ANS + Cardiac (Drugs/monitors/physiology)

Sympathomimetics

Drugs that act like catecholamines but have a different structure

Sympatholytics

Drugs that oppose the effects of the sympathetic nervous system

Propranolol (Inderal)

Prototypical non-specific beta antagonist May help treat sympathetic symptoms of thyrotoxicosis (thyroid storm) and pheochromocytoma (after alpha 1 blockade!) Side effects: bronchospasm

Glycopyrrolate

Quaternary ammonium = Charged! Does not cross BBB- devoid of CNS/opthalmic activity Good predmedication for antisialagogue Concentration and dose are half of atropine Longer duration of action (2-4 hours) than atropine

Aldosterone

Save sodium Pee potassium

DA receptors

renal perfusion, diuresis

Low dose dopamine

<2 mcg/kg/min This dose acts at DA receptor Renal vasodilation, diuresis Inhibit renal/splanchnic NE release "renal dose" dopamine is considered outdated

High dose dopamine

10-20 mcg/kg/min This dose acts at alpha 1 receptors INC PVR DEC renal perfusion Risk for dysrhythmias Coronary/pulmonary vasoconstriction increased PA pressures

Beta antagonists "beta blockers" general info

1st generation (beta non-selective) and 2nd generation (beta1 selective) Reduce mortality in patients with heart failure --mechanisms include: counteracting the chronic hyperadrenergic state, slowing the HR to improve ventricular filling and contractility, and up-regulation of beta-1 receptor density Reduce incidence of perioperative MI by reducing myocardial oxygen requirement Control of tachydysrhythmias--slows ventricular response to SVT, VT Sd effects: bradycardia, AV heart block, CHF exacerbation --Hypotension-due to dec myocardial contractility, HR, renin release -Withdrawal syndrome: rebound HTN, tachycardia, angina--due to up-regulation of beta receptors

Med dose dopamine

2-10 mcg/kg/min This dose acts at Beta 1 receptors INC contractility, HR, CO Myocardial demand > O2 supply

Angiotensin II receptor blockers

A2RBs Act later in the renin-angiotensin-aldosterone pathway Losartan (Cozaar), Valsartan (Diovan) Inhibit hypertensive effect of angiotensin II Less incidence of cough Hyperkalemia-especially if used together with K sparing diuretics Drug and its active metabolites--hepatic metabolism Otherwise similar to ACEIs--may want to discontinue prior to major surgery

A patient is seen in your preop clinic for an elective removal of a mass on her lower back. She takes metoprolol, captopril, and losartan for hypertension along with simvastatin for hyperlipidemia. In what manner does the antihypertensive drug captopril reduce this patient's blood pressure? Select one: a. Inducing smooth muscle arteriolar dilation b. Increasing secretion of aldosterone c. Blocking angiotensin receptors directly d. Blocking conversion from angiotensin I to angiotensin II e. Blocking conversion from angiotensin I to renin

ACE inhibitors are frequently used to treat hypertension and may be used as first-line agents in many conditions including congestive heart failure and diabetes. They work by blocking conversion of angiotensin I to angiotensin II, a potent arterial vasoconstrictor. It also decreases secretion of aldosterone. The most common side effect is cough and upper respiratory symptoms, which are relieved if the ACEI is stopped. Angioedema may also be seen rarely and is a serious condition requiring close monitoring and treatment. ACE inhibitors should be stopped 12 to 24 hours prior to surgery as significant hypotension has been seen in patients receiving anesthesia. If hypotension occurs, standard fluid and pressor therapy may be used. If unsuccessful vasopressin is another good choice that may be more efficacious. The correct answer is: Blocking conversion from angiotensin I to angiotensin II

Which sorts of patients might have abnormal endogenous norepinephrine stores?

Abnormal endogenous norepinephrine stores may occur with the use of some antihypertensive medications or MAOIs. Intraoperative hypotension in these patients should be treated with direct agonists, as their response to indirect agonists will be altered.

Atenolol (Tenormin)

Renal excretion Elimination half life 6-7 hours

A 19 year old female with moderate asthma is in your preoperative holding area. She is to undergo knee arthroscopy and you are doing her immediately preoperative evaluation. You note some moderate wheezes to auscultation, but the patient denies any recent upper respiratory infection or fever and states that she has not required medication for her asthma for several months. Which of the following, when inhaled, treats the bronchial inflammation seen in asthma through increasing cAMP? Select one: a. Cromolyn sodium b. Salmeterol c. Albuterol d. Ipratropium e. Racemic epinephrine

Albuterol works upon the activation of beta 2 receptors after inhalation of the aerosolized drug. Beta 2 receptor activation causes relaxation of the bronchial smooth muscles through activating adenylate cyclase and thus increasing cAMP. Albuterol is useful in treating asthmatic or other inflammatory processes effecting the bronchial tree. It also works against the actions of histamine and inflammatory mediator release, making it particularly useful in asthmatics (this is true of albuterol but not the anticholinergic ipratropium, which doesn't feature action against inflammatory leukotrienes). It can be administered as a metered dose inhaler (MDI) or through nebulizer. In the anesthetized patient several "puffs" are administered and ventilated into the circuit at one time. In the awake patient, treatments are typically given every 2-4 hours or continued for prolonged treatments depending on severity of the attack. One treatment lasts about 3-4 hours with peak effects in 30 minutes to 2 hours after inhalation. As beta agonists cause shifting of potassium into the cell, albuterol can cause hypokalemia and in fact can be used in the treatment of hyperkalemia. Albuterol also has some beta 1 effects including tachycardia and some patients may shake or feel nervous after being administered a treatment. Some patients with asthma may benefit from pre-induction treatment with albuterol before intubation if wheezing is noted to auscultation or the patient has subjective dyspnea.

phentolamine, phenoxybenzamine

Alpha 1 and alpha 2 (non-selective) receptor antagonsists New receptors must be synthesized before complete offset of its effects occurs "Chemical sympathectomy" Almost exclusively for management of pheochromocytoma (but becoming less common) alpha blockade before beta-blockade Phentolamine: can be used as IV bolus (5 mg) or infusion --reversibly binds to alpha receptor --other uses (due to vasodilation_: intercavernosal injection for treatment of impotence; injection for treatment of NE extravasation; reversal of LA injection Phenoxybenzamine: used orally for pre-operative management --Irreversibly binds to alpha receptor (but tx overdose with NE--some receptors are still free)

Alpha antagonists

Alpha 1 receptor blockade--smooth muscle relaxation vessels with higher initial tone--greater response to alpha blockade Side effects: hypotension, orthostatic hypotension, tachycardia --Worse with hypovolemia, standing position Other side effects: nasal stuffiness, cholinomimetic side effects (diarrhea, hyperperistalsis-can be treated with atropine, glycopyrrolate) Chronic use--blunted sympathetic response Phenylephrine response is completely blocked NE response: tachycardia due to beta 1 activation epi response: tachycardia and SEVERE hypotension due to beta 2 mediated vasodialtion alpha 2 receptor blockade--eliminates negative feedback--more NE release--tachycardia

Alpha 1 receptors (M&M)

Alpha 1 receptors are postsynaptic adrenoceptors and are located in smooth muscle throughout the body. Activation of these receptors increases intracellular calcium ion concentration which leads to contraction of smooth muscles. The myocardium possesses alpha 1 receptors that have a positive inotropic effect, which might play a role in catecholamine-induced arrhythmias.

Prazosin (similar: terazosin, doxazosin, tamulosin)

Alpha 1 selective competitive antagonist Less tachycardia than with non-selective alpha antagonists, but still some orthostatic hypotension Used for HTN and BPH as well as pheochromocytoma

Alpha 2 receptors (M&M)

Alpha 2 receptors are located primarily on the presynaptic nerve terminals. Activation of these adrenoceptors inhibits adenylate cyclase activity. This deccreases the entry of calcium ions into the neuronal terminal, which limits exocytosis of storage vesicles containing norepinephrine. Thus, alpha 2 receptors create a negative feedback loop that inhibits further norepinephrine release from the neuron

A 73 year old patient with severe depression has admitted to taking her entire supply of propranolol. She admits to hoarding from previous prescriptions and estimates she may have taken over 100 pills. What treatments are LEAST likely to be indicated in the management of this overdose patient? Select one: a. Atropine b. Insulin and glucose c. Calcium chloride d. Glucagon e. Dobutamine

Beta agonist drugs (like ephedrine or dobutamine) are least likely to be beneficial as beta receptors may be effectively blocked, requiring other means to increase cardiac output and heart rate. Beta blockers are widely used to treat a range of disorders, from tremors to migraines and aneurysms. Beta blocker toxicity, however, is related to significant adverse outcomes, usually relating to excessive beta adrenergic blockade or pro-arrhythmic effects on cardiac conduction. Other agents such as calcium channel blockers and tricyclic antidepressants, commonly taken by many patients on beta blockers, increase mortality after beta blockade overdosing. Beta 1 selective blockade (metoprolol, esmolol) results in primarily depressed myocardial contractility and conduction, whereas nonselective beta blockade (as seen in propranolol) effects the heart as well as causing bronchoconstriction, impaired gluconeogenesis, and decreased insulin release. Lipid soluble beta blockers, such as propranolol, also rapidly cross the blood brain barrier and can create neurologic issues such as altered mental status and seizures. While beta blockers are often metabolized via the liver, they do not cause hepatotoxicity in and of themselves. Bradycardia and hypotension are the most common effects seen. Ventricular arrhythmias can also be seen following propranolol overdose. An ECG is a very important test to obtain, and a baseline should be gathered for comparison. Any bradydysrhythmia is possible, and constant monitoring of a rhythm strip should be undertaken as progression to asystole or complete heart block can occur very suddenly. Atropine should be used for bradycardic patients, and pretreating patients prior to induction and intubation should be considered. Blood sugars should be watched closely, as hypoglycemia is common and should be treated with dextrose. Glucagon is considered a possible antidote to beta blocker overdose. It is first given as a bolus dose, followed by continuous infusion. If effective, an increase in heart rate or blood pressure may be seen. Vomiting is common following administration of glucagon, and prophylaxis should be given. Despite anecdotal evidence, studies have not shown for sure that glucagon is efficacious in beta blocker overdose but is still used for treatment. Calcium has been shown to be efficacious in case reports, probably by increasing inotropy and thus cardiac output. Calcium levels should be monitored if therapy is provided. Insulin and glucose therapy may become the next first line treatment for beta blocker overdose therapy, and case reports have been promising in improvement of beta blockade overdose patients. The correct answer is: Dobutamine

Metoprolol (Lopressor)

Bolus dose: 2-5 mg IV Hepatic metabolism Elimination half life= 3-4 hours

Systemic effects of anticholinergic drugs

CV: Reversing bradycardia due to vagal reflexes Transient slowing of HR at low doses Block vagal activity in SA node Facilitate conduction through AV node Pulmonary: relaxation of bronchial smooth muscle Opthalmic: mydriasis (pupillary dilation) GU: urinary retention

Clinidine

Centrally acting alpha 2 agonist (A2:A1 = 220:1) Uses: Treat hypertension by stimulating negative feedback at pre-synaptic A2 receptors, reducing NE secretion Sedation, anxiolysis, decreases MAC --Stimulation of alpha 2 receptors in vasomotor center of the brainstem--decreased sympathetic outflow Effective against post-operative shivering (0.5-1 mcg/kg) Adjunct for analgesia: add to local anesthetic or opioids for epidural/spinal/nerve block Treatment of opioid withdrawal syndrome Commonly taken PO, TD patch, IM; not commonly used IV Side effects: bradycardia, hypotension, dry mouth Withdrawal syndrome: hypertensive crisis (tx with vasodilator)

Anticholinergic drugs

Cholinergic antagonists Specifically, acting at the muscarinic receptor Aromatic acid esters--competitively bind to muscarinic receptor and block activation by ACh

Metabolism of circulating catecholamines

Circulating catecholamines (NE + Epi) are metabolized by the liver and the kidney Catechol-O-methyltransferase (COMT) Metabolite is vanillylmandelic acid (VMA)--used in the diagnosis of pheochromocytoma Longer duration of catecholamine activity (minutes vs milliseconds) Systemic catecholamines DO NOT cross the BBB

Nitrates

Deliver NO (nitric oxide) to vascular smooth muscle-->vasodilation NO release is part of normal endothelial function-->autoregulation Sildenafil (viagra) increases local availability of endogenous NO Inhibits platelet activation/aggregation/adhesion NO is rapidly inactivated by hemoglobin (may explain vasospasm after subarachnoid hemorrhage)

Dexmedetomidine (M&M)

Dexmedetomidine is a lipophylic alpha-methylol derivative with a higher affinity for alpha 2 receptors than clonidine. It has sedative, analgesic, and sympatholytic effects that blunt many of the cardiovascular responses seen during the perioperative period. Long-term use of alpha 2 agonists such as clonidine and dexmedetomidine leads to super-sensitization and up-regulation of receptors; with abrupt discontinuation of either drug, an acute withdrawal syndrome manifested as a hypertensive crisis can occur.

Digoxin improves cardiac contractility while slowing AV nodal conduction and is occasionally used in the treatment of congestive heart failure. Through what mechanism does digoxin increase myocardial contractility? Select one: a. Inhibition of sodium/potassium ATPase b. Inhibition of L-type calcium channels c. Inhibition of T-type calcium channels d. Inhibition of fast sodium channels e. Inhibition of potassium channels

Digitalis works to inhibit the sodium/potassium ATPase pump in myocardial cells to increase intracellular calcium, promoting calcium influx and increasing cardiac contractility. It also directly suppresses the AV nodal conduction and increases the refractory period as well as decrease conduction velocity. It works as a positive inotrope, while enhancing vagal tone and decreasing the rate of atrial arrhythmias (including atrial fibrillation with rapid ventricular response). Dihydropyridine calcium channel blockers (nifedipine) work on the L-type channels. The correct answer is: Inhibition of sodium/potassium ATPase

Which of the following medications is the most efficacious for the treatment of atrial fibrillation with rapid ventricular response? Select one: a. Nimodipine b. Nicardipine c. Nifedipine d. Diltiazem e. Amlodipine

Diltiazem is a benzothiazepine calcium channel blocker that is unique in its action compared to other CCBs. It is frequently used in the treatment of SVT and rapid rate atrial fibrillation due to its ability to block the calcium channels of the AV node. It does not cause great cardiac depression and can be safely used with beta blockade in most patients. Diltiazem also may decrease intracellular sodium by inhibiting the sodium-potassium pump and also prevent binding of the calcium-calmodulin units. Typical dosing is 0.3 mg/kg (or 15-20 mg for typical adult patient) IV over 2 minutes followed by a diltiazem drip of 5-15 mg/hour if first dose is successful. If initial bolus dose is unsuccessful, it may be repeated in 15 minutes again at 0.3 mg/kg or 15-20 mg IV. It is largely protein bound and has a half life of 5 hours. Nifedipine and nicardipine do not have effects on the SA or AV nodes. Nimodipine is similar to nifedipine but has greater central nervous system effects. Verapamil is a calcium channel blocker like nifedipine and nicardipine are, but verapamil is like diltiazem in that it does slow conduction through the AV node. Amlodipine is a calcium channel blocker used to treat hypertension. It is sometimes combined with other drugs to provide dual benefit in one pill. For instance, atorvastatin (an HMG-CoA reductase inhibitor used to treat high cholesterol and dyslipidemia) has been combined with amlodipine as hypertension and dyslipidemia frequently coexist. The correct answer is: Diltiazem

Epinephrine

Direct adrenergic agonist Variable peripheral effects: alpha (skin, mucosa, and kidney) and beta (skeletal muscle) B1--INC HR, contractility, myocardial demand INC SBP B2--bronchodilation, skeletal muscle dilation DEC DBP? A1--Splanchnic/renal blood flow, INC coronary/cerebral perfusion Used to treat anaphylaxis and ventricular fibrillation Risks: cerebral hemorrhage, coronary ischemia, ventricular dysrhythmias --Volatile anesthetics, especially halothane, potentiate dysrhythmias with epi

Norepinephrine (Levophed)

Direct alpha 1 stimulation without Beta 2 activity--intense arterial and venous vasoconstriction INC BP Little change in HR, possible DEC HR (reflex bradycardia) DEC renal perfusion and INC myocardial O2 requirements -Ensure adequate volume resuscitation Can see end-organ ischemia/necrosis Not a good first line treatment for cardiogenic shock pulmonary vasoconstriction Used to treat refractory hypotension (shock, sepsis)

Hydralazine (Apresoline)

Directly causes vascular smooth muscle relaxation arterioles > veins Largest effect: coronary, cerebral, renal, splanchnic circulation Decreases DBP > SBPP Reflex tachycardia (may also have a direct effect on HR) Dose: 2.5-10 mg IV (also available PO) Effect starts in 10-20 minutes (not a fast acting drug) Lasts 3-6 hours (unpredictable) Liver metabolism--> renal excretion

An 81 year old male suffers cardiac arrest and is resuscitated after the administration of epinephrine, lidocaine, and biphasic defibrillation with 200 joules. He is currently in a sinus rhythm and has a blood pressure of 76/40 as shown on arterial transducing. Which of the following medications would provide this patient with no beta 2 agonism while producing alpha effects at doses greater than 10 mcg/kg per minute? Select one: a. Phenylephrine b. Dopamine c. Norepinephrine d. Isoproterenol e. Dobutamine

Doses from 1-3 mcg/kg/min activate dopamine 1 receptors which produces renal dilation (this was once believed helpful to patients needing renal protection but evidence does not support the usefulness of dopamine for this). From 3-10 mcg/kg/min beta 1 receptors are activated, and from 10 mcg/kg/min to greater concentrations alpha receptors are activated causing vasoconstriction. Dopamine is an endogenous catecholamine that moderates cardiovascular function as well as being an important neurotransmitter. Intravenous dopamine administration activates different receptors based on the dose being given at the time. Heart rate and cardiac output is increased by dopamine's activation of beta 1 receptors but the inotropic effects of dopamine may be due to dopamine causing release of endogenous norepinephrine stores. Dopamine induced alpha stimulation is responsible for the increase in systemic vascular resistance. Dopamine being given IV does not cross the blood brain barrier and as such does not produce central dopamine-mediated effects. Dopamine is effective at increasing cardiac contraction, glomerular filtration rate, and renal blood flow. It increases diuresis as well as increasing sodium excretion. Dopamine also seems to inhibit the body's response to arterial hypoxemia and depress ventilatory response by interfering with the carotid bodies. Phenylephrine is an alpha 1 agonist only at all doses. Dobutamine has only beta 1 effects, and isoproterenol has beta 1 and beta 2 agonisim only. Norepinephrine produces both beta 1 and very minor beta 2 effects. The correct answer is: Dopamine

Vasoplegic syndrome

Dysregulation of NO synthesis and vascular guanylate cyclase (GC) activation May require vasopressin if unresponsive to fluid bolus or other sympathomimetic drugs Methylene blue: inhibits NO synthesis and GC, decreasing GMP and vascular smooth muscle relaxation Especially after cardiac surgery: Bolus 1-2 mg/kg over 15-30 min (0.25-2 mg/kg/hr infusion may be needed)

Peripheral autonomic nervous system

Efferent (motor) component of the system Autonomic system: two-neuron unit 1st neuron from the CNS--ganglion (myelinated) 2nd neuron from the ganglion--target organ (unmyelinated) Compare with somatic nerves: single myelinated axon with cell body in spinal cord

In what way does ephedrine exert its pharmacological actions? Select one: a. Indirect beta 1 agonism only b. Direct beta 1 and 2 agonism c. Indirect alpha 1 agonism and direct beta 1 and beta 2 agonism d. Direct alpha 1 agonism and indirect beta 1 and beta 2 agonism e. Indirect alpha 1 agonism only

Ephedrine is an indirect-acting synthetic drug that has both alpha and beta adrenergic responses. Ephedrine is known to cause a release of endogenous norepinphrine stores stimulating alpha 1 receptors, but also has some direct beta 1 and beta 2 actions. The overall effect is an increase in heart rate and cardiac output, as well as increase in systemic vascular vasoconstriction. Ephedrine has a longer duration of action than phenylephrine and epinephrine, and is given in bolus from 5-25 mg IV as a treatment for low blood pressure. The correct answer is: Indirect alpha 1 agonism and direct beta 1 and beta 2 agonism

Esmolol M&M

Esmolol is an ultrashort acting selective beta1 antagonist that reduces HR and to a lesser extent BP Esmolol is as effective as propranolol in controlling the ventricular rate of patients with atrial fibrillation or flutter. The short duration of action of esmolol is due to rapid redistribution (2 min) and hydrolysis by red blood cell esterase (elimination 1/2 life is 9 min)

After a difficult intubation, an otherwise healthy patient has a heart rate of 138 as a sinus tachycardia and a blood pressure of 182/100. As this is likely a transient increase in blood pressure, you choose to administer esmolol for its short duration of action. Esmolol has a short duration of action due to: Select one: a. Redistribution b. Rapid breakdown by acetylcholinesterase c. Rapid breakdown by plasma esterase d. Quick diffusion from beta adrenergic receptors e. Rapid breakdown by erythrocyte esterase

Esmolol is broken down by Erythrocyte Esterase hence its short duration of action. Anemic patients can experience a prolonged effect when administered Esmolol. Esmolol is a rapid and short acting beta 1 selective adrengeric antagonist. Beta blockers are negative inotropes and chronotropes, providing a good treatment for tachycardias and hypertension. Dosing is 0.5 mg/kg but is frequently given as 10 - 20 mg bolus IV with full onset within 5 minutes sometimes as quick as 1 minute. It lasts for approximately 10 to 30 minutes, making it good for transient changes in blood pressures or short durations of stimulation (such as during direct laryngoscopy). It is terminated by Erythrocyte Esterase quickly after administration. Like all beta blockers, they have the potential to cause myocardial depression and increase airway resistance. Even though esmolol is beta 1 selective, high doses can still cause adverse effects in patients with COPD and asthma so care should be used. Beta blockers are contraindicated in patients with heart blocks, and should be used cautiously in CHF patients as decompensation can lead to overt heart failure. The correct answer is: Rapid breakdown by erythrocyte esterase

Beta 1 selective antagonists general

Ex: Metoprolol, atenolol, esmolol Better choice in patient with reactive airway disease Consider carefully before using in patients with very severe lung disease Available IV and PO

What is the exception to SNS ganglia that are closer to spinal cord than to the target organ?

Exception: pre-ganglionic fibers go directly to the adrenal gland Adrenal chromaffin cells take the place of post-ganglionic neurons Adrenal stimulation--release of epi (80%) and norepi (20%)

EPI dosing

FOR ACLS: 1 mg IV ( 10 mL of 1:10,000 or 1 ml of 1:1,000) Math note: 1:1,000 = 0.1% = 1 mg/mL For anaphylaxis, shock: 10-100 mcg IV or 100-500 mcg IM/SQ Continuous infusion 0.01-0.1 mcg/kg/min for improved contractility Used topically or infiltration for vasoconstriction--decreased bleeding Add to local anesthetic solutions at 1:200,000- 1:600,000 to prolong block Math note: Add 0.1 ml of 1:1,000 epinephrine to a 30 ml syringe of local anesthetic to get 1:300,000 Add 0.1 ml to a 20 ml syringe to get 1:200,000

A patient who is on a daily tricylic antidepressant is suffering from recurring hypotension during an exporatory laparotomy. You wish to administer ephedrine as the patient's heart rate is below 60 beats per minute. Which of the following effects is most likely to occur in a patient who is taking a tricyclic antidepressant and is administered ephedrine: Select one: a. There will be an exagerated increase in blood pressure b. There will be a decreased response to ephedrine in raising blood pressure c. There will be a normal reaction to ephedrine d. Any of the above responses are possible

For clinicians, one of the greatest challenges in treating the patient on tricyclic antidepressants is the unpredictability of the patient's blood pressure. As there is an increased amount of available norepinephrine, use of ephedrine may produce a greater than normal raise in blood pressure, or the response may appear blunted or normal. Chronic use of the tricyclics also may cause down-regulation of beta-adrenergic receptors. A good guideline is to use less vasopressor initially on a patient who is being treated with a tricylcic antidepressant, and be aware that the patient may either have an exaggerated or a decreased response. If the patient has depleted catecholamine stores, a direct acting sympathomimetic such as norepinephrine may be required to support blood pressure. The correct answer is: Any of the above responses are possible

Methyldopa (Aldomet)

For treatment of HTN, especially in pregnancy induced HTN Inhibits DOPA decarboxylase which converts DOPA into dopamine--NE--Epi THUS, lower catecholamines--lower BP Metabolized into an alpha 2 agonist- similar to clonidine

Special paired sympathetic ganglia

T1-T4 Superior cervical Middle cervical Stellate

Nitroglycerin dosing

Give sublingually/transmucosally (avoids 1st pass effect), transdermally 0.3 mg SL or 2% ointment for angina pectoris Increases coronary perfusion to ischemic subendocardium IV dosing: 10-100 mcg IV bolus or infuse at 0.5-2 mcg/kg/min Potential for absorption of drug into plastic tubing Tolerance develops within 24 hours of sustained treatment

Isoproterenol (Isuprel)

Highly potent beta 1 and beta 2 agonist, no alpha activity Increases HR, contractility Use as an inotrope now replaced by beta 1 specific agonists (dobutamine) and PDE inhibitors Risk for arrhythmias May increase cardiac O2 requirements as well as decrease myocardial perfusion --also, coronary artery dilation...coronary steal? Decrease in SVR due to peripheral vasodilation, but overall effect is INC SBP and DEC DBP Useful as a bronchodilator--now replaced by beta 2 specific agonists Used to increase HR in presence of heart block--maintains HR until pacemaker can be placed

A 49 year old female with a femur fracture is undergoing general anesthesia for repair. She has a history of hypertension, and has received 2mg hydromorphone as well as 4 mg of metoprolol in the treatment of her pain and elevated blood pressure. Her current vital signs are heart rate of 48, blood pressure of 172/95, and is being ventilated at 12 breaths per minute with a tidal volume of 550 ml and a PEEP of 6. You choose to administer hydralazine to treat her hypertension through which of the following effects on the vascular system? Select one: a. Direct dilation of arterioles b. Alpha 2 induced dilation of the venous system c. Alpha 1 mediated vasodilation d. Central dopaminergic antagonism decreasing sympathetic outflow e. T-type calcium channel blockade

Hydralazine decreases blood pressure by direct vasodilation of the arterioles, with little effect on the venous system. Hydralazine is now known to be a hyperpolarizing agent working through potassium channels. Systemic vascular resistance is decreased, but heart rate and stroke volume are increased in response to the decreased SVR. After administration there is a sympathetic reflex response causing tachycardia making it a good choice for bradycardic patients who would not be good candidates for beta blockade. Hydralazine is sometime used for hypertension after other therapies have failed. Onset is generally from 5 to 20 minutes after dosing, and lasts anywhere from 1 to 4 hours after intravenous administration. Significant hypotension is not uncommon and dosing should be started low around 2.5 to 5 mg IV. It has extensive first pass metabolism and is hepatically metabolised with urinary excretion. Hydralazine can cause a lupus-like syndrome, most often seen after chronic (greater than 6 months) use. This is not a true lupus and ceases when the drug is discontinued. The correct answer is: Direct dilation of arterioles

A 42 year old female with rheumatoid arthritis, acid reflux, and chronic refractory hypertension has undergone anesthesia for removal of a large lipoma on her back. It is now two days after the procedure, and you are called by the patient to be evaluated for new symptoms that she believes are related to her anesthetic care. Upon arrival to your clinic, the patient complains of increased joint and muscle pains as well as fever. She states that this is unlike her typical rheumatoid arthritis flare-ups. In addition she states that she develops a rash when she goes outside in the sunlight and that her skin is very sensitive to certain lighting. Upon reviewing a list of the following medications she was administered during anesthesia, you determine the drug most likely to cause this syndrome is: Select one: a. Atracurium b. Propranolol c. Ketorolac d. Gentamicin e. Hydralazine

Hydralazine has been implicated in causing right vocal cord paralysis and laryngeal edema in a lupus-like syndrome (also known as drug-induced lupus erythematosus or DILE). Patients who are predisoposed to autoimmune disease like rheumatoid arthritis (possibly due to the HLA DR4 antigen) may be at higher risk for a lupus-like syndrome to occur with hydralazine. Up to 10% of patients that develop drug-induced lupus erythematosus while taking hydralazine may develop a glomerularnephritis, although mortality is rare. Procainamide and quinidine also can produce lupus-like syndrome, with procainamide having the highest risk. In all of these cases, these drugs produce anti-nuclear antibodies which are the likely culprits. Signs of drug-induced lupus erythematosus include arthralgias, fever, and development of rash on sun-exposed areas of skin. Most patients with drug-induced lupus erythematosus only develop arthralgias, although many develop myalgias as well. Other drugs may cause a characteristic looking malar rash. Malar rash of the face is a sign of true SLE (Lupus), but is only seen in about 1/3 of patients receiving this diagnosis. Some drugs that have been implicated include: amiodarone, diltiazem, captopril, atenolol, tetracycline, and simvastatin. Patients that have true lupus erythematosus (SLE) also can have flare-ups caused by receiving certain medications. Drugs known to induce a flare-up of lupus include cimetidine, HCTZ, hydralazine, penicillin, PABA, and sulfonamides. Ciprofloxacin, a fluoroquinolone antibiotic, may cause UV light sensitivity, but not the other symptoms that may be seen in a lupus-like syndrome.

Beta adrenergic receptors (general)

INCREASE cAMP

Ephedrine

Indirect (and direct) acting adrenergic agonist with similar effect to epinephrine Non-catecholamine sympathomimetic action on both alpha and beta receptors Causes NE release-->rapid tachyphylaxis due to depletion of NE stores Duration of effect is ~10 x longer than with epi Venoconstriction > arteriolar constriction --redistribution of blood centrally, improved venous return (preload) Mild direct beta action--INC HR NO LONGER drug of choice in OB -was thought to preserve uterine blood flow better than direct-acting alpha agonist -now data shows that phenylephrine may be preferable -BUT consider the reflex bradycardia in the setting of sympathectomy due to high epidural/spinal -Sometimes ephedrine may be the better choice May have anti-emetic properties (25 mg IM)

A 45 year old man presents to you for outpatient shoulder arthroscopy. He was injured in a fight three weeks ago and has baseline left shoulder pain, but today he seems anxious and agitated and is complaining of pain all over his chest. The pain is worsened when he breathes in but nothing relieves it. He has a history of ethanol and cocaine abuse. You assess his vital signs and monitor his ECG. Blood pressure is 235/120, HR 133, respiratory rate 26, and EKG shows a sinus tachycardia with ST depression in anterior leads of greater than 4 mm as well as frequent multifocal PVCs. In the treatment of this patient, which of the following interventions should be avoided? Select one: a. Phentolamine b. Labetalol c. Nitroglycerin d. Nitroprusside e. All are safe to use if clinically indicated

Labetalol should be avoided. Beta blockade with unopposed alpha agonism can cause pulmonary edema, congestive heart failure and death. Cocaine is a very common drug of abuse in the United States, and death and morbidity is very common. Cocaine is well absorbed following contact with any mucosal surface, or via the pulmonary alveoli. It has high bioavailability, and is effective due to blocking presynaptic reuptake of catecholamines and serotonin. Adrenergic receptors are heavily stimulated, largely via norepinephrine, which causes vasoconstriction in both cardiac and peripheral vasculature. Cocaine also blocks nerve conduction via slowing the recovery of sodium channels, making it useful as an anesthetic. The euphoric properties are probably related to inhibition of serotonin reuptake in the CNS. Clinically, cocaine use causes cardiovascular vasoconstriction and increases thrombus formation. It also causes supraventricular and ventricular dysrhythmias, and aortic dissection or rupture has been reported after cocaine use. Cocaine produces dose dependent increases in heart rate and blood pressure while also causing heightened sense of alertness and euphoria. Anesthesia providers should be aware that crack cocaine requires high temperatures to be smoked, causing angioedema and pharyngeal burns. Inhalational use is associated with pneumothorax, pneumomediastinum, and pneumopericardium. The increased incidence of thrombus formation can also lead to pulmonary infarction, and patients with this may present with shortness of breath or pleuritic chest pain that may mimic pulmonary embolism. Succinylcholine is probably not recommend for intubation in these patients, as plasma cholinesterase metabolizes both succinylcholine and cocaine. Coadministration of these two can prolong both succinylcholine and cocaine. Rocuronium is preferred. Beta blockers should NOT be administered, as unopposed alpha adrenergic stimulation is associated with coronary vasoconstriction and organ ischemia. This also includes labetalol, as beta blockade effects predominate over its alpha effects. Phentolamine is a good choice to treat alpha stimulation, as it is a direct alpha-1 antagonist. Nitroglycerin may be another good choice. Ephedrine may not be efficacious for hypotension, as cocaine users tend to have depleted stores of catecholamines and will not release more upon administration of this drug. In addition, many cocaine users will mix stimulants like ephedrine and caffeine. Phenylephrine is usually a better choice for hypotension if present.

Oral nitrates

Isosorbide mononitrate (imdur) for prevention of angina pectoris Isosorbide dinitrate (isordil) for prevention of angina pectoris and treatment of CHF Side effects: headache, orthostatic hypotension

Renin-Angiotensin-Aldosterone Pathway

Liver secretes angiotensinogen Kidney secretes renin Renin converts angiotensinogmen into angiotensin I Lungs secrete Angiotensin converting enzyme Angiotensin converting enzyme converts angiotensin I into angiotensin II Angiotensin II causes vasoconstriction and Na, H2O retention Angiotensin II also acts on the adrenal glands and causes them to secrete aldosterone Aldosterone causes Na and H2O retention

Nitroglycerin

Mainly venous dilation NO is release through glutathione dependent pathway Can be used for controlled hypotension, but less potent than SNP Reflex tachycardia Cerebral vasodilation (INC ICP, CBF, headache) Can be used for uterine relaxation (50-200 mcg IV bolus) Risk of methemoglobinemia but rare due to rapid hepatic metabolism---tx methylene blue

Alpha 2 adrenergic receptors

Many subtypes exist Inhibitory receptor--decrease in cAMP Post-synaptic: arterial/venous vasoconstriction, platelet aggregation, inhibition of insulin release and gut motility, inhibition of ADH Pre-synaptic: inhibit NE release--reduce sympathetic outflow; vasodilation; sedation

Methylene Blue

Methylene blue: inhibits NO synthesis and GC, decreasing GMP and vascular smooth muscle relaxation Especially after cardiac surgery: Bolus 1-2 mg/kg over 15-30 min (0.25-2 mg/kg/hr infusion may be needed)

A 65 year old female with a cardiac ejection fraction of 20% is admitted to the ICU for treatment of volume overload in the form of pulmonary congestion and hypoxemia along with abdominal pain. She is started on diuretics and an inotropic agent to increase her cardiac output, and is continued on this medication during the emergent procedure to remove presumed dead bowel that was discovered on CT scan. As she is placed on this inotropic medication to increase her cardiac output, a drop in systolic and diastolic blood pressure is noted. Which of the following medications is most likely to cause a decrease in this patient's systemic vascular resistance while increasing cardiac output? Select one: a. Dobutamine b. Midrodine c. Digoxin d. Norepinepherine e. Milrinone

Milrinone is a pharmacologic agent indicated in the treatment of severe, systolic heart failure. It is a selective agonist of phosphodiesterase receptors in the cardiac musculature and blood vessels. It results in increased inotropy without an effect on chronotropy. It also causes vasodilation and therefore, hypotension which will require either discontinuation of the medicine, a reduction in dosage, or IVF to prevent continued hypotension. Patients with renal failure may have prolonged duration of the hypotensive episodes. Midrodine, dobutamine, and norepinepherine all increase peripheral vascular resistance and would cause an elevation in blood pressure. Digoxin has no effect on peripheral vascular resistance or blood pressure.

Labetalol

Mixed antagonist (alpha and beta receptor antagonism) Anti alpha is mostly alpha 1; beta is non-selective (no reflex tachycardia) --alpha: beta is 1:3 (oral) and 1:7 (IV) Bronchospasm NOT reported as a common complication despite being beta non-selective Decreased peripheral vascular resistance and renin, some decrease in HR common drug of choice for intraoperative HTN Initial bolus: 2.5-10 mg IV works in minutes Hepatic elimination half life 5-6 hours

Heart transplant

Nerve connections are severed during the transplant Some degree of re-innervation will occur over years-decades No baseline parasympathetic activity- lack of vagal tone Resting HR= 90-100 Cannot respond to drugs that block the parasympathetic system (atropine, glycopyrrolate) Treat bradycardia with agents that directly affect the heart: Isoproterenol, glucagon commonly used EPI/NE may have exaggerated beta mimetic effects on HR Increased BP will not lead to a reflex slowing of HR (normally mediated by the vagus nerve) Atropine/glycopyrrolate may cause paradoxical slowing of HR and high-degree AV block Lack the normal tachycardia and contractility response to hypotension/hypovolemia --Need to have adequate preload/intravascular volume

A medication that dilates coronary arteries through formation of nitric oxide is: Select one: a. Nitroglycerin b. Fenoldopam c. Hydralazine d. Phenteramine e. Adenosine

Nitroglycerin functions by forming the free radical nitric oxide. This will not only dilate peripheral veins but also coronary arteries, making it an ideal medication for patients with acute coronary syndrome. Nitric oxide causes relaxation of smooth muscle through activation of cGMP. These effects are most seen in the peripheral veins and arteries, but has greater effects on veins. Preload is decreased through venous dilation, decreasing myocardial oxygen demand. It also dilates coronary arteries, making it a drug of choice for the treatment of acute coronary ischemia. It may be given IV drip or sublingual, and also may be applied as a patch. As nitroglycerin produces a decrease in preload, patients with hypertrophic obstructive cardiomyopathy or aortic stenosis should not be given this drug as they are largely dependent on preload. Nitroglycerin, by dilating cerebral vessels, also increases intracranial pressure. Nitroglycerin will decrease pulmonary vascular resistance but tolerance develops rapidly. It also inhibits hypoxic pulmonary vasoconstriction. The correct answer is: Nitroglycerin

Carvedilol (Coreg)

Non-selective beta antagonist + alpha 1 antagonist Oral medication for managing heart failure, left ventricular dysfunction after MI, and HTN

A 78 year old male is admitted to the hospital for hypotension and low grade fever with an elevated lactate level. He has been complaining of worsening lower abdominal pain over the past several days but has not had this complaint medically evaluated. His family practice physician admits this patient to the medical intensive care unit with a presumptive diagnosis of sepsis. Your anesthesia service is consulted to provide expert opinion on ventilator management and pharmacologic support of the critically ill. The physician requests your opinion on what agent would best increase cardiac output and increase systemic vascular resistance without providing beta 2 agonism. Which of the following drugs would be the best choice for this? Select one: a. Norepinephrine b. Epinephrine c. Dobutamine d. Dopamine e. Isoproterenol

Norepinephrine is an endogenous catecholamine. It is frequently used to treat serious low blood pressure states such as sepsis and other forms of shock. It has beta 1 effects similar to epinephrine, but unlike epinephrine it does not have beta 2 effects. It is a very potent arterial and venous vasoconstrictor causing increased systemic vascular resistance through alpha 1 agonism. Infusions of 4-16 mcg/min are used to treat hypotension as seen during cardiac surgery or after resection of a pheochromocytoma. A decrease in cardiac output is seen as decreased venous return and reflex bradycardia occurs with norepinephrine, but there are increases in systolic and diastolic blood pressures. Vasoconstriction can be so great that tissue ischemia and death can occur distally. Liver, kidneys, and skeletal muscles all see intense vasoconstriction with decreased blood flows. The correct answer is: Norepinephrine

Nicotinic cholinergic receptors

On cell bodies of all post ganglionic neurons, within ganglia of both SNS and PNS ACh (or nicotine) will excite both systems (SNS and PNS) Low dose--adrenal medulla--epi, NE-- HTN tachycardia High dose--ganglionic blocker--hypotension, weakness Neuromuscular junction also has n-ACh-R --Blocked by non-depolarizing neuromuscular blocking agents

Muscarinic cholinergic receptors

On cell membranes of effector tissues ACh (or muscarine) will mimic the PNS Excitatory OR inhibitory, depending on the target tissue NOTE: m-ACh-R also on pre-synaptic membrane of sympathetic (SNS) nerve terminals -->Stimulation inhibits the release of NE

Alpha 1 adrenergic receptors

Only found on post-synaptic membrane--most abundant Excitatory receptor--increased intracellular Ca2+ Smooth muscle of coronary arteries, skin, uterus, intestines, renal/splanchnic beds Vasoconstriction and GI relaxation Cardiac contractility

Beta 1 adrenergic receptors

Only post-synaptic Mostly in the heart: INC HR, contractility, renin release; coronary dilation Affinity for epi = NE

Minoxidil

Oral medication, action like hydralazine (reflex tachycardia) Used for the most severe forms of hypertension Fluid retention, edema, pericardial effusion Hypertrichosis = hair growth (minoxidil = Rogaine)

Parasympathetic nervous system

PNS Cholinergic= rest and digest Also known as the cranio-sacral system Vagus nerve (CN X) accounts for >75% of all parasympathetic fibers Pre-ganglionic neurons originate in brainstem or sacral segments of the spinal cord PNS ganglia are on or near the target organ Ratio of pre- to post-ganglionic fibers is close to 1:1, thus parasympathetic effects are more discrete and localized than sympathetic effects (ie no parasympathetic mass discharge) Release of acetylcholine (ACh) at effector tissues ACh is removed from the vicinity of the receptor by acetylcholinesterase (<1 msec)

Autonomic nervous system

Part of the nervous system that regulates cardiac/smooth muscle, visceral and gland function --subconscious functions and reflexes--involuntary --influences homeostasis of virtually every tissue and organ system--using only 3 substances! Two separate divisions of the ANS: Sympathetic nervous system (SNS)= adrenergic (adrenalin=epi) Parasympathetic nervous system (PNS)= cholinergic (acetylcholine) Both SNS and PNS are tonically active- have baseline activity that can increase or decrease--Thus there is more than one way to accomplish an effect with precision

Synthesis of endogenous catecholamines

Phenylalanine-->Tyrosine-*->DOPA --> DA --> NE --> Epi *Tyrosine hydroxylase- this enzyme is the rate limiting step NE causes negative feedback at this point Almost all endogenous NE undergoes re-uptake into the pre-synaptic terminal **Tricyclic antidepressants (TCAs) and cocaine inhibit NE re-uptake-->leads to high plasma levels of NE Can then be metabolized by monoamine oxidase (MAO)

Phenylephrine (Neo-Synephrine)

Predominantly direct alpha 1- agonist (pure alpha) Primary effect: peripheral vasoconstriction (venous and arterial) Increased venous return and stroke volume (preload) Reflex bradycardia (vagal reflex--probably mediated through baroreceptors) --THUS, CO is not changed in most patients Increased coronary blood flow Dec renal perfusion at higher infusion doses Tachyphylaxis--requiring upward titration of infusion, but more common with ephedrine

Beta 2 adrenergic receptors

Primarily post-synaptic Tend to be inhibitory: vasodilation; bronchodilation; renal vessel relaxation Affinity for Epi > NE; stimulated by circulating epi instead of direct sympathetic activity Some cardiac effects: INC HR and contractility Also some pre-synaptic: accelerates NE release; vasoconstriction

Beta 2 receptors (M&M)

Primarily postsynaptic adrenoceptors located in smooth muscle and gland cells. They share a common mechanism of action with beta 1 receptors: adenylate cyclase activation. Despite this commonality, Beta2 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 beta2 receptor activation. Beta 2 agonists also activate the Na-K-ATPase pump which drives potassium intracellularly and can induce hypokalemia and dysrhythmias

Dobutamine (M&M)

Primary cardiovascular effect is a rise in cardiac output as a result of increased myocardial contractility. A decline in peripheral vascular resistance caused by beta 2 activation usually prevents much of a rise in arterial BP. LV filling pressure decreases, whereas coronary blood flow increases. Favorable effects on myocardial oxygen balance are believed to make dobutamine a good choice for patients with the combination of congestive heart failure and coronary artery disease, particularly if PVR is elevated.

Central Nervous system and ANS

Principal site of organization in the hypothalamus, brainstem, spinal cord Vagus nerve (CN X) transmits sensory input from the thoracic and abdominal organs Regulation of HR, BP, GI system, temperature, hunger, thirst, osmolarity, gland secretions (Ex: baroreceptor reflex) --Emotional responses (blushing, fainting, anxiety): cortex, limbic system

ACEI and GA

Prolonged hypotension observed under general anesthesia Consider holding medication for 24 + hours before surgery

Atropine

Prototype muscarinic blocker Sympathomimetic activity

Angiotensin Converting Enzyme Inhibitors

Renin-Angiotensin-Aldosterone Pathway Free from many common side effects seen with other anti-hypertensive agents (depression, insomnia, sexual dysfunction, electrolyte imbalances) First line therapy for systemic hypertension, CHF May reverse LVH Improved outcomes in diabetics DEC plasma aldosterone = reduced Na and water retention Enalapril (Vasotec), Quinapril (Accupril), Lisinopril (Zestril), Ramipril (Altace) Side effects: cough, allergic-like symptoms (due to bradykinin accumulation?) Decreased glomerular filtration in renal dysfn Possible hyperkalemia due to DEC aldosterone Allergy: Angioedema Renal Excretion

Sympathetic nervous system

SNS Adrenergic Fight or Flight Also known as the thoraco-lumbar system Short pre-ganglionic fibers (T1-L3) originate from the spinal cord--sympathetic ganglia Paravertebral sympathetic ganglionic chain--paired (one on each side) -->Pre-ganglionic fiber can synapse with post-ganglionic neuron at the same level, or fibers can course up or down the ganglionic chain and synapse at another level Sympathetic collateral ganglia (celiac plexus, inferior mesenteric plexus)- unpaired T1-T4 form special paired ganglia (superior cervical, middle cervical, stellate) SNS ganglia are closer to spinal cord than to the target organ

All of the following side effects can occur with the administration of scopolamine except: Select one: a. Increased secretions b. Retrograde amnesia c. Delirium d. Sedation e. Increased HR

Scopolamine has a strong antisialogogue effect and will decrease secretions. The correct answer is: Increased secretions

Dobutamine (altose)

Selective beta 1 agonist Inc CO due to contractility = INOTROPE Coronary vasodilation Tachycardia--increases myocardial O2 demand Potential to cause arrhythmias, esp at higher doses (>10 mcg/kg/min) Weak beta 2 activity --some pulmonary vasodilation --systemic vasodilation (DEC SVR and hypotension) Some alpha 1 activity (unmasked when a beta-blocker is given--HTN) Dose 2-20 mcg/kg/min Fast onset and short acting

Milrinone (Primacor)

Selective phosphodiesterase inhibitor (PDE) Non adrenergic Inhibition of cardiac PDE III--> increased myocardial cAMP--facilitate inward movement of Ca2+ Positive inotropic effect + vascular/airway smooth muscle relaxation = INODILATOR Minimal effect on HR and myocardial O2 demand Also an effective pulmonary vasodilator Significant effect on SVR--HYPOTENSION Dose 50 mcg/kg over 10 min followed by 0.5 mcg/kg/min infusion Slow onset (5-15 min) and offset: elimination half time= 2.7 hours Excreted by the kidneys (caution in patients with severe renal disease)

inhaled nitric oxide

Selective pulmonary vasodilatory, bronchodilation, improved V/Q matching Used to treat: pulmonary hypertension, ARDS/ acute lung injury NO combines with Hgb to form met-Hgb (monitor met-Hgb levels)

Dopamine M&M

Small doses (approximately 2 mcg/kg/min) of dopamine have minimal adrenergic effects but activate dopaminergic receptors. Stimulation of these nonadrenergic receptors (specifically DA1 receptors) vasodilates the renal vasculature and promotes diuresis. Commonly used in the treatment of shock to improve cardiac output, support BP, and maintain renal function. It is often used in combination with a vasodilator (eg, nitroglycerin or nitroprusside) which reduces afterload and further improves cardiac output.

Atropine

Tertiary amine Cardiac: first choice for bradyarrhythmias Sd effect: tachycardia Caution in CAD (increased O2 demand) Pulmonary: inhaled derivative: ipratropium (atrovent)--minimal systemic absorption due to quaternary ammonium structure Neuro: can cross the BBB Usually minimal effect Can cause memory deficits, CNS excitement Central anticholinergic syndrome-treat with physostigmine (crosses BBB) Anti-sialagogue--decrease salivation/oral secretions CAUTION in narrow angle glaucoma and BPH Usual adult dose: 0.4-0.6 mg IV (may need 1-2 mg for total vagal blockade) Duration of action ~30 min

Scopolamine

Tertiary amine More potent anti-sialogogue than atropine greater CNS effects than atropine--sedation/amnesia Anti-emetic (patch commonly used for PONV) CAUTION in narrow angle glaucoma, elderly patients

How is the action of norepinephrine primarily terminated?

The action of norepinephrine is primarily terminated by reuptake into the post-ganglionic nerve ending This is inhibited by tricyclic antidepressants! Action also terminated by diffusion from receptor sites, or via metabolism by monoamine oxidase (inhibited by MAOIs)

Ephedrine (M&M)

The cardiovascular effects of ephedrine, a noncatecholamine sympathomimetic are similar to those of epinephrine: increase in BP, HR, contractility, and CO. Ephedrine is also a bronchodilator!!! There are important differences between ephedrine and epi: ephedrine has a longer duration of action, is much less potent, and stimulates the central nervous system (raises MAC). The indirect agonist properties of ephedrine may be due to peripheral postsynaptic NE release, or by inhibition of NE reuptake. Administration should be viewed as a temporizing measure while the cause of hypotension is determined and remedied.

Beta 1 receptors (M&M)

The catecholamines norepinephrine and epinephrine are equipotent on Beta1 receptors but epinephrine is significantly more potent than norepinephrine on beta 2 receptors. The most important beta 1 receptors are located on the postsynaptic membranes in the heart. Stimulation of these receptors 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)

Altose comments on adrenergic agonists and other sympathomimetics

There is varying selectivity (specificity) for various adrenergic receptors There can be overlapping activity at different receptors Balance of activity can shift at different doses

Post-ganglionic fibers originate in the sympathetic ganglion and go to effector tissues:

Travel within spinal nerves outnumber pre-ganglionic fibers 20-30:1 Allows concurrent stimulation of many organs at once= mass sympathetic discharge Release of NOREPINEPHRINE at effector tissues (exception: sweat glands ACh and adrenal medulla epi + NE)

In which of the following patients will use of the drug vasopressin LEAST likely to provide benefit to the patient? Select one: a. Hypotensive patient having inferior myocardial infarction b. Patient in anaphylactic shock c. Patient in ventricular fibrillation d. Patient in septic shock e. Patient with diabetes insipidus

Vasopressin is least beneficial in a hypotensive patient having inferior myocardial infarction. Vasopressin causes increased systemic and pulmonary blood pressures through vasoconstriction in vascular smooth muscles. It also causes selective vasoconstriction of coronary arteries that can lead to ischemia or infarction, even in lower doses. Vasopressin is a drug used to provide the pharmacologic effects of the body's own arginine vasopressin. It has many useful functions, including in the treatment of diabetes insipidus, hypotension, septic or hypovolemic shock, and in the ACLS pathway for cardiac arrest (replaces a dose of epinephrine). Treatment of diabetes insipidus with vasopressin is beneficial as vasopressin replaces the body's normal release of endogenous vasopressin causing antidiuretic effects through increases in cAMP at the renal tubules. In diabetes insipidus, arginine vasopressin is either not produced (due to hypoperfusion after trauma) or the kidney nephron does not appropriately respond to its presence. Patients with hypotension that is refractory to conventional treatment may also benefit from vasopressin. Studies have shown vasopressin is useful to treat refractory hypotension in patients with catecholamine resistant shock (sepsis), in anaphylaxis, and in patients with depleted catecholamine stores. Infusion of vasopressin also has use in the treatment of esophageal varices as it can greatly decrease hepatic blood flow and cause splanchnic vasoconstriction, decreasing bleeding from the varices. Treatment of hypotension and variceal bleeding requires higher doses than is used in the therapy for diabetes insipidus. The vasoconstriction is a direct effect that is not antagonised by adrenergic blockade. Vasopressin also does not have any inotropic or chronotropic effects. Gastrointestinal side effects including nausea and abdominal pain are not uncommon.

Your 17 year old male patient is having an uneventful surgical hernia repair when you notice a sudden rise in body temperature and in end tidal CO2. You determine this condition to require immediate treatment with a calcium channel blocker and pharmacological support. Which of the following combination of drug treatments could potentially lead to hyperkalemia and cardiovascular collapse in this patient? Select one: a. Calcium and dantrolene b. Furosemide and sodium bicarbonate c. Diltiazem and insulin with glucose d. Dantrolene and sodium bicarbonate e. Verapamil and dantrolene

Verapamil theoretically would be beneficial in malignant hyperthermia patients as it works to decrease the influx of calcium. As dantrolene also inhibits calcium release from the sarcoplasmic reticulum, one would think this combination would be of benefit to the patient. However, no improvement in outcomes has been demonstrated with this combination. In addition the administration of diltiazem or verapamil has resulted in hyperkalemia and cardiac arrest. Thus calcium channel blockers are contraindicated in malignant hyperthermia. Dantrolene is the drug of choice to treat this condition. Hyperkalemia should be monitored by watching for peaked T waves - treatment should be administered through the use of calcium, insulin with glucose, and sodium bicarbonate. The correct answer is: Verapamil and dantrolene

Phentolamine

alpha antagonist nonselective Produces a competitive (reversible) blockade of both alpha1 and alpha2 receptors. Alpha1 antagonism and direct muscle relaxation are responsible for peripheral vasodilation and a decline in arterial bp. The drop in bp provokes reflex tachycardia!! This tachycardia is augmented in the heart because alpha2 blockade promotes NE release by eliminating negative feedback

Sympathetic collateral ganglia

celiac, superior mesenteric, inferior mesenteric UNPAIRED

Endogenous catecholamines

epinephrine, norepinephrine, dopamine--have sympathetic activity Dopamine: CNS neurotransmitter Norepinephrine: synthesized/stored in post-ganglionic neurons and adrenal medulla Epinephrine: synthesized/stored in adrenal medulla

Dexmedtomidine

even more highly selective alpha 2 agonist than clonidine (A2:A1 = 1,620:1) Used primarily for sedation, but does cause hypotension as a side effect

Vasopressin

non-adrenergic sympathomimetic--activation of smooth muscle V1 receptors Exogenous version of ADH (antidiuretic hormone, secreted from the pituitary gland) --Induces reabsorption of water from renal collecting ducts-->extracellular fluid --Used in treatment of diabetes insipidus (lack of ADH secretion) Can be used to support BP in septic shock, cardiac arrest, post-CPB vasoplegia, interaction between ACE-I and general anesthesia Effective vasoconstrictor (binds to vascular smooth muscle) IV bolus dose (ACLS) 40 units (not in the latest guidelines) Continuous infusion: 2-4 units/hr Other notes: Vasoconstriction of skin, skeletal muscle, intestine and adipose tissue Decreases splanchnic blood flow (may elevate liver enzymes)--abdominal/uterine cramping, nausea Lactic acidosis may develop Actions may be better preserved during hypoxia and acidosis, unlike catecholamines Thru central access only (extravasation--tissue necrosis)

Esmolol (Brevibloc)

ultra short acting beta 1 selective antagonist beta 2 antagonism at higher doses prevent tachycardia/hypertension during intubation, emergence, ECT Rapid redistribution (2 min) and ester hydrolysis (9 min) RBC esters? Not Plasma cholinesterase Bolus dose: 0.25-0.5 mg/kg IV infusion: 50-200 mcg/kg/min