ANTIPARKINSONIAN AGENTS

MA. LENY ALDA G. JUSAYAN, MD

DEPARTMENT OF PHARMACOLOGY
NEURODEGENERATIVE
DISORDERS
THE BRAIN CONTROLS MOVEMENT
 CASE 1
F.B., 70 year old male, living in a nursing home
was noticed to have episodes of crying spells
and labile mood. He also had difficulty in
initiating sleep and had night time awakenings.
Caregivers noticed also progressive slowing
down of movement associated with fine
tremors of the hands at rest. Few days PTC
there were noticeable rigidity & impairment of
body movements.
 PARKINSONISM
• Paralysis Agitans
• “SHAKING PALSY”
• Tremors are present even
at rest
• Rigidity & impairment of
voluntary movements
• Postural tremor,
intention tremors
 The UK Parkinson's Disease Society Brain
Bank Criteria For Clinical Diagnosis:

• Bradykinesia plus one of rigidity, tremor, or

postural instability
• At least three of rest tremor, progressive
symptoms, unilateral onset, early response
to levodopa, revodopa-induced dyskinesia
• No identifiable cause for the parkinsonism.
 Motor Symptoms:
 Tremor:
 70% of patients suffer resting tremor
pill rolling quality
 can affect all of the limbs as well as the
face, neck, head and jaw.
 Rigidity:
 increased tone or stiffness in the muscles
 mask-like face and clog-like release of
muscles.
 Bradykinesia
difficulty initiating and continuing
movement.
Postural Instability
Forward flexion of neck, hips, knees and
elbows leads to poor balance.
Gait disorders
 Shuffling, small steps described as
festination, reduced arm swing and sudden
freezing spells lead to problems walking
Swallowing (dysphagia) and Speech
disorders (dysarthria)
Handwriting: Micrographia
 Nonmotor Symptoms:

• Depression:
– 20-90% major depressive episode, reactive or
endogenous

• Dementia:
– 20% of patients will become demented (have
impairments of 3 of the following in the
presence of clear consciousness: language,
memory, visuospatial skills, emotionality,
personality and cognition
Sleep disturbances:
 Problems with sleep fragmentation,
sleep initiation, early morning
awakening, excessive daytime
somnolence and parasomnias.
Sexual dysfunction
Ability to drive a car
Ability to gain employment
Constipation
 What causes Parkinson’s Disease?
• A viral cause: •
Other causes:
• In 1918 there was an outbreak of •
Head injuries.
Encephalitis Lethargica and many
•
Oxidative stress.
sufferers developed postencephalitic
Parkinsonism. •
Heavy metal ion exposure from
fillings etc.
• A toxic substance:
• It is proposed that these factors
• For instance, the illegal drug MPTP (1-
cause the neurone's mechanisms
methyl-4-phenyl-1,2,3,6-
for proteolysis to go awry leading
tetrahydropyridine).
to the formation of the
• A genetic cause: characteristic Lewy bodies seen
on autopsy of Parkinson’s patients.
• Research by the NHGRI (National Human
The cells then fail to function
Genome Research Institute) suggests
correctly and ultimately die.
that a mutated gene, which codes the
alpha synuclein protein located on
chromosome 4, has a role in familial
parkinsonism.
 PATHOGENESIS:
• Idiopathic
• Genetic (<50 y/o)
• Exposure to unrecognized neurotoxins
• Oxidation reaction with generation of
free radicals
• Reduced level of dopamine in the basal
ganglia
 MOTOR SYMPTOMS:
POSITIVE SYMPTOMS NEGATIVE SYMPTOMS
• Tremor • Bradykinesia
• Chorea, • Akinesia
• Athetosis • Loss of postural reflexes.
• Ballismus
 CHOREA
• Irregular, unpredictable involuntary jerks
• Impaired voluntary activity
• ballismus
 TICS
• Sudden coordinated abnormal movements
• Repetitive sniffing
• shoulder shrugging
• face & head movement
 ATHETOSIS

• Slow & writhing movements

• Abnormal postures (dystonia)
• Pyramidal System:
– begins in the primary motor cortex
– descends through the corticospinal and
corticobulbar tracts
– affects the lower motor neurons in the brain
stem and spinal cord.
•Extrapyramidal System:
•basal ganglia and their cortical connection
•basal ganglia are made up of the:
Caudate Nucleus
 Putamen (Striatum)
 Globus Pallidus interna (Gpi)
 Globus Pallidus externa (Gpe)
 Subthalamic Nucleus
 Substantia Nigra
Main Outputs:
Substantia Nigra
 Globus pallidus interna
Both of which feed to the ventrolateral
thalamus
The main Pathological feature of
Parkinson ’ s disease is the loss of the
dopaminergic nigrostriatal pathway

 Dopaminergic neurons in the

substantia nigra that normally inhibit
the output of GABAergic cells in the
striatum are lost

80% of the Dopamine producing cells

must be lost before symptoms begin to
show
WHAT CAN BE DONE TO HELP
PARKINSON’S SUFFERERS?
 GOALS OF TREATMENT:
• Pharmacologic attempt to
restore dopaminergic
activity with levodopa
and dopamine agonists

• Restore normal balance

of cholinergic &
dopaminergic influences
on the basal ganglia
 PATHOPHYSIOLOGIC BASIS OF
TREATMENT:
• Dopaminergic
neurons in the
substantia nigra
that normally
inhibit the output of
GABAergic cells in
the corpus striatum
are lost
 CASE 2
F.B., was brought to the clinic for evaluation ,
diagnosed to have Parkinson’s disease.
• What is the goal in the management of this
case?
• What is the first line drug that can relieve the
signs and symptoms of parkinsonism
 REMEDIES FOR STEP 1:
DOPAMINE REPLACEMENT
 LEVODOPA
• (-) -3-(3-4 dihydroxyphenyl) L- alanine
• Immediate metabolic precursor of dopamine
• Levorotatory stereoisomer of dopamine
• D1 receptors stimulate adenylcyclase, located in the
zona compacta of the substantia nigra
• D2 receptors inhibit adenylcylase, located
postsynaptically on striatal neurons &presynaptically
in the substantia nigra
 PHARMACOKINETICS:
• Rapidly absorbed from the SI
• Food delays absorption
• Amino acids in food compete with drug
• Peak plasma concentration: 1-2 hrs
• Plasma t ½ : 1-3 hrs
• HVA, DOPAC (dihydroxyphenylacetic acid) are
main metabolites
• 1-3% enters the brain
 CLINICAL USE:
• Responsiveness may be lost secondary to
disappearance of dopaminergic nigostriatal
nerve terminals
• Early use lowers mortality rate
• Combined with Carbidopa & Benseraside
• Sinemet – dopa preparation containing
levodopa in fixed proportion (1:10 or 1:4)
• Sinemet 25/100 TID
• 30 -60 minutes before meals
 ADVERSE EFFECTS:
• Fluctuations in response
• Misc: mydriasis, blood dyscrasias, hot
flushes, gout, brownish discoloration
of the urine, abnormal smell, priapism,
transient elevations of transaminases
& BUN
 ADVERSE EFFECTS:
• GIT effects: vomiting (CTZ)
–Reduced by carbidopa
–Phenothiazenes are contraindicated
• Cardiovascular: tachycardia,
ventricular extrasystoles, atrial
fibrillation
• Dyskinesias
–Common in patients receiving
carbidopa
• Behavioral effects:
–Common in patients receiving
levodopa
–controlled by clozapine, olanzapine,
resperidone
 DRUG INTERACTIONS:
• Vitamin B6 enhance extracerebral
metabolism of levodopa
–Prevented by decarboxylase
inhibitors
• MAO – A inhibitors
–Hypertensive crisis
 CONTRAINDICATIONS:
• Psychoses
• Angle closure glaucoma
• Cardiac dysrhythmia
– Less incidence in combination with carbidopa
• PUD
• Melanoma or suspicious undiagnosed skin
lesions
 CASE 3
• F.B. Was maintained on low dose of
Levodopa and was titrated until given the
highest dose where he started to had
palpitations and chest pain.
• What is next step in your management?
PERIPHERAL DOPAMINE DECARBOXYLASE INHIBITORS
(PDI)
• Carbidopa, Benseraside
• Does not penetrate the BBB
• Reduce the peripheral metabolism of levodopa
• Increase plasma levels of levodopa
• Prolongs the plasma half life of levodopa
• Increase available amounts of dopa for entry into the
brain
• Reduce the daily requirement of levodopa by 75%
 CASE 4
• F.B. After 1 year of taking Levodopa develop
rigidity and bradykinesia with worsening of
the tremors.
• What treatment option should F.B. receive?
 DOPAMINE AGONISTS
• Do not require enzymatic conversion for an
active metabolite
• No potential toxic metabolites
• Do not compete with other substances for an
active transport
• First line in parkinsonism
• End of dose akinesia to levodopa
• On & off phenomenon refractory to levodopa
 ERGOT ALKALOIDS:

• BROMOCRIPTINE (Parlodel)
– D2 agonists
– Endocrinologic disorders
(hyperprolactinemia)
– Absorbed variably in GIT
– Peak plasma levels: 1-2 hrs
 ERGOT ALKALOID:

• PERGOLIDE
– Stimulates both D1 and D2
– More effective than bromocriptine
– Associated with clinical or subclinical
valvular heart disease
 CLINICAL USE:
BROMOCRIPTINE:
– 7.5 mg & 30 mg
– 1. 25 mg BID after meals X 2-3 months and
increase 2.5 mg q 2 wks
PERGOLIDE:
- 3 mg daily
- 0.05 mg starter dose
 NON-ERGOT DOPAMINE AGONISTS:

PRAMIPEXOLE
Preferential affinity to D3
Monotherapy is effective
Neuroprotective (H scavenger)
Enhance neurotrophic activity
Rapidly absorbed
Peak plasma concentration: 2 hrs
0.125 mg TID then doubled after 1 wk
Increments of 0.75 mg at weekly intervals
 NON-ERGOT ALKALOIDS:
• ROPINIROLE
– Pure D2 receptor agonists
– 0.25 mg TID then total daily dose is
increased by 0.75 mg at weekly intervals
until the 4th wk & increased by 1.5 mg
thereafter
ADVERSE EFFECTS:

• GIT: anorexia, nausea,

vomiting, bleeding PUD,
reflux esophagitis
• Cardiovascular: postural
hypotension, painless digital
vasospasm
• Dyskinesias
• Mental disturbances
• Misc: erythromelalgia
 CONTRAINDICATIONS:
• History of psychotic illness
• Recent myocardial infarction
• Peripheral vascular disease
• Peptic ulceration
 APOMORPHINE
• Apokyn
• Potent dopamine agonist
• Temporary relief of off-periods of akinesia
• Rapidly taken by blood and brain (10 minutes)
and persists for 2 hours
• Nausea – trimethobenzamide
• Dyskinesias, drowsiness, sweating,
hypotension, bruising at injection site
 MONOAMINE OXIDASE INHIBITORS

MAO – A: metabolizes NE & serotonin

MAO – B: metabolizes dopamine
 SELEGILINE (Deprenyl)

• Selective irreversible inhibitor of

MAO-B (normal doses)
• Inhibits MAO-A (higher doses)
• Retards breakdown of dopamine
• Prolongs & enhances the effect of levodopa
• Adjunct in fluctuating response to levodopa
 SELEGELINE
• 5 mg with breakfast & lunch
• Cause insomnia when taken later during the
day
• Not to be taken with meperidine, TCAs, SSRIs
• Increase adverse effects of levodopa
• METABOLITES: amphetamine &
metamphetamine
 DRUG INTERACTION:
• Stupor, rigidity, agitation, and hyperthermia -
MEPERIDINE
 RASAGILINE
• MAO-B inhibitor
• Potent than selegiline in preventing
MAO-B toxins induced parkinsonism
(MPTP)
• Combination with levodopa – HPN crisis
CATHECO-O-METHYLTRANSFERASE INHIBITORS:

• Compensatory activation pathways of

levodopa metabolism after dopa
decarboxylase inhibition
• Increase 3-O-methyldopa (3OMD)  poor
therapeutic response to levodopa
– Competes with levodopa for an active carrier
mechanism in the intestinal mucosa & BBB
 CATHECOL-O-METHYLTRANSFERASE INHIBITORS:
(SELECTIVE)

• TOLCAPONE- central & peripheral metabolism

• ENTACAPONE
– peripheral metabolism
– Prolongs the duration of levodopa by decreasing
its peripheral metabolism
– Helpful in patients receiving levodopa who have
fluctuations
– t ½ = 2 hrs
 STALEVO
• Combination of levodopa with both carbidopa
and entacapone
• Simplifies drug regimen
• Requires consumption of a lesser number of
tablets
 SIDE EFFECTS:
• Postural hypotension
• Fatigue
• Somnolence
• Peripheral edema
• Nausea
• Constipation
• Dyskinesias
• Confusion
 AMANTADINE
• Antiviral agent
• Potentiates dopaminergic function by
influencing the synthesis, release, reuptake of
dopamine
PHARMACOKINETICS:
peak plasma concentration: 1-4 hrs after oral
dose
Plasma t ½ = 2-4 hrs
 CLINICAL USE:

• Less potent than levodopa and benefits are short-

lived
• 100 mg BID-TID

ADVERSE REACTIONS:
Restlessness, depression, irritability, insomnia,
agitation, excitement, hallucinations & confusion
Livedo reticularis – clears within a month after drug
withdrawal
 CONTRAINDICATIONS:

• History of seizures
• Heart failure
 ACETYLCHOLINE BLOCKING AGENTS:

• Improve tremor & rigidity of parkinsonism

but have little effect in bradykinesia
• Benztropine mesylate
• Biperiden
• Orphenadrine
• Procyclidine
• Trihexyphenidyl
 ADVERSE EFFECTS:
• CNS
• Mydriasis, urinary retention, constipation,
tachycardia, tachypnea, increase IOP,
palpitations, cardiac arrythmias
• Acute suppurative parotitis
• Dryness of the mouth
 CONTRAINDICATIONS:

• Prostatic hyperplasia
• Obstructive GI diseases
• Angle closure glaucoma
The net result of all of these medications is
the balancing out of the
acetylcholine/dopamine balance and an
improvement in movement
 SURGICAL PROCEDURES:

Thalamotomy –
conspicous tremor
Posteroventral
pallidotomy or
deep-brain
stimulation
 NEURONAL DEATH
EXCITOTOXICITY
• Environmental chemicals may contribute to
neurodegenerative disorders
• Can occur with excessive glutamate and
kainic acids
• Results from sustained rise in intracellular Ca
 NEURONAL DEATH
APOPTOSIS
• Cell is systematically dismantled & shrunken
remnants are removed by macrophages
without causing inflammation
 NEURONAL DEATH

OXIDATIVE STRESS
• Result of excessive production of
oxygen and hydroxyl free radicals and
hydrogen peroxide
 ISCHAEMIC BRAIN DAMAGE
• Interruption of blood supply to the brain
• Cerebral edema & inflammation
TREATMENT:
• Calcium & Na channel blockers
– Nimodipine, fosphenytoin
• NMDA receptor antagonists
– Selfotel, eliprodil, dexrtromethorphan
• Glutamate inhibitors
– Adenosine, lobeluzole
• GABA agonists
– Clormethiazole
• Radical scavengers
– tirilazad
 CLINICAL SCENARIO
• A.D. 70 year old female living in a nursing
home, has gradual onset of difficulty in
recalling what time she has taken her snack
but easily recalls the first ball she had in high
school.
 ALZHEIMER’S DISEASE
• Loss of intellectual ability with age
• Dementia that does not have antecedent
cause
• Associated with brain shrinkage, localized loss
of neurons in the hippocampus & basal
forebrain
• Amyloid plaques, neurofibrillary tangles in the
hippocampus
• Loss of cholinergic neurons
MOLECULAR MODEL FOR THE DEVELOPMENT
OF ALZHEIMERS DISEASE
 PATHOPHYSIOLOGY:
• Decrease in ACETYLCHOLINE
• CHOLINERGIC DEFICIENCY SYNDROME
• Decrease in markers of cholinergic neuron
activity
• Changes in brain glutamate, dopamine,
norepinephrine, serotonin and somatostatin
activity
• Cholinergic and other neurons die or are
destroyed
 PATHOPHYSIOLOGY:
• Abnormal neuronal lipoprotein processing
• Familial form is associated with abnormal
lipoprotein - APOLIPOPROTEIN E4
 AMYLOID PLAQUES
• β AMYLOID PROTEIN – by product of
neuronal death
NEUROFIBRILLARY TANGLES:

• More abundant in AD
•  tangles =  severity of cognitive
impairment
DRUGS FOR ALZHEIMER’S
DISEASE
CHOLINESTERASE INHIBITOR:
 CHOLINESTERASE INHIBITORS:

• TACRINE- central inhibitor

• DONEZEPIL(Aricept) – not hepatotoxic,
selective inhibitor
• RIVASTIGMINE (Excelon)
• GALANTHAMINE (Reminyl)
• For mild to moderate Alzheimer’s disease
 TACRINE
• Tetrahydroaminoacridine, THA
• Long acting anticholinesterase & muscarinic
modulator
• Orally active
• Duration of action: 6-8 hrs
• Blocks both acetylcholinesterase &
butyrylcholinesterase
• Inhibitory effects on M1, M2 & muscarinic
cholinoceptors
• Increases the release of acetylcholine from
cholinergic nerve endings
• Inhibit MAO
• Decrease the release of GABA
• Increase the release of NE, dopamine,
serotonin from nerve endings
 DONAZEPIL, RIVASTIGMINE,
GALANTAMINE
• Newer cholinesterase inhibitors with
adequate penetration to the CNS
• Indirect cholinomimetic effects than tacrine
 ADVERSE EFFECTS:
• Nausea and vomiting
• Hepatotoxicity is increased with tacrine
• Should be used with caution: ketoconazole,
quinidine
NEURONAL NICOTINIC
RECEPTORS (NNRs)
 TARGACEPT
• Neuronal nicotinic receptors (NNRs), serve as
key regulators of nervous system function.
• When the natural neurotransmitter
acetylcholine, or a drug that mimics
acetylcholine, binds to an NNR, the NNR
normalizes chemical signaling, allowing
neurons to communicate properly
(neuromodulation)
• ."
• results in increased signaling when the
nervous system is understimulated and
decreased signaling when the nervous system
is overstimulated
• nervous system's "volume knob
NMDA GLUTAMATE RECEPTOR
INHIBITORS
 MEMANTINE (Ebixa)
• Binds to NMDA receptor channels
• Produces a noncompetitive blockade
• Prevents the effect of excess glutamate
leaking out from the damaged brain cells
• Treatment of moderate to severe form of
Alzheimer’s disease
 TREATMENT:
INHIBITING NEURODEGENERATION
• Anti-inflammatory drugs
– Ibuprofen, indomethacin
• Metal chelating agent
– Clioquinol
 POST –TEST:
A. NMDA glutamate
1. Tacrine receptor inhibitor
2. Targacept B. Neuronal Nicotinic
3. Rivastigmine Receptors
4. Memantadine C. Cholinesterase
5. Donazepil inhbitor
6. SELEGILINE A. MAOI
7. TOLCAPONE B. COMT INHIBITOR
8. ROPINOROLE C. DOPAMINE AGONIST
9. BENSERASIDE D. ACH BLOCKING AGENT
10. BIPERIDEN E. DOPA DECARB
INHIBITOR