Advanced Cardiovascular

Pharmacology UpdateJOHN SHIELDS, DNP, CRNA

Systemic Circulation

BP=CO x SVR

CO dependent on

o Stroke volume

o Preload

o Contractility

o Afterload

o Heart rate

Vascular tone

Blood viscosity

Pulmonary Circulation

Pulmonary vessels are very thin-walled

o Pulmonary circulation resembles venous capacitance vessels

o Diversion of blood from one region to another is facilitated

▪ Recruitment

▪ Distension

▪ HPV

RV function is very afterload dependent

Biventricular Circulation

Management

LV failure managed differently

than RV failure

LV is a stupid pump

o Inotropes

o Volume manipulation via Frank-

Starling Curve

o Ohm’s Law

RV is a bellows that responds best

to contractility drugs and

afterload reduction

o Inodilators

o Ventilation

Drugs Used to Treat Low Systemic

Cardiac Output/HypotensionVasopressors

Alpha-adrenergic drugs

Mixed agonists

Vasopressin

Methylene blue

Other

Inotropes

Beta-adrenergic drugs

Mixed agonists

PDE III

Digitalis

Calcium

Glucagon

Triiodothyronine

Levosimendan

Other

Alpha-Adrenergic Receptor

Pharmacology

Alpha-1 activation results in

increased calcium and

contraction of vascular

smooth muscle (IP3)

Effects include

vasoconstriction, intestinal

relaxation, pupillary dilation

Theory evolving regarding

multiple alpha receptors

Beta-Adrenergic Receptor

Pharmacology

Beta-1 activation results in

chronotropic and inotropic

effects (cAMP)

Counterpart to vagal

system via SNS

Beta-2 activation affects

vascular and pulmonary

smooth muscle

Vasopressin Receptor

Pharmacology

V1 receptor activation results in

IP3 signal pathway and

contraction of vascular smooth

muscle

Effects include vasoconstriction,

similar to alpha with weak

inotropic effect

Side effects include myocardial

ischemia and reduction in

splanchnic blood flow

Dopamine Receptor

Pharmacology

Unique in ability to simultaneously increase

o Myocardial contractility

o Renal/mesenteric blood flow

o GFR, excretion of sodium

o UOP

Dose-dependent pharmacodynamics and effect on cAMP and Ca++

PDE-3 Receptor Pharmacology

cAMP increases contractility

PDE3 breaks down cAMP to

AMP

Inhibition of PDE3 increases

cAMP levels and increases

o Contractility (inotropy)

o Heart rate (chronotropy)

o Conduction velocity (dromotropy)

Calcium Receptor

Pharmacology

Changes in force of

contraction and SVR result

from incremental degrees of

binding between myosin

and actin

Degree of binding depends

on calcium ion

concentration in the cell

Catecholamines affect the

concentration of calcium in

the cell

Muscarinic Receptor Pharmacology

Parasympathetic blockade or

activation can mediate SA node

firing and resting membrane

potential

Parasympathetic receptor

activation can influence IP3, cAMP

and nitric oxide release

Muscarinic receptor blockade

increases cardiac norepinephrine

spillover when HF is not present

Blunting of parasympathetic

influence on sympathetic activity is

present in HF

Dysrhythmia Pharmacology

Dysrhythmias may be due to

disturbances in automaticity,

conduction and/or re-entry

Etiology may be mechanical,

reflex, pharmacologic,

disease, ion channel or

adrenergic

Treatment should target

action potential and

automaticity

Tachyarrhythmias

Bradyarrhythmias

Altered Impulse

Formation

Altered Impulse

Conduction

Enhanced

AutomaticityRe-Entry

Decreased

AutomaticityConduction

Blocks

Phenylephrine

Sympathomimetic amine,

direct alpha agonist, (?) mild

beta agonist

Indicated for hypotension with

low-normal CO

o Useful in counteracting decrease

in SVR from anesthetic agents

o Useful for drop in SVR from spinal

and epidural blocks

Useful in patients with ischemic

heart disease (no inotropic or

chronotropic effects)

Ephedrine

Mild indirect alpha agonist, direct

beta agonist (causes release of NE

from neurons)

Indicated for hypotension with low

CO and low HR

Efficacy is blunted when NE stores

are low, tachyphylaxis (>150 mg)

CV effects of ephedrine resemble

those of epi, but BP ↑ is less intense

and lasts about 10x longer

Vasopressin

Produces direct peripheral

vasoconstriction via V1 receptors

Acts independently of adrenergic

receptors

o Useful in refractory hypotension in

sepsis, patients taking ACE inhibitors

o Useful for hypotension refractory to

phenylephrine or ephedrine

o More effective than alpha or beta in

vasoplegic/acidotic state

Minimal decrease in pulmonary

vascular resistance

Dose is 0.5-2 mcg bolus, infusion

0.04 mcg/minute

Calcium

Increases inotropy without

increase in HR

Increases SVR and PVR in

dose dependent fashion

Reverses hypotension due

to volatile, CCB’s,

hypocalcemia, Mg, K+

Provokes digitalis toxicity

Promotes coronary spasm

and pulmonary

hypertension

Anticholinergic Drugs

Block inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate leading to tachycardia

Atropine inhibits acetylcholine-induced decreases in cAMP by acting as an allosteric PDE type 4 (PDE4) inhibitor

o Increase in HR

o Increase in contractility

Glycopyrrolate increases heart rate but has no real effect on contractility

Ruwan et al. Atropine augments cardiac contractility by inhibiting

cAMP-specific phosphodiesterase type 4Sci Rep. 2017; 7: 15222

Norepinephrine

Potent α1-adrenergic receptor agonist

with β-agonist activity almost equal to

epinephrine, no beta 2

Powerful vasoconstrictor with less potent

direct inotropic properties

o Used for hypotension refractory to

phenylephrine

o Used for heart failure in ischemic heart

disease

o Used in sepsis/vasoplegia

May confer risk of ischemia of bowel and

kidneys at higher doses

Bolus 3-12 mcg/infusion rate 2-30

mcg/minute

Epinephrine

Increases cardiac inotropy and

chronotropy, but alpha effects

predominate at higher doses

o 0.003-0.02 mcg/kg IV for refractory

hypotension/CHF (10-20 mcg)

o Infusion start at 2 mcg/minute for

CO, up to 5 mcg/minute for

hypotension/CHF

Very effective bronchodilator

but also enhances

gluconeogenesis and elevated

lactate

Tachycardia, dysrhythmias and

lactate are dose limiting effects

Dobutamine

Direct beta-1 adrenergic agonist,

limited beta-2 and alpha-1

Higher safety index than epinephrine

Very mild vasodilation, no effect on

glucose

Increases CO with less of an increase

in MVO2 and heart rate

Low cardiac output states, especially

with high SVR or PVR

Excellent drug for right ventricular

failure

Dose as infusion is 2-20 mcg/kg/min

Dopamine Receptor

Pharmacology

Direct alpha 1, beta 1, beta 2

and dopaminergic (DA1)

Indirect release of stored

neuronal NE

Dose response relationship

between DA1, beta-1 and

alpha-1

0.5 – 2 g/kg/min renal vasodilation, ↑ GFR and Na++ excretion (dopamine 1 receptors)

2 – 10 g/kg/min beta1 agonism cardiac contractility and output are increased (beta 1 receptors)

> 10 g/kg/min alpha1 and beta1agonism, alpha-adrenergic vasoconstriction and benefit to renal perfusion may be lost

Digitalis

Positive inotropic effect but minor

compared to catecholamines

and others

Digitalis works by inhibiting sodium-potassium ATPase, and

increases calcium availability by

increasing intracellular sodium

(less extrusion of calcium)

Therapeutic effects develop at

approximately 35% and dysrhythmias typically manifest at

approximately 60% of the fatal

dose

Methylene Blue for

Vasoplegia

Methylene blue seems to be

a potent approach to

refractory vasoplegia

Nitric oxide is a mediator of

systemic inflammatory

response and is inhibited by

methylene blue

Useful when high doses of

norepinephrine are required

1-2 mg/kg over 20”, 1

mg/kg/hr infusion

Steroids??

Hydrocortisone 200 mg every 8 hours for vasoplegia

May reduce catecholamine requirements

Indicated only if adequate fluids and vasopressor use ineffective

Lack of consistent evidence for outcomes

Milrinone

Useful if other receptors are

down-regulated or

desensitized (chronic heart

failure)

High utility with RV dysfunction

Longer half-life (2 hours) than

other inotropes

Milrinone is an inodilator, and is

used at 0.25-0.75

mcg/kg/minute

Mild vasodilation occurs unless

administered as a bolus

(profound > 1 mg)

Isoproterenol

Profound beta-1 affinity,

causing increased heart rate

and contractility

o Bradycardia not responsive

to atropine

o AV block, beta blocker

overdose

Binds to beta-2 receptors to

produce vasodilation

Used clinically for transplanted

heart and electrophysiology

for testing of re-entrant

pathways

Levosimendan

Pharmacology

Increased intracellular calcium may impair relaxation, increase MVO2 and ischemia

Levoisimendan increases contractility and vasodilates

o Increases troponin sensitivity to

calcium

o Activates adenosine triphosphate K+

channels causing vasodilation and

myocardial protection

o Cardiac output increased with

decreased SVR and PVR

Loading dose of 6–12 µg/kg over 10 minutes

Continuous 24-hour infusion of 0.05–0.2 µg/kg/min

Nicardipine

Does not decrease myocardial contractility

Mild suppression of automaticity and conduction

Selective for vascular smooth muscle, especially coronary and cerebral

Dose 50-200 mcg bolus, 1-15 mg/hour infusion

Onset 2 minutes, half-life 40 minutes

Clevidipine (Cleviprex)

Ultra-short-acting (5”)

Little or no effect on

contractility or conduction

Arterial only (no venous dilation

or effect on filling volumes)

Contraindicated in egg/soy

allergies, aortic stenosis, HOCM

Typical initial dosing is 1-2

mg/hour

Epoprosterenol

Potent peripheral

vasodilator of all vascular

beds; also prevents

platelet aggregation

Used primarily to decrease

pulmonary vascular

resistance without

affecting SVR (inhaled)

50/ng/kg/min inhaled via

nebulizer in circuit

2 ng/kg/min IV infusion

pump over 24-48 hours

Nitric Oxide

Selective pulmonary vasodilation (more than epoprosterenol)

Adverse effects include

o Cytotoxic oxygen free radicals

o Antiplatelet effects

o Distraction from patient care

Start at 20 ppm (range 2-80 ppm)

Temporary use only (less than 5 days)

Inhaled Milrinone

Inhaled milrinone offers

pulmonary selectivity, thereby

avoiding systemic side effects

More effective pulmonary

vasodilation than by infusion

Administered via nebulizer as

rescue drug

Single dose of inhaled

milrinone 5 mg (1 mg/ml)

administered over 5 minutes

via a jet nebulizer with bypass

flow of 10 L/minute

Nesiritide

Recombinant human B-type natriuretic peptide

Significant decrease in right and left ventricular filling pressures and systemic vascular resistance

Increase in stroke volume and cardiac output without a change in heart rate

Counteracts the effects of renin-angiotensin aldosterone system

Nitroglycerin and Other Nitrates

Enter smooth muscle and

are converted to nitric

oxide (NO)

Smooth muscle relaxation

results in vasodilation

Enhances myocardial

oxygen delivery and

reduces demand

Starling Curve

manipulation also utilized

Glucagon

Increased inotropy and

chronotropy

Dose 2-5 mg IV

Duration 30”

Mechanism of action is a

combination of calcium

sensitization, adenylyl

cyclase stimulation

(increased cAMP) and

phosphodiesterase

inhibition

Extracorporeal Membrane

Oxygenation (ECMO)

Two types

o Venovenous (VV)

o Venoarterial (VA)

Heat exchanger and

oxygenator

Useful for oxygenation

and heart failure

Higher risk of

embolization

Electrophysiologic Changes of

AnestheticsDrug Action Effects

Inhalational Antagonize calcium and potassium

channels; inhibit repolarization;

increases depolarization in Purkinje

fibers

Junctional rhythm, AV

dyssynchrony, increased

automaticity and sensitivity to

epinephrine/SNS

Propofol Stimulate muscarinic receptors vs.

calcium channel blockade

Bradycardia, lowers DBP

Succinylcholine Activate muscarinic receptors Tachycardia, bradycardia, PVC’s,

PAC’s, asystole, VT, VF

Vecuronium Decrease automaticity ? by

sympathetic blockade

Bradycardia and junctional

rhythm

Local

anesthetics

Block sodium channels, ? calcium

channelsWidening of QRS, prolonged QT,

VF

Opioids Decrease SA node frequency,

prolong AV conduction?Bradycardia

Ketamine Increase SA node frequency by

sympathetic activationTachycardia, dysrhythmias

Dexmedetomidi

ne

Sympathetic blockade Bradycardia, heart block,

conduction

Neostigmine Muscarinic activation Bradycardia, heart block

Risk Factors for DysrhythmiasModifiable Non-Modifiable

Potassium

disturbance

Dilated cardiomyopathy

Magnesium

disturbance

Ischemic cardiomyopathy

Surgical procedure Hypertrophic cardiomyopathy

Myocardial ischemia Autonomic changes of the conduction

system

Heart failure Hyperthyroidism

Drug therapies Congenital long QT syndrome

Respiratory

dysfunction

Congenital cardiac disease

Acid-base imbalance Ion channel modulation

Hypothermia Renal failure

Vaughn Williams Classification of

Antidysrhythmics

Class I (Na+

channel blockers)

o Class Ia

o Class Ib

o Class Ic

Class II (Beta

Blockers)

Class III (Potassium

channel blockers)

Class IV (Calcium

channel blockers)

Other

Class I (Sodium Channel

Blockers)

Ia prolong refractory period

Ib shorten action potential and refractory period and phase 0

o Lesser sodium channel blocker

o Effect on abnormal cells greater than normal cells

o Side effects minimal

Ic do not affect refractory period or decrease automaticity in pacemaker cells (propafenone)

Class II (Beta-Adrenergic

Antagonists)

Reduce or block SNS effect on

automaticity

o Depress phase 4 depolarization

o Suppresses supraventricular and

ventricular dysrhythmias

Reduce conduction velocity

Prolongs action potential

Toxicity

o General myocardial depression

o Bronchospasm/Hypoglycemia

Cardioselectivity lost at high doses

SympatheticBeta Blocker

Commonly Used Beta Blockers

Drug Dose Half-Life Comments

Esmolol Bolus 5-20 mg;

infusion

9.5 minutes Beta blocker, excellent drug

during anesthesia and SCIP

Metoprolol Bolus 1-5 mg 3-6 hours Beta blocker, excellent first

line drug (minimal B2)

Sotalol 80 mg PO bid 12 hours Beta blocker, K+ channel

blocker (amiodarone’s

cousin)

Inderal 1-3 mg 4-5 hours Beta-1, beta-2 blocker

Labetalol 2.5-200 mg 2-6 hours Alpha-1, beta-1, beta-2

Blocker (PACU)

Carvedilol 3.25 mg bid 7-10 hours Alpha-1, beta-1, beta-2

blocker (preop)

Recommendations for

Perioperative Beta Blockade

Beta blockers should be continued throughout

perioperative period in patients with IHD

Beta blockers should be titrated intraoperatively to heart

rate and blood pressure in patients at risk for IHD

Value of perioperative beta blockers is unknown for

patients with risk factors for IHD even for vascular surgery

Beta blockers should be avoided in patients who have

absolute contraindications to therapy

Routine administration of high doses of beta blockers is

to be avoided

Class III (Potassium Channel

Blockers)

Block potassium channels and

delay repolarization of fast

channels

Prolong both the action potential

duration, ERP and QT interval

Most drugs in this class (e.g.,

Amiodarone) have multiple actions

and may affect beta receptors or

sodium channels

Previously reserved for serious

dysrhythmias, now first line drug

Class IV (Calcium Channel

Blockers)

Same effect on action potential as beta blockade but preserved ventricular function

Effects include decreased automaticity in SA node and slowed impulse conduction through the AV node

Most effective against supraventriculardysrhythmias

Toxicity may occur with conduction defect

Effects of Calcium Blockade

Blocking calcium channels

o Reduces force of contraction

o Impairs conduction and automaticity

o Relaxes smooth muscle of vascular tree

Primary action on heart

o Diltiazem

o Verapamil

Primary action on arterioles (Dihydropyridines)

o Nicardipine (Cardene)

o Nifedipine (Procardia)

o Nimodipine (Nimotop)

o Amlodipine (Norvasc)

AntidysrhythmicsDrug Bolus Infusion Half-Life Adverse

EffectsLidocaine 1 mg/kg 2-4 mg/min 15-30 min Neurologic at high

doses

Procainamide 100 mg q5” max

17 mg/kg

2 mg/kg/hr 2-4 hrs Decreased CO, BP

Esmolol 5-50 mg 50-200 mcg/kg/min

9 min Decreased CO, HR, BP

Metoprolol 1-10 mg - 3-4 hrs Decreased CO,

HR, BP

Amiodarone 150 mg 1 mg/min 20-100 days Bradycardia,hypotension

Bretyllium 5-10 mg/kg q 30” 5-10 mg/kg q 6’ 6-24 hours Hypotension

Diltiazem 2.5-20 mg 2.5-15 mg/hr 3-5 hrs Bradycardia,hypotension

Digitalis 0.5 mg - 1.7 days Heart block, brady

Adenosine 6 mg then 12 mg - 2-5 seconds Asystole, hypotension

Epinephrine 0.1-1 mg 1-10 mcg/min 10 min HTN, tachycardia, hyperglycemia

Atropine 0.4-1 mg - 30 minutes Tachycardia

Summary

Cardiovascular

management during

anesthesia is enhanced by

situational awareness and

a quiver full of arrows

The first anesthetic death

was from cardiovascular

collapse not a lost airway

All drugs are poisons and

the enemy of good is

perfect