What Is Rimantadine?

Amantadine is the earliest antiviral drug used to suppress influenza viruses, and the United States approved it as a preventive drug in 1966 when the Asian pandemic became common. In 1976, it was confirmed as a therapeutic drug on the basis of preventive drugs. The efficacy and safety of the drug in adult patients have been widely recognized. However, the therapeutic dose is close to the dose that causes side effects. The dose and administration plan for elderly people and those with chronic heart and lung disease or kidney disease are difficult to determine, so it has not been promoted and applied in clinical practice. In Japan, amantadine has been used as a treatment for Parkinson's disease, and was not approved for the treatment of influenza virus A infectious diseases until 1998.

Chinese name: Amantadine
Foreign name: Amantadine
Alias: Tricyclodecylamine

Full name: Amantadine
Molecular formula: C10H17N
Molecular weight: 151.25

Introduction of Amantadine Compounds

Amantadine Basic Information

Chinese name: Amantadine

Amantadine structural formula ^[1]

English name: Amantadine

Chinese aliases: tricyclodecylamine, tricyclocapranylamine, amantadine hydrochloride

English aliases: Adamantanamine, Amantan, Amazolon, Antadine, Contenton, L-Adamantanamide Hydrochlori, L-Adamantanamine, Mantadan, Mantadine, Mantadix, Protexin, Solu-Contenton, Symmetrel, Trivaline, Virofral, Virosol

Physical and chemical properties of amantadine

Molecular formula: C ₁₀ H ₁₇ N

Molecular weight: 151.25

Exact mass: 151.13600

PSA: 26.02000

LogP: 2.61420

Melting point: 206-208 ° C

Boiling point: 225.7 ° C (standard atmospheric pressure)

Flash point: 96 ° C

Relative density: 1.066g / cm ³

Refractive index: 1.557

Solubility: easily soluble in organic solvents, insoluble in water.

Color: white to light yellow powder or lump.

Storage temperature: Store in a cool, dry place. Keep container tightly closed.

Amantadine Safety Information

WGK Germany: 3

Danger category code: R22; R36 / 37/38

Safety instructions: S26-S36

RTECS number: YD1925000

Dangerous goods sign: Xi ^[2]

Amantadine production method

Derived from the reaction of amantadine with urea after bromination. The process is as follows: Adamantane is added to a dry glass-lined reaction tank, bromine is added dropwise, the temperature is slowly raised, and the temperature is raised from 50 ° C to 65-75 ° C within 1 hour, and the reaction is refluxed for 6 hours. Material changes, the boiling point of the material gradually increases). After the reaction, it was left overnight. Then it was raised to 45 ° C, a 7% sodium bisulfite solution was added dropwise to remove excess bromine, filtered, and the filter cake was washed with water to pH = 7, and naturally dried to obtain bromoadamantane. The bromoadamantane and urea were mixed uniformly, heated to 180 ° C, the reaction started, and the internal temperature rose sharply to 230-240 ° C. After the reaction, the temperature was naturally lowered, and concentrated hydrochloric acid was added to dissolve it, transferred to a distillation tank, sodium hydroxide was added to alkalize, and then steam distillation was performed to obtain amantadine ^[2] .

Amantadine uses

Antivirals are also antitremor paralytics. It is used in the manufacture of synthetic amantadine derivatives, amantadine hydrochloride, etc. ^[2] .

Amantadine Drug Description

Amantadine pharmacological action

The mechanism of treatment of Parkinson's disease is unclear. It may be related to the effect of amantadine on the release of dopamine (DA) from dopaminergic nerve endings in the striatum, and the effect of dopamine and catecholamine on the central nervous system, increasing the dopamine content in neurons. Animal experiments have also shown that dopamine release in the brain of animals is increased after the use of amantadine. Amantadine is also an antiviral drug against RNA viruses, and its mechanism of action is not completely clear. Prevents RNA viruses from penetrating host cells. If the virus has penetrated the host cell, it can also prevent the virus from unshelling and releasing nucleic acids, interfering with the early replication of the virus. In addition, the virus channel on the host cell membrane can be blocked to prevent the virus from penetrating into human cells. In tissue culture, amantadine can prevent infection by myxoviruses and paramyxoviruses, and is also effective against rhabdoviruses in vitro. However, it is only clinically effective against influenza A virus. Although all the latest natural influenza A viruses are sensitive to amantadine, resistance mutations have been observed in tissue cultured strains exposed to amantadine. Its resistance mechanism is RNA mutation. Clinically, amantadine has no effect against influenza B virus and parainfluenza virus. It has a relief effect on all types of Parkinson's disease, and the effect is stronger than anticholinergic drugs but weaker than levodopa. It is effective 2 weeks after taking, and lasts 4-8 weeks. Amantadine has inhibitory activity on influenza A virus in Asia, inhibits virus proliferation, and is effective for patients who have already developed the disease. It can also reduce the body temperature within 24 hours and significantly reduce symptoms within 36 hours. Inactive against Asian influenza B virus, measles virus, mumps virus and herpes simplex virus ^[3] .

Amantadine pharmacokinetics

It is absorbed quickly and completely in the gastrointestinal tract, and is distributed in saliva and nasal secretions after absorption. The content in animal tissues, especially the lungs, is higher than that in serum. This product can pass through the placenta and blood-brain barrier. Those with normal renal function had a half-life of 11 to 15 hours, and those with renal failure had 24 hours. Patients with long-term dialysis can reach 7 to 10 days. The blood drug concentration peaked at about 2 to 4 hours after oral administration, which was about 0.3 g / ml; the daily drug users could reach steady state concentration within 2 to 3 days, and the steady state blood drug concentration was 0.2 to 0.9 g / ml. Excreted mainly by the kidneys. More than 90% are excreted in the urine through the glomerular filtration, and some of them can be passively reabsorbed; the excretion rate in acidic urine can be rapidly increased; a small amount is excreted by milk. For hemodialysis patients, only a small amount (about 4%) can be cleared from the blood.

Amantadine indications

Applicable to primary Parkinson's disease, Parkinson's syndrome after encephalitis, drug-induced extrapyramidal reactions, Parkinson's syndrome after carbon monoxide poisoning, and Parkinson's syndrome in the elderly with cerebral arteriosclerosis. It can also be used to prevent or treat respiratory infections caused by Asian A-II influenza virus. When combined with inactivated influenza A virus vaccine, this product can promote the body to produce preventive antibodies.

Dosage of Amantadine

1. Oral antitremoral paralysis, commonly used in adults: 100mg once, 1 or 2 times a day, the maximum daily amount is 400mg. Renal dysfunction should be reduced. Not for children.

Amantadine Aminopyrine Tablets 2. Oral antiviral, commonly used for adults: 200mg once a day, or 100mg once every 12 hours, the maximum amount is 200mg daily. For renal dysfunction, the dose should be reduced.

Commonly used in children: not used for newborns and infants within 1 year of age; 1.5 to 3 mg / kg of body weight every 8 hours for children 1 to 9 years old or 2.2 to 4.4 mg / kg of body weight every 12 hours, there are also recommended for every 12 hours Use 1.5mg / kg for body weight; the maximum daily amount should not exceed 150mg; children 9 to 12 years old, 100mg orally every 12 hours; children 12 years old or older, generally the same amount as adults.

Amantadine overdose

Because there is no special antidote for amantadine overdose, the overdose can only be used as symptomatic and supportive therapy. Supportive therapies include immediate gastric lavage, vomiting, a large amount of fluid and diuresis, acidification of urine to increase the excretion rate of the product, and monitoring of blood pressure, pulse, respiration, body temperature, electrolytes, urine pH and discharge, and catheterization when necessary; And observe if there is excessive movement, convulsions, arrhythmia and hypotension, etc., give sedatives, anticonvulsants, antiarrhythmic drugs, and add other drugs if necessary. To control the symptoms of central nervous system poisoning, you can slowly inject venomine. Adults give 1-2mg every 1 to 2 hours; children give 0.5 mg every 5 to 10 minutes. The maximum dose can even reach 2 mg per hour.

Amantadine banned with caution

(1) This product can pass through the placenta. In animal experiments, it has been found that when rats use 50mg / kg per day (12 times the amount commonly used by humans), it is toxic to embryos and can cause teratogenesis. Pregnant women should use it with caution.

(2) This product can be excreted by breast milk. It is contraindicated in lactating women.

(3) The following conditions should be used with caution: those with cerebrovascular disease or history; history of recurrent eczema-like rash; peripheral edema; congestive heart failure; mental illness or severe neurosis; renal function Obstacles; those with a history of epilepsy, this product can increase seizures.

Amantadine adverse reactions

(1) The more common adverse reactions are: hallucinations; mental disorders, especially in elderly patients, may be caused by anticholinergic effects; emotional or other mental changes, generally due to stimulation or poisoning of the central nervous system.

(2) The relatively rare adverse reactions are: dysuria, which is caused by anticholinergic effects, mostly in the elderly; syncope, often secondary to orthostatic hypotension.

(3) Rarely rare adverse reactions; vague language or uncontrollable eyeball rolling, which are usually manifested by excessive excitement or poisoning of the central nervous system; pharyngitis and fever may be due to leukopenia and / or neutrality Caused by leukopenia.

(4) Persistent or relatively stubborn hard-to-disappear adverse reactions include: inability to concentrate, dizziness or dizziness, irritability, loss of appetite, nausea, nervousness, purple-red mesh spots on the skin or mesh spots, sleep disorders Or nightmares (stimulation or poisoning of the central nervous system) are common; blurred vision, constipation, dry mouth, nose, and throat, headaches, rashes, frequent fatigue or weakness, and vomiting are rare or rare.

(5) In long-term treatment, common adverse reactions are: swelling of the feet or lower limbs, unexplained shortness of breath, and rapid weight gain. The latter may be caused by congestive heart failure.

(6) The manifestation of overdose poisoning: convulsions, when used 4 times the usual amount; severe emotional or other mental changes, severe sleep disorders or nightmares.

Dizziness, drowsiness, depression, loss of appetite, four skin plaques, ankle edema, hallucinations and delirium, mental disorders or disorders in elderly patients, and congestive heart failure in individual cases. Can cause kidney damage.

Originally, this drug was an antiviral drug, which promotes the release of dopamine from nerve endings and reduces dopamine uptake. 100 to 200 mg per day is well tolerated, but its potency is not as good as levodopa. The two drugs are combined and the effects are additive. Adverse effects of this medicine are nausea, psychotic episodes (mania, hallucinations, agitation, insanity), unsteady calf movements, and convulsions. If the dose is above 200 mg, the risk of these occurrences is increased. Ankle edema is common. Reticulum occurs in about 90% of patients and is common in women. Whether edema or reticular plaques appear, they indicate severe systemic changes. This medicine has mild cardiotoxic effects. Mild adverse reactions are similar to anticholinergic drugs, such as blindness, dry mouth, insomnia, drowsiness, and rash, and photosensitivity is rare.

Amantadine Drug Interactions

1. Amantadine has antipyretic effect. When combined with a variety of anti-inflammatory drugs and antibacterial drugs, the effect is better than that of antibacterial drugs alone.

2. Other anti-parkinsonian drugs, antihistamines, phenothiazine or tricyclic antidepressants combined with amantadine can enhance the anticholinergic effect, especially for patients with mental disorders, hallucinations and nightmares. obvious. The amount of these drugs or amantadine needs to be adjusted when combined.

3. When combined with central nervous stimulants, it can enhance the central nervous system's excitatory effect. In severe cases, it can cause adverse reactions such as convulsions or arrhythmias.

4. In combination with ampicillin, the renal clearance of amantadine is reduced, and the incidence of poisoning reactions is increased. If the two drugs must be used in combination, the toxicity of amantadine should be monitored.

5. Belladonna and amantadine have anticholinergic effects, and when used in combination, they can produce excessive anticholinergic effects.

6. The combination of compound Xinnuoming and amantadine can cause both of them to decrease in the amount of renal tubular secretion, so it can increase central toxicity, symptoms such as insomnia, insanity and so on.

7. Areca nut has a pseudocholine effect, and when used in combination with amantadine, the choline and anticholinergic effects of the two are mutually antagonistic, resulting in a reduction in the effects of the two.

8. Bromperidide can fight the pharmacological effects of amantadine, so it will reduce the efficacy of amantadine.

9. In theory, Carfagen can counteract the dopamine effect of amantadine and reduce the efficacy of amantadine.

10. Zotepine can antagonize the pharmacological effects of amantadine by blocking dopamine receptors.

11. In combination with acetaminophen, the pharmacokinetic parameters of both are not affected, so the combination of the two does not need to adjust the dose.

12. No significant interaction was observed between pramipexole and amantadine.

13. Amantadine should not be used with ethanol, which will strengthen the central adverse reactions, symptoms such as dizziness, syncope, insanity and circulation disorders.

14. Amantadine is not affected by food, so it can be taken on an empty stomach or with food.

15. Combined application with adrenocortical hormone should be cautious.

Precautions for Amantadine

1. (1) People with a history of cerebrovascular disease or history; (2) People with a history of recurrent eczema-like rash; (3) Patients with peripheral edema; (4) Patients with congestive heart failure; (5) Mental illness or severe nerves (6) patients with renal dysfunction; (7) patients with a history of epilepsy; (8) patients with liver disease.

2. The effects of drugs on the elderly: elderly patients have low tolerance and may have hallucinations and delirium.

3. The effects of drugs on pregnancy: Amantadine can pass through the placenta. Animal experiments have found that when rats use 50 mg / kg per day (12 times the amount commonly used by humans), they are toxic to embryos and can cause teratogenesis. Other data reported that the use of amantadine by pregnant women in the first 3 months of pregnancy may affect the cardiovascular of the fetus.

4. Check and monitor before, after and during the medication: (1) Because the amount of amantadine in the body is very small, it is mainly excreted in the urine in the original form. Those with renal dysfunction may easily cause accumulation poisoning, so their blood should be monitored. Drug concentration. The blood drug concentration should not exceed 1.5-2.0 g / ml; (2) Those who exceed 200 mg per day should be closely observed to prevent adverse reactions or poisoning. Pay attention to monitoring blood pressure, pulse, breathing, and temperature, especially within a few days after increasing the dose.

5. Do not drive or operate the machine after taking the medicine.

6. It is generally believed that taking the drug once or twice a day can eliminate or reduce adverse reactions such as dizziness, insomnia and nausea. Some data suggest that when the daily dosage of Parkinson's disease exceeds 200 mg, the efficacy does not increase, but the toxicity gradually increases.

7. The last medication should be taken before 4 pm every day to avoid causing insomnia.

8. For patients with renal dysfunction, patients with congestive heart failure, patients with peripheral edema, patients with orthostatic hypotension, or the elderly who have reduced renal clearance, the amount of amantadine should be reduced or discontinued as appropriate.

9. Large doses (0.3g per day) can cause insomnia, headaches, hallucinations, speech insufficiency, nervousness, dyskinesias, nausea, vomiting, abdominal pain, diarrhea, constipation, dry mouth, rash, etc.

10. Excessive poisoning can manifest as severe emotional or other mental changes, severe sleep disorders or nightmares. When the amount is 4 times the usual amount, convulsions may occur.

11. Overdose treatment: Because there is no special antidote for overdose of amantadine, it can only be used as symptomatic and supportive treatment. Supportive therapies include immediate gastric lavage, vomiting, massive fluid rehydration, and acidification of urine to increase the excretion rate of amantadine, while monitoring blood pressure, pulse, breathing, body temperature, electrolytes, urine pH, and excretion, and catheterization when necessary. Observe for excessive movements, convulsions, arrhythmia, and hypotension. Give sedatives, anticonvulsants, and antiarrhythmic drugs as needed, and add other drugs if necessary. To control the symptoms of central nervous system poisoning, venosine can be slowly injected intravenously. Adults are given 1 to 2 mg every 1 to 2 hours, and children are given 0.5 mg every 5 to 10 minutes. The maximum dose is 2 mg per hour.

12. Do not stop the medicine suddenly after taking the medicine, otherwise the condition of Parkinson's disease will be worsened. It should be gradually reduced when stopping the medicine.

13. It is not advisable to drink alcohol during treatment, and those who are addicted to alcohol are easily drunk ^[3] .

Amantadine poisoning

After the amantadine (tricyclodecanamine, amantadine) enters the brain tissue, it can promote the release of dopamine from nerve endings and reduce the uptake of dopamine to play an anti-tremor paralysis effect; in addition, it has anticholinergic properties. It has obvious curative effect on tremor and paralysis, and has good effect in alleviating tremor and rigidity. Onset of action is relatively fast, obvious after 48 hours. The half-life in vivo is 10 to 28 hours, the distribution volume is 4 to 8 L / kg, and the protein binding rate is 60% to 70%. Its clearance in vivo depends entirely on renal function. In elderly patients with renal insufficiency, treatment volume poisoning can occur. Poisoning can occur when the level of serum amantadine is> 1.5 mg / L. This medicine has therapeutic effect on Asian A ~ influenza virus and has certain antipyretic effect. The common amount of anti-tremor paralysis is 0.lg, 1 2 / d, and the maximum amount is 0.2g, 2 / d. The blood concentration should be controlled below 1.5 2.0 g / ml. When it is used for tremor paralysis, it is more than 200mg / d, it does not increase the curative effect, and the toxicity is gradually increasing. The antiviral dose was 0.1 g, 2 / d, and the maximum dose was 400 mg / d.

Clinical manifestation

1. Frequently used adverse reactions are rare. A few patients have drowsiness, dizziness, depression, nausea, and loss of appetite after oral administration. Reticulum and ankle edema may appear on the skin of the limbs. Edema and reticulum suggest severe systemic changes. Rarely, speech ambiguity, blurred vision, involuntary nystagmus, decreased white blood cells and granulocytes, and rashes are common.

2. Poisoning occurs at 4 times the oral dose, and clinical manifestations of convulsions, severe emotional or mental changes, severe sleep disturbances and nightmares, and anticholinergic symptoms can occur: dry mouth, dilated pupils, and urine retention. Ventricular arrhythmias are rare, such as torsional ventricular tachycardia.

3. Patients may develop fever and tonic seizures within a few days after treatment or after acute overdose.

4. Elderly people have low tolerance to amantadine, and may have hallucinations, delirium, difficulty urinating, and syncope secondary to orthostatic hypotension.

diagnosis

The main points of diagnosis of amantadine poisoning are:

1. Have a history of taking or mistaking amantadine, the above clinical manifestations.

2. Eliminate the possibility of poisoning by other drugs.

treatment

The main points of treatment for amantadine poisoning are:

1. There is no specific antidote for amantadine poisoning, mainly symptomatic supportive treatment.

2. Those who take too much, immediately wash the stomach, induce vomiting, swallow medicinal charcoal. Extensive fluid replacement and acidification of urine.

3. Too much action to give sedatives, convulsions to stop spasm, arrhythmia commonly used antiarrhythmic drugs.

4. Patients with high fever should urgently cool down, and at the same time apply dantroline 1 ~ 2mg / kg, fast intravenous injection, once every 5 ~ 10min, the total amount is 10mg / kg, 4 / d for a total of 2 ~ 3 days. If it occurs during the removal of amantadine, amantadine can also be used as a therapeutic drug.

5. To control the central nervous system symptoms, venosine can be slowly injected intravenously for adults 1 to 2 mg / (l to 2) h.

6. Poisoned persons with renal function must undergo hemodialysis or hemoperfusion ^[4] .

Amantadine Expert Review

Amantadine is an antiviral drug. It was later discovered that it can treat tremor paralysis, but the effect is worse than levodopa, and the long-term effect has not been confirmed. Generally, the effect gradually weakens after 4-8 weeks of treatment, and it can be up to 1 year. Some people think that Can be used again after stopping the medicine for a period of time. The tremor paralysis that has not been treated before is effective at the initial stage and has a synergistic effect with anticholinergic drugs; it can be used as an adjuvant for levodopa and is effective for patients who cannot tolerate large doses of levodopa or fluctuating in efficacy, and has already received levodopa Patients who have achieved results with dopa treatment cannot increase their efficacy. Amantadine can be used in Asian patients with influenza A-III and fever with viral infection. The protection rate for this type of influenza contacts is about 70%. The antipyretic effect of a combination of antibiotics on various inflammations, sepsis and viral pneumonia is better than antibiotics alone. It still has anti-tremor paralysis effect, and has good curative effect on various types of Parkinson's disease. Amantadine is effective for less movement and posture disorders, and is suitable for mild patients. Quick effect, but short maintenance time, can be used in combination with dopamine inhibitors to maintain efficacy or intermittent application. It has obvious curative effect on tremor and paralysis, and the curative effect is better than anticholinergic drugs ^[3] .