antiparkinson's drugs

1. ANTIPARKINSONIAN
DRUGS
Presented by: Patel Arti B. (M.Pharm 3 sem )
Guided by: Dr.M.N.Noolvisir
(SDPC Kim,Surat)

2. PARKINSONISM
• A degenerative and progressive disorder
• Associated with neurological consequences of
decreased dopamine levels produced by the basal
ganglia (substantia nigra)
• Extrapyramidal motor function disorder
symptoms characterized by
1. Rigidity
2. Tremor
3. Hypokinesia/Bradykinesia
4. Impairment of postural balance - falling

3. CAUSES
Parkinson is caused due to imbalance of
dopamine(DA) and acetylcholine (Ach)
Ach and DA need to be balanced for smooth
movement. DA causes muscle relaxation while
Ach causes contraction.
Reduction of DA, in the basal ganglia results
in imbalance of those two and causes motor
disorders
In some cases, at later stages of the disease
reduction of Ach which is also involved in
learning and attention leads to dementia

4. PARKINSONISM - 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 – 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
• 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 (festination); difficulty initiating movement

6. PARKINSONISM (PD) - SIGNS

7. PARKINSONISM - HISTORY
• 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
• Majority of causes are Idiopathic

8. 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
 Striatum – Caudate Nucleus and Putamen
 Substancia nigra pars compacta provide DA
innervation to striatum

9. 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%

10. PD, PATHOPHYSIOLOGY – CONTD.
 Disruption of balance between Acetylcholine
and Dopamine:
Striatum
DA fibres (Nigrostrital
pathway) GABAergic fibres
Substancia
Nigra
Cholinergic

11. PD, PATHOPHYSIOLOGY – CONTD.
 Imbalance primarily between the
excitatory neurotransmitter
Acetylcholine and inhibitory
neurotransmitter Dopamine in the Basal
Ganglia
ACh
DA

12. PARKINSONISM - ETIOLOGY
 Genetic:
 Environmental triggers:
 Infectious agents – Encephalitis lethargica (epidemic)
 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
 Oxidative stress: Free radicals (`OH) – hydrogen peroxide and
oxyradicals : damage to lipid membranes and DNA

13. TREATMENT OF PD

14. CLASSIFICATION OF
ANTIPARKINSONIAN DRUGS
1. Drugs acting on dopaminergic system:
a) Dopamine precursors – Levodopa (l-dopa)
b) Peripheral decarboxylase inhibitors – carbidopa
and benserazide
c) Dopaminergic agonists: Bromocriptyne, Ropinirole
and Pramipexole
d) MAO-B inhibitors – Selegiline, Rasagiline
e) COMT inhibitors – Entacapone, Tolcapone
f) Dopamine facilitator - Amantadine
2. Drugs acting on cholinergic system
a) Central anticholinergics – Teihexyphenidyl
(Benzhexol), Procyclidine, Biperiden
b) Antihistaminics – Orphenadrine, Promethazine

15. QUESTION ?
• 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

16. LEVODOPA
HO HO O
• Single most effective agent in PD
• Inactive by itself but immediate precursor of
Dopamine
• Peripherally - 95% is decarboxylated in
peripheral tissues in gut and liver to dopamine
– This dopamine acts on peripheral organs like heart,
blood vessels and CTZ etc. (NOT CNS)
• 1 - 2% crosses BBB, taken up by neurons and DA
is formed
– Stored and released as neurotransmitter
NH2
HO
L-TYROSINE, 3-HYDROXY
Levodopa

17. ACTIONS OF LEVODOPA – CNS
• Effective in Eliminating Most of the Symptoms of
Parkinson Disease (initially motor)
– Bradykinesia and Rigidity Respond Quickly
– Reduction in Tremor Effect with Continued therapy
• Secondary symptoms - 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
• 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 – psychiatric symptoms

18. ACTIONS OF LEVODOPA – CONTD.
• CVS:
– Cardiac Stimulation Due to Beta adrenergic effect on
Heart
– 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

19. LEVODOPA - PHARMACOKINETICS
• Absorbed rapidly from small intestine – aromatic
amino acid transport system
• High First Pass Effect
– Competition for amino acids present in food competes for
the carrier
– Also depends on gastric emptying and pH
• Peak plasma conc. 1-2 hrs and half life - 1 to 3 Hrs
• 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

20. LEVODOPA - PHARMACOKINETICS
3 – OMD
COMT
Levodopa
DDC
Dopamine
Any drug which can reduce DDC peripherally (called peripheral
decaroxylase inhibitors) - Would be beneficial and cause higher
bioavailability, longer half-life, better availability in CNS and also reduce
the daily dose of levodopa

21. LEVODOPA - ADRS
• Initial Therapy:
 Nausea and vomiting - 80% of patients
 Postural hypotension , but asymptomatic : 30 % of
patients tolerance develops – disappear after
prolonged treatment
 Cardiac arrhythmias (due to beta adrenergic action
and peripheral CA synthesis) - tachycardia,
ventricular extrasystoles and, rarely, atrial
fibrillation
 Exacerbation of angina

22. LEVODOPA (ADVERSE EFFECTS) -
PROLONGED THERAPY
1. Abnormal movements: Facial tics, grimacing,
tongue thrusting, choreoathetoid movements of
limb after few months of treatment
2. 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 (1 - 3 weeks)

23. LEVODOPA (ADVERSE EFFECTS) -
PROLONGED THERAPY – CONTD.
 Fluctuation in Motor Performance:
 Initial therapy – each dose - good duration of action
9more than half-life)
 Suggesting Nigrostriatum retains capacity to store and
release
 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 - "On-off" Phenomenon
 Like a Light Switch: Without Warning
 DYSKINESIA – excessive abnormal involuntary
movements even in on phase (more troublesome)
 Dyskinesia often with high plasma conc. of levodopa
 Dyskinesia = Bradykinesia and Rigidity in terms of
patient comfortness

24. 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

25. LEVODOPA – DRUG INTERACTIONS
 Pyridoxine – abolishes therapeutic effect of levodopa
 Antipsychotic butyrophenon eDsr bulgosc k– tPhhee ancottihonia ozfi nleevs,o dopa by blocking DA receptors.
 aAnndti vdoompeimtiningergic – domperidone abolishes nausea
 vReessiecruplainre u –p tbalkoceks levodopa action by blocking
 gAansttircihco elimnpertygiincsg –– sryendeurcgeidst eicff aecctt ioofn l ebvuotd doeplaayed
 pNeornipspheecriaflilcy M syAnOth Ienshizibeidt oDrsA –– Phryepveernttesn dsievger acrdiastisio bny o f tchhee etsyer,a cmofifneee-,c bheeeers,e p eifcfkelcets ( taynrda mchionceo ilsa tfeo)u, nwdh ienn igsi vneont tbor oak peenr sdoonw tna -k itnrge ma eMnAdoOu sIn rheilbeaitsoer o- ft yramine Norepinephrine)

26. LEVODOPA VS PERIPHERAL
DECARBOXYLASE INHIBITORS
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

27. LEVODOPA VS 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

28. LEVODOPA – CARBIDOPA (MORE
LEVODOPA AVAILABILITY IN CNS )

29. PERIPHERAL DECARBOXYLASE
INHIBITOR CARBIDOPA AND
BENSERAZIDE
 Meachanism of action:
 It is a Dopamine decarboxylase inhibitors.
 It’s purpose is to increase efficacy of L-Dopa by
preventing it’s peripheral metabolic degradation
and thus allowing more L-Dopa to penetrate the
brain
 While Dopamine decarboxylase exists both inside
and outside the brain, Carbidopa only blocks
metabolism outside the brain cause it can’t
penetrate the brain.

30.  Carbidopa

31. DOPAMINERGIC AGONISTS
 Meachanism of action:
 The dopamine agonist can act on straital
dopamine receptor in patient who have largely
lost the capacity to synthesize, store, and release
dopamine from levodopa.
 They can be longer acting, exert subtype selective
Activation of dopamine receptor involved in
parkinsonism and not share the concern
expressed about levodopa of contributing to
dopaminergic neuronal damage by oxidative
metabolism.

32. A. ERGOLINE (ERGOT)
DERIVATIVES
 Natural and semi-synthetic compounds having high affinity (both
agonistic andantagonistic) for monoamine (NE, DA) receptors
 All ergoline derivatives are structurally derived from alkaloid
products produced by the grain fungus Claviceps purpurea
 Bromocriptine mesylate and the more potent pergolide
mesylate are DA-receptor
 agonists used as adjunctive treatment to levodopa in controlling
the symptoms of PD
 Affinity of ergoline derivatives for DA receptors is presumably
related to the presence of a $-arylethylamine structural feature in
these drugs

33. HN
Br H
N
O
HN
O
N O
N
HOH
O
bromocriptine
HN
CH2SCH3
N
H
H
PERGOLIDE

34. B. NON-ERGOLINE DERIVATIVES
 Ropinirole
 an indolinone derivative unrelated instructure to the
ergolines
 high affinity for the D2 family of DAreceptors (D2, D3 and
D4 subtypes)
 formulated for PO administration as HCl salt
NH
O
HN
H3C
H3C Ropinirole

35. • PRAMIPEXOLE
S
N
 a tetrahydrobenzothiazole derivative formulated
as di-HCl salt (side chain NH and hetero N) of
pharmacologically-activesingle (S-(-)) isomer
 high affinity for D2 receptor family
 possesses a low oxidation potential whichmay
function to scavenge (neuroprotection) DA-derived
free radicals and electrophiles:
NH2
HN
H3C
Pramipexole

36. MAO-B INHIBITOR
 These are selective MAO-B inhibitor.
 Two isoenzyemes form of MAO,termed as MAO-A
and MAO-B both present in peripheral
adrenergic structure and intenstinal mucosa;
MAO-B predominates in brain and blood
platelets and is responsible for most of oxidative
metabolism of dopamine in the brain.
 At low doses, selegiline is a selectivve inhibitor of
MOA-B leading to irreversible inhibition of
enzeme.
 Selegiline does not interfere in peripheral
metabolism of catecholamine; thus levodpa can
be taken safely.

37.  Structure of slegiline
CH3
CH2 C
NH CH2
CH3
C CH
H

38. COMT INHIBITOR
 Potent revesible COMT inhibitors and act as
adjuvant to L-DOPA, carbidopa for advance
parkinsons disease.
 When peripheral decarboxlyation of L-dopa is
bloked by caridopa or benesezide, it is mainly
metabolized by COMT to 3-O-methyldopa.
 Bloked of this pathway by entacapone or
tolacapone prolongs the half-life of levodopa and
allows large fraction of administered dose to
cross the BBB

39. O
HO
HO
NO2
CH3
TOLCAPONE
CN
N
O
CH3
CH3
HO
HO
OH
Entacapone

40. DOPAMINE FACILITATOR
 MOA: It casus release of dopamine from
presynaptic nerve ending and blokes its
presynaptic reuptake.
 Its effectiveness is is greatly reduced in the
absence of functional dopaminergic neurons in
corpus striatum.
NH2
AMANTADINE

41. ANTICHOLINERGIC DRUG
 MOA: In that imbalance between the
concentration of dopamine and acetylcholine,
decreased dopamine and increased acetylcholine.
 Eg: Trihexyphenidyl, procyclidine.
 These agent exhibit post-synaptic blocking effect
on central cholinergic excitatory pathway which
in parkinsonismbecome predominant, especially
due to lack of fictional dopamine in corpus
striatum.
 Central anticholinerigic also related reuptack of
dopamine into pre-synaptic nerve ending, there
by blocking its in-activation.

42. N
OH
Trihexyphenidyl
HO
N
Biperidine
N OH
PROCYCLIDINE

43. ANTIHISTAMINE
O
CH3
N
 MOA: This drug is observed to minimize
voluntary muscle spasm by a central effect.
 It exerts its action by relaxing directly the tenes
muscle.
 It has peripheral atropine like action and
minimizes voluntary muscle by virute of its
central inhibitory activity on the cerebral motor
areas.
CH3
CH3
Orphenadrine

44. THANK YOU