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Antiparkinson Drugs

2nd Year MBBS Pharmacology

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Parkinson's Disease - Quick Overview

• Tremor (resting, "pill-rolling")
• Rigidity (cogwheel/leadpipe)
• Akinesia / Bradykinesia
• Postural instability

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Pathophysiology - The Key to Understanding All Drugs

• Reduced dopamine in the corpus striatum (basal ganglia)
• Unopposed cholinergic (ACh) activity in the striatum

1. Increase dopamine activity (most drugs)
2. Decrease cholinergic activity (anticholinergics)

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Classification of Antiparkinson Drugs

A. Drugs that increase dopaminergic activity

1. Dopamine precursor - Levodopa (+ Carbidopa)
2. Dopamine agonists - Bromocriptine, Pramipexole, Ropinirole, Rotigotine, Apomorphine
3. MAO-B inhibitors (prevent dopamine breakdown) - Selegiline, Rasagiline, Safinamide
4. COMT inhibitors (prevent levodopa/dopamine breakdown) - Entacapone, Tolcapone
5. Dopamine releaser - Amantadine

B. Drugs that decrease cholinergic activity

• Anticholinergics - Trihexyphenidyl (Benzhexol), Benztropine, Procyclidine, Biperiden

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DRUG 1: Levodopa (L-DOPA) ★★★ Most Important

Why not give dopamine directly?

Pharmacokinetics

• Given orally; absorbed from small intestine (competition with dietary amino acids - hence best taken on empty stomach)
• ~95-99% of levodopa is decarboxylated peripherally to dopamine if given alone - this peripheral dopamine causes side effects (nausea, vomiting, cardiac arrhythmias)
• Therefore always combined with Carbidopa (a peripheral DOPA decarboxylase inhibitor that cannot cross BBB)

Levodopa + Carbidopa combination (Sinemet)

• Carbidopa blocks peripheral decarboxylation
• More levodopa reaches the brain
• Peripheral side effects reduced
• Dose of levodopa can be reduced by ~75%
• Carbidopa does NOT reduce central side effects (dyskinesias, psychosis)

Therapeutic effects

• Best drug for bradykinesia and rigidity
• Less effective for tremor
• Most effective overall symptomatic treatment of Parkinson's disease

Adverse effects

• Nausea, vomiting (most common early)
• Postural hypotension
• Cardiac arrhythmias (rare)

• Dyskinesias (involuntary movements - most troublesome long-term effect)
• Psychiatric effects: hallucinations, confusion, psychosis
• On-off phenomenon (sudden unpredictable fluctuations between mobile "on" and immobile "off" states)
• Wearing-off effect (end-of-dose deterioration as drug duration shortens over time)

Contraindications

• Psychotic illness
• Angle-closure glaucoma
• Use with non-selective MAO inhibitors (risk of hypertensive crisis) - wait 2 weeks
• Active peptic ulcer

Important drug interactions

• Pyridoxine (Vitamin B6): Increases peripheral decarboxylation of levodopa, reducing CNS levels - this interaction is abolished when carbidopa is also given
• Antipsychotics (D2 blockers): Antagonize the effects of levodopa - avoid
• Non-selective MAO inhibitors: Hypertensive crisis

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DRUG 2: Dopamine Receptor Agonists

• Longer duration of action → less wearing-off
• No conversion needed (not dependent on surviving neurons)
• Less dyskinesia

• Nausea, vomiting
• Postural hypotension
• Psychiatric effects (hallucinations, impulse control disorders - gambling, hypersexuality)
• Ergot-specific: fibrosis (pulmonary, retroperitoneal, cardiac valvular) - reason pergolide was withdrawn

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DRUG 3: MAO-B Inhibitors

• Used as adjunct with levodopa to reduce wearing-off
• Selegiline dose: 5 mg with breakfast + 5 mg with lunch (avoid evening - causes insomnia via amphetamine metabolite)
• Rasagiline: 1 mg once daily; more potent; used as monotherapy in early disease too
• Possible neuroprotective effect (still debated)

• Meperidine/pethidine (risk of serotonin syndrome, hyperpyrexia)
• SSRIs or TCAs (theoretical serotonin syndrome risk)
• Sympathomimetics
• Dextromethorphan

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DRUG 4: COMT Inhibitors

• Entacapone: Peripheral COMT inhibitor; must be given with each dose of levodopa (short half-life). Does NOT cross BBB. Increases levodopa bioavailability by ~35%.
• Tolcapone: Central + peripheral COMT inhibitor; given 3x/day. More effective but causes hepatotoxicity (liver monitoring required, less commonly used now).

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DRUG 5: Amantadine

• Originally an antiviral drug (influenza A)
• Mechanism: Multiple - releases dopamine from nerve terminals, blocks dopamine reuptake, has mild NMDA antagonist (glutamate blocking) effect, mild anticholinergic effect
• Use: Mild early Parkinson's disease, or as adjunct; also used to treat levodopa-induced dyskinesias
• Quick onset of action but tachyphylaxis develops (loses effect within weeks to months)
• Side effects: Livedo reticularis (mottled skin discoloration), ankle edema, confusion, hallucinations

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DRUG 6: Anticholinergics

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Summary Comparison Table

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Important Exam Points

1. Levodopa is always combined with carbidopa (peripheral dopa decarboxylase inhibitor) to reduce peripheral side effects and increase CNS availability.
2. Pyridoxine (B6) reduces levodopa efficacy ONLY when carbidopa is NOT co-administered.
3. Selegiline + pethidine (meperidine) = dangerous serotonin syndrome / hyperpyrexia.
4. Non-selective MAO inhibitors + levodopa = hypertensive crisis.
5. Bromocriptine is an ergot dopamine agonist - also used for hyperprolactinemia, acromegaly, and neuroleptic malignant syndrome.
6. Anticholinergics are preferred for drug-induced parkinsonism (from antipsychotics).
7. Apomorphine is a subcutaneous dopamine agonist used as rescue therapy for severe off episodes.
8. Tolcapone requires liver function monitoring (hepatotoxic); Entacapone does not.
9. The on-off phenomenon and wearing-off effect are long-term complications of levodopa therapy.
10. Amantadine is unique: it causes livedo reticularis and also helps treat levodopa-induced dyskinesias.

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