Case Studies in Toxicology: A Patchwork of Problems in Parkinson Patients

A 76-year-old man with a history of Parkinson disease and hypertension presents with severe extremity weakness, muscle aches, tremulousness, blurred vision, salivation, and lacrimation.

Emergency Medicine. 2014 April;46(4):166-171

April 1, 2014|Emergency Medicine

Larissa Laskowski, DO;Lewis S. Nelson, MD

A 76-year-old man with a history of Parkinson disease and hypertension presents with severe extremity weakness, muscle aches, tremulousness, blurred vision, salivation, and lacrimation.

Case

A 76-year-old man with Parkinson disease (PD) and hypertension presented to the ED with acute onset of severe tremulousness, blurred vision, salivation, lacrimation, diffuse muscle aches, and extremity weakness. His initial vital signs were: blood pressure, 175/74 mm Hg; heart rate, 62 beats/minute; respiratory rate, 16 breaths/minute; temperature, 37°C (98.6°F). Oxygen saturation was 100% on room air. On physical examination, the patient had excessive lacrimation and salivation, a coarse resting tremor, and 2/5 strength in both the upper and lower extremities. The remainder of the examination, including abdominal and pulmonary systems, was unremarkable compared with baseline findings.

How does the pathophysiology of PD explain how treatments are targeted?

Parkinson disease is a neurodegenerative disorder marked by the destruction of dopaminergic neurons of the substantia nigra. Through complex dopamine (DA) pathways modulated by cholinergic input, the substantia nigra regulates neuronal transmission to and from the basal ganglia. Damage to this important brain structure results in four cardinal parkinsonian motor effects: bradykinesia, resting tremor, muscle rigidity, and impairment of postural balance. Together these abnormalities cause gait disturbance and lead to frequent falls. To a lesser extent, PD involves other brain structures, including the brainstem, hippocampus, and neocortex, which likely contribute to the nonmotor features of the disease (eg, sleep disorders, depression, memory impairment). The goal of medical therapy is thus to slow the progression of both motor and cognitive effects.¹ Two main pharmacologic approaches are in common use: (1) improve motor function with DA replacement; and (2) enhance cognitive function through the modulation of cholinergic activity.

What medications are used to treat PD? What are some associated complications?

There are two broad categories of medications used to treat the motor effects of PD (Table). The majority of these drugs enhance dopaminergic function, while a smaller number block the effects of acetylcholine (ACh).

Dopamine Precursors and Agonists

(L-dopa) can be combined with the L-amino acid decarboxylase inhibitor carbidopa to prevent peripheral metabolism by this enzyme and thereby increase brain concentrations of DA following metabolism by DA decarboxylase in the central nervous system (CNS).¹ Dopamine agonists, including bromocriptine, ropinirole, and pramipexole, do not depend on endogenous conversion to DA and have substantially longer durations of action, limiting the dose-related fluctuations in motor function common in some PD patients taking L-dopa.¹ For these reasons, DA agonists have often replaced L-dopa as initial treatment, especially in younger patients. Catechol-O-methyltransferase inhibitors (tolcapone, entacapone) prevent peripheral breakdown of DA, allowing a higher fraction to reach the CNS.

With respect to side effects, all of the dopaminergic medications can cause nausea, hallucinations, confusion, and orthostatic hypotension.

Anticholinergic Drugs

Although the precise mechanism by which anticholinergic drugs improve PD is not fully understood, agents such as trihexyphenidyl, benztropine mesylate, and diphenhydramine hydrochloride were prescribed even before the discovery of L-dopa and continue to be used today.¹ Adverse effects are a function of the antimuscarinic (anticholinergic) properties of the drugs and may include mydriasis and blurred vision, dry flushed skin, tachycardia, hyperthermia, constipation, urinary retention, and altered mental status.

Amantadine

In addition to the anticholinergics, amantadine is also used to treat PD. This antiviral agent alters DA release in the brain, produces anticholinergic effects, and blocks N-methyl-D-aspartate glutamate receptors.¹ Common adverse drug effects include anticholinergic signs as well as nausea, vomiting, dizziness, lethargy, and sleep disturbance, all of which are usually mild and reversible.

Case Continuation

A review of the patient’s medication history revealed he has been taking L-dopa/carbidopa. In addition to L-dopa/carbidopa, he was recently prescribed transdermal rivastigmine patches (13.3 mg/24 h). At bedtime the evening prior to presentation, the patient applied more than 20 rivastigmine patches. Approximately 5 hours later, he awoke with the previously described findings whereupon his wife removed the patches and brought him to the ED.

What is rivastigmine and what is its role in PD

Rivastigmine is a carbamate-type cholinesterase inhibitor (CEI) indicated for the treatment of mild-to-moderate dementia associated with PD and Alzheimer disease.² Tacrine, a medicinal noncarbamate CEI, is also prescribed for this use.² Both drugs increase ACh concentrations in relevant brain regions and foster the formation of new memory.

Cholinesterase inhibitors are mechanistically analogous to the insecticidal carbamates (eg, aldicarb) and the organophosphates (OPs) (eg, malathion). They inhibit the metabolism of ACh by acetylcholinesterase (AChE) in the various cholinergic synapses, increasing the intrasynaptic concentration of ACh.

Additional AChEs include physostigmine, a carbamate commonly used in the ED to treat anticholinergic toxicity. Physostigmine raises the local synaptic concentration of ACh to compete for the muscarinic ACh receptor with drugs such as diphenhydramine or atropine. Other CEIs (eg, neostigmine, pyridostigmine, edrophonium) are used to raise intrasynaptic ACh concentrations and overcome antibody blockade of nicotinic ACh receptors at the neuromuscular junction in patients with myasthenia gravis.

References