusion, N/V, and diarrhea. § Severe: cardiac dysrhythmias, malignant hyperthermia, and methemoglobinemia. o Nurses: Monitor for HTN and titrate gtt's accordingly; monitor for urine discoloration and transient low O2 saturations (obtain ABG if concerned); monitor methemoglobin levels and CB; use caution in pt's with renal impairment or G6PD deficiency.

Lidocaine

o It controls cardiac rate and rhythm by blocking sodium channels, thereby decreasing the duration of the action potential. § It also blocks the initiation and conduction of nerve impulses by decreasing membrane permeability to sodium ions inhibits depolarization and blocking of conduction, which includes slowing conduction in the ischemic myocardium. § Also inhibits automaticity of conduction tissue by intensifying the electrical stimulation threshold of the ventricle and the His-Purkinje system. o Indications: Management of VF or pulseless VT following defibrillation, CPR, and epinephrine. o Dosage: (1-1.5mg/kg bolus; followed by infusion at 1-4mg/min) o SE: dysrhythmias, bradycardia, HB, cardiovascular collapse, HOTN, seizures, somnolence, slurred speech, confusion, metallic taste, bronchospasm, and respiratory depression/arrest. o Nurses: Continuous cardiac monitoring; use with caution with liver dysfunction- can increase risk for lidocaine toxicity or neurologic toxicity; use caution with WPW syndrome, HF, shock, hypovolemia, HB (unless pt has pacemaker).

Alpha2- Receptors:

o Located primarily on the pre-synaptic nerve terminals o Activation of these receptors inhibits adenylate cyclase activity This decreases the entry of calcium ions into the neuronal terminal, which limits subsequent exocytosis of storage vesicles containing norepinephrine. § Create negative-feedback loop that inhibits further norepinephrine release from the neuron. o In addition, vascular smooth muscle contains post-synaptic alpha2-receptors that produce vasoconstriction. o More importantly, stimulation of post-synaptic alpha2-receptors in the CNS causes sedation and reduces sympathetic outflow, which leads to peripheral vasodilation and lower BP.

· Enflurane and Isoflurane:

o May cause laryngospasm, coughing, and breath holding § This predisposes pt to non-cardiogenic pulmonary edema o Can cause post-op shivering increase in myocardial oxygen demand. o Isoflurane: § Not associated with increased cardiac sensitization to catecholamine's; stabilizes the cardiovascular system; and has the least related increase in cerebral blood flow § Benefits: augments effects of nondepolarizing muscle relaxants; coronary artery vasodilator- with increase coronary perfusion; o Enflurane: § SE: Residual CNS depressant effects- manifest during post-op; Decreased BP, stroke volume, and SVR; increased HR; can sensitize the heart to catecholamine's; mild coronary vasodilation and puts pt at increased risk for development of junctional rhythms § Benefits: Low association of PONV § Nurse: anticipation of delayed awakening and extubation

Nitric Oxide:

o Naturally occurring potent vasodilator released by endothelial cells- plays important role in regulating vascular tone throughout the body. It has ultra short half-life (<5s) provides sensitive endogenous control of regional blood flow. o Inhaled Nitric Oxide: selective pulmonary vasodilator- used in treatment of reversible pulmonary HTN.

Propranolol:

o Non-cardioselective blocking of B1 and B2-receptors. § BP is lowered by decreasing HR, myocardial contractility, and diminished rennin release. · CO and myocardial O2 demand decreased o Uses: for myocardial ischemia related to increased BP and HR; impedance of ventricular ejection in pt's with obstructive cardiomyopathy and aortic aneurysm; slows AV conduction and stabilizes myocardial membranes; slowing ventricular response in SVT; occasionally controls recurrent VT or V-fib caused by ischemia; blocks the B-adrenergic affects of thyrotoxicosis and pheochromocytoma. o SE: bronchospasm, CHF, bradycardia, AV block, o IV dose: (0.5mg q3-5min and increasing by 0.5mg increments); cleared by hepatic metabolism; half-life is 100min.

Labetalol:

o Nonselective adrenergic blocking agent that inhibits alpha1, B1, and B2-receptors. The ratio of alpha-blockade to B-blockade has been estimated to be approximately 1:7. o Reduces peripheral vascular resistance and BP. HR and CO are usually slightly depressed or unchanged. § Thus, Labetalol lowers BP without reflex tachycardia, because of its combination of alpha and B-effects (beneficial to pt's with CAD or vascular surgery pt's). o SE: LV failure, paradoxical HTN, and bronchospasm. o Nurses: Contraindicated in pt's with cardiogenic shock, heart blocks, or severe sinus bradycardia; pts with bronchial asthma or COPD. Monitor for signs of HF, blood sugars.

Mannitol:

o Osmotic diuretic § Osmotic: elevates blood plasma osmolality and leads to increased "pull" or flow of water from the tissues into interstitial fluid and plasma (in order to create osmotic equilibrium) as a result, cerebral edema, elevated ICP, and CSF volume and pressure may be reduced. § Diuretic: induces diuresis, because mannitol is not reabsorbed in the renal tubule, thereby increasing the osmolality of the GFR, facilitating the excretion of water, and inhibiting the renal tubular reabsorption of sodium, chloride, and other solutes. It may therefore promote the urinary excretion of toxic materials and protect and nephrotoxicity by preventing the concentration of toxic substances in the tubular fluids. o Indications: Intracranial HTN, oliguric renal failure

Alpha1- Receptors:

o Post-synaptic adrenoceptors located in smooth muscle throughout the body § Eyes, lungs, blood vessels, uterus, gut, and genitourinary system o Activation of these receptors increases intracellular calcium ion concentration, which leads to smooth muscle contraction. Thus, are associated with: § Mydriasis (papillary dilation d/t contraction of radial eye muscles) § Bronchoconstriction § Vasoconstriction § Uterine contraction § Constriction of sphincters in GI and GU tracts. § Inhibits insulin secretion and lipolysis § Cardiovascular: · Myocardium- positive inotropic effect (which might play role in catecholamine-induced arrhythmia) · During myocardial ischemia- enhanced alpha1-receptor coupling with agonists is observed. · Stimulation of vasoconstriction- increased SVR, afterload, BP

Sodium Nitroprusside:

o Potent antihypertensive. IV dose: (0.5-10mcg/kg/min). Rapid onset of action (1-2min) and fleeting duration of action. o Metabolism: § Enters RBC's, where it receives an electron from the iron (Fe2+) of oxyhemoglobin results in an unstable nitroprusside radical and methemoglobin (Hgb Fe3+). The former moiety spontaneously decomposes into five cyanide ions and the active nitroso (N==O) group. § Cyanide ions can be involved in one of three rxn's: · Binding to methemoglobin to form cyanmethemoglobin · Undergoing a reaction in the liver and kidney catalyzed by the enzyme rhodanase (thiosulfate + cyanide= thiocyanate) · Binding to tissue cytochrome oxidase, which interferes with normal oxygen utilization o Responsible for acute cyanide toxicity- characterized by metabolic acidosis (first sign), cardiac arrhythmias, and increased venous oxygen content (as result of inability to utilize oxygen). Along with nausea, disorientation, confusion, psychosis, weakness, muscle spasms, convulsions. o Another early sign is acute resistance to hypotensive effects of increasing doses § Treatment of cyanide toxicity: pt should be mechanically vented 100% FiO2. Depends on increasing the kinetics of the other two reactions by administering: · Sodium thiosulfate (150mg/kg over 15min) · 3% Sodium nitrate (5mg/kg over 5min), which oxidizes hemoglobin to methemoglobin. Hydroxocobalamin combines with the cyanide to form cyanocobalamin (vitamin B12) · The kidneys slowly clear thiocyanate. Accumulation of large amounts of thiocyanate (renal failure) may result in milder toxic reaction thyroid dysfunction, muscle weakness, nausea, hypoxia, an acute toxic psychosis. § Methemoglobinemia: from excessive doses of nitroprusside or sodium nitrate can be treated with methylene blue (1-2mg/kg of a 1% solution over 5min), which reduces methemoglobin to hemoglobin. · Methemoglobinemia: decreases blood's oxygen-carrying capacity. o Effects: Arterial and venous vasodilation (reduction in preload and afterload) § Usually does not improve CO, but might in pt's with CHF, or mitral or aortic regurgitation. § Reflex-mediated responses from drop in blood pressure: · Tachycardia and increased myocardial contractility. Also, dilation of coronary arterioles may result in intracoronary steal of blood flow away from ischemic areas that are already maximally dilated. · Dilates cerebral vessels and abolishes cerebral autoregulation (cerebral blood flow is maintained or increases unless BP is markedly reduced). Increase in cerebral blood volume increases ICP effect can be reduced by slow administration and hypocapnia. · Pulmonary vasculature also dilates may decrease perfusion of normally ventilated alveoli- increasing physiological dead space. Dilation may prevent normal vasoconstrictive response of pulmonary vasculature to hypoxia- these effects tend to mismatch pulmonary ventilation to perfusion and decrease arterial oxygenation. § In response to decreased arterial BP rennin and catecholamines are released. o Nurse: Requires close BP monitoring. Solutions must be protected from light (d/t photodegradation). Monitor daily thiocyanate levels. § Black box warning: Medication must be diluted, frequent blood pressure required, cyanide toxicity can occur (monitor acid-base balance and venous oxygen concentration).

Beta2- Receptors:

o Primarily post-synaptic adrenoceptors located in smooth muscle and gland cells. They share common mechanism of action with beta1-receptors: adenylate cyclase activation. § However, B2 stimulation relaxes smooth muscle, resulting in bronchodilation, vasodilation, and relaxation of the uterus (tocolysis), bladder, and gut. § Glycogenolysis, lipolysis, gluconeogenesis, and insulin release are stimulated by B2-receptors. § B2-agonists also activate the sodium-potassium pump, which drives potassium intracellularly and can induce hypokalemia and dysrhythmias.

Adenosine

o Produces no negative inotropic effects, although transient LV function depression occurs. The latter effect slows SA node impulse formation through the AV node and can interrupt reentry pathways through the AV node. Adenosine produces coronary vasodilation. o Indicated for treatment of paroxysmal SVT; also used to counteract an etiology of narrow or wide-complex SVT's. o Dose: (6mg administered rapidly with flush; additional 12mg doses can be administered twice). Very short half-life: <10sec. o SE: CP, lightheadedness, flushing, nausea, headache, dyspnea. Serious: bradycardias, dysrhythmias, HB, and bronchospasm. o Nurses: Notify pt they will feel "strange sensation"; rapid decrease in HR with brief episode (6sec) of ventricular asystole should be anticipated- have emergency equipment available; baseline and repeat ECG § Contraindicated in pt's with 2nd or 3rd degree HB, bradycardia, SSS, § Should be avoided in heart transplant recipients, revascularized pt's, and individuals with AF and a-flutter.

Furosemide (Lasix):

o Rapid-acting potent sulfonamide loop diuretic and antihypertensive. Inhibits reabsorption of sodium and chloride primarily in the loop of Henle and also in the proximal and distal renal tubules; decreases renal vascular resistance and may increase renal blood flow.

Hydralazine:

o Relaxes arterial smooth muscle, causing dilation of precapillary resistance vessels via increased cGMP. IV dose: (5-20mg). Onset: within 15min. Effect lasts ~2-4 hours. (Can be used to control pregnancy-induced HTN) § Hydralazine undergoes acetylation and hydroxylation in the liver. o Effects: § Lowering of peripheral vascular resistance causes drop in arterial BP body reacts to drop in BP by increasing HR, myocardial contractility, and cardiac output. · These compensatory responses can be detrimental to CAD pt's and are minimized by concurrent administration of beta-blocker. Conversely, decline in afterload often proves beneficial for CHF pt's. § Potent cerebral vasodilator and inhibitor of cerebral blood flow autoregulation. (Unless BP is markedly reduced- cerebral blood flow and ICP will rise). § Renal blood flow is usually maintained.

Nitroglycerin:

o Relaxes vascular smooth muscle, with venous dilation> arterial dilation. o Clinical uses: relieves myocardial ischemia, HTN, and ventricular failure. IV dose: (0.5-10mcg/kg/min). Sublingual (peak effect in 4min). Transdermal (sustained release for 24 hours) § Glass containers and special IV tubing are recommended because of adsorption of NTG to polyvinylchloride § Some pt's appear to develop tolerance- maybe d/t depletion of reactants necessary for nitric oxide formation, compensatory secretion of vasoconstrictive substances, or volume expansion. o Metabolism: § Undergoes rapid reductive hydrolysis in the liver and blood by glutathione-organic nitrate reductase. · One metabolic product is nitrate, which can convert hemoglobin to methemoglobin Methemoglobinemia is rare, but can be treated with methylene blue. § NTG reduces myocardial oxygen demand and increases oxygen supply by: · Pooling blood in the large capacitance vessels reduces preload- accompanying decrease in LVEDP · Afterload reduction from arterial vasodilation will decrease both end-systolic pressure and oxygen demand. (Of course a drop in diastolic pressure may lower coronary perfusion pressure and actually decrease oxygen supply). · NTG redistributes coronary blood flow to ischemic areas of the subendocardium. · Coronary artery vasospasm is relieved. o Much more beneficial to CAD pt's than nitroprusside (coronary steal). o Used on a short-term basis (24-48hrs) to prevent spasm of IMA. § SE: Abrupt discontinuation can cause coronary vasospasm. o Preload reduction helps relieve cardiogenic pulmonary edema; HR is unchanged or minimally increased. o Rebound hypertension is less likely after discontinuation (than nitroprusside) o Effects on cerebral blood flow an ICP are similar to nitroprusside. Headache from cerebral vessel dilation is common SE. o Dilatory effects on pulmonary vasculature and relaxes bronchial smooth muscle § SE: Hypoxia can occur d/t the inhibition of pulmonary vascular vaso-constriction, which increases blood flow through poorly oxygenated areas of the lung (shunting) o Effective (but transient) uterine relaxant- can be beneficial during certain OB procedures if the placenta is still present in uterus. o NTG shown to diminish platelet aggregation- effect enhanced by administration of N-acetylcysteine.

· Sevoflurane and Halothane:

o Respiratory depressant effects o Smooth bronchial muscles, laryngeal, and pharyngeal reflexes are blunted- placing risk for aspiration o SE: decreased responsiveness to oxygenation and ventilation and elevated CO2 levels o Halothane: § Decreases mucociliary function for as long as 6 hours- increase risk for atelectasis and PNA § Myocardial depression and peripheral vasodilation § Benefits: Low incidence of PONV and its bronchodilator properties- useful for pt's with pulmonary diseases o Sevoflurane: Does not appear to irritate the respiratory system or sensitize the heart to catecholamine's; may cause HOTN d/t decrease after load

Dopexamine:

o Structural analogue of DA and has potential advantages over DA because it has less B1-adrenergic (arrhythmogenic) and alpha-adrenergic effects. o Because of the decreased B-adrenergic effects and its specific effect on renal perfusion, it may have advantages over dobutamine. o Drug has not reached widespread acceptance.

Beta1- Receptors:

o The catecholamines norepinephrine and epinephrine are equipotent on B1- receptors, but epinephrine is significantly more potent than norepinephrine on B2-receptors. o B1-receptors are located on the post-synaptic membranes in the heart § Stimulation activates adenylate cyclase, which converts adenosine triphosphate to cyclic adenosine monophosphate and initiates a kinase phosphorylation cascade. · Initiation of the cascade has positive chronotropic (increased HR), dromotropic (increased conduction), and inotropic (increased contractility) effects.

Esmolol:

o Ultrashort-acting cardioselective B1-antagonist that reduces HR and, to a lesser extent, BP. § Has been used to prevent tachycardia and HTN in response to perioperative stimulation, such as intubation, surgical manipulation, and emergence. It is as effective as propranolol in controlling the ventricular rate in AF and a-flutter. Although esmolol is considered to be cardioselective, at higher doses it inhibits B2-receptors in bronchial and vascular smooth muscle. § The short duration of action is d/t rapid redistribution (distribution half-life is 2min) and hydrolysis by red blood cell esterase (elimination half-life is 9min). o Indications: HTN, acute MI, tachyarrhythmias. o Should be avoided in pt's with bradycardia, heart block greater than first degree (PR >0.24), cardiogenic shock, or overt HF. o SE: Bradycardia, CP, HOTN, confusion, headache, dizziness, agitation, dyspnea, wheezing, fatigue, constipation, and N/V, seizures, bronchospasm, and pulmonary edema. o IV bolus dose: (0.2-0.5mg/kg) for short-term therapy; continuous IV infusion dose: (50-200mcg/kg/min). § Due to the short half-life, it is the practical choice in treating pt's with labile BP o Nurses: Esmolol may require large volumes of fluid- not ideal for pt's who may not tolerate excessive fluid intake; standard monitoring, BS.

Dexmedetomidine (Precedex):

§ A lipophylic alpha-methylol derivative with a higher affinity for alpha2-receptors than Clonidine. Also, has shorter half-life (2-3hrs) compared to Clonidine (12-24hrs). § It has sedative, analgesic, and sympatholytic effects that blunt many of the cardiovascular responses seen in perioperative period. · Sedative and analgesic effects are mediated by alpha2-adrenergic receptors in the brain (locus ceruleus) and spinal cord. § Intraoperative use can reduce IV and volatile anesthetic requirements; when used post-op, it can reduce analgesic and sedative requirements. · Useful in post-op sedation, because of its little effect on causing respiratory depression. § SE: Rapid administration may elevate BP, but hypotension and bradycardia can occur with ongoing administration. o Although these medication and adrenergic agonists, they are also considered to be sympatholytic because sympathetic outflow is reduced. o Long-term use (particularly Clonidine and Dexmedetomidine) leads to supersensitization and up-regulation of receptors; with abrupt discontinuation of either drug, an acute withdrawal syndrome manifested by hypertensive crisis can occur. § Because Dexmedetomidine has increased affinity for alpha2-receptors, the syndrome may manifest after only 48hrs when the drug is stopped.

o Acetaminophen (Ofirmev):

§ Acetaminophen is a centrally acting analgesic with likely central COX inhibition and with weak peripheral COX effects resulting in lack of gastric irritation and clotting abnormalities. § Use with caution is pt's with hepatic disease.

Clonidine:

§ Alpha2-agonist used for its antihypertensive and negative chronotropic effects. § Also, is now being increasingly used for its sedative properties · Clonidine seems to decrease anesthetic and analgesic requirements (decreases MAC) and provides sedation and anxiolysis. · General anesthesia: reportedly enhances intraoperative circulatory stability by reducing catecholamine levels. · Regional anesthesia: prolongs duration of the block. · Other effects: decreased post-op shivering, inhibition of opioid-induced muscle rigidity, attenuation of opioid withdrawal symptoms, and treatment of some chronic pain syndromes. § Oral dose: (3-5mcg/kg), IM dose: (2mcg/kg), IV dose: (1-3mcg/kg), Transdermal dose: (0.1-0.3mg/day), intrathecal dose: (75-150mcg), and epidural dose: (1-2mcg/kg). § SE: Bradycardia, hypotension, sedation, respiratory depression, and dry mouth.

o Ketorolac (Toradol):

§ Nonselective COX inhibitor NSAID that provides analgesia by inhibiting prostaglandin synthesis. § Uses: Indicated for short-term (<5 days) management of pain, particularly post-op period. A standard dose of ketorolac provides analgesia equivalent to 6-12mg of morphine; it has similar time of onset as morphine, but lasts much longer (6-8hrs). § Peripheral acting drug, therefore has minimal central nervous system side effects- has become popular alternative to opioids. · Specifically, it does not cause respiratory depression, sedation, or N/V. § SE: Inhibits platelet aggregation and prolongs bleeding time; avoid use in bleeding pt's, GI bleeds, kidney failure

Propofol (Diprivan):

§ sedative, no analgesic properties · Causes less myocardial depression, may cause HOTN (likely d/t venous and arterial vasodilation) · Low incidence of post-op side-effects, less likely to cause PONV than Etomidate · Allows pt to quickly regain consciousness with minimal residual CNS effects, allowing for early extubation

[Adrenoceptor Physiology:]

· "Adrenergic" originally referred to effects of epinephrine (adrenaline), although norepinephrine (noradrenaline) is the primary neurotransmitter responsible for most of the adrenergic activity of the SNS. With the exception of eccrine sweat glands and some blood vessels, norepinephrine is released by post-ganglionic sympathetic fibers at end-organ tissues. · In contrast, acetylcholine is released by pre-ganglionic sympathetic fibers and all parasympathetic fibers. · Norepinephrine is synthesized in the cytoplasm of sympathetic post-ganglionic nerve endings and stored in vesicles. After release by a process of exocytosis, the action of norepinephrine is primarily terminated by reuptake into post-ganglionic nerve endings (inhibited by tricyclic antidepressants), but also by diffusion from receptor sites, or via metabolism by monoamine oxidase (inhibited by MAOI's) and catechol-O-methyltransferase. Prolonged adrenergic activation leads to desensitization and hyporesponsiveness to further stimulation.

Digoxin

· (cardiac glycoside): o Slows conduction at the AV node and increases the refractory period. It also has a positive inotropic effect and causes a decreased sympathetic response and RAAS effect. o Indications: Post-op AF (rate control) in pt's with poor EF, HF, or contraindication to B-blocker therapy o IV or oral dose: (0.25mg q2h to max of 1.5mg); maintenance dose: (0.125-0.375mg orally or 0.125-0.25mg IV daily). Half-life is 38-48hrs, but is longer for pt's with impaired renal function. Administer over 5min. o SE: N/V, anorexia, diarrhea, headache, and visual disturbances (blurred vision, yellow/green halo's); cardiac dysrhythmias. o Nurses: caution when administering to pt with acute MI, AV block, electrolyte imbalance, hypoxia, bradycardia, HF, pulmonary disease, VT, WPW syndrome, renal disease, SSS, or PVC's § Amiodarone can increase digoxin levels § Therapeutic range: 0.8-2ng/ml; obtain levels immediately prior to next dose § Digoxin toxicity: diagnosis based more on presence of "dig toxic" rhythm than serum levels. · Digoxin immune Fab (Digibind): indicated for ventricular dysrhythmias, bradyarrhythmias, 2nd or 3rd degree HB, or hyperkalemia. (If Digibind not available- may need to give atropine if bradyarrhythmia). § Use caution on pt's that received digoxin and require cardioversion- as digoxin potentiates the effects of electricity and the pt may develop a "dig toxic" rhythm.

[Opioid Receptors:]

· All opioid receptors couple to G proteins; binding of an agonist t an opioid receptor causes membrane hyperpolarization. Acute opioid effects are mediated by inhibition of adenylyl cyclase (reductions in intracellular cyclic adenosine monophosphate concentrations) and activation of phospholipase C. Opioids inhibit voltage-gated calcium channels and activate inwardly rectifying potassium channels. Opioid effects vary based on duration of exposure, and opioid tolerance leads to changes in opioid responses. · The opioid drugs mimic endogenous compounds (endorphins, enkephalins, and dynorphins). · Opioid receptor activation inhibits the presynaptic release and postsynaptic response to excitatory neurotransmitters (e.g. acetylcholine, substance P) from nociceptive neurons. · Mu (m): o Clinical effect: supraspinal analgesia, respiratory depression, physical dependence, muscle rigidity. o Agonists: Morphine, Fentanyl, Met-enkephalin, B-Endorphin · Kappa (k): o Clinical effect: Sedation, spinal analgesia o Agonists: Morphine, nalbuphine, butorphanol, Dynorphin, Oxycodone · Delta (d): o Clinical effect: Analgesia, behavioral, epileptogenic o Agonists: Leu-enkephalin, B-Endorphin · Sigma (s): o Clinical effect: Dysphoria, hallucinations, respiratory stimulation o Agonist: Pentazocine, nalorphine, ketamine · Fentanyl: · Oxycodone: · Hydrocodone:

[Beta-blockers:]

· Beta-blockers have variable degrees of selectivity for the B1-receptors. Those that are more B1-selective have less influence on bronchopulmonary and vascular B2-receptors. o Theoretically, a selective B1-blocker would have less of an inhibitory effect on B2-receptors and, therefore, might be preferred in pt's with COPD or PVD. Pt's with PVD could potentially have a decrease in blood flow if B2-receptors, which dilate the arterioles, are blocked. B-receptors blocking agents also reduce intraocular pressure in pt's with glaucoma. o B-blockers are also classified by the amount of intrinsic sympathomimetic activity (ISA) they have. Many B-blockers have some agonist activity; (although they would not produce effects similar to full agonists like epinephrine)- B-blockers with ISA may not be as beneficial as B-blockers without ISA in treating pt's with cardiovascular disease. o B-blockers can be further classified as those that are eliminated by hepatic (metoprolol), those that are excreted by the kidneys unchanged (atenolol), or those that are hydrolyzed in the blood (esmolol). o Discontinuation of B-blocker therapy for 24-48hrs may trigger a withdrawal syndrome characterized by HTN (rebound HTN), tachycardia, and angina pectoris seems to be caused by an increase in the number of B-adrenergic receptors (up-regulation).

Amiodarone

· Class 3 o Creates antiarrhythmic effect by blocking potassium channels, which prolongs the duration of the action potential and decreases membrane excitability § Slows HR by depressing SA node automaticity and increases refractoriness of the AV node. § Also decreases impulse conduction by indirectly blocking sodium channels, blocking beta-receptors, increasing atrial and ventricular refractoriness, and inhibiting alpha-adrenergic receptors and calcium-channels, producing antianginal effects. · The vasodilatory effects, including coronary vasodilation further contribute to antianginal effects. o Indications: Used to convert post-op AF; management of VF and VT; treatment of choice for SVT. o Dose: (150mg over 10min, followed by 24hr infusion at a rate of 1mg/min for 6hrs, then 0.5mg/min for 18hrs). § VF or pulseless VT: 300mg IVP, may repeat 150mg IVP o SE: pulmonary and liver toxicity with long-term use; myocardial depression and HB; HOTN if administered too quickly. o Nurses: Monitor for HOTN and bradycardia; avoid other QT-prolongation medications (quinidine, sotalol, erythromycin, and haloperidol); monitor electrolytes, liver (decreased drug clearance) and pulmonary (ARDS, pulmonary fibrosis, and pneumonitis) function. § Black box warning: grapefruit juice decreases absorption of the medication, skin can turn a gray-blue color, and regular blood work for thyroid problems should be planned.

[Adrenergic Agonists:]

· Differentiation between direct and indirect MOA is important in pt's who have abnormal endogenous norepinephrine stores, as may occur with use of some antihypertensives or MAOI's intraoperative HOTN in these pt's should be treated with direct agonists, as their response to indirect agonists will be altered. o Direct agonists: bind to the receptor. o Indirect agonists: increase endogenous neurotransmitter activity. § Increased release or decreased reuptake of norepinephrine · Another feature that distinguishes adrenergic agonists from each other is their chemical structure: o Adrenergic agonists that have a 3,4-dihydroxybenzene structure are known as catecholamines § These drugs are typically short-acting because of their metabolism by monoamine oxidase and catechol-O-methyltransferase. Pt's taking MAOI's or tricyclic antidepressants may demonstrate exaggerated response to catecholamines. § Naturally occurring catecholamines: epinephrine, norepinephrine, and dopamine. § Synthetic catecholamines: isoproterenol and dobutamine.

[Calcium-channel Antagonists:]

· Dihydropyridine calcium channel blockers (Nicardipine, clevidipine) are arterial selective vasodilators Have minimal effects on cardiac conduction and ventricular contractility. o MOA: Bind to L-type calcium channel and impair calcium entry into vascular smooth muscle. § These L-type receptors are more prevalent on arterial vessels than venous capacitance vessels cardiac filling and preload are less affected by these agents than nitrates. With preload maintained, CO often increases.

[Nitrovasodilators:]

· Relax both arterial and venous smooth muscle. · MOA: As these drugs metabolized, they release nitric oxide, which activates guanylyl cyclase- this enzyme is responsible for the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP), which controls phosphorylation of several proteins, including some involved in the control of free intracellular calcium and smooth muscle contraction.