75

This effect is most pronounced in patients who are hypovolemic. These hemodynamic

changes can result in a decrease of the clearance of several drugs.

J.A. has several risk factors for drug interactions. Many of his risk factors are

patient-specific, including J.A.’s age, organ dysfunction, and acute medical

conditions. Additional risk factors are the extended hospital stay in the ICU and

multiple medications. J.A.’s specific risk factors are outlined below.

Patient Risk Factors

Age: 69 years old—altered pharmacokinetic and pharmacodynamics

Renal dysfunction: baseline SCr 1.0 mg/dL and current SCr 1.8 mg/dL—decreased

renal clearance

Mild hepatic dysfunction: AST 105 U/mL and ALT 85 U/mL—decreased

metabolism

Pneumonia: T 101°F, WBC 14.6 × 10

3μ/L, poly 80%, bands 12%—increased

catabolism

Hypotension (result of shock): BP 95/60 on norepinephrine, vasopressin, and

lactated Ringer’s solution—decreased clearance

Hyperthermia: T 101°F—increased clearance

Hypophosphatemia: phosphate 0.9 mg/dL—increased neuromuscular blockade (see

discussion Case 3-2 Question 2)

p. 46

p. 47

Norepinephrine and vasopressin infusions: potential for decreased blood delivery

to liver and kidneys

Mechanical ventilation: decreased cardiac output

Other Risk Factors

Polypharmacy: risk of adverse drug interaction increases with multiple medications

Duration of hospital stay: 18 days—susceptible to hospital-acquired conditions and

subsequent drug therapy

CASE 3-2, QUESTION 2: The medical team is concerned that J.A.’s condition may have worsened; he may

have had a neurologic event (e.g., stroke) in the night. J.A. is clinically unstable to bring to computed

tomography (CT). The team needs J.A. to be alert for purposes of conducting a neurologic examination. To

undergo the examination, J.A. must have his neuromuscular blockade discontinued and sedation lightened. One

and one-half hours after discontinuation of cisatracurium J.A. is still not moving (TOF 0/4). The medical team

feels J.A.’s cisatracurium’s paralytic effect should have worn off by now and is concerned about his prognosis.

The medical team ask the clinical pharmacist to review J.A.’s case and affirm that the neuromuscular blockade

has worn off.

After reviewing the case, the clinician identifies potential drug-condition/disease

and drug–drug pharmacodynamic interactions that may contribute to the prolonged

neuromuscular blockade. These interactions are discussed below.

Background: The incidence of ICU-acquired weakness (polyneuropathy and

myopathy) in ARDS patients is 34% to 60%. This condition can last for months to

years and can severely affect a patient’s quality of life.

76 There are several risk

factors for ICU-acquired weakness that includes prolonged mechanical ventilation,

number of days with dysfunction in 2 or more organs before wakening,

corticosteroids, female sex,

77

toxins (e.g., botulism), neuromuscular disease states

(e.g., Guillain-Barre Syndrome), severe electrolyte imbalances, prolonged recovery

from neuromuscular blockers, deconditioning, length of vasopressor support, and

hyperglycemia just to name a few.

76,78,79 Neuromuscular blockade alone has been

associated with ICU-acquired weakness. However, in a multicenter, double-blind

trial, investigators found no statistical difference in ICU-acquired paresis between

cisatracurium and placebo groups at day 28 or ICU discharge.

78,80 Prolonged

recovery from neuromuscular blockade may occur in patients with organ failure

and/or conditions that affect the overall clearance of the neuromuscular blocking

agent (e.g., decreased metabolism of a parent drug, decreased elimination of the

parent drug, and/or the active metabolite). In addition to that, certain disease states,

conditions, or drugs that may potentiate a blockade may also lead to an increased

recovery time.

78,79

Drug-Condition/Disease Interactions

PHARMACOKINETICS—DRUG METABOLISM/ELIMINATION

The nondepolarizing agent, cisatracurium, is a benzylisoquinolinium compound. It is

one of the ten isomers of the intermediate-acting neuromuscular blocker, atracurium.

It is primarily eliminated by Hofmann degradation; optimal breakdown occurs at

physiologic temperature (37°C or 98.6°F) and pH (7.40).

72 This process results in

therapeutically inactive metabolites, monoquaternary alcohol, monoquaternary

acrylate, and laudanosine.

81 Cisatracurium’s organ-independent elimination is a

benefit for J.A. because he has renal and hepatic insufficiency. However, because

cisatracurium is degraded by the Hofmann process, alterations in pH and temperature

will affect the elimination of the drug. For example, the neuromuscular blockade

effect is prolonged with acidosis while elimination is enhanced with an increase in

pH. Additionally, hypothermia decreases the elimination of cisatracurium whereas

hyperthermia accelerates it. In ICU patients, the recovery rate from neuromuscular

blockade is reported to range from 45 to 75 minutes after discontinuation of a

prolonged cisatracurium infusion.

82-84 Because J.A. has both a fever (101°F) and

metabolic acidosis (pH 7.30 and HCO3

− 19), it is difficult to predict the clearance of

the neuromuscular blocker.

PHARMACODYNAMIC INTERACTION

A second condition that may add to J.A.’s prolonged blockade is his low phosphate

(phosphate 0.9 mg/dL). Phosphate is a building block of adenosine triphosphate

(ATP). ATP produces energy via an enzymatic reaction by releasing a phosphate

group. This reaction is necessary for physiologic and metabolic functions including

muscle contraction. Therefore, a patient with hypophosphatemia is at risk for a

myopathy.