Module 7 - Psychopharmacology and Anesthesia

Psychopharmacology and Anesthesia

• Psychotropic drugs alter mood, sensation, thinking, and behavior
• Many of these drugs affect neurotransmitter and ionic systems similarly to anesthetic agents
• Perioperative management includes deciding whether to continue or hold psychotropic medications

Depressive Disorders

• Characterized by sadness impacting function and loss of pleasure
• Multifactorial, involving genetics, neurotransmitters, neuroendocrine issues, and psychosocial factors
• Serotonin (5-HT) strongly affects emotions and mood states
  • 5-HT1A receptors are inhibitory and involved in antidepressant effects
  • 5-HT2A receptors are excitatory; agonism can cause anxiety, insomnia, and sexual dysfunction
    • Some antipsychotics antagonize 5-HT2A receptors
    • 5-HT2A receptors are implicated in serotonin syndrome
  • 5-HT3 receptors regulate nausea and vomiting and are targeted by psychotropic and anesthetic drugs

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Examples include fluoxetine, sertraline, paroxetine, citalopram, and escitalopram
• Block serotonin reuptake, increasing synaptic serotonin levels, which can down-regulate 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 suicidal thoughts in young patients
• Can inhibit CYP 450 enzymes, increasing plasma concentrations of other drugs like warfarin which increases bleeding risk
• Citalopram and escitalopram can cause QT prolongation
• Generally, continue perioperatively to avoid discontinuation syndrome like major depressive episode, dizziness and paresthesias

Serotonin Syndrome

• Related to excessive CNS serotonergic activity, often with multiple drugs that increase serotonin levels
  • Implicated drugs include SSRIs, SNRIs, TCAs, MAOIs, phenylpiperidine opioids, tramadol, methadone, and ondansetron
• Symptoms: autonomic instability (tachycardia, hypertension, hyperthermia), neuromuscular abnormalities (hyperreflexia, tremors), and mental status changes (agitation, confusion, seizures)
• Can occur within 12 hours

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

• Examples: venlafaxine, duloxetine, desvenlafaxine, and milnacipran
• Mechanism: block reuptake of both serotonin and norepinephrine, increasing synaptic levels
• Used for depressive disorders, anxiety disorders, and chronic pain syndromes
• Adverse effects: sympathetic activation (tachycardia, hypertension), inhibition of CYP 2D6
• SNRIs can affect alpha-1, NMDA, histamine, and muscarinic receptors and deplete catecholamine stores

Tricyclic Antidepressants (TCAs)

• Examples: 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, sedation, delirium risk (elderly), lowered seizure threshold (pediatrics), extrapyramidal symptoms, tremors
  • Toxicity with MAOIs can cause hyperthermia, seizure, and coma
• Cardiovascular side effects: orthostatic hypotension, increased heart rate, ECG changes, slowed AV conduction, and can enhance depressant effects of anesthetics
• Anesthetic considerations: increase anesthetic requirements, exaggerated response to anticholinergics and indirect-acting vasopressors, exaggerated ventilatory depressant effects of opioids

Monoamine Oxidase Inhibitors (MAOIs)

• Examples: isocarboxazid, phenelzine, selegiline, and tranylcypromine
• Mechanism: Inhibit monoamine oxidase (MAO), increasing the availability of norepinephrine, epinephrine, dopamine, and serotonin
  • 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
• Anesthetic considerations:
  • 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)
  • Contraindicated with indirect-acting sympathomimetics
  • Use direct-acting with caution
  • Avoid ketamine, ephedrine, pancuronium, and epinephrine
  • Phenelzine decreases plasma cholinesterase, prolonging succinylcholine action
  • 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 and increases GABA neurotransmission; modulates other cellular signaling systems
• Side effects: renal (polydipsia, polyuria, nephrogenic DI, chronic kidney disease), endocrine (hypothyroidism), cardiac (T wave changes, SA nodal block, bradycardia)
• Drug interactions: increased lithium levels with thiazide and loop diuretics, NSAIDs, 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 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, sodium bicarbonate

Schizophrenia, Psychoses

• Characterized by psychosis, disorganized speech/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
• 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
• Droperidol: butyrophenone; potent antiemetic and sedative; used off-label for delirium and as a GA adjunct
  • Carries a black box warning due to high-dose cardiac risks (QT prolongation, arrhythmias)
• Perphenazine: phenothiazine; anti-dopaminergic antiemetic with mixed evidence
  • 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), 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, neuroleptic malignant syndrome (NMS)
• Neuroleptic Malignant Syndrome (NMS): possibly related to dopamine antagonism; characterized by hypertonicity of skeletal muscles, autonomic instability, and altered consciousness
  • Differential diagnosis from malignant hyperthermia (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
  • Higher incidence of DM and glucose intolerance
  • Potential weight gain and altered pain response
  • Impaired temperature regulation and altered HPA function
  • Synergistic effects with non-depolarizing muscle relaxants
  • Risk for over-sedation with BZs and CNS depressants
  • 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
• 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 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, disorientation, and agitation
• Treatment: control pain and agitation (pre-emptive multimodal analgesia, sedation); haloperidol is often first-line
  • Benzodiazepines may increase risk in adults

Neurodevelopmental Disorders

• Attention-Deficit/Hyperactivity Disorder (ADHD)
  • Notable characteristics: inattention, hyperactivity, impulsivity; multifactorial
  • Treatment: stimulant drugs, behavioral therapy, and educational interventions
  • Methylphenidate (Ritalin): CNS stimulant; indirect sympathomimetic; 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
    • Side effects include hypotension and bradycardia

Cannabis, Cannabinoids

• Delta-9-THC is the most potent psychoactive cannabinoid; binds to CB1 (CNS) and CB2 (periphery/CNS) 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, potential cardiovascular and airway/pulmonary effects

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 exhibits HTN, tachycardia, agitation, and restlessness, which resembles serotonin syndrome
• Avoid ephedrine, ketamine, amphetamines, sympathomimetics, and over-the-counter cold medicines in the patient taking phenelzine
• Orthostatic hypotension is a common blood pressure side effect with TCAs
• Use phenylephrine (small doses) to treat hypotension in the patient taking an MAOI
• The threshold plasma concentration for lithium toxicity is 1.5-2 mEq/L
• Treat dystonia related to droperidol or other antipsychotic use with diphenhydramine 25-50 mg
• Sodium (hyponatremia) is a lab value of concern in the patient taking lithium with diuretics
• Amphetamines (stimulants) act by indirect sympathetic activation by blocking the reuptake of catecholamines
• Caffeine acts through adenosine antagonism and inhibition of phosphodiesterase
• The two cannabinoid receptor types are CB1 and CB2, which are involved in neurotransmission, pain, immune, learning, memory, reward, addiction, motor dysfunction, psych disorders and cocaine-induced reward.