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Serotonin Syndrome Pathogenesis and Clinical Findings

Serotonin Syndrome: Pathogenesis and Clinical Findings Serotonergic Agents SSR1s, SNRIs, MOAIs, TCAs, atypical antidepressants, antibiotics, mood stabilizers (valporate, lithium), opioids, antiemetic agents, triptans, weight loss agents, drugs of abuse (e.g. cocaine, amphetamines) Therapeutic drug use • Drug interactions (esp. combo of serotonergic agents) Serotonin Syndrome Variable combination of mental status changes, autonomic instability, and neuromuscular hyperactivity ranging from mild to life-threatening with an abrupt onset (within minutes to hours) after medication ingestion and most cases resolving within 24 hours of cessation of offending medication Intentional self-poisoning Excessive serotonergic activity at 5-HT receptors centrally (brainstem) and peripherally serotonin synthesis and release serotonin reuptake and metabolism IN receptor agonism and sensitivity 4, Drug-induced changes in the relative ratio of non-serotonergic neurotransmitters (e.g. increase in noradrenaline) Altered Mental Status Anxiety, confusion, agitation, hypervigilance, pressured speech, delirium, coma Autonomic Instability Shivering, diaphoresis, fever, diarrhea, tachycardia, mydriasis, hypertension Authors: Preeti Kar Reviewers: Erika Russell Usama Malik Aaron Mackie* * MD at time of publication Notes: The Hunter Serotonin Toxicity Criteria is used to make a clinical diagnosis • History of serotonergic agent taken within past 5 weeks + any of the following clinical features: • Spontaneous clonus • Inducible clonus and either agitation or diaphoresis • Ocular clonus and either agitation or diaphoresis • Tremor and hyperreflexia • Hypertonia, temperature > 38 °C, and either ocular clonus or inducible clonus Neuromuscular Hyperactivity Hyperreflexia, muscle rigidity (esp. lower extremities), myoclonus, tremor, incoordination, trismus*, opisthotonus*, ocular clonus*, seizures *Notes: • Trismus or lockjaw, is the reduced opening of the jaw • Opisthotonus is an abnormal body position where the person is usually rigid and arches their back, with their head thrown backwards • Ocular Clonus is rhythmic or equal movements of both eyes; should be distinguished from nystagmus which has a fast and slow component Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Abbreviations: • 5-HT = serotonin • SSRI = selective serotonin reuptake inhibitors • SNRI = selective noradrenaline reuptake inhibitors • MOAI = monoamine oxidase inhibitors • TCA = tricyclic antidepressants

unstable-angina-pathogenesis-and-clinical-findings

Unstable Angina/Unstable Angina Pectoris: Pathogenesis and clinical findings Primary cause: Secondary causes: Coronary artery vasospasm - primary or drug induced (Ex: cocaine, triptans) Coagulopathy (Ex: antiphospholipid antibody syndrome) Vasculitic syndromes (Ex: Takayasu arteritis) Authors: Marisa Vigna Ryan Wilkie Yan Yu* Reviewers: Julena Foglia Davis Maclean Mehul Gupta Andrew Grant* * MD at time of publication Atherosclerosis Fatty plaque accumulates inside the intimal walls of arteries Coronary arterial atherosclerotic plaque rupture or erosion Plaque disruption exposes subendothelial components of damaged vessel wall to platelets, initiating the coagulation cascade and platelet adhesion Aggregation of platelets results in the formation of a thrombus Thrombus partially occludes blood flow through a coronary artery âmyocardial blood supply Congenital anomalies (Ex: myocardial bridge, anomalous coronary) Spontaneous coronary artery dissection Increased blood viscosity (Ex: polycythemia, thrombocytopenia) Factors thatámyocardial (cardiac muscle) oxygen demand (Ex: tachycardia, hypotension, hypertension, anemia, exertion, stress) Coronary embolism (Ex: A. Fib, endocarditis, prosthetic valve thrombus) áheart rate, contractility, and/or wall tension ámyocardial oxygen demand Myocardial ischemia due to imbalance between blood supply and oxygen demand (insufficient blood/oxygen supply) Unstable Angina/Unstable Angina Pectoris Can be new onset angina; typically progressive in frequency, severity, or duration; can occur at rest Subtotal occlusion of a coronary arteryà reduced, but continued, myocardial blood supply Maintained perfusion means cardiomyocytes are still alive and thus do not leak troponin into bloodstream Normal serum troponin Diaphoresis (sweating) Since bloodflow occurs from epicardium to endocardium, myocardial ischemia is more pronounced in the subendocardium (region furthest away from heart’s external surface) Sufficient blood flow is maintained in regions superficial to the subendocardium, resulting in non-transmural (partial thickness) heart wall ischemia Non-inferior wall ischemia triggers a predominantáin sympathetic nervous system activity, given the proximity of cardiac sympathetic nerve innervation Ischemiaâ cardiomyocyte resting membrane potential andâ action potential duration Voltage gradient between normal and subendocardial ischemic zones creates injury currents, shifting the ST- vector on ECG ECG: ST depression and/or T wave inversion Cardiac sensory nerve fibres mix with somatic sensory nerve fibres and enter the spinal cord via the T1-T4 nerve roots Brain perceives increased cardiac sensory nerve signaling as nerve pain coming from the skin of T1-T4 dermatomes (“Referred Pain”) Myocardial ischemia causes hypoxic stress on cardiomyocytesàâaerobic (requiring oxygen) metabolism,áanaerobic (not requiring oxygen) metabolism áanerobic respirationálactic acid production,á[H+], andâcellular pH which impairs cardiomyocyte function Cardiomyocyte dysfunction impairs myocardial relaxation in diastole and/orâ left ventricular contractility in systole âleft ventricular cardiac output àbackup of blood in the left ventricle, atrium, and pulmonary vasculature ápulmonary capillary pressures pushes fluid out of the capillaries into the alveoli in the lungs Fluid filled alveoliâgas exchange andâ oxygenation, triggering harder and faster breathing in order to compensate Dyspnea Activation of sweat glands via acetylcholine release Hormones bind to cardiac β1 receptors Tachycardia (áheart rate) Epinephrine/ Norepinephrine hormone release from the adrenal medulla Hormones bind to arterial smooth muscle α1 receptors ávascular tone (vasoconstriction) Hypertension The Vagus nerve sits in close physical proximity to the inferior wall of the heart àinferior wall ischemia triggers involuntary Vagus nerve activation Since the Vagus nerve coordinates parasympathetic activity,áVagus nerve activity leads to a variety of parasympathetic nervous system responses: Retrosternal discomfort: May present as pain, heaviness, tightness, aching, pressure, burning or squeezing Pain radiation to T1-T4 dermatomes: Left shoulder and arm, lower jaw, neck, abdomen, upper back Syncope (fainting) Bradycardia Nausea Hypotension (âheart rate) (âblood pressure) (áblood pressure) (shortness of breath) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Findings Complications Published Oct 18, 2015, updated Aug 29, 2021 on www.thecalgaryguide.com

Triptans

Triptans: Mechanism of action and side effects Triptans Selective competitive agonists of trigeminovascular serotonin (5-HT) receptors that cause constriction of cranial blood vessels & inhibition of trigeminal pain signaling to abort migraines & cluster headaches Activation of 5-HT₁B receptors on peripheral & visceral blood vessels ↑ Vascular tone Deformation of vessel walls Activation of mechano- sensitive nerve endings in coronary vessels Activation of mechano- sensitive nerve endings in peripheral vessels Transmission of signals via T1- T4 sympathetic fibres Continued use of triptans ↓ activation threshold Central interpretation of signals as painful ↑ Abnormal signaling to CNS Chest tightness Paresthesias Legend: Activation of 5-HT₁B receptors on meningeal artery smooth muscle ↑ Vasoconstriction of dilated meningeal vessels ↓ Mechanical distension ↓ Activation of meningeal nociceptors ↓ Throbbing sensation Activation of 5-HT₁D receptors on V1 segment of the trigeminal nerve ↓ Calcitonin gene- related peptide (CGRP) & other vasoactive neuropeptides ↓ Vasodilation ↓ Neurogenic inflammation ↓ Plasma leakage into tissues ↓ 1st order neuron signaling to trigeminal nucleus caudalis & thalamus 5-HT₁B/₁D (±₁F) receptor agonism directly on trigeminal nucleus caudalis & brainstem ↓ Glutamatergic signaling Transient changes in central excitability Suppression of excessive excitably in thalamus ↓ Integration of retinal & cochlear inputs ↓ Photophobia & phonophobia Authors: Sarah Johns Reviewers: Trevor Low Emily J. Doucette Jean Mah* * MD at time of publication Suppression of excitably in dorsal raphe nucleus ↓ Arousal Fatigue & drowsiness Pathophysiology Mechanism Pharmacologic Effect Side Effects ↓ 2nd order neuron firing ↓ Input to vestibular nuclei ↓ Neuronal activity in nucleus tractus solitarus ↓ Nausea Published Oct 19, 2025 on www.thecalgaryguide.com ↓ Integration of balance & spatial orientation Dizziness & unsteadiness