In my career I have cared for three patients in this boat, and believe you me, it is traumatizing. These are some super sick, but like weird sick folks. While labor intensive, this rare and fascinating patient will live in your memory forever if you ever have the opportunity to care for them. Profound shock on lots of pressors, possibly on super massive high doses of insulin (think 700units/hr IV), glucagon (which might induce projectile vomiting), all while sitting there talking to you. It’s super weird. In this article I’ll discuss the physiology, pharmacodynamics, and management of the patient who has ingested toxic amounts of calcium channel blockers.

Pharmacodynamics

Calcium Channel Blockers (henceforth referred to as CCBs) are essentially the opposite of “pressors.” They are designed by the pharmacy gods to slow that overactive heart down. They have three (ish) primary effects:

• Negative Chronotropy and Dromotropy (rate and AV nodal conduction)

  • Achieved by binding to cardiac pacemaker cells and “blocking” the influx of calcium.

  • Reduced action potential and slowed conduction through SA and AV node (but AV>SA) = reduced HR.

  • Suppressed firing of aberrant pacemaker sites = less arrhythmia.

• Negative Inotropy (contractility)

  • Binds to cardiac myocytes = reduction of calcium influx = reduced cardiac muscle contraction

  • In high doses this induces reduced CO/CI = reduced BP

• Relax Vascular Smooth Muscle (vasodilation)

  • Binding/blocking Ca influx to vascular smooth muscle cells = reduced muscle contraction

  • Hits the coronary blood vessels = coronary vasodilation = increased perfusion to the heart itself

  • Hits the peripheral vasculature = peripheral vasodilation = reduced SVR = reduced BP

• Block Ca channels in pancreatic cells (in higher doses especially, primarily the non-dihydroperidines)

  • Net effect = insulin resistence = hyperglycemia

  • Incidentally this increases a patient’s risk of pancreatitis when on CCBs.
    

Therapeutic Indications and Chemical Classes

Indications: HTN, pulmonary hypertension, angina, vasospasm (coronary and cerebral), supraventricular tachydysrhythmias, hypertrophic cardiomyopathy, some off label uses.

There are two chemical classes of CCBs with different levels of cardioselective receptor binding. What that means is they have different primary outcomes and to complicate things the affinity for these effects vary based on dose. CCBs tend to have either greater cardiac activity or greater vasodilator activity.

• Dihydroperidines (Nifedipine, Amlodipine, Nicardipine, Nimidopine):

  • More effect as a vasodilator, less effects on the pacemaker/chronotropy/dromotropy. Issues with hypotension but HR may be maintained

  • Most often used to treat hypertension

  • Lightheadedness, flushing, headaches, and peripheral edema

  • They may, in fact have a reflex tachycardia because of the peripheral vasodilation (reduced SVR). At higher doses the negative effects equilibrate so there will be more bradycardia as well as vasodilatory effect

• Non-dihydroperidines

  • Phenylalkylamines (Verapamil) and Benzothiapines (Diltiazem)

  • More cardioselective: worsened CO (why this is not good for HFrEF), nodal blocking = bradycardia, hypotension

  • Open up coronaries = great for angina

  • Reduce HR = great for tachyarrhythmias

  • Diltiazem maintains some vascular effect so there is an element of vasodilation. This drug is commonly used in afib/rvr in the hospital and the mechanisms of vasodilation + negative inotropy explans why you see more hypotension with this infusion than say Amiodarone

  • Constipation is a side effect

Toxicity

Onset: 2-3h post ingestion

Symptoms: Dizzy, Fatigue, Lightheaded, Coma (much less common than you would see with a BB overdose, in fact all three I have seen are wide awake/talking and do not present like a patient in massive shock - weird)

Clinical signs: Sinus bradycardia, AV blocks, bundle branch blocks, QT prolongation, refractory cardiac and distributive shock, ARDS. As a downstream effect of treatment you must be vigilant about volume overload.

Treatment:

• Charcoal

• Calcium - to promote calcium influx of the unblocked channels but in severe toxicity this will induce a sub-optimal response as most of the channels are unavailable for binding

• Pressors - lots and lots of pressors

• Methylene Blue

• Insulin - Because it is a direct positive inotrope. We are talking super duper high doses. Like 1-10units/kg/hr IV infusion. To put that in perspective, for a 150 lb patient that is 70-700 units per hour 🤯

  • Glucose/Dextrose - Because of all that insulin. It’s another weird factor, because of the blocked pancreatic Ca channel cells which induce hyperglycemia, you don’t see the degree of hypoglycemia you would expect from massive doses of insulin. Did you watch The Good Nurse? The true story of the ICU nurse who killed an estimated 400 patients by poisoning bags of NS with insulin. This is why high doses of insulin are scary = people die.

  • Even with the hyperglycemia effect there is a net hypoglycemia so they will be on a dextrose infusion and they will also likely have a dedicated staff member checking glucose levels every 15 minutes. Also contributes to lactic acid production.

  • Potassium - to counteract the intracellular K shift seen with insulin administration. Bear in mind this is a pseudohypokalemia so if you aggressively correct it, they will become hyperkalemic as they improve and K shifts back out of the cell. Moral - don’t be too hasty to replete.

  • You’re going to start somewhere (arbitrary selection) and titrate to your target MAP and you’ll see the pressor need drop. Instruct the nurse to start weaning pressors off first (not the insulin).

  • Depending on renal; hepatic function; which drug they took, and whether it is extended release you may need this high dose insulin therapy for a day to several days.

• Lipid emulsion - sequesters lipophylic drugs (Verapamil/Diltiazem) and reduces the volume of distribution. Also provides fatty acid energy source to myocytes so the heart muscles get additional support. Used for the non-dihydroperidine class.

• Glucagon - positive chronotropy and inotropy. Best for BB overdoses though because it bypasses the beta receptor which is blocked in that instance.

  • Side effects: impressive and often instant n/v, hyperglycemia, hypokalemia, ileus.

• ECMO

Monitoring

Surprisingly, these patients actually do well. For someone in severe shock with all hands on deck, to have the patient sitting up asking for the remote without any signs of end organ damage - it is so bizarre you just have to experience it to believe it. The one patient I saw who did not survive, in large part had complications from the volume overload. This is the chief downside to the treatment, especially insulin, it is a massive amount of volume administration. For the pt with baseline cardiac co-morbidities, especially heart failure, this overdose is going to be very hard to manage. The intravascular volume they will receive is massive. Another difficult to manage co-morbidity is renal failure for similar reasons but also the additional need for CRRT is a high likelihood. This is why avoiding excess IV fluid administration from the get go is key. This patient is in distributive and/or cardiogenic shock, not hypovolemic.

References:

https://litfl.com/calcium-channel-blocker-toxicity/

https://www.ncbi.nlm.nih.gov/books/NBK482473/

https://pubmed.ncbi.nlm.nih.gov/17855820/

https://pubmed.ncbi.nlm.nih.gov/17101581/