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Parkinson's Disease in the United States

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Parkinson's Disease in the United States Drugs used in Parkinson’s disease Parkinson’s disease – paralysis agitans, was first described by the British physician James Parkinson in 1817. 150 years later the neurobiochemical etiology of this disease was established. Parkinson’s disease is a degenerative disease which progressively destroys the nervous cells of the substantia nigra in the brain stem. These cells control the coordination of movements by releasing dopamine to the striatum. 1 Parkinson’s disease – symptoms and causes • While the neurons producing dopamine atrophy the deficiency of dopamine in the striatum causes the neurons producing ACh to become overactive and triggers a chain of defective signals which lead to movement impairment. • Dopamine deficiency is also accompanied by the increased activity of glutamate neurons. 2 Symptoms of Parkinson’s disease (1) The following symptoms are characteristic of Parkinson’s disease: • muscle tremor - rhythmical shaking in an arm or leg, especially when it is not being moved, in the initial stage of Parkinson’s disease • suppression of voluntary movements (hypokinesis) - slower movements – a sick person can freeze (monumental form) and his or her handwriting changes (the letters become smaller and smaller) • rigor – the stiffening of muscles - which causes posture disorders as a result of changes in the centre of gravity in the body, such as leaning forward (rarely backwards), walking with short steps and shuffling the feet, problems with balance and motor coordination, diminished command of the hands, reduced mimical facial movements and increasingly slurred speech to the point of incomprehensibility. 3 Symptoms of Parkinson’s disease (2) • Motor disorders are accompanied by functional disorders of the vegetative nervous system (increased salivation, hyperhidrosis) and of the CNS (depression gradually turning into dementia, the slowing of thinking processes). Nonmotor symptoms are results of the necrobiosis of other neurons in other areas of the brain. Initially most of the motor and nonmotor symptoms are slight but over time they intensify and, usually after 5-15 years, the patient is totally incapacitated. • The symptoms of Parkinson’s disease are observed when approx. 70% of the dopaminergic neurons of the substantia nigra are destroyed. 4 The causes of Parkinson’s disease (1) The cause of damage which leads to the atrophy of various types of neurons has not been explained. The hypothetical causes of the atrophy of neurons are: • oxidative stress (overproduction of free radicals in microglia such as nitrogen oxide and superoxide anionradical) • genetic factors; In some cases the cause of the disease can be the defect of chromosome 4, which contains the encoding section of DNA for -synuclein. -Synuclein occurs in the neuronal nuclei of presynaptic nerve endings. It is believed that this protein plays an important role in maintaining the plasticity of neurons. In families genetically predisposed to PD a punctual mutation of a gene has been observed. This mutation involves replacement of alanine with threonine and a change in the conformation of the protein. However, it isn’t known if this change leads to PD because, for example, rodents with threonine in the coding fragment do not develop PD. 5 The causes of Parkinson’s disease (2) • environmental factors – a history of virus infections, e.g. viral brain inflammation (inflammatory-induced parkinsonism) – the influence of toxic factors – manganese (Mn), copper (Cu), mercury (Hg), carbon disulphide, carbon oxide, methanol, MPP+ (the metabolite of MPTP = (N-methyl-4-propionoxy-4-phenylpiperidine) – drug-induced parkinsonism (certain neuroleptics) – others (brain tumors, apoplexy, serious head trauma). 6 The incidence of PD is between 0.1%-0.2% of the general population. It is a disease that affects people in the second half of their lives, and in the population above age 60 the incidence reaches 1%. A history of PD in families is observed in about 40% of patients. The risk of developing PD by lineal descendants (direct relatives) is known to be 3.5 times greater than by a control group of healthy individuals. 7 The treatment of PD To treat PD the following methods are used: • pharmacological treatment • non pharmacological treatment • operative treatment 8 Pharmacological treatment (1) • In 1867 it was observed that an extract from belladonna relieves PD symptoms. For over 100 years extracts containing hioscyjamine from belladonna, datura or henbane were the only drugs used in the treatment of PD. The mechanism of their action was understood 100 years later. At present it is known that these drugs block muscarinic receptors for ACh. They were effective in the treatment of PD but did not eliminate most symptoms and had many adverse effects such as blurred vision and impaired memory. • The degeneration of the nigrostrial tract and neurohormonal imbalance in the extrapyramidal system lead to diminished dopamine concentration and the functional dominance of the cholinergic and glutaminergic systems over the dopaminergic system. • The treatment of PD is only symptomatic. 9 Pharmacological treatment (2) At present the goal of treating PD is to restore neurohormonal balance in the extrapyramidal system. It is achieved in the following ways: • increasing dopamine concentration by using – levodopa (precursor for dopamine) – drugs inhibiting the metabolism of dopamine – drugs increasing the release of dopamine from synaptic granules • using dopamine receptor agonists • blocking striatal NMDA-receptors by amantadine • blocking cholinergic receptors in the extrapyramidal system by anticholinergic drugs 10 Drugs increasing dopamine concentration (2) COOH NH2 MAO-B MT HVA Because dopamine does not OCH3 OCH3 OH OH permeate through the blood- Selegiline COMT Tolcapone Tolcapone COMT Rasagiline brain barrier, its administration COOH does not increase dopamine MAO-B DOPAMINE DOPAC concentration in the brain. OH Central L-aromatic amino acid decarboxylase OH L-DOPA The drug levodopa (L-DOPA) Blood -brain barrier has been used in the treatment Stereoselective active transport Peripheral L-aromatic amino of PD for many years. COMT acid decarboxylase 3-Me-L-DOPA L-DOPA DOPAMINE (DA) H H NH COOH Entacapone COOH Benserazide 2 It can easily permeate through NH NH2 Tolcapone 2 Carbidopa the blood-brain barrier. OH OH OCH3 OH OH OH Inactive Stereoselective active transport from the intestines after oral administration Levodopa, L-DOPA, (-)-3-(3,4- Dihydroxyphenyl)-L- alanine 11 Drugs increasing dopamine concentration (1) In the peripheral and central nervous systems COOH NH2 levodopa is rapidly MAO-B MT HVA converted into dopamine OCH3 OCH3 OH OH under the influence of Selegiline COMT Tolcapone Tolcapone COMT Rasagiline L-aromatic amino acid COOH decarboxylase. MAO-B DOPAMINE DOPAC OH Central L-aromatic amino acid decarboxylase OH This is a desirable L-DOPA change in the CNS. Blood -brain barrier Stereoselective However, such a rapid active transport Peripheral L-aromatic amino change in the PNS is COMT acid decarboxylase 3-Me-L-DOPA L-DOPA DOPAMINE (DA) undesirable in PD H H NH COOH Entacapone COOH Benserazide 2 NH because it decreases by NH2 Tolcapone 2 Carbidopa OH about 90% the activity of OH OCH3 OH OH OH dopamine in the CNS Inactive Stereoselective active transport from the intestines after oral administration and causes many adverse effects in the PNS such as gastrointestinal and cardiovascular disorders.12 Drugs increasing dopamine concentration (3) COOH The transformation of NH 2 L-DOPA in the PNS can be MAO-B OCH MT HVA 3 OCH3 reduced by simultaneous OH OH Selegiline COMT Tolcapone administration of Tolcapone COMT Rasagiline COOH decarboxylase inhibitors MAO-B DOPAMINE DOPAC which do not permeate OH Central L-aromatic amino acid decarboxylase OH through the blood-brain L-DOPA barrier but act only Blood -brain barrier Stereoselective peripherally. active transport Peripheral L-aromatic amino Carbidopa and benserazide COMT acid decarboxylase 3-Me-L-DOPA L-DOPA DOPAMINE (DA) H H are peripheral decarboxylase NH COOH Entacapone COOH Benserazide 2 NH NH2 Tolcapone 2 Carbidopa inhibitors and demonstrate OH OH peripheral action. They are OCH3 OH OH OH Inactive Stereoselective active transport from the intestines used to treat PD together with after oral administration L-DOPA. 13 Drugs increasing dopamine concentration (4) The following preparations are used: • MADOPAR = levodopa + benserazide (4:1) • NAKOM = levodopa + S-Carbidopa (4:1) • POLDOMET = levodopa + S-Carbidopa (4:1 i 10:1) • PARDOPA = levodopa + S-Carbidopa (10:1) • SINEMET = levodopa + S-Carbidopa (10:1) CH3 O H COOH N N * OH NH NH2 H OH NH2 OH OH OH OH (S)-Carbidopa (R,S)-Benserazide 14 Drugs increasing dopamine concentration (5) In therapy only the levo COOH NH2 isomer of DOPA is used in MAO-B MT HVA spite of the fact that the OCH3 OCH3 OH OH product of decarboxylation Selegiline COMT Tolcapone Tolcapone COMT Rasagiline of the chiral pro-drug COOH L-DOPA is an achiral drug MAO-B DOPAMINE DOPAC OH – dopamine. Central L-aromatic amino acid decarboxylase OH L-DOPA Blood -brain barrier The exclusive use of Stereoselective L-DOPA is determined by active transport Peripheral L-aromatic amino COMT acid decarboxylase the pharmacodynamic and 3-Me-L-DOPA L-DOPA DOPAMINE (DA) H H NH toxic properties of COOH Entacapone COOH Benserazide 2 NH NH2 Tolcapone 2 Carbidopa enantiomers. OH OH OCH3 OH OH OH Inactive Stereoselective active transport from the intestines after oral administration 15 Drugs increasing dopamine concentration (5)
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