Successfully reported this slideshow.
Activate your 14 day free trial to unlock unlimited reading.
Dr. Mohit Kulmi
Post-Graduate Resident, Dept. of Pharmacology
Parkinsonism is a clinical syndrome with 4 cardinal
• Bradykinesia (slowness and poverty of movement)
• Muscular rigidity
• Resting tremor (which usually abates during voluntary
• An impairment of postural balance leading to
disturbances of gait and to falling
• The most common form of parkinsonism is idiopathic
• first described by James Parkinson in 1817 as paralysis
agitans, or the “shaking palsy.”
• The pathological hallmark of PD is the loss of the
pigmented, dopaminergic neurons of the substantia
nigra pars compacta,
• with the appearance of intracellular inclusions known
as Lewy bodies.
• A loss of 70-80% of these dopamine-containing neurons
accompanies symptomatic PD.
• Without treatment, PD progresses over 5-10 years to a
rigid, akinetic state in which patients are incapable of
caring for themselves.
• Death frequently results from complications of
immobility, including aspiration pneumonia or
• The availability of effective pharmacological treatment
has radically altered the prognosis of PD;
• in most cases, good functional mobility can be
maintained for many years.
• Life expectancy of adequately treated patients is
increased substantially, but overall mortality remains
higher than that of the general population.
• PD affects a wide range of other brain structures,
including the brainstem, hippocampus, and cerebral
• This pathology is likely responsible for the “non-motor”
features of PD, which include sleep disorders,
depression, and memory impairment.
• Several disorders other than idiopathic PD also may
• Drugs that may cause parkinsonism include
antipsychotics such as haloperidol and chlorpromazine
• and antiemetics such as prochlorperazine and
• The distinction between idiopathic PD and other causes
of parkinsonism is important because parkinsonism
arising from other causes usually is refractory to all
forms of treatment.
• The possible role of aging in the pathogenesis of PD is
suggested by its usual occurrence in late middle age,
and by marked increases in its prevalence at older ages.
• with the discovery in 1983 that exposure to MPTP is
capable of inducing parkinsonism in humans.
• The most important advances in PD research in recent
years - the identification of specific disease-causing
• making it possible for the first time to begin to explore
pathogenesis at the molecular level.
• best documented and most widely investigated genetic
causes being - synuclein and parkin.
THE BASAL GANGLIA
•Consists of a group of nuclei in the deep part of the
cerebrum and upper brain stem: caudate, putamen,
globus pallidus, subthalamic nucleus, substantia nigra
•Coordinates muscle actions and voluntary movements
•Controls the higher-order, cognitive aspects of
voluntary movement: the planning and execution of
complex motor strategies
•Cognitive functions (procedural memory - skills &
•Structural defects and neurotransmitter imbalance
cause movement disorders: hypokinesia or
• Degeneration of dopamine-producing neurons in the
substantia nigra of the midbrain
• Disrupts the balance of:
• dopamine (DA) – neurotransmitter for normal
functioning of the extrapyramidal motor system
(control of posture, support, and voluntary
• Acetylcholine (Ach)
• in the basal ganglia
• Symptoms do not occur until 80% of the neurons in the
substantia nigra are lost.
• Five Stages
• Flexion of affected arm - tremor / leaning toward
• Slow shuffling gate
• Increased difficulty walking – looks for support to
• Further progression of weakness – assistance with
• Profound disability – may be confined to wheelchair
• First sign
• Affects handwriting – trailing off at ends of words
• More prominent at rest
• Aggravated by emotional stress or increased
• “Pill rolling” – rotary motion of thumb and forefinger
• Increased resistance to passive motion when limbs are
moved through their range of motion
• “Cogwheel rigidity” -- Jerky quality – intermittent
catches of movement
• Caused by sustained muscle contraction
• Muscle soreness; feeling tired & achy
• Slowness of movement due to inhibition of alternating
muscle group contraction & relaxation in opposing
• Loss of automatic movements:
• Blinking of eyes, swinging of arms while walking,
• swallowing of saliva, self-expression with facial and
• lack of spontaneous activity, lack of postural
• Results in: stooped posture, masked face, drooling
of saliva, shuffling gait; difficulty initiating
• Objectives of antiparkinsonian
• The dopaminergic/cholinergic balance may be restored
by two mechanisms-
• 1. Enhancement of DA-ergic activity by drugs
• replenish neuronal DA by supplying levodopa, which
• is its natural precursor; administration of DA itself is
• ineffective as it does not cross the BBB;
• act as DA agonists (bromocriptine, pergolide,
• prolong the action of DA through selective inhibition of
its metabolism (selegiline);
• release DA from stores and inhibit reuptake
• 2. Reduction of cholinergic activity by
• this approach is most effective against tremor and
• and less effective in the treatment of bradykinesia.
1. Because dopamine does not cross the blood-brain
barrier levodopa, the precursor of dopamine, is given
2. Levodopa is formed L-tyrosine and is an
intermediate in the synthesis of catecholamines.
3. Levodopa itself has minimal pharmacologic activity,
in contrast to its decarboxylated product, dopamine.
4. Levodopa is rapidly decarboxylated in the
gastrointestinal tract. Prior to the advent of
decarboxylase inhibitors (carbidopa), large oral
doses of levodopa were required; thus, toxicity from
dopamine was a limiting factor.
(1) Levodopa is well absorbed from the small bowel;
however, 95% is rapidly decarboxylated in periphery.
(2) Peripheral dopamine is metabolized in the liver to
dihydroxyphenylacetic acid (DOPAC) and
homovanillic acid (HVA), which are then excreted in
• Pharmacologic effects:
(1) The effects on bradykinesia and rigidity are more
rapid and complete than the effects on tremor. Other
motor defects in PD improve. The psychological well-
being of patient is also improved.
(2) (2) Tolerance to both beneficial and adverse effects
occurs with time. Levodopa is most effective in the
first 2-5 years of treatment. After 5 years of therapy,
patients have dose-related dyskinesia, inadequate
response, or toxicity.
• Adverse effect:
Principal adverse effects include:
(1) Anorexia, nausea, and vomiting upon initial
administration, which often limit the initial dosage.
(2) Cardiovascular effects, including tachycardia,
arrhythmias, and orthostatic hypotension.
(3) Mental disturbances, including vivid dreams,
delusions, and hallucination.
(5) On-off phenomena
Sudden discontinuation can result in fever, rigidity,
and confusion. The drug should be withdrawn
gradually over 4 days.
• Vit B6 reduces the beneficial effects of Levodopa by
enhancing its extracerebral metabolism.
• Therapy with MAO inhibitors must be stopped 14 days
prior to the initiation of levodopa therapy.
• Phenothiazines, reserpine, and butyrophenones
antagonize the effects of levodopa because they lead to
a junctional blockade of dopamine action.
• Carbidopa is an inhibitor of dopa decarboxylase.
• Because it is unable to penetrate the blood-brain
barrier, it acts to reduce the peripheral conversion of
levodopa to dopamine.
• As a result, when carbidopa and levodopa are given
a. It can decrease the dosage of levodopa.
b. It can reduce toxic side effects of levodopa.
• a derivative of ergot.
• It is a D2-receptor agonist, but also a weak alpha-
• Bromocriptine is commonly used with levodopa.
• It should be started at very low doses, increasing at
weekly interval and according to clinical response.
• It is also used for treatment of prolactin-secreting
adenomas, amenorrhea/galactorrhea to
hyperprolactinemia, to stop lactation, acromegaly.
• ADRs: Nausea and vomiting, which may be prevented
with domperidone; postural hypotension (may cause
dizziness or syncope); after prolonged use – pleural
effusion and retroperitoneal fibrosis.
• Pergolide, another ergot derivative, directly stimulates
dopamine receptors. It too has been widely used for
• but has been associated with the development of valvular
• CABERGOLINE, also an ergot derivative, has a t1/2
• This allows it to be used in a single daily (or even twice
• Cabergoline alleviates night-time problems in
• Pramipexole is not an ergot derivative, but it has
preferential affinity for the D family of receptors.
• It is effective as monotherapy for mild parkinsonism
and is also helpful in patients with advanced disease,
permitting the dose of levodopa to be reduced and
• smoothing out response fluctuations.
• is a relatively pure D receptor agonist that is effective as
monotherapy in patients with mild disease and as a
means of smoothing the response to levodopa in
patients with advanced disease and response
• The dopamine agonist rotigotine, delivered daily
through a skin patch, was approved in 2007 by the
Food and Drug Administration (FDA) for treatment of
early Parkinsons disease.
• It supposedly provides more continuous dopaminergic
stimulation than oral medication in early disease; its
efficacy in more advanced disease is less clear.
• Side effects of dopamine agonists –
1. GI – nausea, vomitting, constipation, dyspepsia.
2. CVS – postural hypotension
4. Mental disturbences
MAO INHIBITORS• Selegiline –
• a selective irreversible inhibitor of monoamine oxidase
B at normal doses (at higher doses it inhibits
monoamine oxidase A as well),
• retard the breakdown of dopamine, in consequence it
enhances and prolongs the antiparkinsonism effect of
levodop (thereby allowing the dose of levodopa to be
• It is therefore used as adjunctive therapy for patients
with a declining or fluctuating response to levodopa.
• The standard dose of selegiline is 5 mg with breakfast
and 5 mg with lunch. Selegiline may cause insomnia
when taken later during the day.
• Rasagiline, another monoamine oxidase B inhibitor, is
more potent than selegiline in preventing MPTP-
induced parkinsonism and is being used for early
• The problem with nonselective MAO inhibitors is that
they prevent degradation of dietary adrenomimetic
amines, especially tyramine, by MAO-A inhibition
which causes hypertensive “cheese reaction”.
• Selegiline does not cause the cheese reaction, because
MAO-A is still present in the liver to metabolize
• MAO-A also metabolizes tyramine in the sympathetic
nerve endings in periphery.
• Selegiline inhibits selectively only MAO-B in
the CNS and protects DA from intraneuronal
• It is used as an adjunct drug in PD if
levodopa/carbidopa or levodopa/benserazide therapy is
• Inhibition of dopa decarboxylase is associated with
compensatory activation of other pathways of levodopa
metabolism, especially catechol- O –methyltransferase
(COMT), and this increases plasma levels of 3- O-
• Elevated levels of 3-OMD have been associated with
poor therapeutic response to levodopa,
• Selective COMT inhibitors such as tolcapone and
entacapone also prolong the action of levodopa by
diminishing its peripheral metabolism.
• Levodopa clearance is decreased, and relative
bioavailability of levodopa is thus increased.
• These agents may be helpful in patients receiving
levodopa who have developed response fluctuations
leading to a smoother response, more prolonged on-
• Tolcapone has both central and peripheral effects,
whereas the effect of entacapone is peripheral.
• Adverse effects of the COMT inhibitors relate in part to
increased levodopa exposure and include dyskinesias,
nausea, and confusion.
• is an antiviral drug which, given for influenza to a
parkinsonian patient, was noted to be beneficial.
• Antiviral and antiparkinsonian effects of amantadine
• Antiparkinsonian effect is due to increase synthesis and
release of DA, and diminish neuronal reuptake too.
• Amantadine also has slight antimuscarinic effect.
• Amantadine ARs, includes ankle edema (probably a
local effect on blood vessels), orthostatic hypotension,
insomnia, hallucinations, rarely – fits.
• Central antimuscarinic drugs
• BIPERIDEN, TRIHEXYPHENIDYL, TRIPERIDEN
• are synthetic compounds (central parasympatholytics).
• They benefit parkinsonism by blocking ACh receptors in
the CNS, thereby partially redressing the imbalance
created by decreased DA-ergic activity.
• They also produce modest improvement in tremor,
rigidity, sialorrhoea (hypersalivation), muscular
stiffness and leg cramp, but little in bradykinesia, which
is the most disabling symptom of Parkinson’s disease.
• ARs of antimuscarinic drugs include
• dry mouth (xerostomia),
• blurred vision,
• urine retention, glaucoma,
• hallucinations, memory defects, toxic confusional states
and psychoses (which should be distinguish from
PHARMACOTHERAPY OF PD
• The main features that require alleviation are tremor,
rigidity and bradykinesia.
• Drug therapy has the most important role in symptom
relief, but it does not alter the progressive course of PD.
• Treatment should begin only when it is judged necessary in
each individual case.
• Two objectives have to be balanced: the desire for
satisfactory relief of current symptoms and the avoidance of
ARs as a result of long-continued treatment.
• Levodopa provides the biggest improvement in motor
activity but its use is associated with the development of
dyskinesia (involuntary movement of the face and
limbs) after 5–10 years, and sometimes sooner.
• DA agonists have a much less powerful motor effect but
are less likely to produce dyskinesias.
• The treatment usually begins with levodopa in low
doses to get a good motor response and adds a DA
agonist when the initial benefit begins to wane.
• A typical course is that for about 2–4 years on
treatment with levodopa or DA agonist, the patient’s
disability and motor performance remains near normal
despite progression of the underlying disease.
• After some 5 years about 50% of patients exhibit
problems of long-term treatment, namely, dyskinesia
and end-of-dose deterioration with the “on-off”
• After 10 years virtually 100% of patients are affected.
• End-of-dose deterioration is managed by increasing the
frequency of dosing with levodopa (e.g. to 2 or 3-
hourly), but this tends to worsen the dyskinesia.
• The motor response then becomes more brittle with abrupt
swings between hyper- and hypomobility (the on-off
• In this case a more effective approach is to use a COMT
inhibitor, e.g. entacapone, which can sometimes allay early
end-of-dose deterioration without causing dyskinesia.
• Some 20% of the patients with Parkinson’s disease, notably
the Elderly ones, develop impairment of memory and speech
with a fluctuating confusional state and hallucinations.
• As these symptoms are often aggravated by medication, it is
preferable gradually to reduce the antiparkinsonian
1. MAOI – safinamide
2. DA – sumanirole
3. Antidyskinesia drugs – sarizotan, istradefyllin, fipamazole,
4. Trophic drugs – CERE120 (CERE-120 is an adeno
assosiated virus rtype 2 encoding human NTN),
Neutrophic factor such as neurturin (NTN), Glial cell lined
derived neurotrophic factors (GDNF)
5. Neuroprotective drugs – CoQ10, TCH346, CEP1347.
6. Surgery – Deep Brain Stimulation
• Creating a lesion in the subthalamic nucleus or globus
• Thalamotomy, pallidotomy, spheramine,
• Retinal pigment epithelial cells