Toxidromes

Hyperthermic Toxidromes; Serotonin Syndrome, Malignant Hyperthermia, and Neuroleptic Malignant Syndrome

• Temperature > 38.5–39°C. Altered sensorium ± rigidity ± autonomic instability

• Excess serotonin (5HT1A/B) -> SS [CNS excitation => neurologica hyperactive]

• Dopamine blockade [D2 receptor] -> NMS [Dopamine motor suppression => centrally suppressed but rigid]

• Uncontrolled Ca2+ release -> MH [Peripheral muscle defect]

• Different triggers. Same terminal physiology. The final common pathway -> Skeletal muscle contraction + autonomic dysfunction

• All causes ↑ Muscle activity → ↑ ATP consumption → ↑ Heat → Rhabdomyolysis → Hyperkalemia → Organ failure

• Antipyretics are useless in all three (This is heat from muscle activity, not fever). Cooling + muscle control is life-saving.

Clinical difference

1. SS -> Hyperthemia + Agitation + Clonus [Hunter criteria] & Hypereflexia of LL.  (hours) ; Mod CK

2. NMS -> Hyperthermia + Lead-pipe Rigid + Antipsychotic history.  (days/slow onset) ; high CK

3. MH -> Intraoperative + sudden ETCO2 spike.   (minutes) ; Very high CK + Hyperkalemia

Typical trigger (& Treatment drug)

• SS -> Fluoxetine/Linezolid/tramadol (Rx; oral Cyproheptadine + Benzodiazapine) 

• NMS -> Haloperidol (Rx; Bromocriptine; dopamien blocker / Dadnrolene )

• MH -> Succinyl Scoline (Rx; iv Dantrolene + Treat hyperkalemia) ; Mechanism: Ryanodine receptor mutation

Hyperthermia Approach

• Clonus + Hyperreflexia (LL>UL) → SEROTONIN SYNDROME

• Lead-pipe rigidity + antipsychotic history + slow onset → NMS

• Intraoperative + sudden ETCO₂ rise + severe acidosis → MH

Clue;

• Linezolid + SSRI → Serotonin syndrome

• Dopamine withdrawal in Parkinson’s → NMS

• Antipyretics are ineffective in all three

• Hyperthermia is due to muscle activity, not hypothalamic set-point change

• Lower limb hyperreflexia strongly favours SS

• Clonus = Serotonin

• Lead-pipe rigidity = NMS

• ETCO₂ spike = MH

• Dry skin = Anticholinergic

• Very high BP + cocaine history = Sympathomimetic

• Hypotension + lactate + no neuromuscular signs = Sepsis

• Clonus = Serotonin

• Lead-pipe rigidity + days = NMS

• Intraoperative + ETCO₂ spike = MH

• Dry skin = Anticholinergic

• Very high BP + cocaine history = Sympathomimetic

• Hypotension + lactate + no neuromuscular signs = Sepsis

• MDMA can cause sympathomimetic toxidrome + severe hyponatremia (SIADH/excess water).

Toxidromes:

1. Sympathomimetic (Excess catecholamine)

   1. 1. • Examples: Cocaine / Amphetamine / MDMA

         • Pattern: Agitation / Tachycardia / Hypertension / Sweaty /Mydriasis / Hyperthermia

         • First-line: Benzodiazepine, Active cooling, Avoid pure β-blockers (risk unopposed α)

2. Anticholinergic (Muscarinic receptor blockade)

   1. 1. • Examples: Amitriptyline / Diphenhydramine / Atropine

         • Pattern: Hot as a hare/Blind as a bat/Dry as a bone/Red as a beet/Mad as a hat

         • Benzodiazepines, Cooling, Sodium bicarbonate if TCA (QRS widening), Physostigmine (selected cases)

3. Serotonin syndrome (Excess serotonin (5-HT1A/2A))

• Triggers: Fluoxetine, Linezolid

• Pattern: Rapid onset (hours)/Clonus/Hyperreflexia (legs > arms)

• Benzodiazepines, Cooling, Cyproheptadine

4. Neuroleptic Malignant Syndrome (Dopamine blockade)

• Trigger: Haloperidol

• Pattern: Slow onset (days), Lead-pipe rigidity, High CK

• Cooling, IV fluids, Dantrolene

5. Opioid

• Examples: Morphine, Heroin

• Pattern: ↓ Respiratory rate, Pinpoint pupils, ↓ LOC, Hypotension

• Airway support, Naloxone

6. Cholinergic (Organophosphate; Acetylcholinesterase inhibition)

• Examples: Malathion

• Pattern (SLUDGE): Salivation, Lacrimation, Urination, Diarrhea, GI cramps, Emesis, Bronchorrhea, Bradycardia, Miosis

• Atropine, Pralidoxime

Dry + delirium + urinary retention → Anticholinergic

Clonus → Serotonin

Rigid + slow onset → NMS

Pinpoint + slow breathing → Opioid

Sweaty + very hypertensive → Sympathomimetic

Wet + bradycardic → Cholinergic

Cheese Reaction (Hypertensive Crisis with MAO Inhibitors)

The cheese reaction is an acute hypertensive crisis triggered by ingestion of tyramine-rich foods in patients taking monoamine oxidase inhibitors (MAOIs). Tyramine is an indirect sympathomimetic amine found in aged/fermented foods.

Normally, Tyramine is metabolised by MAO-A in the gut and liver. If the patient is on MAOI (e.g. Phenelzine or Tranylcypromine):

→ Tyramine is not broken down

→ Enters systemic circulation

→ Displaces norepinephrine from presynaptic vesicles

→ Massive catecholamine release (note; It does not directly stimulate receptors)

→ Severe hypertension

This is a sympathomimetic surge, not serotonin syndrome. Here reflexes will be normal

May mimic: Pheochromocytoma crisis / Cocaine toxicity

Treatment (hypertension); 

• IV phentolamine (alpha-blocker)

• Nitroprusside infusion

• Nicardipine

• Avoid: Pure beta-blockers alone (unopposed alpha effect)

• Do NOT give pure beta-blocker → risk unopposed alpha vasoconstriction

• No clonus → no serotonin syndrome

• No rigidity → not NMS

• Cyproheptadine treats serotonin syndrome, not hypertensive crisis

  1. 1. 1. • MAOI + cheese → Hypertensive crisis

           • SSRI + MAOI → Serotonin syndrome

Coccain Vs Tyramine

• Cocaine blocks NE reuptake

• Tyramine releases stored NE

Both → hypertension (different mechanism)

SS Vs Hypertensive crisis

Linezolid is a weak MAO inhibitor

• Linezolid + SSRI → serotonin syndrome

• Linezolid + tyramine → hypertensive crisis

Both → hypertension (different mechanism)

Unopposed ⍺ phenomenon

Pure β-blocker in catecholamine surge:

→ α vasoconstriction unopposed

→ worsening hypertension

Seen in:

• Cocaine toxicity

• Tyramine crisis

Drug interactions

• MAOI + SSRI → serotonin syndrome

• MAOI + tyramine → hypertensive crisis

• MAOI + TCA → severe toxicity

• MAOI + tramadol → serotonin syndrome

Drug interactions

• MAOI + SSRI → serotonin syndrome

• MAOI + tyramine → hypertensive crisis (cheese reaction)

• MAOI + TCA → severe toxicity

• MAOI + tramadol → serotonin syndrome

• MAOI + Linezolid → Serotonin syndrome OR hypertensive crisis

Hypertensive crisis causes

1. 1. Food history → cheese reaction

   2. Recreational drug → cocaine

   3. Episodic triad (headache, sweating, palpitations) → pheochromocytoma

Concept:

• Indirect sympathomimetics: Tyramine/Amphetamine

• Direct: Epinephrine

• Mixed: Ephedrine

• If vesicles empty → only direct agents work.

Focused Hypertensive Emergency Algorith

STEP 1 — Confirm Hypertensive Emergency (BP ≥ 180/120 mmHg plus acute target-organ damage:

• CNS: encephalopathy, ICH, stroke

• Cardiac: ACS, pulmonary oedema

• Renal: AKI

• Vascular: aortic dissection

• Obstetric: eclampsia

Principle: treat the organ injury, not the number.

Step 2: 

• ↓ MAP by ≤ 25% in first hour

• Then to 160/100–110 over next 2–6 h

STEP 3 — Identify the Phenotype

A) Sympathomimetic Surge: 

• Examples: Cocaine, tyramine + Phenelzine

• Clues: severe agitation, sweating, mydriasis, tachycardia

• First-line: IV benzodiazepines (reduce catecholamine drive)

• Add if needed: Phentolamine (alpha blockade) / Nicardipine infusion

• Avoid: pure beta-blockers (unopposed alpha)

B) Aortic Dissection

• Clues: tearing chest/back pain, pulse deficit

• Goal: rapid HR + BP control 

• Target HR < 60, SBP 100–120

• Drugs: IV esmolol (beta first)

• Then add nitroprusside if BP is still high

C) Acute Pulmonary Oedema

• Clues: dyspnea, crackles, CXR congestion

• Drugs: IV nitroglycerin (high dose) / Loop diuretic / Non-invasive ventilation

• Avoid aggressive fluid boluses.

D) Hypertensive Encephalopathy

• Clues: confusion, seizures, headache, papilledema

• Drugs: Nicardipine infusion/Labetalol IV bolus/Avoid rapid overcorrection → risk cerebral hypoperfusion.

E) Intracerebral Haemorrhage

• Target: SBP 140–160 (based on local protocol)

• Nicardipine or labetalol preferred.

F) Eclampsia / Severe Preeclampsia

• IV labetalol or hydralazine

• Magnesium sulfate

G) Pheochromocytoma Crisis

• Clues: episodic headache, sweating, palpitations

• Alpha blockade first (phentolamine)

• Then beta blockade if needed

Drug selection in hypertensive crisis

1. Nicardipine     | Encephalopathy, stroke

2. Labetalol       | Neuro, pregnancy

3. Nitroprusside   | Rapid titratable (careful cyanide risk)

4. Nitroglycerin   | Pulmonary edema, ACS

5. Esmolol         | Aortic dissection

6. Phentolamine    | Catecholamine crisis

7. Benzodiazepines | Stimulant-induced 

• Chest/back tearing pain → beta first (dissection)

• Wet lungs → nitrates

• Confused neuro → nicardipine

• Stimulant/agitated → benzos first

• Pregnancy → labetalol + MgSO₄