DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

influence adrenergic receptors selectively have resulted
in a class of drugs with a large number of important
therapeutic uses.
Shock. Shock is a clinical syndrome characterized by inadequate
perfusion of tissues; it usually is associated with hypotension and
ultimately with the failure of organ systems (Hollenberg et al., 1999).
Shock is an immediately life-threatening impairment of delivery of
oxygen and nutrients to the organs of the body. Causes of shock
include hypovolemia (due to dehydration or blood loss), cardiac failure
(extensive myocardial infarction, severe arrhythmia, or cardiac
mechanical defects such as ventricular septal defect), obstruction to
cardiac output (due to pulmonary embolism, pericardial tamponade,
or aortic dissection), and peripheral circulatory dysfunction (sepsis
or anaphylaxis). Recent research on shock has focused on the accompanying
increased permeability of the GI mucosa to pancreatic
proteases, and on the role of these degradative enzymes on microvascular
inflammation and multi-organ failure (Schmid-Schoenbein and
Hugli, 2005). The treatment of shock consists of specific efforts to
reverse the underlying pathogenesis as well as nonspecific measures
aimed at correcting hemodynamic abnormalities. Regardless of etiology,
the accompanying fall in blood pressure generally leads to
marked activation of the sympathetic nervous system. This, in turn,
causes peripheral vasoconstriction and an increase in the rate and
force of cardiac contraction. In the initial stages of shock these mechanisms
may maintain blood pressure and cerebral blood flow,
although blood flow to the kidneys, skin, and other organs may be
decreased, leading to impaired production of urine and metabolic
acidosis.
The initial therapy of shock involves basic life-support measures.
It is essential to maintain blood volume, which often requires
monitoring of hemodynamic parameters. Specific therapy (e.g.,
antibiotics for patients in septic shock) should be initiated immediately.
If these measures do not lead to an adequate therapeutic
response, it may be necessary to use vasoactive drugs in an effort to
improve abnormalities in blood pressure and flow. This therapy generally
is empirically based on response to hemodynamic measurements.
Many of these pharmacological approaches, while apparently
clinically reasonable, are of uncertain efficacy. Adrenergic receptor
agonists may be used in an attempt to increase myocardial contractility
or to modify peripheral vascular resistance. In general terms, β
receptor agonists increase heart rate and force of contraction, α receptor
agonists increase peripheral vascular resistance, and DA promotes
dilation of renal and splanchnic vascular beds, in addition to activating
β and α receptors (Breslow and Ligier, 1991).
Cardiogenic shock due to myocardial infarction has a poor
prognosis; therapy is aimed at improving peripheral blood flow.
Definitive therapy, such as emergency cardiac catheterization followed
by surgical revascularization or angioplasty, may be very
important. Mechanical left ventricular assist devices also may help
to maintain cardiac output and coronary perfusion in critically ill
patients. In the setting of severely impaired cardiac output, falling
blood pressure leads to intense sympathetic outflow and vasoconstriction.
This may further decrease cardiac output as the damaged
heart pumps against a higher peripheral resistance. Medical intervention
is designed to optimize cardiac filling pressure (preload),
myocardial contractility, and peripheral resistance (afterload).
Preload may be increased by administration of intravenous fluids or
reduced with drugs such as diuretics and nitrates. A number of sympathomimetic
amines have been used to increase the force of contraction
of the heart. Some of these drugs have disadvantages:
isoproterenol is a powerful chronotropic agent and can greatly
increase myocardial O 2
demand; NE intensifies peripheral vasoconstriction;
and epinephrine increases heart rate and may predispose
the heart to dangerous arrhythmias. DA is an effective inotropic
agent that causes less increase in heart rate than does isoproterenol.
DA also promotes renal arterial dilation; this may be useful in preserving
renal function. When given in high doses ( > 10-20 μg/kg per
minute), DA activates α receptors, causing peripheral and renal vasoconstriction.
Dobutamine has complex pharmacological actions that
are mediated by its stereoisomers; the clinical effects of the drug are
to increase myocardial contractility with little increase in heart rate
or peripheral resistance.
In some patients in shock, hypotension is so severe that vasoconstricting
drugs are required to maintain a blood pressure that is
adequate for CNS perfusion. Alpha agonists such as NE, phenylephrine,
metaraminol, mephentermine, midodrine, ephedrine, epinephrine,
DA, and methoxamine all have been used for this purpose.
This approach may be advantageous in patients with hypotension
due to failure of the sympathetic nervous system (e.g., after spinal
anesthesia or injury). However, in patients with other forms of shock,
such as cardiogenic shock, reflex vasoconstriction generally is
intense, and α receptor agonists may further compromise blood flow
to organs such as the kidneys and gut and adversely increase the
work of the heart. Indeed, vasodilating drugs such as nitroprusside
are more likely to improve blood flow and decrease cardiac work in
such patients by decreasing afterload if a minimally adequate blood
pressure can be maintained.
The hemodynamic abnormalities in septic shock are complex
and poorly understood. Most patients with septic shock initially have
low or barely normal peripheral vascular resistance, possibly owing
to excessive effects of endogenously produced NO as well as normal
or increased cardiac output. If the syndrome progresses, myocardial
depression, increased peripheral resistance, and impaired tissue oxygenation
occur. The primary treatment of septic shock is antibiotics.
Data on the comparative value of various adrenergic agents in the
treatment of septic shock are limited. Therapy with drugs such as
DA or dobutamine is guided by hemodynamic monitoring, with individualization
of therapy depending on the patient’s overall clinical
condition.
Hypotension. Drugs with predominantly α agonist activity can be
used to raise blood pressure in patients with decreased peripheral
resistance in conditions such as spinal anesthesia or intoxication with
antihypertensive medications. However, hypotension per se is not
an indication for treatment with these agents unless there is inadequate
perfusion of organs such as the brain, heart, or kidneys.
Furthermore, adequate replacement of fluid or blood may be more
appropriate than drug therapy for many patients with hypotension. In
patients with spinal anesthesia that interrupts sympathetic activation
of the heart, injections of ephedrine increase heart rate as well as
peripheral vascular resistance; tachyphylaxis may occur with repetitive
injections, necessitating the use of a directly acting drug.
Patients with orthostatic hypotension (excessive fall in blood
pressure with standing) often represent a pharmacological challenge.
There are diverse causes for this disorder, including the Shy-Drager
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CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS