MD PHARMACOLOGY in Government medical college Anatpur,AP

1. ANTIPARKINSON
DRUGS

2. Parkinsonism is a clinical syndrome with 4 cardinal
features:
 Bradykinesia(slowness and poverty of
movement)
 Muscular rigidity
 Resting tremor(usually abates during
vountary movement)
 An impairement of postural balance leading
to disturbance of gait to falling

4.  Aging :>65 yrs
 Environmental factors:
exposure to MPTP
Poisoning due to manganese and
carbon monoxide.
 Genetic:
Alpha synuclein
parkin
ubiquitin

7.  First sign
 Affects handwriting
 Aggravated by emotional stress or increased
concentration
 Pill rolling- rotatory motion of thumb and
forefinger

9. • Objectives of antiparkinsonian
pharmacotherapy
• Objectives of antiparkinsonian
pharmacotherapy
• The dopaminergic/cholinergic balance
may be restored
• by two mechanisms-
• The dopaminergic/cholinergic balance may be restored
 by two mechanisms-

10. DRUGS ACTING ON DOPAMINERGIC SYSTEM:
Dopamine precursors – Levodopa (l-dopa)-(0.5g)
Peripheral decarboxylase inhibitors – carbidopa,benserazide
COMT inhibitors – Entacapone, Tolcapone.
Dopamine facilitator – Amantadine.
MAO-B inhibitors – Selegiline, Rasagiline.
Dopaminergic agonists:-Bromocriptine, cabergoline,
Ropinirole, Pramipexole
DRUGS ACTING ON CHOLINERGIC SYSTEM
Central anticholinergics – Teihexyphenidyl (Benzhexol), Procyclidine,
Biperiden,Benztropine.
Antihistaminics – Orphenadrine, Promethazine,Diphenhydramine.

11.  Mechanism
dopamine doesnot cross BBB ,Levodopa
,precrsor of dopamine is given instead
has minimal pharmacological activity
rapidly decarboxylated in GIT

12.  Pharmacokinetic:
1. Absorbed rapidly from small intestine
2. High first pass effect
3. Peak plasma conc 1-2hrs,t1/2 1-3hrs
4. Competition for amino acids present in food
competes for the carrier
5. Metabolized in liver and peripherally –
secreted in urine unchanged or conjugated
with glucoronyl sulfate

13. • 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.

14. • 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.

15.  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

16. • 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.

17. Psychoses
(shizophrenia)
 NARROW angle
glaucoma
 Cardiac arrhythmias
 Melanoma
 Gout
 Peptic ulcer

18.  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

19. • 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

21. • 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.

22. 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

24. • 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

25. • Side effects of dopamine agonists –
1. GI – nausea, vomitting, constipation,
dyspepsia.
2. CVS – postural hypotension
3. Dyskinesias
4. Mental disturbences

26.  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.
 •

27. • 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”.

29. • 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.

30. • 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.

31. • Levodopa clearance is decreased, and relative
bioavailability of levodopa is thus
increase
d.
• 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.

32. • 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.

34. • 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.

35. • 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).

36.  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.