Calcium channel blockers (CCBs) are split into two categories, dihydropyridines (DHP), such as amlodipine and nicardipine, and non-dihydropyridines (non-DHP), such as verapamil and diltiazem. While these two drug classes are both CCBs, there are some key similarities and differences that are important to take into consideration when prescribing or encountering these medications in practice. In this article, we’ll provide a calcium channel blocker comparison and contrast dihydropyridine versus non-dihydropyridine medications.
Similarities Between CCBs
CCBs work by blocking the inward movement of calcium into a cell by binding to L-type voltage-gated calcium channels located in various regions of the body. This decreases heart and vascular smooth muscle contractions, which in turn lowers blood pressure, giving them their antihypertensive effects, and increases the amount of oxygenated blood the heart receives, helping to treat angina.
CCBs are highly protein-bound and are excreted renally after metabolism by liver enzyme CYP3A4. This liver enzyme is a common component in the metabolism of various medications which can result in drug-drug interactions. Some examples include verapamil, diltiazem, and nicardipine all increasing plasma levels of cyclosporine, or grapefruit juice affecting the bioavailability of felodipine, nifedipine, nicardipine, nisoldipine, and verapamil. Due to their mechanism of metabolism and excretion, caution should be taken for both classes when prescribing to patients with renal or hepatic impairments.
Contraindications for the use of a CCB include patients with a hypersensitivity to CCBs, sick sinus syndrome (unless an artificial pacemaker is placed), severe hypotension, acute MI, and pulmonary congestion. Toxicity for these medications often first shows up as hypotension, bradycardia, and possibly hyperglycemia. Let’s now dig into our calcium channel blocker comparison and go into some factors that make these two CCBs different.
Nondihydropyridines Versus Dihydropyridines
Compared to DHPs, non-DHPs have a significant effect on the sinoatrial and atrioventricular valves. This means reduced cardiac conduction and contraction, which helps treat hypertension, reduces oxygen demands, and provides cardiac rate control which can be important for patients with cardiac dysrhythmias such as tachycardia. While both verapamil and diltiazem exhibit these effects, verapamil has been shown to lower heart rate and contractility more than diltiazem.
While both classes are substrates of CYP3A4, non-DHPs are also inhibitors of 3A4 and, therefore, cause more drug-drug interactions. Verapamil has also been shown to modestly inhibit CYP2C9, 2C19, and 1A2. Due to this, as well as the increased risk of bradycardia and atrioventricular block, verapamil and higher doses of diltiazem often are not recommended to be taken with beta-blockers.
Non-DHP’s side effect profile is also slightly different than DHPs, due to the difference in targets mentioned previously. Non-DHP CCBs carry a risk of lower cardiac output and bradycardia. Verapamil has also been shown to have a higher incidence of constipation at higher doses. In addition to the general CCB contraindications, non-DHPs are also contraindicated in patients with HFrEF (EF <40%), 2nd and 3rd AV block, and sick sinus syndrome (definitely a good board exam nugget!).
In comparison to non-DHPs, DHPs have little effect on the myocardium and target peripheral vasodilators. Due to this, side effects caused by DHPs include lightheadedness, flushing, headaches, peripheral edema, and (for short-acting formulations) reflex tachycardia. A brief table can be found below depicting the main differences between the DHPs and Non-DHPs.
| DHP vs Non-DHP Calcium Channel Blocker Comparison | ||
| Drug Class | DHP | Non-DHP |
| Examples | Amlodipine, nicardipine, nifedipine, felodipine | Verapamil, diltiazem |
| FDA Approved Uses | Hypertension, angina | Hypertension, angina, atrial dysrhythmias, tachycardia |
| Targeted Area | Smooth muscle | Heart Muscles and Smooth Muscle |
| Vasodilation | More vasodilation | Less vasodilation |
| Systemic Vascular Resistance (SVR) | Decreased SVR | Less SVR decrease |
| Contractility | No effect | Decreased contractility |
| Sinus Node Rate | No effect | Decreased rate |
| AV Node Rate | No effect | Decreased rate |
| Class Specific AEs | Dizziness, flushing, headaches, peripheral edema, palpitations | Constipation, bradycardia, lowered cardiac output |
As we can see in our calcium channel blocker comparison, these medications may have the same overall grouping of CCBs due to their general mechanism of action, but they differ in key ways that affect how we can utilize these therapies.
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This article was written by Emily States, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP
References:
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- Kuruvilla, M. E. & Sanan, N. (2018). Amlodipine-Induced Angioedema: An Unusual Complication of a Common Medication. Allergy & Rhinology, 9: 1–3. DOI: 10.1177/2152656718764139
- Richards TR, Tobe SW. Combining other antihypertensive drugs with β-blockers in hypertension: a focus on safety and tolerability. Can J Cardiol. 2014 May;30(5 Suppl):S42-6. doi: 10.1016/j.cjca.2013.08.012. Epub 2014 Feb 8. PMID: 24518661.
- Major side effects and safety of calcium channel blockers. Bloch, M. UpToDate. Updated August 3, 2022.
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