NCM 117
Lecturer: Sir Mark Angelo Cristino || 24 March 2022
Anti-Parkinsonian Drugs
᷿ Pertains to Parkinson’s disease and
extrapyramidal side effects (EPSEs)
Person experiences:
Rigidity and trembling of head
Forward tilt of trunk
Reduced arm swing
Shuffling gait with short steps
Rigidity and trembling of extremeties
Parkinsonism
᷿ It is a extrapyramidal motor disorder occurs due
to degeneration of dopaminergic neurons in
the substantia nigra pars compacta (SN-PC)
result in dopamine deficiency
᷿ EPSEs are serious and sometimes dangerous
complications of treating people with
psychotropic drugs
᷿ Antipsychotic agents typically cause these
adverse responses, but other drugs can also
produce EPSEs. EPSEs are the result of the
biochemical changes similar to those found in
Parkinson’s Disease (PD). (Pseudoparkinsonism -
a side effect of some antipsychotic medications;
imitates the symptoms and appearance of
Parkinson's disease - tremor, shuffling gait,
drooling, rigidity *symptoms may appear 1 to 5
days following initiation of antipsychotic
medication; occurs most often in women, the
elderly, and dehydrated clients)
᷿ It occurs in 2% elderly population
᷿ Classifically disease of 7th decade of life
᷿ An imbalance between dopaminergic
(inhibitory neuron) and excitatory cholinergic
neuron -- cholinergic over activity
Parkinson’s Disease
᷿ A progressive, chronic, degenerative disease of
unknown cause that involves the area of the
brain called the extrapyramidal system
᷿ A well-regulated extrapyramidal system is
needed for normal coordination of involuntary
movement, which, in turn supports voluntary
movement
᷿ For example, when a person walks down the
street, a host of involuntary movements
facilitate the voluntary movements associated
with walking
᷿ PD is characterized by four cardinal sypmtoms:
1) Tremors - resting tremors; pill-rolling
motion of hand; suppressed by
activity/sleep
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2) Bradykinesia - slow onset of
movement/paucity of movement
3) Rigidity - an increase in resistance to
passive movement
4) Postural instability/Gait disturbances -
imbalance and loss of righting reflexes
᷿ A balance of two neurotransmitters -
acetylcholine (ACh) and dopamine is required
for normal functioning of the extrapyramidal
system
᷿ Four primary symptoms and other associated
symptoms (difficulty swallowing, drooling,
weight loss, choking, impaired breathingm,
urinary retention, constipation) occur when
these two neurotransmitter are out of balance
᷿ Dopamine is synthesized in the midbrain by
pigmented cells in an area called the substantia
nigra (Latin for “black substance”)
᷿ Cell bodies are located in the substantia nigra,
and their axons project to a specific area of the
extrapyramidal system called the basal ganglia
(aka corpus striatum)
᷿ The axon terminals of these neurons release
dopamine which in turn activates the dopamine
receptors there
᷿ This pathway, from the midbrain to the basal
ganglia, is known as the nigrostriatal tract
᷿ In PD, the pigmented neurons of the substantia
nigra lose their pigmentation (blackness) -
indicating a decline in dopamine production. A
deficiency in dopamine and a subsequent
decrease in dopamine transmission to basal
ganglia result in imbalance with ACh in the basal
ganglia
᷿ Basal ganglia is referred to as a coronal cu of the
brain (slice that runs from top to bottom with
the outer edges of this view being close to the
ears)
᷿ Substantia nigra and locus ceruleus (where
norepinephrine is synthesized).
The effects of aging and disease on cathecolamine
centers in the brainstem. A, normal pigment in the
susbtantia nigra (left) and locus ceruleus (right) of a
young man. B, mild age-related loss of pigment in
the brainstem of normal individual (right) and loss of
pigmented neurons in the brainstem of an individual
with PD (left). C, mild dipegmentation of the locus
ceruleus (site of norepinephrine synthesis) in an aged
individual (right) and severe depigmentation in PD
(left)
᷿ Normal aging, which results in loss of
pigmented neurons, and demonstrates that PD
dramatically acclerates the process
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Lecturer: Sir Mark Angelo Cristino || 24 March 2022

᷿ EPSEs are also caused by imbalance between

ACh and dopamine, but with an importance
difference.
᷿ PD is related to neurodegeneration of the
substantia nigra at the beginning of the
dopamine tracts, EPSEs are caused by blockade
of dopamine receptors in the basal ganglia at
the end of the dopamine tracts
᷿ PD is treated with antiparkinsonian agents that
increase dopamine (or dopaminergic) levels,
such as Sinemet and levodopa, with
anticholinergic agents (e.g., benztropine
[Cogentin]), or with both.
᷿ EPSEs are treated ONLY with anticholinergics
because psychosis is thought to be related to an EPSEs are divided into at least seven distinct types:
increase in dopamine levels ᷿ Akathasia - a subjective feeling of restlessness
᷿ To give dopamine-enhancing drug (levodop) to a that elicits restless legs, jittery feelings, and
patient with schizoprenia - cause psychotic nervous energy. Akathasia is the most common
symptoms to increase EPSE and responds poorly to treatment. (restless,
agitated, need to move, rock or pace,
Pathophysiology and Treatment frantic/panicked)
᷿ Akinesia and bradykinesia - Akinesia refers to
an absence of movement, but a slowed
movement (bradykinesia) is more likely.
Symptoms include weakness, fatigue, painful
muscles, and anergia. Akinesia responds to
anticholinergics.

᷿ Dystonias - abnormal postures (i.e., muscle

freezing) caused by involuntary muscle spams.
Symptoms manifest as sustained, twisted, and
contracted positioning of the limbs, trunk, neck,
or mouth. It tends to appear early in treatment
(within about 3 days) and respond to
anticholinergic drugs. These agents must
occasionally be given parenterally because of the
gravity of the situation
Types of Dystonias:
Torticollis - contracted positioning of the neck
Oculogyric crisis - contracted positioning of the eyes
1. Degeneration of darkly pigmented dopaminergic
upward
neurons in substantia nigra
Laryngeal-pharyngeal constriction (potentially life-
2. Dopamine (oxidation) Neuromelanin
threatening)
3. Decrease dopamine in neostriatum

᷿ Drug-induced Parkinsonism - the cardinal

symptoms of PD are experienced: tremor,
rigidity, bradykinesia, and postural instability
᷿ Tardive Dyskinesia (TD) - tardive means “late
Idiopathic Parkinsonism - Unknown cause. The most appearing.” This EPSE tends to develop late, after
common symptoms of idiopathic Parkinson’s about 6 months of antipsychotic therapy. It is
are tremor, rigidity and slowness of movement. not the dopamine ACh imbalance per se that
causes tardive dyskinesia; as a result,
anticholinergics generally worsens TD. Chronic

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Lecturer: Sir Mark Angelo Cristino || 24 March 2022
use antipsychotics is thought to cause dopamine
receptors in the basal ganglia to become
hypersensitive. Symptoms are bothersome and
can be embarrassing. Typical symptoms: tongue
writhing, tongue portrusion, teeth grinding, and
lip smacking. TD stops with sleep. Although TD
movements can be suppressed willfully for a
short time, they soon reappear. NO satisfactory
pharmacologic treatment has yet been
developed.
᷿ Neuroleptic malignant syndrome (NMS) - is a
potentially lethal side effect of antipsychotic
agents. Fewer than 1% of patients taking
antipsychotics will develop this problem, but 5%
to 20% of those untreated will die. Cardinal
symptoms: hyperthermia (38.3 °C to 39.4 °C, but
can rise to 42.2 °C), rigidity, and autonomic
dysfunction. NMS can be treated with muscle
relaxants (e.g., dantrolene [Dantrium]) and with
centrally acting dopaminergics (e.g.,
bromocriptine [Parlodel])
᷿ Pisa syndrome - is a condition marked by the
patient learning to one side. It can be acute or
tardive, and older adults are more vulnerable.
Anti-Parkinsonian Drugs
Levodopa (l-dopa)
᷿ Metabolic precursor of dopamine
᷿ Inactive by itself
᷿ 95% of an oral dose is dcarboxylated in the
peripheral tissues (mainly gut & liver) and
converted into DA
᷿ Only about 1-2% of administered levodopo
crosses to the brain
᷿ Always used in combination with
carbidopa/benserazide (Peripheral
decarboxylase inhibitor)
᷿ Advantages of the combination: (1) less dose of
levodopa required and more effect of levodopa,
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NCM 117
(2) increased half life of levodopa, (3) less side
effects of levodopa, peripherally, (4) Vit B6
interaction does not occur)
Pharmacokinetics
᷿ Absorption: orally by active transport; decreased
by the presence of food especially amino acids);
administered on empty stomach
᷿ Bioavailability affected by: amino acids present
in food compete for the same carrier for
absorption (should be given 30-60 min before
meal)
᷿ Distribution: L-dopa crosses BBB (CNS
disturbance)
᷿ The plasma t1/2 levodopa is 1-2 hours
᷿ Metabolism: Levodopa undergoes high first pass
metabolism in GI mucosa & liver
᷿ Excretion: urine
Pharmacodynamics
᷿ On CNS: marked by symptomatic improvement
occurs in Parkinsonian patients; effect on
behavior: General alerting response
᷿ On CVS: (+ inotropic action) the peripherally
formed DA can cause tachycardia acting on beta
adrenergic receptors; DA and NA formed in
brain decreased central sympathetic flow -
postural hypotension
᷿ On CTZ: dopaminergic receptors are present in
this area and DA acts as an excitatory
transmitter; peripherally formed DA gains access
to the CTZ elicits nausea & vomiting
᷿ Endocrine action: DA acts on pituitary
mammotropes to inhibit prolactin release
᷿ Uses: in PD, Levodopa can reduce all sign and
symptoms of PD. It doesn’t stop the progression
of disease.
Adverse Effects
a) CNS manifestations
᷿ Euphoria, anxiety, agitation, insomnia,
psychological disturbances as confusion,
delusions, hallucinations
᷿ Dyskinesia (abnormal involuntary movements
which is corrected by dose reduction)
(b) GIT manifestations
᷿ Anorexia, nausea and vomiting due to
stimulation of D-2 receptors in CTZ
᷿ Tolerance may develop to this adverse effect,
but if nausea and vomiting persist, antiemetics
are given e.g., domperidone (D2 antagonist
which does not pass BBB)
᷿ Constipation and bleeding peptic ulcer may
occur
(c) CVS manifestations
᷿ Postural hypotension - central sympathetic flow
᷿ Tachycardia (direct β1 stimulation)
᷿ Hypertension occurs with large doses or with
non-selective MAO inhibitors (α1stimulation)
Others
᷿ Alteration of smell, taste sensation
᷿ Abnormal movements - facial tics
After prolong therapy:
Wearing off Phenomenon
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Lecturer: Sir Mark Angelo Cristino || 24 March 2022

1. Parkinsonism: can be used alone, use as adjuent

to levodopa; serves improve control “wearing of
dose” & “on off fluctuation”
2. Use in suppression of lactation (safer tha estrogen)
3. Acromegaly and ACTH dependent tumors
Adverse Effect
᷿ Hallucination, confusion, vomiting
Contraindication
᷿ Peptic ulcer, MI, mental illness
This may be due to the interaction of DOPAC with
H2O2 leading to formation of toxic oxygen free Pergolide
radicals which destroy dopamine storage vesicles ᷿ Ergot derivative
(this can be prevented by adding selective MAO-B ᷿ Mechanism: agonist at D1, D2 receptor
inhibitors as seligeline) Pharmacokinetics
On-off Phenomenon ᷿ Absorption: rapidly orally
᷿ May be due to variable levels of dopamine in ᷿ Metabolism: liver by CYP-450 system; 50% BA
CNS (undergo first pass metablism)
᷿ In on state: patient enjoys normal mobility ᷿ Excretion: urine
᷿ On off state: loss of beneficial effect on drugs Uses
(patient unable to raise from chair on which he ᷿ Idiopathic PD treatment
had sat few min ago) Interaction
᷿ Flucutation in plasma level because of short half ᷿ Pergolide X CYP1A2 inhibitor (Cibtrofloxacin,
life Diltiazem)
᷿ Treatment: (1) sustained released formulation of
(L-dopa + carbidopa), (2) COM=T inhibitors, (3) Ropinirole
frequent administration of levodopa ᷿ MOA: selectivity at D2 receptor and less or no
Interaction acitivity at D1 class site
᷿ Levodopa X non selective MAO-inhibitor Pharmacokinetics
(hypertensive crisis) ᷿ Rapidly absorbed maximum plasma
᷿ Levodopa X Vit B6 (increased metabolism, concentration is generally reached in; 1-2 hours
therapeutic failure) after oral absorption
᷿ Levodopa X Reserpine, phenothiazine (block ᷿ Bioavailability is 50% because of first pass
dopamine effect) metabolism
᷿ Levodopa X Tricylic antidepressant (decreased ᷿ Metabolized by the liver by cytochrome P450 to
absorption of levodopa) inactive metabolites
Contraindications ᷿ Less than 10% excreted unchanged urine
᷿ Psychoses Uses
᷿ Narrow angle glaucoma ᷿ For treatment of idiopathic PD for early and
᷿ Melanoma advanced PD alone
Adverse Effects
Carbidopa ᷿ Dyspepsia, constipation, and hallucinations
᷿ Decrease peripheral decarboxylation of L-dopa
᷿ Don’t cross BBB Pramipexole
᷿ Currently use fixed dose combinations: L-dopa + ᷿ Non-ergot derivative dopamine antagonist
carbidopa (4:1/10:1) ratio; L-dopa + Benserazide ᷿ It binds to presynaptic & postsynaptic dopamine
(4:1) D2 & D3 receptors but has the highest affinity
᷿ Advantages: (1) BA-dopamine in BG. Hence dose for the D3 receptor subtype
of L-dopa can be reduced by 75%, (2) ᷿ MOA: it stimulates presynaptic and postsynaptic
prolongation of half life L-dopa, (3) decreased dopamine D2 receptors
systemic concentration of dopamine, hence Uses
decrease indicidence of GI side effect, (4) ᷿ Used as monotherapy in early PD
cardiovascular complication minimized, (5) as an adjunct to levodopa in patients with
better patient compliance advanced PD
Adverse Effect
Dopamine Agonist ᷿ In early PD: nausea, dizziness, constipation, and
᷿ An alternative to Levodopa hallucinations
᷿ These will act on striatal dopamine receptors ᷿ In patients with advanced disease, the most
even in advanced patients common adverse effect is orthostatic
᷿ Do not require enzymatic conversion hypotension
Drug interaction
Bromocriptine ᷿ Cimetidine, ranitidine, diltiazem, verapamil,
᷿ Ergot derivative quinidine, triamterene decrease the oral
᷿ Does not require enzymatic conversion to active clearance of pramipexole by 20%
metabolites
᷿ Longer duration of action that l-dopa MAO-B Inhibitors
᷿ Prevent motor complication ᷿ Two different types of MAO are found (MAO-A
᷿ Mechanism: partial D1-antagonist, strong D2- and MAO-B)
antagonist ᷿ MAO-B is responsible for most of the oxidative
Uses metabolism of dopamine in the brain

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Lecturer: Sir Mark Angelo Cristino || 24 March 2022
Selegiline
᷿ Selective irreversible inhibitors of MAO-B
᷿ Advantages: (1) prolonging T1/2 of
endogenously produce dopamine, (2) decrease
anti-parkinsonism effect of dopamine, (3)
decrease ‘on-off’, ‘wearing off’ phenomena
Mechanism of Action
᷿ Selegiline retard the breakdown of dopamine in
the CNS
᷿ Blockade of presynaptic dopamine receptors
᷿ Inhibition of dopamine reuptake from the
synapse
Pharmacokinetics
᷿ Extensively metabolized in the liver
Adverse Effects
᷿ Postural hypotension, confusion, psychosis
Drug Interaction
᷿ Tricylic antidepressant, Pethidine (excitement,
rigidity), Selective Serotonin reuptake inhibtors
(SSRI)
Contraindication
᷿ Contraindicated in patients with convulsive
disorder
Rasagiline
᷿ Newer selective MAO-B inhibitor
᷿ Advantages: (1) 5 times more potent than
Seligiline, (2) longer acting, (3) not metabolized
to amphetamine, (4) does not produce excitatory
side effects
Entacapone
᷿ Reversible COMT-inhibitors
᷿ Only periphery action
Mechanism of Action
᷿ Entacapone is a selective and reversible inhibitor
of COMT
Adverse Effect
᷿ Dyskinesia, nausea, diarrhea, abdominal pain,
and urinary discoloration
᷿ It increases the side effects of levodopa
Tolcapone
᷿ Selective and reversible inhibitor of COMT
᷿ Both action - peripheral + central action
Side Effects
᷿ Ocassionally associated with hepatotoxicity
Dopamine Facilitator
Amantadine
᷿ Introduced as an antiviral agent
᷿ Effective against influenza A2 virus
Mechanism of Action
᷿ It acts presynaptically and postsynaptically
᷿ Presynaptic: increase release of stored
catecholamine from intact dopaminergic
terminals; inhibits catecholamine reuptake
process at the presynaptic
᷿ Postsynaptic: activation of DA receptors directly;
anticholinergic action; NMDA receptor blocking
effect
Uses
᷿ Only in milder cases as monotherapy
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NCM 117
᷿ Supplement to levodopa for advanced cases
᷿ It serves to suppress motor fluctuations and
abnormal movements
Side Effects
᷿ Insomnia, dizziness, confusion, nightmares
Central Anticholinergic
᷿ These are the only drugs effective in drug
induced parkinsonism
᷿ Antimuscarinic agnets improve tremor and
rigidity but have little effect on bradykinesia
᷿ Uses
᷿ Iatrogenic Parkinsonism: anti-dopaminergic drug
induced
᷿ Idiopathic Parkinsonism: useful in the
management of mild to moderate symptoms of
PD
᷿ Advantages: (1) main action - centrally so
minimal peripheral action (2) cheaper and better
tolerated than L-dopa
Adverse Effects
᷿ Dry mouth, constipation, drowsiness
Antihistamine
Drugs:
Orphenadrine
Promethazine
Mechanism of Action
᷿ H1 blockers addition anti-muscarinic action of
acetylcholine
᷿ Promethiazine - decrease tremors, rigidity,
sialorrhoea
Drug-Induced Parkinsonism
Blocked dopamine receptor in striatum
No deficiency of dopamine
1. Antipsychotic Drugs - Haloperidol, Phenothiazines
high potent D2 blockers drugs induce
parkinsonism
2. Reserpine - dopamine depleting agent
3. Metoclopramide - cross BBB - block D2 receptor
4. MPTP: (1-methyl-4phenyl-1,2,3,6
tetrahydropyridine) - causes permanent symptoms of
Parkinson's disease by destroying dopaminergic
neurons in the substantia nigra of the brain. It has
been used to study disease models in various animal
studies.
MPTP yields large variations in nigral cell loss,
striatal dopamine loss and behavioral deficits. This
neurotoxin exerts it neurotoxicity by causing a
barrage of insults, such as oxidative stress,
mitochondrial apoptosis, inflammation,
excitotoxicity, and formation of inclusion bodies
acting singly and in concert, ultimately leading to
dopaminergic neuronal damage in the substantia
nigra pars compacta and striatum.
Fun fact: MPTP was first discovered by a chemistry
student in 1976, who was trying to synthesize a
synthetic heroin, but instead produced MPTP, which
kills dopaminergic (DAergic) neurons
5. Oxidative Stress - phenomenon caused by
imbalance between production and accumulation of
oxygen reactive species in cells and tissues and the
ability of a biological system to detoxify these
reactive products.
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Lecturer: Sir Mark Angelo Cristino || 24 March 2022

GOOD LUCK
FUTURE RNs!!

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