Calcium Channel Blockers

Introduction

• CCBs are a well-established class of drugs primarily used for cardiovascular conditions, hypertension, and cardiac ischemia. They were originally termed “calcium antagonists” by German physiologist Albrecht Fleckenstein.¹
• CCBs are a group of organic molecules that disrupt the inward movement of calcium by binding to the L-type “long-acting” voltage-gated calcium channels, which relaxes vascular smooth muscle and reduces myocardial contractility.
• CCBs are categorized into two major types, dihydropyridines (DHPs) and non-DHPswhich differ significantly in their molecular structures, sites of action, and physiological effects, leading to qualitative and quantitative differences in their therapeutic applications.²
• Although CCB therapy is well-defined in cardiovascular medicine, there is growing interest in their potential therapeutic utility in Parkinson’s disease and certain neuropsychiatric disorders.¹

Mechanism of Action

• The mechanism of action of CCBs involves the inhibition of voltage-gated L-type channels. The structure of these channels is complex, consisting of a central, voltage-sensitive, Ca²⁺-selective pore formed by the α-1subunit.³
• This α-1 subunit, which determines the channel’s characteristics, comprises four homologous repeats (I-IV), each containing six transmembrane segments. Segments 1-4 act as the voltage-sensor, while segments 5 and 6 form the pore and activation gates.¹
• CCBs function by blocking the inward flow of extracellular calcium through these channels.⁴ They bind to a single, overlapping region on the α-1 subunit, located near the pore and the proposed activation gate.
• By interacting with this site, CCBs act as gating modifiers, interfering with the channel’s normal voltage-dependent cycling through its resting, open, and inactivated states.1
• The net result is reduced Ca²⁺ influx, leading to relaxation of vascular smooth muscle (vasodilation) and decreased myocardial contractility.⁴

Pharmacologic Properties

• CCBs are typically divided into two main categories: dihydropyridines (DHPs) and non-DHPs.²
• Non-DHPs are further subcategorized into phenylalkylamines (with verapamil as the prototype) and benzothiazepines (with diltiazem as the prototype).⁵
• DHPs are usually characterized by greater potency and as vasodilators (vascular selective) acting minimally on the myocardium, while non-DHPs are more cardiac selective and have greater cardiodepressant properties.²
• Non-DHPs primarily inhibit the sinoatrial and atrioventricular nodes, resulting in negative chronotropic and inotropic effects.⁴
• DHP agents are subcategorized into four generations; newer generations exhibit stable pharmacokinetics and reduced negative inotropic effects.
• The pharmacokinetic profile of CCBs is characterized by high oral absorption coupled with extensive first-pass metabolism, primarily by the CYP3A4 isoenzyme system.⁵
• The oral bioavailability of several CCBs can be elevated by concomitant grapefruit juice administration.
• CCBs are typically highly protein-bound, and many possess high volumes of distribution. CCBs are primarily excreted renally after metabolism.⁵
• Dosage adjustments are generally necessary for patients with hepatic impairment but not for those with renal impairment.

Clinical Uses

• CCBs are widely prescribed class of drugs. Their primary established uses include the treatment of hypertension, cardiac ischemia, and various forms of angina pectoris, such as chronic stable angina and vasospastic (Prinzmetal’s) angina.¹
• The utility of CCBs varies significantly depending on their chemical classification: DHPs are preferred for their potent vasodilatory effects and are used extensively for hypertension, coronary artery disease, and chronic stable angina.⁵
• Non-DHPs possess greater cardiodepressant properties and are used to treat hypertension, vasospastic angina, and various supraventricular tachyarrhythmias (including atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia conversion or prophylaxis).
• One DHP agent, nimodipine, is uniquely approved only for subarachnoid hemorrhage
• CCBs are also used for treating non-cardiovascular smooth muscle disorders like diffuse esophageal spasms, intestinal hypermotility, obstetric conditions (premature labor, dysmenorrhea, and eclampsia), urinary incontinence.⁴
• Off label uses of CCBs often target conditions involving peripheral vasospasm, such as Raynaud’s phenomenon, migraine prophylaxis, cluster headache prophylaxis, and high-altitude pulmonary edema. Furthermore, emerging evidence suggests potential new therapeutic indications, including neuroprotection in Parkinson’s disease and treating certain neuropsychiatric disorders.⁴

Administration and Dosage

• CCBs can be administered intravenously (IV) or orally (PO).
• DHPs are almost entirely oral agents, except nicardipine (IV form) and clevidipine
• Non-DHPs (diltiazem, verapamil) are available in both IV and PO forms.
• CCBs are more effective when taken in the evening than in the morning.
• CCBs have a multitude of durations: short-acting (half-life 2-4 hours), long-acting (half-life 12-24 hours), and sustained-release (half-life 35-50 hours) (Table 2).

Adverse Effects/Toxicity

• The adverse effects and toxicity profile of CCBs are diverse and often depend on the specific drug class.
• For DHPs, adverse effects are primarily related to their potent vasodilatory actions on peripheral arteries. Common DHP side effects include flushing, headache, dizziness, and hypotension.³
• Amlodipine, felodipine, and nifedipine frequently cause peripheral edema (ankle swelling) upon long-term use, which may necessitate discontinuation of therapy in some patients.⁴ This edema results from the preferential arteriolar vasodilation, which disturbs microcirculation hemodynamics and causes fluid redistribution from the intravascular space to the interstitium.
• DHP overdose or when used in high therapeutic doses, causes reflex tachycardia and acute hypotension.
• Common non-DHP adverse effects include bradycardia, atrioventricular block, and decreased cardiac output and constipation.³ Other adverse reactions can include orthostatic hypotension, dizziness, and fatigue.
• Verapamil and diltiazem should be avoided in patients with heart failure with reduced ejection fraction or preexisting cardiac disease due to the risk of worsening congestive heart failure.
• In non-DHP overdose, hypotension and bradycardia are the primary life-threatening features, resulting from reduced cardiac contractility and peripheral vasodilation.⁵
• Noncardiac symptoms of CCB toxicity may include nausea, vomiting, metabolic acidosis, and hyperglycemia by inhibition of insulin release in the pancreas secondary to L-type calcium channel blockade. Hyperglycemia has been considered a prognostic indicator of the severity of CCB toxicity.⁵

Contraindications

• The contraindications for CCBs depend primarily on their classification, but major absolute contraindications include hypersensitivity to any CCB and severe hypotension (systolic blood pressure less than 90mmHg).⁴
• Due to their pronounced effects on cardiac conductivity and contractility, the non-DHP agents (verapamil and diltiazem) are not recommended for use in patients with bradycardia (heart rate less than 60 beats per minute), heart failure, severe left ventricular dysfunction, preexisting cardiac disease, second- or third-degree atrioventricular block, and sick sinus syndrome.³
• Non-DHPs are also contraindicated in patients who have atrial fibrillation or flutter complicating the Wolff-Parkinson-White syndrome or other accessory bypass tracts, as they may accelerate the ventricular response.
• The concurrent use of non-DHPs with β-blockers is also cautioned due to the risk of additive negative chronotropic and dromotropic effects, potentially leading to severe bradycardia or complete heart block.⁴
• The combination of intravenous verapamil and dantrolene is associated with a risk of severe hyperkalemia and cardiovascular collapse and is therefore not recommended during the management of malignant hyperthermia.⁶ This interaction has been observed in animal studies, and the mechanism is not fully established.⁶