Pentothal

Generic Name: Thiopental Sodium
Class: Barbiturates
VA Class: CN202
Chemical Name: 5-Ethyl-dihydro-5-(1-methylbutyl)-2-thioxo-4,6(1H,5H)-pyrimidinedione monosodium salt
Molecular Formula: C₁₁H₁₇N₂NaO₂S
CAS Number: 71-73-8

Introduction

Barbiturate anesthetic.^{1 2 3 7 24}

Uses for Pentothal

Induction and Maintenance of Anesthesia

Induction of general anesthesia prior to administration of other anesthetic agents or as the sole anesthetic agent for short (≤15 minutes) surgical procedures.^{1 2 3 4 7 12}

Induction results in dose-related hypnotic effects (progressing from light sleep to unconsciousness) and anterograde amnesia, but not analgesia.^{1 2 12}

Adjunct to regional anesthesia (also called block anesthesia or conduction anesthesia).^{1 2}

As the hypnotic component of balanced anesthesia (e.g., IV hypnotic and/or inhalation anesthetic, analgesic, skeletal muscle relaxant).^{1 2 3 7 12}

Seizures

Management of seizures occurring during or after administration of local or inhalation anesthetics and seizures attributed to various etiologies.^{1 2 3 6 7 12 23 47 78 110}

Control of generalized tonic-clonic status epilepticus refractory to conventional anticonvulsants† in intubated and mechanically ventilated patients.^{3 6 47}

Increased Intracranial Pressure

Management of increased intracranial pressure associated with neurosurgical procedures when adequate ventilation is maintained.^{1 2 3 7 12 13 58}

Has been used to induce coma^{3 12 26 85 86 87 88 89 90 105} in the management of cerebral ischemia† and increased intracranial pressure associated with head trauma injury†/^{3 27 86 87 88 89} stroke†,^{3 85} Reye’s syndrome†,³ or hepatic encephalopathy†;^{3 90} however, pentobarbital is the most commonly used barbiturate.^{26 89} Safety and efficacy for the management of increased intracranial pressure associated with neurotraumas are controversial ^{26 85 86 87 88 105} and are not established.^{26 85 88 105}

Narcoanalysis

Hypnotic agent for narcoanalysis in psychiatric conditions; use historically misnomered as “truth serum.”^{1 2 104 106 123 124}

Sedation in Children

To provide sedation† when administered as extemporaneously prepared rectal suspensions, solutions, or suppositories prior to diagnostic procedures (e.g., computed tomography [CT scan], magnetic resonance imaging [MRI]).^{27 28 29 30 31 108}

Pentothal Dosage and Administration

General

Test Dose

• 
  

  Prior to initiation of therapy, the manufacturers recommend administration of a 25- to 75-mg test dose (1–3 mL of a 2.5% solution) followed by observation of the patient for ≥60 seconds to detect unusual sensitivity and assess tolerance.^{1 2 12} Reduce dosage in particularly sensitive patients.¹²

  
  


• 
  

  If unexpectedly deep anesthesia or respiratory depression occurs, consider factors other than sensitivity (e.g., excessive premedication, unintended use of a more concentrated solution).^{1 2}

  
  

Premedication

• 
  

  The manufacturers state that patients may receive premedication with other drugs (e.g., benzodiazepines [to relieve anxiety and produce anterograde amnesia], other barbiturates [to relieve anxiety and provide sedation]) prior to administration of thiopental for induction of anesthesia.^{1 2 12} Anticholinergic agents (e.g., atropine, scopolamine) also have been used (to suppress vagal reflexes and inhibit secretions).^{1 2} Peak effects of these drugs should be reached shortly before IV induction.^{1 2}

  
  

Administration

IV Administration

For solution and drug compatibility, see Compatibility under Stability.

Administer by IV injection or continuous IV infusion.^{1 2 3}

To decrease pain at the injection site, administer thiopental by slow injection into large veins (rather than into small hand veins); may also administer a local anesthetic or an opiate agonist prior to induction to minimize pain.¹²

Avoid extravasation and intra-arterial administration.^{1 2} (See Local Effects under Cautions.) Prior to IV infusion, check placement of the IV catheter to ensure that it is in the vein.^{1 2}

Observe strict aseptic technique in preparing and handling thiopental solutions as commercially available thiopental sodium for injection contains no preservatives.^{1 2} Reconstituted solutions should not be sterilized by heat.^{1 2} Use promptly and discard any unused portion after 24 hours.^{1 2}

Reconstitution for Intermittent IV Injection

For intermittent IV administration, reconstitute powder for injection with sterile water for injection, 0.9% sodium chloride injection, or 5% dextrose injection to a concentration of 2–5% (usually 2 or 2.5%).^{1 2}

A 3.4% solution of thiopental sodium in sterile water for injection is isotonic.^{1 2} Do not use sterile water for injection for preparing solutions with concentrations <2%, since use of the resulting hypotonic solutions will cause hemolysis.^{1 2}

Use 2.5- or 5-g vials when preparing solutions for several patients.^{1 2}

Preparation of 2% Thiopental Sodium Solution12

Amount of Thiopental Sodium (g in vial)	Volume of Diluent
0.4 g	20 mL
1 g	50 mL
2.5 g	125 mL
5 g	250 mL

Preparation of 2.5% Thiopental Sodium Solution12

Amount of Thiopental Sodium (g in vial)	Volume of Diluent
0.25 g	10 mL
0.5 g	20 mL
1 g	40 mL
2.5 g	100 mL
5 g	200 mL

Preparation of 5% Thiopental Sodium Solution12

Amount of Thiopental Sodium (g in vial)	Volume of Diluent
1 g	20 mL
5 g	100 mL

Reconstitution for IV Infusion

For continuous IV infusion, reconstitute thiopental sodium powder for injection with 0.9% sodium chloride injection, 5% dextrose injection, or Normosol-R (pH 7.4) to a concentration of 0.2–0.4%.^{1 2}

A 3.4% solution of thiopental sodium in sterile water for injection is isotonic.^{1 2} Do not use sterile water for injection for preparing solutions with concentrations <2%, since use of the resulting hypotonic solutions will cause hemolysis.^{1 2}

Preparation of Thiopental for IV Infusion12

Desired Concentration of Final Solution	Amount of Thiopental Sodium (g in vial)	Volume of Diluent
0.2%	1 g	500 mL
0.4%	1 g	250 mL
0.4%	2 g	500 mL

Rate of Administration

IV injection: Administer slowly (see Dosage) to minimize respiratory depression and the possibility of overdosage.^{1 2 120}

Depth of anesthesia is controlled by rate of IV infusion.^{1 2} Clinical assessment of the depth of anesthesia is based on responses to verbal commands and surgical stimulation, EEG changes, autonomic signs, eyelash reflex, and movement.^{4 7 12 119 120 121 122}

Rectal Administration

Preparations for rectal† use no longer commercially available in the US; extemporaneous rectal formulations have been prepared^{7 27 28 29 30} using commercially available thiopental sodium for injection.^{28 108}

Dosage

Available as thiopental sodium; dosage expressed in terms of the salt.^{1 2}

Individual response to thiopental is variable; therefore, adjust dosage according to individual requirements and response, age, weight, gender, physical and clinical status, underlying pathologic conditions (e.g., shock, intestinal obstruction, malnutrition, anemia, burns, advanced malignancy, ulcerative colitis, uremia, alcoholism), and the type and amount of premedication or concomitant medication(s).^{1 2 7 12}

Pediatric Patients

Pediatric patients require relatively larger doses than middle-aged and geriatric adults.^{1 2 11 12 120 121}

Reduce dosage in neonates (because of decreased protein binding¹¹ and reduced clearance).^{11 18}

Induction and Maintenance of Anesthesia

IV

Induction of anesthesia in infants: 7–8 mg/kg administered over 20–30 seconds is recommended by some clinicians; however, this dosage is estimated for healthy individuals and should be titrated to clinical effect.^{4 12}

Induction of anesthesia in children: 5–6 mg/kg administered over 20–30 seconds is recommended by some clinicians; however, this dosage is estimated for healthy individuals and should be titrated to clinical effect.^{4 12}

Seizures

IV

Initial loading dose of 1 mg/kg followed by continuous IV infusion of 10–120 mcg/kg per minute has been used.⁶ A limited number of children receiving conventional anticonvulsants have received thiopental infusions for 3–5 days.⁷

Increased Intracranial Pressure

Increased Intracranial Pressure Associated with Trauma†

IV

Children 3 months to 15 years of age: Initial dose of 5–10 mg/kg followed by continuous IV infusion of 1–4 mg/kg per hour.⁷ A more rapid IV infusion rate of up to 7–12 mg/kg per hour has been maintained for 8–10 days.⁷

Sedation†

Rectal

25–50 mg/kg.^{27 28 29 31}

In one study, dosage was based on both the child’s weight and age.²⁹

Thiopental Sodium Dosage for Sedation Based on Child’s Weight and Age29

Age of Child	Dosage
<6 months	50 mg/kg
6 months to 1 year	35 mg/kg
>1 year	25 mg/kg (maximum 700 mg)

Adults

Younger patients require relatively larger doses than middle-aged and geriatric adults.^{1 2 11 12 120 121} Some clinicians estimate that dosage requirements decrease by 10% per decade over the age range of 20–80 years.⁷

Adult males usually require higher dosages than adult females.^{1 2 11 12 120 121}

Induction and Maintenance of Anesthesia

IV

Moderately slow induction of anesthesia: Initially, 50–75 mg (2–3 mL of a 2.5% solution), usually administered at intervals of 20–40 seconds, based on patient response.^{1 2} Additional doses of 25–50 mg may be given as necessary when patient movements indicate lightening of anesthesia.^{1 2}

Alternatively, some clinicians suggest induction doses administered over 20–30 seconds of 3–5 mg/kg in young adults or 2–4 mg/kg in older adults; however, these dosages are estimated for healthy individuals and should be titrated to clinical effect.^{4 12}

Rapid induction as a component of balanced anesthesia: Initially, 210–280 mg (3–4 mg/kg) given in 2–4 divided doses in an average 70-kg adult.^{1 2}

Maintenance of anesthesia: Intermittent injections or continuous IV infusion of a 0.2 or 0.4% solution may be used without additional anesthetic agents for short (≤15-minute) surgical procedures.^{1 2}

Seizures

IV

75–125 mg (3–5 mL of a 2.5% solution) administered as soon as possible after seizures develop.^{1 2}

Seizures following Administration of Local Anesthesia

IV

125–250 mg administered over 10 minutes;^{1 2 121} dosage depends on the amount of the local anesthetic used and its seizure characteristics.^{1 2}

Generalized Tonic-Clonic Status Epilepticus

IV

Initial loading dose of 5 mg/kg followed in 30 minutes by continuous IV infusion of 1–3 mg/kg per hour for ≥12 hours after seizures abate is recommended by some clinicians.³ Alternatively, an initial loading dose of 250–1000 mg followed by continuous IV infusion of 80–120 mg per hour has been used for up to 13 days.⁴⁷

Increased Intracranial Pressure

Increased Intracranial Pressure Associated with Neurosurgical Procedures

IV

1.5–3.5 mg/kg by intermittent IV infusion.^{1 2}

Alternatively, an initial loading dose of 20 mg/kg administered over 1 hour, followed by a second loading dose of 10 mg/kg per hour over 6 hours and subsequently followed by a continuous IV maintenance infusion of 3 mg/kg per hour, has been used.^{117 118 120} Dosage was adjusted to maintain blood concentrations of 20–40 mcg/mL.¹¹⁷

Increased Intracranial Pressure Associated with Head Injury†

IV

Low-dosage IV infusion (0.5–3 mg/kg per hour) administered in combination with other therapeutic agents (e.g., dihydroergotamine, metoprolol, clonidine) has been used.^{86 87}

Narcoanalysis

IV

Patients usually receive an anticholinergic agent prior to a test dose of thiopental.^{1 2}

Administer at a rate of 100 mg/minute (4 mL/minute of a 2.5% solution) while the patient counts backward from 100.^{1 2} Shortly after the counting becomes confused but before actual sleep occurs, discontinue thiopental, allowing the patient to return to a semidrowsy state under which conversation is coherent.^{1 2}

Alternatively, administer as a 0.2% solution by continuous IV infusion at a rate ≤50 mL/minute (100 mg/minute).^{1 2}

Some clinicians have used an initial IV loading dose of 25 mg followed by continuous IV infusion of 0.5 mg/kg per hour.^{104 123}

Special Populations

Hepatic Impairment

Generally not recommended for use; however, if used, reduce dosage and rate of administration.^{1 2 96 121}

Renal Impairment

Generally not recommended for use; however, if used, reduce dosage and rate of administration.^{1 2 96 121}

Geriatric Patients

Reduce initial dosage.^{1 2 12} Some clinicians estimate that dosage requirements decrease by 10% per decade over the age range of 20–80 years.⁷

Obese Patients

Dosage requirements are proportional to body weight.^{1 2} Obese patients may require larger doses than relatively lean patients of the same weight;^{1 2} however, some clinicians suggest that dosage used in anesthesia⁷ should be based on lean body weight.^{7 12 120}

Other Populations

Reduce dosage and administer slowly in patients with severe cardiovascular disease, hypotension or shock, status asthmaticus, and conditions that might prolong or intensify the hypnotic effect (e.g., excessive premedication, Addison’s disease, myxedema, increased blood urea concentrations, severe anemia, asthma, myasthenia gravis).^{1 2}

Cautions for Pentothal

Contraindications

• 
  

  Known hypersensitivity to barbiturates.^{1 2}

  
  


• 
  

  Patients in whom a suitable vein is not accessible for IV administration.^{1 2}

  
  


• 
  

  History of acute intermittent porphyria or porphyria variegata,^{1 2} since thiopental interferes with porphyrin metabolism.¹²

  
  

• Relative Contraindications (See Other Populations under Dosage and Administration):


• 
  

  Severe cardiovascular disease.^{1 2}

  
  


• 
  

  Hypotension or shock.^{1 2}

  
  


• 
  

  Status asthmaticus.^{1 2}

  
  


• 
  

  Conditions that might prolong or intensify the hypnotic effect (e.g., excessive premedication, Addison’s disease, hepatic or renal impairment, myxedema, increased blood urea concentrations, severe anemia, asthma, myasthenia gravis).^{1 2}

  
  

Warnings/Precautions

Warnings

Respiratory and Cardiovascular Effects

Possible respiratory depression.^{1 2 3 4 7 12 13 14} May depress ventilatory response to carbon dioxide stimulation¹² or cause decreases in tidal volume.¹² Apnea and hypoventilation may result from unusual responsiveness or overdosage.^{1 2}

Laryngospasm may occur during light anesthesia at intubation or, in the absence of intubation, it may be associated with irritation caused by foreign matter or secretions in the respiratory tract.^{1 2 7} Laryngospasm or bronchospasm is more likely caused by premature insertion of oral airways or endotracheal tubes in inadequately anesthetized patients by airway reactivity.¹² Manufacturers state that laryngeal and bronchial vagal reflexes may be suppressed and secretions minimized by premedication with an anticholinergic agent (e.g., atropine, scopolamine) and administration of a barbiturate or an opiate agonist.^{1 2 121}

Possible myocardial depression (proportional to the amount of drug that is in direct contact with the heart),^{1 2 33 36 38} cardiac arrhythmias (occurring rarely in patients with adequate ventilation),^{1 2} increased heart rate,¹² circulatory depression,⁷ vasodilation,¹² and hypotension (especially in hypovolemic patients).^{3 7 38} These effects may be particularly severe in patients with impaired vascular homeostatic mechanisms.^{1 2 7 12 13 120}

Appropriate resuscitative equipment for prevention and treatment of anesthetic emergencies must be readily available.^{1 2} Facilities for intubation, assisted respiration, and administration of oxygen must be available whenever the drug is used.^{1 2}

Supervised Administration

Should be administered only by individuals qualified in the use of IV anesthetics.^{1 2}

Local Effects

Local reactions at the injection site reported; ^{12 33 36 38} IV administration has caused pain,^{12 36 38} venous thrombosis,³³ phlebitis,³³ and thrombophlebitis.³³

Extravasation can cause chemical irritation of perivascular tissues (possibly associated with high alkalinity [pH 10–11] of the injection);^{120 121} local reactions can vary from slight tenderness to venospasm, extensive necrosis, and sloughing.^{1 2}

Inadvertent intra-arterial injection may cause arteriospasm and severe pain along the affected artery; the resulting necrosis can progress to gangrene.^{1 2} Increased risk of intra-arterial administration if aberrant arteries are present (especially at the medial aspect of the antecubital fossa).^{1 2}

Decrease pain at the injection site by slow injection into large veins (rather than into small hand veins) and by administration of a local anesthetic or an opiate agonist prior to induction.¹²

IV solutions in concentrations >2.5% appear to be associated with an increased incidence of local adverse effects;³³ severe tissue injury may occur when solutions of these concentrations are injected sub-Q or intra-arterially.¹²

In a conscious patient, the first manifestation of intra-arterial injection may be a complaint of fiery burning that roughly follows the distribution path of the injected artery with blanching of the arm and fingers; stop the injection immediately and assess the situation.^{1 2}

Treatment of extravasation or inadvertent intra-arterial injection includes application of moist heat and administration of a 1% procaine injection at the affected site.^{1 2 120} The most appropriate therapy for inadvertent intra-arterial injection has not been fully established; efforts aimed at prevention are important; consult the manufacturers’ labeling for suggested therapies that may be beneficial.^{1 2}

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactic or anaphylactoid and other serious hypersensitivity reactions (e.g., urticaria,^{1 2} flushing and/or rash [on the face, neck, and/or upper chest],^{12 33 42} bronchospasm,^{1 2 42 45 61} vasodilation,^{1 2} hypotension,^{42 44} edema,^{1 2 44} angioedema,⁴² cardiovascular collapse,⁴⁵ shock,¹² death^{1 2 3 12 33 34 40 41 42 43 44 61} ) reported rarely.^{1 2}

Allergic reactions often appear to be immediate type I IgE-mediated hypersensitivity reactions,^{33 34 40 41 42 43 44 45} although some reactions may result from direct histamine release.^{33 34 42 43 46} Hypersensitivity reactions are most likely to occur in patients with asthma^{33 34 61} or urticaria⁴² and in those with a history of atopy^{34 40 42 43 61} or allergies to other drugs and/or food.^{33 40 42 43 44 45}

General Precautions

Postoperative Shivering

Postoperative shivering (manifested by facial muscle twitching and occasionally by tremor of arms, head, shoulder, and body) reported in up to 65% of patients receiving general anesthesia.^{1 2 56 57 120} Shivering may lead to increased oxygen demand with increases in minute ventilation and cardiac output.^{56 57}

Management includes administration of chlorpromazine or methylphenidate, raising room temperature to 22°C, and covering patient with blankets.^{1 2}

Concomitant Medical Conditions

Use with caution in patients with advanced cardiac disease, increased intracranial pressure, ophthalmoplegia plus, asthma, myasthenia gravis, and endocrine disorders (e.g., pituitary, thyroid, adrenal, pancreas).^{1 2}

Specific Populations

Pregnancy

Category C.¹

Usual anesthesia induction doses have been used safely in women undergoing cesarean section.¹² Use in pregnant women only when clearly needed.^{1 2}

Lactation

Distributed into colostrum^{7 20 50} and milk.^{1 2 50}

Many clinicians state that nursing women undergoing surgery may receive usual anesthetic induction doses of thiopental;^{12 51 52} however, since trace amounts of the drug may be present in milk, drowsiness of nursing infants may occur on the day of the procedure.¹²

Pediatric Use

Safety and efficacy not established in children.^{1 2 120 121}

Pharmacology of thiopental in infants and children is similar to that in adults; however, pharmacokinetics may be different in neonates and young infants because of their immature organs of elimination (see Distribution and also Elimination, under Pharmacokinetics).^{7 12} Induction doses tend to be higher (relative to weight) in children.¹² (See Pediatric Patients under Dosage and Administration.)

Used rectally to provide sedation.^{27 28 29 30 31 108} However, 1 manufacturer does not recommend such use, because the high alkalinity of thiopental may result in local irritation.¹²¹

Geriatric Use

Possible reduced clearance and prolonged drug-associated effects.^{12 120 121} (See Special Populations under Dosage and Administration.)

Hepatic Impairment

Hypnotic effect may be prolonged.^{1 2} (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Hypnotic effect may be prolonged.^{1 2} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Respiratory depression, myocardial depression, cardiac arrhythmias, prolonged somnolence and recovery, sneezing, coughing, bronchospasm, laryngospasm, shivering.^{1 2}

Interactions for Pentothal

Protein-bound Drugs

Potential for thiopental to be displaced from binding sites by, or to displace from binding sites, other protein-bound drugs.^{3 7 67}

Specific Drugs

Drug	Interaction	Comments
Aminophylline	Administration of low-dose (e.g., 2 mg/kg) IV aminophylline after surgery may partially reverse thiopental-induced sedation in the early phase of recovery1 2 82 83
Aspirin	Thiopental theoretically could be displaced from binding sites by, or could displace from binding sites, aspirin3 7 67 Potentiation of hypnotic effect reported3
Clonidine	IV administration of clonidine 2.5 or 5 mg prior to induction of anesthesia with thiopental reduced thiopental dosage requirements by about 25 or 37%, respectively12 94	Some clinicians recommend reduction of thiopental dosage when clonidine is administered as an adjunct to anesthesia94
CNS depressants (e.g., sedatives, hypnotics, opiates, nitrous oxide, alcohol)	Thiopental may be additive with or potentiate the effects of other CNS depressants;1 2 3 71 65 75 92 premedication with other CNS depressants may potentiate hypnotic effect of thiopental3 71 Possible reduction of antinociceptive effect of opiate analgesics1 2 71	Adjustment of thiopental dosage may be required with concomitant use3 71 Chronic use of CNS depressants (e.g., alcohol) may increase thiopental dosage required to achieve the desired anesthetic effect3 75
Diazoxide	Hypotension reported during induction of anesthesia with thiopental in patients undergoing surgery for insulinoma who were receiving oral diazoxide (a highly protein-bound drug) for several days prior to surgery1 2 84
Ketamine	Additive anesthetic effects reported in 1 study;70 76 in another study, increased thiopental doses required to achieve unconsciousness70 76
Meprobamate	Thiopental theoretically could be displaced from binding sites by, or could displace from binding sites, meprobamate3 7 67 Possible potentiation of hypnotic effects7
Metoclopramide	Administration of metoclopramide prior to induction of anesthesia with thiopental can reduce thiopental dosage requirements64
Midazolam	Possible potentiation of hypnotic effect3 71	Reduce thiopental dosages for induction of anesthesia by about 15% in patients receiving premedication with IM midazolam69
Phenothiazines (e.g., chlorpromazine, promethazine)	Possible potentiation of hypnotic effects;68 concomitant use of thiopental in patients receiving chlorpromazine reported to prolong sleep time and reduce thiopental dosage requirements by 60%68 Possible increased excitatory effects of thiopental3 72 Possible increased hypotension3 72
Probenecid	Thiopental theoretically could be displaced from binding sites by, or could displace from binding sites, probenecid3 7 67 Possible prolongation of hypnotic effects (possibly through competition for protein-binding sites)3 67 81	Reduction of thiopental dosage may be necessary73 81
Sulfisoxazole	Thiopental theoretically could be displaced from binding sites by, or could displace from binding sites, sulfisoxazole3 7 67 Potentiation of hypnotic effects reported7

Pentothal Pharmacokinetics

Absorption

Bioavailability

Rectal absorption may be unpredictable when using a suspension rather than a solution of the drug.³

Onset

Following IV administration of usual induction doses (2.5–5 mg/kg) in adults, hypnosis^{1 2} or unconsciousness^{3 4 7} occurs within 10–40 seconds,^{1 2 3 4 7 11 16} with maximal effects occurring in about 1 minute.^{7 16}

Following rectal administration in children, onset of sedation generally occurs within 3–15 minutes.^{27 28 29 30 31}

Duration

Following IV administration of usual induction doses (2.5–5 mg/kg) in adults, duration of anesthesia persists for 5–8 minutes.^{1 2 3 4 7 11 13 16}

Duration of action is variable;^{7 13 16} the duration of single doses usually is determined by redistribution of the drug from the CNS rather than by the rate of elimination.^{7 13 16} However, the anesthesia effect is prolonged following repeated injections or continuous infusion because of drug accumulation in adipose tissue.^{1 2 4 7 16}

Following rectal administration in children, sedation generally persists for about 0.5–5 hours.^{27 28 29 30 31}

Distribution

Extent

Following IV administration, thiopental is rapidly distributed to all tissues and fluids, with high concentrations in brain and liver.^{4 7}

Penetrates the blood-brain barrier rapidly; rate of entry into the brain is limited only by the rate of cerebral blood flow.^{7 16 24}

Readily crosses the placenta^{1 2 4 7 19 20 49 53 55} and is distributed into fetal blood and umbilical vein blood at delivery.^{1 2 7 19 20 49 53}

Distributed into milk;^{7 20 50} colostrum-to-plasma ratios of 0.67–0.68 reported at 4 and 9 hours after induction of anesthesia.^{7 20}