Advanced Cardiovascular Pharmacology Update JOHN SHIELDS, DNP, CRNA
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