Massive Propranolol Overdose

aka Toxicology Conundrum 044

A 27-year old female weighing 60kg presents to ED approximately one hour after swallowing 70 x 40mg propranolol tablets (= 2.8 grams) with suicidal intent. At the time of assessment she is drowsy (GCS 13) with a heart rate of 46 bpm and BP 100/60. Fifteen minutes earlier she had been awake and able to give a history to paramedics. ECG shows sinus bradycardia of 45 bpm with PR interval 210ms, QRS duration 115ms, QT interval 380ms and a small R wave in aVR of approximately 2mm in height.


Q1. What type of drug is propranolol?

Propranolol is a lipid soluble, non-cardioselective beta blocker with sodium-channel blocking effects.



Q2. Describe the toxicokinetics of propranolol.

  • Absorption: Rapidly absorbed orally. Peak blood levels occur at 1-3 hours following oral administration.
  • Distribution: Highly lipophilic agent with a wide volume of distribution. Rapidly distributed to all tissues, including CNS.
  • Protein Binding: Approximately 93% protein bound.
  • Metabolism: Undergoes extensive hepatic metabolism, with hydroxylation of the aromatic nucleus and degradation of the isoprenaline side-chain. Over 20 metabolites identified. The 4-hydroxy metabolite has active beta-blocking properties.
  • Elimination: 95-100% of an ingested dose is excreted in the urine as metabolites and their conjugates.
  • Half-life: Plasma half-life is around 3-6 hours. The pharmacological effects last much longer than this. Elimination half-life is 12 hours and may be prolonged following overdose.

Q3. How does propranolol exert its toxic effects?

Propranolol exerts its toxic effects via two main mechanisms:

  • Beta-adrenergic receptor blockade (B1 and B2 receptors)
  • Sodium-channel blockade (class I or “TCA-like” effect)
  • Competitive antagonism of beta receptors leads to decreased intracellular cAMP with blunting of the chronotropic, inotropic and metabolic effects of catecholamines.
  • Sodium-channel blockade in the myocardium leads to prolongation of the cardiac action potential with resultant QRS widening and potential for ventricular arrhythmias.
  • Blockade of sodium channels in the CNS produces neurotoxic effects, i.e. seizures and coma.


Effects of Na-channel blockade on the cardiac action potential and ECG tracing

Sodium-channel blockade causes prolongation of phase zero of the cardiac action potential with resultant widening of the QRS complex. Image reproduced from Holstege et al (2006).

Q4. What are the clinical features of propranolol overdose?

Excess beta-adrenergic blockade causes:

  • Hypotension and bradycardia
  • Bradyarrhythmias, including sinus bradycardia, 1st-3rd degree heart block, junctional or ventricular bradycardia
  • Bronchospasm
  • Hyperkalaemia and hypo/hyperglycaemia

Sodium-channel blockade causes:

  • Cardiotoxicity – QRS widening, ventricular arrhythmias and cardiac arrest
  • Neurotoxicity – coma, seizures and delirium

Massive propranolol overdose typically presents with coma, seizures, bradycardia and progressive cardiogenic shock.

Q5. What are the electrocardiographic features of propranolol overdose?

The ECG changes are similar to those seen in tricyclic antidepressant poisoning, except with a much slower ventricular rate.

Beta blockade produces:

  • Sinus, junctional or ventricular bradycardia
  • Prolonged PR interval
  • Atrioventricular block (1st-3rd degree)

Sodium-channel blockade produces:

  • Broad QRS (> 100 ms in lead II)
  • Right axis deviation of the terminal QRS:
    • Terminal R wave > 3 mm in aVR
    • R/S ratio > 0.7 in aVR

R' wave in aVR

The degree of QRS broadening on the ECG is correlated with adverse events:

  • QRS > 100 ms is predictive of seizures
  • QRS > 160 ms is predictive of ventricular arrhythmias

An ECG showing sinus bradycardia with a 1st degree AV block and minor QRS widening (>100ms) indicates early propranolol toxicity.

Example ECG

Sodium-channel blocker toxicity

  • This ECG demonstrates marked sodium-channel blockade with first degree AV block and a relatively slow ventricular rate, in this case due to flecainide poisoning.
  • Propranolol overdose would produce a very similar ECG pattern, albeit with a slower venticular rate.

Q6. What is the lethal dose of propranolol?

  • Any ingested dose of propranolol > 1 g is considered to be potentially lethal.
  • Hence, this history of a 2.8 g ingestion is extremely worrying!


Q7. What is the risk assessment for this patient?


This patient has taken a lethal dose of propranolol and is already manifesting early signs of toxicity, as evidenced by:

  • Mild sedation (GCS 13)
  • Bradycardia (46 bpm)
  • Borderline blood pressure (100/60)
  • First degree AV block (PR 210 ms)
  • QRS broadening (115 ms)

Peak toxicity occurs early with propranolol (within the first 1-3 hours). This patient is likely to develop rapid onset of:

  • Coma
  • Seizures
  • Profound hypotension and bradycardia

She will almost certainly die without aggressive medical management.

The decline in GCS over the past 15 minutes is also worrying, suggesting that this patient is going to crash and burn very soon!

Q8. How should this patient be managed?

 Propranolol overdose is managed primarily as a tricyclic antidepressant overdose (as early life-threats are due to its sodium-channel blocking effects) and secondarily as a beta-blocker overdose.

Basic Supportive Care and Monitoring

  • This patient needs to be managed in a monitored area equipped for airway management and resuscitation.
  • Secure IV access, adminster high flow oxygen and attach monitoring equipment.
  • Treat seizures with IV benzodiazepines (e.g. diazepam 5-10mg).
  • Insert an arterial line for close haemodynamic monitoring.
  • Perform serial 12-lead ECGs to assess for sodium-channel blockade (QRS>100ms).
Management of Sodium Channel Blockade
  • Administer IV sodium bicarbonate 100 mEq (1-2 mEq / kg).
  • Intubate as soon as possible.
  • Hyperventilate to maintain a pH of 7.50 – 7.55.
  • If ventricular arrhythmias occur, the first step is to give more sodium bicarbonate. Lidocaine (1.5mg/kg) IV is a third-line agent (after bicarbonate and hyperventilation) once pH is > 7.5.
  • In established cardiotoxicity, the dose of sodium bicarbonate can be repeated every few minutes until the BP improves and QRS complexes begin to narrow.
  • Avoid Ia (procainamide) and Ic (flecainide) antiarrhythmics and amiodarone as they may worsen hypotension and conduction abnormalities.
Management of Bradycardia and Hypotension
  • Treat hypotension with an initial crystalloid bolus (10-20 mL/kg). If this is unsuccessful in restoring BP, be prepared to rapidly escalate to more advanced circulatory support using inotropes and chronotropes.
  • Atropine (10-30 mcg/kg) can be used as a temporising measure for bradycardia.
  • Persistent bradycardia and hypotension is better treated with a titrated infusion of adrenaline or isoprenaline via a central venous catheter.
  • If inotropes are required, consider early initiation of high-dose insulin euglycaemic therapy (as described in toxicology conundrum 028). This treatment appears to be very effective in massive propranolol overdose but takes time to work (30-45 minutes).
  • Glucagon (once considered to be the “antidote” to beta-blocker poisoning) is no longer recommended as it  is difficult to source in adequate quantities and offers no advantages over standard inotropes and chronotropes.
Screening Tests
  • Paracetamol level, blood sugar and 12-lead ECG are recommended as initial screening tests in all patients with deliberate self-poisoning.
  • Once the airway is secure, place a nasogastric tube and give 50g (1g/kg) of activated charcoal. This may reduce the dose of propranolol absorbed from the gut, limiting the duration and severity of toxicity. As propranolol is rapidly absorbed, this treatment is most likely to be effective if given early, i.e < 1-2 hours post ingestion (NB. Do not give pre-intubation due to risk of charcoal aspiration).
  • Admit the patient to the intensive care unit for ongoing monitoring and supportive care.

Q9. What do you do if the patient arrests?

Cardiac arrest may occur in propranolol overdose due to sudden ventricular arrhythmias (i.e. pulseless VT) or progressive cardiogenic shock culminating in bradycardic PEA.

  • Start CPR – Good quality CPR may be life saving. Conversely, cardioversion / defibrillation is unlikely to be successful in the poisoned heart.
  • Call for help! – Toxicological arrest is approached differently to cardiac arrest from other causes. If you have not yet enlisted the advice and support of a clinical toxicologist in managing this patient, then get them on the phone now! (this is assuming that you have a spare person to talk to them… ideally get help before they arrest!)
  • Push bicarb – Give boluses of IV sodium bicarbonate 1-2 mEq/kg every 1-2 minutes until return of perfusing rhythm.
  • Intubate and hyperventilate (if you have not done so already).
  • Give adrenaline – 1mg every 3-5 minutes as per standard cardiac arrest algorithms.
  • Avoid amiodarone – It will only make things worse.
  • Consider intralipid – The role of intravenous lipid emulsion (IVLE) in propranolol poisoning is not clearly defined, but it may be considered in cardiac arrest refractory to other measures. The dose is 100ml of 20% IVLE (1-1.5ml/kg) as an IV bolus over 1 minute; repeated once or twice at 3-5 minute intervals if required, followed by an infusion.
  • Don’t give up! – There are numerous case reports of excellent outcomes after prolonged CPR (>45 minutes) in patients who have arrested due to poisoning.

To illustrate this last point, we had a 55-year old lady come through our department recently with a 4 gram (i.e. absolutely massive) propranolol ingestion. She had a tonic-clonic seizure in front of paramedics and promptly arrested. The paramedics continued CPR (with no drugs) for 30 minutes prior to arrival in hospital. On arrival to ED, she was treated aggressively with bicarbonate, adrenaline and high-dose insulin and achieved return of spontaneous circulation after a further 15 minutes of CPR. She was transferred to ICU on high-dose insulin (2 units/kg/hr) and adrenaline infusions, which were subsequently weaned off over the following 24-48 hours. Post-arrest echocardiogram was entirely normal (no evidence of LV dysfunction) and serial bloods showed only trivial elevations in troponin and transaminases with preserved renal function (i.e. no evidence of ischaemic ATN). She was discharged home on day 4 entirely neurologically intact!


  • Olsen KR. Poisoning and Drug Overdose (5th edition), McGraw-Hill, USA 2007.
  • MIMS Online (database). Available at Accessed 27/11/2011.
  • Murray L, Daly FFS, Little M, and Cadogan M. Toxicology Handbook (2nd edition), Elsevier Australia 2011. [Google Books Preview].
  • Holstege CP, Eldridge DL, Rowden AK. ECG manifestations: the poisoned patient. Emerg Med Clin North Am. 2006 Feb;24(1):159-77 [abstract].
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  1. Gerard Fennessy says

    Hi Ed,

    Great post, and lots of things to think about. I hope to never see one, because I am sure my brain will be suggesting amiodarone for arrest, when clearly the answer is supportive, bicarb and lignocaine. What is the role of glucagon in these patients?

    • says

      One of the big problems with glucagon is the massive doses required. Glucagon comes in 1mg vials of powder with an accompanying 1ml vial of phenol-containing solvent. So each milligram of glucagon has to be drawn up individually. The recommended loading dose for glucagon in beta blocker poisoning is 5mg IV, followed by a further 5mg IV in 5 minutes if there is no response. This is followed by an infusion at 2-10 mg/hour. So, for example, if a patient with massive propranolol overdose requires inotropic support with glucagon 10mg loading dose plus 5mg/hour for a total of 10 hours, that is potentially up to 60 vials of glucagon that need to be individually opened, drawn up and administered. Not only is this process time consuming, diverting attention away from other more important resuscitative duties, it is also likely to result in the hospital’s entire supply of glucagon being rapidly depleted. There are also problems with dose-dependent nausea and vomiting – not ideal in the drowsy patient with an unprotected airway. There is data now to suggest that high-dose insulin is superior to glucagon for beta-blocker poisoning, with some authors advising that high-dose insulin should be part of the initial management of beta-blocker poisoning (Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila). 2011 Apr;49(4):277-83). If you had a crashing propranolol overdose that you were throwing the kitchen sink at, then you could make a case for a test dose of 10mg IV over 5 minutes… although why not just escalate the adrenaline and insulin doses further?

  2. says

    cracking (ie brilliant…) post.

    I never knew that propanolol had Na channel effects -- is the same true for all the beta blockers (ie bisoprolol and metoprolol being the main ones I see)?

  3. Miriam says

    I’m wondering the same as Andy (see above).
    I’m an ED nurse, so obviously pretty limited in my knowledge of toxicology. I assume that if treatment includes lots of bicarb, propanalol OD’s cause acidosis? Does that have to do with its hepatic clearance? Or sodium effects?

    • says

      Sodium bicarb is used for propanolol overdose for much the same reason it is used for tricyclics (and other sodium channel blockers). There are a number of postulated mechanism of action -- as detailed in the answer to Q% in this tox conundrum on tricyclics:

      This is the excerpt on the mechanism of action of sodium channel blockade (it is easier to read in the orginal post with better formatting):

      The mechanisms for the therapeutic effect are multifactorial and poorly understood. Any or all of the following mechanisms may have role:

      1. Plasma alkalinization and TCA plasma protein binding
      2. Intracellular alkalosis and TCA receptor binding
      3. Intracellular hypopolarization
      4. Sodium load
      5. Correction of metabolic acidosis
      6. Volume loading
      7. Other pharmacokinetic effects

      These potential mechanisms are discussed in (exhaust-ive/ing!) detail below:

      1. Plasma alkalinization and TCA plasma protein binding

      Plasma alkalinization promotes TCA protein binding (especially to alpha1-acid glycoprotein (AAG)), reducing the concentration of free drug available to cause sodium blockade.
      As up to 95% of the drug is protein bound (varies for different TCAs), sodium bicarbonate can make a large difference to its unbound fraction and hence its toxicity.
      Thus plasma proteins can act as a “sink” that sequesters TCAs away from the sites of toxicity (the sodium channels), until they can be redistributed to peripheral tissues.
      The capacity for plasma protein binding to TCAs in an overdose setting depends on many factors but their clinical significance is unknown:
      The amount of TCA to bind.
      The amount of TCA that binds to each AAG protein (up to 2 to 14 times the AAG concentration)
      The amount of AAG there is in the circulation.
      The degree to which the binding capacity (and the affinity of different binding sites) changes with change in pH.
      Other factors may play a role such as variation in the distribution of different TCAs between RBCs and the plasma, the effects of age and disease-states on AAG concentration, and perhaps even lipid levels in the blood.
      However, pH change is effective in the absence of protein in experimental models, so mechanisms other than the effects of protein binding must be important.

      2. Intracellular alkalosis and TCA receptor binding

      Intracellular alkalosis increases the unbinding rate of TCAs from the sodium channel receptor as a result of increased lipid solubility. This promotes dissociation of the neutral form of the drug from the TCA receptor site in the sodium channel.
      The ionized form of TCAs binds the inactivated voltage-depended sodium channel and is trapped in the channel; this leads to sodium channel blockade.
      Alkalinisation favours the nonionized state which does not become bound and trapped in the sodium channel and can thus diffuse through the plasma membrane.
      Presumably the TCA must enter the intracellular space prior to binding the sodium channel as much of the effect of bicarbonate is lost if the cellular bicarbonate pump is blocked to prevent the intracellular accumulation of bicarbonate (Wang’s protein-free perfused heart model).

      3. Intracellular hypopolarization

      High bicarbonate leads to high extracellular pH. This, in turn, results in proton-potassium exchange across plasma membranes leading to low extracellular potassium concentration/ high intracellular potassium concentration and hypopolarization that decreases sodium channel blockade by voltage-dependent drug-binding changes.

      4. Sodium load

      Sodium load has a secondary positive effect by over-riding sodium channel blockade due to an increased sodium concentration gradient across the cell membrane.
      Hypertonic saline was more efficacious than alkalinization at improving cardiac conduction and hypotension in a swine model.
      There are case reports of good responses to rapidly administered boluses of hypertonic saline in TCA toxicity, whereas in a case report of a slow infusion there was no effect.

      5. Correction of metabolic acidosis

      Plasma alkalinisation also counters the metabolic acidosis caused by TCAs. Severe metabolic acidosis is potentially fatal on its own if severe. This may also help reduce tachycardia, and thus decrease use-dependent Na channel blockade.

      6. Volume loading

      The volume effects of sodium bicarbonate may have benefit in the shocked patient, by ameliorating the consequences of shock and allowing more widespread distribution of TCAs to tissues other than the heart and CNS.

      7. Metabolism, tissue distribution, excretion, and urinary alkalinization

      The effects of alkalinization on hepatic metabolism and tissue distribution are not well understood.
      In the context of sodium bicarbonate use, tissue distribution is likely to be important (as alluded to above).
      The early toxicity of TCAs results from the initially high plasma concentrations (rapid oral absorption leads to peak levels within 2 hours) and rapid distribution to highly perfused organs (brain and heart).
      Increased protein binding may allow time for redistribution to other peripheral organs such as skeletal muscle and adipose tissue.
      Metabolism and elimination are probably much less important.
      TCAs are cytochrome P450 metabolized and undergo saturation in an overdose settling, leading to a prolonged half-life.
      Similarly they are highly lipid-soluble and widely distributed leading to a high volume of distribution and thus a long elimination half-life.
      TCAs typically undergo some degree of enterohepatic circulation.
      Urine alkalinization does not confer any therapeutic benefit.
      Renal excretion of TCAs is typically <10% as the active molecules are highly lipid-soluble and undergo extensive metabolism.
      High pH will DECREASE ionization of TCAs, the opposite of what would be necessary to trap TCAs in the urine (and I don’t think trying to acidify the urine is a good idea!)


  4. Lauren says

    I’m not a medical student but I was admitted into hospital a couple of days ago with a life threatening propranolol overdose, worse than the dosage described in the conundrum -- 100 x 40mg, as well as a whole other cocktail of prescription drugs. My BP got as low as 80/40 or something, I’m not too sure and my GSC was 3.

    I wanted to understand what exactly had happened to me and my system, and this did help to explain. I know I came so close to death…

    To all doctors and nurses out there, thank you. Had I not been looked after by such an amazing team, I would not be here today. You are all extraordinary.

    • Quentin says

      Lauren, forgive me for asking but did you take any other meds with the Propranolol OD? can you tell us how long it was after the OD that you were admitted to the ED, and what happened to you (symptoms such as HR and BP) whilst you were in there. Essentially, what did they do to save you. Kind regards, Q