Anti parkinson's drugs

1. ANTI PARKINSONIAN DRUGS
Mohammad Sharique
M Pharm Pharmacology 1st Sem
KLE College of pharmacy, Bangalore
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2. PARKINSON'S DISEASE
Parkinson's disease was first described by Sir James Parkinson. It is a motor
disorder of CNS, outlined as a progressive disorder that affects movement and
results in the loss of dopamine producing cell, causing tremor, rigidity,
bradykinesia and abnormal posture.
TREMOR :
» first sign
» affects handwritiig
» pill rolling.
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3. RIGIDITY :
» increased resistance to passive motion when limbs are moved through their
range of motion.
» muscle soreness, slowness of movement.
BRADYKINESIA :
Loss of automatic movements : blinking of eyes, arm swinging, swallowing of
saliva, lack of postural adjustment.
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4. There is degeneration of dopamine containing neurons in the substantia nigra
results in dopamine deficiency » balance between inhibitory dopaminergic
neurons and excitatory cholinergic neurons disturbed » relative cholinergic
overactivity.
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5. .
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6. Causes :
» both genetic and environmental
factor.
» exposure to pesticides, head
injuries.
» death of cells in substantia nigra.
» mutation on chromosome 4 can
cause PD : this gene produces a
protien which found in presynaptic
terminals and involves in
transmission, have toxic effect to cell.
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7. CLASSIFICATION OF ANTI PARKINSONIAN
DRUGS
1. Drugs influencing brain dopaminergic system :
(a) Dopamine precursor : Levodopa
(b) Dopamine agonists : Bromocriptine, ropinirole, pramipexol, apomorphine
(c) N-methyl-D-aspartate receptor antagonist : amantadine
(d) MAO-B inhibitors : selegiline, resegiline, safinamide(new)
(e) COMT inhibitors : tolcapone, entacapone
2. Drugs influencing brain cholinergic system :
(a) Centrally acting anticholinergic drugs : benztropine, benzhexol,
procyclidine, biperidine 7

8. (b) Antihistaminics (H1 blocker) with anticholinergic activity : promethazine,
dyphenhydramine, orphineadrine
3. Newer Drugs : Safinamide, Istradefylline, pirebedil, pimavanserin, droxidopa.
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9. 0
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10. Levodopa
» Dopamine does not cross BBB, hence its immediate precursor levodopa is
used.
» it is converted to dopamine by decarboxylase.
» large amount of drug converted to dopamine, only small amount of levodopa
reaches to brain, therefore the levodopa is used in combination with
Carbidopa/Benseraside which is a Decarboxylase inhibitor and does not cross
BBB.
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11. Levodopa
» peripheral metabolism of levodopa
is reduced thus its bioavailability
increased in basal ganglia.
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12. Pharmacokinetic and Adverse effect of Levodopa
Pharmacokinetics :
» rapidly absorbed from small intestine.
» amino acid present in food may interfere with levodopa so it shld be given
before meal 30 - 60 minutes.
» main metabolic product of levodopa is homovanillic acid and 3 - 4
dihydroxyphenylacetic acid.
» metabolites excreted in urine.
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13. Levodopa
Adverse effect :
1. GIT : nausea, vomiting, anorexia are common
2. CVS : postural hypotension, also cause tachycardia, palpitation, rarely
arrhythmia.
3. Diskinesia
4. Alterations in taste
5. Insomnia, confusion, dipression, anxiety
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14. CAUTIONS WHEN TAKING LEVODOPA
Cautious use of levodopa is needed in the elderly; patients with ischaemic heart
disease; cerebrovascular, psychiatric, hepatic and renal disease; peptic ulcer;
glaucoma and gout.
Dose: Start with 0.25 g BD after meals, gradually increase till
adequate response is obtained. Usual dose is 2–3 g/day.
LEVOPA, BIDOPAL 0.5 g tab.
Inhaled carbidopa-levodopa : INBRIJA
Carbidopa-levodopa infusion. DUOPA
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15. Levodopa
INTERACTION :
» Pyridoxine : abolishes the therapeutic effect.
» phenothiazine, butyrophen one, metoclopramide : reverse the therpeutic
effect of levodopa by blocking receptors.
Carbidopa and Benserazide :
Levodopa + benserazide (4 : 1)
Levodopa + carbidopa (4 : 1) or (10 : 1)
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16. Levodopa
Advantages :
1. increased half life
2. less amount of levodopa required and more effect of levodopa
3. less side effect of levodopa
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17. Dopamine receptor agonists :
Bromocriptine :
» it is an ergot derivative, has agonistic activity on D2 receptor and partial
agonist at D1.
» Improvement in parkinsonian symptoms occurs within 30 min –1 hr of an oral
dose of bromocriptine and lasts for 6–10 hours.
Dose: Initially 1.25 mg once at night, increase as needed upto 5 mg TDS.
PROCTINAL, SICRIPTIN
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18. Dopamine receptor agonists :
Adverse effect :
» anorexia, vomiting, constipation, postural hypotension, cardiac arrhythmia,
dyskinesia, hallucination, nasal congestion.
» It is contraindicated in patient with history of mental illness, recent MI,peptic
ulcer.
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19. Dopamine receptor agonists :
Ropinirol and pramipexol :
» used in initial treatment of parkinsonism, can be used as monotherapy or in
combination with levodopa- carbidopa.
» Ropinirol is D2 agonist, Pramipexol is more selective for D3.
» they are better tolerated with fewer g.i symptoms
» Ropinirole is rapidly absorbed orally, 40% plasma protein bound, extensively
metabolized, mainly by hepatic CYP1A2, to inactive metabolites, and eliminated
with a terminal t½ of 6 hrs.
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20. Dopamine receptor agonists :
Apmorphine :
» Apomorphine and rotigotine are available in injectable and transdermal
delivery systems.
» Apomorphine is used for acute management of the hypomobility “off”
phenomenon in advanced Parkinson’s disease.
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21. COMT INHIBITORS : TOLCAPONE, ENTACAPONE
MOA :
» Inhibition of COMT by these agents leads to decreased plasma
concentrations of 3-O-methyldopa, increased central uptake of levodopa, and
greater concentrations of brain dopamine.
» Tolcapone has both peripheral and central action, whereas entacapone
inhibits COMT only in periphery.
» combined preparation of Levodopa + Carbidopa + Entacapone is available.
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22. COMT INHIBITORS Cntnd
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23. COMT INHIBITORS Cntnd
PHARMACOKINETICS :
Oral absorption of both drugs occurs readily and is not influenced by food.
Bound to plasma albumin, with a limited volume of distribution. Tolcapone
has a relatively long duration of action compared to entacapone Both drugs are
extensively metabolized and eliminated in feces and urine.
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24. COMT INHIBITORS Cntnd
Adverse effect : diskynesia, nausea, diarrhoea, confusion, hypotension.
MOST SERIOUS : Tolcapone causes hepatotoxicity, but entacapone does not.
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25. MAO-B inhibitors : Selegilline, rasagilline
» selegilline selectively inhibit MAO B enzyme in brain.
» By decreasing the metabolism of dopamine, selegiline increases dopamine
levels in the brain.
» Selegiline is metabolized to methamphetamine and amphetamine
» Rasagilline is more potent and longer acting than selegilline.
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26. Safinamide
It was approved in Europe in February 2015, and in the United States on March
21, 2017.
Safinamide is a unique molecule with multiple mechanisms of action and a very
high therapeutic index. It combines potent, selective, and reversible inhibition of
MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and
inhibition of glutamate release. Safinamide has neuroprotective and
neurorescuing effects in MPTP-treated mice, in the rat kainic acid, and in the
gerbil ischemia model.
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27. Pharmacokinetics :
Rapid with peak plasma concentrations ranging from 2 to 4 h, total
bioavailability is 95%. Food prolonged the rate and did not affect the extent of
absorption of safinamide.
Volume of distribution is 1.8 litres/kg, Protein binding is 88–90%.
Safinamide deaminated acid and the N-dealkylated acid were identified as
major metabolites in urine and plasma. In urine, the β-glucuronide of the N-
dealkylated acid and the monohydroxy safinamide were also characterized.
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28. Elimination half-life: 20–30 hrs
Excretion: 76% Kidney, 1.5% faeces
Adverse effect :
Dyskinesia, falls, and nausea. Other adverse effects include hypertension,
indigestion, hypersensitivity reactions, drowsiness, insomnia, anxiety, and
hallucinations.
XADAGO 50 MG, 100 MG
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29. NMDA receptor antagonist : Amantadine
» amantadine facilitates the synthesis and release of Dopamine.
» also has NMDA receptor antagonist action - decreases glutamate
neurotransmission in basal ganglia which could contribute to its beneficial effect
in parkinsonism.
»acts rapidly but lower efficacy than levodopa.
» therapeutic activity may be increased by combining with levodopa.
» given by oral route.
Adverse effect : heart failure, hallucination, hypotension, constipation, dry
mouth, insomnia, livedo. 29

30. CENTRAL ANTICHOLINERGICS
» treatment of choice in drug induced parkinsonism also effective in idiopathic
parkinsonism.
» reduces increased cholinergic activity.
» mainly effective in relieving tremor and rigidity of parkinsonism with little effect
on hypokinesia.
» Anticholinergics are the only drugs effective in drug (phenothiazine) induced
parkinsonism.
» Trihexyphenidyl It is the most commonly used drug. Start with the lowest dose
in 2–3 divided portions per day and gradually increase till side effects are
tolerated.
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31. Adverse effect : blurry vision, dry mouth, drowsiness, urinary retention.
Advantage : main action centrally, so minimal peripheral action
: cheaper and better tolerated than L dopa
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32. Istradefylline
Istradefylline targets adenosine A2A receptors in the basal ganglia. This region
of the brain is highly involved in motor control.
Istradefylline is indicated as an adjunct treatment to levodopa and carbidopa for
Parkinson's disease.
This drug was first approved in Japan on 25 March 2013. Istradefylline was
granted FDA approval on 27 August 2019.
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33. Istradefylline
Mechanism of Action :
Istradefylline is a selective adenosine A2A receptor inhibitor. These receptors
are found in the basal ganglia, a region of the brain that suffers degeneration in
Parkinson's disease, and is also significantly involved in motor control. A2A
receptors are also expressed on GABAergic medium spiny neurons within the
indirect striato-pallidal pathway. The GABAergic action of this pathway is
thereby reduced.
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35. Istradefylline
Pharmacokinetics :
The apparent volume of distribution of istradefylline is 448-557L.
Istradefylline is approximately 98% protein bound in plasma,1 mostly to serum
albumin and alpha-1-acid glycoprotein.
The primary metabolite found in urine is the active 4'-O-monodesmethyl
istradefylline (M1).1 Istradefylline is metabolized mainly by CYP1A1, CYP3A4,
and CYP3A5.1 CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and
CYP2D6
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36. Istradefylline
A 3mg/kg oral dose given to male rats was 17.6% elminated in the urine and
68.3% eliminated in the feces.
Adverse effects : dyskinesia, dizziness, constipation, nausea, hallucination, and
insomnia.
NOURIANZ 20 mg or 40 mg once daily.
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38. Reference
- Essentials of Medical Pharmacology - K.D Tripathi
- Lippincott Pharmacology 6th edition - Karen Whalen
- https://go.drugbank.com/drugs/DB11757
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