This document discusses drugs used to treat Parkinsonism and other motor disorders. It begins by defining movement disorders and classifying them as either hypokinetic or hyperkinetic. Parkinson's disease is described as a hypokinetic disorder characterized by reduced dopamine activity in the brain. The goal of drug therapy is to restore balance between dopaminergic and cholinergic activity. Several drug classes are covered, including direct dopamine replacers like levodopa, peripheral decarboxylase inhibitors like carbidopa, COMT inhibitors, MAO inhibitors, dopamine agonists, and drugs that potentiate dopamine release like amantadine. Adverse effects and considerations for each drug class are also summarized.

1. CNS PHARMACOLOGY
Drugs for Parkinsonism & Other
Motor Disorders
Gelenta Salopuka
Pharmacology, BMS
April 21 , 2023

2. Learning outcomes
▪ The student should:
1. Know the different types of movement disorders
including Parkinsonism;
2. Know the various drugs used in Parkinson’s
Disease, understand their mechanism of action,
and adverse effects plus contraindications;
3. Attain knowledge on important pharmacokinetic
properties of the drugs.

3. Overview of normal physiological fxn of
cortex, basal ganglia & thalamus
• Basal ganglia regulates flow of information
from cerebral cortex to motor neurons of
spinal cord.
• They have neural connections with both the
cerebral cortex & the thalamus;
– Involved with voluntary movements @ a
subconscious level
• ACh & neuropeptides are used as transmitters
by striatal interneurons.

4. Cont…
• Proper activation or deactivation of these
neurons is vital for proper movement.
• Too much basal ganglia output causes
thalamocortical neurons to become too inhibited
→ impediment of voluntary movement
– These disorders are known as hypokinetic disorders.
• Very low output of basal ganglia → relatively no
inhibition of thalamocortical projection neurons
→ unwanted movements cannot be suppressed.
– These disorders are known as hyperkinetic disorders.

5. Fig 1: Adapted from Study.com How Changes in the Dopaminergic System Affect
Cognitive Aging

6. Movement Disorders
• Result from a dysfunction in:
• basal ganglia,
• the thalamacortical motor circuits,
• or brain stem connections.
• Alterations of basal ganglia output in certain
parts of the brain lead to impairment of
voluntary & involuntary movements.

7. movement disorders cont..
▪ Classified into two gps: (1) hypokinetic (2)
hyperkinetic disorders.
▪ Hypokinetic disorders – characterized by slow,
impaired voluntary movements typically seen in
parkinsonism.
▪ Hyperkinetic disorders – characterized by
involuntary movements e.g. chorea, ballismus,
dystonia, tremor, tic & myoclonus.
▪ Movement disorders are usually assoc. with
psychiatric, cognitive & sleep disorders.

8. Parkinsonism
• Parkinsonism is a hypokinetic disorder;
• A clinical syndrome characterized by varying
degrees of bradykinesia, tremor, rigidity &
postural instability.
• Classified as:
1. Primary or idiopathic, usually referred to as
Parkinson’s Disease (PD)
2. Secondary or acquired
• Examples:
– post encephalitic parkinsonism,
– drug-induced parkinsonism
– syndromes where parkinsonism is a feature of other
degenerative diseases. Bradykinesia is slowness in initiating & carrying
out voluntary movements

9. Cont..
• Associated with reduced dopamine activity in the
brain due to degeneration or damage to neurons in
the basal ganglia.
• Causes of parkinsonism unknown;
– Environmental factors (e.g. head injury, exposure to
pesticides) implicated.
– Genetic factors may increase susceptibility to the disease.

10. Parkinson’s Disease
(formerly known as ‘paralysis agitans’
▪ A progressive neurological disorder of muscle
movement;
▪ Characterized by tremors, muscular rigidity, varying
degrees of bradykinesia & postural & gait
abnormalities;
▪ Due to neurotoxins or free radicals from oxidation
reactions.
▪ Associated with a loss of dopaminergic neurons in
substantia nigra & degeneration of nerve terminals in
the striatum.

11. Cont..
• Leads to striatal dopamine deficiency
– → loss of functional balance between
dopaminergic & cholinergic activity (refer to Fig. 2)
• Clinical Features: a combination of rigidity,
bradykinesia, tremor & postural instability
which may occur due to varied reasons BUT
usually idiopathic.

12. Fig 2: Pathophysiology of PD
Striatum
• main input structure of
basal ganglia;
• receives excitatory
glutamatergic input from
cortex
PD results from an imbalance between
dopaminergic (inhibitory) & cholinergic activity in
the nigrostriatal pathway
DA Dopamine; ACh Acetylcholine; GABA Gamma
amino-butyric acid

13. Treatment of PD
• No cure
• Rx palliative & symptomatic e.g., drug therapy
plus physical therapy, speech therapy, surgery
& transplantation.
• Drug therapy: mainly dopaminergics or
antimuscarinic agents;
– For temporary relief from symptoms;
– DO NOT arrest or reverse neuronal degeneration
caused by the disease.

14. Drug Treatment
• Aim of drug therapy – restore normal balance
btwn dopaminergic & cholinergic activity.
• Two ways of restoring dopaminergic/cholinergic
balance:
– (i)To reduce cholinergic activity by anti-cholinergic
drugs
– (ii) To enhance dopaminergic activity by
dopaminergic drugs which may:
a) Replete neuronal dopamine through giving levodopa (a
natural precursor)
b) Release dopamine from stores & inhibit its re-uptake
(amantadine)
c) Prolong action of dopamine through selective inhibition of
its metabolism (e.g. selegiline)
d) Act as dopamine agonists (e.g. bromocriptine)

15. Fig 3.Sites of action for anti-parkinsonism drugs

16. Cont…
• Dopaminergics act by:
• direct replacement of dopamine e.g. levodopa
• delaying metabolism of endogenous dopamine e.g.
tolcapone, entacapone.
• direct stimulation of dopamine receptors e.g.
bromocriptine, pergolide, lisuride, pramipexole.
• enhancement of release of endog dopamine e.g.
amantadine.
• Anti-muscarinics block muscarinic receptors
preventing release of ACh e.g.,benztropine,
biperiden, orphenadrine.

17. Direct replacers of dopamine
Levodopa
• Description: Levorotatory stereoisomer of dopa; immediate
metabolic precursor of dopamine.
• MOA: L-dopa can cross BBB (unlike dopamine) via an L-amino
acid transporter & undergoes decarboxylation → dopamine.
• Clinical uses: relieves all symptoms of Parkinsonism; effective in
bradykinesia & associated disabilities; used together with
peripherally acting dopa-decarboxylase inhibitors.
• Pharmacokinetics: rapidly absorbed from small intest.,
influenced by rate gastric emptying rate & gastric pH; only 1-3%
enters brain; extensive extracerebral metab thus given in
combination with carbidopa (e.g. Sinemet levodopa:
carbidopa1:4 or 1:10)

18. Cont…
• Adverse effects: GIT- nausea & vomiting; CV-
cardiac arrhythmias & postural hypotension;
dyskinesias - chorea, ballismus, athetosis,
dystonia, myoclonus, tics, tremor; behavioural
effects - depression, anxiety, agitation,
insomnia, delusions, hallucinations;
fluctuations in response (on-off phenomenon)
• Contraindications: phenothiazines, non-
selective MAOIs, sypathomimetics; psychotic
patients.

19. Peripheral dopa-decarboxylase inhibitors
Carbidopa
• Description: a dopa decarboxylase inhibitor that
does not cross BBB.
• MOA: used in combination with L-dopa to reduce
peripheral conversion to dopamine by inhibition
of dopa decarboxylase → ↓ metabolism of L-
dopa in GI tract & peripheral tissues → ↑
availability of L-dopa to CNS. (ref to fig 3)
• Clinical uses: enhances action of L-dopa in all
forms of Parkinsonism other than drug-induced.

20. Fig 4: Schematic effect of oral L-dopa admin alone & in
combination with carbidopa
Source: Katzung 7th ed., Fig. 28-
3, p452 chpt 28
A. Dopa decarboxylase
metabolises L-dopa in the
GIT.
B. Carbidopa prevents
metabolism of L-dopa by
inhibiting dopa
decarboxylase
Increased
proportion of L-dopa dose
reaching the brain
A
B

21. Fig 5: Tolcapone effect on dopa concentration in the brain
Source: Lippincott’s Illustrated Reviews, Pharmacology 2nd ed., Fig 8.11, chpt 8

22. Catechol-O-methyl transferase Inhibitors (COMT)
Tolcapone
• Description: a nitrocatechol derivative
• MOA: selectively & reversibly inhibits both peripheral & central catechol-O-methyl
transferase (COMT) → ↓ plasma [3-O-methyldopa], ↑ central uptake of levodopa
& ↑ brain [dopamine].
• Clinical uses: an adjunct in patients on levodopa/carbidopa
• P’kinetics: oral form readily absorbed - not influenced by food; > 99% albumin -
bound; t1/2 approx 2hrs; extensively metab & eliminated in both urine & faeces.
• Adverse effects: diarrhoea; L-dopa related adverse effects (postural hypotension,
nausea, sleep disorders, anorexia, dyskinesias & hallucinations) increase.
• Precaution: potential for hepatotoxicity so should only be used as adjunct in
patients on levodopa/carbidopa experiencing symptom fluctuations.

23. Monoamine oxidase-B inhibitors
Selegiline
• Description: a selective type B monoamine oxidase
inhibitor.
• MOA: selectively inhibits MAO-B @ normal doses plus ↑
doses which reduces metabolism of dopamine →
• enhances & prolongs its action;
• concurrent use with L-dopa → prolonged action of
dopamine which allows L-dopa dose to be reduced.
• Clinical uses: adjunct for patients with declining or
fluctuating response to L-dopa.
• Pharmacokinetics: rapid GI absorption; crosses BBB;
extensively metab in liver; eliminated mainly in urine &
faeces .

24. Cont…
• Adverse effects: used alone, few side effects.
• Contraindications: patients on pethidine, tricyclic
anti-depressants, serotonin re-uptake inhibitors.
• Points to consider: Selegiline does not inhibit
peripheral metabolism of catecholamines (unlike
non-selective inhibitors) thus safely taken with L-
dopa;
• Safety of long-term use of this combination not certain.

25. Drugs that mimic dopamine @ D₂ & D₃ receptors
Overview: Dopamine agonists do not require transformation
nor facilitated transport across BBB; act directly on
postsynaptic dopamine receptors.
– Available agents: ergot alkaloids bromocriptine, pergolide &
newer non-ergot agents (pramipexole & ropinirole).
– Newer agents offer no advantage over older ones wrt CNS
adverse effects.
Bromocriptine
• Description: Ergotamine deriv.; potent dopamine D₂
agonist & partial agonist of D₁; initially for Rx of
galactorrhoea & gynaecomastia but found to be effective
in PD.
• MOA: directly stimulates dopamine receptor D₂

26. Cont…
• Clinical uses: an adjunct therapy in patients refractory to L-
dopa .
• Pharmacokinetics: plasma t ½ 6-8 hrs; peaks w/in 1-2 hrs
after ‘o’ admin; excreted in bile & faeces.
• Adverse effects: nausea, vomiting, dizziness, postural
hypotension; dyskinesias, psychosis with hallucinations,
delusions, confusion with ↑ doses.
• Contraindications: in patients with Hx of psychosis; recent MI;
avoid in peptic ulceration.
• Points to consider: doses accumulate slowly over 2-3 mths;
also has antimuscarinic effects hence caution in concomitant
use with drugs such as tricyclic antidepressants or
antihistamines.

27. Cont…
Pergolide
• Ergot derivative with D₁ & D₂ receptor activity;
• > effective than bromocriptine in relieving
symptoms & signs of PD;
Pramipexole
• Non-ergot derivative; D₃ agonist;
• Useful in patients with advanced disease,
• allows reduced dose of L-dopa & smooth out
response fluctuations.

28. Drugs that potentiate release of DA
Amantadine
• Description: antiviral agent with anti-parkinsonism
properties.
• MOA: unclear; ? potentiates dopaminergic activity by
influencing synthesis, release or reuptake of dopamine.
• Clinical uses: parkinsonism; < potent than L-dopa &
benefits short-lived but has favourable effect on
bradykinesia, rigidity & tremor.
• P’kinetics: readily absorbed from GIT; peak conc in blood
approx. after 4 hrs; renally excreted unchanged.

29. Cont..
• Adverse effects: CNS effects & psychotic rxns,
most side effects dose-related & relatively
mild.
• Contraindications: in severe renal disease,
epilepsy or gastric ulceration.
• Points to consider: Tolerance may develop; Rx
not to be stopped abruptly.

30. Muscarinic ACh receptor antagonists
Benztropine & Benzhexol
• Description: Tertiary amines
• MOA: inhibit muscarinic receptors in basal ganglia &
reduces imbalance btwn extrapyramidal & pyramidal
pathways.
• Clinical uses: adjunctive Rx for parkinsonism including
drug-induced extrapyramidal syndrome.
• Adverse effects: assoc. with antimuscarinic activity;
blurred vision, confusion, dryness of mouth, thirst &
reduced bronchial secretions, mydriasis.

31. Summary
• Parkinsonism is a movement disorder classified as
hypokinetic and is characterized by slow impaired
voluntary movements associated with reduced
dopamine activity in the brain.
• Motor disorders involving abnormal movements are
known as hyperkinetic disorders.
• Aim of drug therapy in PD is to restore normal balance
between dopaminergic and cholinergic activity.
• Types of drug used in Rx include: direct replacers of
dopamine; dopa-decarboxylase inhibitors; catechol-O-
methyl transferase inhibitors; MAO inhibitors;
dopamimetics & potentiators of dopamine release
(Amantadine).

32. References
1. Basic & Clinical Pharmacology 10th ed. (2007),
electronic by Vishal
2. Katzung (1998), Basic & Clinical Pharmacology,
7th edition
3. Mycek et al.(1992), Lippinott’s Illustrated Review
Pharmacology 2nd ed.
4. Rang & Dale, electronic
5. ACP Medicine, electronic
6. Goodman & Gilman's The pharmacological basis
of therapeutics - 11th Ed. (2006), e-copy
7. Martindale The Extra Pharmacopoeia, 31st
edition