What is amiodarone actually doing after the third shock?

Hi — in this week's newsletter:

• 🫀 What amiodarone actually doing after the third shock — why do we give it acutely when it takes months to achieve steady-state?
• ⏱️ *Try ALS Scribe Mode*** — keep track of arrests using our new tool.
• 📅 Foundation Emergencies teaching starts this Wednesday — A–E and the arrest call, 7pm
• 📈 Most read articles this week

Amiodarone was not designed to treat cardiac arrest. It was not designed to treat arrhythmia at all. It came out of a Belgian laboratory in 1961, from chemistry built on khellin, the active compound of Ammi visnaga — a Mediterranean weed sold as toothpicks and used in Egyptian medicine for the pain of passing a kidney stone.¹ Khellin dilated coronary arteries, so the chemists were after an angina drug, and that is what amiodarone was for the whole of the 1960s. A tablet for chest pain.

The turn came in Oxford in 1970 in a paper titled: The effect of amiodarone, a new anti-anginal drug, on cardiac muscle. Singh and Vaughan Williams found that the up and coming angina tablet protected guinea pigs against ventricular fibrillation, and in rabbit heart muscle produced "a considerable prolongation of the action potential" — a mechanism unlike any antiarrhythmic then in use.² Six years later Rosenbaum's group in Buenos Aires gave it to 251 people with arrhythmias refractory to every other drug, and suppressed them in 82% to 92%.³ Europe adopted it. The FDA, unimpressed by the toxicity, held out until 1985.

So what is it meant to be doing to the heart under your hands during an arrest? The fibrillating ventricle is running dozens of wavefronts at once, each turning back on itself and re-entering muscle it crossed a moment ago. Each survives on one condition: that some muscle ahead has recovered by the time the wave comes back round to it. This allows disorganised waves to perpetuate. Lengthen the recovery and the fibrillation waves arrive at muscle that is still refractory, finds nowhere to go, and stops. That is why the drug goes in after a shock rather than instead of one. The shock clears the circuits. Amiodarone is meant to stop them re-forming.

Figure: the class III action, the one amiodarone is named for, and you can see it on the ECG of anyone taking it as a longer QT. It is also, awkwardly, the one your bolus is least likely to be achieving in the few minutes it has to work during an arrest.

Look at what Singh and Vaughan Williams actually did. The animals with the prolonged action potential had been given amiodarone daily for six weeks.² Its volume of distribution is 40 to 84 litres per kilogram, its half-life 20 to 47 days, and intravenous dosing does not reproduce the class III effect of long-term oral treatment.⁴ A drug that needs weeks of loading is not doing its signature trick ninety seconds after a peripheral bolus. What you get acutely is the rest of the molecule: sodium channel blockade slowing conduction, plus beta and calcium channel blockade.⁴

So why give adrenaline if you then block it with amiodarone?. As we discussed last week, you give adrenaline for its alpha effect, the one that clamps the arterioles and sends the pressure from your compressions towards the coronaries, and you need it. But adrenaline is not only an alpha agonist. It has a beta effect as well, and on a fibrillating ventricle the beta effect is pure liability: it shortens the refractory period, loads the cells with calcium, and makes the muscle easier to fibrillate and harder to keep converted. Amiodarone, ninety seconds after the push, is acting mainly as an antiadrenergic, and what it trims is exactly that beta effect. So the drug you give a minute after adrenaline may be doing its most useful work by removing the half of adrenaline you never wanted.

ARREST, in 1999, randomised 504 patients still fibrillating after three shocks and got more of them to hospital alive: 44% against 34%, with more hypotension and bradycardia.⁵ ALIVE, in 2002, beat lidocaine (Na+ channels only) on the same endpoint, 22.8% against 12.0%.⁶ Getting people through the hospital doors is worth having. It is not the only thing worth having, and neither trial could say whether it bought meaningful neurological outcomes at discharge.

ALPS asked just that in 2016, with 3,026 patients and survival to discharge as the outcome. Amiodarone 24.4%, lidocaine 23.7%, placebo 21.0%: a 3.2-point gap, confidence interval −0.4 to 7.0, p = 0.08.⁷ Neurological outcome was the same in all three arms.

So give it after the third shock, the second dose after the fifth, and do not stop compressions to do it.⁸ You are buying a rhythm somewhat more likely to stay converted once the shock has done the work. Whether that becomes a person leaving hospital is a question the largest trial ever run on it answered with a p value of 0.08.

⏱️ Try ALS Scribe Mode

ALS Scribe Mode is a tool in the app for the person keeping the record during a cardiac arrest. It has a two-minute cycle timer that shows when the next rhythm check is due. One tap records a shock, a dose of adrenaline or amiodarone, or the rhythm found at a check, and each entry is timestamped. The 4 Hs and 4 Ts are listed on the same screen so they can be ticked off as they are considered. When the arrest ends, the full log can be read back or copied into the notes. It is at the top of the Emergencies tab, and the log is stored only on your phone.

📅 Foundation Emergencies teaching starts this Wednesday

Session 1 is A–E assessment and the arrest call — Wednesday 9 September, 7pm, half an hour, free. The structured look at a patient who is deteriorating, when to call for help, and what to do in the first minutes of an arrest before the team arrives. 339 of you have already signed up for it. Then hypotension and the shocked patient the week after, and onwards through the calls you actually get bleeped about.

Register for Foundation Emergencies

📈 Most read this week

• Suspected acute coronary syndrome — 72 opens
• Post-fall assessment — 68
• New oxygen requirement — 66
• The delirious or agitated patient overnight — 60
• Upper GI bleed — 60

---

— Oliver

Med reg in Cambridge; maker of bleep.guide :)

References

1. Tavolinejad H, Soltani D, Zargaran A, Rezaeizadeh H, Vasheghani-Farahani A. "The Story of Amiodarone." European Heart Journal. 2019;40(33):2758–2759. Read the paper. ↩︎
2. Singh BN, Vaughan Williams EM. "The effect of amiodarone, a new anti-anginal drug, on cardiac muscle." British Journal of Pharmacology. 1970;39(4):657–667. Read the paper. ↩︎
3. Rosenbaum MB, Chiale PA, Halpern MS, et al. "Clinical efficacy of amiodarone as an antiarrhythmic agent." American Journal of Cardiology. 1976;38(7):934–944. Oral dosing, 200 to 600 mg a day. Read the paper90807-9). ↩︎
4. Chow MSS. "Intravenous amiodarone: pharmacology, pharmacokinetics, and clinical use." Annals of Pharmacotherapy. 1996;30(6):637–643. Read the paper. ↩︎
5. Kudenchuk PJ, Cobb LA, Copass MK, et al. "Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation" (ARREST). New England Journal of Medicine. 1999;341(12):871–878. Hypotension 59% against 48%, bradycardia 41% against 25%. Read the paper. ↩︎
6. Dorian P, Cass D, Schwartz B, et al. "Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation" (ALIVE). New England Journal of Medicine. 2002;346(12):884–890. Read the paper. ↩︎
7. Kudenchuk PJ, Brown SP, Daya M, et al. "Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest" (ALPS). New England Journal of Medicine. 2016;374(18):1711–1722. Read the paper. ↩︎
8. Resuscitation Council UK. Adult advanced life support Guidelines, 2025. Read the guideline. ↩︎