1. health and fitness
2. disease

Vasopressors & Inotropes
PCTH 400 – Systematic Pharmacology
Donald Griesdale ([email protected])
Objectives
1.
2.
3.
Understand the basic mechanism of action of vasopressors & inotropes
Define shock and have describe the approach to the patient in shock
Describe the use of vasopressors & inotropes in different shock states
Vasopressors & Inotropes
Definitions1,2
 Vasopressor are agents which increase vascular tone and
systemic vascular resistance (SVR)
 Inotropes are agents that alters alter myocardial contractility. A
positive inotrope increases myocardial contractility and cardiac
output. A negative inotropes decrease contractility and cardiac
output.
 Lusitropes are agents which improve myocardial relaxation and
improve myocardial filling. This is mediated by phosphorylation
of phospholamban and troponin I via cAMP-dependent
pathways.
Catacholamines2
 Primarily mediate their effects through 1, β1 and β2 receptors
 1 receptors stimulate contraction of vascular smooth muscle
with ↑SVR
 β1 receptors ↑ myocardial contractility (Ca2+ mediated
facilitation of actin-myosin complex binding with troponin C)
and ↑ chronicity (heart rate) through Ca2+ cannel activation
 β2 receptors on vascular smooth muscle increase Ca2+ uptake
by sarcoplasmic reticulum and vasodilation with ↓ SVR
 Dopaminergic receptors (D1 & D2) in kidney and splanchnic
vasculature results in renal and mesenteric vasodilation
Dopamine: Immediate precursor to norepinephrine. Acts on both
adrenergic and dopaminergic receptors. At low-dose (0.5 – 3.0
g/kg/min), primarily D1 receptors (renal, mesenteric, cerebral
and coronary beds) leading to vasodilation. Intermediate doses (3
– 10 g/kg/min), also stimulates β1 receptors. At higher doses (10
– 20 g/kg/min), stimulates 1 receptors. Dopamine is used
clinically for cardiogenic shock and septic shock.
Table 1 Relative receptor binding for commonly
used agents
Agent
Dopamine
Dobutamine
Epinephrine
Norepinephrine
Isoproterenol
Phenylephrine
Vasopressin
Receptor Binding
+++
1
+++
β1
++
β2
+++++
DA
+
1
+++++
β1
+++
β2
+++++
1
++++
β1
+++
β2
+++++
1
+++
β1
++
β2
0
1
+++++
β1
+++++
β2
+++++
1
0
β1
0
β2
V1: vascular smooth muscle
V2: renal collecting duct
Modified from Garg & colleagues1
References
1. J Pulm Respir Med 2013;02(5):2–5.
2. Circulation 2008;118:1047–56.
3. N Engl J Med 2013;369:1726–34.
4. Clin Chest Med 2003;24:775–89.
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Epinephrine is a direct acting catecholamine used for shock
(cardiogenic, distributive), cardiac arrest, bronchospasm,
anaphylaxis or bradycardia.
Norepinephrine is used primarily in septic shock. Preserves cardiac
output in the setting of 1 stimulation because of its beta effects.
Minimal chronotropic effect.
Figure 1: Clinical approach to vasoactive
therapy. Note that -agonists have a
vasopressor effect (pressure) and βagonists have an inotropic effect (flow).
Taken from Holmes et al.4
Dobutamine is a synthetic analogue of dopamine. Predominantly
an inotrope in cardiogenic shock. Significantly increases
myocardial oxygen consumption.
Phenylephrine is a direct acting 1 agonist leading to
vasoconstriction. Used primarily for rapid correction of
hypotension (e.g. intraoperatively). Because it lacks any direct
cardiac effects, it can induce significant baro-receptor mediated
reflex bradycardia.
Side Effects of catecholamines include: arrhythmias,
tachycardia/bradycardia, cardiac ischemia, hypertension,
peripheral ischemia.
Vasopressin (aka antidiuretic hormone – ADH) is an endogenous
hormone stored and released from the posterior pituitary gland.
Stimulation of V1 receptors on vascular smooth muscle leads of
peripheral and splanchnic beds leads to ↑SVR. V2 receptor
stimulation increases water reabsorption in the renal collecting
duct. It is used clinically for septic shock and cardiac arrest.
Milrinone is a phosphodiesterase inhibitor inhibit the breakdown
of cAMP in cardiac and vascular smooth muscle. This increases
activation of protein kinase A which in turns leads to
phosphorylation of Ca2+ channels and increases myocardial calcium
influx. This ↑myocardial contractility, improves myocardial
relaxation (lusitropy) and ↓SVR. The net results are ↑cardiac
output. Milrinone is primarily used for cardiogenic shock.
Shock
“Shock is the clinical expression of circulatory failure that results in
inadequate cellular oxygen utilization”3
Figure 2: Shock occurs when the
oxygen demand is higher than the
oxygen supply
 Affects about 1/3 of patients in the intensive care unit
 Often associated with hypotension (systolic blood pressure < 90
mmHg or mean arterial pressure < 70 mmHg).
 Clinical signs of tissue hypoperfusion
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Determinants of Stroke Volume
1. Preload: volume returning to the heart
2. Contractility: muscular contractility of the heart
3. Afterload: load against which the heart contracts
Table 2: Determinants of MAP
Pressure = Flow x Resistance
MAP = CO x SVR
CO = SV x HR
Types of Shock & Clinical Manifestations
1. Hypovolemic shock occurs when there is inadequate venous
return to the heart. This can be hemorrhagic or nonhemorrhagic (e.g. burns, GI or renal losses, lack of intake).
Clinically, the jugular venous pressure (JVP) is low and there
are signs of hypoperfusion (altered mentation, poor urine
output and cool, mottled extremities). Treat with fluids.
2. Cardiogenic shock (pump failure) can be due to loss of
contractility (myocardial infarction), impaired diastolic
filling, abnormal rate or rhythm, or valvular abnormalities.
Clinically, the JVP is elevated and there are clinical signs of
hypoperfusion. Furthermore, obstructive causes of shock
(pulmonary embolism, pericardial tamponade, and
pneumothorax) have similar presentation to cardiogenic
shock. Treat with dobutamine or milrinone.
MAP = mean arterial pressure
CO = cardiac output
SVR = systemic vascular resistance
SV = stroke volume
HR = heart rate
Figure 3: Differential of shock
3. Distributive shock occurs with widespread vasodilation
(↓SVR). This occurs in sepsis, anaphylaxis, medication
overdose (e.g. propofol, inhaled anesthetics), neurogenic
shock (spinal cord injury) and adrenal insufficiency.
Clinically, the JVP is often low and there is evidence of warm
skin with hyperdynamic pulses. Treat with norepinephrine.
Table 3: Clinical assessment of shock
Organ
Perfusion
(CO)
Filling
Pressure
(JVP)
Hypovolemic
↓
↓
Cardiogenic
↓
↑
Distributive
↑
↓
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