What Factors Affect a Sufficient Naloxone Dose?

Naloxone is a morphine receptor antagonist. It is not effective orally, and it works quickly by injection. Mainly used for opioid overdose poisoning or diagnosis of opioid addiction. It is also used to relieve respiratory depression and wake up after morphine compound anesthesia ^[1] .

Drug type: Essential medicines
Drug name: Naloxone

English name: Naloxone
Chinese alias: Allyl oxymorphone
English alias: Nalone; Narlan; Narcan

Introduction to Naloxone Compounds

Naloxone Basic Information

Chinese name: naloxone

Chinese alias: (5alpha) -3,14-dihydroxy-17-prop-2-en-1-yl-4,5-epoxymorphinan-6-one; Suno; allyl hydroxymorphone; acrylmorphine Ketone

English name: naloxone

English alias: Narcon; Narcanti; Nalone; [14C] -Naloxone; (4R, 4aS, 7aR, 12bS) -4a, 9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a, 13 -hexahydro-1H-4,12-methanobenzofuro [3,2-e] isoquinoline-7-one; (5) -4,5-Epoxy-3,14-dihydroxy-17- (2-propen-1-yl) morphinan-6-one; Narcan

CAS number: 465-65-6

Molecular formula: C ₁₉ H ₂₁ NO ₄

Molecular weight: 327.37400

Exact mass: 327.14700

PSA: 70.00000

LogP: 1.23930 ^[2]

Naloxone Regulatory Information

China

Morphine analogs

Naloxone physical and chemical properties

Appearance and properties: White to off-white powder. MP 177-178 ° C (184 ° C), soluble in chloroform, almost insoluble in ether. Its hydrochloride salt: white powder MP200-205 , soluble in water, dilute acid and strong base, slightly soluble in ethanol, almost insoluble in chloroform and ether, aqueous solution is L-type, aqueous solution is acidic, 8.07% aqueous solution is isotonic with plasma

Refractive index: -200 ° (C = 1, in chloroform)

Density: 1.43 g / cm ³

Melting point: 184ºC

Boiling point: 532.8ºC at 760 mmHg

Flash point: 276.1ºC

Stability: No particular hygroscopicity; oxidation; relatively stable with hot hydrochloric acid.

Storage conditions: Avoid strong light, avoid excessive moisture, expose to air, and store at 30ºC ^[2] .

Naloxone Pharmacopoeia Standard

[Identification] (1) Take about 2mg of this product, put it in a small test tube, add 3 to 4 drops of citric acid acetic anhydride test solution, and heat it in a water bath at 80 to 90 ° C for 35 minutes, which is purple. (2) Take about 1mg of this product, add 1ml of water to dissolve it, add 1 drop of dilute potassium ferricyanide test solution, it will be blue-green. (3) Dry to constant weight at 105 . The infrared absorption spectrum of this product should be consistent with the control spectrum (spectrum set 646). (4) Identification reaction of this product showing chloride (Appendix III).

[Inspection] Take about 0.30g of this product, weigh it accurately, add 30ml of methanol to dissolve, add 5ml of water and 6-7 drops of fluorescent yellow indicator solution, and titrate with silver nitrate titration solution (0.1mol / L) to the solution Shows pink. Each 1 ml of silver nitrate titration solution (0.1 mol / L) is equivalent to 3.545 mg of Cl. Based on the dry product, the chlorine content should be 9.54% to 9.94%. Relevant substances are taken from this product, accurately weighed, dissolved and quantitatively diluted by adding 0.1 mol / L hydrochloric acid solution to make a solution containing about 5 mg per 1 ml as a test solution; take (-)-4,5a-epoxy -3,14-dihydroxymorphinan-6-one reference substance (impurity I), an appropriate amount, accurately weighed, dissolved and quantitatively diluted by adding 0.1 mol / L hydrochloric acid solution to make a solution containing about 1 mg per 1 ml, as Reference solution; precisely measure 1 ml of the test solution and 5 ml of the reference solution, place them in the same 200 ml volumetric flask, dilute to the mark with 0.1 mol / L hydrochloric acid solution, shake well, and use it as the control solution. Also take an appropriate amount of naloxone hydrochloride reference solution, add 0.1 mol / L hydrochloric acid solution to dissolve and make a solution containing about 0.2mg per ml, take 10ml and place it in a 25ml measuring bottle, add 0.4ml ferric chloride solution 1ml, Heat in a water bath for 10 minutes, let cool, dilute to the mark with water, shake well, and use it as a system suitability test solution containing 2,2'-bisnaloxone (impurity II). Tested according to high performance liquid chromatography (Appendix VD). Use octylsilylpyrene bonded silica gel as the filler; use acetonitrile-tetrahydrofuran-5mmol / L sodium octane sulfonate solution (adjust the pH value to 2.0 with phosphoric acid) (20: 40: 940) as mobile phase A, and use acetonitrile- Tetrahydrofuran-5mmol / L sodium octane sulfonate solution (adjust the pH to 2.0 with phosphoric acid) (255: 60: 685) is mobile phase B, and gradient elution is performed according to the following table; the flow rate is 1.5ml per minute; the detection wavelength is 230 nm; column temperature was 40 ° C. 10 l of the system suitability test solution was injected into the liquid chromatograph, and the order of the peaks was naloxone hydrochloride and impurities , and the retention time of the naloxone hydrochloride peak was about 14 minutes. The resolution of the peak and the naloxone hydrochloride peak should be greater than 4.0. Adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 30% of full scale. Then, accurately measure 10 l of each of the control solution and the test solution, inject them into the liquid chromatograph, and record the chromatogram. If there is a peak in the chromatogram of the test solution consistent with the retention time of impurity I in the chromatogram of the control solution, its peak area must not be larger than the peak area of the impurity in the control solution (0.5%); The peak area of the chromatographic peaks with consistent retention time shall not be larger than the naloxone hydrochloride peak area (0.5%) in the control solution; the area of other single unknown impurities shall not be larger than the naloxone hydrochloride peak area (0.5%) in the control solution; each The sum of the areas of the impurity peaks should not be greater than two times (1.0%) the area of the naloxone hydrochloride peak in the control solution. Any peak in the test solution that is less than 0.05 times the area of the naloxone hydrochloride peak in the control solution can be ignored.

Loss on drying: Take 0.5g of this product, first dry at 90 ° C for 4 hours, and then dry to constant weight at 105 ° C. The weight loss shall not exceed 11.0% (Appendix L).

[Content determination] Take about 0.2g of this product, weigh it accurately, add 40ml of glacial acetic acid and 10ml of acetic anhydride to dissolve it with ultrasound, let it cool, use potentiometric titration (Appendix A), and use perchloric acid titration solution (0. lmol / L) titration, and the results of the titration were corrected with a blank test. Each 1 ml of perchloric acid titration solution (0.1 mol / L) is equivalent to 36.38 mg of C ₁₉ H ₂₁ NO ₄ · HC.

[Category] Morphine antagonists.

[Storage] shading and sealed.

Naloxone Drug Description

Naloxone Pharmacology

Naloxone is similar to morphine and is a specific opioid antagonist. Naloxone is an effective opioid antagonist, which works by competing with opioid receptors (in turn, , , ); it also has an agonistic effect, that is, an agonistic-antagonistic combination. Can relieve opioid overdose and persistent respiratory depression after surgery, and can also make a differential diagnosis for drug users.

Naloxone pharmacokinetics

Although naloxone can be absorbed after oral administration, due to extensive first-pass metabolism, its effect is only 1 / 100th that of intravenous administration. After 2 minutes of intravenous naloxone injection, the effect is obvious, and the maintenance effect is very short (30-60 minutes). Subcutaneous, intramuscular, sublingual or intratracheal administration is slightly later than intravenous. t1 / 2 is about 1h. Its apparent distribution volume is 2.77L / kg. Metabolic inactivation in the liver ^[1] .

Naloxone indication

Treat opioids and other narcotic analgesics (such as pethidine, alfalodine, methadone, fentanyl, dihydroetorphine, etoniqin, etc.) poisoning. Treatment of sedative hypnotics and acute alcoholism. Diagnosis of dependence on opioids and other narcotic analgesics.

Naloxone dosage

Due to different dosage forms and specifications, please read the drug instructions carefully or follow the doctor's advice.

Naloxone adverse reactions

Individual patients develop dry mouth, nausea and vomiting, anorexia, drowsiness or irritability, increased blood pressure and increased heart rate, and most can recover without treatment. However, it has been reported that individual patients can induce arrhythmias, pulmonary edema, and even myocardial infarction.

Naloxone contraindications

(1) Use with caution in patients with hypertension and cardiac dysfunction. (2) Medication Note: According to the specific situation and condition of the patient, an appropriate dose and speed of administration should be selected. Closely observe the patient's physical signs such as respiration, blood pressure and heart rate, and take corresponding measures in time. Addicts of opioids and other narcotic analgesics will immediately experience withdrawal symptoms when injecting this product, so pay attention to the dose.

Naloxone precautions

1. People who are physically dependent on opioids or who have already received large doses of opioids must be used with caution because they can trigger acute withdrawal syndrome.

2. It may also trigger withdrawal syndrome in newborn babies born to opioid-dependent mothers.

3. Patients with heart disease or patients who are receiving cardiotoxic drugs should use naloxone with caution.

4. Sometimes the duration of action of opioids will exceed the duration of naloxone. After administration, pay attention to observe whether the dose of naloxone should be supplemented.

5. Children's dosage must be strictly controlled ^[1] .

Naloxone Drug Interactions

1. Naloxone can antagonize the effects of opioids, including pentazocine.

2. Remove the respiratory depression after opioids.

3. Use the interaction between naloxone and a variety of addictive drugs to differentially diagnose addicts, such as those who are addicted, withdrawal symptoms will occur after using naloxone ^[1] .

Naloxone Expert Reviews

Naloxone poisoning

Naloxone has a similar chemical structure to morphine and is an opioid antagonist. Its mechanism is to block the effects of exogenous opioid receptor agonists and endogenous morphine-like substances, prevent or reverse the central inhibitory and anti-shock effects of respiratory depression caused by opioids. Mainly treats acute opioid poisoning, acute ethanol poisoning, sedative hypnotic poisoning, organophosphorus pesticide poisoning, antihistamine poisoning, carbon monoxide poisoning, septic shock, acute severe cerebral infarction, pulmonary encephalopathy, acute coma, neonatal asphyxia And hypoxic-ischemic encephalopathy. The drug has a rapid effect after intravenous injection, and lasts for 1 to 4 hours, and the plasma half-life is about 1 hour. Metabolized in the liver and excreted through the urine. The usual amount is 0.4 ~ 2mg each time, intramuscular injection, or intravenous injection and intravenous drip.

Clinical manifestation

1. Overdose can cause nausea and vomiting. Arrhythmia such as tremor, sweating, excessive ventilation, increased blood pressure, ventricular tachycardia, and ventricular fibrillation may occur when reversing morphine anesthesia.

2. Occasionally cough, dyspnea, foamy sputum and other pulmonary edema. Part of prothrombin time prolonged and bleeding phenomenon.

3. This drug can cause morphine withdrawal symptoms for opioid addicts.

treatment

The main points of treatment for naloxone poisoning are:

1. Poison responders immediately discontinued. Those with withdrawal symptoms should slow down the infusion rate or stop taking the drug.

2. Keep the airway open.

3. For patients with elevated blood pressure or pulmonary edema, antihypertensive agents and diuretics are given.

4. Symptomatic support ^[3] .

Naloxone

Injection: 1ml: 0.4mg, 1ml: 1mg, 2ml: 2mg; sterile powder for injection: 0.4mg, 1.0mg, 2.0mg ^[4-7]

Naloxone Naloxone Hydrochloride Injection

Common name: Naloxone Hydrochloride Injection

English name: Naloxone Hydrochloride Injection

The main ingredients and chemical name of this product are: 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate.

Molecular formula: C19H21NO4 · HCl · 2H2O

Molecular weight: 399.87

[Character]

This product is a colorless clear liquid.

[Pharmacology and Toxicology]

This product is a pure opioid receptor antagonist and has no intrinsic activity. But it can competitively antagonize various opioid receptors and has a strong affinity for receptors. Naloxone works quickly and has strong antagonistic effects. Naloxone simultaneously reverses all the effects of opioid agonists, including analgesia. In addition, it also has an estrogen effect that is not related to antagonizing opioid receptors. It can quickly reverse the respiratory depression caused by opioid analgesics, can cause high excitement, and increase cardiovascular function. This product still has anti-shock effect. Does not produce morphine-like dependence, withdrawal symptoms, and respiratory depression.

Acute toxicity LD50 (mg / kg): Mice, 565 orally.

Pharmacokinetics

This product is not effective orally and must be administered by injection. The maximum effect is 1 to 3 minutes after intravenous injection, which lasts 45 minutes; the maximum effect is 5 to 10 minutes after intramuscular injection, which lasts 2.5 to 3 hours. This product absorbs quickly, easily penetrates the blood-brain barrier, and has rapid metabolism. The T1 / 2 of human plasma is 30 to 78 minutes. It is mainly biotransformed in the liver, and the product is excreted with urine.

[Indications]

This product is currently the most widely used opioid receptor antagonist. Mainly used:

1. Rescue acute poisoning of narcotic analgesics, antagonize the respiratory depression of such drugs, and make patients awake.

2. Antagonistic Residual Effects of Narcotic Analgesics. Respiratory depression in newborns affected by narcotic analgesics in their mothers can be antagonized with this product.

3 Rescue acute alcoholism: Intravenous naloxone 0.4 0.6mg can make patients awake.

4 For suspected narcotic analgesics addicts, intravenous injection of 0.2 to 0.4 mg can stimulate withdrawal symptoms, which has diagnostic value.

5. Arousal effect, may activate the physiological arousal system through cholinergic effect to make patients awake, used for general anesthesia and anti-shock and some coma patients.

Dosage

Commonly used dose: 5 g / kg of naloxone, 15 g / kg intramuscularly after 15 min. Or first load: 1.5 ~ 3.5g / kg, maintained at 3g / kg · h.

Intramuscular injection or intravenous injection: 0.4 0.8mg each time. In the process of withdrawal from methadone, you can try a small dose of methadone (5-10mg per day), give 1.2mg of naloxone every half hour for several hours (3-6 hours), and then switch to naloxone and use it weekly Rejection can be achieved 3 times.

Adverse reactions

Adverse reactions to this product are rare, and occasionally drowsiness, nausea, vomiting, tachycardia, hypertension and irritability may occur.

Precautions

1. After using naloxone to antagonize high-dose narcotic analgesics, a high degree of excitement can be generated as the pain returns. It is manifested by increased blood pressure, increased heart rate, arrhythmia, and even pulmonary edema and ventricular fibrillation.

2. Due to the short duration of action of this drug, once the effect of the drug has disappeared, the patient can fall into lethargy and respiratory depression again. Care should be taken to maintain the efficacy of the medication.

3 Use with caution in patients with cardiac insufficiency and hypertension.

[Medication for pregnant and lactating women]

still uncertain.

medicine interactions