16 Part I Anaesthesia Refresher Course – 2017 University of Cape Town

Pharmacological Aspects of Serotonin for the Anaesthetist

Dr Kamal Bhagwan

UCT Dept of Anaesthesia & Perioperative Medicine

Serotonin (5HT) Physiology In the CNS serotonergic neurons are found primarily in the brainstem from midbrain to medulla. The rostral end of this system assists in the regulation of wakefulness, affective behaviour, food intake, thermoregulation, migraine, emesis and sexual behaviour. The neurons in the raphe of the lower pons and medulla participate in the regulation of nociception and motor tone. In the PNS, serotonin is produced primarily by intestinal enterochromaffin cells (95% of the total amount of serotonin of the body). Here it regulates gastrointestinal motility, vascular tone, uterine contraction, and bronchoconstriction. It also functions to promote platelet aggregation. Serotonin, released by presynaptic serotonergic neurons in synaptic clefts, activates specific receptors and is partly reuptaken by presynaptic neurons There are seven distinct serotonin receptors (5-HT1to 5-HT7 Rc) with further subtypes. Most are G-protein coupled and via adenyl cyclase or phospholipase C produce their effect. 5-HT3 Rc is unique in that it belongs to the Cys-loop superfamily of ligand-gated ion channels. The activating inward current is cation-selective which is largely with sodium and potassium ions. Biosynthesis In the brain, serotonin biosynthesis depends on the quantity of tryptophan that crosses the blood-brain barrier. Circadian variations determine the concentration of melatonin that increases during the night and decreases during the day. 5-HT is produced by 1. hydroxylation and 2. decarboxylation of L-tryptophan in nerve terminals and is stored in synaptic vesicles

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Inactivation

Serotonin is converted into inactive molecules by biotransformations:

3. Oxidative deamination of the lateral amino chain by monoamine oxidase, leading to 5-hydroxy-indol-acetaldehyde which is then oxidized into 5-hydroxy-indol-acetic acid (5-HIAA) found in urine

4. Conjugation by glucuronic acid or sulfate of the hydroxyl group OH in 5-position.

Exploration of drugs that interact with various 5HT receptors (Rc) follows:

5-HT1 Agonists

Triptans are utilized in the treatment of migraine attacks and are effective in the treating the acute attack. Examples of these drugs are sumatriptan, zolmitriptan, naratriptan, eletriptan, almotriptan and rizatriptan.

Sumatriptan

Most studied of the triptans.

Agonist of 5-HT1, 5-HT1D Rc’s, and to a lesser degree of 5-HT1B

Causes vasoconstriction of cerebral vessels, in particular of carotid arteriovenous anastomose

Indicated for migraine and cluster headache attacks but not for their long- term prevention.

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70% effective but short half-life and potential for coronary vasospasm and arrhythmias limits its

use

Newer agents

longer half-lives and fewer side effects.

Selective carotid vasoconstriction via 5-HT1B receptors and by pre-synaptic inhibition of the trigeminovascular inflammatory response via 5-HT1D/1F receptors.

Anaesthetic implications

Elucidate individual patients’ triggers, symptom patterns, and preferred therapies.

Continue preventive medication.

Minimise variations in arterial blood pressure, temperature, and arterial CO2. Ergotamine

Partial agonist at 5HT1 and alpha receptors vasoconstriction and inhibition of trigeminal nerve transmission.

Duration of action is 24 hrs

Wide side-effect profile limits its clinical use - coronary vasoconstriction, severe nausea and vomiting, uterine contraction and foetal damage.

5-HT3 Antagonists: Anti-emetic Agents (-setrons)

The primary function of these drugs is to inhibit vomiting induced by antineoplastic drugs, such as cisplatin and doxorubicin. These drugs are cytotoxic and release serotonin from the digestive tract. Poor efficacy in the treatment of motion sickness as the vestibulo-ocular component of the afferents to the area postrema may be an important factor. Other examples of drug-induced vomiting are attributed to opiates, radiotherapy and certain antibiotics. General anaesthetics can produce emesis by both peripheral as well as central mechanisms. Mechanisms of action: 1. blocking 5-HT Rc’s in the Chemoreceptor Trigger Zone within the Area Postrema and the Nucleus Tractus Solitarius 2. blocking peripheral afferent vagal impulses originating from 5-HT Rc’s in GIT mucosa and inhibit splanchnic afferent nerve response to painful distension 5-HT3 Rc antagonist drugs: ondansetron, granisetron, tropisetron and dolasetron. Adverse effects: headache, asthenia, drowsiness, arterial hypertension or hypotension, bradycardia, hiccup, constipation.

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Ondansetron

Favourably rated in the treatment of postoperative nausea

More efficacious than metoclopramide and/or droperidol.

Very wide therapeutic “window” with only rarely occurring side effects

Categorisation of chemical structures of the first generation 5-HT3 receptor antagonists

Carbazole derivatives - Ondansetron

Indazoles - Granisetron

Indoles - Dolasetron

Palonosetron

Highly selective 2nd gen 5-HT3 Rc antagonist ( >30 x Rc binding affinity vs 1st gen 5-HT3Ra’s)

Two stereogenic centers and may exist as four steroisomers

Longer half-life (40 h) Adverse effects of 5HT3 Rc Antagonists Generally well-tolerated and side effects are infrequent

Minor headache, flushing and constipations

Higher doses used in chemotherapeutic induced nausea and vomiting (CINV) result in more serious side-effects – sedation, intestinal obstruction and incr ALT Ondansetron for PONV prophylaxis dose in adults is 4mg cf to CINV 32mg

Ondansetron and dolasetron block sodium channels may result in QRS widening, and blocking potassium channels may lead to QT prolongation with resultant ventricular arrhythmias.

PSYCHIATRIC MEDICATION Tricyclic Antidepressants (TCAs) Used to treat depressive illness, nocturnal enuresis and as an adjunct in chronic pain therapy. They competitively block neuronal uptake of noradrenaline and 5-HT, Dopamine thereby increasing the concentration of the transmitter in the synapse. The antidepressant effects take up to 2 weeks to work. They also block muscarinic, histaminergic and α-adrenoceptors, and have non-specific sedative effects. Imipramine, Clomipramine and Trimipramine preferentially inhibit the reuptake of serotonin.

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Monoamine Oxidase Inhibitors (MAOIs) Used in the treatment of resistant depression, obsessive compulsive disorders, chronic pain syndromes and migraine. MAO is present within presynaptic neurones and is responsible for the deamination of amine neurotransmitters. The main effect is rapid and sustained increase in 5HT, Dopamine and NA. They have been classified as types A and B. MAO-A preferentially deaminates 5-HT and catecholamines, MAO-B preferentially deaminates tyramine and phenylethamine The original generation inhibit MAO irreversibly and non-selectively (i.e.MAO-A and -B) The new generation selectively and reversibly inhibit only MAO-A (RIMA).

Neither group is used as first line therapy because of the potential for serious side effects and hepatic toxicity. Non Selective MAOIs e.g. Isocarboxazid, Nialamide, Phenelzine, Hydracarbazine, Tranylcypromine Tranylcypromine is potentially the most dangerous as it possesses stimulant activity. Adverse effects Sedation, blurred vision, orthostatic hypotension and hypertensive crises following tyramine rich foods (cheese, chocolate), indirectly acting sympathomimetics.(e.g. amphetamines, ephedrine)

Interaction with pethidine may precipitate cerebral irritability, hyperpyrexia and cardiovascular instability

Selective reversible MAOIs – RIMA (moclobemide) Moclobemide , primarily used to treat depression and social anxiety, causes less potentiation of tyramine than the older generation MAOIs. Linezolid is an antibiotic indicated for MRSA and vancomycin-resistant enetrococci. It is also a MAOI and as such has the typical range of cautions and contraindications.

Methylene blue (commonly used intraoperatively to delineate lymphovascular channels) is a highly potent, reversible MAOI.

MAOIs and general anaesthesia Pethidine or any indirectly acting sympathomimetic amines (e.g. ephedrine) are contraindicated. Indirect agents (e.g. dopamine) should be avoided because they are metabolized to adrenaline and noradrenaline. Under normal conditions, monoamine oxidase limits the intracellular concentration of these metabolites. When MAO is inhibited, Adrenaline and NA production at the cellular level is uncontrolled, possibly leading to an exaggerated hemodynamic response. Direct-acting agents should be used for CVS support as they are metabolized by COMT and therefore not subject to the same degree of exaggerated response. Nevertheless, used with extreme caution as they may also precipitate exaggerated hypertension. To diminish its effects, MAOI therapy should be withdrawn for 14–21 days before surgery (2 weeks before starting alternative therapy). This however, risks the patient suffering a relapse of their depression. However, the newer agents may control depression more effectively and reduce the chance of a serious peri-operative drug interaction.

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Selective Serotonin Reuptake Inhibitors (SSRIs) Globally, the most widely prescribed antidepressants e.g. Fluoxetine(Prozac ®),Citalopram(Cilift ®), Sertraline (Zoloft® ). There is selective inhibition of the neuronal re-uptake of 5-HT with minimal effect on dopamine and noradrenaline. Although they are no more effective than standard antidepressants, they do not have their associated side-effect profile. (i.e. less sedative, fewer anticholinergic effects and appear less cardiotoxic in overdose although they are associated with gastrointestinal side-effects.)

5HT2 Antagonists: Antipsychotics

The main categories are typical (e.g. chlorpromazine and haloperidol) and atypical antipsychotics (e.g clozapine and risperidone). The distinction is unclear but rests on receptor action, incidence of extra-pyramidal side effects and efficacy.

5-HT2A and 5-HT2C receptor antagonists which cross the blood-brain barrier have antipsychotic properties and are called atypical neuroleptic or atypical antipsychotic agents Clozapine is the reference drug of atypical antipsychotics. In addition to its 5-HT2 antagonist effect, clozapine has several effects: antidopaminergic, antimuscarinic, antihistaminic and alpha-blocking. Its use is limited because of side effects such as agranulocytosis and potential to induce myocarditis. The affinity for 5HT2 Rcs varies and is reflected here in their decreasing level of affinity; Clozapine, Resperidone, Flupenthixol, Chlorpromazine, Thioridazine and Haloperidol.

SEROTONIN SYNDROME (SS)

Is a potentially life- threatening, adverse drug reaction where there is increased serotonergic activity in CNS. It is seen with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning. In patients experiencing chronic pain there is a high incidence of depression and often on dual medication. These medications modulate serotonergic pathways compounding the risk of SS. It is classically described as the triad of Mental status changes, Autonomic hyperactivity, and Neuromuscular abnormalities (MAN). However, it is a spectrum of clinical findings ranging from benign (barely perceptible) to lethal. Mild symptoms could be easily overlooked and inadvertent increase in dose of the culprit agent or addition of a proserotonergic drug may precipitate dramatic clinical deterioration. Mental status changes can include anxiety, agitated delirium, restlessness, and disorientation Patients may startle easily. Autonomic manifestations can include diaphoresis, tachycardia, hyperthermia, hypertension, vomiting, and diarrhea. Neuromuscular hyperactivity can manifest as tremor, muscle rigidity, myoclonus, hyperreflexia, and bilateral Babinski sign.

N Engl J Med 2005;352:1112-20

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Pathophysiology Stimulation of the postsynaptic 5-HT1A/2A receptors in the central grey nuclei and medulla has been implicated in serotonin syndrome. Noradrenergic CNS hyperactivity may play a critical role since the degree to which CNS concentrations are increased may correlate with clinical outcome. Symptoms manifest predictably, with rising intrasynaptic serotonin concentration. Intrasynaptic serotonin excess results from its increased synthesis, decreased reuptake or decreased metabolism.

Epidemiology and Incidence It is observed in all age groups, including newborns and the elderly. The increasing incidence of this condition is thought to mirror the increasing use of serotonergic agents in medical practice. However, the incidence may be under-reported for several reasons. Manifestations may be wrongly attributed to another cause, mild cases (such as tremor or with diarrhea or hypertension) may be viewed as inconsequential, or clinicians may just not suspect the condition. There are numerous drug combinations associated with SS. The syndrome is classically associated with the simultaneous administration of two serotonergic agents, but it can occur after initiation of a single serotonergic drug or increasing the dose of a serotonergic drug in individuals who are particularly sensitive to serotonin. SSRIs are perhaps the most commonly implicated group of medications associated with SS. They may contribute to the development of SS up to several weeks after the drug has been discontinued. The half-life of fluoxetine is one week and that of its metabolite norfluoxetine is up to 2.5 weeks. The drug combination most commonly associated with severe reactions is that of MAOI and SSRIs. Episodes of SS involving a MAOI may be more severe and more often lead to adverse outcomes, including death.

2015 Anaesthesia Patient Safety Foundation (5)

Serotonergic Opioids Opioids remain a mainstay of pain management and are commonly used analgesics prescribed in conjunction with other serotonergic medications. Therefore, there exists a potential to influence the pharmacodynamics of serotonin. Mechanisms for serotonergic action:

weak serotonin reuptake inhibition and an

increased release of intrasynaptic serotonin (through inhibition of GABA presynaptic inhibitory neuron on serotonin neurons)

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Synthetic piperidine opioids - proserotonergic

Fentanyl Augments serotonin release, and is a weak serotonin reuptake inhibitor (SRI) Requires the additive action of other serotonergic agents or use in combination with SSRIs Methadone Greater tendency toward SRIn compared with other opiates. Tramadol (racemic mixture) RR enantiomer is a mu receptor agonist, while the SS enantiomer inhibits reuptake of norepinephrine and releases serotonin. Thus, resulting in increased intrasynaptic serotonin in combination with other serotonergic drugs Dextromethorphan binds 5-HT2A receptors that may cause serotonin syndrome

Phenantherene morphine analogues – may increase the intrasynaptic serotonin levels either through increased release of neurotransmitter e.g. oxycodone, hydromorphone, oxymorphone, and buprenorphine

Assessment of Patient

History A detailed description of prescription drugs, over-the- counter medications (cough syrup ingredient dextromethorphan), illicit substances (ecstasy), and dietary supplements (weight loss drugs fenfluramine and sibutramine), as well as any changes in dosing and formulation (e.g. sustained release) must be recorded. An account of symptoms, their evolution and rate of change should be sought. The majority of cases of SS present within 24 hours(75%), and most within six hours (60%), of a change in dose or initiation of a drug. Many cases typically resolve within 24 hours after the initiation of therapy and the discontinuation of serotonergic drugs. Symptoms may persist where patients are taking drugs with long elimination half-lives, active metabolites, or a protracted duration of action. Physical examination Refer to MAN acronym above Laboratory Evaluation Are of very little use in the diagnosis as serum serotonin concentrations do not correlate with clinical findings. Other findings are nonspecific - elevated white blood cell count, elevated CK, and decreased serum bicarbonate concentration. In severe disease, there may be development of profound complications- including metabolic acidosis, DIC, rhabdomyolysis, renal failure, myoglobinuria, and ARDS.

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Diagnosis and Diagnostic Criteria Hunter Toxicity Criteria is most accurate (84 percent sensitive and 97 percent specific)

Differential Diagnosis Includes neuroleptic malignant syndrome (NMS), anticholinergic toxicity, malignant hyperthermia, intoxication from sympathomimetic agents, sedative-hypnotic withdrawal, meningitis, and encephalitis. Each of these can be differentiated from SS on clinical grounds. Neuroleptic syndrome can be precipitated by use of antipsychotic medications and may present with similar symptoms.

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Management: key principles

Discontinuation of all serotonergic agents

Supportive care aimed at normalization of vital signs

Sedation with benzodiazepines

Administration of serotonin antagonists

Assessment of the need to resume use of causative serotonergic agents after resolution of symptoms

Application of these principles varies with the severity of illness. Common management pitfalls include failure to recognize serotonin syndrome, misdiagnosis and failure to appreciate SS's potentially rapid rate of progression Mild cases Discontinuation of inciting medications, supportive care, and sedation with benzodiazepines are generally sufficient.

Supportive care and sedation is the mainstay of therapy oxygen and intravenous fluids, continuous cardiac monitoring, and correction of vital signs

Chemical restraint is preferred over physical restraint for agitated patients; physical restraints may cause isometric muscle contractions leading to profound lactic acidosis and hyperthermia. Sedation with benzodiazepines is important for controlling agitation as well as blunting the hyperadrenergic component of the syndrome. Improved survival in animal models has been demonstrated.

Butyrophenones (eg, droperidol and haloperidol) should be avoided; these drugs have anticholinergic properties that inhibit sweating and dissipation of body heat.

Moderately ill patients More aggressive treatment of autonomic instability and possibly treatment with a serotonin antagonist (see antidote)

Critically ill These patients are hyperthermic (>41.1°C) and often require neuromuscular paralysis and tracheal intubation. Suxamethonium should be avoided because of its detrimental effects in the context of rhabdomyolysis.

There is no role for antipyretic agents, such as acetaminophen since the temperature elevation is not due to an alteration in the hypothalamic temperature set point, but rather an increase in muscular activity

Autonomic instability The challenge in severely intoxicated patients is that they often exhibit large and rapid changes in blood pressure and heart rate. In patients with severe hypertension and tachycardia, a strategy of titrating short-acting cardiovascular agents, such as esmolol or nitroprusside to maintain autonomic stability, may be successful.

Hypotension from MAOIs in patients with SS should be treated with low doses of direct-acting sympathomimetic amines, such as phenylephrine, epinephrine, or norepinephrine Indirect agents (e.g. dopamine) should be avoided (see explanation above in PSYCH MEDS MAOIs) Antidote If benzodiazepines and supportive care fail to improve agitation and correct vital signs Cyproheptadine

Histamine-1 receptor antagonist weak anticholinergic activity

Non-specific 5-HT1A and 5-HT2A antagonistic properties - may produce transient hypotension due to the reversal of serotonin-mediated increases in vascular tone. Such hypotension usually responds to intravenous fluids.

Only available in an oral form, but it may be crushed to administer through a nasogastric tube (per oral form in 2 mg incremental doses for a maximum of 12–32 mg in 24 h).

Definitive evidence of cyproheptadine's effectiveness is lacking

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Other antidotes — Antipsychotic agents with 5-HT2A antagonist activity, such as olanzapine and chlorpromazine, have been considered for antidotal treatment, but their efficacy is unproven and NOT recommended. Chlorpromazine can cause orthostatic hypotension and increase hyperthermia. Treatment with propranolol, bromocriptine, or dantrolene is not recommended. Propranolol has a long duration of action, may cause prolonged hypotension, and can mask tachycardia that can be used to monitor the effectiveness of treatment. Bromocriptine, a serotonin agonist, may exacerbate serotonin syndrome. Dantrolene has no effect on survival in animal models.

CONCLUSION

Anaesthetists need to be aware of the increased risk of serotonin syndrome in the perioperative setting, where high dose opioids are often administered. Similarly, practitioners in chronic pain management, where use of opioids in conjunction with other serotonergic agents is the norm, must also have heightened sense of awareness. Prognosis is generally favorable, as long as the entity is recognized and complications are treated appropriately. References 1. Allain P. Serotonin, serotoninomimetics, antagonists. Retrieved on 25 February 2017 from http://www.pharmacorama.com/en/Sections/Serotonin_2_1.php 2. Boyer EW. The Serotonin Syndrome. N Engl J Med 2005; 352(11): 1112-1120. 3. Boyer EW. Serotonin syndrome (serotonin toxicity).UpToDate. Retrieved 04 April 2017 from https://www.uptodate.com/contents/serotonin-syndrome 4. Chinniah S et al. Serotonin and anaesthesia. CEACCP 2008; 8: 43-45 5. Gyermek L. Pharmacology of Serotonin Related to Anesthesia. J of Clin Anesth 1996; 8: 402-425 6. Locke A. Methylene Blue and the Risk of Serotonin Toxicity. June 2015. Retrieved on 14 April 2017 from http://www.apsf.org/newsletters/html/2015/June/02blue.htm 7. Mulder R. Serotonin A mediator of our times Part I Anaesthetic Refresher Course 2010, 14:1-12 8. Peck T. Pharmacology for Anaesthesia and Intensive Care. 3

rd Edition, 2008. Cambridge University Press.

9. Rastogi R. Case Scenario: Opioid Association with Serotonin Syndrome. Anesthesiology 2011; 115:1291– 8 10. Walsh J. Serotonin Syndrome. Anaesthesia Tutorial of the Week 166, 2010. Wfsahq.org. Retrieved on 04 April from http://www.frca.co.uk/Documents/166%20serotonin%20syndrome.pdf

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