Internal medicine treatment of Parkinson’s disease 1, PD early treatment PD early nigrostriatal-striatal system deposited DA neurons can be compensated for the increase in DA synthesis, the recommended use of physical therapy (massage, hydrotherapy) and physical therapy (joint activity, walking, balance and language exercises, facial expression muscle drills), etc., and strive for the cooperation of the patient’s family members, to encourage the patient to take more initiative to exercise, and try to delay the time of drug treatment. If the disease affects the patient’s daily life and work, drug treatment is required. 2, drug therapy PD is still mainly drug therapy, restore the balance of striatal DA and Ach transmitter system, apply anticholinergic and improve the function of DA transmitter drugs, improve symptoms, can not stop the development of the disease. Principles of drug use: ① Start with a small dose, slowly increase, try to use a small dose to achieve satisfactory results. ② Individualization of the treatment program, according to the patient’s age, type and degree of symptoms, employment, drug prices and affordability and other choice of drugs. ③ Should not blindly add drugs, should not suddenly stop taking drugs, need to be taken for life. (iv) PD drug therapy is complex, in recent years the introduction of adjuvant drugs DR agonists, MAO-B inhibitors, catechol-oxygen-site-methyltransferase (COMT), etc., combined with compound dopa can enhance the efficacy of the treatment, reduce the fluctuation of symptoms, reduce the dosage of compound dopa, the use of the efficacy of the treatment is not ideal alone, the advantages and disadvantages of the treatment should be weighed and the choice of the appropriate combination of medications. (1) Anticholinergic drugs: effective for tremor and tonicity, less effective for bradykinesia, suitable for patients with obvious tremor and younger age. Commonly used andan (artane) 1 ~ 2 mg orally, 3 times / d, kemadrin (kemadrin) 2.5 mg orally, 3 times / d, gradually increased to 20 ~ 30 mg / d. Others, such as benzyltropine (cogentin), cyclopentylpropanol (cycrimine), and anklespasm (akineton), etc., the role is similar to that of andan. Side effects include dry mouth, blurred vision, constipation and difficulty urinating, and in severe cases, hallucinations and delusions. It is contraindicated in patients with glaucoma and prostate hypertrophy, and can affect memory function, and should be used with caution in elderly patients. (2) amantadine: to promote the release of DA in the nerve endings, prevent reuptake, and has an anticholinergic effect, is a glutamate antagonist, may have a neuroprotective effect, can be a mild improvement in hypomobility, tonicity and tremor, etc., the early stage of can be used alone or in combination with amantadine. Starting dose 50mg, 2-3 times/d, 1 week later increased to 100mg, 2-3 times/d, usually not more than 300mg/d, the elderly not more than 200mg/d. Efficacy can be maintained for several months to 1 year. Side effects are rare, such as restlessness, blurred consciousness, reticular cyanosis of the lower limbs, ankle edema and cardiac arrhythmia, etc. Use with caution in patients with renal insufficiency, epilepsy, severe gastric ulcers and hepatic disease, and is contraindicated in lactating women. Its derivative memantine hydrochloride can also be used. (3) Levodopa (L-dopa) and compound levodopa: L-dopa is an effective drug or gold index for the treatment of PD. As a precursor of DA, it can cross the blood-brain barrier and be decarboxylated into DA after being taken up by brain DA-ergic neurons, which improves the symptoms and has a special curative effect on hyperkinesia. Since more than 95% of L-dopa is decarboxylated into DA in the periphery, and only about 1% enters the brain through the BBB, in order to reduce the peripheral side effects and enhance the therapeutic efficacy, L-dopa is mostly used in the compound preparation made of L-dopa and peripheral dopa decarboxylase inhibitor (DCI) according to the ratio of 4:1, and the dosage is reduced by 3/4 compared with that of L-dopa. The dosage forms of compound L-dopa include the standard tablets, controlled release tablets, water-soluble tablets and so on, Controlled release tablets, water-soluble tablets, etc. Standard tablets such as Madopa (madopar) and Parkinson’s (sinemet): ① Madopar by L-dopa and benserazide according to the composition of 4:1, Madopa 250 L-dopa 200mg + benserazide 50mg, Madopa 125 L-dopa 100mg + benserazide 25mg; Domestic dopazide capsules are the same as the composition of the Madopa; ② Parkinin (Sinemet250 and Sinemet125) consists of L-dopa and Carbidopa at 4:1. 3, the controlled release agent includes two kinds: ① Sinemet Controlled Release Tablets (sinemetCR): L-dopa200mg + CAPEIDOPA 50mg, the preparation with a single layer of molecular matrix structure, the drug is constantly dissolved, to achieve the effect of slow-release, 120 ~ 150min to reach the peak plasma concentration after oral intake, there is a scored in the middle of the tablet, which can be divided into half a tablet, to keep the characteristics of slow-release. ②Madopar-HBS: L-dopa100mg+benserazide 25mg and special excipients, the capsule dissolves when the drug matrix surface to form a hydration layer, and is gradually released through the diffusion effect. Water-soluble tablets are available in the form of diffusible medopa (madopardispersible), with a dose of 125mg, consisting of L-dopa100mg+benserazide 25mg. Its characteristics are easy to dissolve in water, easy to take orally, rapid absorption, and quickly reach the therapeutic threshold concentration, so that the PD patients in the “off” state in a short period of time (10min or so) to rapidly improve the symptoms, and the effect of the maintenance time and the standard tablets are basically the same. This dosage form is suitable for PD patients with swallowing disorder or nasal feeding tube, early morning motor inability, delayed “on” period, prolonged “off” period in the afternoon, and end-dose dystonia. Timing: When to start compound L-dopa treatment is still controversial, long-term use of the drug will produce reduced efficacy, fluctuations in symptoms and movement disorders and other complications. Generally, the decision to use the drug should be based on the patient’s age, nature of work, and type of disease. Young patients can appropriately delay the use of early try to use other anti-PD drugs, patients have to use L-dopa due to occupational requirements should be combined with other drugs to reduce the dose of compound L-dopa. Elderly patients can use L-dopa at an early stage, because of the relatively low chance of motor complications and poor tolerance to the combination of drugs. Dosing method: Start with a small dose, gradually increase the dose according to the condition, and maintain with the lowest effective dose. ① standard tablets: compound L-dopa start with 62.5mg (1/4 tablet), 2 ~ 3 times / d, according to the need to gradually increase to 125mg, 3 ~ 4 times / d; the maximum dose of not more than 250mg, 3 ~ 4 times / d; fasting (1h before meals or 2h after meals) the efficacy of the drug. ② controlled-release tablets: the advantage is to reduce the number of times the drug is taken, the effective blood concentration is stable, the effect of a long time, can control the fluctuation of symptoms; the disadvantage is that the bioavailability is low, slow onset of action, the standard tablet conversion into a controlled-release tablets should be increased accordingly when the dose per day and in advance of the dose for patients with fluctuations in symptoms or early mild disease. Water-soluble tablets: easy to dissolve in water, rapid absorption, 10min onset of action, the effect of maintaining the same time as the standard tablets, suitable for swallowing disorders, early morning movement can not, “switch” phenomenon and the end of the dose of patients with dystonia. Side effects: peripheral side effects such as nausea, vomiting, hypotension and cardiac arrhythmia (occasional) can be gradually adapted to the use of the drug, taking the drug after a meal, the addition of morphine can reduce gastrointestinal symptoms. Central side effects include symptom fluctuation, dyskinesia and psychiatric symptoms, etc. Symptom fluctuation and dyskinesia are common long-term complications, mostly appearing after 4 to 5 years of drug use. Closed angle glaucoma, psychiatric patients are prohibited. (4) DA receptor agonists: DA includes five types of receptors, D1R and D2R subtypes are closely related to the treatment of PD. DR agonists have the following common features: ① direct stimulation of striatal postsynaptic DR, does not depend on the DDC will be converted to DA to play a role in the effect; ② plasma half-life (compared with the compound dopa) is long, (3) may be protective of nigrostriatal DAergic neurons. The combination of early DR agonists and compound dopa not only improves the efficacy and reduces the dosage of compound dopa, but also reduces or avoids the occurrence of symptomatic fluctuations or dyskinesia. Indications: PD patients in the late stage of the disease with compound dopa treatment produces symptomatic fluctuations or dyskinesia, the addition of DR agonists can reduce or eliminate the symptoms and reduce the dosage of compound dopa. In the late stage of the disease, due to the lack of DDC in the nigrostriatal DAergic system, which is unable to decarboxylate exogenous L-dopa into DA, compound dopa is completely ineffective, and DR agonists may be effective. DA receptor agonists alone have poor efficacy, and are generally advocated in combination with compound L-dopa, which can be applied alone in early-stage patients with mild age of onset. It should be started with small doses and tapered until satisfactory efficacy is achieved without side effects. Side effects are similar to those of compound L-dopa, with a low incidence of fluctuating symptoms and dyskinesia, and a higher incidence of postural hypotension and psychiatric symptoms. Commonly used preparations: mainly bromocriptine, pergolide. ① bromocriptine (bromocriptine): activation of D2 receptors, start 0.625mg/d, increase 0.625mg every 3-5 days, the usual therapeutic dose of 7.5-15mg/d, divided into 3 times; side effects are similar to levodopa, illusion and hallucinations are common, patients with a history of psychiatric disorders are contraindicated, and relative contraindications include recent myocardial infarction, severe peripheral vascular disease and active Relative contraindications include recent myocardial infarction, severe peripheral vascular disease and active peptic ulcer. ② Pergolide (pergolide): activation of D1 and D2 receptors, the beginning of 0.025mg / d, every 5 days to increase 0.025mg, the general effective dose of 0.375 ~ 1.5mg / d, the maximum maximum of not more than 2.0mg / d, 1 ~ 3h to reach the peak plasma concentration, half-life is longer (an average of 30h), than the bromocriptine anti-PD effect is slightly stronger, and also the duration of action. Long, bromocriptine treatment is ineffective when switching to Pergolide may be effective. ③TrastalSR: the chemical composition is piribedil, is a selective D2/D3 dopamine agonist, the dose of 150-250mg/d, on the midbrain-cortical and limbic pathway D3R agonist effect, improve the effect of tremor is obvious, on the tonic and hypokinesis also have a role. ④ lisuride: it has strong selective D2R agonism and weak effect on D1R, starting from a small dose of 0.05～0.1mg/d, gradually incrementing, with an average effective dose of 2.4～4.8mg/d; according to the effect-dose ratio, the effect is 10～20 times stronger than that of bromocriptine, with a short half-life (2.2h on average), short duration of action, water-soluble, and can be administered intravenously or by subcutaneous infusion pumps. It is water-soluble, can be applied by intravenous or subcutaneous infusion pumps, and is used in the treatment of compound dopa with obvious “on-off” phenomenon. ⑤ Apomorphine (apomorphine): D1 and D2R agonists, can significantly reduce the “off” state, the fluctuation of symptoms, especially the “on-off” phenomenon and dystonia have obvious efficacy, take the pen injection method of administration after 5 ~ 15min onset of effect, the effective effect of the pen injection method, the effective effect of the pen injection method of administration after 5 ~ 15min onset of effect. 15min onset of action, the effective time of action 60min, each time to give 0.5 ~ 2mg, available several times a day, portable micro-pump subcutaneous continuous perfusion method can make the patient every day to maintain good motor function; can also be given through the nasal cavity, but long-term use of the drug can stimulate the nasal mucosa. (6) cabergoline (cabaser): it is the longest half-life (70h) and the longest duration of action among all DR agonists, suitable for patients with symptomatic fluctuation and dyskinesia in the late stage of PD with long-term application of compound dopa, with an effective dose of 2-10mg/d, an average of 4mg/d, and only 1 time/d, which is more convenient. (7) Pramipexole (Pramipexole, 0.125mg, 3 times/d, gradually increase the dosage to 0.5-1.0mg, 3 times/d) and Ropinirole (Ropinirole, 0.25mg, 3 times/d, gradually increase the dosage to 2-4mg, 3 times/d), both are non-ergot derivatives without ergot side-effects, are used in the early or progressive PD with symptomatic fluctuations and low incidence of dyskinesia, common blurred consciousness, hallucinations and upright hypotension. (5) Monoamine oxidase B (MAO-B) inhibitor: inhibit DA decomposition in neurons and increase DA content in brain. Combined with the compound L-dopa has a synergistic effect, reducing the dosage of L-dopa by about 1/4, delaying the switch phenomenon, and having a neuroprotective effect. Commonly used selegiline (selegiline) that is propargylamphetamine (deprenyl) 2.5-5mg, 2 times / d, it is advisable to take in the morning, afternoon, evening consumption can cause insomnia. Side effects include dry mouth, low gastric appetite and postural hypotension, etc. Lazabemide (Ro19-6327) is also a MAO-B inhibitor, and there are few reports on its clinical application. (6) Catechol-oxygen methyltransferase (COMT) inhibitors: inhibit the peripheral metabolism of L-dopa, maintain a stable plasma concentration of L-dopa, accelerate the passage of the BBB, prevent the degradation of DA in the glial cells, and increase the content of DA in the brain. Combined with Medopa or Benzoin to enhance the efficacy of the latter and reduce the symptomatic fluctuation response, ineffective when used alone. Side effects may include diarrhea, headache, excessive sweating, dry mouth, elevated aminotransferases, abdominal pain, and light-colored urine, etc. Liver function must be monitored during the use of the drug. 4, commonly used preparations: ① tolcapone (tolcapone): also known as the answer is the United States (tasmar), 100 ~ 200mg orally, 3 times / d, side effects of diarrhea, confusion, dyskinesia and aminotransferase elevation, etc., should pay attention to the liver toxicity; with peripheral and central COMT inhibitory effect, clinical trials have shown that the application of the complex dopa efficacy of the 69 cases of PD with the addition of tolcapone 100 ~ 150mg, clinical trial. Cocopone 100 ~ 150mg, 3 times / d, 6 months of treatment, the effective rate of 98.5%, no obvious toxic side effects, can be combined with compound dopa and MAO-B inhibitors. ② Entacapone (entacapone): also known as kotan (comtan), is a peripheral COMT inhibitor, 100 to 200 mg orally, 5 times / d is appropriate, and tokopen is different from the so far no serious hepatic function damage reported. (7) Excitatory amino acid (EAA) receptor antagonists and release inhibitors: EAA can damage the nigrostriatal cells, inhibitors have a neuroprotective effect, can enhance the effect of L-dopa. However, there are no reports of clinically effective treatment. (8) Iron chelators: PD patients have a significant increase in the concentration of Fe2 in the substantia nigra and a significant decrease in ferritin content. The administration of iron chelators can reduce Fe2 concentration and decrease oxidative reactions. At present, 21-aminosteroids (21-aminosteroide) are commonly used, which can be combined with Fe2 through the blood-brain barrier, inhibit lipid peroxidation, and have a protective effect on the nigrostriatal cells. (9) Neurotrophic factors (neurotrophicfactors): play an important role in neuronal development, differentiation and survival, and selective action on the neurotrophic factors of DA-energy neurons can help prevent and control PD. Neurotrophic factors include acidic and basic fibroblast growth factor (aFGF, bFGF), epithelial growth factor (EGF), ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and Neurturin, etc. GDNF and Neurturin have strong specificity for the DAergic neuron of midbrain. GDNF and Neurturin have strong specificity for DAergic neurons in the midbrain. (10) Traditional Chinese medicine or acupuncture has a certain complementary effect on the treatment of PD, and should be used in combination with western medicines, the efficacy of single use is not satisfactory. 5. Rehabilitation therapy The training and guidance of patients in language, feeding, walking and various daily life is very important to improve the quality of life. Late bedridden patients should be strengthened care to reduce complications. Rehabilitation includes voice tone training, facial muscle exercise, hand, limb and trunk exercise, relaxation of respiratory muscle exercise, gait and balance exercise, posture restoration exercise and so on. Prognosis: PD is a chronic progressive disease, there is no cure, most patients can continue to work for several years after the onset of the disease, but can also develop rapidly and become disabled. In the late stage of the disease, patients may become bedridden due to severe muscle ankylosis and generalized stiffness. The cause of death is often pneumonia, fractures and other complications.