Module 7- Tricyclic Antidepressants and Serotonin Receptors

• Psychopharmacology is the study of the effects of drugs on mood, sensation, thinking, and behavior.
• It is also the study of medication for the treatment of mental disorders.
• One in five individuals in the U.S., or 51.5 million people, were affected in 2019.

Psychopharmacology & Anesthesia

• Long-term drug treatments may interact with anesthetics.
• They can impact neurotransmitter and ionic mechanisms.
• There are risks related to withdrawal and symptom recurrence/relapse.

Depressive Disorders

• It is a variety of mood disorders.
• Characteristics include sadness interfering with daily function alongside decreased or lost interest or pleasure in activities.
• Genetic, neurotransmitter changes, altered neuroendocrine function, and psychosocial factors are all multifactorial causes.
• Treatments include psychotherapy and pharmacologic intervention.
• Electroconvulsive therapy and transcranial magnetic stimulation are also treatment options.

Physiology of Serotonin (5-HT)

• There are seven families of serotonin (5-HT) receptors widely distributed.
• Outside of the CNS, it plays roles in PLT aggregation, vascular tone, inflammatory response, hematopoiesis, and genital arousal.
• Within the CNS, serotonergic receptors extend from the brainstem to the cortex, cerebellum, and spinal cord.
• It regulates the release of various neurotransmitters and peptide hormones.
• It influences social, affective, and cognitive function, mood, sleep, aggression, appetite, sex, and memory.
• 5-HT1A regulates serotonergic neuronal activity and affects the neurogenic effects of antidepressants.
• 5-HT2A is excitatory and is antagonized by second-generation atypical antipsychotics.
• Agonism by 5-HT2A regulates cognition, attention, and working memory relevant to psychosis.
• It also may be implicated in serotonin syndrome.
• 5-HT3 regulates nausea and vomiting.

Neuromodulating Effects

• Serotonin is involved with anxiety, impulse, irritability, and mood.
• Norepinephrine affects alertness, concentration, and energy.
• Dopamine influences reward and motivation.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Fluoxetine, sertraline, paroxetine, citalopram, and escitalopram are SSRIs.
• They treat mild to moderate depression, panic disorder, obsessive-compulsive disorder, phobias, and PTSD.
• SSRIs block the 5-HT reuptake transporter, increasing synaptic serotonin.
• This eventually leads to antidepressant and anxiolytic effects via 5-HT1A.
• This eventually leads to anxiety, insomnia, and sexual dysfunction via 5-HT2A.
• This eventually leads to nausea and headaches via 5-HT3.
• Common side effects include agitation, headache, nausea, and diarrhea.
• Hyponatremia (SIADH) is also a side effect, especially in the elderly, women, and those with cardiovascular disease.
• A USDA Black Box (2004) warning indicates increased suicidal thoughts and behaviors in children and adolescents.
• It can inhibit CYP 450, leading to increased plasma concentrations of other drugs.
• SSRIs should be continued perioperatively.
• Abrupt discontinuation can lead to SSRI Discontinuation Syndrome, including depression, dizziness, paresthesias, myalgias, irritability, insomnia, and visual disturbances.

Serotonin Syndrome

• Serotonin syndrome involves excessive CNS serotonergic activity.
• It is linked to SSRIs, SNRIs, TCAs, MAOIs, phenylpiperidine opioids, tramadol, methadone, metoclopramide, erythromycin, and metronidazole.
• Caution when administering with drugs which may inhibit CYP 450 enzymes (2D6, 3A4)
• Autonomic instability, neuromuscular abnormalities, and mental status changes can result.
• Autonomic instability presents as HTN, tachypnea, and diaphoresis.
• Neuromuscular abnormalities are tremors, myoclonus, trismus, and muscle rigidity.
• Mental status changes manifest as restlessness and visual hallucinations.
• Hallucinations, disorientation, confusion, seizures, and coma might indicate full blown presentation.

Serotonin Syndrome Case Reports

• In one case, a healthy patient on fluoxetine for depression experienced clonus, diaphoresis, and nystagmus after orthopedic surgery with regional and general anesthesia.
• In another case, a patient with a recent SSRI increase developed autonomic instability, mental status change, and lower limb clonus after a dental procedure and OTC cough suppressant use.
• Serotonin Syndrome is similar to Neuroleptic Malignant Syndrome, Anticholinergic Toxicity and Malignant Hyperthermia.
• Clonus and hyperreflexia with hyperactive bowel sounds is a sign of Serotonin Syndrome.

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)

• Venlafaxine, duloxetine, desvenlafaxine, and milnacipran are SNRIs.
• They are first- or second-line therapies for depressive and anxiety disorders, as well as chronic pain syndromes.
• They enhance descending pain pathway modulation and suppress ascending pain transmission.
• These block 5HT and NE reuptake transporters to Increase synaptic levels of serotonin and norepinephrine
• Elevated systolic and diastolic BP is an adverse effect. Adrenergic agonists can exacerbate HTN and tachycardia.
• CYP 2D6 enzymes are inhibited by antiarrhythmics,opioids, beta blockers, and antidepressants.

Tricyclic Antidepressants (TCAs)

• Amitriptyline, nortriptyline, imipramine, clomipramine, and desipramine are TCAs.
• They treat major depressive disorder, chronic pain syndromes, and obsessive-compulsive disorder.
• They affect serotonin, norepinephrine, histamine, and acetylcholine neurochemical systems.
• They inhibit 5-HT and NE reuptake transporters and act as receptor antagonists; 5-HT2A, Alpha-1, NMDA H1, H2, and mACh receptors.
• Intravenous anesthetics should be used with caution.
• Cardiovascular side effects include orthostatic HOTN, increased HR, ECG changes, QRS widening, T wave inversion, QT prolongation, and slowed AV conduction.
• CNS side effects include dry mouth, blurred vision, tachycardia, urinary retention, ileus and sedation.
• Overdose occurs with rapid progression and can be fatal and agitation, seizures, cardiorespiratory and neuro depression.
• Treatment of TCA overdose includes diazepam or phenytoin for seizures, lidocaine or sodium bicarb for dysrhythmias, and IV fluids, sympathomimetics, or inotropes for HOTN.
• Considerations during anesthesia include exaggerates responses to anticholinergics (esp. atropine), delirium, confusion risks, indirect acting vasopressors and ventilatory depressant effects.
• Avoid pancuronium, ketamine, meperidine, and epinephrine .

Monoamine Oxidase Inhibitors (MAOIs)

• Isocarboxazid, phenelzine, selegiline, and tranylcypromine are MAOIs that treat major depressive disorder, panic disorder, Parkinson's disease, and phobias.
• Monoamine oxidase is a mitochondrial enzyme, inactivates and removes NE, E, DA and 5-HT.
• Older MAOIs form a stable, irreversible complex with cerebral neuronal MAO, which increases NT release .
• Newer MAOIs are RIMAS, inhibitors of monoamine oxidase.
• Side effects include anticholinergic-like effects, sedation, paresthesias, weight gain, and hepatitis.
• Hyperadrenergic crisis is related to tyramine increase in the diet along with HTN, hyperpyrexia, CVA, and dysrhythmias.
• Type I (excitatory) reaction to anesthetic considerations is treated by administration of morphine, hydromorphone.
• Type II (depressive) reactions involves MAO inhibition of hepatic enzymes enhanced by all opiods.
• Phenelzine decreases plasma cholinesterase levels and prolongs action - reduce dose of barbiturates
• Propofol, etomidate, BZs, inhalation agents, and anticholinergics are safely used
• HOTN is treated with IV fluids and cautious use of phenylephrine.

Miscellaneous Monoamine Altering Drugs

• Trazadone treats MDD and insomnia with a multimodal mechanism of action including SRI activity, 5-HT2A and Alpha-1 antagonism with Side effects being Orthostatic HOTN, Dry mouth and rare dysrhythmias.
• Buspirone treats Generalized Anxiety Disorder through partial agonist effects at 5-HT receptors.
• Mirtazapine treats MDD as a Tetracyclic and multimodal mechanisms; Alpha-2 antagonism (increases NE), 5- HT2A, 5-HT3 antagonism, and H1 antagonism.
• Associated with lower risk of serotonin syndrome.
• MDD, smoking cessation, ADHD is treated with Bupropion and has some benefit in management with a mechanism that inhibits DA, NE reuptake. Seizures and Stimulant-like effects are side effects.

Bipolar Disorders

• Bipolar disorders are a variety of mood disorders.
• Characteristics include episodes of mania, episodes of depression and unknown exact causes.
• Genetics, dysregulation of 5-HT, NE, DA in brain and Psychosocial factors are causes.
• Stabilizing mood is a treatment as well as antidepressants, antipsychotics, anticonvulsants and psychotherapy.

Lithium

• It treats bipolar disorders, MDD (treatment resistant) and suicide risk as a inorganic ion and has a variety of neurobiologic effects .
• It inhibits excitatory neurotransmission (dopamine, glutamate) and Downregulation of receptors.
• It Increases GABA neurotransmission and modulates other cellular signaling systems.
• Side effects are renal, polydipsia, polyuria, nephrogenic diabetes insipidus, chronic kidney disease, endocrine, and hypothyroidism . Cardiac effects include T wave changes and SA nodal block.
• Toxicity is avoided with containing IV fluids and avoiding diuretics and NSAIDs.
• Increased toxicity occurs with widened QRS, AV block, dysrhythmias, HOTN, Skeletal muscle weakness, ataxia Seizures, confusion .
• Treated with dialysis and sodium bicarb administration

Schizophrenia & Psychoses

• Notable characteristics include psychosis, hallucinations, delusions, disorganized speech and behavior, flattened affect and cognitive deficits.
• Cause is Unknown with Genetic evidence Environmental influence. Treatment is Pharmacologic therapy, Cognitive therapy Psychosocial rehab.
• Typical (neuroleptic) APs are first generation (FGAs) with Dopamine (D2) receptor antagonists (CNS) resulting in side effects.
• Atypical antipsychotics are 2nd generation (SGAs) with D2 antagonism + effects on H1, 5-HT2, mACh and alpha.
• Little/no tendency to cause extrapyramidal side effect

Antipsychotics Mechanism of Action

• Contemporary Atypical Antipsychotics and Serotonin are the regulators of DA and are involved in Schizophrenia and is disinhibited. Typical FGAs exhibit less response due to side effects , commonly used in emergency settings and have High therapeutic index and no physical dependance.
• DA receptor interaction in CRTZ effects Opioid –Induced N/V
• May decrease Psychosis-related anxiety off label and Used off-label for Emergencies such as severe agitation/aggression as a D1, D2 antagonist:

Haloperidol Pharmacokenetics

• Dosing requires 2-10m IV
• Repeat dosing(double) every 15-30 m
• Onset up to 3-20m IV, 30m IM
• Hepatically metabolised (CYP450, 3A4)

Postoperative, Emergence Delirium

• Occurs after minutes up to 7 days postoperatively via inflammatory markers.
• Factors are Age, gender, Cognitive Function, and substance use.
• Differentiated from Hypoxia an Hypothermia Also, treated with Increased risk with BZs in Adults (?)

Droperidol

• Butyrophenone antipsychotic (FGA), is Good Anti-Emetic as well as Sedative
• Effective adjunct Delirium through for Immediate effects for agitation But with Risks for high Cardiac effects

• Onset 3-10 min IV,Hepatic metabolism.

Perphenazine

Phenothiazine antipsychotic (Typical, FGA), Anti-dopaminergic antiemetic. With Dosing of 2.5 – 8mh

Extrapyramidal Effects

+Tardive Dyskinesia Muscle rigidity and tremors which are commonly observed in acute settings

FGA sides Effects:

CV instability, dysrhythmia, and hepatic dysfunction occurs NMS is also commonly characterized hypertonicity Muscle rigitidt as well as Altered temperatureregulation

FGA Consideration

Synergist effect while on Anesthetic and monitor Neuromuscular function.

Atypical Considerations

Involve high effect over cognitive Function as well as other uses: Manic, depressive. Can be dosd for those with irritable conditions as well, with Clozapine being known for reducing Agranulocytosis Olanzapine is also Used with Sedations

Methylphidate

Blocks reuptake of Ne, DA, Increases ARousal.

Amphetamine:

Blocks reuptake of Ne, DA, increases presynaptic firing

Cannabis Compounds

D9 THC - MOST COMMON, effects receptors which effects learning mery and motor dysfunction

For uses

Mainly for N and V Acute - euphoria and less motor skills, high chance for HOTN May results in high anesthetic needs

Explore the side effects of TCAs on the cardiovascular system and their dangers in overdose situations. Learn about atypical antipsychotics, serotonin receptors and the treatment of seizures due to TCA overdose. The content discusses the regulation of cognitive function and conditions such as nausea.