What is the difference between azivudine, monogravir and nematvir/ritonavir?💫💫💫

Azivudine, monogravir and nematvir/ritonavir are all clinical drugs used to treat the new coronavirus. What's the difference between them? 

What is the anti-coronavirus mechanism?

The new coronavirus is composed of RNA and protein. The raw material for RNA synthesis is cytosine nucleoside. Azivudine and monogravir are cytosine nucleoside analogs. They will synthesize poor RNA with the new coronavirus and inhibit the replication of the virus. Nematvir is a peptidomimetic substance. It will prevent the virus from synthesizing functional proteins by inhibiting 3C-like protease, and the replication of the virus will be inhibited. Although ritonavir has no effect against the new coronavirus, it will inhibit the elimination of nematvir and enhance its effect.

What are the properties of azivudine, monogravir and nematvir/ritonavir?

Due to their different chemical structures, they have different adverse reactions and metabolic processes in the body. 

Bone and Cartilage Toxicity: In trials, rats were repeatedly dosed with monogravir, which caused toxicity to the bones and cartilage of rats. Therefore, monogravir may affect bone and cartilage development in children.

Dosage in Patients with Hepatic or Renal Impairment: Monolavir is not eliminated primarily through the liver or kidneys, so no dose adjustment is required in patients with hepatic or renal impairment.

Drug interactions:

• Azivudine: Caution is required when combined with amiodarone, colchicine, dabigatran, digoxin, dronedarone, voriconazole, grapefruit juice, etc.
• Monolavir: Due to limited available data, no drug interactions have been found.
• Nematvir/ritonavir: These interact with many medicines.

What are the treatment differences between azivudine, monogravir, and nematvir/ritonavir?

Azivudine: It is mainly used to treat adult patients with characteristic pneumonia manifestations of new coronavirus infection visible on imaging (moderate infection). It is not intended for use in pregnant or breastfeeding women. If Azivudine is used, breastfeeding should be discontinued during treatment and for 4 days after treatment.

Monolavir: It is indicated for the treatment of adult patients with mild or moderate infections within five days of onset and who are at high risk for progression to severe disease. It has fetal toxicity similar to that of azivudine. If monogravir is used, breastfeeding should be discontinued during treatment and for 4 days after the end of treatment.

Nematrevir/ritonavir: Same indications as monogravir. However, it may still be used when the potential benefit to the mother outweighs the potential risk to the fetus. If nematvir/ritonavir is used, breastfeeding should be discontinued during treatment and for 7 days after the end of treatment.

What are the dosages of azivudine, monogravir, and nematvir/ritonavir?

Azivudine: If taken after meals, its absorption rate and total amount will be increased. Changes in drug concentration in the blood will also increase, thereby increasing the risk of adverse reactions. Its recommended usage is to take it orally once on an empty stomach before going to bed, 5mg each time (generally each tablet is 1mg, 5 pills taken orally each time), and the course of treatment should not exceed 14 days.

Monolavir: Take on an empty stomach or with food, once every 12 hours, 0.8g each time (usually 0.2g per tablet, 4 tablets taken orally each time) for 5 consecutive days.

Nematrevir/ritonavir: Take on an empty stomach or with food, once every 12 hours, 300 mg of nematvir (each tablet is 150 mg, 2 tablets taken orally each time) and 100 mg of ritonavir ( Each tablet is 100mg, 1 tablet taken orally at a time), taken continuously for 5 days.

What are the adverse reactions of azivudine, monogravir, and nematvir/ritonavir?

Azivudine: Common adverse reactions include diarrhea, increased transaminases, increased breathing, and occasionally increased the level of blood glucose. It may cause moderate to severe damage to the liver, so patients with moderate to severe liver damage should use it with caution.

Monolavir: Common adverse reactions include diarrhea, nausea, dizziness, and occasionally rash and urticaria.

Nematrevir/ritonavir: Common adverse reactions include diarrhea and taste problems, and occasionally elevated transaminases. It may cause severe liver damage and is therefore contraindicated in patients with severe hepatic impairment.

Additionally, they can affect fertility. Therefore, it recommends the use of effective contraception during and for 4 days after treatment with azivudine and monogravir, and the use of effective contraception during and for 7 days after treatment with nematvir/ritonavir.

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What is the difference between acetaminophen and ibuprofen?👀👀👀

Acetaminophen and ibuprofen are very commonly used antipyretic and
analgesic drugs in clinical practice. However, their chemical structure, intensity of action and adverse reactions will differ. Will there be any difference in clinical use?

Difference in effectiveness of acetaminophen and ibuprofen.

The analgesic and antipyretic effect of ibuprofen is slightly stronger than that of acetaminophen, and its duration is also longer (ibuprofen <183 minutes, acetaminophen <134 minutes). However, ibuprofen takes a slightly slower onset of action. Patients will experience a more significant decrease in body temperature within 30 minutes of taking acetaminophen than ibuprofen. Both of them can be used to treat headaches, migraines, toothaches, muscle pain, dysmenorrhea (ibuprofen is more effective), and osteoarthritis (ibuprofen is more effective). However, acute attacks of gout and rheumatoid arthritis can only be treated with ibuprofen. Neither of them can be used to treat abdominal pain. In terms of effectiveness alone, ibuprofen is superior to acetaminophen.

Comparison of the safety of acetaminophen and ibuprofen.

Acetaminophen: Excessive doses of acetaminophen can cause life-threatening liver failure. Patients who are dehydrated or malnourished also have an increased risk of liver damage. It is less damaging to the gastrointestinal tract. It is contraindicated in patients with viral hepatitis and favismia. It should be used with caution in patients with renal insufficiency, active peptic ulcer, or aspirin allergy. Acetaminophen may also be used during pregnancy and in patients with severe heart failure.

Ibuprofen: It can cause irreversible damage to the kidneys. Overdose or use while dehydrated may increase a patient's risk of kidney damage. It also increases the risk of myocardial infarction and cerebral infarction. Although it can also cause gastrointestinal bleeding, ulceration, and perforation, the risk is lower than other NSAIDs. Ibuprofen is contraindicated in patients with renal insufficiency, active peptic ulcer, severe heart failure, pregnancy, and aspirin allergy. However, it can be used in patients with viral hepatitis and favismia.

Precautions when using acetaminophen and ibuprofen.

Acetaminophen: It can be used in children older than 3 months and can be taken before meals. The maximum daily dose for children is 15 mg/kg and for adults it is 2 g/day, once every 4 to 6 hours, and should not be taken more than 4 times a day. Alcohol and other hepatotoxic drugs can worsen liver damage when combined with acetaminophen. Acetaminophen is occasionally used concomitantly with coumarin anticoagulants without significant effects.

Ibuprofen: It can be used in children older than 6 months, with or after meals. The maximum daily dose for children is 10mg/kg and for adults it is 1.2g/day, once every 6 to 8 hours, and should not be taken more than 4 times a day. When ibuprofen is combined with alcohol, it can aggravate gastrointestinal damage. When used together with antihypertensive drugs, it will also reduce the antihypertensive effect. It may also reduce the effectiveness of low-dose aspirin in preventing cardiovascular disease and stroke. Other nephrotoxic drugs may worsen kidney damage when used with ibuprofen. When anticoagulant drugs such as heparin and dicoumarol are used together with it, it will prolong the prothrombin time and increase the risk of bleeding.

Conclusion.

For children, the elderly over 60 years old, and patients with multiple underlying diseases (except those with liver dysfunction), it is recommended to use acetaminophen first.

For patients who require long-term medication and those with arthritis, it is recommended to give priority to ibuprofen (because acetaminophen has no anti-inflammatory effect).

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When should lipid-lowering drugs be taken?⌚⌚⌚

Dyslipidemia generally refers to elevated levels of cholesterol and/or
triglycerides (TG) in the blood. It is also called hyperlipidemia. At the same time, it also includes various dyslipidemias including low high-density lipoprotein cholesterol (HDL-C). The main clinical lipid-lowering drugs currently include cholesterol absorption inhibitors, HMG-CoA inhibitors (statins), fibrates, anti-lipid peroxidation drugs (probucol), niacin drugs, and PCSK9 inhibitors. , bile acid chelators, high-purity fish oil preparations and other lipid-lowering drugs, etc.

Lipid-lowering drugs can generally be divided into three categories.

1. Drugs that mainly lower cholesterol: Such drugs include statins, cholesterol absorption inhibitors, probucol, bile acid chelators. They reduce cholesterol levels by inhibiting cholesterol synthesis in liver cells, accelerating low-density lipoprotein cholesterol (LDL-C) catabolism, or reducing intestinal cholesterol absorption.
2. Drugs mainly aimed at lowering triglycerides: These drugs include fibrates, niacin and high-purity fish oil preparations. They can lower blood levels of triglycerides in patients.
3. PCSK9-inhibitors: such as evolocumab. It prevents the degradation of LDL-receptors by inhibiting PCSK9, thereby promoting the body's clearance of LDL-C. It reduces blood levels of LDL-C and has a powerful cholesterol-lowering effect.
4. Microsomal triglyceride transfer protein inhibitors: such as lomitapide. It lowers blood levels of LDL-C.
5. Apolipoprotein B-100 synthesis inhibitors: such as mipomexan. It reduces the production and secretion of VLDL. At the same time, it will also reduce the blood level of LDL-C.

The timing of taking lipid-lowering medications.

Drugs that mainly lower cholesterol:

1. Statins: Lovastatin, simvastatin, pravastatin, fluvastatin (tablets) and other statins with short half-lives are recommended to be taken before going to bed. While cholesterol will reach its synthesis peak at night, these drugs will also reach their concentration peak. Statins with long half-lives such as fluvastatin (sustained-release preparation), atorvastatin, rosuvastatin, and pitavastatin can be taken at any time, but it is recommended that patients take them at the same time every day to avoid missing doses. 
2. Cholesterol absorption inhibitors: such as ezetimibe. It inhibits the intestinal absorption of cholesterol. Statins will have a good synergistic effect when combined with it. At the same time, it will not affect the absorption of other drugs and fat-soluble vitamins. Food will not affect its absorption. Therefore, it is generally taken once daily, with or without food.
3. Probucol: It is mainly suitable for hypercholesterolemia. It will enter the core of LDL and affect lipoprotein metabolism. LDL becomes easily eliminated through non-receptor pathways. It can also reduce xanthomas on the skin. Food increases its absorption, so patients are advised to take it with a meal. Generally, it needs to be taken twice a day, with breakfast and dinner.

Drugs mainly aimed at lowering triglycerides: 

1. Fibrates: such as bezafibrate, fenofibrate, gemfibrozil. Bezafibrate generally needs to be taken with or after meals. To reduce stomach upset caused by fenofibrate, it is recommended to take it with food. Gemfibrozil is generally taken twice daily, and it is recommended to take it 30 minutes before breakfast and dinner. Additionally, when they are combined with statins, it is recommended to take fibrates in the morning and statins at bedtime. This reduces the occurrence of drug interactions.
2. Niacin drugs: This type of drugs includes acipimox and niacin extended-release tablets. The usual dose of acipimox is two or three times a day, taken with or after meals. Acipimox dispersible tablets need to be taken after meals. The usual dose of niacin extended-release tablets is once daily, taken before bed.

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Basic knowledge about febuxostat.📃📃📃

Febuxostat is a xanthine oxidase inhibitor. It inhibits the production of uric acid. While allopurinol can only inhibit the reduced form of xanthine oxidase, febuxostat can inhibit both the reduced and oxidized forms of xanthine oxidase. Therefore, febuxostat's ability to lower uric acid is faster and stronger. 80% of blood uric acid is synthesized in the body, and only 20% is absorbed from food. Patients with gout need to control their blood uric acid within the target range (<360 μmol/mL) throughout their lives to reduce the frequency of gout attacks, prevent tophi formation, prevent bone destruction, and reduce the risk of death. Therefore, they may need to take long-term uric acid-lowering medications.

What are the indications for Febuxostat?

Allopurinol, febuxostat, and benzbromarone are recommended for patients with gout. However, febuxostat is not recommended for use in asymptomatic hyperuricemia. In patients with asymptomatic hyperuricemia in stages 3 and 4 chronic kidney disease, the dose of allopurinol needs to be adjusted and severe hypersensitivity reactions may occur. Therefore, febuxostat may be a better treatment. Febuxostat is indicated for the long-term treatment of hyperuricemia in patients with gout. However, it is not recommended for use in patients with asymptomatic hyperuricemia. Febuxostat has little effect on renal function. No dose adjustment is required in patients with renal insufficiency.

When should uric acid-lowering drugs be used?

Some guidelines recommend that patients with gout can start uric acid-lowering drug treatment after the acute gout attack is completely relieved for 2 to 4 weeks. This is because urate-lowering medications can worsen the symptoms of gouty arthritis. However, if gout attacks are frequent, uric acid-lowering medication can be started at the time of the gout attack. Therefore, they should not be used until the symptoms of acute inflammation of gouty arthritis have resolved. In addition, allopurinol is generally recommended as the first-choice uric acid-lowering drug, but HLA-B*5801 genotype monitoring should be performed before use. Allopurinol is contraindicated in patients with positive HLA-B*5801 genotype.

What is the dosage of Febuxostat?

Common tablet doses of febuxostat are 20mg, 40 mg and 80 mg. The recommended starting dose of febuxostat is 20 mg daily. Patients whose serum uric acid levels do not reach the target value after 2 to 4 weeks of treatment can be increased to 40 mg per day, with a maximum dose of 80 mg per day. Febuxostat tablets can usually be taken in split doses without affecting the effectiveness of the medicine. Its uric acid-lowering effect is not affected by food. 

What are the adverse effects of Febuxostat?

Common adverse reactions generally refer to adverse reactions that occur in at least 1% of patients and are at least 0.5% higher than those in the placebo group. Abnormal liver function, arthralgia, nausea, and rash are common adverse reactions of febuxostat. Abnormal liver function is the most common adverse reaction causing patients to discontinue febuxostat treatment. Therefore, patients should undergo a liver function test before doctors prescribe febuxostat. In addition, if patients experience fatigue, loss of appetite, right upper quadrant discomfort, soy sauce-colored urine or jaundice during the medication period, they should seek medical treatment in time.

Side effect	Placebo group	Allopurinol	Febuxostat
			40 mg/day	80 mg/day
Abnormal liver function	0.7%	4.2%	6.6%	4.6%
Arthralgia	0%	0.7%	1.1%	0.7%
Nausea	0.7%	0.8%	1.1%	1.3%
Rash	0.7%	1.6%	0.5%	1.6%

Febuxostat is more likely to increase the risk of cardiovascular death in patients with gout than allopurinol. Therefore, febuxostat should be used with caution in elderly patients with gout and cardiovascular and cerebrovascular diseases. Allopurinol is the first-line treatment for gout patients with severe cardiovascular disease (such as myocardial infarction, history of stroke, unstable angina). During the medication period, patients should seek medical attention immediately if they develop symptoms such as chest pain, shortness of breath, fast or irregular heartbeat, numbness or weakness on one side of the body, dizziness, difficulty speaking, or sudden severe headache.

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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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