Intravenous Anesthetics

Intravenous anesthetics have been used in modern anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts practice since the 20th century. Modern anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts began with inhaled anesthetics Inhaled anesthetics Inhaled anesthetics are chemical compounds that can induce and maintain general anesthesia when delivered by inhalation. Inhaled anesthetics can be divided into 2 groups: volatile anesthetics and gases. Volatile anesthetics include halothane, isoflurane, desflurane, and sevoflurane. 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 Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines, and dissociatives), but the most widely used are fentanyl, midazolam, and propofol.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Overview

Continuum of sedation and anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts

  • 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 Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts
    • 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 Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts 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 Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts
  • Thiopental:
    • Used for induction and maintenance of general anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts
    • Until supplanted by propofol, thiopental was the most common intravenous agent.
    • An effective anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs
    • Short acting
  • Methohexital:
    • Indicated for short duration procedural sedation (e.g., cardioversion, fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures reduction, or intubation)
    • Short acting
    • An effective anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs
  • Phenobarbital and pentobarbital:
    • Mostly used in the ICU setting for neurologic emergencies
    • Uses include: 
      • Seizure management
      • Lowering intracranial pressure ( ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP))
      • Medical coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma induction

Chemistry

  • Barbiturates are derived from barbituric acid.
  • The medications within the class have variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 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 ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (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 Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disorders
  • Preoperative anxiety
  • Medical coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma induction → ↓ in ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP)
  • Adjunct in management of ↑ ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP)
  • Induction of anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts
  • Maintenance of general anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts

Adverse effects and contraindications

Adverse effects:

  • Respiratory depression
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Tolerance
  • Anaphylactic reactions (rare)

Drug interactions:

  • Contrast media and sulfonamides potentiate the effect by increasing the available concentration.
  • Ethanol, opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics, and antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines potentiate sedative effects via synergy. 

Contraindications:

  • Status asthmaticus 
  • Acute and intermittent porphyrias Porphyrias Porphyrias are a group of metabolic disorders caused by a disturbance in the synthesis of heme. In most cases, porphyria is caused by a hereditary enzyme defect. The disease patterns differ depending on the affected enzyme, and the variants of porphyria can be clinically differentiated between acute and nonacute forms. 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 Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts.
  • Midazolam:
    • Most commonly used benzodiazepine
    • Used for multiple purposes (from sedation to mitigation of seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. 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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 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 Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics → myocardial depression and arterial hypotension
  • Respiratory: ↓ response to hypercapnia
  • CNS:
    • ↓ O2 consumption
    • Slight ↓ of CBF → ↓ ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (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 Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts (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 Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
  • Nausea/vomiting
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. 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 Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
  • Closed-angle glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma

Overdose and toxicity

Clinical presentation:

  • CNS depression
  • Respiratory depression and failure
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension

Management:

  • Antidote Antidote An antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications. Overview of Antidotes: flumazenil 
  • Activated charcoal administration is contraindicated due to the risk of aspiration.

Ketamine

Overview

  • Approved for general anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts with or without other anesthetic agents
  • Closest agent to a “complete anesthetic” 
  • Often utilized for short-term sedation/ anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts (e.g., reduction of fractures or dislocations)

Chemistry

Ketamine is similar to phencyclidine ( PCP PCP Pneumocystis jiroveci is a yeast-like fungus causing pneumocystis pneumonia (PCP) in immunocompromised patients. Pneumocystis pneumonia is spread through airborne transmission and classically affects patients with AIDS, functioning as an AIDS-defining illness. Patients may present with insidious onset of fever, chills, dry cough, chest pain, and shortness of breath. Pneumocystis jiroveci/Pneumocystis Pneumonia (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 Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts 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 Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma
    • ↑ Salivation
  • CNS:
    • ↑ O2 consumption → ↑ CBF → ↑ ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (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 Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts
  • Acute or chronic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP)
  • Associated with postoperative emergence reactions:
    • Disorientation
    • Excitation
    • Hallucinations
  • Tonic-clonic movements during administration
  • Seizures
  • Tolerance

Drug interactions:

  • Coadministration with opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics produces apnea.
  • Synergistic interaction with volatile anesthetics (e.g., nitrous oxide (N2O))
  • Additive interaction with GABA receptor-mediated agents (e.g., benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines)

Contraindications:

  • Prior hypersensitivity
  • Pregnant or breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding women
  • Schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia
  • Aortic dissection Aortic dissection Aortic dissection occurs due to shearing stress from pulsatile pressure causing a tear in the tunica intima of the aortic wall. This tear allows blood to flow into the media, creating a "false lumen." Aortic dissection is most commonly caused by uncontrolled hypertension. Aortic Dissection
  • Myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction

Cautious administration in:

  • Coronary artery disease
  • Uncontrolled hypertension Uncontrolled hypertension Although hypertension is defined as a blood pressure of > 130/80 mm Hg, individuals can present with comorbidities of severe asymptomatic or "uncontrolled" hypertension (≥ 180 mm Hg systolic and/or ≥ 120 mm Hg diastolic) that carries with it a significant risk of morbidity and mortality. Uncontrolled Hypertension
  • Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. 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 Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of 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 ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP)
  • Endocrine: inhibition of enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics 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 Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes and plasma esterases
    • Inactive metabolite
  • Excretion: renal

Indications

  • Induction of general anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts:
    • Minimal hemodynamic effects
    • Onset and recovery is rapid.
  • Procedural sedation
  • Cushing syndrome treatment (off label)

Adverse effects and contraindications

Adverse effects:

  • Adrenal suppression
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension at induction
  • Postoperative nausea and vomiting
  • Myoclonus and transient muscle movements

Drug interactions:

  • Coadministration with opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics produces apnea.
  • Fentanyl increases plasma levels and prolongs elimination.

Cautious use:

  • Sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock
  • Chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
  • Underlying liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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 Neurotransmission The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. The plasma membranes of the 2 neurons are placed very close together, and the space between the 2 neurons is called the synaptic cleft. The molecules that mediate the interaction are called neurotransmitters. Synapses and 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 ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (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 Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts:
    • 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 Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension at induction
  • Respiratory depression
  • Bradycardia
  • Hypertriglyceridemia (can lead to pancreatitis)
  • Myoclonus, muscle twitching, opisthotonus, and/or hiccups
  • Occasionally causes ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG) changes (prolonged QT interval), but rarely clinically significant
  • Discolored green-tinted urine (rare)
  • Anaphylaxis and angioedema Angioedema Angioedema is a localized, self-limited (but potentially life-threatening), nonpitting, asymmetrical edema occurring in the deep layers of the skin and mucosal tissue. The common underlying pathophysiology involves inflammatory mediators triggering significant vasodilation and increased capillary permeability. 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 Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
  • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
  • Hyperlipidemia
  • Rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis
  • Bradycardia
  • May progress to: 
    • Renal failure
    • Cardiovascular collapse
    • Death

Management:

  • Discontinuation of propofol 
  • Supportive care

Fentanyl

Overview

  • Commonly used opioid in modern anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts 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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain perception and increases pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain threshold
  • 100x more potent than morphine

Physiologic effects

  • Cardiovascular: vagal activation → ↓ heart rate and slightly ↓ arterial blood pressure
  • Respiratory: respiratory depression
  • CNS:
    • ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (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 Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts (often as an adjuvant therapy)
  • Sedation
  • Analgesia:
    • Postoperative pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Severe nonoperative pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain:
      • Includes cancer-related chronic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium 
  • Dyskinesia
  • Narcotic ileus
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation

Drug interactions:

  • Respiratory depressant and potentiation of the CNS in conjunction with:
    • Benzodiazepines
    • Skeletal muscle relaxants
    • Intoxicants
    • Other anesthetics
  • Serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome can occur in conjunction with:
    • Selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications
    • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants
    • Triptans Triptans Triptans and ergot alkaloids are agents used mainly for the management of acute migraines. The therapeutic effect is induced by binding to serotonin receptors, which causes reduced vasoactive neuropeptide release, pain conduction, and intracranial vasoconstriction. Triptans and Ergot Alkaloids
  • 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 Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
  • Significant respiratory depression
  • Acute or severe bronchial asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma
  • GI obstruction or ileus
  • Liver failure
  • Head trauma Head trauma Head trauma occurs when external forces are directed to the skull and brain structures, resulting in damage to the skull, brain, and intracranial structures. Head injuries can be classified as open (penetrating) or closed (blunt), and primary (from the initial trauma) or secondary (indirect brain injury), and range from mild to severe and life-threatening. Head Trauma or ↑ ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (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 Antidote An antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications. Overview of Antidotes: 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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