Overdose in a Patient with Parkinson Disease

History of Present Illness

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.
A review of the patient’s medication history revealed that he was recently
prescribed rivastigmine (13.3 mg/24 h transdermal patch). At bedtime, the
evening prior to presentation, the patient applied 40 rivastigmine patches,
the entire contents of his new prescription, to his body. Approximately 5 h
later, he awoke with the previously described findings, at which point his
wife removed the patches and brought him to the ED.

Physical Examination

General: Patient lying in bed, uncomfortable

Neurologic: Alert and oriented to person and place (baseline?); pupils 3
mm, equal, round, reactive to light; coarse resting tremor, motor strength 2/5
in upper and lower extremities
HEENT: Excessive lacrimation and salivation
Cardiovascular: Regular rate and rhythm, no murmurs
Pulmonary: Clear to auscultation, symmetric breath sounds
Abdominal: Soft, non-tender, normal bowel sounds
Skin: Warm and well perfused; w/o excessive dryness or diaphoresis
ED Management
The patient’s skin was cleansed thoroughly with soap and water. Supportive
and conservative management with IV fluid hydration and close monitoring
was provided. The patient was admitted to the medicine floor.
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
non-motor features of the disease (e.g., sleep disorders,
depression, memory impairment).
 The goal of medical therapy is thus to slow the progression of both
motor and cognitive effects

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.
 The majority of these drugs enhance dopaminergic function and
improve motor function, while a smaller number block the effects
of acetylcholine (ACh) to enhance cognitive function.
  Dopamine Precursors and Agonists
 Anticholinergic Drugs
 Amantadine

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
 Tacrine, a medicinal noncarbamate CEI, is also prescribed for
this use.
 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 (e.g., aldicarb) and the
organophosphates (OPs) (e.g., 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 (e.g., 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.
 Rivastigmine is formulated as a novel transdermal matrix patch,
available in three different daily doses, and prescribed as a
monthly supply of patches. It is the first patch-formulated
medication available for Alzheimer disease.
 Due to the potential for error in administering an uncommon
formulation of a drug indicated for patients with cognitive
impairment, exceptional care must be taken to adequately educate
patients and caregivers of the appropriate technique for
administration and removal, along with the signs and symptoms of
overdose.
 According to the package insert, one patch should be applied and
replaced once every 24 h to clean, dry, hairless, intact health
skin (Exelon™) patch.
 Recommended sites for application include the upper or lower
back, upper arm or chest; sites should not be reused within 14
days.

What Is the Toxidrome Associated with Carbamate Overdose?

 The cholinergic toxicologic syndrome is expected following

excessive use of a carbamate, whether insecticidal or
medicinal.
 Effects can be categorized by autonomic division, cholinergic
receptor, and associated organ systems involved, and vary
somewhat among patients.
 In the parasympathetic division of the autonomic nervous
system, agonism of pre-ganglionic nicotinic receptors and post-
ganglionic muscarinic receptors produce effects such as
salivation, lacrimation, urination, defecation,
gastrointestinal upset, and emesis.
 Miosis, bradycardia, bronchoconstriction, and
bronchorrhea can result. In the sympathetic division, agonism
of pre-ganglionic nicotinic receptors causes catecholamine
release that can produce hypertension, tachycardia, and
mydriasis.
 Stimulation of nicotinic receptors at the neuromuscular
junction produces fasciculations and muscle weakness that
can progress to paralysis.
 Stimulation of receptors in the CNS may result in altered
mental status, seizure, and/or coma.
 Carbamate toxicity, as manifested by the cholinergic
toxidrome, largely resembles OP toxicity but with an
important difference: Both OPs and carbamates function by
binding to and inhibiting AChE; however, the carbamate-AChE
bond undergoes spontaneous hydrolysis, thereby reactivating
the enzyme.
 Consequently, the clinical effects of carbamate toxicity, though
potentially severe, are self-limited and typically last 24 h or
less.
How Should This Patient Be Managed?

 The general approach to a patient with medical carbamate

toxicity is similar to that of a patient with OP poisoning.
 Dermal exposure, as in this patient, should prompt skin
decontamination to minimize ongoing exposure.
 Patch removal is necessary but is not sufficient to
prevent ongoing absorption since a depot of medication
typically forms in the dermal tissue.
 In the presence of significant or life-threatening
muscarinic effects (e.g. bronchorrhea, bronchospasm,
seizure), an anti-muscarinic agent such as atropine is
indicated.
 Various dosing schemes of atropine exist; an initial dose of
1–3 mg intravenously (IV), with escalating doses every 5
min until reversal of bronchorrhea and bronchospasm
occur.
 This is followed by initiation of an atropine infusion at a
rate of 10% to 20% of the total loading dose per hour (to
a maximum of 2 mg/h).
 Pralidoxime (2-PAM) and other oximes accelerate the
reactivation of carbamate-inhibited AChE and have
effects at both the nicotinic and muscarinic synapses.
 Reactivation results in the enhanced metabolism of
intrasynaptic ACh and decreased clinical cholinergic
effects. Since atropine is only effective at muscarinic
receptors, oximes were administered in this case to
reverse neuromuscular weakness.
 Although early administration of 2-PAM is indicated in the
setting of significant OP poisoning (due to irreversible
inhibition of AChE), its use for medical carbamate toxicity
is controversial.
 Early animal studies of carbamate toxicity suggested that
treatment with oximes worsened outcomes.
 Therefore, although 2-PAM may be beneficial in treating
cases of clinically significant carbamate poisoning (which
can be prolonged and severe), these benefits should be
weighed against the potential risks.