Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) modulate the renin-angiotensin axis. They are commonly used as first-line agents in the treatment of hypertension and are therefore widely encountered.

ACEi include: Captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril and trandolapril.

ARBs include: candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan.

When taken in isolation they generally do not cause significant toxicity, but when taken in combination with other cardiovascular drugs, particularly calcium channel blockers (CCB) or beta blockers, can cause severe hypotension. This is particularly relevant as many of these agents are available in coformulations with dihydropyridine CCB. Coformulations with diuretics are also available but these combinations due not lead to increased toxicity.

ACEi inhibit angiotensin-converting enzyme (ACE) which converts angiotensin I to angiotensin II, a potent vasoconstrictor, and stimulator of aldosterone release. ARBs block the action of angiotensin at its receptor.

In overdose these drugs do not seem to have any additional effects and the toxicity seen is very similar to that seen with the first dose in therapeutic use.

Given that overdose of these agents is generally benign a defined toxic dose in adults is not clinically relevant.

In children, ingestion of less than twice the ‘defined daily dose’ of either an ACEi or ARB is unlikely to result in toxicity and, providing they are asymptomatic, they can be safety observed at home.

Most ACE inhibitors (except captopril, lisinopril and any -prilat drugs) are given as pro-drugs, which have little activity. These pro-drugs have good bioavailability and are generally well absorbed. They are then rapidly metabolised by esterases to active metabolites (-prilats).

Captopril and lisinopril are not as well absorbed and have lower bioavailability than the pro-drugs.

There is a wide range in the volumes of distribution and extent of plasma protein binding, but these have little relevance to their toxicity in overdose.

ACEi and ARBs are both primarily metabolized in the liver.

The elimination of both classes typically occurs through renal excretion, with a portion of the drug excreted unchanged in the urine. In patients with impaired kidney function, the elimination of ACEi and ARBs may be slowed.

Generally, agents in both classes have long half-lives, allowing for once-daily dosing in many cases.

Overdose generally leads to only mild hypotension secondary to peripheral vasodilation. Onset of hypotension, if it occurs, happens early (3-6hr post overdose).

Renal impairment and hyperkalaemia may rarely occur but is reversible.

Co-ingestion with other cardiovascular agents, particularly relevant to coformulations with dihydropyridine CCB can cause severe, life-threatening vasoplegia.

In patients being observed in hospital post overdose, it is reasonable to check renal function and electrolytes, particularly if there is a history of renal impairment.

Most ingestions can be managed with supportive care alone. In most cases patients will be asymptomatic and require only a period of observation.

In those that develop hypotension, intravenous fluids should be given to maintain a satisfactory blood pressure and urine output.

For those that do not respond to intravenous fluid (usually only relevant to those with co-ingestion) start a vasopressor. Use:

Adults: Noradrenaline 3 to 50mcg/minute titrated to desired blood pressure target
Children: Noradrenaline 0.05 to 1 mcg/kg/minute titrated to desired bloods pressure target

If blood pressure is refractory to noradrenaline, discuss with a clinical toxicologist. This is most commonly seen with co-ingestion of dihydropyridine CCBs, where much higher doses of noradrenaline and the addition of additional agents to treat vasoplegia may be needed (vasopressin, methylene blue, hydroxocobalamin).

In those ingesting ACEi or ARBs in isolation, significant toxicity is not expected, and as such decontamination with activated charcoal is not warranted.

When ACEi or ARBs are taken in combination with other cardiovascular drugs, activated charcoal should be offered to alert and cooperative patients who present within 2 hours of ingestion.

Enhanced elimination is not indicated following ACEi/ARB ingestion.

Whilst angiotensin II would logically act as an antidote for ACEi ingestion, it is not generally available and given most ingestions are benign, not required.

The antihypertensive effects of these agents is in part attributed to decreased metabolism of endogenous endorphins. As such, naloxone has been suggested as a potential antidote, however the level of evidence is low (case reports), and it is not recommended for routine use.

Discharge patients with if they remain asymptomatic for at least 6 hours after ingestion.

Children who have ingested less than twice the ‘defined daily dose’ and are asymptomatic can be safely managed at home.

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