What are the potential side effects of 5-HT (5-hydroxytryptamine) receptor agonists, particularly in patients with a history of cardiovascular disease?

5-HT Receptor Agonist Side Effects

5-HT receptor agonists carry significant cardiovascular risks, particularly in patients with pre-existing heart disease, including chest pain, tachycardia, coronary vasospasm, and potentially life-threatening arrhythmias, with contraindications for those with ischemic heart disease, stroke history, or uncontrolled hypertension. 1

Cardiovascular Side Effects (Critical in Patients with Heart Disease)

Acute Cardiac Events

• Myocardial ischemia and infarction can occur within hours of administration, even in patients without known coronary artery disease (CAD), as 5-HT receptor agonists cause coronary artery vasospasm (Prinzmetal's angina). 1
• Life-threatening arrhythmias including ventricular tachycardia and ventricular fibrillation leading to death have been reported within hours of 5-HT1 agonist administration. 1
• Chest, throat, neck, and jaw pain/tightness/pressure commonly occur after treatment, though usually non-cardiac in origin; however, cardiac evaluation is mandatory in high-risk patients. 1

Vascular Events

• Cerebrovascular events including cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred with 5-HT1 agonists, some resulting in fatalities. 1
• Peripheral vasospastic reactions such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome can occur. 1
• Transient and permanent blindness and significant partial vision loss have been reported with 5-HT1 agonist use. 1

Hemodynamic Effects

• Tachycardia (occasionally preceded by brief reflex bradycardia), increased atrial contractility, and atrial arrhythmias are acute cardiac effects mediated through 5-HT4 receptors. 2
• Hypertension or hypotension can occur depending on the receptor subtype activated and vascular bed involved. 3

Neurological Side Effects

Common Neurological Symptoms

• Paresthesia (tingling sensations) is one of the most common adverse reactions (≥2% and >placebo). 1
• Dizziness and vertigo occur frequently with 5-HT receptor agonist use. 1, 4
• Headache is a common side effect, particularly with 5-HT3 receptor antagonists. 4
• Fatigue and malaise are frequently reported adverse reactions. 1, 4

Serious Neurological Events

• Seizures may occur; use with caution in patients with epilepsy or lowered seizure threshold. 1

Gastrointestinal Side Effects

• Nausea is a common side effect, particularly with 5-HT2C receptor agonists used for weight management (lorcaserin). 4
• Constipation occurs frequently, especially with 5-HT2C receptor agonists. 4
• Dry mouth is a common adverse effect. 4
• Gastrointestinal ischemia can occur as a vasospastic reaction, presenting with abdominal pain and bloody diarrhea. 1

Serotonin Syndrome (Life-Threatening)

Serotonin syndrome is a potentially fatal complication that occurs particularly during co-administration with SSRIs, SNRIs, tricyclic antidepressants, and MAO inhibitors. 1

Clinical Presentation

• Mental status changes including agitation, hallucinations, and coma. 1
• Autonomic instability with tachycardia, labile blood pressure, and hyperthermia. 1
• Neuromuscular aberrations such as hyperreflexia and incoordination. 1
• Gastrointestinal symptoms including nausea, vomiting, and diarrhea. 1
• Onset occurs within minutes to hours of receiving a new or greater dose of serotonergic medication; discontinue immediately if suspected. 1

Receptor-Specific Side Effects

5-HT2C Receptor Agonists (e.g., Lorcaserin)

• Headache, dizziness, fatigue, nausea, dry mouth, constipation are the most common side effects. 4
• Hypoglycemia can occur, particularly in diabetic patients. 4
• Back pain and cough are reported adverse effects. 4
• Contraindicated with other serotonergic medications and in patients with known cardiac valvular disease. 4

5-HT3 Receptor Antagonists (e.g., Ondansetron)

• QTc prolongation is a significant concern; baseline ECG is advised before initiation. 4, 5
• Constipation is the most common side effect and may limit tolerability. 4
• Headache occurs frequently. 4

5-HT1B/1D Receptor Agonists (Triptans)

• Chest discomfort, fatigue, dizziness, paresthesia are common. 4
• Unpleasant taste particularly with nasal formulations. 4
• Contraindicated in ischemic heart disease, stroke, peripheral vascular disease, or uncontrolled hypertension. 4, 1

Chronic Exposure Risks

• Valvular heart disease with proliferative changes and thickening of cardiac valves occurs with chronic exposure to high 5-HT levels, mediated through 5-HT2B receptors (seen with carcinoid tumors, fenfluramine, and MDMA). 2
• Pulmonary hypertension can develop through activation of constrictor 5-HT1B receptors and proliferative 5-HT2B receptors. 2, 6

Medication Overuse Headache

• Overuse of 5-HT1 agonists (triptans) for 10 or more days per month may lead to medication overuse headache, presenting as migraine-like daily headaches or marked increase in migraine frequency. 1
• Detoxification including withdrawal of overused drugs and treatment of withdrawal symptoms (often with transient worsening of headache) may be necessary. 1

Absolute Contraindications for 5-HT1 Agonists

• History of coronary artery disease or coronary artery vasospasm 1
• Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders 1
• History of stroke, transient ischemic attack, hemiplegic or basilar migraine 1
• Peripheral vascular disease 1
• Ischemic bowel disease 1
• Uncontrolled hypertension 1
• Recent (within 24 hours) use of another 5-HT1 agonist or ergotamine-containing medication 1
• Concurrent or recent (past 2 weeks) use of MAO-A inhibitor 1
• Severe hepatic impairment 1

Critical Drug Interactions

• MAO inhibitors: Absolutely contraindicated with 5-HT receptor agonists due to risk of serotonin syndrome and hypertensive crisis; require 2-week washout period. 1
• Other serotonergic agents (SSRIs, SNRIs, TCAs): Increase risk of serotonin syndrome when combined with 5-HT agonists. 1
• Sympathomimetic agents: Avoid all over-the-counter cold medications containing pseudoephedrine, phenylephrine, or dextromethorphan when using 5-HT agonists, particularly in combination with MAOIs. 7

Special Populations

Cardiovascular Risk Assessment

• Perform cardiovascular evaluation in triptan-naive patients with multiple cardiovascular risk factors (increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to first dose. 1
• Consider administering first dose in medically supervised setting with immediate post-dose ECG for high-risk patients. 1
• Periodic cardiovascular evaluation should be considered in intermittent long-term users. 1

Hepatic Impairment

• Maximum single dose should not exceed 50 mg in patients with mild to moderate hepatic impairment. 1
• Severe hepatic impairment is an absolute contraindication. 1