Pharmacy Consult: Beta Blockers and Epinephrine

I had an interesting discussions in the ED the otherday when I was talking about the importance of administering epi via IM for anaphylaxis.  Is there a diminished response to epi if a patients is on a beta-blocker?

Let’s clarify: patients on chronic non-selective beta-blocker therapy may have a blunted effect of epinephrine in anaphylaxis but epinephrine administration may also result in profound hypertension and bradycardia or heart block.

Non-selective beta-blockers will blunt the bronchodilatory effects of epinephrine causing a sort of “resistance” to epinephrine in anaphylaxis. The same will hold true if epi is administered via nebulization or albuterol is given. If a patient is on chronic cardioselective beta-blocker therapy, this is generally not a concern, unless they’re on a high dose since these agents loose selectivity (for metoprololgreater than 100mg/day will do the trick). Alternatively, glucagon (1-5mg IV) can be given since it has sympathomimetic activity through cAMP, not alpha or beta receptor activation.

The mechanisms at play causing a significant blood pressure elevations and bradycardia share similarities. In this case, an unopposed alpha-adrenergic receptor activation causes profound vasoconstriction. Normally, epinephrine activates both alpha 1,2 and beta 1,2. Though the alpha activation leads to vasoconstriction, there is a balance of beta 2 mediated vasodilation. But by blocking this beta 2 activation you’ll have unchecked alpha 1 mediated vasoconstriction. The resulting effects are significant increases in blood pressure and subsequent reflex (vagally mediated) bradycardia. Again, in cases where the patients are on chronic cardioselective beta-blocker therapy, this effect is generally not observed if they’re on normal beta-blocker doses. Here is an interesting case report highlighting the concern.

Non-Selective (beta 1 and beta 2)	Cardioselective (beta 1)
Carteolol Carvedilol (has additional α-blocking activity) Labetalol (has additional α-blocking activity) Nadolol Penbutolol Pindolol Propranolol Sotalol (but really a class III antiarrhythmic) Timolol	Acebutolol Atenolol Betaxolol Bisoprolol Esmolol Metoprolol Nebivolol

Ticagrelor (Brilinta) and Aspirin Interaction - Fact or Fiction

When the literature behind ticagrelor hit, there seemed to be a short-lived cheer. Where prasugrel (Effient) fell short, this drug excelled - superior (composite endpoint of vascular death, MI and stroke) to clopidogrel (Plavix) with no excess bleeding. What followed was a resounding thud since 10% of the population in PLATO, who were from North America, did not see this benefit. But the confusion didn’t end there.  Especially for pharmacists…

In a mysterious turn of events, patients who received > 100mg of aspirin seemed to have no benefit (composite endpoint of vascular death, MI or stroke) with ticagrelor and more bleeding.  The mechanism of this interaction as theorized by the PLATO authors is that by administering aspirin at doses greater than 80 mg /day, the inhibition of prostacyclin production at these concentrations will offset the potent P2Y12 inhibition and additional prostacyclin release caused by ticagrelor (circa 1983). 

Although this makes sense, it’s not the whole story. We know that prostacyclin (specifically PGI2) inhibits platelet aggregation and causes vasodilation. Its production by COX-1 is readily inhibited by aspirin, however, its production by COX-2 is still maintained at normal daily aspirin doses. But at the end of the day, the suppression of PGI2 from higher doses of aspirin isn't enough to overcome the inhibitory effects of TXA2 to initiate or predispose a patient to thrombosis (unlike COX-2 inhibitors)

Moreover, if P2Y12 inhibition mediated prostacycline release was blunted in a clinically significant manner by aspirin, we should see this effect with clopidogrel and prasugrel – which we don’t.  There is a difference between showing no difference in clinical outcomes based on the dose of aspirin you use with clopidogrel (CURRENT-OASIS 7) and saying higher dose aspirin causes worse outcomes.

Or perhaps in everyone got aspirin 325mg daily in the region where ticagrelor did terribly (N. America) and virtually nobody received that dose elsewhere.

In the words of one of the ED pharmacists I work with, “I smell a fart with this one.” The FDA advisory panel regarding ticagrelor seems to agree.