BDS Pharmacology Lecture Slides

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Dr. Shivankan Kakkar, MD
Antiparkinsonian drugs
Parkinson’s disease (PD) was first described by Sir
James Parkinson. It is characterized by tremor, rigidity,
bradykinesia (slowness of movements) and the loss of
postural reflexes.
In idiopathic parkinsonism, there is degeneration of the
dopamine-containing neurons in the substantia nigra,
resulting in dopamine deficiency.

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Dr. Shivankan Kakkar, MD
Hence, the balance between inhibitory dopaminergic
neurons and excitatory cholinergic neurons is disturbed
resulting in relative cholinergic overactivity.

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Dr. Shivankan Kakkar, MD
Classification
1. Drugs influencing brain dopaminergic system:
(a) Dopamine precursor: Levodopa.
(b) Dopamine agonists: Bromocriptine, pramipexole,
ropinirole.
(c) N-methyl-D-aspartate (NMDA) receptor
antagonist: Amantadine.
(d) MAO-B inhibitors: Selegiline, rasagiline.
(e) COMT inhibitors: Tolcapone, entacapone.

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Dr. Shivankan Kakkar, MD
2. Drugs influencing brain cholinergic system :
(a) Centrally acting anticholinergic drugs:
Benztropine, benzhexol (trihexyphenidyl),
procyclidine, biperiden.
(b) Antihistaminics (H1-blockers) with
anticholinergic activity: Promethazine,
diphenhydramine, orphenadrine.
The main aim of drug therapy in parkinsonism is to
either enhance dopamine activity or reduce cholinergic
activity in the striatum.

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Dr. Shivankan Kakkar, MD
Dopamine precursor: Levodopa
Levodopa (L-Dopa) is the main drug for the treatment
of idiopathic parkinsonism. Dopamine does not cross
BBB, hence its immediate precursor levodopa (prodrug)
is used. It is converted to dopamine by decarboxylase
enzyme in the dopaminergic neurons of the striatum.
Dopamine produced then interacts with D2 receptors in
the basal ganglia to produce antiparkinsonian effect. In
early stages of the disease, improvement is almost
complete.

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Dr. Shivankan Kakkar, MD
All the clinical symptoms (rigidity, bradykinesia and
tremor) of parkinsonism improve, but the progression of
the disease is not stopped. A large amount of the drug is
converted to dopamine in the peripheral tissues by
peripheral decarboxylase enzyme. Only a small amount
(2–3%) of levodopa enters the brain. Therefore,
levodopa is used in combination with
carbidopa/benserazide (peripheral decarboxylase
inhibitor) which does not cross the BBB; the peripheral
metabolism of levodopa is reduced, thus increasing its
bioavailability in the basal ganglia.

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Dr. Shivankan Kakkar, MD

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Dr. Shivankan Kakkar, MD
Pharmacokinetics.
On oral administration, levodopa is rapidly absorbed
from the small intestine by an active transport system.
Amino acids present in food may interfere with the
absorption of levodopa, hence it should be given 30–60
minutes before meal. Active transport of levodopa into
the brain may be inhibited by competition from dietary
amino acids.

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Dr. Shivankan Kakkar, MD
The main metabolic products of levodopa are
homovanillic acid (HVA) and 3,4-
dihydroxyphenylacetic acid (DOPAC). The metabolites
are excreted in urine.

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Dr. Shivankan Kakkar, MD

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Dr. Shivankan Kakkar, MD
Adverse effects
1. GIT: Nausea, vomiting and anorexia are common
during initial treatment with levodopa. Tolerance to
emetic effect develops slowly.
2. CVS: The commonest cardiovascular side effect is
postural hypotension, which is usually asymptomatic. It
can also cause tachycardia, palpitation and rarely
cardiac arrhythmias.

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Dr. Shivankan Kakkar, MD
3. Dyskinesias (abnormal involuntary movements):
Tics, tremors and choreoathetoid movements may
occur. Tolerance does not develop to abnormal
movements.
4. Alteration in taste sensation.
5. Mental changes like insomnia, confusion, delusions,
euphoria, depression, anxiety, hallucinations and
nightmares.

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Dr. Shivankan Kakkar, MD
6. Fluctuations in response: After 3–5 years of
therapy, with progressing disease, control becomes poor
and fluctuations in symptoms occur frequently.
Wearing off (end-of-dose) is due to decrease in plasma
concentration of levodopa towards the end-of-a-dose
interval. Patient may show fluctuation in response—
being ‘off’ (loss of beneficial effect of the drug) and
being ‘on’ (relief of most of the symptoms but with
disabling dyskinesias) called the on/off phenomenon.
Sustained release formulation of levodopa–carbidopa
produces more stable plasma levodopa levels and helps
to reduce fluctuation in response (on/off phenomena).

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Dr. Shivankan Kakkar, MD
End-of-dose deterioration can also be improved by
administering levodopa in smaller and more frequent
doses.
Peripheral decarboxylase inhibitors: Carbidopa and
benserazide
Carbidopa and benserazide are peripheral
decarboxylase inhibitors.

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Dr. Shivankan Kakkar, MD
These drugs do not cross BBB. Levodopa is always
given in combination with carbidopa/benserazide. The
currently used combinations are:
Levodopa + carbidopa (4:1 or 10:1 ratio).
Levodopa + Benserazide (4:1).
The advantages of these fixed-dose combinations
are:
1. Increased bioavailability of dopamine in the basal
ganglia. Hence, the dose of levodopa can be reduced by
75%.
2. Prolongation of plasma half-life of levodopa.

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Dr. Shivankan Kakkar, MD
3. Reduction in the incidence of GI side effects like
nausea and vomiting.
4. Cardiovascular side effects like tachycardia,
hypotension and cardiac arrhythmias are minimized.
5. Better patient compliance.
6. Sustained release preparation of levodopa–carbidopa
helps to reduce on/off phenomenon.

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Dr. Shivankan Kakkar, MD
Dopamine receptor agonists: Bromocriptine,
ropinirole and pramipexole
These drugs have direct action on dopamine receptors.
Like levodopa, they can relieve signs and symptoms of
parkinsonism. They are administered orally. The
duration of action of these drugs is longer than that of
levodopa and these are used particularly in patients who
have frequent fluctuation of symptoms (on/off
phenomena).

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Dr. Shivankan Kakkar, MD
Bromocriptine
Bromocriptine is an ergot derivative; has agonistic
action at D2 and partial agonist at D1 receptors.
Adverse effects
Adverse effects include anorexia, nausea, vomiting,
constipation, postural hypotension, cardiac
arrhythmias, digital vasospasm, dyskinesias, headache,
confusion, hallucinations and nasal congestion. It is
contraindicated in patients with history of mental
illness, recent MI, peptic ulcer and peripheral vascular
diseases.

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Dr. Shivankan Kakkar, MD
Ropinirole and pramipexole
These are non-ergoline derivatives, hence ergot related
side effects are not seen. These drugs are often used in
the initial treatment of parkinsonism. They can be used
as monotherapy or in combination with levodopa–
carbidopa. The other indication of these non-ergolines
is in ‘restless leg syndrome’.

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Dr. Shivankan Kakkar, MD
Adverse effects.
Nausea, vomiting, confusion, fatigue, somnolence,
hallucinations, postural hypotension, dyskinesia and
rarely sudden attacks of irresistible sleep during day
time.

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Dr. Shivankan Kakkar, MD
COMT inhibitors: Tolcapone, entacapone
Tolcapone and entacapone are reversible COMT
inhibitors. By inhibiting the peripheral metabolism of
levodopa to 3-O-methyldopa, they increase the half-life
of levodopa and also enhance its bioavailability in the
CNS. The ‘on’ time is prolonged and the dose of
levodopa can be reduced. Tolcapone has both peripheral
and central actions with relatively longer duration of
action, whereas entacapone inhibits COMT only in the
periphery.

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Dr. Shivankan Kakkar, MD
These drugs are used as adjunct to levodopa-carbidopa
for advanced cases of PD. Combined preparation of
levodopa + carbidopa + entacapone is available.
Adverse effects.
These include dyskinesia, nausea, diarrhoea, confusion,
hypotension and hallucinations.
Tolcapone may rarely cause fulminant hepatitis, hence
it should be avoided in patients with liver disease.
Entacapone does not cause hepatotoxicity.

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Dr. Shivankan Kakkar, MD
MAO-B inhibitors: Selegiline and rasagiline
They selectively and irreversibly inhibit MAO-B
enzyme in the brain. They are administered orally. They
do not inhibit MAO in the periphery. They retard the
metabolism of DA in the brain and prevent the
formation of toxic metabolites. Thus, they produce
neuroprotective effect in idiopathic PD and retard the
progression of disease. They enhance as well as prolong
the effect of levodopa. They also reduce ‘on-off’ and
‘wearing off’ phenomena.

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Dr. Shivankan Kakkar, MD
Rasagiline is more potent and longer acting than
selegiline; hence single daily dose is adequate. The
metabolites of selegiline are amphetamine and
methamphetamine which cause side effects like
insomnia, anxiety, nausea and vomiting.
NMDA receptor antagonist: Amantadine
Amantadine is an antiviral drug used for the treatment
and prophylaxis of influenza A. It is also used in
parkinsonism. It facilitates the synthesis and release of
dopamine from dopaminergic neurons in the brain.

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Dr. Shivankan Kakkar, MD
It also has NMDA receptor antagonist action –
decreases glutamate neurotransmission in the basal
ganglia which could contribute to its beneficial effect in
parkinsonism. It is less effective than levodopa and
hence used for the initial treatment of mild
parkinsonism. Its therapeutic activity may be increased
by combining with levodopa. It is given by oral route
and is well tolerated.

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Dr. Shivankan Kakkar, MD
Adverse effects
They include headache, heart failure, hypotension,
hallucinations, nausea, vomiting, constipation, dry
mouth, insomnia and livedo reticularis (discoloured
patches on the skin).
Central anticholinergics
Centrally acting anticholinergics like benzhexol
(trihexyphenidyl) and benztropine are the treatment of
choice in drug-induced parkinsonism and are also
effective in idiopathic parkinsonism. They have mainly

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Dr. Shivankan Kakkar, MD
central action with minimal peripheral action. They act
by reducing the increased cholinergic activity in the
striatum. They are less effective than levodopa, but are
cheap and better tolerated. They are mainly effective in
relieving tremor and rigidity of parkinsonism with little
effect on hypokinesia. Adverse effects are dry mouth,
confusion, constipation, blurring of vision, drowsiness,
hallucinations and urinary retention.
Antihistaminics with anticholinergic effects like
promethazine, diphenhydramine, orphenadrine, etc. are
also effective in decreasing cholinergic overactivity in
basal ganglia.

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Dr. Shivankan Kakkar, MD
Levodopa is not effective in drug-induced
parkinsonism, because:
(a) dopamine receptors are blocked.
(b) there is no deficiency of dopamine.
Drug interactions
1. Levodopa × MAO inhibitors (nonselective):
Inhibition of MAO retards the metabolism of dopamine
. plasma concentration of dopamine increases . may
precipitate hypertensive crisis.

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Dr. Shivankan Kakkar, MD
2. Levodopa × pyridoxine: Pyridoxine promotes the
peripheral conversion of levodopa to dopamine and
reduces the therapeutic effect of levodopa.
3. Levodopa × antihypertensive agents: Worsening of
postural hypotension.
4. Levodopa × metoclopramide: Metoclopramide
crosses the BBB, blocks the D2 receptors in the basal
ganglia and causes drug induced parkinsonism (i.e.
interferes with antiparkinsonian effect of levodopa);
domperidone poorly crosses BBB, hence there is no
interference with therapeutic effect of levodopa.