Calcium channel antagonists
- also known as calcium channel blockers (CCBs),
- have been widely used for many indications.
- often classified into two major categories,
- non-dihydropyridines
- dihydropyridines.
1. Indication
This cardiovascular drug class is one of the leading causes of drug-related fatalities.
two major categories
- non-dihydropyridines include
- verapamil---------a phenylalkylamine
- diltiazem----------a benzothiazepine.
- dihydropyridines include many other drugs,
- most of which end in "pine"
- i.e., amlodipine and nicardipine
Cardiovascular indications include
- hypertension,
- coronary spasm,
- angina pectoris, 心绞痛
- supraventricular dysrhythmias, 室上性心律失常
- hypertrophic cardiomyopathy, 肥厚型心肌病
- pulmonary hypertension. 肺动脉高压
also prescribed for
- Raynaud phenomenon,
- subarachnoid hemorrhage, 蛛网膜下腔出血
- migraine headaches. 偏头痛
2. Mechanism
Calcium channel antagonists
- block the inward movement of calcium by binding to the L-type “long-acting” voltage-gated calcium channels in the heart, vascular smooth muscle, and pancreas.
There are two major categories of calcium channel antagonists based on their primary physiologic effects.
The non-dihydropyridines:
- have inhibitory effects on the sinoatrial (SA), and atrioventricular (AV) nodes
- resulting in a slowing of cardiac conduction and contractility.
- This allows for the treatment of hypertension, reduces oxygen demand, and helps to control the rate in tachydysrhythmias.
The dihydropyridines, in therapeutic dosing,
- have a little direct effect on the myocardium, and instead, are more often peripheral vasodilators,
- which is why they are useful for hypertension, post-intracranial hemorrhage associated vasospasm, and migraines.
Absorption: Calcium channel antagonists are absorbed well orally, however many have low bioavailability due to hepatic first-pass metabolism, primarily by CYP3A4.
吸收好，bioavailability低
Distribution: Calcium channel antagonists are highly protein-bound, and many have high volumes of distribution.
蛋白质结合性，并且许多具有高分布容积
Metabolism: In repeated doses, or overdose, the hepatic enzymes responsible for metabolism become saturated and reduce first-pass effects, which therefore increases absorption of the active drug. Modified release formulations and saturation of metabolism of these drugs increase the half-life of various calcium channel antagonists.
在重复剂量或过量服用时，负责代谢的肝酶变得饱和并降低首过效应，从而增加活性药物的吸收。 这些药物的缓释制剂和代谢饱和度增加了各种钙通道拮抗剂的半衰期。
Excretion: Calcium channel antagonists are primarily excreted renally after metabolism.
There is the potential for drug-drug interactions because calcium channel antagonists are metabolized by CYP3A4, which is responsible for the metabolism of many other xenobiotics.
存在药物相互作用的潜力。
3. Administration
via the intravenous or oral routes.
4. Adverse Effects
Non-dihydropyridines
- constipation
- worsening cardiac output
- bradycardia.
Dihydropyridines
- lightheadedness
- flushing
- headaches
- peripheral edema.
- likely related to the redistribution of fluid from the intravascular space to the interstitium.
There have also been reports of gingival hyperplasia.
5. Contraindications
Non-dihydropyridines:
- contraindicated in those with heart failure with reduced ejection fraction, second or third-degree AV blockade, and sick sinus syndrome
- because of the possibility of causing bradycardia and worsening cardiac output.
Calcium channel antagonists
- also contraindicated in patients with known hypersensitivity to the drug or its components.
Other contraindications include
- sick sinus syndrome (except in patients with an artificial pacemaker),
- severe hypotension,
- acute myocardial infarction
- pulmonary congestion.
Calcium channel antagonists
- AV blockade or sinus bradycardia, especially if taken with agents known to slow cardiac conduction.
There are reports of dermatologic reactions and hypotension with or without syncope with calcium channel antagonist use.
Peripheral edema may occur within 2 to 3 weeks of initiating calcium channel blocker therapy.
Use with caution in renal and hepatic impairment.
Consider starting treatment at a lower dose.
6. Monitoring
- Patients require close monitoring.
- The improvement of their symptoms of angina or maintenance of their blood pressure is an indication of efficacy. 心绞痛症状的改善或血压的维持
- A patient should undergo regular assessment if the clinician is titrating these medications quickly
7. Toxicity
Hypotension and bradycardia are the primary features seen in calcium channel antagonist poisoning.
These findings are due to peripheral vasodilatation and reduced cardiac contractility.
Hypotension
- may be profound and life-threatening
- results from peripheral vasodilation, bradycardia, and decreased ionotropy.
- Cardiac conduction may also suffer impairment with AV conduction abnormalities, complete heart block, and idioventricular rhythms.
Patients may present asymptomatic initially → progress rapidly to severe hypoperfusion and cardiovascular collapse.
Symptoms may include
- lightheadedness,
- fatigue,
- change in mentation,
- syncope,
- coma,
- sudden death.
Non-cardiac symptoms may include
- nausea and vomiting,
- metabolic acidosis secondary to hypoperfusion,
- hyperglycemia from the blockade of insulin release in the pancreas.
The insulin blockade also impairs the uptake of glucose by myocardial cells,
- further contributes to the reduction of cardiac contractility and worsens hypotension.
Severe poisoning can lead to pulmonary edema, presumably as a result of precapillary vasodilation and increased transcapillary pressure.
Overdose
Dihydropyridines
- in mild to moderate overdose
- may cause reflex tachycardia;
- in severe overdose,
- maybe a loss of receptor selectivity leading to bradycardia.
为什么会过量？
Many factors may affect the severity of overdose, including the
- calcium-channel antagonist dose,
- the formulation,
- ingestion with other cardioactive medications
- such as beta-blockers, the patient’s age, and comorbidities.
These medications may also be life-threatening with as little as one tablet in small pediatric patients.
Hyperglycemia has been considered a prognostic indicator of the severity of calcium channel antagonist toxicity.
- Beta-islet cells in the pancreas depend on the influx of calcium through the L-type calcium channels to release insulin.
- In the case of calcium channel antagonist overdose, there is a reduction in the release of insulin and subsequent hyperglycemia.
补救（？
As in any other overdose, it is crucial to maintain a patent airway. 保持呼吸道通畅至关重要
要检查：
- electrocardiogram and place the patient on continuous monitoring, including pulse oximetry.
- chest X-ray and basic labs
- including acetaminophen and salicylate levels if warranted
- Initiate gastrointestinal (GI) decontamination early尽早开始胃肠 (GI) 净化
- especially in the cases of large ingestions or those with sustained-release formulations in the appropriate settings
- normal mental status, recent ingestion, among others就是是正常，但大量摄入药物，还是要净化
- Administer activated charcoal
- if the patient has presented early and is awake, alert, oriented, and protecting their airway.
- Whole bowel irrigation全肠冲洗
- important option for those patients with massive overdoses or overdoses of sustained or extended-release formulations that do not already have an ileus.大量过量服用或过量服用缓释或缓释制剂但尚未出现肠梗阻的患者来说是一个重要的选择。
In the case of hypotension,
- initial treatment with intravenous fluids requires caution in those who have congestive heart failure, pulmonary edema, or kidney disease.
Intravenous calcium administration may reverse the decreased cardiac contractility.
- Calcium chloride 10% (10 ml for 0.1 to 0.2 ml/kg) or calcium gluconate 10% (20 to 30 ml 0.3 to 0.4 ml/kg)
- may be administered intravenously
- may be repeated every 5 to 10 minutes.
- Caution must be used with calcium chloride
- as it may cause skin necrosis when given through a peripheral line.
Atropine is a reasonable initial treatment option,
- but it typically does not reverse the effects of calcium channel antagonist poisoning. 不会逆转钙通道拮抗剂中毒的影响
吐的补救方法？
Give glucagon as a bolus of 5 to 10 mg intravenously with caution for nausea and vomiting, and patients may be pre-medicated with antiemetics to help avoid this.
If the patient is refractory to these interventions, initiate vasopressor therapy using intravenous norepinephrine or push-dose phenylephrine while preparing hyperinsulinemia/euglycemia (HIE) therapy.
- HIE increases cardiac contractility by enhancing the transport of glucose into the myocardial cells, which corrects they hypo-insulinemia.
- Administer a bolus of insulin 1 unit/kg, followed by an infusion of 1 to 10 units/kg per hour.
- Monitor the patient’s glucose for hypoglycemia initially every 10 minutes and then every 30 to 60 minutes to maintain glucose between 100 to 200 mg/dL.
- Use a concomitant dextrose infusion to maintain these levels.
- If the initial glucose is less than 200 mg/dL, administer a bolus dose of glucose.
- Monitor glucose levels and potassium levels closely.
- Intravenous lipid emulsion therapy lacks clear evidence for efficacy but is a consideration if all else fails.
- Administer a bolus of intravenous lipid emulsion 20% 1.5 ml/kg, repeat if needed, and then start an infusion of 0.25 to 0.5 ml/kg per minute for an hour.
Reports suggest that the use of methylene blue, especially in those with amlodipine overdose resulting in vasodilatory shock, may be effective.
Phosphodiesterase inhibitors are also an option in calcium channel antagonist therapy.
They increase cardiac output by inhibiting the breakdown of cAMP.
Extracorporeal membrane oxygenation (ECMO) has proven successful in cases refractory to all of the above interventions since it maintains perfusion to vital organs and continues hepatic metabolism.
8. Reference
McKeever RG, Hamilton RJ. Calcium Channel Blockers. [Updated 2021 Jul 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482473/
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