What are the indications, dosage and precautions of warfarin?💊💊💊

More and more new oral anticoagulants are being developed. As an older oral anticoagulant, warfarin has disadvantages such as large individual dose variability, narrow therapeutic window, interactions with many drugs and foods, and the need for drug monitoring in patients when used. Warfarin has so many disadvantages. Should it be eliminated from anticoagulation? Although there are many new anticoagulant drugs, it does not mean that warfarin can be completely replaced. Warfarin still plays an important role in anticoagulation therapy. 

What kind of medicine is warfarin?

Warfarin is an anticoagulant drug derived from dicoumarin. Vitamin K epoxide reductase is inhibited by warfarin. This will limit the synthesis of coagulation factors II, VII, IX, and X to produce anticoagulant effects. In addition, some anticoagulant proteins are also inhibited by warfarin. Therefore, patients may experience transient procoagulant effects during the initial period of treatment with warfarin. Its clinical manifestations are gangrene of the limbs and skin necrosis. They generally appear on the third to eighth day after dosing.

What are the indications for warfarin?

It can be used to prevent and treat pulmonary embolism and deep vein thrombosis. It also prevents thromboembolic complications following myocardial infarction, atrial fibrillation, heart valve disease, or prosthetic valve replacement. For patients with mechanical valve replacement, moderate to severe mitral stenosis, or bioprosthetic valve replacement in the first 3 months, warfarin is an irreplaceable alternative to other novel oral anticoagulants.

Dosage of warfarin.

The starting dose of warfarin is generally recommended to be 1 to 3 mg once daily. Certain patients with congestive heart failure, high risk of bleeding, impaired hepatic function, or the elderly require individual dose adjustment. Their starting dose can be reduced as appropriate. Rapid anticoagulation is required for diseases such as venous thromboembolism. Patients need to use unfractionated heparin or low molecular weight heparin overlapping with warfarin for 5 to 7 days. Patients were given warfarin immediately on day 1 or day 2 of heparin. Adjust the drug dose until the INR reaches the target value for more than 2 days before discontinuing parenteral anticoagulants. 

Indications	INR target range	Course of treatment
Venous embolism	2.5 (Range 2 to 3)	Patients secondary to transient risk factors require 3 months of use. Patients with unprovoked venous embolism need to use it for at least 3 months. After 3 months, the risk-benefit ratio of the patient's treatment was evaluated before deciding whether to extend the course of treatment. Long-term treatment is required for patients with two unprovoked venous embolisms, and the risk-benefit ratio of treatment is regularly assessed.
Myocardial infarction prognosis	2 to 3	For patients at high risk of myocardial infarction, combined use of low-dose aspirin is recommended for at least 3 months. (Daily take ≤100mg aspirin)
Atrial fibrillation (non-valvular and valvular)	2 to 3	It recommends long-term anticoagulation in patients at intermediate and high risk of stroke. Nonvalvular atrial fibrillation: Warfarin is not the drug of choice for these patients. The treatment plan needs to be determined based on the evaluation. Valvular atrial fibrillation: Warfarin is the drug of choice for these patients. Most new oral anticoagulants are contraindicated in patients with atrial fibrillation complicated by moderate-to-severe mitral stenosis, mechanical valve replacement, or bioprosthetic replacement (the first 3 months).
Mechanical valve replacement	The INR range needs to be adjusted appropriately according to the valve type and location, and it is generally 2 to 3.	Lifelong treatment.
Bioprosthetic replacement	2 to 3	It is generally 3 to 6 months. After 3 months of treatment, patients can be switched to new oral anticoagulant drugs or discontinued according to the situation.

Pharmaceutical monitoring of warfarin.

Efficacy monitoring:

INR (International Normalized Ratio) and PT (Prothrombin Time) are its main monitoring items. INR can evaluate its anticoagulation strength, and the general target range of INR is 2 to 3. 

Adverse reaction monitoring:

The main adverse reaction of warfarin is bleeding. Although a patient's risk of embolism increases with increased bleeding risk, the benefit of anticoagulation is generally greater. Therefore, bleeding should not be considered a contraindication to anticoagulation. Reversible factors that increase their bleeding risk should be screened for and corrected for in patients who require anticoagulation but are at greater risk of bleeding. They should also strengthen their monitoring and conduct regular evaluations. 

Compliance Monitoring:

Compliance monitoring is mainly to monitor whether the patient takes the medicine on time and according to the dose, and whether there is any self-adjustment of the dose.

Instructions for dosing warfarin.

Dosing time: Warfarin is recommended to be taken at a fixed time in the evening. It is mainly due to the fact that pharmaceutical monitoring is generally performed during the day. When patients take warfarin at night, the dose can be adjusted immediately based on monitoring results.

Dosage: After the patient's INR reaches the target and is stable, frequent dose adjustments are not required. However, the patient should record each dose adjustment and the next monitoring time.

Precautions while taking the medicine:

1. Missed dose: The patient should make up the dose immediately unless it is close to the next dose. A single dose should not be doubled in the event of a missed dose.
2. Diet: In the past, patients were told to avoid foods containing vitamin K as much as possible. However, more and more studies have pointed out that as long as the daily diet structure is relatively stable and do not suddenly consume large amounts of foods containing vitamin K, the efficacy of warfarin will not cause much impact.
3. Self-monitoring: Patients should monitor themselves for signs of bleeding or embolism.
4. Pregnancy and lactation: Warin is generally not recommended for patients during pregnancy. Low molecular weight heparin is preferred for pregnant patients. Patients can continue to use warfarin while breastfeeding because it does not pass into breast milk.

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What diseases can vitamin B6 be used for?😵😵😵

In 1926, it was discovered that a lack of a vitamin in mice's diet caused them to induce pellagra. In 1934, a doctor discovered an ingredient that had therapeutic effects on dermatitis in mice and named it vitamin B6. It wasn't until around 1938-1939 that vitamin B6 could be isolated and synthesized. It is a water-soluble vitamin. Pyridoxamine, pyridoxal, and pyridoxine are the three forms of vitamin B6 found in food. The three of them can be transformed into each other. Since pyridoxine is photosensitizing, it gradually breaks down when exposed to light. There are many foods that contain vitamin B6. Meat, whole grain products (especially wheat), nuts and vegetables are rich in vitamin B6.

Pharmacological mechanism of action of vitamin B6.

Vitamin B6 is converted to pyridoxal phosphate in red blood cells. It is a coenzyme and plays a role in the synthesis or metabolism of some neuromediators, nucleic acids, DNA, vitamin B2, vitamin B12, lipids and proteins. In addition, it is also involved in the conversion of homocysteine to methionine. It also plays a role in the metabolism of sphingomyelin, steroids and glycogen.

Clinical application of vitamin B6.

1. Dermatology.

In dermatology, the clinical application of vitamin B6 is very extensive. When the human body lacks vitamin B6, seborrheic-like damage will appear in the eyes, nose and corners of the mouth. Patients also have stomatitis, glossitis, eczema or acne. Therefore, vitamin B6 is often used in the treatment of alopecia areata, androgenetic alopecia, acne, cheilitis, stomatitis, folliculitis, seborrheic dermatitis, and the like. Vitamin B6 is also used as adjunctive therapy for lupus erythematosus and vitiligo.

2. Neurology.

Peripheral neuritis is the clinical manifestation of vitamin B6 deficiency in the nervous system. It is accompanied by tenderness and swelling of synovial fluid (especially in the wrist). Convulsions, restlessness, excitement and vomiting are also clinical manifestations of vitamin B6 deficiency. Therefore, vitamin B6 is used in the adjuvant treatment of autism, epilepsy, drug-induced neuritis, peripheral neuritis, facial neuritis, cognitive impairment, tic disorder, tardive dyskinesia, hand-foot syndrome, and limb numbness. In addition, studies have pointed out that increasing the intake of vitamin B6 in the daily diet can help reduce the incidence of Parkinson's disease. This is because brain cells can be protected from damage by harmful substances such as free radicals by vitamin B6.

3. Gynecology.

For vomiting of pregnancy, vitamin B6 can play a role in reducing. The FDA approved the combined use of 75mg of vitamin B6, 12ug of vitamin B12, 1mg of folic acid, and 200mg of calcium to treat nausea and vomiting during pregnancy. Although efficacy is unclear, 50 to 100 mg of vitamin B6 daily can be used for premenstrual syndrome. However, daily use of more than 100 mg of vitamin B6 has not been shown to provide additional benefits and may also increase the risk of adverse effects. In addition, because vitamin B6 can pass through the placenta of pregnant women, if a woman takes a large amount of vitamin B6 during pregnancy, it can cause vitamin B6 dependence syndrome in newborns.

4. Cardiology.

Patients are at increased risk of dementia and stroke due to hyperhomocysteinemia. The use of 50 to 200 mg of vitamin B6 daily alone or in combination with 100 mg of vitamin B6, 1 mg of folic acid, and 1500 μg of vitamin B12 daily can reduce the level of hyperhomocysteinemia. However, long-term daily use of more than 1 mg of folic acid may increase the risk of cancers such as prostate and colorectal cancer.

5. Urology.

The most common type of urinary stones are calcium oxalate stones. Because vitamin B6 can reduce the production of oxalic acid, it can be used clinically for the prevention and treatment of urinary calculi.

6. Oncology.

Studies have pointed out that a lack of vitamin B6 may increase the risk of cancer. Although not confirmed by research, some experts believe that increasing the intake of vitamin B6 in the daily diet can reduce the risk of cancers such as esophageal, breast, stomach, pancreatic and colorectal cancers. In addition, high-dose vitamin B6 is also commonly used clinically to prevent hand-foot syndrome caused by capecitabine (an antineoplastic drug).

7. Other.

Neonatal hereditary vitamin B6-dependent syndrome, hereditary sideroblastic anemia, leukopenia, vascular restenosis, primary urinary hyperoxalate, metabolic disorders (eg, homocystinuria and cystathione) etheruria), anti-tremor paralysis, cerebral dysfunction syndrome, etc. can also use vitamin B6 as adjuvant therapy.

Adverse effects of vitamin B6.

Peripheral neuropathy such as limb numbness is the main adverse reaction of long-term or high-dose vitamin B6. It is manifested by an unsteady gait. Patients first experience numbness in the feet, then numbness in the hands, followed by severe impairment of vibration and distal position sensation in the extremities. It generally has less effect on pain, touch and temperature. Symptoms generally disappear when vitamin B6 is stopped. However, some patients on high doses of vitamin B6 experience irreversible symptoms. The patient's own disease and the adverse reactions of vitamin B6 are easily confused. Clinical use of vitamin B6 (especially when used in high doses) should closely monitor patients. Drowsiness, headache, nausea, and paresthesia are also common adverse effects of vitamin B6. In severe cases, it can also damage the function of organs. Anaphylactic shock may also occur in patients with intravenous use. In general, regular doses of vitamin B6 are relatively safe. However, long-term or high-dose use should pay attention to the occurrence of adverse reactions.

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How to use nebulized medicine?💫💫💫

One of the important ways of treating respiratory diseases is aerosol inhalation therapy. One of the important means of treating respiratory diseases is aerosol inhalation therapy. Therefore, it is very important to understand the correct usage of nebulized drugs.

The process of inhaling a drug in the body.

Compared with administration methods such as injection or oral administration, the biggest advantage of aerosol inhalation administration is that the drug can be directly sent to the airway or lungs for local treatment. This advantage can make the drug less systemic adverse effects. The particle size of the aerosol inhalation drug is preferably 1 to 5 μm. If the particle size is larger than 5 μm, most of the drug will stay in the oropharynx and be swallowed into the body. If the particle size is less than 0.5 μm, although the drug can enter the alveoli and bronchioles, most of the drug will be excreted by exhalation.

Medication treatment of nebulized drugs.

Commonly used nebulized inhaled drugs are short-acting β-agonists (such as albuterol), short-acting anticholinergic drugs (such as ipratropium bromide), inhaled glucocorticoids (such as budesonide) and expectorants (such as ambroxol). 

Disease	Short-acting β-agonists	Short-acting anticholinergic drugs	Inhaled glucocorticoids	Expectorants
Acute exacerbation of bronchial asthma.	✔	Use when necessary.	✔	✖
Long-term control of bronchial asthma.	Use when necessary.	✖	✔	✖
Cough variant asthma.	✖	✖	✔	✖
Variant cough.	✖	✖	✔	✖
Eosinophilic bronchitis.	✖	✖	✔	Use when necessary.
Asthmatic bronchitis.	✔	Use when necessary.	✔	✖
Acute laryngotracheobronchitis.	✖	✖	✔	✖
Bronchiolitis obliterans.	Use when necessary.	Use when necessary.	✔	✔
Bronchiolitis.	✔	Use when necessary.	✔	✖
Pneumonia.	Use when necessary.	Use when necessary.	✖	✔
Acute epiglottitis.	✖	✖	✔	✖
Pertussis or pertussis-like syndrome.	Use when necessary.	Use when necessary.	✔	✖
Bronchopulmonary dysplasia.	✖	✔	✔	✖
Bronchiectasis.	Use when necessary.	Use when necessary.	✔	✔
Endotracheal intubation or throat surgery.	✖	✖	✔	✖
Cough after infection.	Use when necessary.	✖	✔	✖

 Commonly used nebulized drugs and their adverse reactions.

The nebulized drugs stay on the surface of the airway mucosa for a short time and have a short half-life in the blood, but have a long residence time in the local tissue.

1. Short-acting β-agonists: Commonly used drugs are salbutamol and terbutaline. Their common adverse reactions were headache, tremor and tachycardia.
2. Short-acting anticholinergic drugs: Commonly used drugs are ipratropium. Its common adverse reactions are headache, dizziness, dry mouth and vomiting.
3. Inhaled glucocorticoids: Commonly used drugs are beclomethasone dipropionate, fluticasone propionate and budesonide. Their common adverse reactions are pharyngitis, hoarseness and oropharyngeal candidiasis.
4. Expectorants: Commonly used drugs are acetylcysteine and ambroxol. Their common adverse reactions are stomatitis, oral numbness (ambroxol), disturbance of taste, nausea and vomiting.

What is the difference between inhaled glucocorticoids?

Commonly used drugs are beclomethasone dipropionate, fluticasone propionate and budesonide. Inhaled glucocorticoids have two mechanisms of action. The first is the genetic pathway. Their lipid solubility allows them to enter cells, where they bind to cytoplasmic receptors and then enter the nucleus. Once in the nucleus, they initiate gene transcription. It promotes anti-inflammatory protein synthesis and inhibits pro-inflammatory protein synthesis. They develop an anti-inflammatory effect after about a few hours. The second is the non-genetic pathway. They bind to hormone receptors on cell membranes. Cell energy metabolism and lysosomes are affected by it. They act as anti-inflammatory within minutes.

1. Beclomethasone dipropionate: It is the only prodrug of the three glucocorticoids. Its elimination half-life is approximately 0.5 hours. It has the highest rates of oropharyngeal candida infections and pharyngitis of the three.
2. Fluticasone propionate: It has better receptor affinity. Its stagnation time in the lungs is the shortest of the three. Its elimination half-life is approximately 8 hours. In addition, its inhibitory effect on the adrenal cortex is the strongest of the three.
3. Budesonide: It has the best hydrophilicity. Its stagnation time in the lungs is the longest of the three. Its elimination half-life is approximately 3 hours.

What is the combined use of nebulized drugs?

Short-acting β-agonist and inhaled glucocorticoid act synergistically, so they are the most commonly used combination. Short-acting β-agonist and short-acting anticholinergic drug are also more commonly used in combination.

1. Dual therapy: Short-acting β-agonist + short-acting anticholinergic drug, inhaled glucocorticoid + short-acting anticholinergic drug, acetylcysteine + short-acting β-agonist/short-acting anticholinergic drug/inhaled glucocorticoid.
2. Triple therapy: Short-acting β-agonist + short-acting anticholinergic drug + inhaled glucocorticoid, short-acting β-agonist/short-acting anticholinergic drug + inhaled glucocorticoid + acetylcysteine.
3. Quadruple Therapy: Short-acting β-agonist + short-acting anticholinergic drug + inhaled glucocorticoid + acetylcysteine.

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What is the difference between piperacillin combined with tazobactam and cefoperazone combined with sulbactam?📣📣📣

Due to the extensive use of antibiotics, bacterial resistance to antibiotics continues to rise. The most common pathogens of bacterial infectious diseases are caused by Gram-negative bacteria. The mechanism of resistance in Gram-negative bacteria is mainly the generation of different β-lactamases, such as penicillinase, cephalosporinase, carbapenemase and extended-spectrum β-lactamases (ESBLs). Most β-lactamases produced by bacteria are inactivated by binding to β-lactamase inhibitors. β-lactamase inhibitors can prevent the β-lactam ring in antibiotics from being hydrolyzed, thereby protecting the antibacterial effect of β-lactam antibiotics. In the combination of β-lactamase inhibitor and antibiotics, piperacillin combined with tazobactam and cefoperazone combined with sulbactam are drugs with high clinical use and good efficacy. However, what are the differences between them and how should choose them?

Comparison of antibacterial spectrum of piperacillin combined with tazobactam and cefoperazone combined with sulbactam.

	Piperacillin/tazobactam	Cefoperazone/sulbactamzxad
Acinetobacter	+	+++
Enterobacter	++	+++
Enterococcus	+	-
Escherichia coli	++++	++++
Haemophilus influenzae	+++	+++
Klebsiella	+++	++++
Methicillin-sensitive Staphylococcus aureus	+	+
Moraxella catarrhalis	+	+
Pseudomonas aeruginosa	++++	+++
Stenotrophomonas maltophilia	-	+++
Streptococcus	+	+
"-" means no effect. "+" means it works. The more "+" the table has, the stronger the effect.

Can they treat gram-positive infections?

In general, piperacillin combined with tazobactam and cefoperazone combined with sulbactam will not be used to treat pure gram-positive infections. Although cefoperazone combined with sulbactam may be effective against enterococci (eg, Streptococcus faecalis), cefoperazone combined with sulbactam is generally considered to be ineffective against enterococci. Ampicillin in combination with sulbactam and amoxicillin in combination with clavulanic acid are commonly used drugs for the treatment of gram-positive infections. They have a certain antibacterial ability against methicillin-sensitive staphylococcus aureus, enterococcus and streptococcus.

How effective are they in the treatment of bacterial infections that produce extended-spectrum β-lactamases?

In the in vitro drug susceptibility test, their sensitivity were over 80% to the ESBLs-producing strains. For patients with mild to moderate infection without secondary severe sepsis or septic shock, one of them can be selected according to the results of drug susceptibility testing. However, they are not the first choice for patients with severe infections. Carbapenems are the most effective and reliable drugs for the treatment of various infections caused by enterobacteriaceae that produce extended-spectrum β-lactamases. Studies have shown that the high-dose extended infusion regimen of piperacillin/tazobactam can achieve the best pharmacodynamics, but any regimen of cefoperazone/sulbactam can not achieve the desired pharmacodynamics . Therefore, piperacillin combined with tazobactam is more suitable for the empirical treatment of extended-spectrum β-lactamase-producing bacterial infections.

How effective are they in the treatment of stenotrophomonas maltophilia infections?

Patients with more severe infections generally require combination therapy. Usually, sulfamethoxazole-trimethoprim or tigecycline or quinolones are used as the basic drugs in combination with sensitive β-lactamase inhibitor complexes, usually cefoperazone/sulbactam is more commonly used.

How effective are they in the treatment of acinetobacter baumannii infections?

Piperacillin combined with tazobactam and cefoperazone combined with sulbactam both have potential antimicrobial activity. According to drug susceptibility testing, they can be used to treat acinetobacter baumannii infection. However, sulbactam has strong antibacterial activity against Acinetobacter spp. The combination of cefoperazone and it has synergistic antibacterial activity, and their susceptibility is higher than that of piperacillin/tazobactam. 

How effective are they in the treatment of pseudomonas aeruginosa infections?

Although they have antibacterial activity, some studies indicate that piperacillin/tazobactam is slightly more sensitive than cefoperazone/sulbactam. Although they have antibacterial activity, some studies indicate that piperacillin/tazobactam is slightly more sensitive than cefoperazone/sulbactam. Both of them can be used to treat patients with non-multidrug-resistant pseudomonas aeruginosa infections or with milder disease. Patients with multidrug-resistant pseudomonas aeruginosa infection or severe disease require combination with fluoroquinolone or aminoglycoside antibiotics.

How effective are they in the treatment of anaerobic bacteria infections?

Piperacillin/tazobactam is effective against most anaerobic infections. Cefoperazone/sulbactam is effective against infections such as Preobacterium melanogenum, Peptococcus, Peptococcus, Clostridium, Fusobacterium, Bacteroides, Eubacterium, and Lactobacillus.

What are their clinical applications?

Pneumonia:

• Community-acquired pneumonia: Patients who are hospitalized and have underlying diseases or are older than 65 years old, have high risk factors for Pseudomonas aeruginosa infection, or need to be admitted to the ICU can choose piperacillin/tazobactam or cefoperazone//sulbactam.
• Hospital-acquired pneumonia: They are not the first choice for patients with mild to moderate disease and no risk factors for drug resistance. As long as there are risk factors for multidrug resistance, patients with mild to moderate or severe disease need to be combined with other antibiotics.
• Structural lung disease: For patients with high risk factors for Pseudomonas aeruginosa infection, choose one of them. Depending on the patient's condition, monotherapy or in combination with other antibiotics may be used.
• Aspiration pneumonia: Neither of them would be the drug of choice for patients without high-risk factors for drug-resistant bacteria. Patients with community-acquired pneumonia and with inhalation factors should be treated according to the principles of hospital-acquired pneumonia and need to be covered with anaerobic bacteria.

Blood Infections:

For neutropenic, immunocompromised, and severe systemic infections, treatment should be empirical coverage of multidrug-resistant Gram-negative bacilli. β-lactamase inhibitor complexes are the preferred treatment option, and then the treatment can be adjusted based on the test results.

Abdominal infection:

Patients with mild or moderate infection: Combination of third-generation cephalosporins with metronidazole or β-lactamase inhibitor.

Severe infection in patients: β-lactamase inhibitor combination preparations or carbapenems are recommended as the drugs of choice.

Urinary tract infection:

Hospitalized and Severely Infected: When a patient has a pseudomonas aeruginosa infection, they can use either one and usually require a combination of other medications.

Complicated urinary tract infection: Hospitalization is required in patients with severe infection and/or suspected bacteremia. Piperacillin/tazobactam can be used for empirical antimicrobial therapy. Aminoglycosides can be combined if necessary, and treatment can then be adjusted based on bacterial susceptibility testing.

Fever with agranulocytosis:

High-risk patients should be treated with broad-spectrum antibiotics that cover Pseudomonas aeruginosa and other Gram-negative bacteria. Piperacillin combined with tazobactam and cefoperazone combined with sulbactam are both optional.

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