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Anti parkinsonian drugs

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Anti parkinsonian drugs

  1. 1. ANTI-PARKINSONIAN DRUGS Dr. Mohit Kulmi Post-Graduate Resident, Dept. of Pharmacology SAIMS, Indore
  2. 2. INTRODUCTION Parkinsonism is a clinical syndrome with 4 cardinal features: • Bradykinesia (slowness and poverty of movement) • Muscular rigidity • Resting tremor (which usually abates during voluntary movement) • An impairment of postural balance leading to disturbances of gait and to falling
  3. 3. • The most common form of parkinsonism is idiopathic PD, • first described by James Parkinson in 1817 as paralysis agitans, or the “shaking palsy.” • The pathological hallmark of PD is the loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta, • with the appearance of intracellular inclusions known as Lewy bodies. • A loss of 70-80% of these dopamine-containing neurons accompanies symptomatic PD.
  4. 4. • Without treatment, PD progresses over 5-10 years to a rigid, akinetic state in which patients are incapable of caring for themselves. • Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. • The availability of effective pharmacological treatment has radically altered the prognosis of PD; • in most cases, good functional mobility can be maintained for many years. • Life expectancy of adequately treated patients is increased substantially, but overall mortality remains higher than that of the general population. • PD affects a wide range of other brain structures, including the brainstem, hippocampus, and cerebral cortex.
  5. 5. • This pathology is likely responsible for the “non-motor” features of PD, which include sleep disorders, depression, and memory impairment. • Several disorders other than idiopathic PD also may produce parkinsonism, • Drugs that may cause parkinsonism include antipsychotics such as haloperidol and chlorpromazine • and antiemetics such as prochlorperazine and metoclopramide. • The distinction between idiopathic PD and other causes of parkinsonism is important because parkinsonism arising from other causes usually is refractory to all forms of treatment.
  6. 6. ETIOLOGIC FACTORS Aging: • The possible role of aging in the pathogenesis of PD is suggested by its usual occurrence in late middle age, and by marked increases in its prevalence at older ages. Environmental Factors: • with the discovery in 1983 that exposure to MPTP is capable of inducing parkinsonism in humans.
  7. 7. Genetic: • The most important advances in PD research in recent years - the identification of specific disease-causing mutations, • making it possible for the first time to begin to explore pathogenesis at the molecular level. • best documented and most widely investigated genetic causes being - synuclein and parkin.
  8. 8. THE BASAL GANGLIA •Consists of a group of nuclei in the deep part of the cerebrum and upper brain stem: caudate, putamen, globus pallidus, subthalamic nucleus, substantia nigra •Coordinates muscle actions and voluntary movements •Controls the higher-order, cognitive aspects of voluntary movement: the planning and execution of complex motor strategies •Cognitive functions (procedural memory - skills & habits) •Structural defects and neurotransmitter imbalance cause movement disorders: hypokinesia or hyperkinesia
  9. 9. • Add pic
  10. 10. PATHOGENESIS • Degeneration of dopamine-producing neurons in the substantia nigra of the midbrain • Disrupts the balance of: • dopamine (DA) – neurotransmitter for normal functioning of the extrapyramidal motor system (control of posture, support, and voluntary motion) • Acetylcholine (Ach) • in the basal ganglia • Symptoms do not occur until 80% of the neurons in the substantia nigra are lost.
  11. 11. CNS ANTIPARKINSONIAN DRUGS
  12. 12. CLINICAL SYMPTOMS • Five Stages • Flexion of affected arm - tremor / leaning toward unaffected side • Slow shuffling gate • Increased difficulty walking – looks for support to prevent falls • Further progression of weakness – assistance with ambulation • Profound disability – may be confined to wheelchair
  13. 13. • Tremor • First sign • Affects handwriting – trailing off at ends of words • More prominent at rest • Aggravated by emotional stress or increased concentration • “Pill rolling” – rotary motion of thumb and forefinger
  14. 14.  Rigidity • Increased resistance to passive motion when limbs are moved through their range of motion • “Cogwheel rigidity” -- Jerky quality – intermittent catches of movement • Caused by sustained muscle contraction • Muscle soreness; feeling tired & achy • Slowness of movement due to inhibition of alternating muscle group contraction & relaxation in opposing muscle groups
  15. 15. • Bradykinesia • Loss of automatic movements: • Blinking of eyes, swinging of arms while walking, • swallowing of saliva, self-expression with facial and hand movements, • lack of spontaneous activity, lack of postural adjustment • Results in: stooped posture, masked face, drooling of saliva, shuffling gait; difficulty initiating movement
  16. 16. TREATMENT • Objectives of antiparkinsonian pharmacotherapy • The dopaminergic/cholinergic balance may be restored by two mechanisms-
  17. 17. • 1. Enhancement of DA-ergic activity by drugs which may: • replenish neuronal DA by supplying levodopa, which • is its natural precursor; administration of DA itself is • ineffective as it does not cross the BBB; • act as DA agonists (bromocriptine, pergolide, cabergoline, etc.); • prolong the action of DA through selective inhibition of its metabolism (selegiline); • release DA from stores and inhibit reuptake (amantadine).
  18. 18. • 2. Reduction of cholinergic activity by antimuscarinic drugs • this approach is most effective against tremor and rigidity, • and less effective in the treatment of bradykinesia.
  19. 19. CLASSIFICATION
  20. 20. LEVODOPA • Mechanism: 1. Because dopamine does not cross the blood-brain barrier levodopa, the precursor of dopamine, is given instead. 2. Levodopa is formed L-tyrosine and is an intermediate in the synthesis of catecholamines. 3. Levodopa itself has minimal pharmacologic activity, in contrast to its decarboxylated product, dopamine. 4. Levodopa is rapidly decarboxylated in the gastrointestinal tract. Prior to the advent of decarboxylase inhibitors (carbidopa), large oral doses of levodopa were required; thus, toxicity from dopamine was a limiting factor.
  21. 21. LEVODOPA • Pharmacokinetics: (1) Levodopa is well absorbed from the small bowel; however, 95% is rapidly decarboxylated in periphery. (2) Peripheral dopamine is metabolized in the liver to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), which are then excreted in urine.
  22. 22. LEVODOPA • Pharmacologic effects: (1) The effects on bradykinesia and rigidity are more rapid and complete than the effects on tremor. Other motor defects in PD improve. The psychological well- being of patient is also improved. (2) (2) Tolerance to both beneficial and adverse effects occurs with time. Levodopa is most effective in the first 2-5 years of treatment. After 5 years of therapy, patients have dose-related dyskinesia, inadequate response, or toxicity.
  23. 23. LEVODOPA • Adverse effect: Principal adverse effects include: (1) Anorexia, nausea, and vomiting upon initial administration, which often limit the initial dosage. (2) Cardiovascular effects, including tachycardia, arrhythmias, and orthostatic hypotension. (3) Mental disturbances, including vivid dreams, delusions, and hallucination. (4) Hyperkinesia (5) On-off phenomena Sudden discontinuation can result in fever, rigidity, and confusion. The drug should be withdrawn gradually over 4 days.
  24. 24. LEVODOPA Drug interactions: • Vit B6 reduces the beneficial effects of Levodopa by enhancing its extracerebral metabolism. • Therapy with MAO inhibitors must be stopped 14 days prior to the initiation of levodopa therapy. • Phenothiazines, reserpine, and butyrophenones antagonize the effects of levodopa because they lead to a junctional blockade of dopamine action.
  25. 25. CARBIDOPA • Carbidopa is an inhibitor of dopa decarboxylase. • Because it is unable to penetrate the blood-brain barrier, it acts to reduce the peripheral conversion of levodopa to dopamine. • As a result, when carbidopa and levodopa are given concomitantly: a. It can decrease the dosage of levodopa. b. It can reduce toxic side effects of levodopa.
  26. 26. • BROMOCRIPTINE • a derivative of ergot. • It is a D2-receptor agonist, but also a weak alpha- blocker. • Bromocriptine is commonly used with levodopa. • It should be started at very low doses, increasing at weekly interval and according to clinical response. • It is also used for treatment of prolactin-secreting adenomas, amenorrhea/galactorrhea to hyperprolactinemia, to stop lactation, acromegaly. • ADRs: Nausea and vomiting, which may be prevented with domperidone; postural hypotension (may cause dizziness or syncope); after prolonged use – pleural effusion and retroperitoneal fibrosis.
  27. 27. • Pergolide, another ergot derivative, directly stimulates dopamine receptors. It too has been widely used for parkinsonism. • but has been associated with the development of valvular heart disease. • CABERGOLINE, also an ergot derivative, has a t1/2 >80h. • This allows it to be used in a single daily (or even twice weekly) dose. • Cabergoline alleviates night-time problems in parkinsonian patients.
  28. 28. PRAMIPEXOLE • Pramipexole is not an ergot derivative, but it has preferential affinity for the D family of receptors. • It is effective as monotherapy for mild parkinsonism and is also helpful in patients with advanced disease, permitting the dose of levodopa to be reduced and • smoothing out response fluctuations. ROPINIROLE • is a relatively pure D receptor agonist that is effective as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa in patients with advanced disease and response fluctuations.
  29. 29. • Rotigotine • The dopamine agonist rotigotine, delivered daily through a skin patch, was approved in 2007 by the Food and Drug Administration (FDA) for treatment of early Parkinsons disease. • It supposedly provides more continuous dopaminergic stimulation than oral medication in early disease; its efficacy in more advanced disease is less clear.
  30. 30. • Side effects of dopamine agonists – 1. GI – nausea, vomitting, constipation, dyspepsia. 2. CVS – postural hypotension 3. Dyskinesias 4. Mental disturbences
  31. 31. MAO INHIBITORS• Selegiline – • a selective irreversible inhibitor of monoamine oxidase B at normal doses (at higher doses it inhibits monoamine oxidase A as well), • retard the breakdown of dopamine, in consequence it enhances and prolongs the antiparkinsonism effect of levodop (thereby allowing the dose of levodopa to be reduced) • It is therefore used as adjunctive therapy for patients with a declining or fluctuating response to levodopa. •
  32. 32. • The standard dose of selegiline is 5 mg with breakfast and 5 mg with lunch. Selegiline may cause insomnia when taken later during the day. • Rasagiline, another monoamine oxidase B inhibitor, is more potent than selegiline in preventing MPTP- induced parkinsonism and is being used for early symptomatic treatment. • The problem with nonselective MAO inhibitors is that they prevent degradation of dietary adrenomimetic amines, especially tyramine, by MAO-A inhibition which causes hypertensive “cheese reaction”.
  33. 33. • Selegiline does not cause the cheese reaction, because MAO-A is still present in the liver to metabolize tyramine. • MAO-A also metabolizes tyramine in the sympathetic nerve endings in periphery. • Selegiline inhibits selectively only MAO-B in the CNS and protects DA from intraneuronal degradation. • It is used as an adjunct drug in PD if levodopa/carbidopa or levodopa/benserazide therapy is deteriorating.
  34. 34. CATECHOL-O-METHYLTRANSFERASE INHIBITORS • Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of levodopa metabolism, especially catechol- O –methyltransferase (COMT), and this increases plasma levels of 3- O- methyldopa (3-OMD). • Elevated levels of 3-OMD have been associated with poor therapeutic response to levodopa, • Selective COMT inhibitors such as tolcapone and entacapone also prolong the action of levodopa by diminishing its peripheral metabolism.
  35. 35. • Levodopa clearance is decreased, and relative bioavailability of levodopa is thus increased. • These agents may be helpful in patients receiving levodopa who have developed response fluctuations leading to a smoother response, more prolonged on- time. • Tolcapone has both central and peripheral effects, whereas the effect of entacapone is peripheral. • Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion.
  36. 36. AMANTADINE • is an antiviral drug which, given for influenza to a parkinsonian patient, was noted to be beneficial. • Antiviral and antiparkinsonian effects of amantadine are unrelated. • Antiparkinsonian effect is due to increase synthesis and release of DA, and diminish neuronal reuptake too. • Amantadine also has slight antimuscarinic effect. • Amantadine ARs, includes ankle edema (probably a local effect on blood vessels), orthostatic hypotension, insomnia, hallucinations, rarely – fits.
  37. 37. • Central antimuscarinic drugs • BIPERIDEN, TRIHEXYPHENIDYL, TRIPERIDEN • are synthetic compounds (central parasympatholytics). • They benefit parkinsonism by blocking ACh receptors in the CNS, thereby partially redressing the imbalance created by decreased DA-ergic activity. • They also produce modest improvement in tremor, rigidity, sialorrhoea (hypersalivation), muscular stiffness and leg cramp, but little in bradykinesia, which is the most disabling symptom of Parkinson’s disease.
  38. 38. • ARs of antimuscarinic drugs include • dry mouth (xerostomia), • blurred vision, • constipation, • urine retention, glaucoma, • hallucinations, memory defects, toxic confusional states and psychoses (which should be distinguish from presenile dementia).
  39. 39. PHARMACOTHERAPY OF PD • The main features that require alleviation are tremor, rigidity and bradykinesia. • Drug therapy has the most important role in symptom relief, but it does not alter the progressive course of PD. • Treatment should begin only when it is judged necessary in each individual case. • Two objectives have to be balanced: the desire for satisfactory relief of current symptoms and the avoidance of ARs as a result of long-continued treatment.
  40. 40. • Levodopa provides the biggest improvement in motor activity but its use is associated with the development of dyskinesia (involuntary movement of the face and limbs) after 5–10 years, and sometimes sooner. • DA agonists have a much less powerful motor effect but are less likely to produce dyskinesias. • The treatment usually begins with levodopa in low doses to get a good motor response and adds a DA agonist when the initial benefit begins to wane.
  41. 41. • A typical course is that for about 2–4 years on treatment with levodopa or DA agonist, the patient’s disability and motor performance remains near normal despite progression of the underlying disease. • After some 5 years about 50% of patients exhibit problems of long-term treatment, namely, dyskinesia and end-of-dose deterioration with the “on-off” phenomenon. • After 10 years virtually 100% of patients are affected. • End-of-dose deterioration is managed by increasing the frequency of dosing with levodopa (e.g. to 2 or 3- hourly), but this tends to worsen the dyskinesia.
  42. 42. • The motor response then becomes more brittle with abrupt swings between hyper- and hypomobility (the on-off phenomenon). • In this case a more effective approach is to use a COMT inhibitor, e.g. entacapone, which can sometimes allay early end-of-dose deterioration without causing dyskinesia. • Some 20% of the patients with Parkinson’s disease, notably the Elderly ones, develop impairment of memory and speech with a fluctuating confusional state and hallucinations. • As these symptoms are often aggravated by medication, it is preferable gradually to reduce the antiparkinsonian treatment.
  43. 43. FUTURE THERAPIES 1. MAOI – safinamide 2. DA – sumanirole 3. Antidyskinesia drugs – sarizotan, istradefyllin, fipamazole, levetiracetem. 4. Trophic drugs – CERE120 (CERE-120 is an adeno assosiated virus rtype 2 encoding human NTN), Neutrophic factor such as neurturin (NTN), Glial cell lined derived neurotrophic factors (GDNF) 5. Neuroprotective drugs – CoQ10, TCH346, CEP1347. 6. Surgery – Deep Brain Stimulation • Creating a lesion in the subthalamic nucleus or globus pallidus • Thalamotomy, pallidotomy, spheramine, • Retinal pigment epithelial cells

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