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CAMPRAL: A NEW
APPROACH FOR THE
TREATMENT OF ALCOHOL
DEPENDENCY

Arthur Yeung, Pharm.D. Candidate


Alcohol abuse has a dramatic impact on
many lives. Annually, more than 100,000 deaths
are alcohol-related.1 Approximately 7.4% of
Americans meet the diagnostic criteria for alcohol
abuse or alcoholism. The economic burden of alco-
hol abuse to society exceeds that of both illicit drug
or tobacco abuse.1 The annual cost associated with
alcohol abuse was estimated at $184.6 billion in
1998.1 The disease's major economic impact is on
productivity losses due to alcohol-related illness
and premature death. Over $26 billion of the total
cost of alcohol abuse is related to treatment and
prevention. Medical care costs for this sector are up
to three times more than that of the general popula-
tion. Fifty percent of all alcohol is consumed by
10% of the drinking population. The burden of dis-
ease is age-related. More people drink heavily in
the 21- to 34-year age group while those over 65
years old drink the least. The mental and physical
behaviors induced by alcohol involve the serotoner-
gic, noradrenergic, and GABAergic receptor sys-
tems. The GABAergic system appears to be re-
sponsible for the action of alcohol on the central
nervous system.
Cirrhosis of the liver and hepatic impair-
ment are the most common complications of alco-


holism. Alcoholic hepatitis and alcoholic cirrhosis
develop in approximately 15-20 percent of chronic
alcoholics. Liver disease can progress to fulminant
hepatic failure and gastrointestinal hemorrhage,
infection, or kidney failure. Also, liver transplanta-
tion is prohibited for patients who abuse alcohol.
The FDA approved acamprosate
(Campral) on July 29th, 2004. It is indicated for
the maintenance of abstinence from alcohol in alco-
holics who are abstinent at treatment initiation.
Acamprosate has been a therapeutic option in other
countries for some time and is currently available
in more than 20 countries. The four manufacturers
who are currently distributing acamprosate are For-
est, Merck, Lipha, and Almirall. The four available
brand names for acamprosate are Campral
(Forest), Sobrial (Merck), Aotal (Lipha), and
Almirall (Almirall). Acamprosate is marketed as
Campral by Forest Pharmaceuticals in the United
States.
The objectives of this article are to discuss
the pharmacology, pharmacokinetics, and clinical
trials involving acamprosate as well as to review
information pertinent to the effective integration of
this agent into clinical practice.




INSIDE THIS ISSUE:

CAMPRAL : A NEW APPROACH FOR THE
TREATMENT OF ALCOHOL DEPENDENCY

OVERVIEW OF VASOPRESSORS AND
INOTROPES IN THE ICU


mm
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Pharmacology and Pharmacokinetics
The mechanism of action of acamprosate is
not completely understood. GABAmimetic drugs
such as acamprosate reduce alcohol withdrawal
symptoms whereas antagonists produce symptoms
similar to those observed during alcohol with-
drawal. The mechanism of action for acamprosate
is believed to involve stimulation of GABAergic
neurotransmission in the brain. It may also antago-
nize the effects of certain excitatory amino acids. It
is active at postsynaptic GABA(B) receptors that
decrease electrical excitability, though it does not
change membrane potential.
The bioavailability of acamprosate is ap-
proximately 11%.3 The rate of absorption is slow
and food reduces its absorption. However, this ef-
fect does not appear to be clinically significant, and
no dosage adjustments are needed. Acamprosate
crosses the blood-brain barrier; therefore, it is ex-
pected that adverse reactions will involve the cen-
tral nervous system. There are no active metabo-
lites and the major route of excretion is renal.

Clinical Trials
A double-blind, placebo-controlled, 24-
week study evaluated the efficacy and safety of
acamprosate in the treatment of alcohol depend-
ence.4 The sample comprised 75 patients, 18-60
years of age, diagnosed with alcohol dependence.
The patients were randomly divided into two
groups one week after alcohol cessation and treated
with either acamprosate 1998 mg/day in 3 divided
doses or placebo. During the first 12 weeks, pa-
tients did not receive any additional medications.
The main outcome measures were relapse rates,
side effects and time to first relapse. Statistically,
the effect of acamprosate on preventing relapse
rates was significantly greater than placebo (p
= .02). The investigators concluded that acam-
prosate is an effective treatment for alcohol de-
pendence.
A 6-month, randomized controlled study
compared acamprosate with placebo in preventing
relapse after withdrawal from alcohol. The study
was done in 20 locations throughout England.5 Pa-
tients with alcohol-dependence were detoxified
within the first 5 weeks and randomly assigned to
treatment with either acamprosate 666 mg three
times daily or matching placebo. A total of 581


individuals qualified for the study. One-third of the
patients were episodic drinkers, 84% were male,
and 44% were unmarried. On average, medication
was begun 24 days after the start of detoxification.
Thirty-two percent of patients had relapsed and re-
commenced drinking at this point. The 6-month
study period was completed by 35% of patients.
Adverse events led to withdrawal in 14% of acam-
prosate-treated patients and 9% of placebo-treated
patients. Compliance was poor during the study.
Only 57% of patients were taking at least 90% of
their tablets by week 2. The mean total number of
abstinent days was 77 in the treatment group and 81
in the control group (p > 0.05). Complete absti-
nence for 6 months was achieved by 12% in the
acamprosate group and 11% of the placebo group
(p > 0.05). However, the mean percentage reduc-
tion in alcohol craving measured via visual ana-
logue scale was greater in the acamprosate group at
week 2 and week 4 (p < 0.001), and the mean de-
crease in the Hamilton Anxiety score at week 4 was
greater in the acamprosate than placebo patients (p
= 0.017). Compared with other published trials of
acamprosate, treatment was initiated later in the
cessation process, more patients had relapsed be-
fore medication was started, and the drop-out rate
was higher. This may have contributed to the lack
of a more impressive treatment effect in the study.9
A one-year study was designed to evaluate
the effectiveness of acamprosate as a treatment to
maintain abstinence in alcohol-dependent patients.
Within three weeks after cessation, 272 patients
entered a randomized, double-blind, placebo-
controlled study.6 Patients received either acam-
prosate or placebo for 48 weeks. Following the 48-
week treatment-phase, patients were followed with-

out medication for an additional 48 weeks. Patients
who were receiving acamprosate showed a signifi-
cantly higher abstinence rate within the first 60
days of treatment compared with patients who were
assigned to placebo (67% vs. 50%, P < 0.05). The
effect was maintained through completion of the
treatment period (43% vs. 21%, p = .005). Subjects
treated with acamprosate also had significantly
longer mean abstinence duration, 224 vs. 163 days
(62% vs. 45% days abstinent, p < .001). However,
there was no difference in psychiatric symptoms.
Of the patients who received acamprosate, 41%
dropped out, compared to 60% of placebo-treated


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Table 1. Percent of Alcohol Dependent Subjects with Adverse Events by Medication Treatment Assignment
Acamprosate 1332 Acamprosate 1998 Acamprosate
Body System Placebo mg/d mg/d Pooled
Number of subjects 1706 397 1539 2039
Number with adverse event (%) 955 (56) 248 (62) 910 (59) 1231 (61)
Body as a Whole 517 (30) 121 (30) 513 (33) 685 (34)
Digestive System
Nausea 58 (3) 11(3) 69(4) 87(4)
Diarrhea 166 (10) 39 (10) 257 (17) 329 (16)
Anorexia 44 (3) 20 (5) 35 (2) 57 (3)
Nervous System
Anxiety 98(6) 32(8) 80(5) 118(6)
Dizziness 44 (3) 15 (4) 49 (3) 67 (3)
Insomnia 121 (7) 34 (9) 94 (6) 137 (7)
Skin and Appendages 169 (10) 34 (9) 994 (6) 137 (7)


patients. At the end of the 48-week observation
phase, 39% and 17% of the acamprosate- and pla-
cebo-treated patients, respectively, had remained
abstinent (p = .003). Acamprosate appeared to be a
safe and effective adjunct in treating alcohol-
dependent patients and in maintaining abstinence at
2 years.
Naltrexone and acamprosate are thought to
provide benefits in relapse prevention of alcohol-
ism through unique mechanisms. A controlled
study was conducted to explore whether differences
exist in the efficacy of the two drugs and whether
the combination offers any advantage. After the
cessation of alcohol abuse, 160 patients with alco-
holism participated in a randomized, double-blind,
placebo-controlled protocol. Patients were divided
into four groups: naltrexone, acamprosate, naltrex-
one and acamprosate, or placebo.7 Patients were
assessed weekly for 12 weeks by interview, self-
report, questionnaires, and laboratory screening.
The primary outcomes were time to first drink, time
to relapse, and the cumulative abstinence time.
Time-to-event analyses were used to examine the
non-relapse rates for the 4 treatment groups for
lapse events, such as time to first drink. They re-
vealed statistically significant differences among
the treatment groups (p < 0.001). Significant differ-
ences emerged between naltrexone and placebo (p
= 0.03), between acamprosate andplacebo (p =


0.04), and between dual therapy and placebo (p =
0.002). There was no significant difference in time
to first drink between naltrexone and acamprosate.
The combined medication was significantly more
effective than acamprosate alone (p = 0.04) but not
different from naltrexone alone. In summary, the
combination was more effective than placebo and
acamprosate but similar to naltrexone, thus the
merit of combination treatment requires further
study.

Dosing and Administration
Treatment with acamprosate should be part
of a comprehensive treatment program that in-
cludes psychosocial support. The approved dose of
acamprosate is 666 mg three times daily. A lower
dose may be effective in some patients. Alternative
dosage regimens have been used in some studies.4
One study used 1332 mg/day in patients lighter
than 60 kg, administered as 666 mg in the morning,
333 mg in the after oon, and 333 mg in the eve-
ning. Acamprosate is not approved for use in chil-
dren or adolescents. Acamprosate may be dosed
without regard to meals; however, dosing with
meals was used in clinical trials, and it may help
with compliance in patients who regularly eat three
meals daily.
Acamprosate is contraindicated in patients
with severe renal insufficiency, defined as a


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creatinine clearance less than 30 mL/min. Patients
with a creatinine clearance between 30 and 50 mL/
min should receive 333 mg three times daily, half
the usual maintenance dose. Since acamprosate is
not metabolized by the liver, dosage alterations are
not necessary in patients with mild to moderate he-
patic impairment.

Adverse Drug Reaction (ADR)
Adverse reactions are common in acam-
prosate-treated patients. Some of the most common
are nausea, diarrhea, headache, and fatigue. The-
Combining Medications and Behavioral Interven-
tions (COMBINE) study allows for comparison of
ADRs across patients treated with acamprosate,
naltrexone, and placebp.8 Seventeen different types
of ADRs were systematically recorded. Physical
complaints and symptoms are significant within
this population (Table 1). One subject in the
naltrexone group and one subject in the acam-
prosate group could not tolerate the medication be-
cause of adverse effects.
In another study, 288 patients were random-
ized to acamprosate or placebo. 12 The overall inci-
dence of adverse events was similar in both groups.
However, there was a trend for gastrointestinal
symptoms to be reported more frequently in the
acamprosate-treated group (n = 61) versus placebo-
treated patients (n = 46). Other symptoms that were
reported more frequently in the acamprosate-treated
patients included diarrhea, dyspepsia, constipation,
and flatulence.
A trial performed in 18 different outpatient
centers in Italy enrolled 330 subjects.13 One group
was treated with standard dose acamprosate and the
other group was treated with placebo. The most
common ADR was headache (7.3% in acamprosate
group and 6.6% in placebo group), diarrhea (3.0%
in acamprosate patients and 2.4% in placebo pa-
tients), and gastrointestinal discomfort (1.2% of
acamprosate patients and 5.6% in placebo group).
There was no significant difference between the
two treatment groups. In both COMBINE and the
Italian study gastrointestinal complaints occurred
numerically less frequently; however, this pattern
was not supported in the study by Gual et al.12

Cost
The average retail cost for a one month sup-


ply of acamprosate, based on a survey of three re-
tail pharmacies in Gainesville, FL, is $134.64.

Summary
The likelihood of maintaining abstinence
from alcohol is increased if acamprosate is adminis-
tered as an adjunct to a comprehensive abstinence
program. Clinical trials have shown that patients
treated with acamprosate experience lower relapse
rates compared with those who do not receive phar-
macological intervention. The combination of
acamprosate and naltrexone may offer additional
benefit over acamprosate alone, but did not appear
more effective than naltrexone. Thus, additional
studies are needed to fully elucidate the role of
combination drug therapy in this population. In
conclusion, acamprosate is a welcomed addition to
the limited repertoire of drugs to treat alcohol de-
pendence. Because it is really eliminated and does
not appear to cause hepatic injury, acamprosate of-
fers patients with hepatic impairment an alternative
to naltrexone. Health professionals should consider
acamprosate as an adjunct to cognitive behavioral
therapy for increasing the likelihood of long-term
abstinence from alcohol.

References
1. U.S. Department of Health and Human Ser-
vices. The tenth special report to the U.S. Con-
gress on alcohol and health. Rockville, MD:
Public Health Service, National Institutes of
Health, National Institute on Alcohol Abuse and
Alcoholism 2000;XIII, 14-17,30,273,283-
295,364,365.
2. Mason BJ, Goodman AM, Dixon RM, Hameed
MH, Hulot T, Wesnes K, Hunter JA, Boyeson
MG. A pharmacokinetic and pharmacodynamic
drug interaction study of acamprosate and
naltrexone. Neuropsychopharmacology
2002;27:596-606.
3. Saivin S, Hulot T, Chabac S, Potgieter A,
Durbin P, Houin G. Clinical pharmacokinetics
of acamprosate. Clin Pharmacokinet
1998;35:331-45.
4. Baltieri DA, De Andrade AG. Acamprosate in
alcohol dependence: a randomized controlled
efficacy study in a standard clinical setting. J
Stud Alcohol 2004;65:136-9.
5. Chick J, Howlett H, Morgan MY, Ritson B.


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United Kingdom Multicentre Acamprosate
Study (UKMAS): a 6-month prospective study
of acamprosate versus placebo in preventing
relapse after withdrawal from alcohol. Alcohol
Alcohol 2000;35:176-87.
6. Sass H, Soyka M, Mann K, Zieglgansberger
W.Relapse prevention by acamprosate. Results
from a placebo-controlled study on alcohol de-
pendence. Arch Gen Psychiatry 1996;53:673-
80.
7. Kiefer F, Jahn H, Tarnaske T, et al. Comparing
and combining naltrexone and acamprosate in
relapse prevention of alcoholism: a double-
blind, placebo-controlled study. Arch Gen Psy-
chiatry 2003;60:92-9.
8. COMBINE Study Research Group. Testing
combined pharmacotherapies and behavioral
interventions for alcohol dependence (the
COMBINE study): a pilot feasibility study. Al-
cohol Clin Exp Res 2003;27:1123-31.
9. Overman GP, Teter CJ, Guthrie SK. Acam-
prosate for the adjunctive treatment of alcohol
dependence. Ann Pharmacother 2003;37:1090-
9.
10. Singh AN, Srivastava S, Jainar AK. Pharmaco-
therapy of chronic alcoholism: a review.
Drugs Today (Barc). 1999;35:27-33.
11. Mann K, Lehert P, Morgan MY. The efficacy
of acamprosate in the maintenance of absti-
nence in alcohol-dependent individuals: results
of a meta-analysis. Alcohol Clin Exp Res
2004;28:51-63.
12. Gual A, Lehert P. Acamprosate during and af-
ter acute alcohol withdrawal: a double-blind
placebo-controlled study in Spain. Alcohol Al-
cohol 2001;36:413-8.
13. Tempesta E, Janiri L, Bignamini A, Chabac S,
Potgieter A. Acamprosate and relapse preven-
tion in the treatment of alcohol dependence: a
placebo-controlled study. Alcohol
2000;35:202-9.


OVERVIEW OF VASOPRESSORS
AND INOTROPES IN THE ICU



Abbey Kinsey, Pharm.D. Candidate


Intensive care units (ICU) are faced with an
ever growing influx of patients. Moreover, patients
admitted to the ICU are much sicker than in past
years, making the safe and effective use of vaso-
pressors and inotropes of paramount importance.
Given the ambiguity and relative obscurity of these
agents paired with the degree of complexity of se-
verely ill patients, it is no surprise that selecting the
optimal agent can be a daunting task. Unfortu-
nately, there are no guidelines to facilitate this
process. The intent of this article is to streamline
information on vasopressors and positive inotropes
into a comprehensive model.

Indications for use
In the acute setting, many situations arise in
which vasopressors and inotropes are life saving.
These situations include, but are not limited to,
shock, advanced cardiac life support (ACLS), and
bradycardia. There are a multitude of patient-
specific factors that should be considered when de-
ciding which agent to prescribe. These considera-
tions include heart rate (HR), blood pressure (BP),
pulse, cardiac output (CO), cardiac index (CI), right
arterial pressure (RAP), pulmonary capillary wedge
pressure (PCWP), and pH. A working knowledge
of these parameters and knowing how individual
pharmacological agents influence them will facili-
tate appropriate drug selection (Figure 1).

Norepinephrine
Norepinephrine acts as a potent al-
adrenergic agonist, though it activates 01-
adrenergic receptors to a lesser degree (Table 1 and
Figure 2). Arteriolar vasoconstriction is mediated
by al-receptor activation, thereby increasing sys-


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Figure 1. Primary Determinants of Cardiac Output, Arterial Pressure, and Oxygen Delivery


P re lo ad
A fterlo ad
Co ntractility


= o Stroke Volume


Heart R a te


02 C onten t


Cardiac Output


02 Delivery


temic vascular resistance (SVR)1 (Table 2). This
increase in SVR results in an increase in systemic
arterial and coronary perfusion pressures. Secondly,
activation of Pi receptors in the myocardium in-
creases contractility and stroke volume. Heart rate
and CO usually do not change; in fact, a slight de-
crease in CO may accompany the increase in after-
load and perfusion pressure. As a result of in-
creased BP, particularly diastolic, myocardial oxy-
gen consumption is increased. Consequently, myo-
cardial ischemia and arrhythmias may be intensi-
fied or provoked, and left ventricular function com-
promised.2 Norepinephrine is commonly used in
the treatment of acute hypotension resulting from
conditions such as myocardial infarction, septice-
mia, and spinal anesthesia.2

Phenylephrine
Phenylephrine functions as a pure a1 ago-
nist, increasing both systolic and diastolic BP. As a
result of increased BP, afterload and myocardial
oxygen consumption are increased (Table 1 and
Figure 2).2 Phenylephrine may be especially useful
in refractory hypotension complicated by atrial or
ventricular arrhythmias because it has minimal di-
rect effects on the heart.3 On the other hand, this
medication must be used cautiously in patients with
decreased CO due to the loss of capillary hydro-
static pressure, resulting in decreased preload. This
action, along with reflex bradycardia and increased
afterload, may further reduce CO in an already
compromised patient.2
Dopamine
Dopamine is often considered a first line


PharmaNote


Arterial Pressure


agent in multiple conditions due to its various ino-
tropic, chronotropic, and vasoactive properties. A
mixture of activity is seen in a dose-dependent
manner (Table 1 and Figure 2). At low doses, the
primary effect of dopamine is on P1 receptors. This
leads to increased ventricular contractility and HR.
Tachycardia and tachydysrhythmias can occur in
patients treated with dopamine, especially in the
elderly, those with preexisting or concurrent car-
diac ischemia or dysrhythmias, and when adminis-
tered concomitantly with other arrhythmogenic
agents. As the dose is increased, activity shifts to
include al receptors, eliciting an increase in arterial
pressure and SVR. Dopamine is generally preferred
in patients with depressed CO, normal to moder-
ately elevated PCWP, and moderate to severe hy-
potension.2

Epinephrine
Epinephrine is a mixed al/01 agonist. It acts
as a vasoconstrictor, and a positive inotropic and
chronotropic agent (Table 1 and Figure 2). At low
doses, 31-adrenoceptor effects are most prevalent,
leading to increased HR and contractility. This
leads to an increase in CO that further increases
systolic BP (Figure 1). If higher doses are adminis-
tered, al agonist activity predominates and vaso-
constrictive effects become more apparent.4

Dobutamine
Dobutamine is a positive inotrope that
works primarily through 31-receptors and, to a
lesser extent, through al- and 32-receptors (Table 1
and Figure 2).2 These actions increase stroke index,


Volume 20, Issue 9, June 2005


SVR


FI








Table 1. Receptor Profile and Clinical Response of Select Medications Applied in the Setting of Shock.

Receptor Specificity Pharmacologic Response

Drug Usual Dose a1 D1 P2 VD VC INT CHT
Milrinone 0.75 mg/kg bolus, then 5-20 0 0 0 + 0 + +
Milrnone 0 0 0 + 0 +++ +
ug/kg/min

Dobutamine 2.5-15 pg/kg/min + +++ ++ ++ 0 +++ +
0.5-2 pg/kg/min 0 0 0 0 0 0 0
2-5 pg/kg/min 0 + 0 0 + + +
Dopamine5-10 g/kg/mi + ++ 0 0 ++ ++ ++
15-20 pg/kg/min +++ +++ 0 0 +++ ++ ++

0.01-0.1 pg/kg/min + +++ ++ ++ 0 +++ ++
Epinephrine 0.1 g/kg/min ++ ++ ++ 0 +++ ++ ++

Isoproterenol 0.01-0.1 pg/kg/min 0- ++++ +++ +++ 0 +++ +++
2-10 pg/min
(0.5-1 tg/kg/min) 0- 0 ++++
Norepinephrine (0.5-++++ g/ ++++ ++ 0- 0 + +
Titrate to SBP 90-100mm
Hg

Phenyle e 20-200 pg/min Titrate to 0- 0 0 ++ 0 0
Phenylephrine +++ 0- 0 0 +++ 0 0
effect

VD = Peripheral vascular vasodilatation; VC = Peripheral vascular vasoconstriction; INT = Positive inotropy; CHT = Positive chronotropy
Scale: (0) no effect, (+) weak, (++) mild, (+++) moderate, (++++) strong. Adapted from Reference 2

left ventricular stroke work index, CI and oxygen because it has both positive inotropic ("ino-") and
delivery without increasing the pulmonary artery vasodilatory dilatoror) effects (Table 1 and Figure
occlusion pressure. Dopamine and dobutamine are 2). The distinction between this agent and many
often considered in similar settings, heart failure for others is that milrinone does not work through a or
example. One noteworthy difference is that while 0 receptors. This drug inhibits the enzyme phos-
dopamine increases pulmonary artery occlusion phodiesterase, thereby increasing cAMP leading to
pressure, dobutamine does not. Dobutamine's' most inotropic and vasodilatory properties, which in-
prominent effects occur in patients with low CO crease stroke volume and CO. There is often little
and high filling pressures,3 making dobutamine an change in HR. Despite the increase in CI, mean ar-
acceptable option in the setting of low output states. trial pressure decreases due to peripheral vasodila-
Using dobutamine as a single agent to increase BP tion.6 This action could possibly lead to reflex
may be of limited value due to compensatory vaso- tachycardia. Milrinone should be used in patients
dilatotion and P2-receptor activation.5 In this situa- with a low CI, adequate BP, and an elevated left
tion, a combination of dobutamine along with an- ventricular filling pressure.3 Milrinone is the pre-
other catecholamine with more predominant a ferred inotrope in patients with decompensated
adrenergic receptor-mediated effects may be used. heart failure receiving p-blockers.
In patients with decompensated heart failure who
are concomitatly treated with p-blockers it is possi- Isoproterenol
ble that response to dobutamine will be poor since Isoproterenol is a mixed P1/02-adrenergic
these two agents exert antagonistic effects. receptor agonist that may be used in situations of
atrioventricular block or bradycardia (Table 1 and
Milrinone Figure 2).7 This medication has fallen out of favor
Milrinone is referred to as an "inodilator" of late because of the potential it has to cause tach-

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Figure 2. The Sympathomimetic Spectrum.


yarrythmias. Further, the availability of other
agents such as atropine and nonpharmacological
modalities such as pacing are more effective and
safer to use.

Vasopressin
Vasopressin is unique in that it does not
work on the same receptor system as any of the
aforementioned medications. Mechanistically,
vasopressin works on V-1 receptors on the arterial
smooth muscle and V-2 receptors found in renal
tubules. Vasopressin effectively increases arterial
BP and SVR through vasoconstriction. It is often
applied as a last line agent in patients who have re-
ceived adequate fluid resuscitation and are refrac-
tory to other vasopressors. In this circumstance, it
is usually added to existing therapies.8 This medica-
tion may also be used as an alternative to epineph-
rine for the treatment of cardiac arrest during
ACLS.9 Vasopressin should be avoided in patients
with hypovolemia, cardiogenic shock or septic
shock with myocardial depression. In this setting, it
may further decrease CO and cause profound cuta-
neous vasoconstriction and necrosis.10

Selection of a Vasopressor or Inotrope
The following case vignettes are intended to
provide examples of how these agents might be se-
lected in certain situations. The discussion focuses
on pharmacological interventions and does not rep-
resent all of the actions that should be initiated in
such patients. In most cases, there are several ap-
propriate actions.


Pressors
Vasoconstrictors


OC agonist


Cardiogenic Shock
AL is a 58 year-old Caucasian female who
recently underwent four-vessel coronary artery by-
pass graft (CABG) surgery and is now in the ICU.
Her vital signs are stable with a mean arterial pres-
sure of 63 mm Hg. AL's past medical history in-
cludes two myocardial infarctions and hyperten-
sion. Current medications include nitroglycerin,
metoprolol, hydrochlorothiazide, aspirin, and sim-
vastatin. Forty-five minutes after admission to the
ICU AL's BP dropped. Her hemodynamic profile
was as follows: BP 90/50 mm Hg; pulse 108 beats/
min; CO 2.8 L/min; CI 1.65 L/min/m'; PCWP 22
mm Hg; RAP 12 mm Hg; pH 7.38; HCO3 20 mEq/
L; respiratory rate 26/min; urine output 25mL/hr;
temp 36C (normal values seen in Table 3).
Assessment of AL's clinical presentation
suggests that she was experiencing decompensated
heart failure which resulted in cardiogenic shock.
The hemodynamic criteria consistent with cardio-
genic shock are hypotension with a systolic BP <90
mm Hg, a reduced cardiac index of <2.2 L/min/m2,
and the presence of elevated PCWP of >15 mm
Hg.11 According to AL's presentation, dopamine
could be initiated at a dose of 3 pg/kg/min based on
its ability to directly stimulate 31 adrenergic recep-
tors. This effect will increase stroke volume, HR
and CO. The goal of therapy is to increase CI to at
least 2.5 L/min/m2 and to maintain MAP around 80
mm Hg depending on clinical signs of hypoperfu-
sion, reduce PCWP, while maintaining HR below
than 125 beats per minute. Due to dopamine's rapid
onset of action, it may be titrated upward at a rate


m:m
PharmaNote Volume 20, Issue 9, June 2005


Inotropes
Chronotropic/
Inotropic
3 agonist


lMixed


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Table 2. Adrenoreceptor Types and Location.
Receptor Response when
Type Location stimulated

a1 Arteries, arterioles, veins Constriction

Decreased tone,
u2 Gastrointestinal tract motility, and secre-
tions

Increased heart rate
Pi Heart and force of contrac-
tion
Skeletal muscle vasculature Dilation
P2 Coronary arteries Dilation
Bronchial smooth muscle Dilation

Adapted from reference 4.

of 1-2 [tg/kg/min every 10 minutes depending on
the hemodynamic data and clinical status. A rate of
greater than 10 [tg/kg/min might be considered a
threshold in this case, given dopamine's tendency
to increase left ventricular filling pressure, which
may exacerbate pulmonary edema. Patients should
be monitored for tachycardia, anginal pain, arrhyth-
mias, headache, hypertension, vasoconstriction,
nausea and vomiting.2

Septic Shock
PD is a 57 year-old Asian male admitted to
the ICU five days ago with a chief complaint of
acute abdominal pain for three days, bloody diar-
rhea, fever, tachypnea, and hypotension. A diagno-
sis of superior mesenteric artery occlusion with ne-
crotic bowl was established. Following diagnosis,
PD underwent surgery for removal of necrotic
bowel tissue. Between days 1 and 4 of postopera-
tively, there was a continual climb in serum
creatinine and the patient could not be completely
weaned from ventilatory support. His vital signs
were stable and appropriate antibiotic treatment
was implemented. PD has a past medical history
that is positive for CHF and coronary artery disease
with stable angina pectoris that had been treated
with carvedilol, enalapril, digoxin, furosemide, and
NTG tablets. On postoperative day 5, PD com-
plained of chills and was noted to have a fever of
39.40C. Physical findings included: BP 98/60 mm


Table 3. Normal Hemodynamic Values and Indices.


Blood Pressure

Cardiac Output

Heart Rate
Pulmonary Capillary Wedge
Pressure (PCWP)
Cardiac index
Mean Arterial Pressure
(MAP)
Stroke Volume (SV)
Right Arterial pressure
Pulmonary Vascular Resis-
tance (PVR)
Systemic Vascular resistance
(SVR)


120-140/80-90 mm Hg

4-7 L/min

60-80 beats/min (BPM)

5-12 mm Hg

2.5-4.2 L/min/m2

80-100 mm Hg
60-130 mL/beat
2-6 mm Hg
20-120 dynes*sec*cm5

800-1440 dynes*sec*cm5


Hg; pulse 126 beats/min; RR 27 beats/min; urine
output decreased to 25 mL/hr and absent bowel
sounds. A chest X-ray was preformed that showed
an enlarged heart with bilateral pulmonary infil-
trates and right lower lobe atelectasis. Over a short
time period, PD became confused and disoriented.
Urine, sputum, and blood samples were sent for
culture and sensitivity. A 500 mL normal saline
fluid bolus was given and pulmonary and arterial
catheters were inserted. The following hemody-
namic profile was obtained: BP 90/50 mm Hg;
pulse 118 beats/min; CO 6.2 L/min; CI 3.5 L/min/
m2; RAP 8 mm Hg; PCWP 11 mm Hg; SVR 733
dyne*sec*cm-5; inspiratory oxygen concentration of
40%; PaO2 76 mm Hg; PaCO2 34 mm Hg; pH 7.3.
PD expressed signs and symptoms consis-
tent with septic shock that included hypotension,
tachycardia, low SVR, worsening heart function,
declining urinary output, altered sensory percep-
tion, spiking fever, and his CO was on the upper
end of normal. Even though CO of 6.2 L/min is on
the upper end of normal for a patient in septic
shock, it is not sufficient in this case to perfuse es-
sential organs, evidenced by the SVR of 733
dyne*sec*cm-5. In addition, PD had metabolic aci-
dosis, which indicated the presence of anaerobic
metabolism, and a CO that is insufficient to meet
the oxygen demand.
When treating septic shock there are three
primary considerations. First is eradication of the
source of infection; second, hemodynamic support;
and thirdly, inhibition or attenuation of the initia-


Phara~ot Volme 2, Isue 9 Jun 200


Volume 20, Issue 9, June 2005


PharmaNote







tors and mediators of sepsis.2
After appropriate antibiotic treatment and
fluid boluses were given to PD, focus should be
shifted to other areas of hemodynamic support. Do-
pamine is the initial vasopressor of choice, but
dobutamine has also been utilized based on its
similarity to dopamine (increased CO and mean
arterial pressure). The advantage of dobutamine is
its ability to lower PCWP, decrease myocardial
oxygen consumption, and cause less pulmonary
shunting than dopamine; however, dopamine's al
receptor activity may provide much needed
additional vasopressor support. Dobutamine could
be considered initially at a rate of 2.5 [tg/kg/min in
PD because his CO was below 3.5 L/min/m2. This
dose may be titrated upwards every five to ten min-
utes, according to PD's response, to 15 or 20 atg/kg/
min.
When a patient presents to the ICU, there
are many factors that must be addressed. Most pa-
tients will not fall neatly into the shock classes; in-
stead, the various reasons for instability must be
considered when selecting an initial agent. If the
patient has not stabilized within a short period of
time, another agent may be added. Combination
therapy will often be necessary to take advantage of
different receptor systems in the pursuit of hemody-
namic equilibrium.

Summary
There are various vasopressors and ino-
tropes used to treat shock. Confusion arises due to
the numerous mechanisms of action that these
agents work through and the diverse ways that the
human body responds to them. The most important
aspect in the process of choosing an appropriate
agent is to consider individual patient factors and
clinical presentations. Each agent should be chosen
based on its ability to directly or indirectly affect
the most vital area of concern while having mini-
mal impact on unrelated organ systems. In many
cases, one agent is insufficient to resolve all hemo-
dynamic derangements and additional agents must
be added. In such instances, agents that work via an
alternate receptor system should be selected. Inte-
gration of these considerations and concepts will
hopefully facilitate selection of an optimal pharma-
cological regimen.


References
1. Clinical Pharmacology. Version 2.14. Refer-
enced Mar 15th, 2005.
2. Koda-Kimble MA et al. Applied therapeutics:
The Clinical Use of Drugs. 8th ed. 2004.
3. Kee VR. Hemodynamic Pharmacology of Intra-
venous Vasopressors. Critical Care Nurse 2003;
23:79-81.
4. Rudis MI et al. Is it time to reposition Vasopres-
sors and inotropes in sepsis? Critical Care Medi-
cine 1996;24:525-537.
5. Dipiro JT et al. Pharmacotherapy: A Pathophysi-
ological Approach, 5th ed.; Appleton and Lange;
2002.
6. Leier CV, Binkley PF. Parenteral inotropic sup-
port for advanced congestive heart failure. Prog
Cardiovasc Dis 1998;28:376-382.
7. ACC/AHA Guidelines for the Management of
Patients With Acute Myocardial Infarction-
Part V. American Heart Association. 1999.
8. Beale RJ et al. Vasopressor and inotropic support
in septic chock: An evidence-based review.
Critical Care Medicine 2004;32:S455-S463.
9. Nolan JP, et al. Vasopressin versus Epinephrine
for Cardiopulmonary Resuscitation. N Engl J
Med 2004;350:2206-209.
10. Forrest P. Vasopressin and shock. Anaesth In-
tensive Care 2000;29:463-472.
11. Abdlekader MA. Is higher blood pressure al-
ways better for patients with post-MI cardio-
genic shock? Postgrad Med J 2004.


The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor
Pharm.D.

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