Antidepressant drugs and Serotonin receptors Flashcards
What is the components of most “antidepressants”?
Most drugs classified as “antidepressants” impact either serotonergic neurotransmission or noradrenergic (norepinephrine) neurotransmission
What do serotonin drugs do?
increase amount of serotonin in CNS synapses or by altering serotonin receptor signaling
What do serotonin signalling mediate?
by large family of serotonin receptors located within the CNS (6 of these receptor-types signal via excitatory or inhibitory G proteins and 1 [5-HT3] is ligand-gated ion channel)
Define serotonin?
a neurotransmitter; within the CNS, influences mood, sleep, aggression, appetite, sex, and memory
What is the components of serotonin reuptake inhibitors?
consist of several classes of medications which bind and inhibit the serotonin transporter protein (SERT) which blocks reuptake of serotonin from synaptic cleft into the presynaptic neuron – leads to enhanced serotonergic neurotransmission
Define the drug classes involved in serotonin reuptake inhibitors.
selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic-serotonin reuptake inhibitors
What are adverse effects of serotonin reuptake inhibitors?
insomnia, agitation, headache, nausea, diarrhea
What are serios adverse effects of serotonin reuptake inhibitors?
increased suicidality; sudden discontinuation may precipitate withdrawal symptoms – dizziness, increased irritability, insomnia, visual disturbances, paresthesias/”brain zaps”: shock-like sensations in the head; withdrawal symptoms resolve with reintroduction of SRI medication; increased bleeding risk, hyponatremia
What is important about the discontinuation of serotonin reuptake inhibitors?
Outpatient SRI medications should be continued in acute care settings & not discontinued abruptly; must be tapered if discontinued
Define Serotonin syndrome.
attributed to toxic levels of synaptic & extracellular serotonin; presents with classic triad: neuromuscular excitability, autonomic nervous system excitability, & mental status changes
What are the neuromuscular components of Serotonin syndrome?
Neuromuscular excitability: hyperreflexia, clonus, myoclonus, rigidity
What are the autonomic components of Serotonin syndrome?
diarrhea, tachycardia, hypertension, fever, diaphoresis, flushing, mydriasis
What are the Mental status components of Serotonin syndrome?
insomnia, agitation, anxiety, confusion, coma
What are the Severe cases components of Serotonin syndrome?
life-threatening hyperpyrexia, rigidity leading to rhabdomyolysis, multiorgan failure, DIC
What is the cause of Serotonin syndrome?
Serotonin syndrome typically results from combo of different classes of serotonergic medications; most dangerous combo: SRI w/MAO inhibitor drug; rarely results from single serotonergic medication at therapeutic dose
What other drugs can trigger Serotonin syndrome?
nonpsychiatric/nonserotonergic, may trigger serotonin syndrome in conjunction with SRI or other serotonergic drugs: linezolid; methylene blue; lithium; opioids (tramadol, fentanyl, dextromethorphan); stimulants (amphetamine, methamphetamine, methylphenidate, phentermine); muscle relaxants (cyclobenzaprine); recreational drugs (ecstasy)
What is true about drug interactions that can lead to Serotonin syndrome?
Drugs that cause rapid elevation in serum level of SRI medications via drug interaction (ciprofloxacin, fluconazole, ritonavir, & erythromycin) may lead to serotonin syndrome
Where is Serotonin syndrome a concern?
Serotonin syndrome is of particular concern in the PACU or ICU as serotonergic agonists (known or unknown) may have been administered during surgery & used during anesthesia
When do symptoms for Serotonin syndrome develop?
Symptoms typically develop acutely within hours after introduction of causative medication
What do the symptoms of Serotonin syndrome resemble?
Symptoms can resemble alcohol withdrawal, encephalitis, & neuroleptic malignant syndrome
What is the treatment for Serotonin syndrome?
discontinue serotonergic drug (s), initiate supportive care, benzodiazepine, IV fluids, cooling; life-threatening cases may require paralysis, intubation, & ventilation
What are examples of Selective serotonin reuptake inhibitors?
fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, & escitalopram
What do Selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, & escitalopram) block?
Selectively block neuronal reuptake of serotonin
What is the first line therapy for majority of depressive and anxiety disorders?
Selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, & escitalopram)
How do various SSRIs differ?
differ from each other on basis of anticholinergic effects, elimination half-time, & pharmacokinetic interactions – some are potent inhibitors of CYP450 enzymes which can lead to significant risk of drug-drug interactions
What are specific side effects of Citalopram?
may cause dose-dependent QT interval prolongation, increases risk for torsades de pointes; escitalopram also can cause prolonged QT interval, but to less degree
What are Tricyclic antidepressant drugs examples?
desipramine, nortriptyline, amitriptyline, imipramine, clomipramine
What do Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine) do?
These drugs block reuptake of serotonin and/or norepinephrine at presynaptic terminals – increases availability of these neurotransmitters within the CNS
What is the clinical use of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine)?
Highly effective antidepressant medications but are no longer considered 1st line d/t unfavorable side effect profile resulting from anticholinergic & antihistamine properties
What are side effects groups of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine)?
Side effect groups: anticholinergic effects, cardiovascular effects, & CNS effects
What are the anticholinergic side effects of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine)?
dry mouth, blurred vision, tachycardia, urinary retention, slowed gastric emptying, ileus; elderly more sensitive to effects;
How does anticholinergic toxicity occur?
; anticholinergic toxicity can result from polypharmacy with more than one anticholinergic drug (TCA + OTC drug w/anticholinergic effects [tx of diarrhea or insomnia])
What are the cardiovascular effects of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine)?
orthostatic hypotension, modest increases in heart rate
What are the CNS effects of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine)?
sedation, weakness, fatigue; TCAs lower seizure threshold; TCAs may enhance the CNS-stimulating effects of enflurane
How are Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine) metabolized?
CYP450 IA2 enzymes
What drugs can increase Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine) concentrations?
Drugs that inhibit CYP450 IA2: verapamil, cimetidine
What drugs could reduce & duration of action Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine)?
Drugs that induce CYP450 IA2: rifampin, omeprazole, insulin, barbiturates, & carbamazepine
What is the relationship between Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine) and sympathomimetics?
Patients recently started on TCAs may demonstrate exaggerated pressor response to direct-acting or indirect-acting sympathomimetics (phenylephrine/ephedrin)
Pressor response may be more pronounced ________
w/indirect-acting drug (ephedrine)
Titrating smaller-than-usual doses of _______ recommended
direct-acting sympathomimetic
What is the dose of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine) and sympathomimetics for chronic use ?
Pts chronically tx w/TCAs >6 weeks, can administer either direct or indirect-acting sympathomimetic, decrease dose to 1/3 usual dose
What may not be effected with chronic use of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine) and sympathomimetics?
Pts chronically tx w/TCAs: conventional sympathomimetics (phenylephrine, ephedrine) may not be effective in tx hypotension d/t catecholamine depletion, may require potent direct-acting sympathomimetic (norepinephrine)
What is the interaction of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine) and anticholinergics?
Pts receiving TCA + an anticholinergic drug preop are more susceptible to postop delirium & confusion (central anticholinergic syndrome) – less likely w/glycopyrrolate
What is the interaction of Tricyclic antihypertensives drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine) and anticholinergics?
rebound HTN from sudden DC of clonidine can be more intense in pts taking TCA
What is the interaction of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine) and MAOIs?
Combination of a TCA & MAOI may result in fatal serotonin syndrome; combining TCAs & MAOIs are relatively contraindicated
What is a life threatening situation with Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine)?
TCA overdose
What is the s/s of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine) overdose?
CNS & cardiac toxicity; can cause intractable myocardial depression & ventricular arrhythmias; may initially see agitation, seizures, hypoventilation, hypotension, QRS prolongation
What is the treatment for CNS symptoms of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine?
Airway support, benzodiazepine, possibly phenytoin for seizures
What is the treatment for cardiotoxicity symptoms of Tricyclic antidepressant drugs (desipramine, nortriptyline, amitriptyline, imipramine, clomipramine?
- Alkalinize plasma – sodium bicarbonate, hyperventilation
- lidocaine, phenytoin for ventricular arrhythmias
- atropine, sympathomimetics, inotropic drugs may still be used if slow cardiac rhythm & hypotensive despite fluid administration
What are MOA inhibitors?
phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate) moclobemide, selegiline (Eldepryl/Zelapar),
What is the function of Monoamine oxidase inhibitors (phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate) moclobemide, selegiline (Eldepryl/Zelapar)?
block the enzyme monoamine oxidase (MAO) – especially cerebral neuronal MAO, which metabolizes amines: serotonin, epinephrine, norepinephrine, dopamine
What are the two forms of MAO?
MAO-A deaminates serotonin, epinephrine, norepinephrine, dopamine
What do MAOIs result in?
increased amounts of neurotransmitter available for release from CNS neurons and also within the sympathetic nervous system
What re the adverse effects of MAOIs (phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate) moclobemide, selegiline (Eldepryl/Zelapar)?
orthostatic hypotension (elderly); pts taking MAOIs may require dietary tyramine restriction b/c MAO inhibition prevents dietary tyramine metabolism & produce indirect sympathomimetic response & HTN (dietary tyramine can then enter systemic circulation & be taken up by sympathetic nervous system nerve endings resulting in release of endogenous catecholamines and result in HTN, hyperpyrexia, poss CVA)
What medications do MAOIs (MAOIs (phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate) moclobemide, selegiline (Eldepryl/Zelapar)) adverse interact wtih?
opioids, ephedrine, TCAs, & SSRIs: HTN crisis, serotonin syndrome
What is imperative to recognize about MAOIs?
***it is imperative to identify MAOI medications on the patient medication list during the preanesthetic evaluation to incorporate this data into the patient’s anesthetic plan
What is the FDA warning with Opioids?
FDA warning – risk of serotonin syndrome for all opioid medications administered w/serotonergic drugs
What can happen withh MAOIs and meperidine?
MAOIs & meperidine can result in an excitatory response (agitation, HA, skeletal muscle rigidity) or depressive response (hypotension, hypoventilation, coma);
adverse rxns of MAOIs can also occur w/ _____________, __________, _________
fentanyl, sufentanil, alfentanil but incidence less than meperidine
What is the response of Monoamine oxidase inhibitor drug interactions given with ephedrine?
Potential for exaggerated hypertensive response to indirect-acting pressor (ephedrine) administration d/t increased release of norepinephrine from neuronal nerve endings
What symmpathomimetic is okay to treat hypotension for a patient with MAIOs?
Direct-acting sympathomimetic preferred (phenylephrine); receptor hypersensitivity may result in exaggerated pressor response to phenylephrine
What is the recommended dose of phenylephrine when given with MAOIs?
Decrease dose of phenylephrine to 1/3 of normal dose, titrate additional doses to cardiovascular response
What is the S/S of MAOIs overdose?
reflected in signs of excessive SNS activity (tachycardia, hyperthermia, mydriasis, seizures, coma)
What is the treatment for MAOIs overdose?
tx supportive; Dantrolene has possible role in treatment of hypermetabolic signs asso/w MAOI overdose
What is the recommendation for MAOIs during the preop phase?
No longer recommended to hold MAOIs preoperatively; recommendation is to continue these meds preoperatively & avoid administration of drugs w/interactions, especially meperidine
What is important to know about the anesthetic technique for MAOIs?
minimize SNS stimulation or drug-induced hypotension; regional anesthesia acceptable
What should be avoided for hypotension treatment with MAOIs?
avoid ephedrine in tx hypotension)
What is the indication for Lithium?
Current use: bipolar disorders, treatment-resistant depressive disorder
What is the history of Lithium use?
Used in treatment of mood disorders since the 1890s
What is the pk of Lithium?
Has narrow therapeutic index & significant potential for toxicity & drug interactions
What is true about the plasma concentrations of Lithium?
Safe & effective use can be achieved only by monitoring lithium plasma concentrations
How often do blood levels need to be monitored with Lithium?
Lithium blood levels, electrolytes, BUN/creatinine, & TSH should be measured every 6 months
What are renal effects of Lithium?
nephrogenic diabetes insipidus (polyuria) resulting in hypovolemia, hypernatremia, hyperchloremic metabolic acidosis, distal renal tubular acidosis; chronic kidney disease can develop with chronic lithium therapy
What endocrine dx can Lithium cause?
hypothyroidism
Lithium May cause serotonin syndrome when combined with ____ or ______
SRIs or MAOIs
What is the anesthetic requirements with lithium?
Anesthetic requirements for injected & inhaled drugs could be decreased (sedation w/lithium therapy)
What can lithium prolong?
prolonged responses to depolarizing & nondepolarizing neuromuscular blocking drugs with lithium therapy
What is lithium toxicity?
may occur with increased plasma concentrations (diuretic therapy, NSAIDs, sodium restriction or sodium wasting)
What occurs with lithium levels of Mild (lithium level 1.0-1.5)?
sedation, skeletal muscle weakness, widened QRS complex on ECG, slurred speech, nausea
What occurs with lithium levels of Moderate (lithium level 1.6-2.5?
confusion, drowsiness, tremor, skeletal muscle fasciculations
What occurs with lithium levels of Moderate Severe (lithium level >2.5)?
impaired consciousness, coma, delirium, ataxia, extrapyramidal symptoms, seizures, impaired renal function
What lithium level can cause cardiac effects?
AV heart block, hypotension, cardiac dysrhythmias may occur at lithium levels > 2mEq/L
What is the treatment of lithium toxicity?
Treatment: hemodialysis; if adequate renal function, lithium excretion accelerated by osmotic diuresis & IV sodium bicarbonate
