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Parkinsonism

Parkinsonism is characterized by a
combination of rigidity, bradykinesia,
tremor, and postural instability that
can occur for a variety of reasons but
is usually idiopathic (Parkinson's
disease or paralysis agitans).
Cognitive decline occurs in many
patients as the disease advances

Top: Dopaminergic neurons (red) originating in the substantia nigra


normally inhibit the GABAergic output from the striatum, whereas
cholinergic neurons (orange) exert an excitatory effect. Bottom: In
parkinsonism, there is a selective loss of dopaminergic neurons

Cardinal Features
Bradykinesia
Postural instability
Resting tremor (may have postural and
action components)
Rigidity

Motor Symptoms
Decreased dexterity
Dysarthria
Dysphagia
Festinating gait
Flexed posture
Freezing at initiation of movement
Hypomimia
Hypophonia
Micrographia
Slow turning

Autonomic Symptoms
Bladder and anal sphincter disturbances
Constipation
Diaphoresis
Orthostatic blood pressure changes
Paroxysmal flushing
Sexual disturbances

Mental Status Changes


Bradyphrenia
Confusional state
Dementia
Psychosis (paranoia, hallucinosis)
Sleep disturbance

Other
Fatiguability
Oily skin
Pedal edema
Seborrhea
Weight loss

Common types of gait abnormalities

General algorithm for treating early idiopathic


Parkinson's disease.

Algorithm for treating advanced idiopathic


Parkinson's disease. CR, controlled release; COMT,
catechol-O-methyltransferase

Anticholinergic Medications
Anticholinergic drugs can be effective
for tremor and dystonic features in
some patients but rarely show
substantial benefit for bradykinesia or
other disabilities.
They can be used as monotherapy or
in conjunction with other
antiparkinsonian drugs.

Amantadine
Amantadine is often effective for mild symptoms,
especially tremor. It may also decrease dyskinesia at
relatively high doses (400 mg/day).
Its precise mechanism of action is unknown but may
involve dopaminergic or nondopaminergic mechanisms
such as inhibition of N-methyl-d-aspartate receptors.
Adverse effects include sedation, vivid dreams, dry
mouth, depression, hallucinations, anxiety, dizziness,
psychosis, and confusion. Livedo reticularis (a diffuse
mottling of the skin) is a common but reversible side
effect

Levodopa and Carbidopa/Levodopa


Levodopa, the most effective drug
available, is the immediate precursor of
dopamine. It crosses the blood-brain
barrier, whereas dopamine does not.
The decision to start L-dopa as soon as the
diagnosis is made or only when symptoms
compromise social, occupational, or
psychological well-being has
generated controversy

Cholinergic nerves are shown in blue; noradrenergic in red; and dopaminergic in green.
Note that some sympathetic postganglionic fibers release acetylcholine or dopamine
rather than norepinephrine. The adrenal medulla, a modified sympathetic ganglion,
receives sympathetic preganglionic fibers and releases epinephrine and norepinephrine
into the blood. ACh, acetylcholine; D, dopamine; Epi, epinephrine; M, muscarinic

Cholinoceptor-Activating &
Cholinesterase-Inhibiting Drugs
Acetylcholine-receptor stimulants and cholinesterase
inhibitors together make up a large group of drugs
that mimic acetylcholine (cholinomimetic agents)
Cholinoceptor stimulants are classified
pharmacologically by their spectrum of action,
depending on the type of receptormuscarinic or
nicotinicthat is activated.
Cholinomimetics are also classified by their
mechanism of action because some bind directly to
(and activate) cholinoceptors whereas others act
indirectly by inhibiting the hydrolysis of endogenous
acetylcholine

Anticholinergic
Cholinergic blocking drugs also are
called anticholinergics or
parasympathomimetic blocking
drugs.
Examples of cholinergic blocking
drugs include atropine, scopolamine,
and propantheline

ACTIONS
Cholinergic blocking drugs inhibit the
activity of acetylcholine in
parasympathetic nerve fibers
When the activity of acetylcholine is
inhibited, nerve impulses traveling
along parasympathetic nerve fibers
cannot pass from the nerve fiber to
the effector organ or structure.

Sites of actions of cholinergic antagonists

Antimuscarinic Agents
Atropine
a tertiary amine belladonna alkaloid, has a
high affinity for muscarinic receptors,
where it binds competitively, preventing
acetylcholine from binding to those sites .
Atropine acts both centrally and
peripherally.

Competition of atropine and scopolamine with


acetylcholine for the muscarinic receptor

Dose-dependent effects of atropine

Pharmacokinetics:
Atropine is readily absorbed, partially
metabolized by the liver, and
eliminated primarily in the urine.
It has a half-life of about 4 hours.

Therapeutic uses
Ophthalmic: In the eye, topical atropine
exerts both mydriatic and cycloplegic
effects
Shorter-acting antimuscarinics
(cyclopentolante and tropicamide) have
largely replaced atropine due to
prolonged mydriasis observed with
atropine (7-14 days versus 6-24 hours
with other agents).

Antispasmodic: Atropine is used as an


antispasmodic agent to relax the GI tract and
bladder.
Antidote for cholinergic agonists: Atropine is used
for the treatment of overdoses of cholinesterase
inhibitor insecticides and some types of mushroom
poisoning (certain mushrooms contain cholinergic
substances that block cholinesterases).
Antisecretory: The drug is sometimes used as an
antisecretory agent to block secretions in the
upper and lower respiratory tracts prior to surgery.

Adverse effects:
Depending on the dose, atropine may
cause dry mouth, blurred vision,
tachycardia, and constipation.
Effects on the CNS include restlessness,
confusion, hallucinations, and delirium,
which may progress to depression, collapse
of the circulatory and respiratory systems,
and death.
Low doses of cholinesterase inhibitors such
as physostigmine may be used to
overcome atropine toxicity.

In older individuals, the use of atropine to


induce mydriasis and cycloplegia is considered
to be too risky, because it may exacerbate an
attack of glaucoma in someone with a latent
condition.
In other older individuals, atropine may induce
urinary retention that is troublesome.
Children are sensitive to effects of atropine,
the rapid increases in body temperature that it
may elicit. This may be dangerous in children.

Scopolamine
Actions:
Scopolamine is one of the most
effective antimotion sickness drugs .
Scopolamine also has the unusual effect
of blocking short-term memory.
In contrast to atropine, scopolamine
produces sedation, but at higher doses
it can produce excitement instead.
Scopolamine may produce euphoria and
is subject to abuse

Pharmacokinetics and adverse effects:


These aspects are similar to those of
atropine

Tropicamide and cyclopentolate


These agents are used as ophthalmic
solutions for similar conditions as
atropine (mydriasis and cyclopegia).
Duration of action is shorter than
that of atropine; tropicamide
produces mydriasis for 6 hours and
cyclopentolate for 24 hours.

Effects of the Cholinergic


Blocking
Drugs

ADVERSE REACTIONS
Central nervous systemheadache, flushing,
nervousness, drowsiness, weakness, insomnia,
nasal congestion, fever
Eyesblurred vision, mydriasis, photophobia,
cycloplegia, increased ocular tension
Gastrointestinal tractnausea, vomiting, difficulty
in swallowing, heartburn
Urinary tracturinary hesitancy and retention,
dysuria
Cardiovascular systempalpitations, bradycardia
(after low doses of atropine), tachycardia (after
higher doses of atropine)
Otherurticaria, anaphylactic shock, other skin
manifestations

Adverse effects commonly observed with


cholinergic antagonists

CONTRAINDICATIONS