Intravenous Anesthetics

Intravenous anesthetics have been used in modern anesthesia practice since the 20th century. Modern anesthesia began with inhaled anesthetics; however, intravenous agents were adopted because injected or infused doses could be more closely controlled with little wasted medication. Several groups of agents are currently available (e.g., barbiturates, benzodiazepines, and dissociatives), but the most widely used are fentanyl, midazolam, and propofol.

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Overview

Continuum of sedation and anesthesia

  • Light or minimal sedation: administration of anxiolytics and analgesics to achieve a mild level of sedation with preserved responsiveness:
    • Responsive to voice
    • Airway remains patent. 
    • Respiration remains spontaneous.
    • No cardiovascular depression 
  • Moderate sedation (also known as conscious sedation): administration of anxiolytics and analgesics to achieve a deeper level of sedation with less-preserved responsiveness:
    • Responsive to voice
    • Airway remains patent. 
    • Respiration remains spontaneous.
    • Mild cardiovascular depression → reduced blood pressure
  • Deep sedation: administration of anxiolytics, analgesics, and/or anesthetics to achieve a deep level of sedation with minimally preserved responsiveness:
    • No longer responsive to voice
    • Airway patency may become compromised. 
    • Respiratory support may be needed.
    • Cardiovascular depression → potentially significant blood pressure reduction
    • Response to noxious stimuli
  • General anesthesia: 
    • Administration of anxiolytics, analgesics, and/or anesthetics to achieve a very deep level of sedation eliminating responsiveness:
      • No longer responsive to voice
      • Airway patency may become compromised. 
      • Respiration support may be needed.
      • Cardiovascular depression → potentially significant blood pressure reduction
      • No response to noxious stimuli
    • General anesthesia is intended to create a reversible state of sedation, including:
      • Hypnosis
      • Amnesia
      • Analgesia
      • Immobility
      • Autonomic blockade
      • Sensory blockade

Anesthetic agents

The intravenous anesthetics include:

  • Barbiturates
  • Benzodiazepines 
  • Ketamine (dissociative)
  • Etomidate
  • Propofol
  • Fentanyl

Barbiturates

Agents in the class

  • Diethylbarbituric acid (barbital): the 1st barbiturate used for induction of anesthesia
  • Thiopental:
    • Used for induction and maintenance of general anesthesia
    • Until supplanted by propofol, thiopental was the most common intravenous agent.
    • An effective anticonvulsant
    • Short acting
  • Methohexital:
    • Indicated for short duration procedural sedation (e.g., cardioversion, fracture reduction, or intubation)
    • Short acting
    • An effective anticonvulsant
  • Phenobarbital and pentobarbital:
    • Mostly used in the ICU setting for neurologic emergencies
    • Uses include: 
      • Seizure management
      • Lowering intracranial pressure (ICP)
      • Medical coma induction

Chemistry

  • Barbiturates are derived from barbituric acid.
  • The medications within the class have variable side chains branching from the ring structure.
  • Barbiturates are prepared as sodium salts (mixed with either sodium chloride or sterile water) and packaged as solutions used for intravenous injection.
Barbituric acid

The chemical structure of barbituric acid

Image: “Barbituric Acid Structural formula” by Jü. License: Public Domain

Mechanism of action

  • Occupation/activation of the γ-aminobutyric acid A (GABAA) receptor → ↑ duration of chloride flow through the open channel
  • Depresses the reticular activating system in the brainstem
Diagram of the GABA-A receptor

Diagram of the γ-aminobutyric acid A (GABAA) receptor:
Notice the different binding sites for the different families of medications.

Image by Lecturio.

Physiologic effects

  • Cardiovascular:
    • Depression of the medullary vasomotor center → peripheral vasodilation → peripheral pooling of blood
    • ↓ Blood pressure → ↑ heart rate
    • Negative inotrope
  • Respiratory: depression of the medullary ventilatory center → reduced response to hypercapnia and hypoxia
  • CNS:
    • Cerebral vasoconstriction → ↓ cerebral blood flow (CBF) → ↓ ICP
    • ↓ Cerebral O2 consumption
  • Renal: ↓ renal blood flow → ↓ urinary output
  • Hepatic: ↓ hepatic blood flow

Pharmacokinetics

  • Distribution: 
    • Highly lipid soluble → able to cross the blood-brain barrier → rapid brain uptake
    • Brain uptake: approximately 30 seconds
    • Peak plasma concentration: 20–30 minutes 
  • Metabolism: hepatic 
  • Excretion: 
    • Renal 
    • Fecal
  • Context sensitivity: 
    • Repetitive doses fill-up/saturate the peripheral compartments, minimizing the effect of redistribution.
    • The duration of effect is dependent on the speed of elimination.

Indications

Barbiturates are a group of sedative-hypnotic medications with the following indications:

  • Epileptic disorders
  • Withdrawal syndromes
  • Sleep disorders
  • Preoperative anxiety
  • Medical coma induction → ↓ in ICP
  • Adjunct in management of ↑ ICP
  • Induction of anesthesia
  • Maintenance of general anesthesia

Adverse effects and contraindications

Adverse effects:

  • Respiratory depression
  • Hypotension
  • Tolerance
  • Anaphylactic reactions (rare)

Drug interactions:

  • Contrast media and sulfonamides potentiate the effect by increasing the available concentration.
  • Ethanol, opioids, and antihistamines potentiate sedative effects via synergy. 

Contraindications:

  • Status asthmaticus 
  • Acute and intermittent porphyrias
  • Hypovolemia due to propensity for cardiovascular depression

Benzodiazepines

Overview

  • Chlordiazepoxide was discovered in 1955 and released for clinical use in 1960.
  • Diazepam, lorazepam, and midazolam followed the release of chlordiazepoxide and are used extensively for premedication, conscious sedation, and induction of general anesthesia.
  • Midazolam:
    • Most commonly used benzodiazepine
    • Used for multiple purposes (from sedation to mitigation of seizures)

Chemistry

  • Base structure: a benzene ring and a 7-member diazepine ring
  • Different side groups affect the binding affinity and interaction with GABA receptors.
Benzodiazepine basic ring structure

The basic ring structure of the benzodiazepine class:
Medications within the class have variable R groups.

Image: “Benzodiazepine Structural Formula” by Jü. License: Public Domain

Mechanism of action

Occupation/activation of the GABAA receptor increases the opening frequency of the associated chloride (Cl-) channel, resulting in action potential inhibition:

Physiologic effects

  • Cardiovascular:
    • ↓ Cardiac output and peripheral vascular resistance → ↓ arterial blood pressure
    • Coadministration with opioids → myocardial depression and arterial hypotension
  • Respiratory: ↓ response to hypercapnia
  • CNS:
    • ↓ O2 consumption
    • Slight ↓ of CBF → ↓ ICP
    • Sedation
    • Confusion and anterograde amnesia 
    • Disinhibition and motor inhibition
    • Anxiolysis
    • Muscle relaxation

Pharmacokinetics

  • Distribution: 
    • Lipid solubility → quick brain uptake
    • Half-life: 
      • Lorazepam: 15 hours
      • Diazepam: 2 hours
      • Midazolam: 2 hours
  • Metabolism: hepatic (cytochrome P450): into active and nonactive hydrosoluble metabolites
  • Excretion: primarily renal

Indications

  • Induction of general anesthesia (midazolam):
    • Slower loss of consciousness and longer recovery than propofol 
    • Slower loss of consciousness and longer recovery than etomidate
  • Premedication
  • Conscious sedation
  • Other uses:
    • Anxiety states (lorazepam and diazepam)
    • Muscle spasticity (diazepam)
    • Ethanol withdrawal (chlordiazepoxide and diazepam)

Adverse effects and contraindications

Adverse effects:

  • Respiratory depression and arrest
  • Confusion
  • Headache
  • Syncope
  • Nausea/vomiting
  • Diarrhea
  • Tremors
  • Laryngospasm and/or bronchospasm in neonates (rare)
  • Tolerance and dependence

Drug interactions:

  • Cimetidine slows down the metabolism of diazepam at cytochrome P450.
  • Erythromycin inhibits the metabolism of midazolam → prolongs and intensifies effects
  • Opioids potentiate myocardial depression, respiratory depression, and CNS depression.
  • Ethanol potentiates myocardial depression, respiratory depression, and CNS depression.
  • Barbiturates potentiate myocardial depression, respiratory depression, and CNS depression.

Contraindications:

  • Hypersensitivity to benzodiazepines
  • Closed-angle glaucoma

Overdose and toxicity

Clinical presentation:

  • CNS depression
  • Respiratory depression and failure
  • Hypotension

Management:

  • Antidote: flumazenil 
  • Activated charcoal administration is contraindicated due to the risk of aspiration.

Ketamine

Overview

  • Approved for general anesthesia with or without other anesthetic agents
  • Closest agent to a “complete anesthetic” 
  • Often utilized for short-term sedation/anesthesia (e.g., reduction of fractures or dislocations)

Chemistry

Ketamine is similar to phencyclidine (PCP), a hallucinogen.

Ketamine

The chemical structure of ketamine

Image: “Structure of ketamine” by Brenton. License: Public Domain

Mechanism of action

  • Inhibits NMDA channels (glutamate transmission) and neuronal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels
  • The exact mechanism of anesthesia and analgesia is still controversial → dissociates sensory impulses from the limbic cortex (impairs awareness of sensation)

Physiologic effects

  • Cardiovascular:
    • ↑ Cardiac output and arterial blood pressure
    • Myocardial depression with large doses
  • Respiratory:
    • Potent bronchodilator (used with bronchospasm and asthma) 
    • ↑ Salivation
  • CNS:
    • ↑ O2 consumption → ↑ CBF → ↑ ICP
    • Mood modulator
    • Sympathetic stimulation and inhibition of epinephrine reuptake
    • Hallucinations
    • Dissociation

Pharmacokinetics

  • Distribution: 
    • Highly lipid soluble + increased cerebral perfusion + increased cardiac output → quick brain uptake
    • Half-life: 2 hours
  • Metabolism: 
    • Hepatic 
    • Metabolites: norketamine (retains anesthetic activity) and several other water-soluble metabolites
  • Excretion: renal

Indications

  • Induction and maintenance of anesthesia
  • Acute or chronic pain
  • Other uses:
    • Status epilepticus
    • Coadministration with propofol or midazolam in small bolus or infusion for conscious sedation
    • Treatment-resistant or severe depression

Adverse effects and contraindications

Adverse effects:

  • Cardiovascular stimulant
  • Respiratory depression and apnea
  • May ↑ ICP
  • Associated with postoperative emergence reactions:
    • Disorientation
    • Excitation
    • Hallucinations
  • Tonic-clonic movements during administration
  • Seizures
  • Tolerance

Drug interactions:

  • Coadministration with opioids produces apnea.
  • Synergistic interaction with volatile anesthetics (e.g., nitrous oxide (N2O))
  • Additive interaction with GABA receptor-mediated agents (e.g., benzodiazepines)

Contraindications:

  • Prior hypersensitivity
  • Pregnant or breastfeeding women
  • Schizophrenia
  • Aortic dissection
  • Myocardial infarction

Cautious administration in:

  • Coronary artery disease
  • Uncontrolled hypertension
  • Congestive heart failure
  • Arterial aneurysms
  • Alcohol dependence or intoxication

Etomidate

Overview

Etomidate is an intravenous anesthetic agent with the following characteristics:

  • Ultrashort acting (i.e., fast onset and short duration)
  • Hypnotic
  • Minimal blood pressure depression (used in shock trauma)
  • Rapid metabolism

Chemistry

  • Carboxylated imidazole ring:
    • Water solubility at acidic pH 
    • Lipid solubility at physiological pH
  • Structurally unrelated to the other anesthetics
The chemical structure of etomidate

The chemical structure of etomidate

Image: “Etomidate” by Vaccinationist. License: Public Domain

Mechanism of action

Occupation/activation of the GABAA receptor increases sensitivity for GABA to reduce neuroexcitation.

Physiologic effects

  • Cardiovascular: mild ↓ in peripheral vascular resistance
  • CNS: ↓ cerebral O2 consumption → ↓ CBF → ↓ ICP
  • Endocrine: inhibition of enzymes involved in cortisol and aldosterone synthesis
  • Antiemetic properties

Pharmacokinetics

  • Distribution: 
    • Lipid soluble → quick brain uptake (30–60 seconds)
    • Half-life: 2–5 minutes
  • Metabolism: 
    • Hydrolyzation by hepatic enzymes and plasma esterases
    • Inactive metabolite
  • Excretion: renal

Indications

  • Induction of general anesthesia:
    • Minimal hemodynamic effects
    • Onset and recovery is rapid.
  • Procedural sedation
  • Cushing syndrome treatment (off label)

Adverse effects and contraindications

Adverse effects:

  • Adrenal suppression
  • Hypotension at induction
  • Postoperative nausea and vomiting
  • Myoclonus and transient muscle movements

Drug interactions:

  • Coadministration with opioids produces apnea.
  • Fentanyl increases plasma levels and prolongs elimination.

Cautious use:

  • Sepsis
  • Chronic kidney disease
  • Underlying liver disease

Propofol

Overview

Propofol is the most widely used induction agent.

Chemistry

The chemical structure of propofol includes a phenol ring substituted with 2 isopropyl groups.

The chemical structure for propofol

The chemical structure of propofol

Image: “Propofol” by Harbin. License: Public Domain

Mechanism of action

  • Not fully understood
  • May involve facilitation of inhibitory neurotransmission mediated by binding of the GABAA receptor
  • Other receptors and ion channels may be involved in the effect.

Physiologic effects

  • Cardiovascular:
    • ↓ Systemic vascular resistance → ↓ arterial blood pressure
    • ↓ Preload
    • ↓ Inotropy 
    • Impaired baroreflex response to hypotension
  • Respiratory:
    • Profound respiratory depression and apnea
    • ↓ Upper airway reflexes
  • CNS:
    • ↓ CBF → ↓ ICP
    • Antiemetic actions

Pharmacokinetics

  • Distribution: 
    • Lipid soluble → quick brain uptake
    • More rapid induction and less “hangover”
    • Half-life: 40 minutes
  • Metabolism: 
    • Hepatic conjugation into inactive metabolites
    • Extrahepatic metabolism to a lesser extent
  • Excretion: renal

Indications

  • Induction of general anesthesia:
    • Quick onset and recovery
    • Bronchodilating effect
    • No dosing adjustment for renal or hepatic impairment
  • Procedural sedation
  • Other uses:
    • Used in the ICU for prolonged sedation
    • Status epilepticus

Adverse effects and contraindications

Adverse effects:

  • Hypotension at induction
  • Respiratory depression
  • Bradycardia
  • Hypertriglyceridemia (can lead to pancreatitis)
  • Myoclonus, muscle twitching, opisthotonus, and/or hiccups
  • Occasionally causes ECG changes (prolonged QT interval), but rarely clinically significant
  • Discolored green-tinted urine (rare)
  • Anaphylaxis and angioedema

Drug interactions:

  • Coadministration of midazolam can reduce the required dose of propofol for induction.

Contraindications:

  • Previous hypersensitivity
  • Severe allergy to egg and soy products

Overdose and toxicity

Propofol infusion syndrome (PRIS) occurs in individuals with prolonged infusions of propofol:

Clinical presentation:

  • Metabolic acidosis
  • Hyperkalemia
  • Hyperlipidemia
  • Rhabdomyolysis
  • Bradycardia
  • May progress to: 
    • Renal failure
    • Cardiovascular collapse
    • Death

Management:

  • Discontinuation of propofol 
  • Supportive care

Fentanyl

Overview

  • Commonly used opioid in modern anesthesia practice
  • A very potent synthetic opioid (50–100x more potent than morphine)
  • Most frequently used as a sedative in intubated individuals

Chemistry

  • Monocarboxylic acid amide
  • Related to the phenylpiperidines
The chemical structure of fentanyl

The chemical structure of fentanyl

Image: “2D structure of fentanyl” by Harbin. License: Public Domain

Mechanism of action

  • Mu-selective opioid agonist → alters pain perception and increases pain threshold
  • 100x more potent than morphine

Physiologic effects

  • Cardiovascular: vagal activation → ↓ heart rate and slightly ↓ arterial blood pressure
  • Respiratory: respiratory depression
  • CNS:
    • ↑ ICP
    • Relaxation
    • Sedation
    • Analgesia
    • Euphoria
    • Nausea and vomiting
    • Muscle rigidity 

Pharmacokinetics

  • Distribution: 
    • Highly lipid soluble → quick brain uptake
    • Half-life: 2–4 hours after continuous infusion
  • Metabolism: hepatic (CYP3A4)
  • Excretion: renal (predominantly) and fecal

Indications

  • Induction of general anesthesia (often as an adjuvant therapy)
  • Sedation
  • Analgesia:
    • Postoperative pain
    • Severe nonoperative pain:
      • Includes cancer-related chronic pain 
      • Transcutaneous patch available
      • Rapid-acting oral transmucosal formulations available

Adverse effects and contraindications

Adverse effects:

  • Respiratory depression or arrest
  • Confusion
  • Drowsiness
  • Nausea and vomiting
  • Visual disturbances
  • Hallucinations
  • Delirium 
  • Dyskinesia
  • Narcotic ileus
  • Constipation

Drug interactions:

  • Respiratory depressant and potentiation of the CNS in conjunction with:
    • Benzodiazepines
    • Skeletal muscle relaxants
    • Intoxicants
    • Other anesthetics
  • Serotonin syndrome can occur in conjunction with:
    • Selective serotonin reuptake inhibitors
    • Tricyclic antidepressants
    • Triptans
  • CYP3A4 inhibitors prolong duration of effect and/or drug levels.
  • CYP3A4 inducers may decrease duration of effect and/or drug levels.

Contraindications:

  • Known intolerance to opioids
  • Significant respiratory depression
  • Acute or severe bronchial asthma
  • GI obstruction or ileus
  • Liver failure
  • Head trauma or ↑ ICP

Overdose and toxicity

Clinical presentation:

  • Generalized CNS depression
  • Respiratory depression
  • Miosis
  • Moderate-to-severe hypotension
  • Nausea and vomiting
  • Anxiety, agitation, hallucinations, or dysphoria may be displayed.

Management:

  • Antidote: naloxone
  • Supportive care

References

  1. The practice of anesthesiology. Butterworth IV, J. F., Mackey, D. C., & Wasnick, J. D. (Eds.), (2018). Morgan & Mikhail’s Clinical Anesthesiology, 6e. McGraw-Hill. https://accessmedicine-mhmedical-com.ezproxy.unbosque.edu.co/content.aspx?bookid=2444&sectionid=189634971 
  2. Intravenous anesthetics. Butterworth IV, J. F., Mackey, D. C., & Wasnick, J. D. (Eds.), (2018). Morgan & Mikhail’s Clinical Anesthesiology, 6e. McGraw-Hill. https://accessmedicine-mhmedical-com.ezproxy.unbosque.edu.co/content.aspx?bookid=2444&sectionid=189636049
  3. Skibiski, J., & Abdijadid, S. (2021). Barbiturates. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK539731/ 
  4. Bounds, C. G., & Nelson, V. L. (2021). Benzodiazepines. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK470159/ 
  5. Rosenbaum, S. B., Gupta, V., & Palacios, J. L. (2021). Ketamine. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK470357/
  6. Orhurhu, V. J., Vashisht, R., Claus, L. E., & Cohen, S. P. (2021). Ketamine toxicity. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK541087/ 
  7. Williams, L. M., Boyd, K. L., & Fitzgerald, B. M. (2021). Etomidate. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK535364/ 
  8. Folino, T. B., Muco, E., Safadi, A. O., & Parks, L. J. (2021). Propofol. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK430884/ 
  9. Egan, T. D., & Newberry, C. (2018). Opioids. In M. C., Pardo, & Miller, R. D., (eds.), pp. 123–138. https://doi.org/http://dx.doi.org/10.1016/B978-0-323-40115-9.00009-8
  10. National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 3345, Fentanyl. Retrieved June 23, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Fentanyl 
  11. Ramos-Matos, C. F., Bistas, K. G., & Lopez-Ojeda, W. (2021). Fentanyl. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK459275/ 
  12. Yaksh, T., & Wallace, M. Opioids, Analgesia, and Pain Management. In Brunton, L. L., Hilal-Dandan, R., Knollmann, B. C. (eds.) Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw-Hill. Retrieved June 23, 2021, from https://accessmedicine-mhmedical-com.ezproxy.unbosque.edu.co/content.aspx?bookid=2189&sectionid=170269577 
  13. Schiller, E. Y., Goyal, A., & Mechanic, O. J. (2021). Opioid overdose. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK470415/ 

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