Page 466 - Basic _ Clinical Pharmacology ( PDFDrive )

452 SECTION V Drugs That Act in the Central Nervous System

administering intravenous anesthetics for neuroprotection during 3 and 8 mcg/mL (typically requiring a continuous infusion rate
neurosurgical procedures. Evidence from animal studies suggests between 100 and 200 mcg/kg/min) when combined with nitrous
that propofol’s neuroprotective effects during focal ischemia are oxide or opioids.
similar to those of thiopental and isoflurane. When used for sedation of mechanically ventilated patients
in the ICU or for sedation during procedures, the required
B. Cardiovascular Effects plasma concentration is 1–2 mcg/mL, which can be achieved
Compared with other induction drugs, propofol produces the most with a continuous infusion at 25–75 mcg/kg/min. Because of its
pronounced decrease in systemic blood pressure; this is a result of pronounced respiratory depressant effect and narrow therapeu-
profound vasodilation in both arterial and venous circulations lead- tic range, propofol should be administered only by individuals
ing to reductions in preload and afterload. This effect on systemic trained in airway management.
blood pressure is more pronounced with increased age, in patients Subanesthetic doses of propofol can be used to treat postopera-
with reduced intravascular fluid volume, and with rapid injection. tive nausea and vomiting (10–20 mg IV as bolus or 10 mcg/kg/
Because the hypotensive effects are further augmented by the inhi- min as an infusion).
bition of the normal baroreflex response, the vasodilation only leads
to a small increase in heart rate. In fact, profound bradycardia and
asystole after the administration of propofol have been described in FOSPROPOFOL
healthy adults despite prophylactic anticholinergic drugs.
As previously noted, injection pain during administration of
C. Respiratory Effects propofol is often perceived as severe, and the lipid emulsion
Propofol is a potent respiratory depressant and generally pro- has several disadvantages. Intense research has focused on find-
ing alternative formulations or related drugs that would address
duces apnea after an induction dose. A maintenance infusion some of these problems. Fospropofol is a water-soluble prodrug
reduces minute ventilation through reductions in tidal volume of propofol, is rapidly metabolized by alkaline phosphatase, and
and respiratory rate, with the effect on tidal volume being more produces propofol, phosphate, and formaldehyde. The formalde-
pronounced. In addition, the ventilatory response to hypoxia and hyde is metabolized by aldehyde dehydrogenase in the liver and
hypercapnia is reduced. Propofol causes a greater reduction in in erythrocytes. The available fospropofol formulation is a sterile,
upper airway reflexes than thiopental does, which makes it well aqueous, colorless, and clear solution that is supplied in a single-
suited for instrumentation of the airway, such as placement of a dose vial at a concentration of 35 mg/mL under the trade name
laryngeal mask airway.
Lusedra.
D. Other Effects Pharmacokinetics & Organ System Effects
Although propofol, unlike volatile anesthetics, does not augment
neuromuscular block, studies have found good intubating condi- Because the active compound is propofol and fospropofol is a
tions after propofol induction without the use of neuromuscular prodrug that requires metabolism to form propofol, the pharma-
blocking agents. Unexpected tachycardia occurring during pro- cokinetics are more complex than for propofol itself. Multicom-
pofol anesthesia should prompt laboratory evaluation for possible partment models with two compartments for fospropofol and
metabolic acidosis (propofol infusion syndrome). An interesting three for propofol have been used to describe the kinetics.
and desirable side effect of propofol is its antiemetic activity. The effect profile of fospropofol is similar to that of propofol,
Pain on injection is a common complaint and can be reduced by but onset and recovery are prolonged compared with propofol
premedication with an opioid or coadministration with lidocaine. because the prodrug must first be converted into an active form.
Dilution of propofol and the use of larger veins for injection can Although patients receiving fospropofol do not appear to experi-
also reduce the incidence and severity of injection pain. ence the injection pain typical of propofol, a common adverse
effect is the experience of paresthesia, often in the perianal region,
Clinical Uses & Dosage which occurs in up to 74% of patients. The mechanism for this
effect is unknown.
The most common use of propofol is to facilitate induction of
general anesthesia by bolus injection of 1–2.5 mg/kg IV. Increas- Clinical Uses & Dosage
ing age, reduced cardiovascular reserve, or premedication with
benzodiazepines or opioids reduces the required induction dose; Fospropofol is approved for sedation during monitored anesthesia
children require higher doses (2.5–3.5 mg/kg IV). Generally, titra- care. Supplemental oxygen must be administered to all patients
tion of the induction dose helps to prevent severe hemodynamic receiving the drug. As with propofol, airway compromise is a
changes. Propofol is often used for maintenance of anesthesia major concern. Hence, it is recommended that fospropofol be
either as part of a balanced anesthesia regimen in combination administered only by personnel trained in airway management.
with volatile anesthetics, nitrous oxide, sedative-hypnotics, and The recommended standard dosage is an initial bolus dose of
opioids or as part of a total intravenous anesthetic technique, 6.5 mg/kg IV followed by supplemental doses of 1.6 mg/kg IV as
usually in combination with opioids. Therapeutic plasma concen- needed. For patients weighing more than 90 kg or less than 60 kg,
trations for maintenance of anesthesia normally range between 90 or 60 kg should be used to calculate the dose, respectively.