1/16/2022
ANTIPARKINSONISM AGENTS
Mohamad Mroueh, Ph.D.
School of Pharmacy
Spring 2022
Parkinson’s Disease
• Neurological disorder affecting > 4 million
patients worldwide
• Most common in elderly, BUT can affect
individuals at any age
• Average age of onset is 55 years, BUT 10% of
cases affect those under age of 40
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Parkinson’s Disease
Main symptoms:
– Tremor: usually at rest, but stops when person
attempts to grab something
– Rigidity: increase muscle tone and increase
resistance to movement
– Akinesia (bradykinesia): slow in movement
initiation
– Postural instability: abnormal fixation of a
posture
Parkinson’s Disease - cause
• Imbalance between dopaminergic inputs
(inhibitory) and cholinergic (excitatory) inputs
to the Corpus striatum.
• Degeneration of DA neurons in Substantia
nigra projecting to Corpus striatum
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Imbalance: due to deficiency in the function of
dopamine secreting neurons, without a change
in cholinergic inputs.
Old strategy: Use of anticholinergic agents!!!
Dopaminergic neurons originating
in the substantia nigra normally
inhibit the GABAergic output from
the striatum, whereas cholinergic
neurons exert an excitatory effect.
In parkinsonism, there is a
selective loss of
dopaminergic neurons.
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Parkinson’s Disease - cause
• Imbalance primarily between excitatory
neurotransmitter Acetylcholine and inhibitory
neurotransmitter Dopamine in the Basal
Ganglia
Parkinson’s like symptoms
These symptoms can be produced/aggravated
by
• Dopamine depleting agents
• Dopamine receptor antagonists
• Acetylcholine esterase inhibitors
• Dopamine neurotoxins
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Etiology of Parkinson’s Disease
• Unknown!!!
• Viral encephalitis
• Some cases of Parkinson's disease may be
caused by environmental toxins
• Manganese miners in South America have a
high risk of developing the disease
• High correlation between the incidence of
Parkinson's disease and sale of pesticides in
Quebec (Canada)!!!!
Smoking and Parkinsonism
incidence of Parkinson's Disease is lower in
cigarette smokers than in non-smokers !!!
Explanation?
• carbon monoxide may detoxify free radicals!!!
• compounds in cigarette smoke, or the metabolites of
these compounds, may inhibit monoamine oxidase
(MAO)-B activity!!!!
MAO-B is the main enzyme responsible for
metabolism of dopamine in brain.
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Etiology of Parkinson’s Disease
• Normally, people lose 5 to 8% of the cells in
substantia nigra each decade of their lives and
suffer no serious consequences.
• Once approximately 80% of these cells are
gone, the symptoms appear.
Parkinsonism caused by MPTP
MPTP: (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces
parkinsonism in humans and monkeys.
MPTP analog of “designer heroin” or “synthetic heroin”
MPPP: N-Methyl-4-propionoxy-4-phenylpiperidine
MPPP: is the reversed ester of meperidine.
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Parkinsonism caused by MPTP
• In 1976, a 23-year-old Maryland chemistry graduate named
Barry Kidston, in the attempt to synthesize MPPP to explore
its potential as a recreational drug. This led to the synthesis of
3 % of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
as a by-product of MPPP. Within 3 days following MPTP
intake, Kidston developed parkinsonism, which was
successfully treated with L-DOPA. However, he died 18 months
later due to cocaine overdosing.
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Toxicity of MPTP
• Inhalation of MPTP may lead to Parkinsonism
and not necessarily by IV
• A 37-year-old chemist developed
parkinsonism by just working with MPTP
without ingestion.
Treatment of Parkinsonism
• Anticholinergic therapy
• Dopaminergic therapy
– Agents that increase dopamine synthesis
– Agents that decrease dopamine metabolism
– Agents that increase dopamine release
– Agents that inhibit DA reuptake
– Dopamine receptor agonists
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Anticholinergic Therapy
Anticholinergic Therapy
• Few centrally acting antimuscarinic agents
such as benztropine, orphenadrine,
procyclidine and trihexyphenidyl.
• Have limited use because they produce about
20% improvements
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Anticholinergic Therapy
• may improve tremor and rigidity but little on
bradykinesia.
• usually given with dopaminergic therapy
• produce severe central and peripheral
anticholinergic side effects
DOPAMINERGIC THERAPY
– Agents that increase dopamine synthesis
– Agents that decrease dopamine metabolism
– Agents that increase dopamine release
– Agents that inhibit DA reuptake
– Dopamine receptor agonists
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Dopaminergic Therapy
Why not to use dopamine?
Dopamine
•
•
•
•
pka = 10.6 for NH2
protonated?
cross BBB?
Metabolism?
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Dopamine Therapy - Levodopa therapy
• Levodopa (L-DOPA) is a precursor of dopamine
is less basic (pka = 8.72 for NH2)
• given orally
• absorbed from GI tract
by active transport
• Enters brain by active transport
• converted to DA in the brain.
• only 1-3% of L-DOPA reaches the brain.
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L-DOPA
L-DOPA is also converted to dopamine in the
periphery:
• causing gastric upset : nausea and vomiting
(possibly due to CTZ stimulation in the medulla)
• other side effects of L-dopa involve activation of
peripheral adrenergic and dopaminergic receptors by
dopamine, causing orthostatic hypotension, renal
vasodilation and cardiac arrhythmias.
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Question
How to increase the Levodopa levels
reaching the brain?
Inhibit metabolism of L-DOPA in the
periphery!!!
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L-DOPA
• Inhibit metabolism of L-DOPA in the
periphery.
• Use a peripherally acting L-dopa
decrboxylase inhibitor (Carbidopa)
→ delivers more levodopa to the brain →
more dopamine formation in the brain .
Carbidopa
• Carbidopa does not cross BBB
• acts peripherally to inhibit the
metabolism of L-dopa.
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Carbidopa + L DOPA
• Carbidopa does not cross BBB and acts
peripherally to inhibit the metabolism of Ldopa.
• combination of Carbidopa and levodopa
decreases the required L-dopa to about 5
mes → lowering the cost.
• Sinement – 25/100 (25 mg carbidopa, 100
mg levodopa) delivers about 10% of levodopa
to the brain.
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Dopamine Therapy
• Agents Inhibit Dopamine Metabolism
– MAO-B inhibitors
– COMT inhibitors
MAO-B Inhibitors
• Dopamine is the main substrate of MAO-B in
the CNS
• Selegiline (1st generation) and Rasagiline (2nd
generation) are irreversible MAO-B inhibitors.
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MAO-B Inhibitors
• MAO-B inhibi on →inhibits inac va on of
dopamine in the brain → enhancing
dopamine effects.
• Both selelgiline and rasagiline are orally active
MAO-B Inhibitors
• Both are extensively metabolized.
• Selegiline undergoes N-dealkylation to form:
– desmethylselegiline and
– Despropylselegiline (metamphetamine) and
subsequently to (-)-amphetamine (<potent than damphetamine).
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COMT Inhibitors
• Reversible inhibitors of COMT
• Dopamine is undergoes bioinactivation by
COMT into 3-methoxytyramine.
COMT Inhibitors
Tolcapone and Entacapone
• inhibi on of COMT → block the inac va on of
dopamine → prolonging the effects of
dopamine.
• They are non specific and they inhibit COMT
metabolism of L-DOPA, norepiephrine and
epinephrine.
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COMT Inhibitors
Tolcapone and Entacapone
• Both act in brain and periphery.
• Tolcapone is longer acting (8-12 hrs) and acts
centrally and peripherally, while entacapone
(2 hrs) acts mostly in the periphery.
COMT Inhibitors
• Have common side effects due to
increased levels of dopamine in the brain
such as nausea and hallucination.
• A potential fatal adverse effect:
– hepatic failure occurs ONLY with tolcapone
→ restricting its use to patient who do not
respond to other therapies.
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Dopamine Releasing Agents
• Amantadine and Memantine
Amantadine and Memantine
• They are admantane derivatives
• Promote dopamine release from
DA neurons
• Inhibit dopamine reuptake.
• Also:
– Amantadine is antiviral, anticholinergic
– Memantine is NMDA antagonist
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Amantadine and Memantine
• Amantadine has a primary amine (pka
= 10.8)
• Mainly protonated at physiological pH.
• BUT still can enter the brain by active
transport
Amantadine
• Less potent than levodopa
• Short-lived benefits: last for few weeks only.
• Has cage-like structure: increases lipophilicity
and provides protection from metabolism
→ undergoes unchanged renal excre on.
• Adverse Effects: reversible and include
insomnia, hallucination, depression, confusion
and agitation.
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Question
How effective this therapy:
– Agents that increase dopamine synthesis
• L-DOPA + L-DOPA decarboxylase inhibitor
– Agents that decrease dopamine metabolism
• MAO inhibitors
• COMT inhibitors
– Agents that increase dopamine release
– Agents that inhibit DA reuptake
Dopamine Receptor Agonists
• Act directly to stimulate dopamine receptors
• Do not require functioning dopaminergic
neuron
• The currently available are nonselective:
– Act on D1-type and D2-type receptors.
– full or partial agonists primarily at D2-type
receptors
• Cause nausea, vomiting, sedation, and hallucinations
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Dopamine Receptor Agonists
Bromocriptine
• ergot peptide derivative
• partial agonist at D1-type
• full agonist at D2-type
• It was the first direct dopamine receptor
agonist used in treatment of Parkinson's
disease.
Dopamine Receptor Agonists
Bromocriptine
• At low doses is an effective prolactin inhibitor
• Antiparkinsonism obtained at higher doses
• Given orally
• undergoes extensive 1st pass pass metabolism
• half-life is relatively short (~3 hours).
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Dopamine Receptor Agonists
Pergolide
• nonpeptide ergot derivative
– compared to bromocriptine.
• equivalent D2 agonist activity
• higher potency and efficacy as a D1- agonist
• More potent than bromocriptine
for Parkinsonism and lactation inhibition
• Pergolide remains effective in patients who have
become tolerant to bromocriptine.
Dopamine Receptor Agonists
Pergolide
•
•
•
•
•
Orally active
undergoes hepatic metabolism to 10 metabolites
some metabolites are pharmacologically active
Undergoes mainly renal elimination
half-life is approximately 27 hours.
• However, withdrawn from US market
due to heart valve damage
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Dopamine Receptor Agonists
Ropinirole and Pramipexole
• non-ergot compounds
• full and selective agonists for D2 and D3
receptors
Dopamine Receptor Agonists
Ropinirole
•
•
•
•
orally active
metabolized mainly via CYP1A2
Undergoes hydroxylation and N-dealkyla on→ inac ve
half-life is about 6 hours.
Pramipexole
• orally absorbed
• Undergoes mainly unchanged renal elimination
• half-life about 8-12 hours.
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Dopamine Receptor Agonists
Apomorphine
• an aporphine alkaloid
• obtained by boiling morphine in concentrated
acid.
• Acts centrally, produce effects similar to those of
dopamine: antiparkinsonism and emesis.
Dopamine Receptor Agonists
Apomorphine
• has pka of 9 (highly ionized at physiologic pH)
• still lipophilic enough to cross the BBB.
• (R)-(-)-apomorphine: potent D1 and D2 agonist
and produces an antiparkinsonism effects
• S-(+)-apomorphine:
– postsynaptic D2-antagonist
– presynaptic D2-type (autoreceptor) agonist →
decreases dopamine release.
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Dopamine Receptor Agonists
Apomorphine
• Drawbacks:
– first-pass metabolism into inactive metabolites
– potent emetic effects (requires pre- and posttreatment
antiemetic therapy)
– QT prolongation
- administered by subcutaneous injection
- approved to treat late-stage Parkinson's disease.
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SPASTICITY DISORDERS
Spasmolytics
• Have diverse chemical structures
• Have different sites and mechanisms of action
• Usually referred to centrally acting skeletal
muscle relaxants.
• They block interneuronal activity at the spinal
cord level → inhibit polysynap c transmission
→ muscle relaxa on
SPASTICITY DISORDERS
Skeletal Muscle relaxation can be produced:
1- Peripherally
2- Centrally
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Centrally Acting Muscle Relaxants
Chemical Classifications
• Glycerol monoethers
• Alkanediol derivatives
• Benzodiazepines
• GABA derivatives
• Hydantoin derivatives
• Benzazole
Antodyne: 3-phenoxy-1,2-propandiol was the
first centrally acting muscle relaxant.
• Main drawback : short DOA
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Glycerol Monoethers
Mephenesin
 is weakly active
 short acting due to rapid metabolism:
– the primary alcohol
– para hydroxylation
Glycerol Monoethers
• Carbamylation of the primary alcohol
increases activity
• p-chlorination increases lipophilicity: ↗potency
• p-chlorination inhibits p-hydroxylation
• BUT the secondary alcohol can still undergo
glucuronidation
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Glycerol Monoethers
CH2
OH
CH2
OH
CH
OH
CH
OH
CH2
O
CH2
O
CH3
Mephenesin
CH3O
Guaifenesin
Modification of mephenesin:
• replacing the ortho methyl by ortho methoxy
→ guaifenesin (expectorant): Benylin, Robitussin
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• Orphenadrine is muscle relaxant
• Diphenhydramine is anti-histaminic agent
Propanediol Derivatives
• Replace one “H” of the carbamate hydrogens
by isopropyl group → increase ac vity (muscle
relaxant) plus anxiolytic
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BACLOFEN
• [3-p-chlorophenyl]-GABA
• GABA-B receptor agonist
• one of the most commonly used antispastic
agents.
• orally active with minimal hepatic metabolism
• undergoes excretion mainly unchanged in
urine and feces.
TIZANIDINE
• Analogue of clonidine
• Centrally active muscle relaxant
• Approved for use in reducing spasticity
associated with cerebral or spinal cord injury
• Its MOA: presynaptic inhibition of motor
neurons at the α2-adrenergic receptor site
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TIZANIDINE
• Rapidly and almost completely absorbed from the
gastrointestinal tract
• Estimated bioavailability: 10 to 15% due to extensive
first-pass metabolism, mainly by CYP1A2
• Its blood pressure lowering potency is about 10 to
20% that of clonidine
• Nevertheless, patients may experience hypotension
with tizanidine, together with muscle weakness.
• Other frequently reported side effects: drowsiness
and dry mouth
DANTROLENE
 hydantoin derivative
 acts peripherally to reduce muscle spasm
 site of action: sarcoplasmic reticulum in
skeletal muscle cells to inhibit calcium release.
 It is specific to skeletal muscle with minimal
effects on cardiac muscle and smooth muscle.
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DANTROLENE
• weak base (pka = 7.5)
• can cross the blood-brain barrier → cause CNS
depression such as sedation
• orally active with slow absorption
• half-life of approximately 9 hours.
DANTROLENE
• slowly metabolized by the liver to give the
5-hydroxy and acetamido (nitro reduction and
acetylation) metabolites.
• Main indication: treatment of
Malignant Hyperthermia:
a common side effect
of inhalation anesthetics
– muscle rigidity, high fever,
fast heart rate.
and a
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