ANTIPARKINSON DRUG By Dr.shaila
- 2. Parkinsonism is a clinical syndrome with 4 cardinal features: Bradykinesia(slowness and poverty of movement) Muscular rigidity Resting tremor(usually abates during vountary movement) An impairement of postural balance leading to disturbance of gait to falling
- 4. Aging :>65 yrs Environmental factors: exposure to MPTP Poisoning due to manganese and carbon monoxide. Genetic: Alpha synuclein parkin ubiquitin
- 7. First sign Affects handwriting Aggravated by emotional stress or increased concentration Pill rolling- rotatory motion of thumb and forefinger
- 9. • Objectives of antiparkinsonian pharmacotherapy • Objectives of antiparkinsonian pharmacotherapy • The dopaminergic/cholinergic balance may be restored • by two mechanisms- • The dopaminergic/cholinergic balance may be restored by two mechanisms-
- 10. DRUGS ACTING ON DOPAMINERGIC SYSTEM: Dopamine precursors – Levodopa (l-dopa)-(0.5g) Peripheral decarboxylase inhibitors – carbidopa,benserazide COMT inhibitors – Entacapone, Tolcapone. Dopamine facilitator – Amantadine. MAO-B inhibitors – Selegiline, Rasagiline. Dopaminergic agonists:-Bromocriptine, cabergoline, Ropinirole, Pramipexole DRUGS ACTING ON CHOLINERGIC SYSTEM Central anticholinergics – Teihexyphenidyl (Benzhexol), Procyclidine, Biperiden,Benztropine. Antihistaminics – Orphenadrine, Promethazine,Diphenhydramine.
- 11. Mechanism dopamine doesnot cross BBB ,Levodopa ,precrsor of dopamine is given instead has minimal pharmacological activity rapidly decarboxylated in GIT
- 12. Pharmacokinetic: 1. Absorbed rapidly from small intestine 2. High first pass effect 3. Peak plasma conc 1-2hrs,t1/2 1-3hrs 4. Competition for amino acids present in food competes for the carrier 5. Metabolized in liver and peripherally – secreted in urine unchanged or conjugated with glucoronyl sulfate
- 13. • 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) 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.
- 14. • 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,sleep disturbances including vivid dreams, delusions, and hallucination. (4) Hyperkinesia (5) On-off phenomena Sudden discontinuation can result in malignant hyperthermia,fever, rigidity, and confusion. The drug should be withdrawn gradually over 4 days.
- 15. 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. • Protein diet interfere with l-dopa absorption both in brain and git
- 16. • 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.
- 17. Psychoses (shizophrenia) NARROW angle glaucoma Cardiac arrhythmias Melanoma Gout Peptic ulcer
- 18. D1 and D2 receptors express differentially – different areas of brain D1 is excitatory (cAMP and PIP3) D2 is inhibitory (Adenylyl cyclase and K+ and Ca++ Channels) Both present in striatum – involved in therapeutic response of levodopa Stimulation of Both – smoothening movement and reduced muscle tone Bromocriptine, pergolide, Ropinirole and Pramipexole: Bromocryptine – potent D2 agonist and D1 partial agonist and antagonist Pergolide – Both D1 and D2 agonist Newer (Pramipexole and Ropinirole) – D2 and D3 effect with low D1 effect
- 19. • BROMOCRIPTINE- proctinal-( 1.25mg) • a derivative of ergot. • It is a D2-receptor agonist, but also a weak alpha 1- blocker ( decrease gastric motility) • 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. ERYTHROMYALGIA
- 21. • 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.(VALVE FIBROSIS) • Causes vasoconstriction. • 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.
- 22. PRAMIPEXOLE- pramiprex 0.5mg • 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 its on-off response fluctuations. ROPINIROLE- ropitor 0.25mg • 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. • Also used in RESTLESS LEG SYNDROME
- 24. • ROTIGOTINE • Also non ergot 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 is D2 and D3 receptor agonist
- 25. • Side effects of dopamine agonists – 1. GI – nausea, vomitting, constipation, dyspepsia. 2. CVS – postural hypotension 3. Dyskinesias 4. Mental disturbences
- 26. SELEGILINE – selerin (5mg tab) • a selective irreversible inhibitor of monoamine oxidase B at normal doses (at higher doses it inhibits monoamine oxidase A(depression) 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. •
- 27. • 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, relgin (0.5mg) 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”.
- 29. • 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.
- 30. • 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.
- 31. • Levodopa clearance is decreased, and relative bioavailability of levodopa is thus increase d. • These agents may be helpful in patients receiving levodopa who have developed response fluctuations leading to a smoother response, more prolonged on- time. • Tolcapone (100mg) has both central and peripheral effects, whereas the effect of entacapone (200mg)is peripheral. • Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion.
- 32. • 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 ( 100mg) also has slight antimuscarinic effect. • Block glutamate & NMDA receptor. • Amantadine ARs, includes ankle edema (probably a local effect on blood vessels), orthostatic hypotension, insomnia, hallucinations, rarely – fits. • Causes LIVEDO RETICULARIS.
- 34. • BIPERIDEN, TRIHEXYPHENIDYL(2-10mg), TRIPERIDEN,PROCYCLIDINE. • 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.
- 35. • 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).
- 36. Antipsychotics: Chlorpromazine, Fluphen- zine and Haloperidol Antihypertensive like Reserpine Antiemetics: Metoclopramide (Reglan) and Prochlorperazine (Compazine), Not associated with loss of nerve cells in the substantia nigra Differ from the permanent PD associated with the nerve toxin MPTP - loss of nerve cells in the substantia nigra.