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PARKINSONISM.pptx
- 1. PARKINSONISM BY NITESH KUMAR B. PHARM 2017-21 JAIPUR COLLEGE OF PHARMACY JAIPUR, RAJASTHAN
- 2. Definition a. Progressive neurodegenerative disorder b. Mostly affect older people c. First described by James Parkinson in 1817 d. Causes of Parkinson are still unknown. Signs & Symptoms a. Tremor (Involuntary shakiness) b. Rigidity (Stiffness, defective posture, expressionless face) c. Bradykinesia (Slow movements) d. Hypokinesia (lessened movements) e. Akinesia (Absence of movements) **Eventually a person becomes totally rigid, unable to move or breath and die.
- 4. Basal Ganglia- it is a part of the brain (particularly mid-brain) that controls motor movements and emotions Substantia Nigra Pars compacta (substantia= region; nigra= black)- part of the basal ganglia from where dopamine is released. Striatum (putamen + caudate nucleus) - Another part of the basal ganglia which consists of Dopamine receptors. D1 excitatory & D2- inhibitory Nigrostriatal pathway- It is pathway through which dopamine released from Substantia Nigra reaches Striatum to act on dopamine receptors. **During Parkinson disease neurons in Substantia Nigra Pars compacta gets degenerated which leads to deficiency of dopamine in our brain. Deficiency of dopamine disrupts the control of striatum on motor movements.
- 5. ANTIPARKINSONS DRUG CLASSIFICATION 1. Drugs affecting brain dopaminergic system a. Dopamine precursor: Levodopa b. Peripheral decarboxylase inhibitor: Carbidopa, Benserazole c. Dopaminergic agonist: Bromocriptine, ropinirole, pramipexole d. MAO-B Inhibitor: Selegiline e. COMT inhibitor: Entacapone, Tolcapone f. Dopamine facilitator: Amantadine 2. Drugs affecting brain cholinergic System a. Central anticholinergics: Trihexyphenidyl, Procyclidine, Biperiden b. Antihistaminics: Orphenadrine, Promethazine
- 7. LEVODOPA Pharmacological Actions Dopamine cannot itself cross blood brain barrier Levodopa, an inactive precursor of Dopamine, crosses blood brain barrier and releases dopamine after decraboxylation. 95% drug decarboxylates peripherally (acts on heart, blood vessels, other peripheral organs and on CTZ) and only 1 % actually produces dopamine in brain. Effect on CNS- Marked symptomatic improvement occurs in parkinsonian patients. Hypokinesia and rigidity resolve first, later tremor as well Effect on CVS- The peripherally formed DA can cause tachycardia by acting on 硫 adrenergic receptors. Postural hypotension is quite common Effect on CTZ (chemoreceptor trigger zone)- elicits nausea and vomiting Effect on Endocrine- inhibit Prolactin release & increase GH release
- 8. Adverse effects Side effects of levodopa therapy are frequent and often troublesome. Nausea and vomiting Postural hypotension Cardiac arrhythmias (Due to 硫 adrenergic stimulation) Abnormal movements (dyskinesias) Behavioural effects (mild anxiety, nightmares & depression) Fluctuation in motor performance (produces on-off effects)- With time all or none response develops, i.e. the patient is alternately well and disabled. Abnormal movements may jeopardize even the on phase.
- 9. PERIPHERAL DECARBOXYLASE INHIBITORS CARBIDOPA AND BENSERAZIDE They do not penetrate blood-brain barrier and thus do not inhibit conversion of levodopa to DA in the brain Administered along with levodopa, they increase its t遜 in the periphery and make more of it available to cross blood-brain barrier and reach its site of action. Levodopa dose is reduced to approximately 1/4th reduced nausea and vomiting Cardiac complications are minimized On-off effect is minimized
- 10. DOPAMINERGIC AGONISTS The DA agonists can act on striatal DA receptors Bromocriptine Ergot derivative Potent agonist on D2 and partial agonist or antagonist on D1 receptors Expensive and often produce intolerable side effects like Vomiting, hallucinations, hypotension, nasal stuffiness and marked fall in BP. Bromocriptine has been largely replaced by the newer DA agonists ropinirole and pramipexole. Ropinirole and Pramipexole Non-Ergot derivative Selective D2 receptor agonists and negligible affinity for D1 Better tolerated with fewer g.i. symptoms Side-effects are nausea, dizziness, hallucinations, and postural hypotension. Ropinirole is FDA approved for use in restless leg syndrome
- 11. MAO-B INHIBITOR Selegiline (Deprenyl) Selective and irreversible MAO-B inhibitor (large amount of MAO-B with very little MAO-A in the striatum). Does not interfere with peripheral metabolism of dietary amines; Accumulation of CAs and hypertensive reaction does not develop. Administered with levodopa, it prolongs levodopa action, attenuates motor fluctuations and decreases wearing off effect. Adverse effects like Postural hypotension, nausea, confusion, accentuation of levodopa induced involuntary movements and psychosis. Selegiline is partly metabolized by liver into amphetamine which sometimes causes insomnia and agitation and thus is contraindicated in patients with convulsive disorders.
- 12. COMT INHIBITORS Entacapone and Tolcapone Adjuvants to levodopa-carbidopa for advanced PD When peripheral decarboxylation of levodopa is blocked by carbidopa/ benserazide, it is mainly metabolized by COMT to 3-O-methyldopa Entacapone acts only in the periphery (probably because of short duration of action ~2 hr). Tolcapone also acts centrally Used to smoothen wearing off, increase on time, decrease off time, improve activities
- 13. GLUTAMATE (NMDA receptor) ANTAGONIST (Dopamine facilitator) Amantadine Developed as an antiviral drug for prophylaxis of influenza A2. Amantadine promotes presynaptic synthesis and release of DA in the brain and has anticholinergic property.