* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Clinical Cases in Toxicology
Survey
Document related concepts
Drug discovery wikipedia , lookup
Orphan drug wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Pharmacognosy wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Theralizumab wikipedia , lookup
Prescription costs wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Drug interaction wikipedia , lookup
Neuropharmacology wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Transcript
Clinical Cases in Toxicology Tom Heaps Consultant Acute Physician “ All things are poison and nothing is without poison; only the dose makes a thing not a poison. - Paracelsus, 1538 Case 1 > 82-year-old female; COPD, HTN, depression, dementia > seretide, tiotropium, risperidone 1mg BD, ramipril 2.5mg, bendroflumethiazide 2.5mg, citalopram 20mg > allergic to penicillin > presents to ED with increasing SOB and productive cough > vitals stable, AMTS 10/10 > Na 132, CRP 26, WCC 11.9, CXR unremarkable > treated for AECOPD (antibiotics, nebs, steroids) > transferred to AMU Case 1 cont. > 48h post-admission > GCS 13/15 > delirious +++ > sweating, T 38.9°C, HR 112, BP 137/68, SpO2 95% OA > CT head (why?) NAD > repeat bloods: CK 397, otherwise unremarkable > dilated pupils > increased tone and generalized rigidity > hyperreflexia, bilateral extensor plantars, ankle clonus Diagnosis = serotonin syndrome (severe serotonergic toxicity) Mechanism = reduced metabolism of citalopram due to introduction of p450 inhibitor (clarithromycin) Causes of Serotonin Syndrome 1. intentional overdose with serotonergic drugs 2. ingestion of legal / illegal recreational drugs with serotonergic effects (MDMA, PMA / PMMA, MDAI, 5-APB, 5-IAI, cocaine, amphetamines, BZP) 3. initiating or increasing dose of a serotonergic drug 4. co-prescription of multiple drugs with serotonergic actions (often accidentally) 5. introduction of drugs which inhibit CYP450 enzymes in patients already taking SSRIs Drugs with Serotonergic Action tramadol SSRIs SNRIs MAOIs TCAs esp. clomipramine trazodone carbamazepine lithium metoclopramide recreational / illicit triptans fentanyl sibutramine linezolid St. John’s wort Drugs that may increase SSRI toxicity CYP2D6 inhibitors > amiodarone > terbinafine > chlorphenamine > cimetidine > metoclopramide > antipsychotics > cocaine CYP3A4 inhibitors > macrolides > fluconazole > verapamil > ciprofloxacin > metronidazole > antiretrovirals > grapefruit juice Diagnostic Features of Serotonin Syndrome 1. Altered mental status > agitation, confusion, disorientation, delirium > hallucinations > drowsiness, coma 2. Neuromuscular hyperactivity > profound shivering, tremor, teeth grinding > hypertonia, hyperreflexia, bilateral Babinski > spontaneous or inducible clonus, ocular clonus, myoclonus 3. Autonomic instability > tachycardia, hypertension or hypotension > flushing, sweating > diarrhoea and vomiting Other Features of Serotonin Syndrome leucocytosis elevated CK transaminitis metabolic acidosis DIC AKI secondary to rhabdomyolysis ARDS seizures malignant hyperthermia fulminant hepatic failure Management of Serotonin Syndrome stop all offending drugs fluid and electrolyte replacement IV benzodiazepines + + + IV sodium bicarbonate for persistent / arrhythmias 1mg /acidosis kg bolus 5HT2A antagonists (cyproheptadine, chlorpromazine, olanzapine) repeated up to 10mg / kg in 24h IV labetalol/GTN or noradrenaline for hyper/hypotension conventional cooling measures (paracetamol ineffective) ice baths, IV dantrolene, paralysis/intubation for hyperpyrexia rapid improvement within 24-48h is the rule (unless MOF) SS vs. NLMS Serotonin Syndrome Neuroleptic Malignant Syndrome Onset Acute, <24h Insidious, days-weeks Neuromuscular Hyperreactivity, tremor, clonus, hyperreflexia Muscular rigidity, bradyreflexia Causative agents Serotonergic agonists Dopaminergic antagonists Treatment Benzodiazepines, cyproheptadine Dantrolene, bromocriptine Resolution Rapid, 24-48h Slow, days-weeks Prognosis Generally good Variable, mortality up to 20% Case 2 > 84-year-old female > 2/52 Hx of vomiting, reduced oral intake and increasing confusion > HTN, AF, MVD, bowel cancer, hypothyroidism > furosemide 80mg OD, lansoprazole 30mg OD, digoxin 250mcg OD, levothyroxine 50mcg OD > observations unremarkable > confused on examination, no other significant signs > initial ED impression ?bowel obstruction > ECG – ‘LVH, ST elevation in aVR, inferolateral ST depression’ > no chest/abdominal pain or breathlessness Case 2 Seen by Cardiac ANP – ‘unlikely STEMI ?falls due to chronic valvular disease’ Diagnosis = Referred to Cardiology SpR for ECHO – ‘no RWMAs to suggest acute MI, admit under medics for Ix of falls’ AKI digoxin toxicity WCC 16, CRP 15, urea 9.9, creatinine 169 (120), K+ 3.1, hs-TnI 135 Seen by RMO3 – ‘Imp Acute5.3µg/L MI, ACS treatment, cardiology review ?for - level (0.8-2.0) angiogram’ Digoxin Toxicity: Sx Acute-on-chronic > acute > chronic Increased risk with AKI / CKD (reduce dose) and thiazides Nausea, vomiting, diarrhoea, delirium, xanthopsia Hyperkalaemia due to blockade of Na-K-ATPase pump - prognostic marker in ACUTE overdose Bradycardia, hypotension, AV block, sinus arrest, atrial tachycardia, ectopics, bigeminy, TdP, VT/VF Risk of arrhythmias increased by hypokalaemia Digoxin Toxicity: Rx stop digoxin (and nephrotoxics / diuretics) cardiac monitor IV fluids correct electrolytes (especially hypokalaemia / magnesaemia) IV bicarbonate (QRS prolongation / metabolic acidosis) IV magnesium (QTc prolongation / ventricular arrhythmias) IV atropine / isoprenaline / pacing (bradycardia) digoxin-specific antibodies ® Digibind & ® DigiFab Indications: > > > > > > Acute overdose of ≥10mg Severe hyperkalaemia Digoxin level ≥10ng/mL 6h post acute overdose or ≥15ng/mL at any time Chronic toxicity associated with significant arrhythmias or confusion Bradyarrhythmias unresponsive to atropine Life-threatening ventricular arrhythmias Dosing information on Toxbase® (half dose if acute or chronic) effective within 15-30min of administration Risk of anaphylactoid reactions Rebound effect if low GFR (reduced excretion of Fab-digoxin complexes) ‘Falsely’ elevated digoxin levels post-administration Case 3 > 57-year-old female > Background of HTN, AF, depression > Overdose of 17x verapamil 240mg MR 8h prior to admission > Sweating ++, mildly confused, CRT 5s, GCS 14/15 > HR 78 (Mobitz type 1 AVB on ECG) > BP 68/45mmHg > CBG 11.2 > Bloods unremarkable > Venous lactate 3.2, pH7.21, BE -7.5 Management? > Activated charcoal 50g (sustained release preparation) > IV Hartmann’s x3L > IV calcium gluconate 30mL 10% followed by infusion @ 30mL/h > IV sodium bicarbonate 50mmol (333mL of 1.26%) > BP 76/50mmHg > HR 64/min > Catheterized: urine output 20mL over 2h Other Rx Options? > Vasopressors Hyperinsulinaemia Euglycaemia Therapy Protocol > 1. Glucagon (directly stimulates Check plasma glucose and K+ cAMP, more effective in β-blocker OD) > 2. High dose insulin (increases myocardial If plasma glucose <10mmol/L give 50mL carbohydrate of 50% glucoseutilization, improves endovascular perfusion, prevents formation of FFAs) 3. Correct hypokalaemia > 4. Levosimendan (inotropic agent) titrated IV actrapid 1unit/kg boluscalcium followedchannel-sensitizing by infusion 0.5-2unit/kg/hour to clinical response > Atropine / isoprenaline / temporary pacing 5. Maintain on 10% glucose (5-10mL/kg/h) during insulin infusion > IABP 6. CBG every 20min during dose changes then hourly when on stable dose > 7. ECMO Check potassium hourly 8. Target sBP >100mmHg and heart rate >50/min for 6h Case progression > Glucagon 10mg IV (plus ondansetron) > Started on noradrenaline > Transferred to ITU > BP dropped further 66/40mmHg, anuric > Adrenaline commenced > Bradycardic @ 37/min with prolonged QRS > GCS 10 > Periarrest What did we try next? IV fat emulsion (20% Intralipid®) 90mL bolus (1.5mg/kg) followed by 30mL/min (0.5ml/kg/min) until 500mL total given rapid sustained improvement in BP, HR and urine output adrenaline discontinued and noradrenaline weaned down no arrhythmias discharged from ITU 24h later IV Lipid Emulsion (20% Intralipid®) originally used for TPN antidote for LA (bupivacaine) toxicity since late 1990s growing body of evidence for use in overdose with other drugs tricyclic antidepressants lipophilic calcium channel blockers e.g. diltiazem, verapamil lipophilic β-blockers e.g. propanolol, metoprolol, carvedilol, labetalol antipsychotics e.g. quetiapine mechanism of action becoming more clear ‘lipid sink’ which reduces free active drug concentrations and redistributes drug away from site of cardiotoxic action (usually to liver) energy source (free fatty acids) for supressed myocardium (inotropic effect) Key Learning Points 1. consider effects of drugs (prescribed or otherwise) and effects on drugs in every presentation 2. serotonin syndrome may affect all ages and can be caused by introduction of CYP450 inhibitors in patients on SSRIs 3. chronic digoxin toxicity is common; use Digibind® or DigiFab® in selected cases 4. remember HDI and ‘Lipid Resus’ in severe CCB (and other drug) poisonings