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Ketamine

N01A - Anesthetics, general ATC N01AX03 Small molecule approved 1970 Parenteral Natural product

JFDA label: Tekam 50 Vials

Mechanism of Action

Produces a cataleptic-like state in which the patient is dissociated from the surrounding environment by direct action on the cortex and limbic system. Ketamine is a noncompetitive NMDA receptor antagonist that blocks glutamate. Low (subanesthetic) doses produce analgesia, and modulate central sensitization, hyperalgesia and opioid tolerance. Reduces polysynaptic spinal reflexes.

Indications

Approved

  • Anesthesia

Off-label

  • Analgesia (subanesthetic dosing)
  • Complex regional pain syndrome
  • Depressive episode associated with major depressive disorder and bipolar disorder, treatment Refractory
  • Procedural sedation/analgesia
  • Status epilepticus (refractory)

Contraindications

Source: Lexicomp

  • Additional contraindications (not in US labeling): History of cerebrovascular accident Absolute
  • Hypersensitivity to ketamine or any component of the formulation Absolute
  • conditions in which an increase in blood pressure would be hazardous Note: In the emergency department, the following additional absolute contraindications according to the American College of Emergency Physicians have been asserted (ACEP [Green 2011]): Infants Absolute
  • severe cardiac decompensation Absolute
  • surgery of the pharynx, larynx, or bronchial tree unless adequate muscle relaxants are used Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (5)

Not Known Bradycardia · cardiac arrhythmia · hypotension · increased blood pressure · increased pulse

Nervous system disorders (3)

Not Known Drug dependence · hypertonia (tonic-clonic movements sometimes resembling seizures) · increased cerebrospinal fluid pressure

Renal and urinary disorders (1)

Not Known Hydronephrosis

Immune system disorders (1)

Not Known Anaphylaxis

Metabolism and nutrition disorders (1)

Not Known Central diabetes insipidus (Hatab 2014)

Gastrointestinal disorders (4)

Not Known Anorexia · nausea · sialorrhea (Hatab 2014) · vomiting

Skin and subcutaneous tissue disorders (3)

Not Known Erythema (transient) · morbilliform rash (transient) · rash at injection site

Musculoskeletal and connective tissue disorders (1)

Not Known Laryngospasm

Eye disorders (3)

Not Known Diplopia · increased intraocular pressure · nystagmus

General disorders and administration site conditions (1)

Not Known Pain at injection site

Other (1)

Very Common Central nervous system: Prolonged emergence from anesthesia

Respiratory, thoracic and mediastinal disorders (3)

Not Known Airway obstruction · apnea · respiratory depression

Dosing

Source: Lexicomp

May administer atropine, scopolamine, or another drying agent prior to induction and at appropriate intervals to decrease hypersalivation. Note: Titrate dose for desired effect. Anesthesia: Induction of anesthesia: Manufacturer's labeling: IM: 6.5 to 13 mg/kg IV: 1 to 4.5 mg/kg Alternate recommendations (off-label dosing): Note: lower doses may be used if adjuvant drugs (eg, midazolam) are administered (Miller 2010) IM: 4 to 10 mg/kg (Green 1990; Miller 2010; White 1982) IV: 0.5 to 2 mg/kg (Miller 2010; White 1982) Maintenance of anesthesia: May administer supplemental doses of one-half to the full induction dose or a continuous infusion of 0.1 to 0.5 mg/minute (per manufacturer). Note: To maintain an adequate concentration of ketamine for maintenance of anesthesia, 1 to 2 mg/minute has been recommended (White 1982); doses in the range of 15 to 90 mcg/kg/minute (~1 to 6 mg/minute in a 70-kg patient) have also been suggested (Miller 2010). Concurrent use of nitrous oxide reduces ketamine requirements. Recent laboratory/clinical studies support the use of low-dose ketamine to improve postoperative analgesia/outcome (Adam 2005; Menigaux 2000). Analgesia (subanesthetic dosing) (off-label use): Acute pain: Intranasal (off-label route): 0.5 to 1 mg/kg; may repeat in 10 to 15 minutes with 0.25 to 0.5 mg/kg if necessary (Andolfatto 2013; Corrigan 2015; Yeaman 2014) Chronic pain: Intranasal (off-label route): 10 mg every 90 seconds as needed until a maximum total dose of 50 mg is reached or pain relieved (Carr 2004). IV: Note: Various dosing protocols have been utilized. One suggested inpatient protocol is presented. Consider the concomitant use of a benzodiazepine (eg, lorazepam) to prevent or reduce psychotomimetic effects and glycopyrrolate for excessive salivation or lacrimation. Initial: IV infusion: 0.5 mg/kg over 6 hours. If pain improved by 50% or more after completion of initial dose, then continue infusion at 1.5 mg/kg/24 hours for 48 hours. If pain not improved after completion of initial dose, increase to 2 mg/kg over 12 hours. If pain recurs after initial improvement, titrate upwards by 50% to 100% every 24 hours as needed. Discontinue infusion if pulse >110 bpm, SBP increases >25% of baseline, sustained respiratory rate Oral (off-label route): Initial: 0.5 mg/kg as a single dose to evaluate effect on pain and duration of effect; may increase dose in increments of 0.5 mg/kg as appropriate. For a continuous analgesic effect, may administer 3 to 4 times daily (Blonk 2010). Acute on chronic episodes of neuropathic pain, severe: Continuous IV or SubQ (off-label route) infusion: 2.3 to 6.7 mcg/kg/minute (equivalent to 0.14 to 0.4 mg/kg/hour) (Hocking 2003). Postoperative opioid sparing: IM: 2 to 4 mg/kg (Miller 2010; White 1982); may follow with a continuous infusion if necessary. IV: 0.2 to 0.8 mg/kg bolus (Miller 2010; Remérand 2009; White 1982; Zakine 2008); a maximum bolus dose of 50 mg was used in one study (Remérand 2009). May follow bolus d
(For additional information see "Ketamine: Pediatric drug information") May administer atropine, scopolamine, or another drying agent prior to induction and at appropriate intervals to decrease hypersalivation. Note: Titrate dose to effect. Anesthesia: Pre-anesthetic sedation: Limited data available: Intranasal: Infants ≥6 months: 3 mg/kg/dose (half dose per nostril) administered at least 15 minutes prior to mask induction (Diaz 1997; Lin 1990) Children Children 2 to 7 years: 3 to 6 mg/kg/dose (half dose per nostril) administered 15 to 40 minutes prior to induction (Diaz 1997; Gautam 2007; Lin 1990; Roelofse 2004; Weksler 1993) Oral: Children ≤8 years: 6 to 8 mg/kg/dose 20 to 30 minutes prior to surgery (Gutstein 1992; Turhanoglu 2003). Rectal: Reported effective range: Infants 2 to 6 months: 8 mg/kg/dose; Infants ≥7 months and Children: 8 to 10 mg/kg/dose; administer 15 to 45 minutes prior to surgery as a single agent (Lin 1990; Tanaka 2000; Van der Bijl 1991; Wang 2010; Zanette 2010). Note: When used in combination with midazolam, a lower rectal dose of 3 mg/kg/dose has been effective (Beebe 1992). Induction of anesthesia: Infants ≥3 months, Children, and Adolescents IM: 5 to 10 mg/kg has been reported and suggested by experts (Coté 2013; Lin 2005; Sungur Ulke 2008) IV: 1 to 3 mg/kg has been reported and suggested by experts (Coté 2013; Lin 2005) Adolescents ≥16 years: IM: 6.5 to 13 mg/kg IV: 1 to 4.5 mg/kg Maintenance of anesthesia: Adolescents ≥16 years: May administer supplemental doses of one-half to the full induction dose as needed. Endotracheal intubation: Limited data available: Infants, Children, and Adolescents: IV: 1 to 2 mg/kg as part of rapid sequence sedation (Ballow 2012; Furhman 2011; Hegenbarth 2008) Sedation/analgesia, procedural (off-label use): Infants, Children, and Adolescents: Note: Due to risk of airway obstruction, laryngospasm, and apnea, ACEP only recommends use in patients ≥3 months of age (ACEP [Green 2011]). Ketamine without propofol: IM: 4 to 5 mg/kg as a single dose; may give a repeat dose (range: 2 to 5 mg/kg) if sedation inadequate after 5 to 10 minutes or if additional doses are required (ACEP [Green 2011]). Some have recommended smaller doses (2 to 2.5 mg/kg) for minor procedures (eg, wound suture with local anesthetic) (McGlone 2004). IV: 1 to 2 mg/kg over 30 to 60 seconds. If initial sedation inadequate or repeated doses are necessary to accomplish a longer procedure, may administer additional doses of 0.5 to 1 mg/kg every 5 to 15 minutes as needed (ACEP [Green 2011]; Asadi 2013; Berkenbosch 2004, Koruk 2010). Intranasal: Infants ≥3 months and Children: 3 to 6 mg/kg (half dose per nostril) (Gyanesh 2014). Oral: Children and Adolescents: 3 to 5 mg/kg with oral midazolam 30 to 45 minutes before procedure (Barkan 2014; Norambuena 2013; Ozdemir 2004). Note: A higher dose (10 mg/kg) has been used successfully as monotherapy prior to procedures (Tobias 1992). Rectal: Children 1 to 8 years: 1.5 to 3 mg/kg with mid
Refer to adult dosing.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.

Warnings & Precautions

Source: Lexicomp

Airway complications

When used for procedural sedation for major procedures involving the posterior pharynx (eg, endoscopy) or when used for patients with an active pulmonary infection or disease (including upper respiratory disease or asthma), the use of ketamine increases the risk of laryngospasm. Patients with a history of airway instability, tracheal surgery, or tracheal stenosis may be at a higher risk of airway complications. The American College of Emergency Physicians considers these situations relative contraindications for the use of ketamine (ACEP [Green 2011]). The manufacturer recommends against the use of ketamine alone in surgery or diagnostic procedures of the pharynx, larynx, or bronchial tree; mechanical stimulation of the pharynx should be avoided, whenever possible, if ketamine is used alone.

CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving). When used for outpatient surgery, the patient should be accompanied by a responsible adult. Driving, operating hazardous machinery, or engaging in hazardous activities should not be undertaken for ≥24 hours after anesthesia, according to the manufacturer.

Dependence

May cause dependence (withdrawal symptoms on discontinuation) and tolerance with prolonged use. A withdrawal syndrome with psychotic features has been described following discontinuation of long-term use.

Emergence reactions

Postanesthetic emergence reactions, which can manifest as vivid dreams, hallucinations, and/or frank delirium, occur; these reactions are less common in patients 65 years and when given IM (White 1982). Emergence reactions, confusion, or irrational behavior may occur up to 24 hours postoperatively and may be reduced by pretreatment with a benzodiazepine, use of ketamine at the lower end of the dosing range, and minimizing verbal and tactile stimulation of the patient during the recovery period. Avoid use in patients with schizophrenia; may exacerbate psychotic symptoms (Lahti 1995; Malhotra 1997). The American College of Emergency Physicians considers the use of ketamine in patients with known or suspected schizophrenia (even if currently stable or controlled with medications) an absolute contraindication (ACEP [Green 2011]).

Increased intracranial pressure

Some consider the use of ketamine in patients with CNS masses, CNS abnormalities, or hydrocephalus a relative contraindication due to multiple reports that ketamine may increase intracranial pressure in these patients (ACEP [Green 2011]). However, assuming adequate ventilation, some evidence suggests that ketamine has minimal effects on intracranial pressure and may even improve cerebral perfusion and reduce intracranial pressure (Albanese 1997; Bowles 2012; Zeiler 2014).

Increased ocular pressure

Use with caution in patients with increased intraocular pressure (IOP). Some recommend avoiding use in patients with an open eye injury or other ophthalmologic disorder where an increase in IOP would prove to be detrimental; however, the effects of ketamine on IOP is mixed with some evidence demonstrating no clinically significant effect on IOP (ACEP [Green 2011]; Cunningham 1986; Drayna 2012; Miller 2010; Nagdeve 2006).

Porphyria

The American College of Emergency Physicians considers the use of ketamine in patients with porphyria a relative contraindication due to enhanced sympathomimetic effect produced by ketamine (ACEP [Green 2011]).

Respiratory depression

Rapid IV administration or overdose may cause respiratory depression or apnea. Resuscitative equipment should be available during use.

Thyroid disorders

The American College of Emergency Physicians considers the use of ketamine in patients with a thyroid disorder or receiving a thyroid medication a relative contraindication due to enhanced sympathomimetic effect produced by ketamine (ACEP [Green 2011]). Disease-related concerns:

Cardiovascular disease

Use with caution in patients with coronary artery disease, catecholamine depletion, hypertension, and tachycardia. Cardiac function should be continuously monitored in patients with increased blood pressure or cardiac decompensation. Ketamine increases blood pressure, heart rate, and cardiac output thereby increasing myocardial oxygen demand. The mechanism by which ketamine causes a sympathetic surge to stimulate the cardiovascular system has yet to be elucidated. The use of concurrent benzodiazepine, inhaled anesthetics, and propofol or administration of ketamine as a continuous infusion may reduce these cardiovascular effects (Miller 2010). The American College of Emergency Physicians recommends avoidance in patients who are already hypertensive and in older adults with risk factors for coronary artery disease (ACEP [Green 2011]). In a scientific statement from the American Heart Association, ketamine has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).

Cerebrospinal fluid (CSF) pressure elevation

Use with caution in patients with CSF pressure elevation; an increase in CSF pressure may be associated with use.

Ethanol use

Use with caution in the chronic alcoholic or acutely alcohol-intoxicated. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Pediatric neurotoxicity

In pediatric and neonatal patients Other warnings/precautions:

Experienced personnel

Use requires careful patient monitoring, should only be used by experienced personnel who are not actively engaged in the procedure or surgery. If used in a nonintubated and/or nonmechanically ventilated patient, qualified personnel and appropriate equipment for rapid institution of respiratory and/or cardiovascular support must be immediately available. Use to induce moderate (conscious) sedation in patients warrants monitoring equivalent to that seen with deep anesthesia. Consult local regulations and individual institutional policies and procedures.

Pregnancy & Lactation

Pregnancy

Adverse events have been observed in animal reproduction studies. Ketamine crosses the placenta and can be detected in fetal tissue. Ketamine produces dose dependent increases in uterine contractions; effects may vary by trimester. The plasma clearance of ketamine is reduced during pregnancy. Dose related neonatal depression and decreased APGAR scores have been reported with large doses administered at delivery (Ghoneim 1977; Little 1972; White 1982). Although ketamine has been used during vaginal delivery and cesarean section, use in pregnancy, including obstetrics (either vaginal or abdominal delivery) is not recommended by the manufacturer (Akamatsu 1974; Little 1972; Mercier 1998). Based on animal data, repeated or prolonged use of general anesthetic and sedation medications that block N-methyl-D- aspartate (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity, may affect brain development. Human fetuses may be most vulnerable during the third trimester. Unti

Lactation

It is not known if ketamine is present in breast milk.

Monitoring

Clinical pearlHeart rate, blood pressure, respiratory rate, transcutaneous O2 saturation, emergence reactions; cardiac function should be continuously monitored in patients with increased blood pressure or cardiac decompensation

Chemistry & Properties

2D structure
FormulaC13H16ClNO
Molecular weight237.73 g/mol
IUPAC name2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one
CAS6740-88-1
PubChem CID3821
InChIKeyYQEZLKZALYSWHR-UHFFFAOYSA-N
logP2.9 (XLogP 2.2)
Polar surface area29.1 Ų
H-bond acceptors / donors2 / 1
Drug-likeness (QED)0.86
Lipinski violations0
SMILESCNC1(c2ccccc2Cl)CCCCC1=O

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrantYes

Enzyme interactions

EnzymeRoleDetail
CYP1A2Substrate
CYP2B6Inhibitor
CYP2B6Substrate
CYP2C19Inhibitor
CYP2C19Substrate
CYP2C9Substrate
CYP2D6Substrate
CYP3A4Inhibitor
CYP3A4Substrate

Receptor binding (top 2)

TargetActionAffinity
NMDA Binding pKi 6.2
GluN2C (GRIN2C) Channel blocker pIC50 6.2

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)OCT3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)OCT1 (Substrate)P-gp (Substrate)

Drug–drug interactions (93, DDInter)

Interacting drugSeverityManagement
Alimemazine moderate
Alpelisib moderate
Aminophylline moderate
Azatadine moderate
Azelastine (nasal) moderate
Brimonidine (ophthalmic) moderate
Brimonidine (topical) moderate
Brompheniramine moderate
Carbinoxamine moderate
Cetirizine moderate
Chlorphenesin moderate
Chlorpheniramine moderate
Clemastine moderate
Clofedanol moderate
Cocaine (nasal) moderate
Codeine moderate
Cyclizine moderate
Cyproheptadine moderate
Dabrafenib moderate
Dexbrompheniramine moderate
Dextromethorphan moderate
Diphenhydramine moderate
Diphenoxylate moderate
Doxepin moderate
Doxepin (topical) moderate
Doxylamine moderate
Dronabinol moderate
Dyphylline moderate
Ephedrine moderate
Epinephrine (topical) moderate
Ethanol moderate
Fenfluramine moderate
Formoterol moderate
Fostamatinib moderate
Hydrocodone moderate
Idelalisib moderate
Indacaterol moderate
Ioflupane I-123 moderate
Isometheptene moderate
Isoprenaline moderate

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Registered Products (9)

BrandForm / strengthPackAgentCitizen (JOD)
Katiax 200mg/20ml Solution for Injection/Infusion Infusion 200 mg/20 ml 10 vial MS PHARMA/JORDAN
Katiax 500mg/10ml Solution for Injection/Infusion Infusion 500 mg/10 ml 1 vial pack varies MS PHARMA/JORDAN
Katiax 500mg/10ml Solution for Injection/Infusion Infusion 500 mg/10 ml 10 vial pack varies MS PHARMA/JORDAN
Katiax 500mg/5ml Solution for Injection/Infusion Infusion 500 mg/5 ml 1 vial pack varies MS PHARMA/JORDAN
Katiax 500mg/5ml Solution for Injection/Infusion Infusion 500 mg/5 ml 10 vial pack varies MS PHARMA/JORDAN
Tekam 10 Vials Vial 10 mg/ml 10 pack varies Hikma Pharmaceuticals Co.Ltd/Jordan
Tekam 10 Vials Vial 10 mg/ml 1 pack varies Hikma Pharmaceuticals Co.Ltd/Jordan
Tekam 50 Vials Vial 50 mg/ml 1 vial pack varies Hikma Pharmaceuticals Co.Ltd/Jordan
Tekam 50 Vials Vial 50 mg/ml 10 vial pack varies Hikma Pharmaceuticals Co.Ltd/Jordan