1. CHAPTER 28 Pharmacologic Management of Parkinsonism and Other Movement Disorders

2. Neurodegenerative Diseases Neurodegenerative diseases are characterized by the progressive and irreversible loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both The neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis

3. Neurodegenerative Diseases Most neurodegenerative disorders are of unknown etiology, affect the elderly, & are progressive Drug therapy is currently very limited, except in the case of Parkinson's disease (PD) There are some inherited forms of these disorders; however, most are sporadic occurrences (idiopathic) with genetic predisposition, environmental factors, and aging contributing as risk factors

4. Overview of Parkinson's Disease PD is a progressive neurological disorder of muscle movement, characterized by combination of rigidity, bradykinesia, resting tremor, and postural instability. Cognitive decline occurs as the disease advances It generally affects the elderly and is estimated to afflict more than 1% of individuals over the age of 65 PD is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum

6. Overview of Parkinson's Disease Thus, the normal modulating inhibitory influence of dopamine on cholinergic neurons in the neostriatum is significantly diminished, resulting in overproduction or a relative overactivity of acetylcholine by the stimulatory neurons This triggers a chain of abnormal signaling, resulting in loss of the control of muscle movements The mechanisms responsible for the degeneration of dopamine neurons are not known, but it may be the result of cerebral ischemia, viral encephalitis or other types of pathological damage

7. Overview of Parkinson's Disease The pathophysiologic basis of the idiopathic disorder may relate to exposure to some unrecognized neurotoxin or to oxidation reactions free radicals generation Genes?? Studies in twins suggest that genetic factors may be important, especially in patients under age 50 Drugs?? Dopamine receptor antagonists (eg, antipsychotic agents) or drugs that lead to destruction of the dopaminergic nigrostriatal neurons (e.g. 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine [MPTP] may induce parkinsonian syndrome

8. Strategy of treatment Since there is no cure for PD, the aim of pharmacological therapy is to provide symptomatic relief to alleviate many of the motor features of the disorder This is obtained re-establishing the correct dopamine/acetylcholine balance through the use of drugs that either increase dopaminergic actions or antagonizing the excitatory effect of cholinergic neurons

9. Drugs Used in Parkinson's Disease Drugs used in Parkinson’s disease include: 1) Levodopa-carbidopa 2) Dopamine agonists 3) Monoamine oxidase (MAO) inhibitors 4) Cathechol-O-methyl transferase (COMT( inhibitors 5) Anticholinergic agents 6) Amantadine

10. Levodopa-carbidopa Dopamine does not cross the BBB…..if given into the peripheral circulation has no therapeutic effect in parkinsonism Levodopa (the immediate metabolic precursor of DA) is the single most effective agent in the treatment of PD Oral levodopa is absorbed rapidly from the small intestine and transported into the brain by the transport system for aromatic amino acids Levodopa is itself largely inert Therapeutic and adverse effects of levodopa result from its decarboxylation to dopamine

12. Levodopa-carbidopa Certain a.as from ingested food can compete with levodopa for absorption from gut & for transport from blood to brain About 1–3% of administered levodopa actually enters the brain unaltered; the remainder is metabolized extracerebrally, predominantly by decarboxylation to dopamine in the periphery……does not penetrate the BBB ??? ……. It is combined with a peripheral dopa decarboxylase inhibitor (e.g.carbidopa)

14. Levodopa-carbidopa A dopa decarboxylase inhibitor that does not cross the BBB Carbidopa: a. Reduce the metabolism of L-dopa in the GIT and periphery b. Plasma levels are higher, and plasma half-life is longer c. Increases the availability of levodopa to the CNS d. Reduce the daily requirements of levodopa by approximately 75% e. Decreases the severity of the side effects arising from peripherally formed dopamine

15. Levodopa-carbidopa Clinical use Levodopa is widely used for treatment of all types of PD except those associated with antipsychotic drug therapy Levodopa substantially reduces the severity of all the signs and symptoms of PD in the first few years of treatment Patients then typically experience a decline in response after 3 or 4 years of therapy……. due to progression of the disease and loss of striatal dopamine nerve terminals as well as reduction of the daily dose to avoid adverse effects

16. Levodopa ADRs A. Gastrointestinal tract (GIT) Anorexia, nausea, and vomiting (likely due to dopamine’s stimulation of the CTZ but outside the BBB) Minimized by taking the drug in divided doses, with or immediately after meals, and increasing the total daily dose very slowly. Antacids 30–60 min before levodopa may also be beneficial When levodopa is given in combination with carbidopa, adverse GIT effects are much less frequent & patients can tolerate proportionately higher doses

17. Levodopa ADRs B. Cardiovascular effects Cardiac arrhythmias: caused by increased catecholamine formation peripherally (incidence is low) Peripheral decarboxylation of levodopa and release of DA into the circulation may activate vascular DA receptors and produce orthostatic hypotension Administration with nonspecific MAOI, accentuates the actions of levodopa and may precipitate life-threatening hypertensive crisis Incidence reduced if taken with carbidopa

18. Levodopa ADRs C. Dyskinesias Occur in up to 80% of patients receiving levodopa for more than 10 years Choreoathetosis of the face and distal extremities is the most common presentation The development of dyskinesias is dose-related but there is considerable individual variation in the dose required to produce them

19. Levodopa ADRs E. Fluctuations in Response Ooccur with increasing frequency as treatment continues… I. Wearing-off phenomenon/ end-of-dose akinesia: Related to the timing of levodopa intake Each dose of levodopa effectively improves mobility for a period of time (1–2 hrs), but rigidity and akinesia return rapidly at the end of the dosing interval Increasing the dose and frequency of administration can improve this situation

20. Levodopa ADRs E. Fluctuations in Response II. On-off phenomenon Fluctuations in response unrelated to timing of doses Off-periods of marked akinesia alternate with on-periods of improved mobility but often marked dyskineisa Lower incidence occur when levodopa is administered more continuously

21. Levodopa ADRs F. Behavioral Effects Depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria, and other changes in mood or personality More common in patients taking levodopa in combination with carbidopa (higher levels are reached in the brain) Several “atypical” antipsychotic agents with low D2 affinity are now available and effective in the treatment of psychosis

22. Drug Interactions of levodopa Pyridoxine (vitamin B6): increase extracerebral metabolism of levodopa and may prevent its therapeutic effect unless carbidopa is also taken Nonspecific MAO inhibitors (e.g. phenelzine): Accentuates the actions of levodopa and may precipitate life- threatening hypertensive crisis MAO inhibitors must be discontinued at least 14 days before levodopa is administered

23. Levodopa Contraindications: 1) Psychotic patients 2) Angle-closure glaucoma (cause severe mydriasis) Careful management in patients with: a) History of cardiac arrhythmias or recent cardiac infarction….(+ carbidopa) b) Active peptic ulcer must be managed carefully (GI bleeding occasionally occurred with levodopa) c) History of melanoma or with suspicious undiagnosed skin lesions (precursor of melanin)

25. Monoamine Oxidase Inhibitors Two types of monoamine oxidase in the nervous system: (MAO-A and MAO-B)….non-selective & selective The isoenzyme MAO-B is the predominant form in the striatum and is responsible for most of the oxidative metabolism of dopamine in the brain Blockade of dopamine metabolism makes more dopamine available for stimulation of its receptors Selective MAO-B Inhibitors: Selegiline & Rasagiline

26. Selegiline Irreversible inhibitor of MAO-B…..retards the breakdown of dopamine Higher doses lose selectivity Used as adjunctive therapy for patients with declining or fluctuating response to levodopa Enhances and prolongs the antiparkinsonism effect of levodopa (less doses are needed) and may reduce mild on- off or wearing-off phenomena

27. Irreversible and selective inhibitor of brain (MAO) Type B It is more potent than selegiline in preventing MPTP- induced parkinsonism and is being used for early symptomatic treatment Rasagiline is also used as adjunctive therapy to prolong the effects of levodopa-carbidopa in patients with advanced disease Rasagiline

28. Monoamine Oxidase Inhibitors Neither selegiline nor rasagiline should be taken by patients receiving opioid analgesic (stupor, rigidity, agitation, and hyperthermia) They should be used with care in patients receiving TCAs or SSRIs b/c of the theoretical risk of acute toxic interactions of the serotonin syndrome type (rare) ADEs: o Most related to the increased levels of dopamine o Anxiety, insomnia (selegiline)

29. Catechol-O-Methyltransferase Inhibitors Methylation of L-DOPA by catechol-O-methyltransferase (COMT) to 3-O-methyldopa is a minor pathway High 3-OMD levels have been associated with a poor therapeutic response to levodopa 3-OMD competes with L-DOPA for its transportation across the intestinal mucosa and the BBB….. 2 Selective COMT inhibitors: Tolcapone & Entacapone

30. Effect of entacapone on dopa concentration in the central nervous system (CNS). COMT = catechol-O-methyltransferase Levodopa

31. Are particularly helpful in patients receiving levodopa who have developed response fluctuations—thus leading to a smoother response, more prolonged on-time, and the option of reducing total daily levodopa dose Catechol-O-Methyltransferase Inhibitors

32. Tolcapone is more potent than entacapone with longer duration of action…..taken 3 times daily while, entacapone taken with each dose of levodopa, up to five times daily In addition tolcapone has both central and peripheral effects, while entacapone just peripheral ADRs: o Due to high L-DOPA exposure; dyskinesias, nausea & confusion o Orange discoloration of the urine o Tolcapone requires signed patient consent….hepatoxicity, and monitor liver functions Catechol-O-Methyltransferase Inhibitors

33. Dopamine Receptor Agonists Drugs acting directly on DA receptors may have a beneficial effect in addition to that of levodopa: 1) Do not require enzymatic conversion to an active metabolite 2) Have no potentially toxic metabolites 3) Do not compete with other substances for active transport into the blood and across the BBB 4) Selectively affect certain dopamine receptors 5) More limited adverse effects than levodopa 6) Longer durations of action than of levodopa…..thus are effective in patients exhibiting fluctuations in their response to L-dopa

34. Dopamine Receptor Agonists Dopamine agonists may delay the need to employ levodopa therapy in early PD and may decrease the dose of levodopa in advanced Parkinson's disease Dopamine receptor agonists: 1. Ergot derivatives e.g. bromocriptine & pergolide 2. Non-ergot derivatives e.g. apomorphine, pramipexole, ropinirole, and rotigotine The differences between the ergot derivatives and the newer/ non- ergot agents reside primarily in their adverse effects, and tolerability

35. Dopamine receptors The actions of dopamine in the brain are mediated by a family of dopamine-receptor proteins All the dopamine receptors are heptahelical G protein-coupled receptors (GPCRs) Five dopamine receptors have been identified, and they fall into two groups on the basis of their pharmacological and structural properties: D 1 -like receptors (D 1 & D 5 ) D 2 -like receptors (D 2, D 3, D 4 ) D 1 receptors, which stimulate the synthesis of the intracellular second messenger cyclic AMP, and D 2 receptors, which inhibit cyclic AMP synthesis

37. Dopamine receptors The benefits of dopaminergic antiparkinsonism drugs depend mostly on stimulation of D 2 receptors located postsynaptically on striatal neurons and presynaptically on axons in the substantia nigra belonging to neurons in the basal ganglia Whereas certain dopamine blockers that are selective D 2 antagonists can induce parkinsonism Dopamine receptors of the D 1 type are located in the pars compacta of the substantia nigra and presynaptically on striatal axons coming from cortical neurons and from dopaminergic cells in the substantia nigra

38. Dopamine Receptor Agonists Ergot derivatives: BROMOCRIPTINE & PERGOLIDE Bromocriptine is a D 2 receptor agonist, whereas pergolide is an agonist of both D 1 and D 2 receptors Postural hypotension, nausea, somnolence, and fatigue are ADRs of both therapy and can limit their use Because of these ADRs, the drugs are generally first administered at low doses and then the dose is gradually increased over weeks or months as tolerance to the adverse effects develops

39. Dopamine Receptor Agonists Non-ergot derivatives: PRAMIPEXOLE & ROPINIROLE Pramipexole has selective activity at D 3, whereas ropinirole is a relatively pure D 2 receptor Can be initiated more quickly, achieving therapeutically useful doses in a week or less and generally cause less GI disturbance than do the ergot derivatives Effective as monotherapy for mild parkinsonism, in patients with advanced disease, permit the dose of levodopa to be reduced and smoothing out response fluctuations

40. Dopamine Receptor Agonists ROTIGOTINE Available as a transdermal patch…..administered once- daily and provides continuous dopaminergic supply Used in the Tx of the signs and symptoms of early stage PD Recalled in USA because of crystal formation on the patches, affecting the availability and efficacy of the agonist….still available in europe

41. Dopamine Receptor Agonists APOMORPHINE (Apokyn®) Apomorphine is an injectable (s.c) potent dopamine agonists It is effective for the temporary relief ("rescue") of off- periods of akinesia in patients on optimized dopaminergic therapy It is rapidly taken up in the blood and then the brain, leading to clinical benefit that begins within about 10 minutes of injection and persists for up to 2 hours

42. Dopamine Receptor Agonists ADRs A. Gastrointestinal tract effects: Anorexia, N & V: can be minimized by taking the medication with meals Constipation, dyspepsia, and symptoms of reflux esophagitis Bleeding from peptic ulceration N.B: nausea is often severe with apomorphine….pretreatment with the antiemetic for 3 days is recommended

43. Dopamine Receptor Agonists ADRs B. Cardiovascular effeects: Postural hypotension common at the initiation of therapy especially with the ergot derivatives Dose-related painless digital vasospasm with the ergot derivatives Cardiac arrhythmias (discontinuation) Peripheral edema may be problematic Cardiac valvulopathy with pergolide (withdrawn in the US)

44. C. Dyskinesias: abnormal movements similar to those introduced by levodopa reversed by reducing the total dose of dopaminergic drugs D. Mental Disturbances: Include confusion, hallucinations, delusions, and other psychiatric reactions which are more common and severe with dopamine receptor agonists than with levodopa Dopamine Receptor Agonists ADRs

45. E. Miscellaneous Adverse Effects (ergot derivatives) o Headache, Nasal congestion o Increased arousal, Pulmonary infiltrates o Erythromelalgia (red, tender, painful, swollen feet &, occasionally, hands, at times associated with arthralgia) ….Signs clear within a few days of withdrawal of the causal drug Dopamine Receptor Agonists ADRs

47. Dopamine Receptor Agonists Contraindications 1. History of psychotic illness 2. Recent MI 3. Active peptic ulceration 4. Peripheral vascular disease (ergot derivatives)

48. Amantadine Antiviral agent, was by chance found to have antiparkinsonism properties Its MOA in parkinsonism is unclear. However it may: a. Influencing the synthesis, release, or reuptake of dopamine b. Antagonize the effects of adenosine at adenosine A 2A receptors c. Release of catecholamines from peripheral stores Less effective than L-dopa, benefits is short-lived (few weeks)

49. ADRs …..reversible by stopping the drug 1) CNS: restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, & confusion 2) Acute toxic psychosis & convulsions (overdosage) 3) Peripheral edema….respond to diuretics 4) HF, Postural hypotension 5) Urinary retention, constipation, & dry mouth 6) GI disturbances: anorexia & nausea

50. Acetylcholine-Blocking Drugs Centrally acting antimuscarinic drugs include: benzotropine mesylate, biperiden, orphenadrine, procyclidine, & trihexphenidyl Improve tremor and rigidity with little effect on bradykinesia Less efficacious than L-DOPA and thus are most commonly used during the early stages of the disease or as an adjunct to levodopa therapy

51. ADRs The adverse effects of these drugs are a result of their anticholinergic properties (CNS & peripheral effects) 1. CNS: mental confusion, delirium, and hallucinations 2. Peripheral: constipation, urinary retention, and blurred vision through cycloplegia, sinus tachycardia, & dry mouth Are contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis