Parkinson's Disease and Myasthenia Gravis

Core

Introduction

Two illustrative neurological disorders close out the SimpleMed pharmacology series: Parkinson's disease, where the central problem is loss of a single neurotransmitter (dopamine), and myasthenia gravis, where the central problem is failure of neurotransmission at the muscle end-plate. Both are good examples of how rational pharmacology can transform an otherwise progressive disease.

Parkinson's Disease

Pathology

Parkinson's disease is a progressive neurodegenerative disease characterised by:

• Loss of dopaminergic neurons in the substantia nigra pars compacta. Symptoms emerge once around 50% of these neurons have been lost.
• Lewy bodies in surviving neurons: intracellular aggregates of misfolded α-synuclein.
• Loss of inhibitory dopaminergic input to the striatum unbalances the basal ganglia output, producing the characteristic motor features.

Several conditions can mimic idiopathic Parkinson's disease (collectively called "Parkinson-plus syndromes" or atypical parkinsonism): drug-induced parkinsonism, vascular parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and dementia with Lewy bodies. The cardinal pharmacological feature distinguishing idiopathic PD from these mimics is a response to levodopa.

Clinical Features

The cardinal motor features:

• Bradykinesia: slowness of movement, "masked face" (reduced facial expression), micrographia (progressively smaller handwriting), reduced arm swing on walking. Required for diagnosis.
• Resting tremor: classic 4-6 Hz "pill-rolling" of the thumb and fingers; disappears with movement and during sleep.
• Rigidity: "lead pipe" or "cogwheel" rigidity (the cogwheeling reflects superimposed tremor).
• Postural instability: later feature.

Non-motor features (often pre-dating motor symptoms by years):

• REM sleep behaviour disorder, anosmia, constipation.
• Depression and anxiety.
• Cognitive decline and dementia in late disease (Parkinson's disease dementia).
• Autonomic features: postural hypotension, urinary urgency, drooling.

Levodopa

Dopamine itself does not cross the blood-brain barrier. Levodopa (L-DOPA) is the immediate biosynthetic precursor; it does cross, and is converted to dopamine in the brain by surviving dopaminergic neurons via aromatic L-amino acid decarboxylase (AADC, also known as DOPA decarboxylase). The remaining nigrostriatal neurons take up levodopa, convert it, and release dopamine.

Levodopa is the most effective single agent for Parkinson's symptoms and remains the cornerstone of treatment. Two important pharmacological problems are managed by combination therapy:

• Peripheral conversion of levodopa to dopamine by AADC produces side effects (nausea, hypotension) and reduces central availability. To prevent this, levodopa is always co-administered with a peripheral AADC inhibitor:
  • Co-careldopa (Sinemet) = levodopa + carbidopa.
  • Co-beneldopa (Madopar) = levodopa + benserazide.
  The decarboxylase inhibitors do not cross the blood-brain barrier, so peripheral conversion is blocked but central conversion is unaffected. This reduces the levodopa dose required by around 75% and improves tolerability.
• Active intestinal absorption of levodopa competes with dietary amino acids; large protein meals reduce its uptake. Patients are advised to take levodopa around 30 minutes before meals or to time the largest protein meal of the day to avoid the most important dose.

Side effects:

• Nausea, usually transient. Domperidone (peripheral D₂ antagonist) is preferred to metoclopramide (which crosses the blood-brain barrier and worsens parkinsonism).
• Postural hypotension.
• Cardiovascular effects (arrhythmia, rare).
• Visual hallucinations and confusion, particularly in the elderly and in dementia with Lewy bodies.
• Motor fluctuations with prolonged use: "on-off" phenomena, end-of-dose wearing off, and dyskinesias (see below).

Important interactions:

• Pyridoxine (vitamin B₆): cofactor for peripheral AADC, increases peripheral metabolism of levodopa. Less of an issue with modern AADC-inhibitor combinations.
• Non-selective MAOIs: risk of hypertensive crisis (avoid; safe washout period required).
• Antipsychotics: D₂ blockade antagonises levodopa effect and can precipitate or worsen parkinsonism. Atypical antipsychotics (quetiapine, clozapine) are preferred when antipsychotic treatment is unavoidable.

Dopamine Receptor Agonists

These directly stimulate dopamine receptors, bypassing the need for a functioning nigrostriatal terminal. NICE NG71 recommends offering levodopa as first-line therapy in patients whose motor symptoms affect quality of life; in those with milder symptoms, levodopa, a dopamine agonist, or an MAO-B inhibitor are all reasonable starting options, chosen with the patient after discussing the trade-offs (notably the risk of impulse control disorders with agonists, and motor fluctuations with long-term levodopa).

Dopamine agonists are also useful as add-on therapy to levodopa:

• Non-ergot dopamine agonists: ropinirole, pramipexole, rotigotine (transdermal patch). These are now the standard.
• Ergot-derived agonists: bromocriptine, pergolide, cabergoline. Largely abandoned because of fibrotic complications (cardiac valve, pulmonary, retroperitoneal fibrosis).
• Apomorphine: subcutaneous (injection or pump); used for severe motor fluctuations; can produce dramatic "rescue" of off-periods.

Side effects are similar to levodopa, plus a distinctive class effect:

• Impulse control disorders (ICDs): pathological gambling, hypersexuality, compulsive shopping, binge eating, "punding" (repetitive purposeless activity). Reported in around 15% of patients on dopamine agonists; warn patients and their families explicitly. Reversible on stopping.
• Sedation and sudden onset of sleep ("sleep attacks"): impacts driving safety.
• Hallucinations and psychosis.
• Postural hypotension, peripheral oedema.

MAO-B Inhibitors

Monoamine oxidase B (MAO-B) is the enzyme that metabolises dopamine in the brain. Selegiline and rasagiline selectively inhibit MAO-B, prolonging the action of endogenous and levodopa-derived dopamine.

Used as monotherapy in early disease (modest symptom benefit) or as add-on therapy to smooth out motor fluctuations in established disease. Generally well tolerated; the selectivity for MAO-B (over MAO-A) at therapeutic doses avoids the "cheese reaction" (hypertensive crisis with tyramine-containing foods) of non-selective MAOIs; although selectivity can be lost at higher doses.

COMT Inhibitors

Catechol-O-methyltransferase (COMT) is the second major enzyme that metabolises levodopa peripherally. Entacapone and tolcapone inhibit COMT and prolong the half-life of levodopa, reducing end-of-dose wearing off.

Entacapone is given with each levodopa dose; the combination tablet co-careldopa + entacapone is marketed as Stalevo. COMT inhibitors have no effect alone (they slow levodopa metabolism but do not increase dopamine synthesis themselves).

Tolcapone has greater efficacy but causes serious hepatotoxicity in rare cases, restricting its use.

Anticholinergics

Loss of dopamine in the striatum allows the cholinergic interneurons to dominate. Procyclidine, benzatropine and trihexyphenidyl are anticholinergics that partially restore the balance, helping particularly with tremor.

Their side-effect profile (confusion, dry mouth, urinary retention, constipation, glaucoma) limits use, particularly in older patients. They retain a role in younger patients with tremor-predominant disease, and in drug-induced parkinsonism (where the antipsychotic cannot be reduced).

Amantadine

Amantadine has a complex mechanism (NMDA antagonism, dopamine release, anticholinergic effect). Used mainly to manage levodopa-induced dyskinesias.

Motor Fluctuations and Impulse Control Disorders

The principal pharmacological problem of long-term Parkinson's treatment is the development of motor fluctuations:

• End-of-dose "wearing off": reduced response as plasma levodopa falls. Manage by adding COMT inhibitor, MAO-B inhibitor, or dopamine agonist; or switch to slow-release / dispersible levodopa formulations; or shorten the dose interval.
• "On-off" phenomena: unpredictable transitions between mobility ("on") and immobility ("off"). Apomorphine rescue or duodopa (continuous intestinal levodopa infusion) are options for severe cases.
• Dyskinesias: involuntary chorea-like movements at peak levodopa concentration. Reduce levodopa dose, add amantadine.

Surgical Treatment

For selected patients with motor fluctuations refractory to medical therapy:

• Deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus internus. Now the surgical mainstay.
• Lesional surgery (thalamotomy for tremor, pallidotomy for dyskinesia) is largely historical.

Myasthenia Gravis

Pathology

Myasthenia gravis (MG) is an autoimmune disease in which IgG antibodies are directed against the nicotinic acetylcholine receptor (AChR) at the post-synaptic membrane of the neuromuscular junction. In around 10% of patients, antibodies target instead the muscle-specific tyrosine kinase (MuSK), producing a related but distinct phenotype.

The antibodies block acetylcholine binding, increase receptor turnover, and activate complement-mediated post-synaptic membrane damage. Acetylcholine is then broken down by acetylcholinesterase before sufficient receptors are activated. The result is failure of neuromuscular transmission.

The thymus is abnormal in around 75% of patients (hyperplasia in young patients, thymoma in 10-15%). Thymectomy is part of routine management.

Clinical Features

The cardinal feature is "fatiguable" weakness: muscle strength declines with repeated or sustained use and recovers with rest. Patterns of involvement:

• Ocular: ptosis and diplopia. The most common presenting symptom and may be the only manifestation in around 15% (ocular myasthenia).
• Bulbar (the brainstem-innervated muscles of speech and swallowing): dysarthria, dysphagia, weakness of mastication. Patients may "fade" through a meal.
• Limb weakness: proximal, symmetrical.
• Respiratory weakness: the cause of death in myasthenic crisis.

Diagnosis is supported by anti-AChR (or anti-MuSK) antibodies, characteristic findings on repetitive nerve stimulation or single-fibre EMG, and the response to anticholinesterase challenge (now rarely used). All patients should have CT or MRI of the chest to look for thymoma.

Pyridostigmine

Pyridostigmine is the first-line symptomatic treatment. It is a reversible acetylcholinesterase inhibitor that increases the concentration of acetylcholine at the neuromuscular junction, improving the chance of receptor activation despite the antibody-mediated reduction in functional receptor numbers.

Pharmacokinetics: oral, onset ~30 minutes, duration 3-6 hours, so given several times daily. Does not cross the blood-brain barrier (quaternary amine).

Side effects arise from off-target muscarinic stimulation, summarised by the standard pre-clinical mnemonic:

Cholinergic effects: SLUDGE
S: Salivation
L: Lacrimation
U: Urination
D: Defecation (diarrhoea, abdominal cramps)
G: Gastric upset
E: Emesis

Plus miosis, bradycardia (DUMBELS adds these as the Bradycardia and Miosis components).

Pyridostigmine treats symptoms but does not modify the autoimmune process, so most patients also receive immunosuppression.

Immunosuppression and Other Treatments

• Corticosteroids: prednisolone, started gradually (rapid initiation can transiently worsen weakness). Often used long-term at the lowest effective dose.
• Steroid-sparing immunosuppression: azathioprine first-line, with mycophenolate mofetil, ciclosporin, methotrexate or rituximab as alternatives.
• Thymectomy: indicated in any patient with a thymoma, and offered in selected young (typically under 65) AChR-antibody-positive patients with generalised disease, where it has been shown to reduce steroid requirement. Thymectomy is not routine in ocular-only myasthenia, MuSK-antibody disease, or in older patients without thymoma.
• Intravenous immunoglobulin (IVIG) or plasmapheresis (plasma exchange): rapid, short-acting treatments for myasthenic crisis or pre-operative optimisation.
• Newer biologics: eculizumab (anti-C5 complement; refractory AChR-positive disease), efgartigimod (FcRn antagonist that lowers IgG levels).

Myasthenic and Cholinergic Crisis

Two opposing emergencies, with similar symptoms but opposite causes:

• Myasthenic crisis: severe muscle weakness and respiratory failure due to under-treatment. Triggered by infection, surgery, certain drugs (see below), or pregnancy. Treatment: ICU support (intubation if needed), IVIG or plasmapheresis, increase immunosuppression.
• Cholinergic crisis: muscle weakness with prominent muscarinic features (SLUDGE) due to over-treatment with pyridostigmine, producing a depolarising blockade similar to suxamethonium. Treatment: stop pyridostigmine, supportive care; atropine to reduce muscarinic effects.

The clinical distinction can be difficult; pupil size and the presence of fasciculations and SLUDGE features favour cholinergic crisis. Historically, the edrophonium (Tensilon) test was used to differentiate (transient improvement with edrophonium suggests myasthenic crisis), but it is now rarely used.

Drugs to Avoid in Myasthenia

Several common drugs can worsen myasthenia by interfering with neuromuscular transmission; an essential prescribing point. The list is long but the most commonly tested:

• Aminoglycosides (gentamicin, streptomycin): pre-synaptic neuromuscular blockade.
• Macrolides (especially erythromycin, clarithromycin, telithromycin).
• Fluoroquinolones (ciprofloxacin, levofloxacin): explicit MHRA caution about exacerbation of myasthenic muscle weakness.
• β-blockers.
• Quinine.
• Magnesium at high doses (e.g. IV magnesium for eclampsia: major caveat).
• Lithium, phenytoin.
• Botulinum toxin.
• Neuromuscular blocking drugs: myasthenic patients are resistant to depolarising agents (suxamethonium often needs higher doses) but markedly more sensitive to non-depolarising agents (rocuronium, atracurium need much lower doses with careful monitoring). Concurrent pyridostigmine can also prolong suxamethonium effect.

Summary

• Parkinson's disease is loss of dopaminergic neurons in the substantia nigra. Pharmacology aims to restore dopamine signalling.
• Levodopa + peripheral DOPA decarboxylase inhibitor (co-careldopa, co-beneldopa) is the most effective treatment. Limitations: motor fluctuations and dyskinesias with long-term use.
• Other PD classes: dopamine agonists (ropinirole, rotigotine, apomorphine; watch for impulse control disorders), MAO-B inhibitors (selegiline, rasagiline), COMT inhibitors (entacapone), anticholinergics (procyclidine), amantadine.
• Avoid metoclopramide and antipsychotics in Parkinson's; use domperidone for nausea; use atypical antipsychotics (quetiapine, clozapine) when needed.
• Myasthenia gravis is autoimmune destruction of the nicotinic AChR at the NMJ. Cardinal feature: fatiguable weakness, classically ocular and bulbar.
• First-line treatment: pyridostigmine (acetylcholinesterase inhibitor; SLUDGE side effects) plus immunosuppression (steroids, azathioprine).
• Myasthenic crisis: under-treatment, respiratory failure; treat with IVIG / plasmapheresis. Cholinergic crisis: over-treatment, prominent muscarinic features; stop pyridostigmine.
• Drugs to avoid in MG: aminoglycosides, macrolides, fluoroquinolones, β-blockers, quinine, magnesium, suxamethonium.

Drug Summary Table

Parkinson's drugs (top) and myasthenia gravis drugs (bottom).

Reviewed by: Dr. Marcus Judge

Quiz

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