Lecture slides for Medical Undergraduate teaching in Pharmacology. Study material is based on Essentials of medical pharmacology by KD tripathi and Katzung. Figures are obtained from google image search and above mentioned textbooks.
6. Parkinson’s Disease
Extrapyramidal motor disorder
Progressive, Degenerative
Rigidity, tremor and Hypokinesia
Defective posture, Gait, Mask like face
Sialorrhoea, Dementia.
7. Environmental Toxins
Protein Damage
Lipid Peroxidation
DNA Damage
AgingNeuronal Metabolism
Selective Vulnerability of
neuronal cells
Free radical formation,
Oxidative stress
Excitotoxicity
Cell
death
17. Levodopa
Inactive, Precursor of Dopamine
95% converted into dopamine peripherally by
decarboxylation
Which exerts systemic action
Remaining enters brain, converted into dopamine
18. Levodopa: CNS
Symptomatic relief in Hypokinesia, rigidity and tremors
Person become more alert
Gradual Normalization of symptoms
No effect on dementia
22. Levodopa: ADRs
After Chronic Use
•Abnormal movements
•Behavioral abnormalities
•Fluctuations in Beneficial effects
•Wearing off phenomena
•On-off phenomenon
23. Wearing off (End of Dose)
Occur at later stage on chronic use
Each dose improves mobility
Rigidity and akinesia return at the end of dosing interval
24. On-OFF Phenomena
All or None response
On phase may be complicated by dyskinesia
Off phase with severe disease
28. Amount of Levodopa in CNS ↑ , so dose ↓ up to 1/4th
Systemic ADRs of Levodopa ↓
Minimization of cardiac ADRs
Minimization of on-off effect
Degree of improvement higher
30. Dopamine Agonist
Can act on striatal DA receptors
Even in advanced patient who lost ability to synthesize, Store
and Release DA
Longer acting
Exert Subtype selective activation of DA receptors
31. Bromocriptine
Potent D2 agonist, Partial agonist/antagonist at D1 receptor
Symptomatic improvement with in 30-60 minutes, last for 6-10 hours
High dose needed for monotherapy, which produces intolerable side
effects
Vomiting, Hallucinations, Hypotension, Nasal Stuffiness
Used to smoothen ‘on off’ fluctuations with l-dopa
32. Ropinirole & Pramipexole
Selective D2/D3 agonist
Pramipexole has greater affinity for D3 receptors
Used as supplementary drug to L-dopa with tolerable S/E in
advanced cases
Dose titration take 1-2 weeks
33. Ropinirole & Pramipexole
Used as monotherapy in early cases
Lower chances of motor fluctuations and dyskinesia in
comparison to L-dopa
Slower rate of neuronal degeneration in clinical studies
Alternative to L-Dopa for longer symptom free life
35. Ropinirole & Pramipexole: S/E
Nausea
Dizziness, Hallucinations
Postural hypotension
Episodes of day time sleep
Patients advised not drive
36. MAO-B Inhibitor: Selegiline
Selective, Irreversible MAO-B Inhibitor
Retard intracerebral degradation of dopamine
In low doses does not interfere with peripheral metabolism of
dietary amines
Less chances of accumulation of CAs and hypertensive reactions
37. MAO-B Inhibitor: Selegiline
Mild action as monotherapy
With L-dopa, attenuates motor fluctuations, ↓ ‘wearing off’
20-30% reduction in L-dopa dose
Advanced cases with ’on-off’ effect not improved
Worsening of dyskinesia, mental confusion and hallucinations
38. Selegiline: Adverse effects
Postural hypotension, Nausea, confusion
Accentuation of L-dopa induced involuntary movements and
psychosis
Insomnia and agitation due to metabolism into amphetamine
Contraindicated in epilepsy
40. Rasagiline
5 time potent, longer acting
Not metabolised to amphetamine
Does not produce excitatory side effects
Some evidence of neuro protective effects
42. Entacapone, Tolcapone
Selective, reversible inhibitors of COMT
Prevent metabolism of L-dopa by COMT peripherally
Preserve DA formed in striatum
Enhance therapeutic effect of L-dopa
43. Entacapone, Tolcapone
Smoothen ‘wearing off’
Increase ‘on’ time, decrease ‘off’ time
Improves daily activities
Dose of L-dopa can be decreased
Not given for early cases
44. Entacapone, Tolcapone: A/Es
Worsening of L-dopa A/Es
Nausea, Vomiting, Dyskinesia, Postural Hypotension, Hallucinations
Diarrhoea
Orange yellow discoloration of urine
Acute fatal hepatitis and Rhabdomyolysis: Tolcapone
45. NMDA antagonist: Amantadine
Rapidly acting, lower efficacy than L-dopa
Tolerance develops in months and efficacy is lost
Promotes presynaptic synthesis and release of DA in brain,
Has some anticholinergic property
Inhibit NMDA glutamate receptors
46. Amantadine
Can be used in mild cases
Short course to supplement L-dopa
Supress motor fluctuations and abnormal movements
S/Es – Insomnia, restlessness, confusion, nightmares, Anticholinergic
effects
Livedo reticularis – Local release of Cas, edema of ankles
47. Central anticholinergics
Higher central: peripheral anticholinergic ration
Reduce the unbalanced cholinergic activity
Efficacy is lower than Levodopa
Only drug effective in drug induced parkinsonism
Trihexyphenidyl, Procyclidine, Promethazine
48. Central anticholinergics
10-25 % improvement symptomatically for 4-8 hours
Tremor is well controlled than rigidity, Hypokinesia not affected
Sialorrhoea controlled by peripheral action
Monotherapy in mild cases or when L-dopa is contraindicated
Combined with L-dopa to reduce the dose
49. Central Anticholinergics
S/E – similar to atropine
Impairment of memory, confusion and blurred vision in elderly
Urinary retention in elderly males
50. No drug can alter basic pathology of disease
Drugs used to provide symptomatic relief, additional happier and
productive life
In case of mild cases – anticholinergics or Selegiline
Ropinirole/ Pramipexole in early cases in young patients
Selegiline can be combined with L-dopa to overcome ‘ wearing off’
phenomena
51. L-dopa+ Decarboxylase is standard therapy,
Combination reduces early complications not late
Start with lower dose and titration in 2-3 months
Benefit last for 2-3 years before decline
Subsequently ‘wearing off’ is seen, dyskinesia appear
Drug holiday not practised now
52. L-dopa alone used only in patients who develop intolerable
dyskinesia
Amantadine used for brief period of exacerbation
Ropinirole/ Pramipexole – to supplement L-dopa in late cases to
smoothen ‘on off’, to reduce the dose and dyskinesia
Entacapone in advanced cases with L-dopa+ carbidopa –
Prolong action and smoothen ‘on off’ fluctuations
Notas del editor
first clear medical description was written in 1817 by James Parkinson.
Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes.
- Extrapyramidal motor disorder characterized by rigidity, tremor and Hypokinesia with secondary manifestations like defective posture and gait, mask like face and Sialorrhoea and dementia.
Functional circuitry between the cortex, basal ganglia, and thalamus. The major neurotransmitters are indicated. In Parkinson’s disease, there is degeneration of the pars compacta of the substantia nigra, leading to overactivity in the indirect pathway (red) and increased glutamatergic activity by the subthalamic nucleus.
Striatum receive Excitatory Glu input from motor cortex and modulatory Dopaminergic input from SN-PC. Balancing Cholinergic interneurons in striatum
Output from Stritum to GP I and SN-PR via direct and indirect pathway. Direct pathway releases GABA while dominant indirect pathway hay GABA (Inhibitory) and Glu (Excitatory) relay.
Degenrative lesion in SN-PC decreases dopaminergic input to the striatum leading to imbalance between DA and Ach and producing Hypokinesia, Rigidity and tremor.
Direct pathway facilitates BG output to the thalamus and motor areas
Indirect pathway disinhibits the STN and in turn inhibits thalamus and motor areas.
BG plays a important role in planning and programming of movement by selecting and inhibiting specific motor strategies.
BG plays a role in some cognitive processes in awareness of body orientation in space, ability to adapt behaviour as task requirements change and motivation
Loss of dopamine results in an overactive indirect pathway that is thought to underlie Akinesia and Rigidity.
Underactive direct pathway is responsible for Bradykinesia.
Posture, Gait, Handwriting, Speech, Facial expression, Mood and self-care gradually normalize
some patients this progresses to excitement— frank psychosis may occur. Embarrassingly disproportionate increase in sexual activity has also been noted
Dopamine decrease central sympathetic outflow
Gradual tolerance develops to both cardiac stimulant and hypotensive actions.
AbN Movt – fascial tics, grimacing, tounge thrusting, Choreoathetoid movt, - develops within months.
Behavioral AbN – Mild anxiety, Nightmares, Depression, Mania, Hallucination, Confusion, Psychosis
Fluctuation in motor fn – after 2-5 yrs of therapy.
Increasing the dose and frequency can give relief but limited by development of dyskinesia
Reflection of progression of disease
Neurons loss ability to store and release DA
Dose fractionation and frequent administration tends to diminish this for a time.
Pyridoxine – nullify therapeutic effect by enhancing per. Decarboxylation
Phenothiazines, butyrophenones and Metoclopramide
Mao Inhibitors – HTN crisis can occur due to inhibition of peripheral DA
AntiHTN – Postural Hypotension
Atropine – Retard absorption,More time available for per degradation
Two isoenzyme forms of MAO, termed MAO-A and MAO-B are recognized; both are present in peripheral adrenergic structures and intestinal mucosa, while the latter predominates in the brain and blood platelets.
clinical benefits derived from selegiline are short lived (6–26 months).
Based on the hypothesis that oxidation of DA and/or environmental toxins (MPTP-like) in the striatum by MAO to free radicals was causative in parkinsonism, it was proposed that early therapy with selegiline might delay progression of the disorder. However, no difference in the course of the disease has been detected on follow up of selegiline treated patients in large multicentric studies