Parkinson's disease is a progressive nervous system disorder that affects movement. It results from loss of dopamine neurons in the substantia nigra. Symptoms include tremor, rigidity, bradykinesia, and impaired balance. While the cause is largely unknown, risk increases with age. Treatment focuses on managing symptoms, primarily through dopamine replacement therapy using levodopa and dopamine agonists. Adverse effects can include dyskinesia and psychiatric issues. Managing Parkinson's becomes more challenging over time as symptoms fluctuate and complications arise.

1. Parkinsonism and Anti-
Parkinson’s Drugs

2. Introduction
 Parkinson's disease (PD) is a degenerative; progressive; movement
disorder of the central nervous system affecting the basal ganglia.
 It was first described in 1817 by James Parkinson, a British physician
who published a paper on what he called "the shaking palsy." In this
paper, he set forth the major symptoms of the disease that would later
bear his name.
 The risk of Parkinson's disease increases with age, so analysts expect the
financial and public health impact of this disease to increase as the
population gets older.

3. Etiology of Parkinson’s
 Autosomal dominant pattern of inheritance. Genetic mutations in three
proteins have been identified thus far. These genes encode
for alpha-synuclein, parkin and ubiquitin carboxy terminal hydroxylase.
 Viral inflammation (e.g., the postencephalitic parkinsonism of the early
1900s)
 Brain trauma, Stroke.
 Poisoning by manganese, carbon monoxide, pesticide, or 1-methyl-4-
phenyl,-1,2,3,6-tetrahydropyridine (MPTP).

4.  Mitochondrial Damage may play a role in the development of
Parkinson's disease. This damage is often referred to as oxidative stress.
Oxidative stress-related changes, including free radical damage to
proteins, and fats, have been detected in brains of Parkinson's disease
patients.
 There is a progressive loss of dopamine neurons with age. Relatively
smooth functioning of motor control is maintained until neuronal loss is
such that it causes an 80% reduction of dopamine in the striatum.
 At this time, clinical symptoms appear and then worsen with increasing
neuronal loss.

5. Iatrogenic Parkinsonism
 Drug-induced Parkinson that is, iatrogenic parkinsonism
 It is often a complication of antipsychotic therapy, especially
following the use of the butyrophenone and phenothiazine
drug
classes

7. Clinical Findings
 Parkinson's disease belongs to a group of conditions called
movement disorders. The four main symptoms are:
 Tremor, or trembling in hands, arms, legs, jaw, or head;
 Rigidity, or stiffness of the limbs and trunk;
 Bradykinesia, or slowness of movement; and
 Postural instability, or impaired balance.

8. A number of other symptoms may accompany Parkinson's disease. Some are
minor; others are not.
 Depression.
 Emotional changes.
 Difficulty with swallowing and chewing
 Speech changes
 Urinary problems or constipation
 Skin problems.
 Sleep problems.
 Dementia or other cognitive problems.
 Orthostatic hypotension
 Muscle cramps and dystonia.
 Fatigue and loss of energy.
 Sexual dysfunction.

9. Clinical Findings

10. Clinical Findings

11. Clinical Findings

12. Clinical Findings

13. Diagnosis
 The diagnosis is based on medical history and a neurological
examination.
 The disease can be difficult to diagnose accurately.
 Early signs and symptoms of Parkinson's disease may sometimes be
dismissed as the effects of normal aging.
 The physician may need to observe the person for some time until it
is apparent that the symptoms are consistently present.
 However, CT and MRI brain scans of people with Parkinson's disease
usually appear normal.

14. Pathophysiology
The Basal Ganglia Consists of Five Large Subcortical Nuclei
that Participate in Control of Movement:
 Striatum (Caudate nucleus , Putamen)
 Globus Pallidus
 Subthalamic Nucleus
 Substantia Nigra

15. Pathophysiology
 Striatum – Caudate Nucleus and
Putamen
 Substancia nigra pars compacta
provide DA innervation to
striatum
 Degeneration of neurones in the
substantia nigra pars compacta
 Degeneration of nigrostriatal
(dopaminergic) tract Results in
deficiency of Dopamine in
Striatum - >80%

16.  Disruption of balance between Acetylcholine and Dopamine:
 Cholinergic
 DA fibres
(Nigrostrital pathway)
GABAergic fibres
Striatum
Substancia Nigra

17.  Imbalance primarily between the excitatory
neurotransmitter Acetylcholine and inhibitory
neurotransmitter Dopamine in the Basal Ganglia
Ach
DA

18. Treatment
Drug Classification
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

19. Anti-Parkinson Drugs
 Dopamine and Tyrosine Are Not Used for Parkinson Disease Therapy,
Why?
 Dopamine Doesn't Cross the Blood Brain Barrier
 If Dopamine is given into the peripheral circulation has no
therapeutic effect
 Huge amount of tyrosine decreases activity of rate limiting enzyme
Tyrosine Hydroxylase
 However, (–)-3-(3,4-dihydroxyphenyl)-L-alanine (levodopa), the
immediate metabolic precursor of dopamine.
 Does penetrate the brain, where it is decarboxylated to dopamine.

20. 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
 Levodopa is rapidly absorbed from small intestine.
 Food will delay the appearance of levodopa in the plasma.
 Peak plasma conc. achieved between 1-2 hours after oral dose
 Plasma half- life is 1-3 hours.

21. Levodopa
 About two thirds of the dose appears in the urine as metabolites within 8
hours of an oral dose.
 The main metabolic products being 3- methoxy-4-hydroxyphenylacetic
acid (homovanillic acid, HVA) and dihydroxy-phenylacetic acid (DOPAC).
 Unfortunately, only about 1–3% of administered levodopa actually enters
the brain unaltered, the remainder being metabolized extracerebrally,
predominantly by decarboxylation to dopamine, which does not
penetrate the blood-brain barrier.
 This means that levodopa must be given in large amounts when it is
used alone.

22. Sinement
 When levodopa is used, it is generally given in
combination with carbidopa.
 A peripheral dopa decarboxylase inhibitor,e.g.
Sinemet (carbidopa and levodopa in fixed
proportion ,1:10 or 1:4)
 when it is given in combination with a dopa
decarboxylase inhibitor that does not penetrate the
blood-brain barrier, the peripheral metabolism of
levodopa is reduced.

23. Adverse Effects
 Anorexia and nausea and vomiting occur in about 80% of
patients.
 Cardiac arrhythmias including tachycardia, ventricular extrasystoles
and, rarely, atrial fibrillation.
 Dyskinesias occur in up to 80% of patients
 Depression
 Anxiety
 Agitation
 Insomnia
 Somnolence
 Confusion, delusions,
 Hallucinations, nightmares
 changes in mood or personality.

24. Drug Interactions
 Levodopa should not be given to patients taking monoamine oxidase
A (MAO) inhibitors or within 2 weeks of their discontinuance, because
such a combination can lead to hypertensive crises.
 Antipsychotic Drugs – Phenothiazines, butyrophenones block the
action of levodopa by blocking DA receptors.
 Pyridoxine (vitamin B6) enhance the extracerebral mechanism of
Levodopa.

25. Peripheral decarboxylase
inhibitors
 Carbidopa and Benserazide
 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.
 Plasma t1/2 – prolonged
 Reduction in systemic complications Nausea and Vomiting
– less Cardiac – minimum complications
 Pyridoxine reversal of levodopa – do not occur
 Better overall improvement of patient – even in non
responding patients to levodopa

26. 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

27. Advantages of Newer gent over
Bromocriptine
 less GIT symptoms (vomiting)
 Dose titration for maximum improvement in 1-2
weeks
 Supplementary levodopa is not required (but with
Bromocriptine)
 Meta analysis – slower degeneration

28. Adverse effects of Newer agents
 Nausea
 Dizziness,
 Postural hypotension
 Hallucination Episodes of day time sleep
 Restless leg syndrome

29. 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

30. COMT inhibitors: Entacapone and
Tolcapone

31. Entacapone and Tolcapone
 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

32. 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.

33. 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