3. Parkinsonism (PD)
Extrapyramidal motor function disorder
characterized by
Rigidity
Tremor
Hypokinesia/Bradykinesia
Impairment of postural balance - falling
4. Parkinsonism (PD) – contd.
Rigidity
Increased resistance to passive motion
when limbs are moved through their
range of motion – normal motions
“Cogwheel rigidity” -- Jerky quality –
intermittent catches of movement
Caused by sustained involuntary contraction
of one or more muscles
– Muscle soreness; feeling tired & achy
– Slowness of movement due to inhibition of
alternating muscle group contraction & relaxation
in opposing muscle groups
5. Parkinsonism (PD) – contd.
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
NOT essential tremor – intentional
6. Parkinsonism (PD) – contd.
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 (festinating);
difficulty initiating movement
9. History – Parkinson`s disease
Parkinson's disease was first formally
described in "An Essay on the Shaking
Palsy," published in 1817 by a London
physician named James Parkinson, but it
has probably existed for many thousands
of years. Its symptoms and potential
therapies were mentioned in the Ayurveda,
the system of medicine practiced in India
as early as 5000 BC, and in the first
Chinese medical text, Nei Jing, which
appeared 2500 years ago
10. Parkinson`s disease -
Pathophysiology
The Basal Ganglia
Consists of Five Large
Subcortical Nuclei that
Participate in Control
of Movement:
Caudate Nucleus
Putamen
Globus Pallidus
Subthalamic Nucleus
Substantia Nigra
11. PD, Pathophysiology – contd.
Striatum – Caudate
Nucleus and
Putamen
Substancia nigra
pars compacta
provide DA
innervation to
striatum
12. PD, Pathophysiology – contd.
Degeneration of
neurones in the
substantia nigra pars
compacta
Degeneration of
nigrostriatal
(dopaminergic) tract
Results in deficiency
of Dopamine in
Striatum - >80%
13. PD, Pathophysiology – contd.
Disruption of balance between
Acetylcholine and Dopamine:
Striatum
Substancia
Nigra
DA fibres (Nigrostrital
pathway)
GABAergic fibres
Cholinergic
14. PD, Pathophysiology – contd.
Imbalance primarily between the excitatory
neurotransmitter Acetylcholine and inhibitory
neurotransmitter Dopamine in the Basal Ganglia
ACh
DA
15. PD - Etiology
Oxidation of DA by MAO B and aldehyde dehydrogenase –
free radical (OH) in presence of Iron
Normally quenched by glutathione
Age related changes/or acquired defects – damages DNA and
lipid membranes
Common factors:
Cerebral atherosclerosis
Viral encephalitis
Side effects of several antipsychotic drugs (i.e., phenothiazides,
butyrophenones, reserpine)
Pesticides, herbicides, industrial chemicals - contain
substances that inhibit complex I in the mitochondria
16. Etiology of PD – contd.
Genetic:
α-sinuclein (synaptic protein)
Parkin (a ubiquitin protein ligase)
UCHL1
DJ-1 protein
Environmental triggers:
Infectious agents – Encephalitis lethargica (epidemc)
Environmental toxins - MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
Acquired Brain Injury
Excitotoxicity
Glutamate, the normal excitatory transmitter in neurones in excess
Mediated by activated NMDA receptor
Ca++ overload – destructive processes
Energy metabolism and aging:
Reduction in function of complex 1 of mitochondrial-electron transport chain
MPTP
Oxidative stress: Free radicals (`OH) – hydrogen peroxide and oxyradicals
17. PD - Mechanism
Environmental
Toxins
Neuronal
Metabolism Aging
Free radical formation,
oxidative stress,
excitotoxicity
Selective
vulnerability of
neuronal population
DNA Damage
Lipid
peroxidation Protein Damage
Cell Death
20. Classification of antiparkinsonian
Drugs:
Drugs acting on dopaminergic system:
Dopamine precursors – Levodopa (l-dopa)
Peripheral decarboxylase inhibitors – carbidopa and
benserazide
Dopaminergic agonists: Bromocriptyne, Ropinirole and
Pramipexole
MAO-B inhibitors – Selegiline, Rasagiline
COMT inhibitors – Entacapone, Tolcapone
Dopamine facilitator - Amantadine
Drugs acting on cholinergic system
Central anticholinergics – Teihexyphenidyl (Benzhexol),
Procyclidine, Biperiden
Antihistaminics – Orphenadrine, Promethazine
21. Antiparkinsonian Drugs – contd.
Dopamine and Tyrosine Are Not Used for
Parkinson Disease Therapy, Why?
Dopamine Doesn't Cross the Blood Brain
Barrier
Huge amount of tyrosine decreases activity of
rate limiting enzyme Tyrosine Hydroxylase
23. Individual Drugs
Levodopa:
Single most effective agent in PD
Inert substance – decarboxylation to
dopamine
95% is decarboxylated to dopamine in
gut and liver
1 - 2% crosses BBB, taken up by
neurones and DA is formed
24. Levodopa - Pharmacokinetics
Absorbed rapidly from small intestine – aromatic amino acid
transport system
High First Pass Effect – large doses
Peak plasma conc. 1-2 hrs and half life - 1 to 3 Hrs
Depends on gastric emptying and pH
Competition for amino acids present in food competes for
the carrier
Metabolized in liver and peripherally - secreted in urine
unchanged or conjugated with glucoronyl sulfate
Central entry into CNS (1%) - mediated by membrane
transporter for aromatic amino acids – competition with
dietary protein
In CNS – Decarboxylated and DA is formed – therapeutic
effectiveness
Transport back by presynaptic uptake or metabolized by
MAO and COMT
26. Levodopa (Pharmacological
actions)
CNS:
Effective in Eliminating Most of the Symptoms
of Parkinson Disease
Bradykinesia and Rigidity Respond Quickly
Reduction in Tremor Effect with Continued
therapy
Handwritting , speech, facial expression and
interest in life improves gradually
L Dopa less Effective in Eliminating Postural
Instability and Shuffling Gait Meaning Other
Neurotransmitters Are Involved in Parkinson
Disease
27. Levodopa (Pharmacological
actions) - contd
CVS:
Cardiac Stimulation Due to Beta adrenergic effect on
Heart - Propranolol produces
Though stimulates peripheral adrenergic receptor – no
rise in BP
Orthostatic Hypotension - some individuals – central DA
and NA action
In elderly cardiovascular problems - transient
tachycardia, cardiac arrhythmias and hypertension
Tolerance to CVS action develops within few weeks
CTZ: DA receptors cause stimulation – nausea and vomiting
– tolerance
Endocrine: Decrease in Prolactin level and increase in GH
release
28. Levodopa (adverse effects) -Initial
Therapy:
Nausea and vomiting - 80% of patients
(CTZ outside BBB)
Postural hypotension – 30 % of patients
tolerance develops (Central alpha-2
action)
Cardiac arrhythmias - due to beta
adrenergic action
Exacerbation of angina
29. Levodopa (adverse effects) - Initial
Therapy:
Abnormal movements: Facial tics,
grimacing, tongue thrusting, choreoathetoid
movements
Behavioural effects:
20 to 25% of Population
Trouble in Thinking (Cognitive Effects)
L Dopa can induce: Anxiety, psychosis,
confusion, hallucination, delusion
Hypomania - Inappropriate Sexual Behavior;
"Dirty Old Man", "Flashers“
- Drug Holiday
30. Levodopa (Pharmacological
actions) - contd.
Behavioural Effects:
Partially Changes Mood by elevating
mood, and increases Patient sense of
well being
General alerting response
Disproportionate increase in sexual
activity
No improvement in dementia
31. Levodopa (adverse effects) -
Prolonged therapy – contd.
Fluctuation in Motor Performance:
Initial therapy – each dose - good duration of action
Prolonged therapy – “buffering” capacity is lost – each
dose causes fluctuation of motor state - each dose has
short duration of action– short therapeutic effect (1 – 2
Hrs) – bradykinesia and rigidity comes back quickly
Increase in dose and frequency – DYSKINESIA –
excessive abnormal involuntary movements
Dyskinesia often with high plasma conc. of levodopa
Dyskinesia = Bradykinesia and Rigidity in terms of
patient comfortness
"On/off" Phenomenon
Like a Light Switch: Without Warning
32. Levodopa (adverse effects) -
Prolonged therapy – contd.
Denervation Supersensitivity:
In Basal Ganglia – destruction of Dopaminergic
Neurons –increase in Dopamine Receptors
postsynaptically
L Dopa Therapy - increase Dopamine at
synaptic Cleft - but too many Receptors -
Denervation Supersensitivity
Effect - Increased Postsynaptic Transmission
Initial disappearance of Parkinson Syndrome
Onset of Dyskinesia
33. Levodopa – Drug Interactions
Pyridoxine – abolishes therapeutic effect of levodopa
Antipsychotic Drugs – Phenothiazines, butyrophenones block the
action of levodopa by blocking DA receptors.
Antidopeminergic – domperidone abolishes nausea and vomiting
Reserpine – blocks levodopa action by blocking vesicular uptake
Anticholinergics – synergistic action but delayed gastric emptying –
reduced effect of levodopa
Nonspecific MAO Inhibitors – Prevents degradation of peripherally
synthesized DA – hypertensive crisis by the tyramine-cheese effect
(tyramine is found in cheese, coffee, beer, pickles and chocolate),
when given to a person taking a MAO Inhibitor - tyramine is not
broken down - tremendous release of Norepinephrine)
34. Classification of antiparkinsonian
Drugs:
Drugs acting on dopaminergic system:
Dopamine precursors – Levodopa (l-dopa)
Peripheral decarboxylase inhibitors – carbidopa and
benserazide
Dopaminergic agonists: Bromocriptyne, Ropinirole and
Pramipexole
MAO-B inhibitors – Selegiline, Rasagiline
COMT inhibitors – Entacapone, Tolcapone
Dopamine facilitator - Amantadine
Drugs acting on cholinergic system
Central anticholinergics – Teihexyphenidyl (Benzhexol),
Procyclidine, Biperiden
Antihistaminics – Orphenadrine, Promethazine
35. Levodopa and Peripheral
decarboxylase inhibitors combined –
Why ??
Carbidopa and Benserazide:
In practice, almost always administered
Do not penetrate BBB
Do not inhibit conversion of l-dopa to DA in
brain
Co-administration of Carbidopa - will decrease
metabolism of l-dopa in GI Tract and peripheral
tissues - increase l-dopa conc in CNS -
meaning decrease l-dopa dose and also control
of dose of l-dopa
36. Levodopa and Peripheral
decarboxylase inhibitors – contd.
Benefits:
Plasma t1/2 – prolonged
Dose of levodopa – 30% reduction
Reduction in systemic complications
Nausea and Vomiting – less
Cardiac – minimum complications
Pyridoxine reversal of levodopa – do not occur
On/Off effect – minimum
Better overall improvement of patient – even in
non responding patients to levodopa
38. Dopamine receptors agonists
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
39. Bromocriptine – Synthetic ergot
derivative
Basically used in hyperprolactinemia and acromegally
Levodopa like action in CNS
Quick improvement of PD symptoms and longer lasting (1 hr
and 6-10 Hrs)
Monotherapy:
High doses and expensive
Intolerable side effects – vomiting, hallucinations, hypotension
(1st
dose) and nasal stuffiness
Uses: late cases as supplement to levodopa – 1.25 mg OD
at night and increasing upto 5-10 mg tds
Benefits:
End of Dose phenomenon smoothening and less “on-off” phenomenon
Also less DYSKINESIA
40. Ropinirole and Pramipexole
Newer agents with selective D2/D3 agonist
property with low D1 activity
Like Bromocriptine, both are well absorbed orally
Similar therapeutic action and used in advance
cases as supplementary drugs
Advantages over Bromocriptine
less GIT symptoms (vomiting)
Dose titration for maximum improvement in 1-2 weeks
Started using as monotherapy – comparable
efficacy with levodopa
Supplementary levodopa is not required (but with
Bromocriptine)
Meta analysis – slower degeneration
41. Ropinirole and Pramipexole –
contd.
Adverse effects
Nausea, dizziness, postural hypotension
and hallucination
Episodes of day time sleep
Restless leg syndrome
42. Dopamine receptors agonists –
contd.
Newer Vs Older DA receptor agonists
More tolerable – Nausea, vomiting and fatigue
Dose titration - Slow upward adjustment of dose
Newer ones – Somnolence (Irresistible Sleepiness)
Initial treatment of PD: Newer drugs are used now:
Longer duration of action than L-dopa – less chance of
on/off effect and dyskinesia
No oxidative stress and thereby loss of dopaminergic
neurons
Reduced rate of motor fluctuation
Restless leg syndrome/Wittmaack-Ekbom's
syndrome/the jimmylegs - Ropinirole
44. Entacapone and Tolcapone –
contd.
Reduce wearing off phenomenon in patients with
levodopa and carbidopa
Common adverse effects similar to levodopa
Entacapone:
Peripheral action on COMT
Duration of action short (2 hrs)
No hepatoxicity
Tolcapone:
Central and peripheral inhibition of COMT
Long duration of action – 2 to 3 times daily
Hepatoxicity (2%)
Both are available in fixed dose combinations with
levodopa/carbidopa
45. MAO-B inhibitors: Selegiline
Selective and irreversible MAO-B inhibitor
MAO-A and MAO-B are present in periphery and
intestinal mucosa – inactivate monoamines
MAO-B is also present in Brain and platelets
Low dose of Selegiline (10 mg) – irreversible
inhibition of the enzyme
Does not inhibit peripheral metabolism of dietary amines,
so safely levodopa can be taken
No lethal potentiation of CA action – no cheese reaction,
unlike non-specific inhibitors
Dose more than 10 mg – inhibition of MAO-A should be
avoided.
46. Selegiline – contd.
Selegiline can be used alone in mild early PD
Adjunct to levodopa in early cases - benefits
Prolong levodopa action
Reduction in dose of levodopa
Reduces motor fluctuations
Decreases wearing off phenomenon
Advance cases of on/off – not improved
Levodopa side effects (hallucinations) etc, worsens
Neuroprotective properties – protect dopamine
from free radical and oxidative stress
Protects from MPTP induce parkinsonism
47. Central Anticholinergics: Teihexyphenidyl
(Benzhexol), Procyclidine, Biperiden
These are the Drugs with higher central :
peripheral anticholinergic action than Atropine
Reduce unbalanced cholinergic activity in striatum
Duration af action is 4-8 Hrs
Tremor is benefited more than rigidity – least to
hypokinesia
Overall activity is lower than levodopa
Used alone in mild cases and when levodopa is
contraindicated
Combination with levodopa to reduce its dose
Also used in Drug Induced Parkinsonism
Antihistaminic like Orphenadrine, Promethazine
are used in PD for their anticholinergic action
48. Dopamine facilitators: Amantadine
Antiviral agent
Several pharmacological action
Alter the dopamine release in striatum and
has anticholinergic properties
Blocks NMDA glutamate receptors
Used as initial therapy of mild PD
Also helpful in dose related fluctuations
and dyskinesia
Dose is 100 mg twice daily
Dizziness, lethargy and anticholinergic
effects – mild side effects
49. Drug Induced Parkinsonism:
Antipsychotics: Chlorpromazine, Fluphen-
zine and Haloperidol
Antihypertensive like Reserpine
Antiemetics: Metochlopramide (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.
50. Points to remember:
None of the present drugs alter basic pathology of PD
Initiation of levodopa therapy should be delayed as far as possible
Monotherapy with Selegiline or anticholinergics or amantadine - in
mild cases. Newer Drugs like Ropirinole etc. can also be used
In deterioration phase – levodopa and carbidopa combination, not
levodopa alone. Slow and careful initiation
Benefit from drug therapy wears off – dyskinesia develops. Later
on/off phenomenon develops – patient problem becomes same as
with drugs or without drugs
Peripheral decarboxylase inhibitors decreases early, but not late
complications
DA agonists like Ropinirole are used to supplement levodopa to
prevent on/off phenomenon and reduce levodopa dose
COMT inhibitors like entacapone are added to levodopa carbidopa
to prolong their action and to reduce on/off
51. Newer Fields:
Neurotrophic proteins--These appear to protect
nerve cells from the premature death that
prompts Parkinson's. One hurdle is getting the
proteins past the blood-brain barrier.
Neuroprotective agents--Researchers are
examining naturally occurring enzymes that
appear to deactivate "free radicals,"
Neural tissue transplants
Genetic engineering--Scientists are modifying
the genetic code of individual cells to create
dopamine-producing cells from other cells, such
as those from the skin
Famous sports personality Mohammed Ali (Casius clay) has been suffering from a disease.
1. Muscle rigidity is a condition in which both the active and passive movements of a joint are restricted because of the abnormal, involuntary contraction of one or more muscles. 2.. 3. Rather than being a slowness in initiation (akinesia), bradykinesia describes a slowness in the execution of movement
Muscle rigidity is a condition in which both the active and passive movements of a joint are restricted because of the abnormal, involuntary contraction of one or more muscles
A tremor is an involuntary,[1] somewhat rhythmic, muscle movement involving to-and-fro movements (oscillations) of one or more body parts The tremor, which is classically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk, can be markedly increased by stress or emotions. Onset of parkinsonian tremor is generally after age 60. Movement starts in one limb or on one side of the body and usually progresses to include the other side. The tremor, which is classically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk, can be markedly increased by stress or emotions. Onset of parkinsonian tremor is generally after age 60. Movement starts in one limb or on one side of the body and usually progresses to include the other side. pill-rolling tremor a parkinsonian tremor of the hand consisting of flexion and extension of the fingers in connection with adduction and abduction of the thumb
Rather than being a slowness in initiation (akinesia), bradykinesia describes a slowness in the execution of movement
DA fibres arising from SN tonically active, i.e. tonically inhibit striatum. Loss of inhibitory control leads to bradykinesia. GABA ergic fibres cause reduction of tonic influence of SN. Striatum also receives fibres from cortex ant thlumus – cholinergic fibres. . They are excitatory to striatum. Cholinergic and Dopaminergic fibrews exert opposing actions When DA fibres are reduced thyere is unbalanced overactivity of cholinergic fibres in striatum leading to symptoms of PD
Alpha-synuclein is a synuclein protein of unknown function primarily found in neural tissue, making up to 1% of all proteins in the cytosol.[4] It is predominantly expressed in the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum. It is predominantly a neuronal protein, but can also be found in glial cells. Most cases of PD, HD etc are sporadic, but families with high incidence of these diseases have been identified
In PD mutations in 4 different proteins have been identified: parkin - Proteins are tagged for degradation with a considerably small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases. UCHL1(ubiquitin carboxyl-terminal esterase L1) gene participant in ubiquitin mediated degradation of peroteins in brain. DJ-1 mutations off DJ 1 proteins, a protein involved in neuronal response to stress. ENERGY METABOLOSM – reduction in complex 1 may be due to age related issues lead to damage in dopaminergic neurones. Additionally evidence on metabolism role comes from MPTP. It induces degeneration of nerves similar to that in idiopathic PD and its mechanism to impair mitochondrial metabolism in dopaminergic neurones.
Genetic: Genetically determined PD are infrequent but, it is likely that an individual`s genetic background has an important role in the probability of acquiring this disease.
If slow emptying – prologed exposure of the drug to enzymes – degradation – less therapeutic conc.
eye blinking and throat clearing.[
Wearing off: In early therapy, duration of action exceeds plasma half life suggesting nigrostriatal retains capacity to store and release. On prolonged therapy – Buffering capacity is lost, patients motor state fluctuates with each dose. After each dose mobility improves for a period of time – 1-2hrs but rigidity and akinesia developes developes rapidly after e
Pyridoxine takes part in intermediary metabolism. It increases the metabolism of Levodopa by increasing the activity of peripheral decarboxylase enzyme and thereby low therapeutic concentration. An
Carbidopa does not cross bbb. Therefore, only peripheral decarboxylation is prevented and more production of Dopamine – more drug for CNS
Restless legs syndrome (RLS), also known as Wittmaack-Ekbom's syndrome, and colloquially as "the jimmylegs" is a condition that is characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can also affect the arms or torso, and even phantom limbs.[1] Moving the affected body part modulates the sensations, providing temporary relief.
COMT and MAO are responsible for catabolism of levodopa and dopamine. COMT transferse a methyl group from the donor s-adenosyl-L-methionine, producing pharmacologically inactive 3 –o-methyl DOPA and 3-methoxytyramine. When l-dopa is administered 99% is catabolized and does not reach brain. Most are by peripheral decarboxylases (aromatic L-aminoacid decarboxylase, increases nausea and vomiting. Peripheral decarboxylase inhibitors will reduce dopamine formation but not block methylation by COMT. The principal action of COMT inhibitors is to block peripheral conversion of l-dopa to 3-o-methyl DOPA
MAO-A and MAO_B are two isoenzymes which oxidize monoamines . Both are present in periphery and intestinal mucosa. But, MAO-B is more in basal ganglia and responsible for degradation of dop-amine in brain.
Non-specific MAO inhibitors – phenelzine, tranylcypromine , isocarboxazide