What is the difference between allopurinol, benzbromarone and febuxostat?💫💫💫

Hyperuricemia is a very common metabolic disease today. It not only causes kidney stones, chronic kidney disease and gout in patients, but may also cause diabetes and cardiovascular and cerebrovascular diseases. Allopurinol, benzbromarone and febuxostat are the most commonly used urate-lowering drugs in clinical practice. What is the difference between the three of them?

How to choose uric acid-lowering drugs for treatment?

Febuxostat is approved only for the long-term treatment of hyperuricemia in patients with gout. In addition, due to the potential cardiovascular risks of febuxostat, it is not recommended for the treatment of patients with asymptomatic hyperuricemia. 

The first-line urate-lowering drugs for patients with asymptomatic hyperuricemia are allopurinol or benzbromarone. Patients start with the lowest dose and slowly increase to the highest available dose. If the patient's blood uric acid level does not reach the target range, allopurinol and benzbromarone can be used in combination.

First-line urate-lowering drugs for patients with diagnosed gout are allopurinol, benzbromarone and febuxostat. Patients start with the lowest dose and slowly increase to the highest available dose. If the patient's serum uric acid level fails to reach the target range, allopurinol or febuxostat is used in combination with benzbromarone. In order to reduce the frequency of gout attacks, prevent tophi formation, prevent bone destruction, and reduce the risk of death in gout patients, they need to control their blood uric acid levels to <360 μmol/ml throughout their lives. Therefore, they may need to take urate-lowering medications for life. 

What is the difference in the uric acid-lowering abilities of allopurinol, benzbromarone and febuxostat?

Increased blood uric acid levels are mainly due to increased uric acid synthesis or decreased uric acid excretion in the body. 

1. Allopurinol: It is a hypoxanthine analogue. Its active metabolites are xanthine analogs. Allopurinol inhibits the reduced form of xanthine oxidase and reduces uric acid synthesis.
2. Benzbromarone: It inhibits urate transporter-1 on the renal tubules and reduces uric acid reabsorption. The excretion of uric acid will increase and the patient's blood uric acid level will decrease.
3. Febuxostat: It is a non-purine analogue. It inhibits both the oxidized and reduced forms of xanthine oxidase. Therefore, its ability to inhibit uric acid synthesis will be stronger than that of allopurinol.

Uric acid-lowering intensity: febuxostat > allopurinol ≈ benzbromarone.

What are the advantages and risks of allopurinol?

Some studies have pointed out that allopurinol can improve vascular endothelial function and exercise tolerance in patients with angina pectoris. It can also reduce the morbidity and mortality of heart failure. Both systolic and diastolic blood pressure are lowered by allopurinol. Allopurinol may also increase creatinine clearance and decrease serum creatinine in patients with chronic kidney disease.

However, allopurinol can cause hypersensitivity syndromes such as fatal exfoliative dermatitis. HLA-B*5801 gene positivity is a risk factor for hypersensitivity reactions to allopurinol. Therefore, it is recommended that patients undergo HLA-B*5801 gene testing before using allopurinol. Allopurinol may cause renal damage, so the dose needs to be adjusted based on the patient's renal function.

What are the advantages and risks of febuxostat?

Febuxostat has the strongest uric acid-lowering ability among the three. Moreover, it is mainly cleared by the liver and has little impact on kidney function. Therefore, there is no need to adjust its dose for patients with CrCl ≥ 30ml/min.

However, febuxostat is associated with a greater risk of death from cardiovascular events than allopurinol. Therefore, allopurinol is a first-line treatment for gout patients with severe cardiovascular disease (such as myocardial infarction, history of stroke, or unstable angina).

What are the advantages and risks of benzbromarone?

Benzbromarone is a uricosuric drug. It is generally used as an alternative treatment to xanthine oxidase inhibitors. It is contraindicated in patients with CrCl <30 ml/min or in patients with kidney stones.

What are the drug interactions with uric acid-lowering drugs?

Allopurinol and febuxostat are xanthine oxidase inhibitors. Significant drug interactions may occur when they are combined with drugs that are metabolized by xanthine oxidase (such as aminophylline, azathioprine, mercaptopurine and theophylline). 

Allopurinol: It combined with amoxicillin may increase the incidence of rash. The combination of allopurinol and captopril may result in fatal Stevens-Johnson syndrome, especially in patients with chronic renal failure. Allergy and renal failure may occur when thiazide diuretics are used with it. Aluminum hydroxide may decrease the absorption of allopurinol. It will cause iron-containing hemoglobin deposition when combined with iron, so the two cannot be taken at the same time. It will also increase the bleeding risk of anticoagulant drugs, and it is recommended to monitor the patient's prothrombin time when used together.

Benzbromarone: Diuretics can increase uric acid and reduce the effectiveness of benzbromarone. It is also not suitable for use in combination with anticoagulant drugs.

What are the indications and dosages of uric acid-lowering drugs?

Allopurinol: It is indicated for primary and secondary gout, hyperuricemia secondary to malignancy, hyperuricemia after organ transplantation, and calcium oxalate stone disease. Its initial dose is 50 to 100 mg daily, taken in 1 to 3 divided doses. Its maximum dose is 600mg daily. To prevent the formation of xanthine stones, patients should drink plenty of water while taking medication. Patients need to alkalinize their urine if necessary.

Febuxostat: It is indicated for the long-term treatment of hyperuricemia in patients with gout. Its initial dose is 20 to 40 mg once daily. Its maximum dose is 80mg daily. To prevent the formation of xanthine stones, patients should drink plenty of water while taking medication. Patients need to alkalinize their urine if necessary.

Benzbromarone: It is indicated for primary and secondary hyperuricemia, gout caused by various causes, and gouty arthritis. Its initial dose is 25 to 50 mg once daily. Its maximum dose is 100mg daily. To prevent the formation of uric acid crystals, patients should drink no less than 1.5 to 2L of water per day while taking medication. Patients need to alkalinize their urine if necessary.

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What is methotrexate?😵😵😵

Methotrexate is a drug that can be used to treat both cancer and non-cancer. It prevents cell division and the production of new cells. It can be used to prevent rejection in patients following bone marrow or stem cell transplants. It is also used to treat psoriasis and rheumatoid arthritis.

What are the indications and doses of methotrexate?

Methotrexate is a metabolic inhibitor of folic acid analogues. Dihydrofolate reductase will be inhibited by it and interfere with DNA synthesis, cell repair and replication. It is generally more sensitive to actively proliferating tissues such as malignant cells, bone marrow, fetal cells, oral cavity cells, intestinal mucosal cells, and bladder cells. It is mainly suitable for the treatment of hematological malignancies, solid tumors, psoriasis and various arthritis.

Treatment of adult hematological malignancies:

• Various acute leukemias (especially acute lymphoblastic leukemia), non-Hodgkin lymphoma, malignant lymphoma and mycosis fungoides, multiple myelopathy.
• Intrathecal methotrexate can be used to prevent and treat neural invasion of meningeal leukemias and malignant lymphomas.
• Methotrexate is used in combination with other chemotherapy drugs for the palliative treatment of acute leukemias, especially acute lymphoblastic leukemia. It is also used to treat Burkitt's lymphoma, coronal lymphosarcoma and mycosis fungoides.
• High-dose methotrexate is used to treat non-Hodgkin's disease subtypes but must be combined with rescue therapy with leucovorin.
• Oral administration: Adults take 1 to 2 days a week, once a day, 5 to 10 mg each time. The safe dosage for a course of treatment is 50 to 100 mg. Its maintenance dose for acute lymphoblastic leukemia is 15 to 20 mg/m² once a week.

Treatment of various solid tumors in adults including head and neck cancer, lung cancer, various soft tissue sarcomas, breast cancer, ovarian cancer, cervical cancer, malignant mole, chorioepithelial cancer, and testicular cancer. Commonly used oral tablet dosages are as follows:

• Adults take it orally 1 to 2 days a week, once a day, 5 to 10 mg each time. The safe dose for a course of treatment is 50 to 100 mg.

For the treatment of rheumatoid arthritis in adults. Common dosages are as follows:

• Rheumatoid Arthritis: 7.5 to 15 mg orally once weekly, with the highest dose being 25 mg once weekly. The dose of methotrexate should be reduced when used in combination with other immunosuppressants.
• Psoriatic Arthritis: 15 to 20 mg orally once weekly.
• Peripheral arthritis in ankylosing spondylitis: 7.5 to 10 mg orally once weekly.

Methotrexate is also used to treat severe, refractory and disabling psoriasis in adults who are unresponsive to conventional treatments. Commonly used injectable dosage forms.

What is the pharmacological mechanism of methotrexate?

Its main mechanism of action is to competitively inhibit folate reductase. Folic acid is reduced to tetrahydrofolate by folate reductase during DNA synthesis and cell replication. Folate reductase is inhibited by methotrexate, which interferes with cell replication. Methotrexate is a cell cycle-specific drug and acts primarily on cells during the DNA synthesis phase. 

Tissues and cells with active proliferation such as bladder cells, bone marrow, embryonic cells, intestinal mucosal cells, malignant tumor cells, oral cells, and skin epithelial cells are generally more sensitive to the effects of methotrexate. In addition, most normal tissues proliferate more slowly than malignant tumor tissues, so methotrexate will preferentially weaken the growth of malignant tumors. The skin epithelial cells of patients with psoriasis also have a greater ability to proliferate than normal skin cells, so methotrexate can also be used to control the progression of psoriasis. 

One of the important coenzymes in the synthesis of pyrimidine deoxynucleotides and purine nucleotides in the human body is tetrahydrofolate. Methotrexate is a folate reductase inhibitor. It inhibits dihydrofolate reductase and prevents dihydrofolate from being reduced to active tetrahydrofolate. This blocks the transfer of carbon groups during the biosynthesis of pyrimidine deoxynucleotides and purine nucleotides. DNA biosynthesis will be inhibited. In addition, although methotrexate also inhibits thymus nucleotide synthase, its inhibitory effect on protein and RNA synthesis is weak. It mainly acts in the S phase of the cell cycle. It is a cell cycle specific drug. It also delays cells in the G1/S phase, but the effect is weaker.

What are the common side effects of methotrexate?

Blood and Lymphatic System: Myelosuppression, pancytopenia, agranulocytosis, granulocytopenia, anemia, leukopenia, aplastic anemia, neutropenia, thrombocytopenia, lymphopenia.

Cardiovascular system: palpitations, tachycardia, increased blood pressure.

Gastrointestinal system: nausea, vomiting, oral ulcers, abdominal pain, diarrhea, oral mucositis, oropharyngeal pain, abdominal distension, acid reflux, gastrointestinal bleeding, lip ulcers, indigestion, blood in the stool, flatulence, dry mouth, oral bleeding, Belching, tongue ulcers, dysphagia, bleeding gums, peptic ulcers, melena, anal ulcers, and tongue pain.

Hepatobiliary system: abnormal liver function, liver cell damage, liver damage, hepatitis, jaundice, liver failure.

Immune system: Hypersensitivity reactions, anaphylactoid reactions, graft-versus-host disease.

Infections: infectious pneumonia, cytomegalovirus infection, fungal infection, herpes virus infection, sepsis, herpes zoster, Epstein-Barr virus infection.

Kidney and urinary system: renal damage, hematuria, hemorrhagic cystitis.

Nervous system: dizziness, headache, hypoesthesia, tremor.

Respiratory system: cough, dyspnea, pneumonia, pharyngitis, interstitial lung disease, pulmonary fibrosis, respiratory failure.

Skin and subcutaneous tissue: rash, pruritus, alopecia, erythema, skin ulcers, ecchymosis, erythema multiforme, maculopapular rash, vesicular rash, papules, erythematous eruption, urticaria, peeling, dermatitis, pruritic rash, purpura, Petechiae, exfoliative dermatitis, skin erosions.

Systemic reactions: fatigue, fever, mucosal ulcers, chest tightness, pain, chills, mucosal erosion, chills, facial edema, high fever, peripheral edema.

Others: loss of appetite, appetite disorder, joint pain, irregular menstruation, blurred vision, visual impairment, flushing, tinnitus.

Adverse effects of methotrexate can be prevented by using low-dose folic acid, but it should be used 24 hours after the patient takes the drug. It is recommended that patients supplement 5mg of folic acid every week to reduce gastrointestinal adverse reactions and liver function damage. Leucovorin and levofolinic acid are antidotes for methotrexate overdose. Patients with methotrexate overdose should be given an antidote as soon as possible and should undergo hydration and alkalinization of the urine.

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What are the differences in the usage of different lipid-lowering drugs?🔠🔠🔠

Among people who die from diseases in the world, deaths caused by atherosclerotic cardiovascular disease rank at the forefront. One of the important pathogenic risk factors in the development of atherosclerotic cardiovascular disease is dyslipidemia. Therefore, lipid-lowering drugs play an important role in preventing and controlling atherosclerotic cardiovascular disease.

What are the items in the blood lipid examination?

Name	Abbreviation	Normal range values
Total Cholesterol	TC	3.4-6.1mmol/L
Triglycerides	TG	0.57-1.7mmol/L
Low density lipoprotein cholesterol	LDL-C	2.7-3.1mmol/L
Apolipoprotein B	ApoB	0.8-1.1g/L
Lipoprotein(a)	Lp(a)	0-300mg/L
High density lipoprotein cholesterol	HDL-C	1.16-1.55mmol/L
Apolipoprotein A1	ApoA1	1.2-1.6g/L

Atherosclerotic cardiovascular disease is positively correlated with TC, TG, LDL-C, ApoB, and Lp(a), and negatively correlated with HDL-C and ApoA1.

What types of lipid-lowering drugs are there?

Lipid-lowering drugs generally reduce LDL-C through the absorption, synthesis and elimination of cholesterol.

Drugs that inhibit cholesterol absorption: such as ezetimibe.

Drugs that inhibit cholesterol synthesis: HMG-CoA reductase inhibitors such as atorvastatin. ATP-citrate lyase inhibitors such as bempedoic acid.

Drugs that promote cholesterol degradation: PCSK9 inhibitors such as evolocumab and alirocumab. PCSK9 synthesis inhibitors such as inclisiran.

Angiopoietin-like protein 3 inhibitor: such as evinacumab.

Apolipoprotein B synthesis inhibitors: such as mipomexan.

Microsomal triglyceride transfer protein inhibitor: such as lomitapide.

How strong are commonly used lipid-lowering drugs?

HMG-CoA reductase inhibitors are the clinically preferred lipid-lowering drugs. When HMG-CoA reductase inhibitors fail to reduce LDL-C to the target value at tolerable doses, it may be considered to add ezetimibe or/and PCSK9 inhibitors. 

	Reduce the average LDL-C level.
Ezetimibe	About 20%.
Moderate-strength HMG-CoA reductase inhibitors (such as simvastatin, pravastatin)	About 30%.
High-strength HMG-CoA reductase inhibitors (such as atorvastatin, rosuvastatin)	About 50%.
PCSK9 inhibitors	About 60%.
High-strength HMG-CoA reductase inhibitors + Ezetimibe	About 65%.
High-strength HMG-CoA reductase inhibitors + PCSK9 inhibitors	About 75%.
High-strength HMG-CoA reductase inhibitors + PCSK9 inhibitors + Ezetimibe	About 85%.

Drugs that inhibit cholesterol absorption.

The absorption of cholesterol in the small intestine is inhibited by this type of drug, thereby reducing blood cholesterol levels. They can reduce ApoB, LDL-C and TC in patients.

• Ezetimibe: Ezetimibe is rapidly absorbed when taken orally. It is extensively conjugated in the body to the pharmacologically active ezetimibe-glucuronide. Ezetimibe-glucuronide has significant enterohepatic circulation. Its half-life is 22 hours. Its recommended dose is 10 mg once daily. It can be taken at any time throughout the day. Ezetimibe can be taken on an empty stomach or with food.

Drugs that inhibit cholesterol synthesis.

Acetyl coenzyme A, a common metabolite of sugar and fat, is the raw material for cholesterol synthesis. 

• HMG-CoA reductase inhibitors directly prevent cholesterol synthesis by inhibiting HMG-CoA reductase. This type of drug is the most widely used lipid-lowering drug in clinical practice. Their main adverse reactions include hepatotoxicity, myotoxicity and increased risk of new-onset diabetes in patients.

1. Moderate-potency HMG-CoA reductase inhibitors: They lower a patient's LDL-C by approximately 30%. Commonly used clinically are simvastatin and pravastatin. The recommended starting dose of simvastatin is 10 to 20 mg once daily in the evening. The recommended starting dose of pravastatin is 10 to 20 mg once daily before bedtime, with the maximum daily dose being 40 mg.
2. High-intensity HMG-CoA reductase inhibitors: They can lower a patient's LDL-C by approximately 50%. Commonly used clinically are atorvastatin and rosuvastatin. The recommended starting dose of atorvastatin is 10 mg once daily, with a maximum daily dose of 80 mg. The recommended starting dose of rosuvastatin is 5 mg once daily, with a maximum daily dose of 20 mg. Both atorvastatin and rosuvastatin can be taken once daily at any time and are not affected by food.

• Bempedoic acid: It reduces patients' LDL-C levels by about 30%. Its half-life is 21 hours. The recommended dose is 180mg taken once daily, on an empty stomach or after a meal. Common adverse reactions include upper respiratory tract infection, muscle cramps, hyperuricemia, anemia, and elevated liver enzymes. It is less myotoxic than HMG-CoA reductase inhibitors.

Drugs that promote cholesterol degradation.

The LDL receptor on the surface of liver cells binds to LDL-C and transports it to the liver cells for elimination. Therefore, the number of LDL receptors on the surface of liver cells affects the level of LDL-C in the blood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that binds to the LDL receptor. The combination of the two will degrade the LDL receptor and reduce its number.

• PCSK9 Inhibitors: They bind to PCSK9 and inhibit the binding of LDL receptors to PCSK9. It lowers LDL-C levels by increasing the number of LDL receptors. PCSK9 monotherapy can reduce patients' LDL-C by approximately 60%. Evolocumab: The recommended dose is subcutaneous injection of 140 mg once every 2 weeks or 420 mg once monthly. Alircumab: The recommended dose is subcutaneous injection of 75 mg once every 2 weeks.
• PCSK9 synthesis inhibitors: Inclisiran is a chemically modified double-stranded RNA. The synthesis of PCSK9 in the liver is directly inhibited by it. It can reduce patients' LDL-C by about 50%. Its recommended dose is 284 mg as a subcutaneous injection, with a second dose after three months and then every six months.

Angiopoietin-like protein 3 inhibitor.

Lipoprotein lipase and endothelial lipase are inhibited by angiopoietin-like protein 3. It will increase the levels of HDL-C, LDL-C and TG. 

• Evinacumab: It is a human angiopoietin-like protein 3 monoclonal antibody. Angiopoietin-like protein 3 binds to it and inhibits its activity. The levels of HDL-C, LDL-C and TG will be reduced as a result. The main cause of homozygous familial hypercholesterolemia (HoFH) is that they lack the gene that expresses low density lipoprotein receptor. It reduces the liver's ability to clear LDL-C. Since the lipid-lowering effect of evinacumab does not depend on the activity of LDL receptors, it can significantly reduce blood lipid levels in patients with HoFH. Evinacumab is used as an adjuvant treatment with other LDL-C lowering therapies. It is approved for the treatment of patients aged 12 years and older with homozygous familial hypercholesterolemia. Its recommended dose is 140 mg subcutaneously every two weeks or 420 mg subcutaneously once monthly.

Apolipoprotein B synthesis inhibitors.

• Mipomexan: It is an antisense nucleotide that binds to and degrades the messenger RNA of ApoB-100. The synthesis and transport of apolipoprotein B are therefore inhibited. Mipomexan is approved for the treatment of patients with homozygous familial hypercholesterolemia, either alone or in combination with other lipid-lowering drugs. Its recommended dose is 200 mg subcutaneously once weekly.

Microsomal triglyceride transfer protein inhibitor.

Microsomal triglyceride transfer protein exist in the microsomal lumen of liver cells and intestinal cells. It is involved in the transport of triglycerides and the assembly of very low-density lipoproteins. 

• Lomitapide: It is a microsomal triglyceride transfer protein inhibitor. It can significantly reduces the levels of LDL-C and apolipoprotein B. Its recommended starting dose is 5 mg taken orally once daily. It should not be taken with food.

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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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What antihypertensive drugs should be used in patients with diastolic hypertension?💓💓💓

Isolated diastolic hypertension (IDH) refers to patients with systolic blood
pressure < 140 mmHg and diastolic blood pressure ≥ 90 mmHg. Isolated diastolic hypertension is common in people younger than 65 and is often accompanied by a rapid heart rate.

What is arterial compliance? What is Peripheral Resistance?

Arterial compliance is arterial elasticity. When the heart contracts, blood rushes into the aorta putting pressure on it, known as systolic pressure. If the arterial elasticity of the patient is poor, the degree of dilation of the large arteries decreases and the volume of the blood vessels decreases, resulting in an increase in systolic blood pressure.

Peripheral resistance refers to resistance to blood flow by arterioles. when the heart is in diastole, the large arteries elastically recoil as they expand, pushing blood into the arterioles. When the heart is at the end of diastole, there will still be a certain amount of blood remaining in the aorta, which will exert pressure on it and that is the diastolic pressure. If the patient's arteriolar resistance increases, blood will flow into the arteriole less. As a result, more blood will remain in the aorta and diastolic blood pressure will increase. In addition, the increased heart rate of the patient will shorten the diastolic period of the heart. Blood flow into arterioles will also be reduced. The aorta will also retain more blood and increase the diastolic pressure. There is usually no obvious abnormality in the elasticity of the large arteries in young and middle-aged people. However, a significant increase in peripheral resistance is often accompanied by an increase in heart rate. Therefore, they are prone to isolated elevated diastolic blood pressure.

What is the mechanism of action of commonly used antihypertensive drugs?

Antihypertensive drugs commonly used in clinical practice include angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), β-blockers, dihydropyridine calcium channel blockers and thiazides diuretics.

1. Angiotensin-converting enzyme inhibitor (ACEI): It inhibits angiotensin-converting enzyme and blocks the production of the renin angiotensin II. It has no effect on heart rate but increases blood potassium levels. It can inhibit the synthesis of angiotensin II and reduce the level of angiotensin II. 
2. Angiotensin Receptor Blocker (ARB): It inhibits the angiotensin II receptor (AT1 type). It does not affect the patient's heart rate but increases his potassium levels. It inhibits the action of angiotensin II.
3. β-blockers: It suppresses sympathetic nerve activity and cardiac contractility and slows the heart rate. It also raises the level of blood potassium. It reduces renin secretion and lowers the level of angiotensin II.
4. Calcium channel blockers: It dilates blood vessels by inhibiting calcium channels on vascular smooth muscle cells. It reflexively activates the sympathetic nerves to increase the heart rate.
5. Diuretics: These decrease volume overload by increasing urination. It does not affect the patient's heart rate but lowers blood potassium levels. It decreases the secretion of renin and the level of angiotensin II.

What are the pathophysiological characteristics of hypertensive patients in young and middle-aged patients?

Activation of the sympathetic nervous system: The biological marker of sympathetic nervous activation is increased heart rate, hypertensive patients in young and middle-aged are often accompanied by increased heart rate.

Activation of the renin-angiotensin system: hypertensive patients in young and middle-aged , especially those with risk factors such as abdominal obesity, dyslipidemia, and smoking, have higher plasma renin activity and angiotensin II levels than the elderly.

What antihypertensive drug should be preferred in patients with isolated elevated diastolic blood pressure?

ACEI and ARB inhibit the renin-angiotensin system. β-blockers inhibit the sympathetic nervous system. 

If the patient's heart rate is >80 beats/min, β-blockers such as bisoprolol, carvedilol, and metoprolol are preferred.

If the heart rate of the patient is ≤80 beats/min, ACEIs (such as enalapril, perindopril) or ARBs (such as losartan, valsartan) are preferred.

Calcium channel blockers reflexively activate the sympathetic nerves. Diuretics can increase renin secretion and thereby promote the synthesis of angiotensin I and II. They are ineffective in the treatment of isolated diastolic hypertension.

In addition, studies have pointed out that about 200 patients who use β-blockers for 1 year will suffer from erectile dysfunction. ACEIs and ARBs are generally considered to have no adverse effects on sexual function, and some studies even suggest that they can improve.

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What are the normal values of blood pressure, blood sugar, blood lipids and uric acid for people of different ages?👀👀👀

Blood pressure, blood sugar, blood lipids and uric acid are the four basic
indicators for evaluating the health of the human body. However, the values of these indicators are not fixed and it will change with age. Therefore, some people will mistakenly think that they are unhealthy when they find that the value of the index is different from the standard value after the physical examination.

What is the normal blood pressure value?

A person's blood pressure should neither be too high nor too low. Excessive blood pressure can damage organs or tissues such as the cardiovascular system and kidneys. It also increases the risk of stroke. Low blood pressure prevents sufficient delivery of oxygen and blood to all parts of the body. It can cause fatigue, weakness, dizziness, and even fainting. Low blood pressure also increases the risk of stroke. However, in fact, people's blood pressure is not always stable. A person's blood pressure can vary at different times of the day and in different physical conditions. The following is the reference value of normal blood pressure for people of various ages:

Age	Systolic blood pressure (Male)	Diastolic blood pressure (Male)	Systolic blood pressure (Female)	Diastolic blood pressure (Female)
16-20 y/o	115	73	110	70
21-25 y/o	115	73	110	71
26-30 y/o	115	75	112	73
31-35 y/o	117	76	114	74
36-40 y/o	120	80	116	77
41-45 y/o	124	81	122	78
46-50 y/o	128	82	128	79
51-55 y/o	134	84	134	80
56-60 y/o	137	84	139	82
61-65 y/o	148	86	145	83

The following table will indicate the blood pressure status represented by each blood pressure range:

Type	Systolic blood pressure	Diastolic blood pressure
Hypotension	Below 90	Below 60
Ideal blood pressure	About 120	About 80
Normal blood pressure	Below 130	Below 85
Normal hypertension	130-139	85-89
Borderline hypertension	140-149	90-94
Mild hypertension	140-159	90-99
Simple systolic hypertension	Over140	Below 90
Moderately hypertension	160-179	100-109
Highly hypertension	Over 180	Over110

However, many factors such as mood, exercise and temperature can affect blood pressure values. Therefore, a single blood pressure measurement cannot be used as a diagnostic result.

What is the normal blood glucose value?

Similarly, too high or too low blood sugar will also have adverse effects on the human body. Excessive blood glucose can cause disease in the patient's large blood vessels. These lesions include atherosclerosis in the basilar arteries, coronary arteries, aorta, renal arteries, and peripheral arteries. These patients tend to have severe atherosclerosis and high mortality. About 70 to 80% of diabetic patients die of diabetic macrovascular disease. In addition, hypoglycemia will also damage the patient's health. Hypoglycemia may lead to memory loss, slow reaction time, dementia, coma, and even death. Hypoglycemia may also induce arrhythmia and myocardial infarction in patients. People's blood glucose levels change as they eat, digest and absorb food. Therefore, fasting blood glucose and postprandial blood glucose are generally used as reference values. 

	Venous (whole blood)	Capillary	Venous (plasma)
Normal value - fasting	3.9 – 6.1
Normal values – 2hrs after meals	Below 7.8
Diabetics - fasting	Over 6.1	Over 6.1	Over 7.0
Diabetics - 2hrs after meals	Over 10	Over 11.1	Over 11.1
Impaired glucose tolerance - fasting	Below 6.1	Below 6.1	Below 7.0
Impaired glucose tolerance - 2hrs after meals	6.7 – 10.0	7.8 – 11.1	7.8 – 11.1
Impaired fasting glucose - fasting	5.6 – 6.1	5.6 – 6.1	6.1 – 7.0
Impaired fasting glucose - 2hrs after meals	Below 6.7	Below 7.8	Below 7.8

What is the normal blood lipid value?

Patients with hyperlipidemia will make the blood thicken. Blood becomes prone to deposits on the walls of blood vessels, gradually forming plaques. These plaques can gradually build up and grow and clog blood vessels. It slows or even blocks blood flow. However, blood lipid levels are not as low as possible. Some studies have pointed out that when the cholesterol level of the elderly over 70 years old is lower than 4.16mmol/L, their risk of acute cardiovascular and cerebrovascular events is similar to that of the elderly whose cholesterol level is higher than 6.24 mmol/L. The normal reference values of blood lipids are as follows:

Types	Normal values
Total Cholesterol	2.8 – 5.17 mmol/L
Triglycerides	0.56 – 1.7 mmol/L
High Density Lipoprotein (Male)	0.96 – 1.15 mmol/L
High Density Lipoprotein (Female)	0.90 – 1.55 mmol/L
Low Density Lipoprotein	0 – 3.1 mmol/L

What is the normal uric acid value?

Under a normal diet, hyperuricemia is clinically diagnosed when the blood uric acid value of males exceeds 420 μmol/L and that of females exceeds 360 μmol/L in two tests on different days. 

	The range of normal blood uric acid level
Male	237.9 – 420 μmol/L
Female	178.4 – 360 μmol/L

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