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Chapter (3)
PHARMACOLOGY
Propofol
Propofol is the most frequently used IV anesthetic today. It is
used for induction and maintenance of anesthesia and for sedation in
and outside the operating room.(69)
Chemical structure:
Propofol (2, 6-diisopropylphenol) consists of a phenol ring
with two isopropyl groups attached. Altering the side-chain length of
this alkylphenol influences potency, induction, and recovery
characteristics.(70)
Propofol is not water soluble, but a 1% aqueous solution
(10mg/mL) is available for intravenous administration as an oil-inwater emulsion containing soybean oil, glycerol, and egg lecithin. (71)
This formulation can cause pain during injection (less common in
elderly patients) that can be decreased by prior injection of lidocaine
or by mixing lidocaine with propofol prior to injection (2mL of 1%
lidocaine in 18 mL propofol).
(72)
Propofol formulations can support
the growth of bacteria, so good sterile technique must be observed in
preparation and handling.(73)
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Mechanisms of Action:
The mechanism by which propofol induces a state of general
anesthesia may involve facilitation of inhibitory neurotransmission
mediated by GABA.(74)
Pharmacodynamics:
I.
Central nervous system
Anaesthesia is induced within 20-40 s after IV administration
in otherwise healthy young adults.(75)Transfer from blood to the sites
of action in the brain is slower than with thiopental, and there is a
delay in disappearance of the eyelash reflex, normally used as a sign
of unconsciousness after administration of barbiturate anaesthetic
agents. Over dosage of propofol, with exaggerated side-effects, may
result if this clinical sign is used; loss of verbal contact is a better
end-point.(76)
Propofol reduces the duration of seizures induced by ECT in
humans. However, there have been reports of convulsions following
the use of propofol and it is recommended that caution be exercised
in administration of propofol to epileptic patients.(77) Normally
cerebral metabolic rate (CMR), cerebral blood flow (CBF) and
intracranial pressure (ICP) are reduced.(78)
Recovery of consciousness is rapid and there is a minimal
'hangover' effect even in the immediate post-anaesthetic period. (79)
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Cardiovascular system
In healthy patients, arterial pressure decreases to a greater
degree after induction of anaesthesia with propofol than with
thiopental; the reduction results predominantly from vasodilatation
although there is a slight negative inotropic effect. In some patients,
large decreases (> 40%) occur. The degree of hypotension is
substantially reduced by decreasing the rate of administration of the
drug and by appreciation of the kinetics of transfer from blood to
brain.(77)
The pressor response to tracheal intubation is attenuated to a
greater degree by propofol than thiopental. Heart rate may increase
slightly after induction of anaesthesia with propofol.(80)
However, there have been occasional reports of severe
bradycardia and asystole during or shortly after administration of
propofol, and it is recommended that a vagolytic agent (e.g.
glycopyrronium or atropine) should be considered in patients with a
preexisting bradycardia or when propofol is used in conjunction with
other drugs which are likely to cause bradycardia.(80)
III.
Respiratory system
After induction, apnea occurs more commonly, and for a
longer duration, than after thiopental. During infusion of propofol,
tidal volume is lower and respiratory rate higher than in the
conscious state. There is decreased ventilatory response to carbon
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dioxide. As with other agents; ventilatory depression is more marked
if opioids are administered.(81)
Propofol has no effect on bronchial muscle tone and
laryngospasm is particularly uncommon. The suppression of
laryngeal reflexes results in a low incidence of coughing or
laryngospasm when a laryngeal mask airway (LMA) is introduced,
and propofol is regarded by most anesthetists as the drug of choice
for induction of anaesthesia when the LMA is to be used.(82)
IV.
Skeletal muscle
Tone is reduced, but movements may occur in response to
surgical stimulation.(83)
V.
Gastrointestinal system
Propofol has no effect on gastrointestinal motility in animals.
Its use is associated with a low incidence of postoperative nausea
and vomiting.(84)
VI.
Uterus and placenta
Propofol has been used extensively in patients undergoing
gynecological surgery, and it does not appear to have any clinically
significant effect on uterine tone.(85) Propofol crosses the placenta.
Its safety to the neonate has not been established and its use in
pregnancy (except for termination), in obstetric practice and in
breastfeeding mothers is not recommended by the manufacturers.(86)
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Hepatorenal
There is a transient decrease in renal function, but the
impairment is less than that associated with thiopental.(87) Hepatic
blood flow (HBF) is decreased by the reductions in arterial pressure
and cardiac output (CO). Liver function tests are not deranged after
infusion of propofol for 24 h.(88)
VIII.
Endocrine
Plasma concentrations of cortisol are not decreased after
administration of propofol and a normal response occurs to
administration of Synacthen.(89)
Pharmakokinetics:
Propofol is highly protein-bound in vivo and is metabolized
by conjugation in the liver.(90) Its rate of clearance exceeds hepatic
blood flow, suggesting an extrahepatic site of elimination as well.(91)
The half life of elimination of propofol has been estimated at
between 2 and 24 hours. However, its duration of clinical effect is
much shorter, because propofol is rapidly distributed into peripheral
tissues. When used for IV sedation, a single dose of propofol
typically wears off within minutes. Propofol is versatile; the drug
can be given for short or prolonged sedation as well as for general
anesthesia. Its use is not associated with nausea as is often seen with
opioid medications. These characteristics of rapid onset and recovery
along with its amnestic effects have led to its widespread use for
sedation and anesthesia.(91)
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Uses & dosage:
Induction and Maintenance of Anesthesia
Propofol is suitable for the induction and maintenance of
anesthesia. The induction dose is 1 to 2.5 mg/kg. Physiologic
characteristics that best determine the induction dose are age, lean
body mass, and central blood volume.(92)Premedication with an
opiate or a benzodiazepine, or both, markedly reduces the induction
dose.(93)
For induction in children, the ED95 (2 to 3 mg/kg) is
increased, primarily because of pharmacokinetic differences.(94)
Table 1: Uses and Doses of Intravenous Propofol (92)
Induction of general
1-2.5 mg/kg IV dose reduced with
anesthesia
increasing age
Maintenance of
50-150 µg/kg/min IV combined with N2O
general anesthesia
or an opiate
Sedation
25-75 µg/kg/min IV
Antiemetic
10-20 mg IV, can repeat every 5-10 min
or start infusion of 10 µg/kg/min
N2O, nitrous oxide.
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Propofol, when used for induction of anesthesia in briefer
procedures, results in a significantly quicker recovery and an earlier
return of psychomotor function compared with thiopental or
methohexital, regardless of the anesthetic used for maintenance of
anesthesia. The incidence of nausea and vomiting when propofol is
used for induction also is markedly less than after the use of other IV
anesthetics, probably because of the antiemetic properties of
propofol.(95)
Because of its pharmacokinetics, propofol provides a rapid
recovery and is superior to barbiturates for maintenance of
anesthesia, and it seems to be equal to enflurane, isoflurane and
sevoflurane.(96)
Several infusion schemes have been used to achieve adequate
plasma concentrations of propofol. After an induction dose, an
infusion of 100 to 200µg/kg/min is usually needed.
(97)
The infusion
rate is titrated to individual requirements and the surgical
stimulus.(98)
When combined with propofol, the required infusion rate and
concentration of opiates, midazolam, clonidine, or ketamine is
reduced. Because opioids alter the concentration of propofol
required for adequate anesthesia, the relative dose of either opioid or
propofol markedly affects the time from termination of drug to
awakening and recovery.(98) Increasing age is associated with a
decrease in propofol infusion requirements, whereas these
requirements are higher in children and infants.(99)
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Sedation
Propofol has been evaluated for sedation during surgical
procedures(100) and for patients receiving mechanical ventilation in
the ICU.(101) Propofol by continuous infusion provides the ability to
titrate to a desired level of sedation and provide a rapid recovery
after infusion is terminated, regardless of the duration of the
infusion.(102)
Infusion rates required for sedation to supplement regional
anesthesia in healthy patients are half or less than the rates required
for general anesthesia (i.e., 30 to 60µg/kg/min). In elderly patients
(>65 years old) and in sicker patients, the infusion rates that are
necessary are markedly reduced. It is important to titrate the infusion
individually to the desired effect.(102)
Although the pharmacokinetic profile and to a large extent the
pharmacology of propofol make it an excellent choice for long-term
(days) sedation, this always must be weighed against the
hemodynamic effects, the often concomitant need for an analgesic,
tolerance, and rare occurrences of hypertriglyceridemia (and
potential pancreatitis) or propofol infusion syndrome. The
recommended
maximal
dose of propofol infusion rate is
80 µg/kg/min (<5 mg/kg/hr).(103)
Side Effects and Contraindications:
Induction of anesthesia with propofol is associated with
several side effects, including pain on injection, myoclonus, apnea,
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hypotension, and, rarely, thrombophlebitis of the vein into which
propofol is injected. Pain on injection is reduced by using a large
vein, avoiding veins in the dorsum of the hand, and adding lidocaine
to the propofol solution or changing the propofol formulation.(104)
The most common side effect during induction of anesthesia is
hypotension, which is augmented by the concomitant administration
of opioids. Conversely, with laryngoscopy and endotracheal
intubation, the changes in MAP, heart rate, and systemic vascular
resistance are less significant after propofol compared with
thiopental.(105)
Propofol infusion syndrome is a rare but lethal syndrome
associated with infusion of propofol at 5 mg/kg/hr or more for 48
hours or longer. It was first described in children, but subsequently
has been observed in critically ill adults. The clinical features of
propofol infusion syndrome are acute refractory bradycardia leading
to asystole, in the presence of one or more of the following:
metabolic acidosis (base deficit >10 mmol/L-1), rhabdomyolysis,
hyperlipidemia, and enlarged or fatty liver.(106)
Absolute contraindications:
Airway obstruction and known hypersensitivity to the drug are
probably the only absolute contraindications. Propofol should not be
used for long-term sedation of children in the ICU because of a
number of reports of adverse outcome.(107)
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Sevoflurane
Sevoflurane is a methyl propyl ether which was first
synthesized in 1968 and reported in 1971. The initial development
was slow because of some apparent toxic effects, which were later
found to be caused by flawed experimental design. After its first use
in volunteers in 1981, further work was delayed again because of the
problems of biotransformation and stability with soda lime. The drug
has been available for general clinical use in Japan since 1990, and
by the end of 1993, 1 million patients had received sevoflurane.(108)
Physical properties:
It is non-flammable and has a pleasant smell. The blood/gas
partition coefficient of sevoflurane is 0.69, which is about half of
that of isoflurane (1.43) and closer to that of desflurane (0.42) and
nitrous oxide (0.44).
(109)
The MAC value of sevoflurane in adults is
between 1.7 and 2% in oxygen and 0.66% in 60% nitrous
oxide.(110)The MAC, in common with other volatile agents, is higher
in children (2.6% in oxygen and 2.0% in nitrous oxide) and neonates
(3.3%) and it is reduced in the elderly (1.48%). It is stable and is
stored in amber colored bottles. In the presence of water, it
undergoes some hydrolysis and this reaction also occurs with soda
lime.(111)
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Pharmacokinetics:
Uptake and distribution
It has a low blood/gas partition coefficient and therefore the
rate of equilibration between alveolar and inspired concentrations is
faster than that for halothane, enflurane or isoflurane but slower than
that for desflurane. It is non-irritant to the upper respiratory tract and
therefore the rate of induction of anaesthesia should be faster than
that with any of the other agents.(108)
Because of its higher partition coefficients in vessel-rich
tissues, muscle and fat than corresponding values for desflurane, the
rate of recovery is slower than that after desflurane anaesthesia.(112)
Metabolism
Approximately 5% of the absorbed dose is metabolized in the
liver to two main metabolites(113) :
The major breakdown product is hexafluoroisopropanol:
An organic fluoride molecule which is excreted in the urine as
a glucuronide conjugate.(114)Although this molecule is potentially
hepatotoxic, conjugation of hexafluoroisopropanol occurs so rapidly
that clinically significant liver damage seems theoretically
impossible.(115)
The second breakdown product is inorganic fluoride ion:
The mean peak fluoride ion concentration after 60 min of
anaesthesia at 1 MAC is 22µmol/L, which is similar to that produced
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after enflurane anaesthesia and significantly higher than that after an
equivalent dose of isoflurane.(114)
Pharmacodynamics:
I.
Respiratory system
The drug is non-irritant to the upper respiratory tract. It
produces dose-dependent ventilatory depression.The ventilatory
depression associated with sevoflurane may result from a
combination of central depression of medullary respiratory neurones
and depression of diaphragmatic function and contractility. It relaxes
bronchial smooth muscle but not as effectively as halothane.(116)
II.
Cardiovascular system
Sevoflurane have smaller effects on heart rate and causes less
marked coronary vasodilatation. It decreases arterial pressure mainly
by reducing peripheral vascular resistance, but cardiac output is well
maintained over the normal anaesthetic maintenance doses. There is
mild myocardial depression resulting from its effect on calcium
channels.(117)Sevoflurane does not sensitize the myocardium to
catecholamines.
(118)
It is a less potent coronary arteriolar dilator(119)
and therefore does not appear to cause 'coronary steal'.(120)
Sevoflurane is associated with lower heart rate and therefore
helps to reduce myocardial oxygen consumption.(121)
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Central nervous system
Intracranial pressure increases at high inspired concentrations
of sevoflurane but this effect is minimal over the 0.5-1.0 MAC
range. It decreases cerebral vascular resistance and cerebral
metabolic rate. It does not cause excitatory effects on the EEG.(122)
IV.
Renal system
The peak concentration of inorganic fluoride after sevoflurane
is similar to that after enflurane anaesthesia(113)and there is a positive
correlation between duration of exposure and the peak concentration
of fluoride ions.(123) However, renal toxicity does not appear to be
related to inorganic fluoride concentrations following anaesthesia
with sevoflurane as opposed to that associated with methoxyflurane.
The apparent lack of renal toxicity with sevoflurane may be
related to its rapid elimination from the body. This reduces the total
amount of drug available for in vivo metabolism.(124) Renal blood
flow is well preserved with sevoflurane.(108)
V.
Musculoskeletal system
The drug potentiates non-depolarizing muscle relaxant.
Sevoflurane can trigger malignant hyperthermia in susceptible
patients and there have been cases reported in the literature.(125)
VI.
Obstetric use
There are limited data on the use of sevoflurane in the obstetric
population.(126)
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Phenylephrine
Clinical Considerations
Phenylephrine is a noncatecholamine chemically known as 3hydroxy-alpha-[(methylamino)methyl] benzyl alcohol available as a
(1:1) hydrochloride salt. It is a sympathomimetic amine that has
primarily
alpha
1-adrenergic
activity
causing
peripheral
vasoconstriction (high doses may stimulate α2- and β-receptors) (fig.
5).(127)
The
primary
effect
of
phenylephrine
is
peripheral
vasoconstriction with a concomitant rise in systemic vascular
resistance and arterial blood pressure. It has no chronotropic or
inotropic effect, however reflex bradycardia can reduce cardiac
output. Coronary blood flow increases because any direct
vasoconstrictive effect of phenylephrine on the coronary arteries is
overridden by vasodilation induced by the release of metabolic
factors.(128)
Fig. 5: Phenylephrine.(129)
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Pharmacokinetics/Dynamics
Phenylephrine is a pure alpha-adrenergic agonist and leads to
vasoconstriction
without
chronotropic
or
inotropic
effects.
Phenylephrine is poorly absorbed orally (<38%), but can be
efficacious via the subcutaneous (SQ) or intramuscular (IM) route.
The onset of action depends on the route of administration, with SQ
and IM administration being 10–15 min, while IV administration is
immediate.(128)
The volume of distribution (Vd) can range from 184 to 543 L,
and metabolism is extensive. Hepatic metabolism involves 50%
deamination, but there is also a degree of sulfation and
glucuronidation before the metabolites are excreted in the urine. The
alpha half-life is about 5 min, but the terminal half-life is about 2–3
hours. The duration of action is about 1–2 hours if given IM, 50 min
if given SQ, and 15–20 min if given IV.(130)
Indications/Dosage/Administration
Phenylephrine may be used to maintain adequate BP during
anesthesia use, shock, or shock-like states. It may also be used to
overcome paroxysmal supraventricular tachycardia from prolonged
spinal anesthesia and as a vasoconstrictor in regional anesthesia.(131)
Phenylephrine can be given as a 100–500 µg bolus dose every
10–15 min, if needed. IV infusions should start at a dose of 100–180
µg/min (or 0.5 µg/kg/min) and be titrated to maintain a low-normal
SBP of 80–100 mm Hg or MAP 60 mm Hg. Tachyphylaxis occurs
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with phenylephrine infusions requiring upward titration of the
infusion. Concentrations of phenylephrine should range from 0.04 to
0.2 µg/mL, and can be mixed with dextrose, saline, or lactated
Ringer’s solutions. (132)
Adverse Effects
Adverse reactions include reflex bradycardia, hypertension,
metabolic acidosis, and gastric irritation and nausea. Phenylephrine
use may lead to anxiety, headache, parasthesias, tremors, and
weakness. Extravasation necrosis at the injection site is a serious
complication that can be minimizedvby dilution and administration
through a large vein.(133)
Drug Interactions
Phenylephrine interacts with tricyclic antidepressants (eg,
amitriptyline, clomipramine, and imipramine), atomoxetine, and
MAO inhibitors with clinical increases in alpha-adrenergic
effects.(132)
Availability
Phenylephrine is available in 10 mg/mL vials of 1 and 5 Ml. (130)
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Sodium Nitroprusside
Mechanism of Action
Sodium nitroprusside relaxes both arteriolar and venous
smooth muscle. Its primary mechanism of action is shared with other
nitrates (eg, hydralazine and nitroglycerin). As these drugs are
metabolized, they release nitric oxide,(134) which activates guanylyl
cyclase. This enzyme is responsible for the synthesis of cyclic
guanosine 3',5'-monophosphate (cGMP), which controls the
phosphorylation of several proteins, including some involved in
control
of
free intracellular
calcium
and
smooth
muscle
contraction.(135)
Nitric oxide, a naturally occurring potent vasodilator released
by endothelial cells (endothelium-derived relaxing factor), plays an
important role in regulating vascular tone throughout the body. Its
ultrashort half-life (< 5 s) provides sensitive endogenous control of
regional blood flow.(136)
Clinical trials have shown that inhaled nitric oxide is a
selective pulmonary vasodilator that may be beneficial in the
treatment of reversible pulmonary hypertension. By improving
perfusion only in ventilated areas of the lung, inhaled nitric oxide
may improve oxygenation in patients with acute respiratory distress
syndrome (ARDS) or during one-lung ventilation. Nitric oxide may
also have antiinflammatory effects that could promote lung
healing.(137)
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Clinical Uses
Sodium nitroprusside is a potent and reliable antihypertensive.
It is usually diluted to a concentration of 100 µg/mL and
administered as a continuous intravenous infusion (0.5–10
µg/kg/min). Its extremely rapid onset of action (1–2 min) and
fleeting duration of action allow precise titration of arterial blood
pressure.
(138)
A bolus of 1–2 µg/kg minimizes blood pressure
elevation during laryngoscopy but can cause transient hypotension
in some patients.
The potency of this drug requires frequent blood pressure
measurements or, preferably, intraarterial monitoring and the use of
mechanical infusion pumps. Solutions of sodium nitroprusside must
be protected from light because of photodegradation. (139)
Metabolism
After parenteral injection, sodium nitroprusside enters red
blood cells, where it receives an electron from the iron (Fe2+) of
oxyhemoglobin. This nonenzymatic electron transfer results in an
unstable nitroprusside radical and methemoglobin (Hgb Fe3+). The
former moiety spontaneously decomposes into five cyanide ions and
the active nitroso group. (140)
The cyanide ions can be involved in one of three possible
reactions: binding to methemoglobin to form cyanmethemoglobin;
(140)
undergoing a reaction in the liver and kidney catalyzed by the
enzyme rhodanase (thiosulfate + cyanide ---> thiocyanate);
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(141)
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binding to tissue cytochrome oxidase, which interferes with normal
oxygen utilization. (142)
The last of these reactions is responsible for the development
of acute cyanide toxicity, characterized by metabolic acidosis,
cardiac arrhythmias, and increased venous oxygen content (as a
result of the inability to utilize oxygen). Another early sign of
cyanide toxicity is the acute resistance to the hypotensive effects of
increasing doses of sodium nitroprusside (tachyphylaxis). (143)
Cyanide toxicity can usually be avoided if the cumulative dose
of sodium nitroprusside is less than 0.5 mg/kg/h. Patients with
cyanide toxicity should be mechanically ventilated with 100%
oxygen to maximize oxygen availability. The pharmacological
treatment of cyanide toxicity depends on increasing the kinetics of
the two reactions by administering sodium thiosulfate (150 mg/kg
over 15 min) or 3% sodium nitrate (5 mg/kg over 5 min), which
oxidizes hemoglobin to methemoglobin.
(144)
Hydroxocobalamin, an
experimental drug, combines with cyanide to form cyanocobalamin
(vitamin B12). (143)
Thiocyanate is slowly cleared by the kidney. Accumulation of
large amounts of thiocyanate (eg, in patients with renal failure) may
result in a milder toxic reaction that includes thyroid dysfunction,
muscle weakness, nausea, hypoxia, and an acute toxic psychosis.
The risk of cyanide toxicity is not increased by renal failure,
however.
(141)
Methemoglobinemia from excessive doses of sodium
nitroprusside or sodium nitrate can be treated with methylene blue
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(1–2 mg/kg of a 1% solution over 5 min), which reduces
methemoglobin to hemoglobin.
Effects on Organ Systems
Cardiovascular
The combined dilation of venous and arteriolar vascular beds
by sodium nitroprusside results in reductions of preload and
afterload. Arterial blood pressure (ABP) falls due to the decrease in
peripheral vascular resistance. (145)
Although cardiac output is usually unchanged in normal
patients, the reduction in afterload may increase cardiac output in
patients with congestive heart failure, mitral regurgitation, or aortic
regurgitation.(134) In contrast to the pure afterload reduction produced
by hydralazine, sodium nitroprusside primarily reduces preload,
which decreases myocardial work and the likelihood of ischemia. In
opposition to any favorable changes in myocardial oxygen
requirements are reflex-mediated responses to the fall in arterial
blood pressure. These include tachycardia (less pronounced than
with hydralazine) and increased myocardial contractility. In
addition, dilation of coronary arterioles by sodium nitroprusside may
result in an intracoronary steal of blood flow away from ischemic
areas that are already maximally dilated. (145)
Cerebral
Sodium nitroprusside dilates cerebral vessels and abolishes
cerebral autoregulation. Cerebral blood flow is maintained or
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increases unless arterial blood pressure is markedly reduced. The
resulting increase in cerebral blood volume tends to increase
intracranial
pressure,
particularly
in
patients
with
reduced
intracranial compliance (eg, brain tumors). This intracranial
hypertension can be minimized by slow administration of sodium
nitroprusside and institution of hypocapnia. (147)
Respiratory
The pulmonary vasculature also dilates in response to sodium
nitroprusside infusion. Reductions in pulmonary artery pressure may
decrease the perfusion of some normally ventilated alveoli,
increasing physiological dead space. By dilating pulmonary vessels,
sodium nitroprusside may prevent the normal vasoconstrictive
response of the pulmonary vasculature to hypoxia (hypoxic
pulmonary vasoconstriction). Both these effects tend to mismatch
pulmonary
ventilation
to
perfusion
and
decrease
arterial
oxygenation. (148)
Renal
In response to decreased arterial blood pressure, renin and
catecholamines are released during administration of nitroprusside.
This hormonal response, which can lead to a pressure rebound after
discontinuation of the drug, is blocked by propranolol or a high
epidural block (T1 level). Renal function is fairly well maintained
during sodium nitroprusside infusion despite moderate drops in
arterial blood pressure and renal perfusion. (149)
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Drug Interactions
Sodium nitroprusside
does
not
directly
interact
with
neuromuscular blocking agents. Nonetheless, a decrease in muscle
blood flow caused by arterial hypotension could indirectly delay the
onset and prolong the duration of neuromuscular blockade.(150) By
inhibiting phosphodiesterase, aminophylline increases cGMP and
potentiates the hypotensive effects of these agents.(151)
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