Barbiturates: Effects and Mechanisms

Barbiturates

• Complete CNS depressants that can produce a coma
• The mechanism of action involves binding to a specific barbiturate binding site on the GABA-a receptor, acting as a GABA agonist

Barbiturates: Mechanism

• Increases Cl- movement into cells by prolonging the duration of channel open time, similar to propofol
• Depresses the Reticular Activating System (RAS)

Barbiturates: Effects and Considerations

• Rapid onset and rapid awakening occur after a single IV dose due to redistribution
• Diffuses across all membranes, including the placenta
• Highly bound to plasma proteins

Barbiturates: Adverse Effects

• Extravascular or arterial injection can cause intense vasoconstriction, ischemia, and tissue necrosis
• Dose-dependent histamine release can lead to bronchoconstriction in asthma patients
• Highly addictive, similar to opioids
  • Withdrawal symptoms include anxiety, tremor, N/V, seizures, and psychiatric reactions
  • Treated with cross-tolerant benzodiazepines like chlordiazepoxide

Barbiturates: Contraindications

• Absolute contraindication in patients with porphyria

Barbiturates: Effects on Organ Systems

• CNS/Neurologic effects include decreased Cerebral Blood Flow (CBF), Cerebral Metabolic Rate of Oxygen consumption (CMRO2), and Intraocular Pressure (IOP)
• It is a potent cerebral vasoconstrictor that decreases Intracranial Pressure (ICP), commonly used for cerebral protection
  • Example: Pentobarbital is used for barbiturate-induced coma in patients with severe brain injury like hemorrhagic stroke or Traumatic Brain Injury (TBI)

Barbiturates: Effects on Respiratory and Cardiovascular Systems

• No significant effect at anesthetic doses
• At anesthetic doses, decreases respirations by depressing the medullary ventilatory center
• Decreases blood pressure
• Vasodilates peripheral capacitance vessels, leading to decreased preload
• Baroreceptor reflex is preserved, resulting in reflex-increased heart rate, so cardiac output usually maintained

Barbiturates: Liver Metabolism

• Metabolized by liver/P450 enzymes; awakening is determined by redistribution, not metabolism
• Characterized by low hepatic extraction ratio and capacity-dependent elimination
• The liver has a large reserve capacity to oxidize barbiturates, so hepatic dysfunction must be extreme for a prolonged duration of action to occur

Barbiturates: Ultra-Short Acting Agents

• Methohexital (10 mg/ml)
  • Dose: 1-2 mg/kg IV
  • Duration: 4-7 minutes
  • Considered the gold standard for Electroconvulsive Therapy (ECT)
• Thiopental (25 mg/ml)
  • 500 mg vial diluted with 20 ml sterile water
  • Dose: 3-4 mg/kg IV
  • Onset: 10-30 seconds
  • Duration: 5-8 minutes with peak effect at 1 minute

Barbiturates: Intermediate and Long Acting Agents

• Intermediate Acting: Pentobarbital, primarily used for barbiturate-induced coma in patients with severe brain injury
• Long Acting: Phenobarbital, used as a sedative and anticonvulsant

Ethanol

• Complete CNS depressant that produces coma

Ethanol: Mechanism

• No specific receptor interactions identified, it affects a multitude of receptors

Ethanol: Effects

• Acute exposure suppresses drug metabolism
• Chronic exposure increases microsomal activity, specifically CYP2E1
• Increases urine output due to the inhibition of Antidiuretic Hormone (ADH)

Ethanol: Absorption and Metabolism

• Rapidly absorbed from the GI tract; crosses the Blood-Brain Barrier(BBB) and placenta; metabolism occurs in the liver

Ethanol Metabolism

• Ethanol (EtOH) is metabolized in the liver, first to Acetaldehyde by Alcohol Dehydrogenase, and then to Acetic Acid by Acetaldehyde Dehydrogenase

Ethanol: Alcohol Abuse Disorder

• Medications that help treat alcohol abuse disorder block acetaldehyde dehydrogenase, causing a build-up of acetaldehyde, which contributes to the hangover effect

Ethanol: Alcohol Withdrawal Treatment

• Administer diazepam or lorazepam for acute withdrawal symptoms to help prevent seizures
  • Lorazepam or oxazepam are alternatives if there's liver disease

Ethanol: Alcohol Use Disorder Treatment

• Disulfiram (Antabuse)
  • It has no clinical effects on its own
  • Inhibits the conversion of acetaldehyde to acetic acid by inhibiting aldehyde dehydrogenase
  • Causes an increase in acetaldehyde levels, leading to unpleasant or toxic events like increased heart rate, N/V, and unconsciousness
  • Patients should be warned about using alcohol-containing products like mouthwash and cough syrups

Benzodiazepines

• Incomplete CNS depressants; do not produce coma
• Mechanism of action: binds to the benzodiazepine binding site on the GABA-a receptor (GABA agonist)

Benzodiazepines: Mechanism and Effects

• Increases the frequency of Cl- channel opening
• No significant direct effects on respiratory, cardiovascular, or gastrointestinal systems, but cause dose-dependent decrease in ventilation
• Produces only anterograde amnesia
• Does not induce CYP's unlike barbiturates

Benzodiazepines: Antagonist

• Flumazenil (Romazicon) is a benzodiazepine antagonist

Benzodiazepines; Ultra-Short Acting

• Remimazolam (Byfavo): has a half-life of 30 minutes, rapidly metabolized by nonspecific tissue esterases and is used in anesthetic or sedative procedures in GI/pulm settings

Benzodiazepines: Short and Intermediate Acting

• Short acting: Midazolam (Versed): anesthetic and pre-anesthetic, half life of 2 hours
• Intermediate acting: Alprazolam (Xanax): anxiolytic, often used for panic attacks, rapid oral absorption/onset, half life of 10-22 hours
• Lorazepam (Ativan): anxiolytic, pre-anesthetic, treats status epilepticus, half life of 10-22 hours

Benzodiazepines: Long Acting

• Clonazepam (Klonopin, Rivotril): anticonvulsant, very long-acting with active metabolites, half life of >24 hours
• Chlordiazepoxide (Librium): anxiolytic, alcohol taper, half life of >24 hours
• Diazepam (Valium): anxiolytic, anticonvulsant, muscle relaxant, half life of >24 hours
• Cirrhosis of the liver = increased elimination half-time of diazepam
• Half life of 43 hours with no old people

Barbiturates: Contraindications

• Contraindicated in patients with porphyria

Porphyria

• Group of rare metabolic disorders caused by deficiencies in enzymes involved in the biosynthetic pathway of heme, a building block of hemoglobin
• Defect in heme synthesis promotes accumulation of heme precursors
  • Limited enzyme availability to create heme
  • Usually, the rate limiting enzyme in the biosynthetic pathway of porphyrins is ALA-synthetase
  • When given a drug that induces ALA-synthase, an acute attack can occur

Porphyria Synthesis

• Synthesis proceeds by: Succinyl-CoA + Glycine -> ALA Synthase -> Precursors -> Heme
• Classified as acute/hepatic (inducible) or non-acute/erythropoietic

Porphyria: Acute Intermittent

• Most dangerous and common type of inducible porphyria
• Acute forms are important to consider in anesthesia
• The rate-limiting step is ALA synthase

Porphyria: Medications to Avoid

• Rate limiting step is ALA synthase and medications that induce this enzyme be avoided, including:
  • Barbiturates (Methohexital, Thiopental, Pentobarbital, Phenobarbital)
  • Etomidate

Porphyria: Symptoms

• Severe abdominal pain
• N/V
• ANS instability
• Electrolyte disturbances
• Muscle weakness/neuropsychiatric manifestations ranging from mild to life-threatening

Methohexital

• Barbiturate that lowers the seizure threshold and produces quality seizures, making it the gold standard for ECT therapy but NOT for the standard "ol" patient

Methohexital: Considerations

• Can cause myoclonus during induction

Neurotransmitter Systems

• Relevant to Anesthesia and Perioperative Drug Effects: Acetylcholine, Dopamine, Norepinephrine, Serotonin, Glutamate, and GABA

Acetylcholine

• Activation of M1 and M3 muscarinic receptors is excitatory
• Activation of M2 receptors is inhibitory
• Activation of nicotinic receptors is excitatory
• Reduction in activity of cholinergic neurons occurs in Alzheimer's disease
  • Drugs are used to increase CNS cholinergic activity

Dopamine

• Activation of D1 receptors is inhibitory
• Activation of D2 receptors is inhibitory
• Responsible for reward, drive, euphoria, orgasm, anger, addiction, love, and pleasure

Norepinephrine

• Activation of A-1 receptors is excitatory
• Activation of A-2 receptors is inhibitory
• Activation of B-1 receptors is excitatory
• Activation of B-2 receptors is inhibitory
• Activation of adrenergic receptors elevates mood and increases wakefulness/attention

Serotonin

• Activation of 5-HT1A receptors is inhibitory
• Activation of 5-HT2A receptors is excitatory
• Activation of 5-HT3 receptors is excitatory

Serotonin: Chemoreceptor Trigger Zone

• CTZ contains receptors for serotonin(5-HT3), dopamine (D2), and NK-1
• Zofran is a 5-HT3 antagonist

Serotonin: Modulation

• Serotonin modulates anger, aggression, body temperature, mood, sleep, human sexuality, appetite, metabolism, and stimulates vomiting
• Agonists that include Activation of 5-HT4 receptors

Glutamate

• Glutamate is a major excitatory neurotransmitter in the brain
• Activation of NMDA receptors is excitatory
• Activation of AMPA or kainite receptors is excitatory
• Activation of metabotropic presynaptic receptors is inhibitory
• Activation of metabotropic postsynaptic receptors is excitatory
• Glutamate-induced excitatory effect is involved in both acute and chronic brain injury

GABA

• GABA is a major inhibitory neurotransmitter in the brain
• Activation of GABA-A is inhibitory
• Activation of GABA-B presynaptic receptors is inhibitory
• Activation of GABA-B postsynaptic receptors is inhibitory
• Decreased GABA activity or increased glutamate activity leads to seizures

Serotonin Syndrome

• Attributed to toxic levels of synaptic and extracellular serotonin
• The classical triad is neuromuscular excitability, ANS excitability, and mental status change
• The most severe consequence is rigidity and hyperpyrexia

Serotonin Syndrome: Severe Cases and Causes

• Severe cases of hyperpyrexia and rigidity may lead to rhabdomyolysis, multisystem organ failure, and DIC
• Can be caused by SSRI alone, but usually due to a combo of different classes of serotonergic meds
• The most dangerous combo is SRI (serotonin reuptake inhibitor) + MAOI

Serotonin Syndrome: Causative Drugs

• At risk are ALL serotonergic drugs including: SSRIs, SNRIs, MAOIs, MDMA (ecstasy)
• Nonpsychotic/non-serotonergic meds that can trigger serotonin syndrome in combo with an SRI: methylene blue and meperidine
• Example: Fentanyl + Venlafaxine
• May take up to 12 hours to show symptoms
• Treated with cyproheptadine