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Psychopharmacology & Anesthesia

• Psychotropic drugs affect mood, sensation, thinking, and behavior
• Many psychotropic drugs affect similar neurotransmitter and ionic systems as anesthetic agents
• This influences anesthetic management and guides decisions on whether to continue or hold medications perioperatively

Depressive Disorders

• Characterized by sadness that interferes with function and loss of pleasure
• Multifactorial, involving genetics, neurotransmitter changes, neuroendocrine issues, and psychosocial factors
• Serotonin (5-HT) is highly implicated in emotions and mood and serves as a major target for treatment
• Different 5-HT receptors have varying actions depending on tissue

Serotonin Receptors

• 5-HT1A receptors are inhibitory and involved in antidepressant effects
• 5-HT2A receptors are excitatory and their agonism can cause anxiety, insomnia, and sexual dysfunction
  • They are antagonized by some antipsychotics and implicated in serotonin syndrome
• 5-HT3 receptors regulate nausea and vomiting and can be targeted by psychotropic and anesthetic drugs

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Include fluoxetine, sertraline, paroxetine, citalopram, escitalopram
• Mechanism: blocking serotonin reuptake, which increases synaptic serotonin levels and can eventually lead to down-regulation of serotonin receptors
• Used for mild to moderate depression, panic disorder, OCD, phobias, and PTSD
• Common side effects: insomnia, agitation, headache, nausea, diarrhea, hyponatremia (SIADH), and increased risk of suicidal thoughts in children and adolescents (black box warning)
• Can inhibit CYP 450 enzymes, increasing plasma concentrations of other drugs and increasing bleeding risk with drugs like warfarin
• Citalopram and escitalopram can cause QT prolongation
• Should generally be continued perioperatively to avoid discontinuation syndrome

Serotonin Syndrome

• Related to excessive CNS serotonergic activity, often with multiple drugs increasing serotonin levels
  • These drugs include SSRIs, SNRIs, TCAs, MAOIs, phenylpiperidine opioids like fentanyl and meperidine, tramadol, methadone, and ondansetron
• Symptoms: autonomic instability (tachycardia, hypertension, hyperthermia, tachypnea, diaphoresis), neuromuscular abnormalities (hyperreflexia, tremors, myoclonus, rigidity), and mental status changes (restlessness, agitation, hallucinations, confusion, seizures)
• Can occur within 12 hours

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

• Include venlafaxine, duloxetine, desvenlafaxine, and milnacipran
• Mechanism: Block reuptake of both serotonin and norepinephrine, increasing their synaptic levels
• Used for depressive disorders, anxiety disorders, and chronic pain syndromes
• Adverse effects: sympathetic activation (tachycardia, hypertension) and inhibition of CYP 2D6
• Can also have effects on alpha-1, NMDA, histamine, and muscarinic receptors, and deplete catecholamine stores

Tricyclic Antidepressants (TCAs)

• Include amitriptyline, nortriptyline, imipramine, clomipramine, and desipramine
• Mechanism: Inhibit reuptake of serotonin and norepinephrine and antagonize various receptors (5-HT2A, alpha-1, NMDA, H1, H2, muscarinic)
• Used for major depressive disorder and chronic pain syndromes
• Central nervous system side effects: anticholinergic effects (dry mouth, blurred vision, tachycardia, urinary retention, ileus), sedation, delirium risk (elderly), lowered seizure threshold (pediatrics), extrapyramidal symptoms, and tremors
• Cardiovascular side effects: orthostatic hypotension, increased heart rate, ECG changes (QRS widening, T wave inversion, QT prolongation), and slowed AV conduction
• Can enhance depressant effects of anesthetics
• Anesthetic considerations: increase anesthetic requirements; exaggerated response to anticholinergics and indirect-acting vasopressors (avoid ephedrine, use smaller doses of direct-acting like phenylephrine); exaggerated ventilatory depressant effects of opioids (avoid pancuronium, ketamine, meperidine, epinephrine)

Monoamine Oxidase Inhibitors (MAOIs)

• Include isocarboxazid, phenelzine, selegiline, and tranylcypromine
• Mechanism: Inhibit monoamine oxidase (MAO), a mitochondrial enzyme that breaks down norepinephrine, epinephrine, dopamine, and serotonin, thus increasing their availability
• Older MAOIs are irreversible; newer ones (RIMAs) are reversible
• Used for major depressive disorder, panic disorder, Parkinson's, and phobias
• Side effects: hypotension, anticholinergic-like effects, sedation, paresthesias, weight gain, hepatitis, and hyperadrenergic crisis with tyramine-rich foods
• Type I (excitatory) reaction resembling serotonin syndrome can occur with meperidine and dextromethorphan
• Type II (depressive) reaction due to enhanced opioid effects (hypotension, ventilatory depression)
  • Treat with naloxone
• Contraindicated with indirect-acting sympathomimetics (risk of fatal hypertensive crisis)
  • Use direct-acting with caution (smaller doses of phenylephrine)
  • Avoid ketamine, ephedrine, pancuronium, and epinephrine
• Phenelzine decreases plasma cholinesterase, prolonging succinylcholine action and may reduce barbiturate metabolism
• Propofol, etomidate, benzodiazepines, inhaled agents, and anticholinergics are generally safe
• Continue perioperatively despite traditional recommendations to stop

Miscellaneous Monoamine Altering Drugs

• Trazodone: SRI, 5-HT2A and alpha-1 antagonist; used for MDD and insomnia; side effects include orthostatic hypotension and dry mouth
• Buspirone: partial agonist at 5-HT receptors; used for GAD; may elevate NE and DA
• Mirtazapine: tetracyclic alpha-2 and 5-HT2A/3 and H1 antagonist; used for MDD; lower risk of serotonin syndrome
• Bupropion: inhibits DA and NE reuptake; used for MDD, smoking cessation, ADHD, and possibly neuropathic pain; side effects include seizures and stimulant-like effects

Bipolar Disorders

• Characterized by episodes of mania and depression
• Treatment involves mood stabilizers, antidepressants, antipsychotics, benzodiazepines, and psychotherapy

Lithium

• Treatment of choice for bipolar disorder, treatment-resistant MDD, and suicide risk
• Mechanism: inhibits excitatory neurotransmission (dopamine, glutamate by downregulating NMDA receptors), and increases GABA neurotransmission (increases GABA levels and upregulates receptors)
• Side effects: renal (polydipsia, polyuria, nephrogenic DI, chronic kidney disease), endocrine (hypothyroidism), and cardiac (T wave changes, SA nodal block, bradycardia)
• Drug interactions: increased lithium levels with thiazide and loop diuretics, NSAIDs, and ACE inhibitors; increased neurotoxicity with neuroleptic drugs and anticonvulsants; prolonged blockade with muscle relaxants; possible decrease in anesthetic requirements with inhaled and IV anesthetics; delayed recovery with barbiturates
• Perioperative discontinuation (1-3 days prior) is recommended due to narrow therapeutic index (1-1.2 mEq/L) and risk of toxicity.
• Avoid sodium depletion, diuretics, and NSAIDs
• Toxicity (plasma level > 1.5-2 mEq/L): widened QRS, AV block, dysrhythmias, hypotension, weakness, ataxia, seizures, confusion
• Treatment: dialysis and sodium bicarbonate

Schizophrenia, Psychoses

• Characterized by psychosis (loss of contact with reality, hallucinations, delusions), disorganized speech and behavior, flattened affect, cognitive deficits, and social dysfunction
• Treatment includes pharmacologic therapy (antipsychotics), cognitive therapy, and psychosocial rehab

Typical (First Generation) Antipsychotics (FGAs) / Neuroleptics

• Examples: haloperidol, chlorpromazine, perphenazine, and fluphenazine
• Mechanism: primarily dopamine (D2) receptor antagonists in the CNS
• Cause extrapyramidal side effects (EPS)
• Less favorable due to side effects but commonly used in emergency and acute care settings
• High therapeutic index and have antiemetic effects by blocking dopamine in the CRTZ
• Haloperidol (Haldol): butyrophenone; used off-label for emergence/ICU delirium and acute agitation/aggression; mechanism is D1 and D2 antagonism and RAS depression; dosing IV 2-10 mg, IM 5 mg; onset 3-20 min IV, 30 min IM
• Droperidol: butyrophenone; potent antiemetic and sedative; used off-label for delirium and as a GA adjunct (neurolept analgesia with opioids)
  • Carries a black box warning due to high-dose cardiac risks (QT prolongation, arrhythmias)
  • Antiemetic dose 0.625-2.5 mg IV/IM
• Perphenazine: phenothiazine; anti-dopaminergic antiemetic with mixed evidence; dosing IV/IM 5-10 mg, PO 8-16 mg; use with caution in older patients, those with EPS/Parkinson's, or on Class III antiarrhythmics
• Extrapyramidal Effects: tardive dyskinesia, akathisia, dystonia (treat with diphenhydramine 25-50 mg IV), and tremors
• Other FGA side effects: hypotension, antidysrhythmic effects, QTc prolongation, gynecomastia, weight gain, sedation, skeletal muscle relaxation, abnormal thermoregulation, decreased seizure threshold, obstructive jaundice, elevated liver enzymes, and neuroleptic malignant syndrome (NMS)
• Neuroleptic Malignant Syndrome (NMS): possibly related to dopamine antagonism; risk factors include young males and dehydration; develops over 24-72 hours; characterized by hypertonicity of skeletal muscles, autonomic instability (labile BP, tachycardia, dysrhythmias), and altered consciousness
  • Differential diagnosis from malignant hyperthermia (MH): non-depolarizing muscle relaxants produce flaccid paralysis in NMS but are ineffective in MH
  • Treatment includes dantrolene, dopamine agonists, benzodiazepines, IV hydration, and cooling
• FGA Anesthetic Considerations: prone to tachycardia and hypotension; higher incidence of CV disease; QTc prolongation risk (monitor ECG); higher incidence of DM and glucose intolerance (monitor blood glucose); potential weight gain and altered pain response; impaired temperature regulation (active warming) and altered HPA function (decreased cortisol); synergistic effects with non-depolarizing muscle relaxants (monitor neuromuscular function); risk for over-sedation with BZs and CNS depressants (monitor for serotonergic symptoms with phenylpiperidines); postoperative surgical stress can worsen psychotic symptoms and increase risk for emergence delirium and infection

Atypical (Second Generation) Antipsychotics (SGAs)

• Examples: clozapine, olanzapine, risperidone, quetiapine, and aripiprazole
• Mechanism: D2 antagonism plus effects on H1, 5-HT2, mACh, and alpha receptors; tend to have lower or no EPS
• Greater benefit for cognitive and affective symptoms due to 5-HT2A antagonism and other serotonergic actions
• Clozapine: most effective SGA; strong 5-HT antagonism, little D2; side effects include agranulocytosis, fever, myocarditis, and excessive salivation
• Olanzapine: used for agitated psychosis and mania; side effects include sedation, hypotension, weight gain/metabolic syndrome; caution with benzodiazepines due to cardiorespiratory depression risk
• Risperidone, paliperidone: similar to FGAs in dopamine antagonism and EPS risks; side effects include hypotension and gynecomastia; being investigated for delirium prophylaxis post cardiac surgery
• Aripiprazole, brexpiprazole: mixed D2 agonist/antagonist; used for bipolar disorder and MDD; side effects include akathisia and risky behaviors
• Ziprasidone, lurasidone: moderately effective; side effects include QTc prolongation and akathisia; minimal metabolic effects
• Quetiapine: primary 5-HT antagonism, little D2 (minimal EPS risk); active metabolite inhibits NE transporter; side effects include sedation and orthostatic hypotension
• SGA Side Effects: similar risk as FGAs for EPS and NMS, but metabolic effects (weight gain, hypercholesterolemia, insulin resistance) and related cardiovascular morbidity are significant

Postoperative, Emergence Delirium

• Can occur minutes to 7 days postoperatively
• Pathophysiology is not fully understood but may involve inflammatory markers and altered balance in sleep/arousal pathways; quick emergence from anesthesia is a risk factor
• Risk factors include extremes of age, male gender, cognitive dysfunction, substance use, prolonged surgery, residual neuromuscular blockade, temperature/BP changes, hypoxemia, pain, and presence of ETT
• Differential diagnosis includes hypoxia, hypercarbia, acidemia, hypothermia, hypoglycemia, stroke, seizure, and central cholinergic syndrome
• Symptoms: disturbed attention/cognition and disorientation/agitation
• Treatment: control pain and agitation (pre-emptive multimodal analgesia, sedation); haloperidol is often first-line; benzodiazepines may increase risk in adults

Neurodevelopmental Disorders

• Notable characteristics: inattention, hyperactivity, and impulsivity; multifactorial
• Treatment: stimulant drugs, behavioral therapy, and educational interventions

Attention-Deficit/Hyperactivity Disorder (ADHD)

• Methylphenidate (Ritalin): CNS stimulant; indirect sympathomimetic (blocks NE and DA reuptake, increases DA release); used for ADHD, ADD, and narcolepsy; side effects include hypertension, tachycardia, arrhythmias, weight loss, and insomnia; may actively induce emergence from inhaled and propofol anesthesia and may result in higher anesthetic requirements
• Mixed Amphetamine Salts (Adderall): block NE and DA reuptake, increase dopamine release; side effects include tolerance, dependency, anxiety, insomnia, exacerbation of tics, and increased HR/BP
• Clonidine: alpha-2 agonist; FDA approved for ADHD; also used for anxiety, opioid withdrawal, and analgesia (neuraxial/regional); side effects include hypotension and bradycardia

Cannabis, Cannabinoids

• Delta-9-THC is the most potent psychoactive cannabinoid; binds to CB1 (CNS, memory, learning, motor, addiction, psych disorders) and CB2 (periphery/CNS, immune, pain) receptors
• Uses: N/V, cachexia, analgesia, and anxiety
• Acute intoxication: euphoria, relaxation, altered perception, decreased reaction time, tachycardia, hypotension, and increased appetite
• Anesthetic considerations: increased anesthetic requirements and potential cardiovascular and airway/pulmonary effects (irritability, laryngospasm, coughing, excess secretions)

MemoryMaster Knowledge Check

• MAO inhibitors interfere with the metabolism of adrenergic neurotransmitters by inhibiting monoamine oxidase
• Dry mouth, blurred vision, tachycardia, urinary retention, and ileus are all symptoms of anticholinergic side effects of TCAs
• A patient taking fluoxetine exhibiting HTN, tachycardia, agitation, and restlessness resembles serotonin syndrome
• Drugs to avoid in a patient taking phenelzine include ephedrine, ketamine, amphetamines, sympathomimetics, and over-the-counter cold medicines (like dextromethorphan)
• A common blood pressure side effect with TCAs is orthostatic hypotension
• In a patient taking an MAOI who suddenly develops hypotension during anesthesia, phenylephrine (small doses) should be used to treat it
• The threshold plasma concentration for lithium toxicity is 1.5-2 mEq/L
• Dystonia related to droperidol or other antipsychotic use can be treated with diphenhydramine 25-50 mg
• In a patient taking lithium, sodium (hyponatremia) is another lab value of concern, and diuretics might contribute
• The mechanism of action of amphetamines (stimulants) is indirect sympathetic activation by blocking the reuptake of catecholamines (norepinephrine and dopamine)
• The mechanism of action of caffeine is adenosine antagonism and inhibition of phosphodiesterase
• The two cannabinoid receptor types are CB1 (neurotransmission, pain, immune, learning, memory, reward, addiction, motor dysfunction, psych disorders) and CB2 (neurotransmission, pain, immune, cocaine-induced reward)