Neuropharmacology: Barbiturates & Neuronal Activity

• Intravenous anesthetics include barbiturates, benzodiazepines, ketamine, etc

Barbiturates: Mechanism of Action

• Barbiturates cause CNS depression by potentiating GABAA channel activity
• At clinical concentrations, they also affect glutamate, adenosine, and neuronal nicotinic acetylcholine receptors
• Excitatory neurotransmitters (e.g., glutamate, acetylcholine) increase the likelihood of a postsynaptic neuron firing an action potential
• Inhibitory neurotransmitters (e.g., GABA, glycine) decrease the likelihood of a postsynaptic neuron firing, often through hyperpolarization
• GABAA receptor activation mediates inhibitory neurotransmission in the CNS via Cl- influx, leading to hyperpolarization
• Drugs enhancing GABAA activity (benzodiazepines, barbiturates, alcohol) can produce calming, sedative, muscle-relaxing, and anti-anxiety effects
• Since GABA reduces excessive neuronal firing, drugs enhancing its function are used to treat epilepsy and seizures
• Allosteric binding is binding to a receptor or enzyme site different from the primary binding site, causing a change in receptor function that enhances or inhibits activity
• Positive allosteric modulation increases the receptor's response to its natural ligand without directly activating it; barbiturates bind allosterically to GABAA receptors
• Negative allosteric modulation reduces the receptor's response to its natural ligand; flumazenil binds to GABAA receptors and blocks the effects of benzodiazepines
• Clinically used barbiturates are derived from barbituric acid, and substitutions on the ring determine their PK/PD profile
• Oxybarbiturates have an oxygen at the second position; examples include methohexital and pentobarbital
• Thiobarbiturates have a sulfur atom at the second position; a sulfur molecule replacing an oxygen increases lipid solubility and hypnotic potency
• Examples include thiopental and thiamylal
• A phenyl group at the fifth position increases the anticonvulsant but not hypnotic potency
• Phenobarbital is an example; hepatic P450 enzymes metabolize most barbiturates, but phenobarbital is excreted unchanged in the urine
• A methyl group on the nitrogen increases hypnotic potency but lowers the seizure threshold and can cause myoclonus during induction, as seen with methohexital
• Methohexital is the gold standard for electroconvulsive therapy, and a better-quality seizure
• Induction dose of methohexital is 1-1.5 mg/kg
• Myoclonus is sudden, involuntary muscle jerks or twitches caused by rapid muscle contractions (positive myoclonus) or brief lapses in muscle activity (negative myoclonus, sudden relaxation)
• A disadvantage of methohexital is the incidence of excitatory phenomena (myoclonus and hiccups), which is dose-dependent and may be reduced with opioid pretreatment

Specific Barbiturates

• Thiopental was the most popular barbiturate in anesthesia, introduced in 1934
• It revolutionized anesthesia by enabling rapid induction via IV medication, avoiding slower and more dangerous diethyl ether induction
• Thiopental is no longer manufactured or imported to the United States due to opposition to its use in lethal injections, but the NBCRNA will still test on it
• The pharmacodynamics and pharmacokinetics of barbiturates, particularly thiopental, are the prototypes for almost all clinically used IV anesthetics
• Inadvertent intra-arterial injection of thiopental will likely cause intense vasoconstriction and pain along the artery's distribution
• Distal arterial pulses diminish, blanching of the extremity is followed by cyanosis
• Crystals form, further occluding blood flow, potentially leading to tissue necrosis, gangrene, and permanent nerve damage.
• Treatment includes a sympathectomy (cutting, blocking, or destroying part of the SNS), injection of a vasodilator (phentolamine, phenoxybenzamine, lidocaine, or papaverine), dilution, and general measures to sustain adequate blood flow
• Thiopental induces rapid onset and awakening due to rapid uptake and redistribution from the brain into inactive tissues
• Elimination depends almost entirely on metabolism, with less than 1% recovered unchanged in the urine
• The context-sensitive half-time of thiopental can be lengthy after long infusions
• Thiopental is sequestered in fat and skeletal muscle, re-entering the circulation and preventing plasma concentration from dropping rapidly
• Thiobarbiturates are primarily metabolized by hepatocytes, and the metabolites (hydroxy thiopental and 5-carboxylic acid) are usually inactive and more water-soluble, facilitating renal excretion
• Hepatic clearance of thiopental has a low hepatic extraction ratio and capacity-dependent elimination, meaning factors affecting hepatic enzyme activity change clearance
• Hepatic dysfunction must be extreme to prolong the duration of action, because the liver has a large capacity to oxidize barbiturates
• In pediatric patients, the elimination half-time is shorter due to increased hepatic clearance
• Recovery after large or repeated doses may be more rapid for infants and children than adults
• Protein binding and volume of distribution are not different in pediatric vs adult patients
• In pregnancy, elimination half-time is prolonged due to increased protein binding
• The induction dose of thiopental decreases with age due to slower passage of barbiturate from the central compartment to peripheral compartments
• The dose of thiopental needed to produce anesthesia in early pregnancy is decreased by about 18% compared with non-pregnant females
• Rectal administration of barbiturates, especially methohexital (20-30 mg/kg), has been used to induce anesthesia in uncooperative or young patients
• Even before thiopental was removed from the market, propofol had replaced it because it produced less nausea and more rapid recovery
• Barbiturates, especially phenobarbital, enhance liver microsomal protein levels (enzyme induction) after 2-7 days of continuous use
• This enzyme activity change can modify drug responses and interactions, as it speeds up the metabolism of oral anticoagulants, phenytoin, tricyclic antidepressants, corticosteroids, bile salts, and vitamin K
• Accelerated heme production exacerbates acute intermittent porphyria
• Hypotension is primarily caused by venodilation and decreased preload, myocardial depression is the secondary cause
• Thiopental causes non-immunogenic histamine release, contributing to transient hypotension
• The baroreceptor reflex is preserved, so reflex tachycardia helps maintain cardiac output
• Thiopental produces less hypotension than propofol when comparing the two drugs
• Non-immunogenic histamine release is the release of histamine from mast cells or basophils without immune system involvement, occurring directly due to certain stimuli
• It is caused by thiopental through directly triggering mast cell degranulation
• This effect is dose-dependent and causes transient hypotension, flushing, and bronchospasms
• Barbiturates produce dose-dependent depression of medullary and pontine ventilatory centers
• Thiopental decreases the sensitivity of the medullary ventilatory center to carbon dioxide stimulation
• Apnea is likely, especially in the presence of other depressants
• A large dose of a barbiturate depresses the cough and laryngeal reflexes
• The carbon dioxide ventilatory response curve relates PaCO2 to minute ventilation

Carbon Dioxide Ventilatory Response Curve

• The CO2 response curve shows how ventilation (breathing rate and tidal volume) changes in response to PaCO2 levels
• The x-axis represents PaCO2
• The y-axis represents minute ventilation, which is the total volume of air moved in and out of the lungs per minute
• A steeper slope indicates a greater response to CO2, a flatter slope indicates a reduced CO2 sensitivity
• A left shift in the CO2 ventilation response curve means ventilation increases at a lower PaCO2 than normal, indicating increased sensitivity to CO2
• In metabolic acidosis, excess H+ ions stimulate central chemoreceptors in the medulla, increasing ventilation to compensate for acidosis
• Hypoxia increases respiratory drive, as do anxiety, fear, pain, or CNS stimulants
• This means the body breathes even when CO2 levels are normal or slightly low and breathing stops at a lower PaCO2 than normal
• A right shift in the CO2 ventilation response curve means ventilation increases at a higher PaCO2 than normal, indicating a reduced CO2 sensitivity
• The body tolerates higher CO2 levels before triggering increased ventilation
• Opioids and sedatives decrease the central respiratory centers in the medulla, blunting the normal response to CO2, leading to respiratory depression and potential chronic CO2 retention (COPD, obesity hypoventilation syndrome)
• Long-term high CO2 levels desensitize central chemoreceptors, reducing their drive to increase ventilation
• Natural sleep (non-REM) decreases CO2 sensitivity, leading to slower breathing and mild CO2 retention
• Essentially, the body requires a higher PaCO2 to stimulate breathing

CNS Effects of Barbiturates

• Decreased cerebral oxygen consumption (CMRO2)
• Decreased cerebral blood flow (cerebral vasoconstriction)
• Decreased intracranial pressure
• Decreased EEG activity (burst suppression)
• No analgesia (lower doses may increase the perception of pain)
• Neuroprotection in focal ischemia (temporary occlusion of cerebral arteries) but not in global ischemia (cardiac arrest)
• Burst suppression is a distinct EEG pattern of alternating high-amplitude bursts of electrical activity followed by low-voltage suppression (flat-line periods), indicating a severely depressed brain state
• High doses of propofol, barbiturates, and volatile anesthetics can cause burst suppression
• Barbiturates decrease ICP by reducing cerebral metabolism and cerebral blood flow through drug-induced cerebral vascular constriction and reduced cerebral blood volume
• Cerebral metabolic suppression (reduced CMRO2) significantly reduces neuronal activity, decreasing demand for oxygen and energy, which reduces cerebral blood flow

Benzodiazepines

• Benzodiazepines exert five pharmacologic effects: anxiolysis, sedation, anticonvulsant actions, spinal-cord-mediated skeletal muscle relaxation, and anterograde amnesia
• Anterograde amnesia impairs memory after the drug is administered but does not provide retrograde amnesia (memories created before drug administration); amnesia is greater than sedation
• Compared to barbiturates, benzodiazepines produce less tolerance, have less potential for abuse, have a greater margin of safety (therapeutic index), have fewer and less serious drug reactions, and do not induce hepatic microsomal enzymes
• Benzodiazepines produce all their pharmacologic effects by facilitating the actions of GABA
• Benzodiazepines enhance the affinity of the receptors for GABA but do not activate GABAA receptors
• Chloride channels open, leading to increased chloride conductance and hyperpolarization of the postsynaptic cell membrane
• Postsynaptic neurons are rendered more resistant to excitation, which is how benzodiazepines produce anxiolysis, sedation, amnesia, alcohol potentiation, anticonvulsant actions, and skeletal muscle relaxation
• Benzodiazepines interact with a site between the α and γ subunits of the GABAA receptor
• The γ subunit is required for benzodiazepine binding
• α1 and α5 containing GABAA receptors are important for sedation
• Anxiolytic activity is due to interaction with α2 and α5 subunit-containing receptors
• α₁-containing GABAA receptors account for 60% of GABAA receptors in the brain; α2 subunits are principally in the hippocampus and amygdala; α5-containing GABAA receptors are mostly extra-synaptic contributing to the alteration of the resting membrane potential
• Benzodiazepines have minimal effects outside of the CNS because of this anatomic distribution of receptors
• The GABAA receptor is a large macromolecule containing physically separate binding sites for α, β, and γ subunits
• By acting on a single receptor at different binding sites, benzodiazepines, barbiturates, and alcohol can produce synergistic effects to increase GABAA receptor-mediated inhibition of the CNS, resulting in pharmacological synergy and CNS depression
• This explains cross-tolerance between drug classes -> benzodiazepines as first choice for detoxification from alcohol
• Benzodiazepines have a ceiling effect that prevents them from exceeding the physiologic maximum of GABA inhibition, resulting in low toxicity and a greater margin of safety
• The GABAA receptor is a pentameric (five-subunit) ligand-gated chloride ion channel that mediates inhibitory neurotransmission in the CNS
• It is composed of five subunits that determine its pharmacological properties, localization, and function, arranged around a central chloride ion channel
• Alpha subunits 1-5 are the most abundant subunit and essential for GABA binding, determining sensitivity to benzodiazepines
• Beta subunits 1-3 are required for GABA binding and channel opening, interacting with barbiturates, anesthetics like propofol, and neurosteroids
• Gamma subunits 1-3 are essential for benzodiazepine sensitivity; the γ₂ subunit is required for classic benzodiazepine binding (diazepam, midazolam)
• The delta and epsilon subunit also exist

Clinical Considerations for Benzodiazepines

• Midazolam is the most frequently used benzodiazepine in the anesthetic setting
• Differences in the onset and duration of action (DOA) reflect differences in potency, lipid solubility, and pharmacokinetics
• Lorazepam and diazepam have prolonged context-sensitive half-times
• The duration of action is determined by the rate of metabolism and elimination
• All benzodiazepines are highly lipid-soluble and highly bound to plasma proteins (albumin)
• If a patient has liver disease with less albumin, less drug will be bound to albumin causing more free drug circulating and greater CNS effects
• Potency: lorazepam > midazolam > diazepam
• Lorazepam is more potent, has a greater effect on the CNS

Pharmacokinetics and Side Effects

• Benzodiazepines are highly lipid-soluble and highly bound to plasma proteins due to their chemical structure and pharmacokinetics
• Their benzodiazepine ring system makes them lipophilic and cross lipid membranes easily
• Due to their lipophilic nature allowing them to interact with hydrophobic binding sites on albumin they are highly bound to plasma proteins, primarily albumin

Side Effects

• Fatigue and drowsiness are the most common side effects
• Synergistic sedative effects occur with other CNS depressants, such as alcohol IV anesthetics, a2 agonists and opioids
• Elderly patients may be intrinsically sensitive to benzodiazepines due to pharmacodynamic and pharmacokinetic components
• Aging and liver disease affect glucuronidation less than oxidative metabolic pathways
• Lorazepam is only metabolized by glucuronidation and has no active metabolites
• Diazepam its metabolized by hepatic microsomal enzymes to active metabolites
• Glucuronidation is a Phase II biotransformation process in which a glucuronic acid molecule is attached to a drug or metabolite to make it more water-soluble

Cardiovascular Effects

• Sedation dose minimal effects
• Induction dose can lower BP and Systemic Vascular Resistance

Respiratory Effects

• Sedation dose minimal effects
• Induction dose of respiratory depression
• Opioids potentiate the respiratory depressant effects, even at sedation doses
• Patients with COPD are more sensitive to the respiratory depressant effects

CNS Effects

• Sedation dose minimal effects on CMRO2 and cerebral blood flow
• Induction dose decreases CMRO2 and cerebral blood floow
• Thiopental cannot produce an isoelectric EEG
• Anterograde amnesia
• Anticonvulsant
• Anxiolysis
• Spinally mediated skeletal muscle relaxation antispasmodic
• No analgesia

Midazolam

• Midazolam has an imidazole ring, which gives it hydrophilic and lipophilic properties
• In the vial having a low pH, midazolam exists in the open-ring form, making it hydrophilic
• When injected into the bloodstream, the imidazole ring closes, and midazolam becomes more lipophilic it allows it to cross the blood-brain barrier freely
• A GABA-A agonist that increases the frequency of channel opening neuronal hyperpolarization but unlike most gaba agonists it increases channel open time
• For IV sedation the does is 0.01 -0.1 mg/kg IV induction is 0.1 - 0.4 mg/kg PO sedation in children 0.5-1.0 mg/kg with PO bioavailability which is 50% due to significant first-pass metabolism
• IV onset of action can be expected within 30-60 seconds and the duration is 20-60 minutes
• The breakdown of midazolam requires Hepatic (P450 enzymes) or Intestinal (P450 enzymes)
• It is metabolized to 1-hydroxymidazolm which is 0.5x efficacy of midazolam it is rapidly conjugated to an inactive compound. As a result of this renal failure prolongs the effect of 1-hydroxymidazolam
• Diazepam has enterohepatic recirculation explaining why it remains in the body for such a long time this can lead to an elimination half-life of = 43 hours
• It is used as an anticonvulsant and as a preventative measure against emergence delirium following ketamine
• Also it is used as an antispasmodic agent by reducing skeletal muscle tone at the level of the spinal neurons
• Lorazepam has an amnesic activity of 6 hours slow onset limits use as an anticonvulsant
• Propylene glycol which is added to diazepam and lorazepam to enhance water solubility can have serious venous irritant to patients

Remimazolam

• It is ultra-short acting benzodiazepine with a high affinity for the GABAA receptor
• This drug is indicated for induction and maintenance for adults undergoing procedural sedation lasting 30 minutes, or less for example Bronchs, endoscopies
• The adult dose for Induction of procedural sedation is 5 mg over 1 minute
• The adul dose for Maintenance is 2.5 mg IV over 15 seconds, 2 minutes must elapse between each dose
• Peak sedation minutes ~ 3-3.5 minutes after administration with a Half-life of 0.5-2 minutes protect the vial from light after removing from package and after reconstitution, the single-use vial must be discarded within 8 hours
• This drug is metabolized by non-specific plasma esterases as the molecule contains ester linkage
• Non-specific plasma esterases are a group of enzymes found in the blood that hydrolyze ester-containing compounds into their inactive or active forms
• The major metabolite is CNS7054 excreted in urine
• Patients with severe hepatic dysfunction should receive a dose reduction even though this drug undergoes organ-independent elimination
• Compared to midazolam, remimazolam has faster onset deeper sedation profile faster recovery
• Compared to propofol, remimazolam causes less respiratory depression better degree of cardiopulmonary stability
• The affect of the agent can be reversed with flumazenil, with minimal risk of re-sedation
• Remimazolam it is rapidly metabolized, leading to a short half-life and fast clearance
• Key factors that minimize Re-sedation risk oultra Rapid metabolism by non-specific plasma esterases which indicates that it can function independent of liver failure
• It is also a Competitive antagonism at GABAA receptors with no active metabolites w/ Prolonged effects predictable pharmacokinetics
• Flumazenil is a benzodiazepine antagonist

Flumazenil

• It is a competitive benzodiazepine antagonist with a high affinity for the GABAA receptor
• This drug will prevent or reverse all agonist effects of benzodiazepines in a dose-dependent manner
• Hepatic microsomal enzymes metabolize flumazenil to inactive metabolites
• Post-operative benzodiazepine reversal has not shown to increase SNS tone, anxiety, or neuroendocrine evidence of stress therefore tends to reverse the sedative effects than the amnestic effects of benzos
• Caution use in benzo dependent patients as it shows signs of withdrawal including seizures
• Titrate the initial dose of flumazenil to the desired level of consciousness, initial dose = 0.2 mg IV titrated in 0.1 mg increments every 1 minute up to a dose of 1 mg
• Doses of range 0.3 to 0.6 mg decrease the degree of sedation so Doses ranges from 0.5 to 1 mg this abolishes the total effect of a therapeutic dose of benzodiazepine
• The continuous infusion to maintain wakefulness is 0.1-0.4 mg/hr, flumazenil has a high affinity but has to be administered cause it has a short duration of action (30-60 min)

Ketamine

Phencyclidine derivative has a role in the process of dissociative amnesia where an EEG shows dissociation between thalamocortical and limbic systems

• The is known as dissociative anesthesia/amnesia, here the is an unresponsive Cataleptic state in which the eyes remain open with a slow nystagmic gaze no communication even though patient appears awake hypertonus and skeletal muscle movements may occur independent of stimulation
• Provides profound analgesia at subanesthetic doses, but emergence delirium limits ketamine as a sole-anesthetic agent.
• A water-soluble molecule that will structurally resemble phencyclidine and can act as an optical isomers that produces the presence of an asymmetric carbon atom
• Some of these isomers are Left-handed optical isomer = S (+) ketamine which produces more intense analgesia, Rapid metabolism and recovery, Less salivation, and has Lower incidence of emergence reactions
• Right-handed optical isomer = R (-) ketamine has an unknown MOA that is due to the ketamine induced analgesia and dissociative amnesia
• Ketamine interacts with multiple CNS receptors, but a definitive association between receptor interaction and behavior has not been established
• Ketamine binds non-competitively to the phencyclidine site on the N-methyl-D-aspartate (NMDA) receptors as well as affect Opioid receptors, Monoaminergic receptors (MAD), what Muscarinic receptors (Ach?), Voltage-gated sodium channels Neuronal nicotinic acetylcholine receptors
• Is a N-methyl-D-aspartate Receptor Antagonism that functions of the presence of Ligand-gated ion channels
• Channel activation requires binding of glutamate, an excitatory neurotransmitter, with glycine as a co-agonist, as ketamine inhibits activation of the NMDA receptors by glutamate and decreases presynaptic release of glutamate
• This agent has a Relatively short DOA, High lipid-solubility pKa=7.5 which helps in that itis not significantly bound to plasma proteins leaves the blood rapidly to be distributed into the tissues
• Due to its Extreme lipid solubility that leads to rapid transfer across BBB and is associated with a High hepatic clearance rate and large volume of distribution of 3 L/kg which all combine to have and elimination half-time of 2-3 hours
• This results in the agent have and important pathway of metabolism that is demyelination of ketamine by cytochrome P450 enzymes which forms norketamine and hydroxynorketamine and this active metabolite, norketamine, may contributes with repeated doses

Analgesia Function

• Subanesthetic doses of ketamine ranges (0.2-0.5 mg/kg IV) can produce intense analgesia this is because Somatic > visceral pain
• Analgesic effects are likely caused by the activity of the agent on the the thalamic and limbic systems which both have roles in the interpretation of painful signals on NMDA receptors
• NMDA receptors are excitatory amino acid receptors that are important in the modulation of pain and the processing of painful stimuli and so cause on Inhibitoioon spinal NMDA receptors this will cause Inhibit spinal pathway receptors, with drugs like ketamine, are useful in the management of postoperative pain and can decrease analgesic opioid consumption as well as blocks central sensitization and wind-up in the dorsal horn of the spinal cord
• This reduces Prevents opioid-induced hyperalgesia such as remifentanil which helps the agent serve as a useful substance for burn patients and chronic pain syndromes due to the

Cardiovascular Effects

• ↑ SNS tone for ↑ cardiac output, ↑ heart rate,↑ SVR, for use as a subhypntoic doses than 0.5 mg/kg which results in a direct actrivation of the SNS response
• This however can be a DIRECT MYOCARDIAL DEPRESSENT cardiovascular effects listed above can cause require an intact SNS however myocardial depressant effects will be unmasked in patients with depleted catecholamine stores or sympathectomy
• However the Respiratory Effects of the agent causes Bronchodilation while leaving the Upper airway muscle tone and airway reflexes which may lead to brief period of apnea that may occur following induction
• There are no significant shift of the CO2 response curve while there can be an increases of ↑ secretions so add glycopyrrolate

CNS Effects

• ↑ cerebral oxygen consumption CMRO2 and blood flow cerebral
• ↑ intracranial pressure if PaCO2 is maintained, ↑ in ICP is minimal
• The electrical affect for activity is ↑ EEG activity
• it also has secondary rotary nystagmus and blepharospasm and the affect for delirium
• It can causes Nightmares or the presence of hallucinations, and may be required to Administer benzodiazepines pre-op to prevent this and is more likely if there are pre-exisiting Risk factors associated that includes age, > 15, female, a dose > 2 mg/kg, and a history of personality disorder
• Lastly Acute intermittent porphyria classified where Porphyrias can as: Acute that is inducible and Chronic that is non-inducible
• The most common and dangerous type of inducible porphyria in Acute intermittent porphyria, This is a Cause due to a defect in heme synthesis that promotes the accumulation of heme precursors
• Heme is a key component of hemoglobin, myoglobin, and cytochrome P450 enzymes it causes or has some affect on those proteins, Succinyl-CoA + glycine ALA synthase which leads to Precursors Heme
• This type od intermittent porphyria can be made worse by: Stimulation of ALA synthase, Emotional stress, Prolonged NPO status, CYP450 induction
• Sings and symptoms of the disorder includes the GI severe abdominal pain which causes N/V but also includes those stemming of CNS -> anxious and confused patients , seizures, psychosis, coma, PNS -> skeletal muscle weakness, and bulbar weakness the Conditions related to emotionaly disturbed patients , Emotional stress Prolonged NPO status
• And avoid administering drugs of Barbiturates Ketamine ketorolac the likes of Etomidate Amiodarone, Calcium channel blocker or if the patient is using Birth control pills.
• Any drug or condition that induces ALA synthase can potentially accelerate the production of heme precursors and must be avoided with inducible forms of porphyria
• Anesthetic management would primarily focus on hydration of the patient by administering Liberal hydration while assisting and giving Glucose supplementation (↓ ALA synthase activity) Heme arginate (↓ ALA synthase activity) Prevention of hypothermia
• Which drugs are safe to give to patients associated with this conditions are Volatile anesthetics, nitrous oxide, NMBs, NMB reversals, narcotics, midazolam, ondansetron, vasopressors, and beta-blockers
• Also to consider that regional anesthesia is not contraindicated, but it might be difficult to distinguish block-related complications vs an acute porphyria attack.

Explore the mechanisms of barbiturates on neuronal activity, including their effects on GABAA receptors and histamine release. This quiz assesses understanding of their clinical implications, especially in scenarios like seizures and asthma.