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Benzodiazepines

Benzodiazepines work on the gamma-aminobutyric acid type A ( GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSA) receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS, the main inhibitory neurotransmitter in humans, but instead potentiate GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS activity. The drug class of benzodiazepines has anxiolytic, muscle-relaxant, hypnotic, sedative, and 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 properties. These agents are not generally recommended for long-term use, as patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship can develop physiological and psychological dependence. Side effects may include cognitive impairment, somnolence, and respiratory depression.

Last updated: Apr 3, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Chemistry and Pharmacodynamics

Chemical structure

  • Benzodiazepines have a typical heterocyclic ring system, which is a fusion between benzene and diazepine rings.
  • There are a variety of drugs in the benzodiazepine class, which vary based on the attached side group.
  • Different side groups affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment the binding affinity and interaction with GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors.
Structure of benzodiazepines

Structure of benzodiazepines:
The image on the left shows the classic 1,4-benzodiazepine ring. The image on the right shows the most common benzodiazepine ring system.

Image: “Core chemical structure of the benzodiazepine ring system” by Boghog2. License: Public Domain

Mechanism of action

  • Benzodiazepines bind BIND Hyperbilirubinemia of the Newborn to the gamma subunit of the GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSA receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → enhance the binding activity of GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS to the pocket between the α and 𝛃 subunits of the GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSA receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors 
  • ↑ Frequency of chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes channel opening → ↑ chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes influx → inhibits action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential 
  • Flumazenil is a competitive antagonist of benzodiazepines at the GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSA receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors.

Physiologic effects

GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS:

  • GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS is the main inhibitory neurotransmitter in the CNS
  • Neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology that use GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS as a transmitter contain an enzyme called glutamic acid Glutamic acid A non-essential amino acid naturally occurring in the l-form. Glutamic acid is the most common excitatory neurotransmitter in the central nervous system. Urea Cycle decarboxylase ( GAD GAD Generalized anxiety disorder (GAD) is a common mental condition defined by excessive, uncontrollable worrying causing distress and occurring frequently for at least 6 months. Generalized anxiety disorder is more common in women. Clinical presentation includes fatigue, low concentration, restlessness, irritability, and sleep disturbance. Generalized Anxiety Disorder), which converts the amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids into GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS.

GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:

  • GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSA and GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSC receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors are ionotropic receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors.
  • GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSB receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors are G-protein-coupled, or metabotropic, receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSA and GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSB receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors modulate the inhibitory activity of the CNS.
  • GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSC receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors are found in the retinal cells of the eye; their exact function is unknown. 
  • GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSA receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors are pentameric structures and consist of:
    • 2 α (alpha) subunits
    • 2 𝛃 (beta) subunits
    • 1 γ (gamma) subunit.  
  • GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNSA receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors locations and effects:
    • Cerebral cortex Cerebral cortex The cerebral cortex is the largest and most developed part of the human brain and CNS. Occupying the upper part of the cranial cavity, the cerebral cortex has 4 lobes and is divided into 2 hemispheres that are joined centrally by the corpus callosum. Cerebral Cortex: Anatomy → confusion, amnesia
    • Thalamus Thalamus The thalamus is a large, ovoid structure in the dorsal part of the diencephalon that is located between the cerebral cortex and midbrain. It consists of several interconnected nuclei of grey matter separated by the laminae of white matter. The thalamus is the main conductor of information that passes between the cerebral cortex and the periphery, spinal cord, or brain stem. Thalamus: Anatomy → disinhibition, sedation, motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology inhibition
    • Limbic structures → anxiolysis, sedation 

Benzodiazepine therapeutic effects:

  • Anxiolytic
  • Skeletal muscle relaxant 
  • Sedative:
    • Mitigates excitement
    • Lessens activity
    • Produces calmness
  • 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: a medication that controls 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
  • Hypnotic: 
    • Induce drowsiness and promote the onset and maintenance of sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep
    • ↓ REM sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep (when dreaming occurs)
  • Anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts
Benzodiazepine dose-response curve

Benzodiazepine dose-response curve:
The dose-response curve for benzodiazepines is shown above. Benzodiazepines exert anxiolytic properties at low doses and have a ceiling effect, in which increasing doses peak at anesthetic effects.

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

Lipophilic benzodiazepines have a more rapid absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption.

Distribution

  • Benzodiazepines and metabolites are highly protein bound.
  • Widely distributed:
    • Enter the CNS (lipid solubility also increases the rate)
    • Cross placenta Placenta A highly vascularized mammalian fetal-maternal organ and major site of transport of oxygen, nutrients, and fetal waste products. It includes a fetal portion (chorionic villi) derived from trophoblasts and a maternal portion (decidua) derived from the uterine endometrium. The placenta produces an array of steroid, protein and peptide hormones (placental hormones). Placenta, Umbilical Cord, and Amniotic Cavity

Metabolism

  • Hepatic
  • Cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury isozymes involved:
  • Some metabolites may be active → increased duration of therapeutic effect
  • Metabolites are conjugated → glucuronides

Excretion

Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy occurs through the kidney (glucuronides are excreted in the urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat).

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics comparison table

The table below highlights important benzodiazepine medications and addresses the properties of each. With respect to pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics, it is important to pay attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment to the onset of action, metabolism, and elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy.

Table: Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics of benzodiazepines
Drug Onset of action Duration Metabolism Major active metabolites
Alprazolam Intermediate Intermediate CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) No
Chlordiazepoxide Intermediate Long CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) Yes
Clonazepam Intermediate Intermediate CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) No
Clorazepate Rapid Long Yes
Diazepam Rapid Long
  • CYP2C19
  • 3A4
Yes
Flurazepam Rapid Long CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) Yes
Lorazepam Intermediate Intermediate Glucuronidation No
Midazolam Rapid Short CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) Yes
Oxazepam Slow Short Glucuronidation No
Temazepam Slow Intermediate Glucuronidation No
Triazolam Rapid Short CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) No
Onset of action: rapid = 15–30 min; intermediate = 30–45 min; slow = 45–90+ min.
Duration: short = < 10 hours; intermediate = 10–36 hours; long = > 48 hours.

Indications

Benzodiazepines are CNS depressants. Therefore, they are clinically useful for situations when a sedating agent may be needed. The table below addresses individual agents and their indications. Here are general indications for benzodiazepines:

  • Seizure disorder: useful in the treatment of prolonged 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 in emergency settings
  • Alcohol withdrawal Alcohol withdrawal With chronic alcohol use, body increases activity of excitatory receptors (e.g., glutamate) while decreasing activation of inhibitory receptors (e.g., GABA). Cessation of alcohol use leads to unchecked glutamate activation, presenting as withdrawal. Alcohol Use Disorder: ease withdrawal symptoms and prevent withdrawal 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
  • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders:
    • Panic disorder Panic disorder Panic disorder is a condition marked by recurrent and episodic panic attacks that occur abruptly and without a trigger. These episodes are time-limited and present with cardiorespiratory (palpitations, shortness of breath, choking), GI (nausea, abdominal distress), and neurologic (paresthesias, lightheadedness) symptoms. Panic Disorder
    • Generalized anxiety disorder Generalized anxiety disorder Generalized anxiety disorder (GAD) is a common mental condition defined by excessive, uncontrollable worrying causing distress and occurring frequently for at least 6 months. Generalized anxiety disorder is more common in women. Clinical presentation includes fatigue, low concentration, restlessness, irritability, and sleep disturbance. Generalized Anxiety Disorder
  • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia: helpful in the short term but are not advised to be given for over a month for this indication
  • Anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts induction
Table: Benzodiazepines and their indications
Medication Formulation Indications
Alprazolam Oral
  • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders
  • Panic disorder Panic disorder Panic disorder is a condition marked by recurrent and episodic panic attacks that occur abruptly and without a trigger. These episodes are time-limited and present with cardiorespiratory (palpitations, shortness of breath, choking), GI (nausea, abdominal distress), and neurologic (paresthesias, lightheadedness) symptoms. Panic Disorder
Chlordiazepoxide Oral
  • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders
  • Alcohol withdrawal Alcohol withdrawal With chronic alcohol use, body increases activity of excitatory receptors (e.g., glutamate) while decreasing activation of inhibitory receptors (e.g., GABA). Cessation of alcohol use leads to unchecked glutamate activation, presenting as withdrawal. Alcohol Use Disorder
  • Preoperative anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
Clonazepam Oral
  • Panic disorder Panic disorder Panic disorder is a condition marked by recurrent and episodic panic attacks that occur abruptly and without a trigger. These episodes are time-limited and present with cardiorespiratory (palpitations, shortness of breath, choking), GI (nausea, abdominal distress), and neurologic (paresthesias, lightheadedness) symptoms. Panic Disorder
  • Seizure disorders (mono- or adjunctive therapy: Lennox-Gastaut syndrome Lennox-Gastaut Syndrome Epilepsy, akinetic, myoclonic, and absence 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 refractory to succinimides)
Clorazepate Oral
  • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders
  • Alcohol withdrawal Alcohol withdrawal With chronic alcohol use, body increases activity of excitatory receptors (e.g., glutamate) while decreasing activation of inhibitory receptors (e.g., GABA). Cessation of alcohol use leads to unchecked glutamate activation, presenting as withdrawal. Alcohol Use Disorder
  • Partial 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: adjunct therapy
Diazepam
  • Oral
  • IV
  • IM
  • Rectal
  • Nasal
  • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders
  • Alcohol withdrawal Alcohol withdrawal With chronic alcohol use, body increases activity of excitatory receptors (e.g., glutamate) while decreasing activation of inhibitory receptors (e.g., GABA). Cessation of alcohol use leads to unchecked glutamate activation, presenting as withdrawal. Alcohol Use Disorder
  • Muscle spasms Spasms An involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle. Ion Channel Myopathy
  • 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: adjunct therapy
  • Status epilepticus Status Epilepticus A prolonged seizure or seizures repeated frequently enough to prevent recovery between episodes occurring over a period of 20-30 minutes. The most common subtype is generalized tonic-clonic status epilepticus, a potentially fatal condition associated with neuronal injury and respiratory and metabolic dysfunction. Nonconvulsive forms include petit mal status and complex partial status, which may manifest as behavioral disturbances. Simple partial status epilepticus consists of persistent motor, sensory, or autonomic seizures that do not impair cognition. Subclinical status epilepticus generally refers to seizures occurring in an unresponsive or comatose individual in the absence of overt signs of seizure activity. Seizures: adjunct therapy (injection only)
Flurazepam Oral Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
Lorazepam (Ativan®)
  • Oral
  • IV
  • IM
  • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders
  • Preanesthesia for anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder or to produce amnesia/sedation
  • Status epilepticus Status Epilepticus A prolonged seizure or seizures repeated frequently enough to prevent recovery between episodes occurring over a period of 20-30 minutes. The most common subtype is generalized tonic-clonic status epilepticus, a potentially fatal condition associated with neuronal injury and respiratory and metabolic dysfunction. Nonconvulsive forms include petit mal status and complex partial status, which may manifest as behavioral disturbances. Simple partial status epilepticus consists of persistent motor, sensory, or autonomic seizures that do not impair cognition. Subclinical status epilepticus generally refers to seizures occurring in an unresponsive or comatose individual in the absence of overt signs of seizure activity. Seizures
Midazolam (Versed®)
  • Oral
  • IV
  • IM
  • Nasal
  • Induction of anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts
  • Preoperative sedation/anxiolysis/amnesia
  • Sedation of intubated/mechanically ventilated patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • Acute intermittent 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
Oxazepam Oral
  • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders
  • Alcohol withdrawal Alcohol withdrawal With chronic alcohol use, body increases activity of excitatory receptors (e.g., glutamate) while decreasing activation of inhibitory receptors (e.g., GABA). Cessation of alcohol use leads to unchecked glutamate activation, presenting as withdrawal. Alcohol Use Disorder
Temazepam (Restoril®) Oral Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
Triazolam (Halcion®) Oral Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia

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Adverse Effects and Contraindications

Overview

There are some high-yield points to pay attention Attention Focusing on certain aspects of current experience to the exclusion of others. It is the act of heeding or taking notice or concentrating. Psychiatric Assessment to when considering benzodiazepines:

  • This class of medication should be used with caution in elderly patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship and those with 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: Anatomy or kidney damage.
    • Major active metabolites, such as nordiazepam and N-Desalkylflurazepam, have long half-lives and accumulate over time. 
    • Thus, in elderly patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship or patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with hepatic/renal impairment, the accumulation of active metabolites can lead to oversedation and anterograde amnesia Anterograde amnesia Loss of the ability to form new memories beyond a certain point in time. This condition may be organic or psychogenic in origin. Organically induced anterograde amnesia may follow craniocerebral trauma; seizures; anoxia; and other conditions which adversely affect neural structures associated with memory formation (e.g., the hippocampus; fornix (brain); mammillary bodies; and anterior thalamic nuclei). Wernicke Encephalopathy and Korsakoff Syndrome
  • Hypnotic effects result in a rebound effect of increased REM sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep that occurs with discontinuation of benzodiazepines. This is especially the case with shorter-acting agents such as triazolam. 
  • All benzodiazepines should be used cautiously 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.

Adverse effects

  • Cardiovascular: 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 
  • Musculoskeletal: muscle weakness
  • Neurologic/psychiatric
    • Amnesia
    • Drowsiness
    • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
    • Sedation
    • Euphoria Euphoria An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. Hepatic Encephalopathy 
    • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
  • Respiratory: respiratory depression
  • Dermatologic: skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions rash Rash Rocky Mountain Spotted Fever
  • Genitourinary: difficulty with micturition

Warnings

  • Beers criteria Beers Criteria Geriatric Care and Screening: increased risk of 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, sedation, and falls in the elderly
  • Abuse potential: may cause euphoria Euphoria An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. Hepatic Encephalopathy with risk of dependence and drug withdrawal  
  • FDA C-IV controlled substances
  • Black-box warning: Concomitant use of benzodiazepines and 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 may result in profound sedation, respiratory depression, 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, or death.

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • Age: 
  • Severe hepatic impairment (clonazepam and diazepam)
  • Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis
  • Respiratory:
    • Sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep apnea 
    • Chronic obstructive pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD))
    • Bronchitis
  • Ophthalmic:
    • Narrow-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
    • Untreated open-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

Drug interactions

  • Avoid other CNS depressants and sedatives (e.g., 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, barbiturates Barbiturates A class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants. Intravenous Anesthetics, ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism
  • Strong CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) or CYP2C19 inhibitors are contraindicated (e.g. itraconazole Itraconazole A triazole antifungal agent that inhibits cytochrome p-450-dependent enzymes required for ergosterol synthesis. Azoles, ketoconazole Ketoconazole Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. Azoles) → ↑ benzodiazepine levels
  • Strong CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers) or CYP2C19 inducers →  ↓ benzodiazepine levels

Overdose

These drugs rarely lead to overdose in isolation. When combined with other classes of drugs, such as alcohol and opiates Opiates 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, there is a much higher risk for toxicity Toxicity Dosage Calculation

  • Symptoms of overdose:
    • Slurred speech Slurred Speech Cerebellar Disorders and drowsiness
    • 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
    • Respiratory depression
    • 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
    • Cardiorespiratory arrest
  • Management:
    • Reversal agent: flumazenil 
      • Benzodiazepine antagonist
      • Beware of the potential for 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 in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship on long-term therapy.
    • Supportive care 
      • Maintain airway Airway ABCDE Assessment and intubate, if required.
      • IV fluids IV fluids Intravenous fluids are one of the most common interventions administered in medicine to approximate physiologic bodily fluids. Intravenous fluids are divided into 2 categories: crystalloid and colloid solutions. Intravenous fluids have a wide variety of indications, including intravascular volume expansion, electrolyte manipulation, and maintenance fluids. Intravenous Fluids for 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; vasopressors Vasopressors Sepsis in Children if the patient is not fluid responsive
      • Bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias should be managed with pharmacologic therapy (e.g., atropine Atropine An alkaloid, originally from atropa belladonna, but found in other plants, mainly solanaceae. Hyoscyamine is the 3(s)-endo isomer of atropine. Anticholinergic Drugs).

Clinical Relevance

The following are therapeutic uses of benzodiazepines:

  • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders: mental disorders that (combined) are the most prevalent type of psychiatric disorder in the United States. Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorders are characterized by excessive worry and fear. Examples include separation anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorder, selective mutism, specific phobias Phobias Neurological Examination, social anxiety disorder Social anxiety disorder Social anxiety disorder, or social phobia, is a psychiatric illness marked by fear and avoidance of social interactions due to concerns about embarrassment. The disorder usually occurs in more than one social situation for more than 6 months and leads to a significant decline in function. Social Anxiety Disorder, panic disorder Panic disorder Panic disorder is a condition marked by recurrent and episodic panic attacks that occur abruptly and without a trigger. These episodes are time-limited and present with cardiorespiratory (palpitations, shortness of breath, choking), GI (nausea, abdominal distress), and neurologic (paresthesias, lightheadedness) symptoms. Panic Disorder, agoraphobia Agoraphobia Agoraphobia is fear or anxiety in a situation that would be difficult to leave or to obtain help in the event that one develops panic-like symptoms. Situations include being in public or open spaces, lines, crowds, or public transport. Agoraphobia, generalized anxiety disorder Generalized anxiety disorder Generalized anxiety disorder (GAD) is a common mental condition defined by excessive, uncontrollable worrying causing distress and occurring frequently for at least 6 months. Generalized anxiety disorder is more common in women. Clinical presentation includes fatigue, low concentration, restlessness, irritability, and sleep disturbance. Generalized Anxiety Disorder, substance- or medication-induced anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorder, and anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorder due to another medical condition.  
  • Panic disorder Panic disorder Panic disorder is a condition marked by recurrent and episodic panic attacks that occur abruptly and without a trigger. These episodes are time-limited and present with cardiorespiratory (palpitations, shortness of breath, choking), GI (nausea, abdominal distress), and neurologic (paresthesias, lightheadedness) symptoms. Panic Disorder: involves recurrent, unexpected (without a cue or trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation) panic attacks. Panic attacks are sudden bursts of intense fear or discomfort that culminate within minutes and may be associated with symptoms of sweating, palpitations Palpitations Ebstein’s Anomaly, fear, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, and shortness of breath Shortness of breath Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Alcohol withdrawal Alcohol withdrawal With chronic alcohol use, body increases activity of excitatory receptors (e.g., glutamate) while decreasing activation of inhibitory receptors (e.g., GABA). Cessation of alcohol use leads to unchecked glutamate activation, presenting as withdrawal. Alcohol Use Disorder: a group of symptoms that manifest upon abrupt cessation of the consumption of ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism when it has been ingested regularly for a prolonged period of time. Symptoms of alcohol withdrawal Alcohol withdrawal With chronic alcohol use, body increases activity of excitatory receptors (e.g., glutamate) while decreasing activation of inhibitory receptors (e.g., GABA). Cessation of alcohol use leads to unchecked glutamate activation, presenting as withdrawal. Alcohol Use Disorder consist of autonomic hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder, hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, and tremors. Fatal complications can also potentially arise, such as 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, 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, and Wernicke-Korsakoff syndrome Wernicke-Korsakoff syndrome 2 different syndromes that are different stages of the same disease including Wernicke’s encephalopathy and Korsakoff psychosis.Wernicke-Korsakoff syndrome is seen in patients with alcohol use disorder 8–10 times more than in the general population. Wernicke Encephalopathy and Korsakoff Syndrome.

References

  1. O’Donnell, JM, Bies, RR, Shelton, RC. (2018). Drug therapy of depression and anxiety disorders. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. New York, NY: McGraw-Hill. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2189&sectionid=169518711
  2. IBM Micromedex® DRUGDEX®. (2021). IBM Watson Health, Greenwood Village, Colorado, USA. Retrieved June 11, 2021, from https://www.micromedexsolutions.com/
  3. Precision Dose Inc. Midazolam hydrochloride syrup. (2015). In: DailyMed. Bethesda (MD): U.S. National Library of Medicine. Retrieved June 11, 2021, from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9a443652-6aff-4e27-83fe-90c65fa0f3c1
  4. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. (2013). Arlington, VA, American Psychiatric Association.
  5. Khanna, AK, et al. (2018). Respiratory depression in low acuity hospital settings-Seeking answers from the PRODIGY trial. J Crit Care. https://doi.org/10.1016/j.jcrc.2018.06.014.  
  6. Griffin, CE, et al. (2013). Benzodiazepine pharmacology and central nervous system-mediated effects. The Ochsner Journal, 13(2): 214–223. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/
  7.  Trevor, AJ, and Way, WL. (2012). Sedative-hypnotic drugs. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 373–382). McGraw-Hill Companies, Inc. https://accesspharmacy.mhmedical.com/content.aspx?bookid=514&sectionid=41817537

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