Parkinson’s disease, also known as Shaking Palsy. The main clinical manifestations of PD are static tremor, increased muscle tone, slow movement and postural disorders, etc. It is a common disease among middle-aged and elderly people. At the end of the 20th century, there were about 100,000 PD patients in the U.S.; it is estimated that there are about 5 million PD patients in China. Epidemiologic surveys have found that about 1/3 (34) of the elderly over 65 years of age have some manifestations of PD or other Parkinson’s syndromes. Pathology has confirmed that the damage is mainly in the substantia nigra compacta (SNc) and is dopaminergic neuronal degeneration. Although there have been many advances in the treatment of PD by surgical procedures (including brain tissue destruction, intracerebral tissue and cell transplantation, etc.), the vast majority of patients with PD are still treated with drugs. 1.Anticholinergic drugs work by correcting the imbalance of DA and acetylcholine through anticholinergic effect. The improvement rates of muscle tonus, hypokinesia and tremor are 38, 28 and 20 respectively. Commonly used drugs: Antan tablets: 2mg, 2~3 times/d; Kaimajun: 2.5mg, 3 times/d, which can be gradually increased to 20mg/d. Benztropine: it has the effects of anticholinergics, antihistamines and muscle relaxation, which can significantly reduce tonus, 2mg/time, 3 times/d. Main side effects: dry mouth, constipation, urinary difficulties, Blurred vision; prohibited for prostate hypertrophy or glaucoma; due to the inhibition of central acetylcholine, can make memory and cognitive function decline, should not be used for >70 years old. 2, dopaminergic enhancers Amantadine anti-PD mechanism of action is not yet very clear. Amantadine in the brain to promote presynaptic nerve endings DA release or delay the reabsorption of DA back into the nerve endings, can increase the concentration of DA between the prominence, thus enhancing the nigrostriatal region of the DAergic effect. There may also be anticholinergic activity. Initially ameliorates tremor and movement reduction in about 2/3 of cases. Oral administration is effective for 48h, with a half-life of 10-28.5 hours, and reduces symptoms.43 About 86 is excreted in the urine in its original form. MAIN SIDE EFFECTS: Side effects include ankle edema, reticular cyanosis, and psychiatric symptoms (hallucinations and hallucinations are common). Synergistic with Antan, ineffective in patients with advanced disease. High doses may aggravate congestive heart failure, use with caution in renal dysfunction. Dose 0.1g, 2 times / d, the daily dose should not exceed 0.2g. 3, compound levodopa preparations ① Meidoba (SM): levodopa and hydroxybenzylhydrazine 4:1 mixture of tablets or capsules, (containing levodopa 200mg, hydroxybenzylhydrazine 50mg). Domestic content is the same as above. Medopar controlled-release capsules (MadoparHBS) contain levodopa 100mg and hydroxybenserazide 25mg. slow absorption, stable blood concentration, long maintenance time. MadoparDM contains 100mg of levodopa and 25mg of benserazide, which is water-soluble and diffusible, with fast onset of action and short duration of action. ② Sinemet tablets (Sinemet): there are two kinds of dosage forms: each tablet contains levodopa 200mg and methyldopa-hydrazine (Carbidopa) 50mg, i.e., 4:1; the other is 10:1, i.e., each tablet contains levodopa 250mg and methyldopa-hydrazine 25mg. ③ Sinemet CR tablets (Controlled release Sinemet): for the controlled-release preparation of Pacrine, made into a single tablet, which is a water-soluble diffusion type with fast onset of action and short duration of action. Controlled release Sinemet: It is the controlled release preparation of Parkin, which makes it a monolayer of molecular particles and is slowly absorbed layer by layer to achieve the purpose of controlled release. Its bioavailability is equivalent to 70% of non-controlled release tablets and should be dosed appropriately. Due to the controlled-release effect, the peak blood concentration is shifted back, the number of doses is reduced, and the blood concentration is relatively smooth, which can reduce gastrointestinal reactions and end-of-dose phenomenon and switch phenomenon. ④ Liposomal levodopa: High concentration of levodopa is loaded into monolayer liposome to achieve the purpose of slow release and maintaining smooth blood concentration. For those who have difficulty in taking drugs orally, levodopa ethyl ester can be used for subcutaneous or intramuscular injection. 4, DA receptor agonists There are five subtypes of dopamine receptors, with the striatum dominated by D1 and D2 receptors, while D3, D4, and D5 are found mainly in the limbic system and other dopaminergic channels.D1 receptors are associated with adenylyl cyclase, while D2 receptors are activated by DA agonists. Although the regulatory functions of D1 and D2 receptors in the striatum are not fully understood, the relationship between D2 receptors and Parkinson’s syndrome appears to be more important. In the brains of PD patients, striatal D1 receptors are reduced (downregulated) and D2 receptors are increased (upregulated). The lack of substantia nigra striata increases the indirectly mediated activity of D2, resulting in disinhibition of the inhibitory (GABA) striatal-pallidal channels to the inner thalamic nuclei (GPi), which are the main output nuclei of the basal ganglia.The increase in the activity of the Gpi in turn leads to the disinhibition of the inhibitory (GABA) striatal-pallidal channels further by the decrease in the direct D1-mediated activity, which produces disinhibition and the D2 receptor activity Enhancement. Advantages of applying DA receptor agonists: they can bypass degenerating neurons and directly stimulate dopamine receptors; they do not depend on the presence of endogenous dopamine and its synthetic enzymes, and are effective when applied alone prior to levodopa; their half-life is longer than that of levodopa in the striatum, which is helpful in overcoming symptomatic fluctuations; they do not produce free radicals or potentially toxic metabolites; and they do not compete for transporter traffic, either at the level of the intestines or at the level of the blood-brain barrier; Selective activation of receptors prolongs the effect of levodopa and delays the appearance of side effects; can be administered non-gastrointestinal. Unfavorable aspects of agonist application: Symptom control is inferior to levodopa when applied alone; receptor downregulation may be more pronounced; higher cost; adverse effects such as psychiatric symptoms, upright hypotension, peptic ulcer, erythematous limb pain, and pulmonary and retroperitoneal fibrosis occur in approximately 40-60 patients who apply DA receptor agonists. The application should start with a small dose and slowly increase the dose, and the maintenance dose should not be too large. Although some movement disorder specialists advocate the application of DA agonists early in the course of drug therapy, some believe that DA agonists should be used when the levodopa dose reaches 300-600 mg/d or when fluctuations in symptoms associated with levodopa occur. Commonly used DA agonists are as follows: 4.1, ergot derivatives: ① Bromocriptine (Bromocriptine): early clinical application, with antagonism of D1 receptors, agonism of D2 receptors. Each tablet 2.5mg, daily maintenance dose of 5mg ~ 10mg, divided into 3 times, more side effects. ②Xie Liang Xing (Pergolide Mesylate): It has agonistic effect on D1 and D2 receptors. Each tablet 50ug, 250ug, 1mg. daily maintenance dose of 150ug~750ug, daily extreme dose of 3mg, divided into 3 times. Gastrointestinal side effects are many, constipation is common. ③α-Dihydroergotryptophylaxis (Cripar): acts on D2, D3 receptors. Each tablet 5mg, 20mg, daily maintenance dose of 30 mg ~ 60mg, divided into 3 times. Compared with bromocriptine and lysergic acid urea, it has the same therapeutic effect but is better tolerated and has fewer side effects. Others: lysergic acid ethylurea (Lisuride), lergotrile masylate (Lergotrile masylate) and so on. 4.2, non-ergot synthetic agonists: ① propyl ergot (Tessuda, Piribedil, TrastalCR): action on D2, D3 receptors. Extended-release tablets of 50 mg, daily maintenance dose of 50 mg to 150 mg, divided into 3 doses. ② Pramipexole hydrochloride tablets (Pramipexole, Mirapex, Mirapex): acts on D2, D3 receptors. Its absolute bioavailability >90, Tmax is 2 hours, half-life 8~12 hours, about 90 in its original form through the kidney. Clearance is higher in males than in females by about 30, and half-life is prolonged (40) and clearance decreases (30) with increasing age, which is related to renal function and has little effect on hepatic function. Daily maintenance dose 1.5-4.5mg in 3 divided doses. Pay attention to side effects especially renal function. ③Ropinirole is also a non-ergot DA receptor agonist. 5, DA degradation enzyme inhibitors 5.1 Propynylamphetamine (Siguirine, Silegiline, Midol, L-Deprenyl, Jumex) Propynylamphetamine is a selective monoamine oxidase (MAO-B) inhibitor. MAO catalyzes the degradation of DA to homovanillic acid, and its inhibitors can prevent the degradation of DA; and to affect the release of DA or catabolism and the re-uptake of DA or its precursors. Propargylamine was synthesized by Hungary in 1961, with a plasma clearance half-life of about 40 h, urinary excretion of 52 in 24 h, and a total excretion rate of 84 in 72 h. After oxidative metabolism in the liver, it generates L-methamphetamine, L-amphetamine, and desmethylsilagiline. Initially used as an antidepressant, Birkmayer was first used in 1975 for PD treatment and was found to increase the efficacy of levodopa and decrease its dosage. Each tablet is 5mg, 5 mg/dose, once in the morning and once in the afternoon. The intensity of the ameliorative effect on myotonia, tremor, and hypomobility is not significantly selective. Good tolerance, occasional hallucinations, insomnia, hyperactivity, etc., disappear within 1 week after stopping the drug. 5.2, catechol oxygen methyltransferase (COMT) inhibitors Catechol oxygen methyltransferase (COMT) inhibitors are another way to block DA degradation. Tolcapone (Ro40-7592, Tolcapone, Tasmar) acts both inside and outside the brain with a half-life of 2 hours. It blocks the conversion of dopa to 3-O-methyldopa (3-OMD), and because 3-OMD competes with levodopa for entry into the brain, its reduction enhances its efficacy by increasing the entry of levodopa into the brain. Effective for PD with levodopa treatment of “end of dose efficacy loss”, “on – off” phenomenon. ② other COMT inhibitors Entacapone, Nitecapone can not pass the blood-brain barrier, only in the outside of the brain, PET studies show that it can inhibit the metabolism of plasma fluorodopa, and increase the uptake of fluorodopa in the striatum, therefore increasing the efficacy of levodopa. Clinical application has been found to be beneficial in overcoming the diminished efficacy of levodopa. Entocapone has passed the phase III clinical verification in China. 6, neuron protection therapy The drug treatment of PD has made great progress in the past twenty years, and some promising new therapeutic methods keep emerging. Although levodopa significantly improves symptoms, its mortality rate is relatively unchanged, and it is believed that levodopa therapy appears to have diminished drug efficiency, accelerating the degenerative progression of the disease. Although the etiology is related to genetic and environmental factors, recent studies have shown that abnormal proteins, oxygen free radicals, glutamate-mediated neurotoxicity, modulatory mechanisms, mitochondrial energy impairment, and nitric oxide (NO) overproduction are involved, providing theoretical rationale for the design of novel therapeutic regimens to slow disease progression. In order to achieve effective therapeutic outcomes, amelioration of disease progression and neuroprotective therapies must be administered early in the course of the disease, hence the importance of early diagnosis. As a result, primary care physicians are becoming increasingly important in neuroprotective treatment programs. Classical drugs such as amantadine, silymarin, and dopamine agonists show only mild neuroprotective effects. Animal studies have found that brain-derived nerve growth factor (BDNF) and basic fibroblast growth factor (bFGF) protect midbrain DA neurons from 6-hydroxydopa (6-OHDA) damage. A large number of promising therapeutic options are under development, including neuroprotective agents and factors that can rescue dopaminergic neurons. Glutamate receptor antagonists, vitamin E, etc. Adenosine A2A receptor inhibitors show significant neuroprotective effects in experimental PD models. (R)- [(N- propargyl- (3R) aminoindan- 5-yl) ethyl methyl carbamate] (TV3326), a novel cholinesterase and brain-selective monoamine I oxidase A/B (MAO) inhibitor, is a drug used for the treatment of extrapyramidal disorders (parkin- sonism)-related dementia and depression. In chronic treatment of mice, it attenuates MPTP-induced striatal dopamine havoc and prevents the reduction of striatal tyrosine hydroxylase activity.TV3326 primarily inhibits MAO-B in the striatum and hippocampus, and the degree of MAO-B inhibition correlates with the preventive effect of MPTP-induced dopamine havoc. Unlike that seen with other MAO-A and -B inhibitors after treatment, the restoration of the inhibition of striatal and hippocampal MAO-A and -B activity by TV3326 was nonfirst-order kinetics (FIRST-ORDER KINETICS), correlating with the amount of the metabolite of TV3326 that was produced that caused the inhibitory effect on the enzyme.TV3326’s inhibition of MAO-A and -B Inhibition of MAO-A and -B by TV3326 also caused significant increases in dopamine, norepinephrine, and serotonin in the striatum and hippocampus. 7, guiding the principle of medication and prognosis (1) It is necessary to treat each patient differently from the practical point of view. The principles of applying levodopa-based therapy are also applicable when guiding the application of other drugs, “fine water, not seeking full effect”, “slow and low”, that is, increase the dose of the drug should be slow and the dose should be small; “the smallest dose, the Best results”; dose titration and “individualization”. Low starting point, small dose. The usage and dosage recommended by a foreign journal or expert are not suitable for Chinese people, especially in the beginning, the starting point is often high and the dosage is large, which is difficult for patients to tolerate. It is a big trend to use small dosage, different angles of multi-kinds of combination drugs, which are effective and have fewer side effects. Let patients understand that the drugs used can only improve symptoms, not cure, to long-term use of drugs, side effects and contraindications of the drugs used, in order to seek cooperation between doctors and patients. (2) The prognosis of PD is related to the clinical type, and the prognosis is better for those with tremor as the main symptom; the prognosis is worse for those with hyperkinetic symptoms, the elderly and malignant PD. The emergence of movement disorders is related to the duration of the disease and the time of application of levodopa. about 2/3 of the patients become disabled within 10 years. reasonable drug treatment and nursing care can improve the quality of survival and delay the time of disability, but it cannot stop the neuronal degeneration and the progression of the disease. Causes of death: decubitus ulcers, sepsis (about 50%), heart failure (28%), pneumonia (14%), urinary tract infections (8%) and exhaustion failure. Take it easy Four scientists are traveling in a helicopter and halfway through the trip they realize that they are running low on fuel and must reduce the weight as much as possible, at least one of them has to jump or they will crash. They meet to discuss who will jump. Agricultural scientists, biologists, economists, and geologists are all important to the progress of the world. But someone has to make a sacrifice. Guess who jumps? The answer is the heaviest man. In fact, the pilot’s contribution to the world was the smallest, but no one suggested that he jump, but instead chose the heaviest man. This shows that in a specific situation a decision can only be made on the basis of the situation, not on how much he has contributed to the world before. The same applies to medication, which should be individualized according to the different conditions of different patients, rather than simply choosing the “best” medication, which is the most important thing.