What are the differences between calcium channel blockers?📋📋📋

Calcium channel blockers are one of the commonly used antihypertensive
drugs in clinical practice. The effect of their antihypertensive drugs is relatively stable, so they are currently a type of antihypertensive drug widely used among patients with hypertension. Commonly used calcium channel blockers include amlodipine, felodipine, nifedipine, nifedipine sustained-release tablets, nifedipine controlled-release tablets, nitrendipine, etc. Although they all lower the patient's blood pressure by dilating blood vessels, their efficacy will also be different.

Introduction to calcium channel blockers.

Since calcium channel blockers have a 1,4-dihydropyridine ring in their molecular structure, they are also called dihydropyridine calcium channel blockers. They were first synthesized in 1882. However, it was not until 1975 that nifedipine was used clinically as a treatment for hypertension and heart disease. There are now three generations of calcium channel blockers. They play an important role in the treatment of cardiovascular and cerebrovascular diseases.

1. First generation: The representative drug is nifedipine. It has the longest clinical use time and has a faster onset of effect. However, due to the short action time of nifedipine, patients need to take the drug multiple times a day and have many adverse reactions, which limits its clinical use.
2. Second generation: Common second generation drugs include nicardipine hydrochloride, nimodipine, nisoldipine, and nitrendipine. They have a long duration of action, good efficacy and fewer side effects than nifedipine.
3. Third generation: Amlodipine is the representative drug of this generation. It is a long-acting calcium channel blocker. It only needs to be taken once a day, and the effect of the drug can be maintained for one day and maintain a steady-state blood concentration. Therefore, it is suitable for the treatment of hypertension and angina pectoris.

Mechanism of action of calcium channel blockers in lowering blood pressure.

Free calcium ions in cells cause vascular smooth muscle to contract. If the transmembrane transport of calcium ions is blocked, the concentration of calcium ions in the cell will decrease. Calcium channel blockers reduce the concentration of calcium ions in cells and relax the smooth muscles of blood vessels. It dilates arteries and reduces total peripheral vascular resistance, thereby lowering blood pressure. The expansion of peripheral blood vessels will reflexively activate sympathetic nerves and increase the heart rate. 

The antihypertensive effect and magnitude of calcium channel blockers are stronger than most other drugs. They are indicated for the treatment of hypertension, coronary heart disease, peripheral vascular disease, cardiac arrhythmias, primary pulmonary hypertension, etc. 

Calcium channel blockers have no absolute contraindications compared with other antihypertensive drugs. Their relative contraindications are tachyarrhythmias, congestive heart failure, severe heart failure, cardiogenic shock and aortic stenosis.

Calcium channel blockers do not significantly affect the patient's glucose and blood lipids. They are also very effective in lowering blood pressure in the elderly. The pathological processes of atherosclerosis, such as smooth muscle hyperplasia, lipid deposition, and fibrosis, all require the participation of calcium. Therefore, calcium channel blockers will reduce the concentration of calcium ions in blood vessel cells, so long-term use of them will have a certain anti-atherosclerotic effect.

Dosage of calcium channel blockers.

Amlodipine: Adults take 2.5 mg to 10 mg once daily. Its recommended starting dose is 5 mg once daily. It has strong vascular selectivity. Because it binds and dissociates slowly from its receptors, it has a slow onset and long-lasting effect (it is the longest-lasting of the calcium channel blockers). Patients will experience maximum blood pressure lowering effects 2 to 4 weeks after taking the drug. Its common side effect is edema of the lower limbs, which will generally disappear on its own with continued medication. Amlodipine has little negative effect on the myocardium, so it can be used for the long-term treatment of chronic congestive heart failure.

Benidipine: Adults take 2 to 8 mg once daily. Its recommended starting dose is 2 mg once daily. It is indicated for the treatment of essential hypertension or angina. It dilates the glomeruli and protects the kidneys. The initial dose in elderly patients should be halved. It is not used to treat cardiogenic shock or pregnancy-induced hypertension.

Felodipine extended-release tablets: Adults take 2.5 to 10 mg once daily. Its recommended starting dose is 5 mg once daily. It mainly blocks the influx of extracellular calcium into the smooth muscle of arterioles. It also selectively dilates arterioles. Additionally, it has no effect on veins. It will not cause orthostatic hypotension and has no obvious inhibitory effect on myocardium.

Lacidipine: Adults take 2 to 8 mg once daily. Its recommended starting dose is 2 mg once daily. It is a third-generation calcium channel blocker. It has the characteristics of fat solubility, long-lasting effect and strong medicinal effect. The starting dose in elderly patients should be halved. Patients with abnormal sinoatrial or atrioventricular conduction, insufficient cardiac reserve, or impaired liver function should use lacidipine with caution. It is not used to treat pregnancy-induced hypertension.

Levamlodipine: Adults take 2.5 to 5 mg once daily. Its recommended starting dose is 2.5 mg once daily. It will have fewer side effects than amlodipine. In addition to treating hypertension, it is also used to treat angina pectoris, left ventricular hypertrophy, cerebrovascular diseases, primary glomerular diseases, etc.

Nifedipine tablets: Adults take 5 to 20 mg 2 to 3 times a day. Its recommended starting dose is 5 mg three times daily. Although nifedipine tablets are still used clinically, they are no longer recommended for routine antihypertensive use due to their inconvenience, poor compliance, and unstable blood pressure control.

Nifedipine controlled-release tablets: Adults take 30 to 60 mg once daily. Its recommended starting dose is 30mg once daily. It releases nifedipine at a constant rate for 24 hours after oral administration. Its blood pressure reducing effect is strong and smooth. Patients have good compliance with it. It can also be used to treat coronary heart disease and chronic stable angina. 

Nifedipine extended-release tablets: Adults take 10 to 20 mg 1 to 2 times daily. Its recommended starting dose is 20 mg twice daily. It can be continuously released in the body for 6-8 hours after oral administration. However, nifedipine extended-release tablets are not as widely used as controlled-release tablets, even though they are cheaper than controlled-release tablets.

Nisoldipine: 5 to 10 mg once daily for adults. Its recommended starting dose is 5 mg once daily. Nisoldipine is lipophilic. It has high permeability to the brain. Some studies have pointed out that it can treat subarachnoid hemorrhage by improving the neurological deficits of subarachnoid hemorrhage. Nisoldipine appears to have little or no inhibitory effect on cardiac contraction or atrioventricular conduction, giving it some vasculoselectivity. It can be used to treat patients with ischemic heart disease, stable angina, congestive heart failure and essential hypertension. It is also suitable for treating patients with coronary heart disease and hypertension. The dose should be reduced in patients with hepatic impairment.

Nitrendipine: Take 10 to 20 mg twice a day. Its recommended starting dose is 10 mg twice daily. It is suitable for treating various types of high blood pressure. The maximum blood pressure lowering effect occurs 1 to 2 hours after patients take it and lasts for 6 to 8 hours. It has a strong selective effect on coronary arteries and peripheral blood vessels, but can easily cause edema in patients. Patients with impaired hepatic function should have a reduced dose.

Nimodipine: Adult patients with ischemic cerebrovascular disease are recommended to take 10 to 40 mg three times a day. Its recommended starting dose is 10 mg three times daily. Adult patients with migraine are recommended to take 40mg three times daily. Its recommended starting dose is 40 mg three times daily. Because it highly selectively acts on brain tissue receptors and easily passes through the blood-brain barrier, it is more suitable for the treatment of patients with cerebral vasospasm, headache-type hypertension caused by insufficient cerebral blood supply, and ischemic sudden deafness. Nimodipine is contraindicated in patients with cerebral edema, liver dysfunction, and severe hypotension.

Common adverse effects of calcium channel blockers.

Dizziness, flushing, headache and tachycardia: It reflexively activates the sympathetic nervous system and causes dizziness, flushing, headache and tachycardia. This adverse reaction occurs more often when patients take antihypertensive drugs for the first time or when the dose of antihypertensive drugs is too high. Short-acting preparations are more likely to occur. Patients who start at the lowest dose or choose long-acting or extended-release formulations will reduce the risk of such adverse reactions. They generally disappear after taking the medicine for a period of time.

Edema: The incidence of edema with calcium channel blockers is approximately 5 to 10%. Calcium channel blockers dilate arterioles and venules when they lower blood pressure. However, the ability to dilate tiny arteries is greater than the ability to dilate tiny veins. It prevents a small amount of blood from being carried through the veins to the heart. Edema usually develops after a patient has been using the medication for some time. Its symptoms are generally mild. Edema is more likely to occur in the feet, ankles, lower part of the calf, and occasionally laryngeal edema. This adverse reaction is more common in women and the elderly. It also depends on the type and dosage of the drug. Patients with mild edema can switch to other calcium channel blockers or reduce the dose. Patients taking calcium channel blockers in combination with ACEIs or ARBs can reduce the adverse effects of lower extremity edema. Diuretics such as hydrochlorothiazide and indapamide can relieve edema. However, the combined use of diuretics and calcium channel blockers may make blood pressure too low. Doses should be adjusted when used together. When the patient's edema symptoms cannot be relieved, other antihypertensive drugs should be considered.

Gastrointestinal symptoms such as abdominal pain, constipation, nausea: The transport of calcium ions in intestinal smooth muscle can also be affected by calcium channel blockers, causing patients to suffer from gastrointestinal symptoms. However, these symptoms are less common. It usually resolves on its own after taking the medication for a period of time or disappears when the medication is stopped.

Hypotension or Orthostatic Hypotension: Overdosage or a drug that lowers blood pressure too strongly may cause hypotension or orthostatic hypotension. Starting with low doses or choosing long-acting or sustained-release antihypertensive drugs can reduce the occurrence of such adverse reactions. Orthostatic hypotension is more likely to occur when calcium channel blockers are combined with other antihypertensive drugs or in elderly patients.

Psychiatric and neurological symptoms such as dizziness, drowsiness, insomnia, paresthesia, and tremor: These symptoms are generally rare. They usually disappear when the medication is stopped.

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What is the difference between apixaban, dabigatran, edoxaban and rivaroxaban?❓❓❓

For a long period of time in the past, warfarin was the only oral anticoagulant drug until the emergence of novel oral anticoagulant drugs. Although they are called "novel" oral anticoagulants, they are only relative to warfarin. New oral anticoagulants include factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) and direct thrombin factor IIa inhibitors (dabigatran). Learn more about these four new oral anticoagulants below.

1. Mechanism of action.

The anticoagulant effect of warfarin is produced through multiple targets. It exerts an anticoagulant effect by inhibiting the hepatic synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X.

Since new oral anticoagulants are anticoagulant drugs that act on a single target, their anticoagulant effects are easier to control. Apixaban, edoxaban, and rivaroxaban exert their anticoagulant effects by inhibiting coagulation factor Xa. Dabigatran exerts its anticoagulant effect by inhibiting coagulation factor IIa.

2. Risk of bleeding.

All of the novel oral anticoagulants were associated with a lower risk of intracranial hemorrhage than warfarin. Additionally, they do not increase the risk of fatal bleeding. Apixaban and edoxaban did not increase the risk of gastrointestinal bleeding compared with warfarin. However, dabigatran and rivaroxaban were associated with an increased risk of gastrointestinal bleeding compared with warfarin.

3. Indications.

a.) The difference between novel oral anticoagulants and warfarin: Atrial fibrillation can be divided into non-valvular atrial fibrillation and valvular atrial fibrillation (moderate to severe mitral stenosis, mechanical valve replacement surgery). Warfarin is recommended for valvular atrial fibrillation. Novel oral anticoagulants are recommended for nonvalvular atrial fibrillation.

b.) Differences between the novel oral anticoagulants:

• Apixaban is generally only used for anticoagulation after hip and knee surgery.
• Edoxaban and dabigatran can be used to prevent stroke in non-valvular atrial fibrillation. They can also be used to prevent deep vein thrombosis.
• Rivaroxaban can be used for more indications. It can be used to prevent non-valvular atrial fibrillation stroke, treat and prevent deep vein thrombosis and pulmonary embolism, anticoagulant therapy after hip and knee replacement, prevent coronary artery disease and peripheral artery disease.

4. Pharmacodynamics and pharmacokinetics.

The difference between novel oral anticoagulants and warfarin:

1. Novel oral anticoagulants reach peak blood concentrations more quickly after taking them, making them more effective. Their short half-life causes patients to lose their anticoagulant effect sooner after discontinuing the drug. It makes novel oral anticoagulants have good dose-response relationships. Activated coagulation factors II, VII, IX, and X are not affected by warfarin. Since the half-life of coagulation factor II is as long as 60 to 72 hours, it takes 2 to 7 days for warfarin to achieve its maximum effect.
2. Novel oral anticoagulants have few drug and food interactions.
3. Novel oral anticoagulants are rarely affected by disease or genetic factors. Patients have good medication compliance with them.
4. Andexanet is the specific reversal agent for apixaban, edoxaban and rivaroxaban. Idarucizumab is the specific reversal agent for dabigatran. If warfarin is overdose, vitamin K can be given intravenously.

5. Dosage of novel oral anticoagulants.

1. Apixaban: It is recommended to be taken at 2.5 mg twice daily. It is not affected by eating.
2. Edoxaban: It is recommended to take 60 mg once daily.
3. Dabigatran: It is recommended to be taken at 150 mg twice daily with meals. Dabigatran may damage the esophagus, so it is generally recommended to take it during or immediately after a meal and drink enough water (more than 100ml). Patients should remain in an upright or sitting position for more than 30 minutes after taking dabigatran.
4. Rivaroxaban: It is recommended to take 10mg once daily with or without food. However, rivaroxaban 15 mg or 20 mg tablets should be taken with food.

The frequency of administration is generally determined based on the half-life of drug efficacy and the half-life of plasma clearance. Patients should fix the time they take their medication every day. Novel oral anticoagulants generally do not require dose adjustment. However, in special circumstances (such as combined medication, the patient is underweight, old, or has liver and kidney problems), the dose may need to be reduced. 

6. How should novel oral anticoagulants replace other anticoagulants? 

Replacement of warfarin with novel oral anticoagulants: Check INR after discontinuing warfarin. Novel oral anticoagulants can be used when INR <2.0.

Substitution between novel oral anticoagulants: Patients should take the new novel oral anticoagulant directly with their next dose. Delayed dosing may be required in patients with renal impairment. 

Replacement of heparins with novel oral anticoagulants: The patient takes novel oral anticoagulants with the next injection of LMWH. The patient can take novel oral anticoagulant directly after stopping UFH.

Replacement of novel oral anticoagulants with injectable anticoagulants: The patient can switch to injectable anticoagulants when taking the next medication. Delayed dosing may be required in patients with renal impairment.

Replacing antiplatelet drugs with novel oral anticoagulants: Patients can take novel oral anticoagulants after they stop taking aspirin or clopidogrel.

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