USE OF VASOPRESSORS AND

INOTROPES
IN THE PHARMACOTHERAPY OF SHOCK

AMALIAH HARUMI KARIM

 Shock is an acute, generalized state of inadequate perfusion of critical organs
that can produce serious pathophysiologic consequences, including death, when
therapy is not optimal

Shock is defined as systolic blood pressure less than 90 mm Hg or reduction of

at least 40 mm Hg from baseline with perfusion abnormalities despite
adequate fluid resuscitation.
 The general goal of therapy during resuscitation from shock is to achieve and
maintain mean arterial pressure (MAP) consistently above 65 mm Hg while
ensuring adequate perfusion to the critical organs.
 Hemodynamic and perfusion monitoring can be categorized into two broad
areas: global versus regional monitoring. Global parameters, such as systemic
blood pressure, oxygen tension, and lactate, assess perfusion and oxygen
utilization of the entire body
 Regional monitoring techniques focus on tissue-specific oxygen delivery and
subsequent changes in functional indices of individual organs
 These measurements include coagulation abnormalities (disseminated
intravascular coagulation), altered renal and/or hepatic function, altered
gastrointestinal perfusion, cool extremities, cardiac ischemia, and altered
sensorium
 VASOPRESSORS AND INOTROPES

Vasopressors and inotropes in patients with septic shock are required when
volume resuscitation fails to maintain adequate blood pressure (MAP more than or
equal to 65 mm Hg) and organs and tissues remain hypoperfused.

Vasopressin and corticosteroids, as they relate to septic shock, also are emphasized
because they have pharmacologic interactions with catecholamine vasopressors,
possess hemodynamic effects, and are frequently used. Other agents such as
phosphodiesterase III inhibitors, naloxone, nitric oxide (NO) synthase (NOS)
inhibitors, and calcium sensitizers have been used as inotropes and vasopressors in
shock states. These therapies are not discussed below as they are rarely used for
septic shock and pharmacologic principles of other shock etiologies are discussed
in other chapters
CATECHOLAMINE RECEPTOR
PHARMACOLOGY
 Comparative receptor activities of endogenous and exogenously administered
catecholamines is summarized in Table 23-3.
endogenous catecholamines are responsible for regulation of vascular and
bronchiolar smooth muscle tone and myocardial contractility. These effects are
mediated by sympathetic adrenergic receptors of the autonomic nervous
system located in the vasculature, myocardium, and bronchioles
 Postsynaptic adrenoceptors are located at or near the synaptic junction. These
receptors can be activated by naturally circulating or exogenous
catecholamines (eg, norepinephrine, epinephrine, and phenylephrine),
whereas presynaptic adrenoceptors are stimulated by locally released
neurotransmitters (eg, norepinephrine) and are controlled by a negative
feedback mechanism.
THE SIGNAL TRANSDUCTION PATHWAYS ASSOCIATED WITH
C ATECHOLAMINE AND VASOPRESSIN -INDUCED EFFECTS IN
THE HEART AND BLOOD VESSELS
Agonists of -adrenoceptors
and dopamine (D1) receptors stimulate
adenylate cyclase by a G-protein (Gs)-
dependent mechanism
Adenylate cyclase generates cyclic
adenosine monophosphate (cAMP) from
adenosine triphosphate (ATP)
cAMP-dependent protein kinase A, which
is activated by elevations in
intracellular cAMP, phosphorylates target
proteins to modify cellular function
PLC- produces inositol trisphosphate
and
diacylglycerol from cell membrane
phosphatidylinositol bisphosphate
Agonists of 1-adrenoceptors stimulate
phospholipase C- (PLC-) through a G-
protein
(Gq)-dependent process
Through these
mechanisms, 1-adrenoceptor activation
exerts positive inotropic and
chronotropic effects in the
heart, and 2-adrenoceptor and D1-
receptor activation induces vascular
smooth muscle relaxation
Diacylglycerol activates
protein kinase C, an enzyme that
phosphorylates several key proteins (eg,
extracellular signalregulated
kinases, c-Jun NH2-terminal kinases, and
mitogen-activated protein kinases) that
modify
cellular function (eg, hypertrophy).
Inositol trisphosphate elicits the release of
calcium from
intracellular stores, such as the
sarcoplasmic reticulum. Calcium forms a
complex with calmodulin,
which then activates calciumcalmodulin-
dependent protein kinases (CaMK
CaMKs phosphorylate
target proteins to alter cellular function.
Myosin light-chain kinase is an example of
a CaMK. Its action
of phosphorylating myosin light chain
leads to vascular smooth muscle
contraction.
 The normal heart contains primarily postsynaptic 1-receptors, which when
stimulated cause increased rate and force of contraction. This effect is
mediated by activation of adenylate cyclase and subsequent generation and
accumulation of cAMP.

Stimulation of postsynaptic cardiac 1-receptors causes a significant increase in

contractility without an increase in rate, an effect mediated by PLC rather than
adenylate cyclase.
 The increased contractility is more pronounced at lower heart rates and
has a slower onset and longer duration in comparison with 1-mediated
inotropic response.
Presynaptic 2-adrenoceptors also are found in the heart and appear to be
activated by
norepinephrine released by the sympathetic nerve itself. Their activation
inhibits further
norepinephrine release from the nerve terminal.
 In critically ill septic patients, derangements in adrenergic receptor activity may result in
resistance to exogenously administered catecholamine

This desensitization frequently is characterized by myocardial and vascular

hyporesponsiveness to high dosages of inotropes and vasopressor agents

Prolonged exposure of vascular endothelial tissue to vasopressor drugs (-adrenergic

agonists) or endogenous catecholamines may promote additional receptor downregulation
 Prolonged exposure of vascular endothelial tissue to vasopressor drugs (-
adrenergic agonists) or endogenous catecholamines may promote additional
receptor downregulation.
Increased endogenous catecholamine concentrations have been reported in
endotoxemic and other critically ill patients, suggesting an acquired adrenergic
receptor defect and desensitization of adrenergic receptors and alteration in
voltage-sensitive calcium channels
 The problem in critically ill patients may be related to decreased receptor activity
or density.
However, in patients with septic shock, catecholamine concentrations are even
higher, so abnormalities in adrenergic receptor function are greater, with associated
reductions in the concentrations of intracellular signal transduction mediators.

The worsened receptor abnormality may be explained by defects distal to the

receptor site, such as uncoupling of adrenergic receptors from adenylate cyclase or
PLC, or dysfunction in the regulatory G-protein unit of signal transduction
pathways.
 In addition to catecholamines, circulating inflammatory cytokines may be partly
responsible for distal alterations.12,42,43 Macrophage-derived IL-1 and tumor necrosis
factor (TNF)- produce impaired coupling of -adrenoceptors to adenylate cyclase.
Patients with septic shock exhibit impaired -adrenergic receptor stimulation of cAMP
associated with myocardial hyporesponsiveness to various vasopressors and inotropes.
However, increased chronotropic sensitivity to -adrenergic stimulation with
hypersensitivity of the adenylate cyclase system to isoproterenol stimulation also has
been reported in animal models of bacteremia and endotoxemia.

In the presence of intrinsic myocardial dysfunction and increased metabolic demands,

this dysfunctional adrenergic system is incapable of mobilizing functional cardiac
reserve to maintain adequate myocardial performance
 IL-1 and TNF- suppress gene expression of 1-adrenoceptors, resulting in fewer receptor
proteins. Overproduction of NO by iNOS directly contributes to vasodilation by cyclic guanosine
monophosphate-mediated smooth muscle relaxation.
NO indirectly produces vasodilation by combining with superoxide to form peroxynitrite, a highly
toxic reactive species that causes endothelial dysfunction, uncoupling of 1-adrenoceptors to PLC,
and deactivation of catecholamines
The result of sepsis-induced inflammation is a system that promotes adrenergic receptor
dysfunction to accentuate vasodilation and shock
 Functional 1-adrenergic receptor changes occur at various stages of sepsis;
thus, adrenoceptor sensitivity may be time dependent during progression of
sepsis to septic shock
The findings are not always consistent in various animal models of sepsis and in
critically ill septic patients.Time-dependent alterations in the production of
NO, a potent vasodilator, may explain the apparent differences in vascular
reactivity to phenylephrine during the phases of endotoxemia. Furthermore, -
adrenergic receptor changes are present within 24 to 48 hours of septic shock.
T
 These findings suggest that the clinical response to vasopressors and possibly
inotropic agents is variable during the stages of hemodynamic, myocardial, and
peripheral vascular derangements of septic shock.

In summary, - and -adrenergic receptor derangements may vary among

patients and during each bacteremic insult; therefore, dose responsiveness of
catecholamines vary among patients and during the
insult.6,7,8,9,10,11,12,39,42,43
For these reasons, these drugs should be dosed to clinical end points and not
to arbitrary maximal dosages. High dosages are frequently required.
 Norepinephrine is a combined - and -agonist that produces vasoconstriction
primarily via its more prominent -effects on all vascular beds, thus increasing
SVR.
Norepinephrine administration generally produces either no change or some
increase in CO.
Norepinephrine is considered the first-line option for initial vasopressor
therapy of septic shock.
 Epinephrine exerts combined - and -agonist effects.6,7,8,9,10,11,12,42,51,52 At the high
epinephrine infusion rates used for patients with septic shock, predominantly -adrenergic
effects are
observed, and SVR and MAP are increased. While epinephrine traditionally has been reserved
as the
vasopressor of last resort due to peripheral vasoconstriction, particularly in the splanchnic and
renal
beds, it is considered second-line therapy in septic shock according to the current guidelines.6
It is
commonly used in other countries where other agents may not be readily available or are
relatively
expensive.
 Dopamine has been described as having dose-related receptor activity at D1-, D2-, 1-, and
1-receptors (see Table 23-4).5,6,7,8,9,10,11,12,42,43,50,51,52 This dose-response relationship
has not been
confirmed in critically ill patients. In patients with septic shock, great overlap of hemodynamic
effects
occur, even at dosages as low as 3 mcg/kg/min. Tachydysrhythmias are common and it is no
longer
considered a first-line therapy for septic shock.6 Dopamine may increase PAOP through
pulmonary
vasoconstriction. It may depress ventilation and worsen hypoxemia in patients dependent on
the
hypoxic ventilatory drive.
 Dobutamine, a synthetic catecholamine, is primarily a selective 1-agonist with
mild 2- and vascular 1-activity, resulting in strong positive inotropic activity
without concomitant vasoconstriction

In comparison with dopamine, dobutamine produces a larger increase in CO

and is less arrhythmogenic.

1-Adrenoceptors in the heart are directly stimulated by the () isomer of

dobutamine, but 1 and 2 activity resides in the (+) isomer
 The strong inotropic action of dobutamine is a function of its structure, the
additive effect of cardiac 1- and 1-agonist activity, and a relatively weak
chronotropic effect limited to the (+) isomer action on the -receptors.

Clinically, 2-induced vasodilation and the increased myocardial contractility

with subsequent reflex reduction in sympathetic tone lead to a decrease in
SVR
 Optimal uses of dobutamine in septic shock are for patients with low CO and
high filling pressures (eg, low CI, left ventricular dysfunction demonstrated with
echogardiography) or ongoing signs of global or regional hypoperfusion despite
adequate resuscitation; however, vasopressors may be needed to counteract
arterial vasodilation