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DRUGS FOR
PARKINSON'S
DISEASE

Instiaty
Department of Pharmacology and
Therapeutics FMUI - 2021
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Parkinson’s disease (1)

• A syndrome manifested
by tremor, rigidity,
bradykinesia,
and postural instability
• First described by
James Parkinson in 1817

Dr. James Parkinson (1755-1825)

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Parkinson’s disease (2)

• Pathophysiology:
• neuro-humoral imbalance
in basal ganglia, esp. the Nigrostriat
al pathway
nigrostriatum tract in
extrapyramidal system:
< dopaminergic,
> cholinergic
• The nigrostriatum tract:
regulates fine movements:
need a balance between
cholinergic & dopaminergic
component.
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Parkinson’s disease (3)

Etiology
• Mostly: Idiopathic

• Side effects of drugs:

Dopa receptor blocking agents à Chlorpromazine &
Haloperidol
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Parkinson’s disease (4)

Main symptoms:
• Tremor: pill rolling tremor, tremor
at rest
• Bradykinesia (slowness of
movement) : shorter steps ,
dragging feet when walking
• Rigidity: limits the range of
movement
• Postural imbalance: stooped,
imbalance
• Impaired movements that require
fine coordination: writing,
buttoning
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Parkinson’s disease (4)

• Additional symptoms:
- Sialorea
- Hyperhydrosis
- mask-like face expression
• Loss of automatic movements: a decreased
ability to perform unconscious movements:
blinking, smiling or swinging arms when walking.
• Speech changes: slur or hesitate before talking,
monotone rather than with the usual inflections.
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Parkinson’s disease (5)

Treatment:
To balance the dopaminergic and cholinergic activity:
1. Increasing central dopamine levels:
a. dopamine precursor: Levodopa
b. dopamine agonist: bromocriptine, pramipexole, ropinirole
c. Inhibition of dopamine degradation:
- MAO B inhibitors (e.g. selegilline):
- COMT inhibitors (e.g. entacapone, tolcapone):
d. Increases the synthesis and release of dopamine:
Amantadine
2. Reducing central cholinergic activity:
trihexylphenidyl, benztropine, biperidin,
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1. Levodopa (1)
• Main drug for Parkinson’s disease
• Percursor of dopamine:
dopamine can not pass the blood brain barrier
• Rapidly absorbed from small intestine.
• ± 22-30% of oral dose will reach the circulation, ≥60% are
metabolized by dopa decarboxylase to dopamine in the GITr &
liver.
• Only ± 5-10% of oral dose enters the brain unaltered.
• Giving levodopa in combination with a l-amino acid decarboxylase
inhibitor (e.g. CARBIDOPA) reduces the formation of dopamine in
the peripheral.
 1. Levodopa (2)
— Mechanism of action:
Replacing the dopamine deficiency in corpus striatum

Dopa decarboxylase
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1. Levodopa (3)

• High efficacy at the beginning of therapy:

motoric symptoms improvement is nearly 100%,
• duration of action exceeds the plasma half life (1-3 hours), due to
the ability of nigrostriatum to store dopamine (buffering capacity)
• Buffering capacity is lost after long-term useà leads to
complications.
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1. Levodopa (4)

Adverse effect
• Mostly caused by the formation of dopamine in various
peripheral organs:
• 80% pts: GITr: nausea, vomitus, lack of appetite
• CVS effects: arrhythmia due to increased of
catecholamine formation
• When taken with carbidopa: GI adverse effects are less
frequent à 20% pts.
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1. Levodopa (5)

Adverse effect (cont’d)

1. Dyskinesia and abnormal spontaneous movement such as
grimacing, choreiform movement:
• 50% pts during 2-4 months treatment.
• 80% pts in 1 year of treatment
• Due to supersensitivity of dopamine post-synaptic
receptors.
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1. Levodopa (6)
Adverse effects (cont’d)
2. Wearing off effect after long term use (1-5 years):
Parkinson’s symptoms appears before the next dose of drug
is taken
3. On-off phenomenone: fluctuation of drug effect in a short
period: better for several hours, then the symptoms are
suddenly appear
4. Freezing effect: sudden halt of movement
5. Depression, psychosis
6. Orthostatic hypotension
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1. Levodopa (7)
Drug interactions
• Peripheral decarboxylase inhibitor (e.g. carbidopa,
benserazid) + levodopa : inhibits biotransformation of
levodopa to dopamine
² Increase the amount of levodopa that reach the brain,
enable dose reduction up to 75%
² Reduce adverse effects such as nausea, vomitus,
cardiovascular side effect
• Pyridoxine (> 5 mg): increases peripheral levodopa
decarboxylation à decrease the amount of levodopa that
reachs the brain.
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1. Levodopa (8)
Contraindicatons
• Psychosis
• Angle-closure glaucoma
• History of melanoma
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2. Dopamine Agonists

• Dopamine agonists:
• do not require enzymatic conversion to an active
metabolite (enzymes responsible for synthesizing
dopamine are depleted in the brain of Parkinson’s
disease patients)
• Drugs:
• bromocriptine
• pramipexole, ropinirole
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2.1. Bromocriptine (1)

• Mechanism of action:
Bromocriptine stimulates dopaminergic receptors
(dopamine agonists, particularly at D2 receptor).
• Anti Parkinson activity is lower than levodopa, but higher than
amantadine & anticholinergic
• Indications:
• Adjunct to levodopa if response to levodopa is not satisfactory
• A substitute for levodopa when levodopa is contraindicated
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2.1. Bromocriptine (2)

• Adverse effects:
• CNS Disorders: hallucinations (more frequently than levodopa)
• CVS: postural hypotension at the start of therapy, vasospasm
• Other: nasal congestion, headache, pleural and retroperitoneal
fibrosis
• Contraindication: history of psychotic illness, recent myocardial
infarction, peripheral vascular disease
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2.2. Pramipexole & Ropinirole

• Pramipexole:
• More selective to D3 receptor
• Does not cause vasospasm
• Can be combined with levodopa/carbidopa therapy to obtain a
therapeutic response with less dyskinesia side effect
• Side effects:
• hallucinations, confusion, nausea, orthostatic hypotension à
start with low-dose, dose titrated slowly.
• Severe drowsiness/sedation à consider changing drug
• Ropinirole: pure D2 agonist.
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3. Central Anticholinergic (1)

• Alternative drug to levodopa in the treatment of parkinsonism.
• Prototype: trihexyphenidyl
• Mechanism of action: act centrally as M1 receptor antagonist ,
reduce the excessive cholinergic activity in the basal ganglia.
• Anticholinergic drugs are particularly useful against drug-
induced parkinsonism
• Milder peripheral anticholinergic effect (antispasmodic,
midriatic, effect on salivary gland) compared to atropine.
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3. Central Anticholinergic (2)

• Indications:
- Patients with new onset, mild Parkinson's
disease: patients with young age are encouraged to delay the
start of levodopa treatment
- Drug of choice to overcome the problems of extrapyramidal side
effects of antipsychotic drugs (phenothiazines, haloperidol)
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3. Central Anticholinergic (3)

Adverse effects:
• Confusion + exitation

• Mental disturbances (agitation disorientation,

delirium)
• Memory disturbance
• Hallucination, paranoid reaction
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Selecting drug for Parkinson’s disease

• Efficacy:
Levodopa-carbidopa combination is the most effective
• Controversion exists over determining when to start levodopa-carbidopa
treatment: the efficacy only lasts for ± 5 years and the treatment does not
prevent the progression of the disease.
• Respons decreases after 2-3 years of levodopa treatment while side
effects increase.
• 3 types of drugs (dopamine agonists, amantadine, anticholinergic) can be
given before starting treatment with or together with levodopa-carbidopa.
No strong guideline on which of them is selected to be used first.
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Antimigraine and Antivertigo

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Migraine
• Chronic neurological disorder characterized
by:
• paroxysmal episodes of headache and
associated symptoms
• typically lasting 4–72 hours
• With aura (classic migraine): 205
• Common migraine (without aura): 80%
• Serotonin is thought to play a role in
migraine headache
• Considered a neurovascular disorder
involving the trigeminovascular system
(Welch 2003; Silberstein 2004; Goadsby 2005).
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Migraine
• Characteristics:
ª Pain:
ªtypically on one side of the head
ªhas a pulsating / throbbing quality

ª Moderate to intense, affects daily activities

ª Nausea or vomiting
ª Sensitivity to light or sound
ª Aura, visual disturbances that signal the beginning, such as
dots, flashing lights, blind spots
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Pathophysiology
- Pain: caused by trigeminal system activation leading to the release
of vasoactive neuropeptides à vasodilation, plasma protein
extravasation, and pain.
- Serotonin (5HT ) receptors, especially 5HT1 and 5HT2 are
involved in migraine pathophysiology
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Pharmacology treatment
Aims:
- Relieving symptoms/pain felt during an attack (abortive
- Prevent attacks (prophylaxis), if attacks occur >3 times a month,
severe, impaired daily activity, symptomatic therapy fails or causes
serious side effects.
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Acute migraine medications

Acute migraine treatment (migraine abortive therapy) is initiated during an
attack to relieve pain and disability and to stop progression of the attack.
1. Specific abortive migraine treatment: à given when nonspecific drugs
fail:
a. Triptans
b. Ergot and its derivatives
2. Nonspecific abortive migraine treatment:
a. Analgesics: NSAIDs, paracetamol
b.Narcotics – Opiate analgesics
c. Antiemetics
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Two primary hypotheses of antimigraine mechanism of action:

1. triptans, ergot alkaloids, and antidepressants may activate 5-
HT1D/1B receptors on presynaptic trigeminal nerve endings to
inhibit the release of vasodilating peptides.
2. the vasoconstrictor actions of direct 5-HT agonists (the triptans
and ergot) may prevent vasodilation and stretching of the pain
endings.
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Sumatriptan (1)
Mechanism of Actions:
• 5-HT1B/1D receptor agonist.
• In acute migraine:
• sumatriptan stimulates 5-HT1B receptors, causing a
relative selective vasoconstriction in cranial blood
vessels (vasoconstriction on peripheral circulatory is
mediated by 5-HT2 receptor).
• Activation of presynaptic 5-HT1D receptor at the afferent
ends of nociceptive trigeminal: decreasing the release of
neuropeptides that producing vasodilatation of cerebral and
meningeal blood vessels
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Sumatriptan (2)

• Contraindications
Patients with history of coronary arterial vasospastic,
peripheral vascular disease, uncontrolled hypertension, or
other severe cardiovascular diseases
• Adverse effects:
• Paresthesia, asthenia, fatigue, flushing, chest-pain, nausea.
• Rarely: coronary arterial vasospasm, myocardial transient
ischemic, atrial & ventricular arrythmia, especially in patients
with coronary arterial diseases.
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Sumatriptan Posology for Acute Migraine

Drug Preparation Dosage

Oral dose: 25-100 mg, can be

Tablet 25 & 50 mg repeated after 2h, total dose 200
mg in 24 h

Nasal spray contains 5 mg or 20

5-20 mg
Sumatriptan mg sumatriptan in 100 µL solution

Indicated for migraine or cluster

Subcutaneous injection::
headache with 6 mg dose.
0.5 mL of 8 mg/mL and 12 mg/mL
Injection can be repeated after 1
solution contains 4 mg and 6 mg
h, with maximum dose of 12 mg
sumatriptan, respectively
in 24 h
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Ergot / ergot derivatives

• Highly specific for migraine pain, not analgesic for any

other condition.
• Has more side effects (nausea, vomiting, peripheral and
coronary vasoconstriction) due to its relatively
nonselective adherence to serotonin, dopamine and
adrenergic receptors
• Indicated for treatment of migraine in patients who do not
respond adequately to triptan therapy
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Ergot / ergot derivatives

1. Ergotamine tartarate: oral, sublingual,rectal suppository, and

inhaler
2. Dihydroergotamine(DHE) :
• ergotamine hydrogenated at position 9,10 as the mesylate salt
• long lasting, anti-migraine drug that can be given parenterally
as SC, IM, IV, or IN routes, for a severe migraine attack.
• Pretreatment with an anti-emetic might be necessary.
• Avoid in patients with known cardiovascular and peripheral
vascular disease
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Ergot / ergot derivatives

Pharmacodynamic
Multi-receptor function:
• alpha-adrenergic antagonist.
• agonist at 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT1F
receptors, resulting in vasoconstricting effect through
contraction of arterial smooth muscle.
• interacts with 5-HT2 and dopamine receptors
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Ergot / ergot derivatives

• Mechanism of action in acute migraine treatment:
• constricting the pain-producing intracranial
extracerebral blood vessels at the 5-HT1B receptors
• inhibiting the trigeminal neurotransmission at the
peripheral and central 5-HT1D receptors (Silberstein and
McCrory 2003).
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Treatment of Migraine
• Acute migraine:
• mild to moderate attack: start with NSAID or paracetamol; if not
effective, use triptan.
• combination therapy: triptan and NSAID or paracetamol can be
given
• Anti-emetic medication can be added, eg. metoclopramide
• Preventive (prophylactic) :
• Topiramate ( the most clinically and cost effective medication)
• Propanolol
• Note: Topiramate is teratogenic and can impair the effectiveness
of hormonal contraceptives
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Vertigo
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Vertigo
• An illusory sensation of motion of either the self or the surroundings in the
absence of true motion:
a. Vestibular vertigo: a spinning sensation that arises in vestibular
disorder:
1) Peripheral vestibular vertigo: lesions located in the labyrinth and
vestibular nerve
2) Central vestibular vertigo: lesions located on the vestibular nucleus
in the brain stem , thalamus, cerebral cortex.
b. Non-vestibular vertigo: a sensation of rocking, floating, caused
by disruption of the proprioceptive system or visual system
• Vestibular forms: often accompanied by an auditory dysfunction (such as
tinnitus, and auricular fullness)
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vNeurotransmitters in vestibular system related to vertigo:

§ Major excitatory neurotransmitters:
Glutamate, Ach
§ Major inhibitory neurotransmitters : GABA
§ Other transmitters:
§ Histamine ,NE
§ Dopamine, Glycine, Serotonine, etc
vThe etiology of vertigo cannot always be identified
vTreatment is often addressed to the symptoms

https://www.dizziness-and-balance.com/anatomy/physiology/neurotransmitters.htm
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• Drugs for vertigo symptomatic treatment :

• Vestibular suppressant
• antiemetic drugs à the vomit center becomes active when vestibular system is strongly
stimulated and nausea and vomiting occurs

• Vestibular suppressants :
• drugs that reduce the intensity of vertigo and nystagmus evoked by a vestibular
imbalance à also reduce the associated motion sensitivity and motion sickness.
• Conventional vestibular suppressants consist of three major drug groups:
• Anticholinergics: central anticholinergic
• Antihistamines (with central anticholinergic activity)
• Benzodiazepines
 Vestibular suppressants
Pharmacologic Adverse
Drug Usual Adult Dose
class reactions
0.25mg to 0.5 mg Mild sedation,
Clonazepam Benzodiazepine
twice a day dependency
2-10 mg given acutely oral/IM, Sedation, dependency,
Benzodiazepine
Diazepam or IV 2 mg twice a day for respiratory depression
chronic dizziness
Mild sedation,
Benzodiazepine
Lorazepam 0.5 mg twice daily depemdency

12.5-50 mg every 4-6 hours, Antihistamine, Sedation, precaution in

Meclizine
chewable tabs 3x a day anticholinergic prostatic hypertrophy

Dimenhydri Antihistamine, Same as meclizine

50 mg every 4-6 hours
nate anticholinergic
Topical allergy, precaution
in glaucoma,
Scopolamine 0.5 mg patch every 3 days Anticholinergic
tachyarrhytmia, prostatic
hyperthropy
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Antiemetics
Adverse
Drug Usual Adult Dose Pharmacologic class
reactions
Granisetron 1 mg oral or IV 5HT3 antagonist headache
Sedation,
12.5-50 mg every 4-6 Antihistamine,
Meclizine precaution in prostatic
hours,chewable tabs 3x a day anticholinergic
hyperthropy
10 mg oral 3x/day or 10 mg Dopamine & 5HT Restless,drowsiness,
Metoclopramide
IM antagonist extrapyramidal
4-8 mg oral,
Ondansetron 5HT3 antagonist Headache, diarrhea, fever
8 mg sublingual
5HT3 antagonist
Palanosetron 0.25 mg IV Headache, constipation

5 or 10 mg IM or oral every
Prochlorperazine phenothiazine Sedation, extrapyramidal
6-8 hrs

25 mg oral evry 6-8 hrs, or

Promethazine 25 mg rectal every 12 hrs, or phenothiazine Sedation, extrapyramidal
12.5 mg IM every 6-8 hrs
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1. Anticholinergics:
• Act on muscarinic receptors, increase motion tolerance.

• Only centrally acting anticholinergics are useful in treating

vertigo, ex: scopolamine
• (nonspecific to M2 that plays important role in vertigo)

• Side effects: dry mouth, dilated pupils, sedation, decreased

alertness, impaired attention.
• withdrawal symptom if not tapered off.
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2. Antihistamines
• only the antihistamine with central anticholinergic activity that
has anti-vertigo property à the antivertigo property might be the
result of their central anticholinergics actions:
• dimenhydrinate,
• diphenhydramine,
• cyclizine
• promethazine
• The most frequent side effect: sedation.
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3. Betahistine
• A partial H1 agonist &H3-receptor antagonist in neuronal
tissue
• Mechanism of action as antivertigo: based on its effect of
enhancing blood flow in cochlea and CNS.
• Side effect: GITr disturbance, nausea, skin rash
• Contraindication: bronchial asthma, peptic ulcer,
phaeochromocytoma, concurrent use with antihistaminics
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4. Calcium channel blockers:

• inhibit neurotransmitter release.
• eg. Cinnarizine: suppress vestibular function and reduce
the response to angular and linear acceleration.
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