Antiparkinson Drugs PDF

ANTIPARKINSON DRUGS 1 PARKINSON'S DISEASE (1817-DR. JAMES PARKINSON) It is a chronic, progressive, idiopathic, neurodegenerative disease that develops as a result of a decrease in dopamine in the basal ganglia (especially the corpus striatum) due to a numerical decrease in the neurons of the nigrost...

ANTIPARKINSON DRUGS 1 PARKINSON'S DISEASE (1817-DR. JAMES PARKINSON) It is a chronic, progressive, idiopathic, neurodegenerative disease that develops as a result of a decrease in dopamine in the basal ganglia (especially the corpus striatum) due to a numerical decrease in the neurons of the nigrostriatal dopaminergic pathway (the largest of the dopaminergic pathways in the brain). 2 PARKINSON’S DISEASE It is a disease of the extrapyramidal motor system, which is responsible for the involuntary control and optimization of movements and striated muscle tone, and works independently of, but in parallel with the pyramidal motor system. 3 BASAL GANGLIA It participates in the regulation of muscle movements, influencing the activities of the motor areas of the cerebral cortex and motor centers in the brain stem. The implementation and management of complex motor movements is carried out through these structures. At the same time, it is a region with high motor control feature, such as controlling the speed of movements. 4 5 Acetylcholine and dopamine are more abundant in the corpus striatum, which controls the normal tone and contractions of the striated muscles, than in many other parts of the brain. These two endogenous substances play a neuromodulatory role in impulse transition at synapses in this location. Nigrostriatal dopaminergic neurons keep intrastriatal cholinergic neurons under inhibitory pressure. Postmortem examinations showed that the dopamine content in the corpus striatum was severely reduced. 6 It is believed that the primary disorder in Parkinson's disease is in the pars compacta of the substantia nigra, where nigrostriatal dopaminergic neuron somas collect in the mesencephalon. As a result of the destruction of the neurons here, the number of neurons has decreased considerably. It has been determined that the dopamine level in the striatum must decrease by more than 80% in order for the symptoms of Parkinson's disease to occur. Excessive increased dopaminergic activity in the striatum causes hyperkinesis such as chorea and Tourette's syndrome, while decreased dopaminergic activity causes various dystonias and Parkinson's disease. 7 Striatumdaki kolinerjik-dopaminerjik sistemler arasındaki denge kolinerjik etkinlik lehine bozulmuştur 8 SYMPTOMS OF PARKİNSON'S 1-Akinesia and bradykinesia Impossibility of moving at will, difficulty in starting movement and slowing down in movements (bradykinesia), mask face (bradymemia) 2-Stiffness in striated muscles (rigidity) 3-Tremors that occur especially at rest (pill rolling) 4- Postural instability, freezing and walking disorder, difficulty (leaning forward, dragging feet and swinging arms) 9 PARKİNSON Apart from these 4 basic symptoms, symptoms such as dementia, depression, poorly described pain, autonomic dysfunctions, frequent urination, constipation, seborrhea can also be found. It usually appears in middle and advanced age. The older you get, the greater the risk of developing the disease. The reason is not clear. The most common type is idiopathic Parkinson's disease. A syndrome similar to Parkinson's occurs with CO, Manganese, mercury, cyanide, methanol and ethanol, poisoning and neuroleptics (blocking dopamine receptors). There are also familial forms of Parkinson's. 10 SIGNS AND SYMPTOMS OF PARKINSON'S DISEASE Typical symptoms are: Tremors in the hand, arm, and leg (only on one side of the body) Stiffness in the muscles Difficulty of taking action Walking with a hunched back and foot dragging An expressionless or mask-like face Slurring in the mouth Depression 11 DRUG-INDUCED PARKINSON'S Chronic treatment with some drugs that act on CNS creates a clinical picture similar to Parkinson's syndrome. One of its most important features is that it is not too dependent on age. The use of such drugs in the elderly may facilitate the appearance of Parkinson's syndrome. Its use in patients with Parkinson's disease is contraindicated. In general, they are effective drugs on dopaminergic and cholinergic systems. Antidopaminergic drugs and cholinergic drugs cause acute extrapyramidal side effects by disrupting the balance of dopamine and acetylcholine in the basal ganglia, especially in the striatum. 12 DRUG-INDUCED PARKİNSON'S Neuroleptics (antidopaminergic drugs), Physostigmine (anticholinesterase), rezerpin (drains dopamine stores), methyldopa (pseudoneurotransmitter), metoclopramide can cause Parkinson's-like symptoms. Epinephrine, terbutaline, theophylline, lithium, tricyclic antidepressants can cause essential tremor as a side effect, as well as worsen tremor in Parkinson's patients. Treatment with neuroleptics often requires a combination with anticholinergic drugs (such as biperidine) to prevent Parkinson's-like extrapyramidal symptoms. These and similar drugs have mild euphoria-causing and activating effects and therefore have the potential to be abused and addictive. They can also cause deterioration in cognitive functions with long-term use. Anticholinergic side effects such as constipation, urinary retention, dry mouth also restrict use. 13 PARKINSON'S TREATMENT 1-Dopaminerjik etkinliği artıranlar 2-Santral antikolinerjikler (kolinerjik etkinliği azaltanlar) 3-Bu ilaçların kombinasyonu 14 All drugs used in the treatment of Parkinson's provide palliative treatment; As long as they are taken, they can improve the symptoms of the disease. After treatment is discontinued, the disease symptoms reappears; In this disease; radical treatment with medication is not possible. 15 DRUGS USED IN TREATMENT 1-Those that increase dopaminergic activity (mainly postsynaptic D2 It depends on the activation of its receptors. Postsynaptic D1 receptor activation, strengthens the activity that occurs through D2 receptors) 2-Central acting anticholinergics 3-Others 16 1. THOSE THAT INCREASE DOPAMINERGIC ACTIVITY Levodopa ( levodopa+benserazide and levodopa+carbidopa) Dopamine receptor agonists: Bromocriptine mesyllate Lyzurid Pergolid mesilicate Cabergoline Ropinirole Pramipexole Rotigotine Amantadine Apomorphine MAO-B inhibitors: Selegiline Rasagiline Selective inhibitor of COMT enzyme: Entacapone Tolcapone 17 PRINCIPLES OF DRUG TREATMENT Drugs are administered in a certain order. In the early period, when the symptoms of the disease do not disrupt daily life, there is no need for drug treatment. In slightly more advanced cases, dopamine receptor agonists, selegiline, anticholinergic drugs or amantadine should be tried first. If the disease is advanced and the patient cannot be rehabilitated with the specified drugs, a combination of levodopa + dopa decarboxylase inhibitor is started. When determining the drug dose, it is aimed not to completely relieve the symptoms, but to make the patient do his daily activities and to keep the dose to a minimum. 18 LEVODOPA In the catecholamine synthesis chain, it is the precursor of dopamine. Since dopamine cannot overcome the blood-brain barrier, Levodopa is used as a precursor. It is uptaken by dopaminergic nerve endings in the basal ganglia. Aromatic L-amino acid is converted to dopamine by the enzyme decarboxylase. It is the drug with the highest therapeutic value in Parkinson's. It is not able to stop the natural progression of the disease, it only shows a palliative activity. 19 LEVODOPA It is not recommended to use it in the early period when the symptoms are mild at the beginning of the disease or can be controlled with other drugs. 1/3 of the patients respond well to this drug, and 1/3 respond with little but sufficient improvement. However, in responding cases, the therapeutic efficacy of levodopa decreases after 2-10 years of administration and disappears over time. In the remaining 30-35% of cases, there is no adequate response or the patient shows drug intolerance. 20 LEVODOPA It is used orally. It is fully and rapidly absorbed from the gastrointestinal tract. When ingested with food, its absorption is delayed and its bioavailability may decrease. During its passage through the intestinal wall and liver, it is converted into dopamine, and a large part of the amount that can pass into the systemic circulation is taken up by the noradrenergic nerve endings in the periphery. Therefore, only a very small part (1-3%) of the administered dose has the opportunity to cross the blood-brain barrier and penetrate the brain and have a central effect; When Dopa is given together with a decarboxylase inhibitor, the fraction that passes into the brain increases (5-10%). 21 LEVODOPA If Dopa is used together with a decarboxylase inhibitor, the fraction that passes into the brain increases, it can act with a smaller dose and its therapeutic effectiveness begins more quickly. As a dopamine breakdown product, homovanillic acid (HVA) is most commonly formed (with MAO and COMT enzymes). The metabolites of levodopa cause red-brown coloration in the urine, especially in the basic environment. 22 LEVODOPA Levodopa significantly corrects the existing limitation of voluntary movements and striated muscle rigidity in Parkinson's disease. It increases the mobility of the patient and makes him able to do his daily work. It has little effect on tremor. There is a great difference between individuals in terms of sensitivity to the therapeutic effect of the drug, and the dose of the drug should be individualized according to the patient's requirement. In the initial years of treatment, levodopa provides adequate improvement in only about 70% of patients. 23 LEVODOPA Due to its side effects, it is not possible to reach a dose that will completely correct the symptoms of the disease. Therefore, it may be necessary to give bromocriptine and similar drugs, selegiline or anticholinergic drugs as an advancing. The occurrence of drug-induced involuntary movements (dyskinesia) is a good indicator that the dose should not be increased further. Dyskinesia occurs in the advanced period of treatment. The efficacy of the drug is strong in the first two years of treatment (progression of the disease, increased neuron destruction, decrease in the number of D2 receptors with prolonged exposure to the agonist). If the dopaminergic nerve ending is lost in the striatum, levodopa cannot convert to dopamine. 24 LEVODOPA It is rarely used alone in treatment. Only levodopa-containing preparations are not produced in Turkey. It is used in the form of combined preparations. Levodopa and other dopaminergic agonist drugs are not used in the treatment of extrapyramidal disorders and parkinsonism, which are caused by various drugs (mainly neuroleptics). In this case, central anticholinergic drugs are preferred. 25 LEVODOPA COMBINED LEVODOPA PREPARATIONS In order to reduce the degradation of levodopa in the periphery and thus to allow it to enter the CNS at a higher rate, the drugs carbidopa and benserazide, which cannot overcome the bloodbrain barrier and inhibit the dopa-decarboxylase enzyme found in the peripheral adrenergic nerve endings, liver and other places, are used as a combined preparation with levodopa. Levodopa (4 parts) + benserazide (1 part) : co-beneldopa Levodopa (10 parts) + carbidopa (1 part) : co-kareldopa Thus, the effect is obtained within a few days, using 1/4 of the usual dose, in a formulation that greatly reduces peripheral side effects. 26 LEVODOPA SIDE EFFECTS It has many peripheral and central side effects. Gastrointestinal disorders (nausea, vomiting (stimulation of the CTZ by dopamine), loss of appetite, etc.-may be given after meals). Cardiovascular (orthostatic hypotension, arrhythmia...). Involuntary abnormal movements (dyskinesias; dose-dependent, leg, hand, tongue-face-mouth; dose-dependent, dyskinesia decreases if the dose is reduced, but causes parkinsonian symptoms to reappear) 27 LEVODOPA SIDE EFFECTS Fluctuations in response (occurring after the first year of treatment, in the form of end-of-dose akinesia (worsening) or onoff event. Towards the end of the dose efficacy period (3-4 hours), as a result of the decrease in the plasma level of the drug, the symptoms of the disease (such as rigidity, tremor, akinesia) return regularly. Giving levodopa at low doses and frequent intervals may be the solution. On-off: means that the effect of the drug disappears immediately from a few minutes to a few hours. It is unpredictable when it will happen. Giving levodopa at low doses and frequent intervals, discontinuation for a while, and combination therapies can be tried. 28 LEVODOPA SIDE EFFECTS Psychic effects (can cause insomnia, euphoria, mania). There may be psychotoxic effects such as hallucinations, depression, paranoid behavior, anxiety, nightmares. Impulse control disorder (hypersexuality, pathological tendency to gambling, overeating). A state of sleepiness that occurs suddenly in the daytime. In case of hallucinations and confusion, clozapine and quetiapine are given for treatment. In some patients, hot flashes on the skin, mydriasis, glaucoma attacks. Sudden discontinuation of Levadopa and other dopaminergic drugs may result in neuroleptic malignant syndrome characterized by confusion, rigidity, and hyperthermia. 29 LEVODOPA INTERACTIONS Pyridoxine (vitamin B6) reduces its central effect by increasing its peripheral decarboxylation. The decarboxylating enzyme is dependent to pyridoxine. The drug should not be used with multivitamins containing pyridoxine. When taken concomitantly with MAO inhibitors, it may cause hypertensive crisis. Neuroleptics that block rezerpin and dopamine receptors cause the symptoms of the disease to reappear. Anticholinergics reduce its bioavailability by delaying its absorption. 30 DOPAMINE RECEPTOR AGONISTS They are drugs that strongly activate dopamine D2 receptors and some of them are derivatives of ergot alkaloids. Gravimetric effect powers are very high compared to levodopa and amantadine. They are commonly called Ergolins. When initiating drug treatment at the onset of the disease, dopamine receptor agonists are generally preferred to levodopa. In advanced cases, they are used together with levodopa as an adjunct. Treatment should be started with a low dose, increased according to response and patient endurance, and discontinued gradually as it is discontinued. With prolonged use of ergot derivatives, lung, pericardial and retroperitoneal fibrosis related heart, lung and GI problems may occur. A rare side effect with dopamine agonists is sudden sleepiness or falling asleep. 31 BROMOCRIPTINE MESILATE It is one of the ergot alkaloids. By activating dopamine D2 receptors, it exerts a strong dopaminergic effect. It is used in combination with these drugs in patients for whom levodopa is contraindicated or who are on levodopa+carbidopa or benserazide treatment, but there is fluctuation in response. When used alone, it can only produce sufficient therapeutic effect in half of the patients. It is preferred at the beginning of the disease. Its effectiveness is low in advanced cases. If it is to be combined with levodopa, the dose of levodopa is reduced. 32 BROMOCRIPTINE MESILATE It should be started with a low dose and discontinued by decreasing while cutting. It should be taken after meals. Systemic bioavailability in oral ingestion is 30%. The elimination half-life is 3 hours. Slow-release preparations are available. The most common side effects are orthostatic hypotension (tolerance is improved by gradually increasing the dose), erythromelalgia (burning pain, warmth and redness spells that occur episodically, triggered by heat and soothing with cold), nausea, vomiting, psychomimetic symptoms, dyskinesia, rhythm disturbances in the heart. It has the potential for hepatotoxic effects. It should not be used in patients with stable angina, recent myocardial infarction, a history of psychosis or active peptic ulcer. 33 LISURIDE It is a semi-synthetic ergot derivative. It strongly activates postsynaptic D2 receptors. It is a partial agonist. It is used alone or often in combination with levodopa. Its side effects are similar to bromocriptine, with a greater incidence than bromocriptine. Contraindicated in pituitary tumor and pregnancy. It should not be given to nursing mothers (Prolactine inhibitor). 34 OTHER ERGOT DERIVATIVES (ERGOLINES) AND SYNTHETIC DOPAMINERGIC DRUGS Semi-synthetic ergot derivatives; One of the most studied is Pergolid mezilate. They affect D3 receptors as well as D2. It was withdrawn from the market because it caused irreversible cardiac valvulopathy that required valve replacement. Another type of ergoline is cabergoline. Due to the risk of valvulopathy, it is mandatory to perform an ECO every 6 months. Synthetic dopaminergic drugs; Ropinirole (D2 agonist) alone in mild cases and then a low dose in addition to the combination of levodopa is started. Pramipexole (D3 agonist) is used in a similar way. Rotigotine is administered with a skin patch. Treatment with all dopaminergic agonist drugs begins with a small dose, increasing according to the response given at intervals of at least 1 week. When treatment is to be discontinued, the dose should be reduced for at least 1 week and should not be discontinued suddenly. 35 AMANTADINE It is an antiviral drug against the influenza A virus, which was discovered by chance with antiparkinsonian properties. It acts by increasing the release of dopamine from dopaminergic nerve endings and preventing re-uptake. It is more effective in the early stage of the disease. It can also block NMDA glutamate receptors and has anticholinergic effects as well. Its therapeutic efficacy is weak. It is often used not alone, but in combination with levodopa and as an adjunct to anticholinergic drugs. Side effects such as restlessness, depression, insomnia, GI complaints, dermatological complaints, postural hypotension, urinary retention, loss of appetite can be seen. 36 APOMORPHINE It shows high affinity for strong dopamine D4 receptors and moderate affinity for D2, D3, D5 and α 1D, α2B and α2C receptors and low affinity for D1 receptor. Because it causes emesis in high doses, it is used in special cases (they provide temporary improvement in akinesias in the form of "kapa"-periods in patients receiving dopaminergic therapy) and under supervision. 37 SELEGILINE It is a derivative of L-amphetamine. It selectively and irreversible inhibits MAO B (Monoamine oxidase), which is more abundant in dopaminergic endings. It also has an inhibitory effect on the formation of free radicals (thought to play a role in the progression of Parkinson's disease). It can be used in initial treatment by participating in single or combined treatments in advanced cases. It is not effective enough in advanced cases. Dopamine receptor agonists alone are generally preferred instead of selegiline alone in treatment. It may cause nausea, dry mouth, hypotension, increased dyskinesia, insomnia (should not be taken later in the night), agitation. Rasajilin has fewer side effects than selegiline. 38 ENTAKAPON It inhibits the inactivation of dopamine by COMT (Catechol-O-methyl transferase) in the brain, it is a selective inhibitor of the enzyme. It is used in combination with the combination in patients who are being given a combination of levodopa + dopa decarboxylase inhibitor but cannot be stabilized and show end-of-dose akinesia. It allows the dose of levodopa to be reduced. Levodopa/carbidopa/entacapone fixed combination tablet is introduced to the market (Stalevo®). It can cause side effects such as nausea, vomiting, diarrhea, constipation, dyskinesia, dizziness, dry mouth. It can dye urine orange. Contraindicated in pregnancy and lactation. While entacapone has a peripheral effect, tolcapone has both a peripheral and central effect and the duration of action is longer than entacapone. Tolcapone has a hepatotoxic effect. 39 CENTRAL ANTICHOLINERGICS They block muscarinic cholinergic acetylcholine receptors in the striatum. Thus, they reduce the dominance of cholinergic activity in the striatum, which occurs upon weakening of the dopaminergic system. Antiparkinsonian effects are generally weaker than those of levodopa and dopamine receptor agonists. It is mostly preferred in patients at a young age and with tremor at the forefront. They also correct sialorrhea. It can weaken memory. Its main uses are in the treatment of dystonia (involuntary contractions) and other extrapyramidal disorders caused by neuroleptic drugs and other antidopaminergic drugs. With prolonged use, tolerance to its effects may develop. 40 CENTRAL ANTICHOLINERGICS Biperiden (Akineton) Trihexyphenidyl Benztropine mesylate Bornaprin HCl (Sormodren) (Controlled drug) Dietazine Etopprosane Diphenhydramine Orfenadrin Chlorphenoxamine 41 CENTRAL ANTICHOLINERGIC Since their side effects are more benign than other drugs, they are the drugs used in the first line in mild cases at the beginning. The most commonly used are biperidine (Akineton®) and bornaprine hydrochloride (Sormodren®). Side effects: peripheral: blurred vision, glare in the light, increased intraocular pressure, dry mouth and throat, constipation, urinary retention. central: ataxia, dysarthria, hyperthermia, amnesia, agitation, hallucinations. It has been reported that biperidine, trihexyphenidyl, benztropine and orphenadrine are rarely abused and addiction to these drugs due to the fact that they cause euphoria and visual hallucinations. Diphenhydramine (antihistamine) can be used in elderly patients who cannot stand the side effects of anticholinergic drugs, as they also have an additional anticholinergic effect. 42 OTHERS TRICIYCLIC ANTIDEPRESSANTS High doses alone can have side effects similar to Parkinson's symptoms, but if used in low doses, increase the therapeutic effects of antiparkinsonian drugs. Antiparkinsonian effects are mainly due to their anticholinergic effects. 43 PRINCIPLES OF DRUG TREATMENT Drugs are administered in a certain order. In the early period, when the symptoms of the disease do not disrupt daily life, there is no need for drug treatment. In slightly more advanced cases, dopamine receptor agonists, selegiline, anticholinergic drugs or amantadine should be tried first. If the patient is young and/or tremors are significant, anticholinergic drugs are preferable to amantadine. Anticholinergics are not preferred in elderly patients due to their central side effects and peripheral side effects. 44 PRINCIPLES OF DRUG TREATMENT If the disease is advanced and the patient cannot be rehabilitated with the specified drugs, a combination of levodopa + dopa decarboxylase inhibitor is started. However, MAO B inhibitor selegiline and dopamine agonists (such as lysuride, pergolide) are used to reduce advanced complications. The COMT inhibitor entacapone is given when it is necessary to prolong the duration of action of levodopa. When determining the drug dose, it is aimed not to completely relieve the symptoms, but to make the patient do his daily activities and to keep the dose to a minimum. 45 PRINCIPLES OF DRUG TREATMENT Along with levodopa, amantadine, selegiline, anticholinergics, and bromocriptine or lysurid can be given to keep the dose to a minimum. Dopamine agonists may be given alone or in combination with auxilliary drugs in patients who do not respond to levodopa or who have fluctuation in response. 46 47 48 PHARMACOLOGICAL TREATMENT OF OTHER MOVEMENT DISORDERS 49 TREMOR Rhythmic oscillator movements. Normal physiological postural tremor increases with anxiety, fatigue, thyrotoxicosis and iv given adrenaline or isoproterenol. Bronchodilators, valproate, tricyclic antidepressants and lithium may cause dose-dependent increases. With the discontinuation of medications, the condition returns. The fact that tremor is prevented with propranolol but not with metoprolol suggests that tremor is mediated by β2 receptors. 50 TREMOR Essential tremor, which is similar to physiological tremor, may be an autosomal dominant, inherited familial condition. Propranolol 120 mg (60-240 mg, divided into 2 doses per day). In those with respiratory system disorders, metaprolol may also be partially beneficial. Antiepileptics such as primidone, topiramate. Alprazolam and Gabapentin 51 TREMOR Intentional tremor that occurs during movement can occur as a toxic effect of alcohol or drugs such as phenytoin. Discontinuation of the drug corrects tremor. There is no satisfactory pharmacological treatment. Tremor that occurs at rest is usually due to Parkinson's. 52 CHOREA AND BALLISMUS Chorea is irregular, rapid, leaping or flowing, involuntary movements with small amplitudes, usually involving the distal part of the extremities. If the amplitude of this involuntary movement is large and involves the proximal part of the limb, it is called ballismus. Dopamine blocking agents are used in treatment. 53 HUNTINGTON'S DISEASE It is an autosomal dominant inherited disease (it may also have a recessive form) caused by an anomaly of the Huntington's gene on chromosome 4. It is characterized by progressive chorea and dementia that begin in adulthood. The development of chorea is associated with an imbalance of dopamine, ACh, GABA and other neurotransmitters in the basal ganglia. That it is caused by excessive activity in dopaminergic nigrostriatal pathways due to a deficiency of a neurotransmitter that antagonizes dopamine or an increase in the responses of postsynaptic dopamine receptors. Rezerpin depletes cerebral dopamine, preventing intraneuronal storage of tetrabenazine. Haloperidol (small dose), Perphenazine, Olanzapine 54 OTHER CHOREAN TYPES Benign hereditary chorea can occur by inheritance or spontaneously. It develops in early childhood and dementia is not observed. Chorea may occur as a complication in thyrotoxicosis, polycythemia vera, Systemic lupus eritrematosus, hypocalcemia and cirrhosis of the liver. Levodopa, antimuscarinic drugs, amphetamines, lithium, phenytoin and oral contraceptives can also cause chorea. Treatment is aimed at the cause. In hereditary disorders, symptomatic treatment is carried out. 55 ATHETOSIS AND DYSTONIA Athetosis can also be seen on the feet and face. They differ from choreic movements in that they are not sudden and rapid. It is important to note that some involuntary movements can resemble both chorea and athetosis. This is referred to as choreathetosis. It is seen in children with congenital brain damage, cernicterus and some degenerative basal ganglia diseases. There is no satisfactory treatment. Some patients are prescribed levodopa, some patients are prescribed diazepam, amantadine, antimuscarinic drugs (high dose), carbamazepine, baclofen, haloperidol, phenothiazines. Botulinum toxin in patients with focal dystonia such as blepharospasm or torticollis. 56 TICKS They are involuntary movements that are often seen on the face, neck and shoulder. Blinking, forehead wrinkling, sniffling, shrugging are common. It occurs in childhood and in tense situations. It has a compulsive aspect. In other words, if the patient wants to keep his tic under control, the tension increases, and the appearance of the tic provides temporary relief. Tics are usually in stereotypic movements. However, it is seen that the child, who repeats the same tic for a while, abandons it after a while and starts a new tic. In Gilles de la Tourette's Syndrome, multitics are accompanied by abusive words (coprolalia). Neuroleptics such as haloperidol, pimozide, fluphenazine, risperidone, aripiprazole. Clonazepam and carbamezapine Botulinum toxin Clonidine and guanfazine 57 DYSKINESIA CAUSED BY DRUGS Levodopa and dopamine antagonists cause dyskinesia Phenytoin, carbamazepine, amphetamines, lithium and OCS can make chorea Administration of dopaminergic agonists, lithium, SSRIs, carbamazepine and methochlorpramide causes dystonia, Theophylline, caffeine, lithium, valproic acid, thyroid hormone, tricyclic antidepressants and isoproterenol cause postural tremor. 58 RESTLESS LEGS SYNDROME It is characterized by an uncomfortable chill of the legs, sometimes starting from the depths of the arms. It occurs when the patient is lying down or sitting. It can delay the onset of sleep. It often occurs in pregnant women, diabetic or uremic patients with neuropathy. Correction of concomitant iron deficiency dopamine agonists, levodopa, diazepam, clonazepa, gabapentin, pregabalin and opiates often responds. Treatment with dopamine agonists such as pramipexole or ropinirole is initiated. 59 WILSON’S DISEASE It is a recessively inherited disorder of copper metabolism. It is a condition characterized by low serum copper and ceruloplasmin levels, increased copper concentrations in the brain and viscers, and clinically signs of hepatic and neurological dysfunction. Tremor, choreiform movements, rigidity, hypokinesia, dysarthria and dysphagia may ocur. Chelators such as penicillamine, trientine hydrochloride, tetrathiomolybdate can be used. Zinc acetate, zinc sulfate reduce the absorption of copper. They have less toxicity. Liver transplantation may be required. 60