4. INTRODUCTION
Parkinsonism is a clinical syndrome with 4 cardinal
features:
•Bradykinesia (slowness and poverty of movement)
•Muscular rigidity
•Resting tremor (which usually abates during
voluntary movement)
•An impairment of postural balance leading to
disturbances of gait and to falling
5. • The most common form of parkinsonism is idiopathic
PD,
• 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.
6.
7. • 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
pulmonary embolism.
• 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 cortex.
8. • 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
produce parkinsonism,
• Drugs that may cause parkinsonism include
antipsychotics such as haloperidol and chlorpromazine
• and antiemetics such as prochlorperazine and
metoclopramide.
• 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.
9. ETIOLOGIC FACTORS
AGING:
• 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.
• mostly age group > 65 years.
ENVIRONMENTAL FACTORS:
• with the discovery in 1983 that exposure to MPTP is
capable of inducing parkinsonism in humans.
• Poisoning due to manganese and carbon monoxide.
10. GENETIC:
• The most important advances in PD research in recent
years - the identification of specific disease-causing
mutations,
• 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 - alpha synuclein, parkin and ubiquitin.
12. 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 &
habits)
•Structural defects and neurotransmitter imbalance
cause movement disorders: hypokinesia or
hyperkinesia
13.
14.
15.
16.
17. PATHOGENESIS
• 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
motion)
• Acetylcholine (Ach)
• in the basal ganglia
• Symptoms do not occur until 80% of the neurons in the
substantia nigra are lost.
22. • TREMORS
• First sign
• Affects handwriting – trailing off at ends of words
• More prominent at rest
• Aggravated by emotional stress or increased
concentration
• “Pill rolling” – rotary motion of thumb and forefinger
23.
24. RIGIDITY
• 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
muscle groups
25.
26. • BRADYKINESIA
• Loss of automatic movements:
• Blinking of eyes, swinging of arms while walking,
• swallowing of saliva, self-expression with facial and
hand movements,
• lack of spontaneous activity, lack of postural
adjustment
• Results in: stooped posture, masked face, drooling
of saliva, shuffling gait; difficulty initiating
movement
27.
28. TREATMENT
• Objectives of antiparkinsonian
pharmacotherapy
• The dopaminergic/cholinergic balance may be restored
by two mechanisms-
34. LEVODOPA
• Mechanism:
1. Because dopamine does not cross the blood-brain
barrier levodopa, the precursor of dopamine, is given
instead.
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.
35. Levodopa - Pharmacokinetics
• Absorbed rapidly from small intestine – aromatic amino
acid transport system
• High First Pass Effect – large doses
• Peak plasma conc. 1-2 hrs and half life - 1 to 3 Hrs
Depends on gastric emptying and pH
• Competition for amino acids present in food competes for
the carrier
• Metabolized in liver and peripherally - secreted in urine
unchanged or conjugated with glucoronyl sulfate
• Central entry into CNS (1%) - mediated by membrane
transporter for aromatic amino acids – competition with
dietary protein
• In CNS – Decarboxylated and DA is formed – therapeutic
effectiveness
• Transport back by presynaptic uptake or metabolized by
MAO and COMT
36. LEVODOPA
• Pharmacokinetics:
(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
urine.
37. LEVODOPA
• 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) 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.
38. LEVODOPA
• 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,sleep disturbances including vivid
dreams, delusions, and hallucination.
(4) Hyperkinesia
(5) On-off phenomena
Sudden discontinuation can result in malignant
hyperthermia,fever, rigidity, and confusion. The drug
should be withdrawn gradually over 4 days.
39. LEVODOPA
Drug interactions:
• 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.
• Protein diet interfere with l-dopa absorption both in
brain and git
40. CARBIDOPA
• 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
concomitantly:
a. It can decrease the dosage of levodopa.
b. It can reduce toxic side effects of levodopa.
44. Dopamine receptors agonists
D1 and D2 receptors express differentially – different areas of
brain
D1 is excitatory (cAMP and PIP3)
D2 is inhibitory (Adenylyl cyclase and K+ and Ca++ Channels)
Both present in striatum – involved in therapeutic response of levodopa
Stimulation of Both – smoothening movement and reduced muscle tone
Bromocriptine, pergolide, Ropinirole and Pramipexole: Bromocryptine
– potent D2 agonist and D1 partial agonist and antagonist
Pergolide – Both D1 and D2 agonist
Newer (Pramipexole and Ropinirole) – D2 and D3 effect with low D1 effect
45. • BROMOCRIPTINE- proctinal-( 1.25mg)
• a derivative of ergot.
• It is a D2-receptor agonist, but also a weak alpha 1-
blocker ( decrease gastric motility)
• 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. ERYTHROMYALGIA
46.
47. • PERGOLIDE,( another ergot derivative, directly
stimulates dopamine receptors. It too has been widely
used for parkinsonism.
• but has been associated with the development of valvular
heart disease.(VALVE FIBROSIS)
• Causes vasoconstriction.
• CABERGOLINE, also an ergot derivative, has a t1/2
>80h.
• This allows it to be used in a single daily (or even twice
weekly) dose.
• Cabergoline alleviates night-time problems in
parkinsonian patients.
48. PRAMIPEXOLE- pramiprex 0.5mg
• 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 its on-off response fluctuations.
ROPINIROLE- ropitor 0.25mg
• 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
fluctuations.
• Also used in RESTLESS LEG SYNDROME
49.
50. • ROTIGOTINE
• Also non ergot 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 is D2 and D3 receptor agonist
51. • Side effects of dopamine agonists –
1. GI – nausea, vomitting, constipation, dyspepsia.
2. CVS – postural hypotension
3. Dyskinesias
4. Mental disturbences
52. MAO INHIBITORS
• SELEGILINE – selerin (5mg tab)
• a selective irreversible inhibitor of monoamine oxidase
B at normal doses (at higher doses it inhibits
monoamine oxidase A(depression) 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
reduced)
• It is therefore used as adjunctive therapy for patients
with a declining or fluctuating response to levodopa.
•
53. • 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, relgin (0.5mg) another monoamine
oxidase B inhibitor, is more potent than selegiline in
preventing MPTP- induced parkinsonism and is being
used for early symptomatic treatment.
• 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”.
54.
55. • Selegiline does not cause the cheese reaction, because
MAO-A is still present in the liver to metabolize
tyramine.
• 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
degradation.
• It is used as an adjunct drug in PD if
levodopa/carbidopa or levodopa/benserazide therapy is
deteriorating.
56. CATECHOL-O-METHYLTRANSFERASE INHIBITORS
• 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-
methyldopa (3-OMD).
• 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.
58. • 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- time.
• Tolcapone (100mg) has both central and peripheral
effects, whereas the effect of entacapone (200mg)is
peripheral.
• Adverse effects of the COMT inhibitors relate in part to
increased levodopa exposure and include dyskinesias, nausea,
and confusion.
59.
60. AMANTADINE
• is an antiviral drug which, given for influenza to a
parkinsonian patient, was noted to be beneficial.
• Antiviral and antiparkinsonian effects of amantadine
are unrelated.
• Antiparkinsonian effect is due to increase synthesis and
release of DA, and diminish neuronal reuptake too.
• Amantadine ( 100mg) also has slight antimuscarinic effect.
• Block glutamate & NMDA receptor.
• Amantadine ARs, includes ankle edema (probably a local
effect on blood vessels), orthostatic hypotension,
insomnia, hallucinations, rarely – fits.
• Causes LIVEDO RETICULARIS.
61.
62. • CENTRAL ANTIMUSCARINIC DRUGS
• BIPERIDEN, TRIHEXYPHENIDYL(2-10mg),
TRIPERIDEN,PROCYCLIDINE.
• 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.
63. • ARs of antimuscarinic drugs include
• dry mouth (xerostomia),
• blurred vision,
• constipation,
• urine retention, glaucoma,
• hallucinations, memory defects, toxic confusional states
and psychoses (which should be distinguish from
presenile dementia).
64. Drug Induced Parkinsonism:
Antipsychotics: Chlorpromazine, Fluphen-zine and
Haloperidol
Antihypertensive like Reserpine
Antiemetics: Metoclopramide (Reglan) and
Prochlorperazine (Compazine),
Not associated with loss of nerve cells in the
substantia nigra
Differ from the permanent PD associated with the
nerve toxin MPTP - loss of nerve cells in the
substantia nigra.
66. 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.
67. • 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.
68. • 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”
phenomenon.
• 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.
69. • The motor response then becomes more brittle with abrupt
swings between hyper- and hypomobility (the on-off
phenomenon).
• 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
treatment.
70. FUTURE THERAPIES
1. MAOI – safinamide
2. DA – sumanirole
3. Antidyskinesia drugs – sarizotan, istradefyllin, fipamazole,
levetiracetem.
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
pallidus
• Thalamotomy, pallidotomy, spheramine,
• Retinal pigment epithelial cells
