Continuing Education Activity

Pramipexole is a medication used in the management and treatment of Parkinsonism and restless leg syndrome. It is in the anti-parkinsonian class of drugs. This activity describes pramipexole's indications, action, and contraindications as a valuable agent in managing parkinsonism and restless leg syndrome. In addition, this activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent to the interprofessional team members of patients with parkinsonism and restless leg syndrome.

Objectives:

• Identify the mechanism of action of pramipexole.
• Describe the potential adverse effects of pramipexole.
• Review the appropriate monitoring for patients receiving therapy with pramipexole.
• Outline some interprofessional team strategies for improving care coordination and communication to advance pramipexole and improve outcomes.

Indications

Dopaminergic agonists have been used for the treatment of parkinsonism. They can be categorized into ergot-derived and non-ergot-derived medicines. The focus of this review is pramipexole, a non-ergot-derived dopaminergic agonist used broadly in the treatment of Parkinson disease (PD) and restless leg syndrome (RLS). The FDA approved pramipexole for the treatment of PD in 1997 as a monotherapy or add-on drug to other first-line agents.[1] Younger patients are more prone to the motor fluctuations seen in patients treated with levodopa-carbidopa, the most effective agent in treating PD. Hence, treatment with pramipexole should initiate as monotherapy in young patients with PD. On the other hand, elderly patients are more susceptible to the adverse effects of pramipexole-it should only be used when there are motor fluctuations with levodopa-carbidopa therapy. Using pramipexole can permit levodopa-carbidopa dose reduction, thus helping overcome the “off” periods seen.[2]

Two years later, the first randomized control trial was conducted on pramipexole to explore its efficacy in treating RLS. After several studies, the FDA approved pramipexole for RLS treatment in 2006, shortly after it approved ropinirole in 2005.[3] 

Apart from the FDA-approved indications, studies have shown that pramipexole has been effective in treating bipolar depression and treatment-resistant depression.[4] Besides, a study yielded promising results regarding the efficacy of pramipexole in essential tremors.[5] However, all the studies, though promising, suggested that further trials are necessary to prove the efficacy of pramipexole in the above conditions.

Pramipexole’s role has also been discovered in patients chronically treated with morphine. A very recent study suggested that it can effectively reduce tolerance to morphine and shorten the duration of its withdrawal symptoms. This result led to the conclusion that pramipexole could restore the analgesic effects of morphine in a patient once they weaned off it.[6]

Mechanism of Action

Pramipexole is a selective dopaminergic agonist with a minor agonistic activity at other receptors. According to the dissociation constant (Km in nmol/L), the lower the value, the higher the drug's affinity to a receptor. Pramipexole recorded the lowest Km value with the D3 dopaminergic receptor and a slightly higher value for the D2 receptor. Therefore, pramipexole is highly specific to D3 and D2 receptors, with affinity to D3 being about eight times higher than D2. Affinity to D1 receptors is insignificant, being around 200000 times lower than D3. Apart from dopaminergic activity, pramipexole exhibits a small affinity to some serotonergic and adrenergic receptors.[3]

Pramipexole's efficacy in PD is attributed to its D3 selectivity. It binds to presynaptic dopamine autoreceptors exerting negative feedback on endogenous dopamine synthesis. This process leads to a decrease in oxidative stress, which mitigates the damage to the nigrostriatal pathways.[7]

Although the exact pathophysiology of RLS has remained undiscovered, studies strongly suggest a dopaminergic involvement. Unlike in PD, where the nigrostriatal pathways are affected, a set of neurons in the midbrain appears to be the target in RLS. These neurons project into the dorsal horn of the spinal cord, modulating nociception. Pramipexole, given to RLS patients, restores optimal neurotransmission in these pathways.[8]

Pramipexole exerts an anti-depressant effect in PD and cases of major depressive disorder. Studies show that such patients have downregulation of dopaminergic receptors, increasing their suicidal propensity. Pramipexole plays a role in the upregulation of such receptors and their potentiation in the mesolimbic system, an area of the brain responsible for mood regulation.[9][10]

Pharmacokinetics

According to product labeling, pramipexole exhibits linear pharmacokinetics over the clinical dosage range. Its terminal half-life is approximately 8 hours in young, healthy volunteers and about 12 hours in elderly volunteers. Steady-state concentrations are attained within two days of dosing.

Absorption:  Pramipexole is quickly absorbed, reaching plasma peak concentrations in approximately 2 hours. Food does not affect pramipexole absorption, but the time of maximum plasma concentration (T max) is delayed by about one hour when the drug is taken with a meal. The absolute bioavailability of pramipexole is more than 90%, indicating that it is well absorbed and undergoes low first-pass metabolism. 

Distribution: It is extensively distributed and has a volume of distribution of about 500 L. About 15% of the pramipexole is bound to plasma proteins.

Metabolism: Pramipexole is metabolized to a negligible extent (less than 10%). Therefore, no specific active metabolite has been identified in human urine or plasma.

Elimination: Pramipexole is primarily excreted via kidneys, with 90% of a pramipexole dose recovered in urine, almost all as an unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min, approximately three times higher than the glomerular filtration rate. A cross-study comparison of records suggests that the clearance of pramipexole may be reduced by about 30% in patients with Parkinson disease compared with healthy elderly volunteers. This difference results from reduced renal function in patients with Parkinson disease, which may be related to their poorer general health. Due to the high intrasubject variability in plasma concentrations at the same dosage, monitoring plasma pramipexole might be helpful.[11]

Administration

Pramipexole is administered orally and is available in the form of tablets. As soon as it got approved for PD treatment, the immediate release (IR) tablet form became available in 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, and 1.5 mg doses. In 2010, pramipexole became available in extended-release (ER) in larger doses of 0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, and 4.5 mg,  permitting a simplified single daily dosing. Both IR and ER have an identical mechanism of action and efficacy.[12] For instance, 4.5 mg ER administered once daily is clinically equivalent to 1.5 mg IR administered three times daily.[13]

In PD, pramipexole is initiated at 0.125 mg thrice daily and gradually increased every week to a maximum dose of 1.5 mg thrice daily, depending on the clinical response. This slow titration is to minimize the adverse effects of the drug.[3] In patients with renal insufficiency, pramipexole has to be titrated according to its degree, as it is almost entirely excreted unchanged through the kidneys.

Pramipexole is given as a single dose 2 to 3 hours before bedtime for RLS treatment. The dose can be increased every 4 to 7 days to attain maximum symptom relief. Usually, most patients are free of symptoms in the dose range of 0.125 mg to 0.75 mg. Hence, IR tablets are most suitable in RLS, given the small dose required for symptoms to diminish.[8]

Use in Specific Population 

Renal Impairment:  The elimination half-life of 8 to 12 hours in individuals with normal renal function increases to 36 hours in patients with moderate to severe renal function.

• In patients with creatinine clearance (CrCL) of 35 to 59 ml/min, the initial dose should be 0.125 mg twice daily and increased gradually over a longer period of two weeks compared to a week in patients with normal renal function.
• For severe renal impairment (CrCL of 15-34 ml/min), the initial dose should be 0.125 once daily.[13]

Hepatic Impairment: No dose adjustments should be made in cases of hepatic insufficiency since pramipexole undergoes minimal hepatic metabolism.[14]

Pregnancy considerations:  Studies conducted on rats showed that pramipexole could affect fetal development at higher doses. The evidence of teratogenicity remains insufficient. Hence, the advice is to avoid pramipexole in pregnancy. According to the product labeling, there is no adequate data on the developmental risk associated with using pramipexole dihydrochloride tablets in pregnant women. 

Breastfeeding Considerations: According to the package insert, the judgment during breastfeeding and therapy should consider the risk versus benefit to the infant and the benefits of treatment to the mother. Being a dopaminergic agonist, it is contraindicated in lactating mothers since it suppresses lactation. It is around six times more concentrated in milk than in plasma, and hence the risk of transmission to the nursing baby increases. Pramipexole interferes with prolactin secretion in humans, and that may inhibit lactation.[8]

Adverse Effects

The most common adverse reactions (incidence >5% and greater than placebo)

• Patients with RLS: Nausea, somnolence, fatigue, and headache.
• Early PD without levodopa: Nausea, dizziness, constipation, asthenia, hallucinations, somnolence, and sleep attacks[15]
• Advanced PD with levodopa: Accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, orthostatic hypotension, dyskinesia, extrapyramidal symptoms, and hallucinations

The adverse effects of pramipexole are attributed to both peripheral and central dopaminergic stimulation. A severe adverse effect is the sudden onset of sleep, leading to road traffic accidents. Consequently, manufacturers issued a warning concerning the use of pramipexole in patients involved in driving or activities demanding vigilance. Compulsive behaviors like punding and impulse control disorders like gambling, excessive shopping, and hypersexuality are known serious adverse effects of treatment with pramipexole.[2]

Contraindications

There are no absolute contraindications listed in the product labeling. However, significant warnings and precautions are as below. 

• Falling asleep during activities of daily living: Sudden onset of sleep may occur without warning; advise patients to report symptoms.[14]

• Symptomatic orthostatic hypotension: Monitor during dose escalation.

• Impulse control/compulsive behaviors: Patients may experience compulsive behaviors like gambling, excessive shopping, and hypersexuality.[2]

• Hallucinations and psychotic-like behavior: May occur; risk increases with age.

• Dyskinesia: May be caused or exacerbated by pramipexole dihydrochloride tablets.

• Postural deformity: Consider reducing the dose or discontinuing pramipexole dihydrochloride tablets if postural deformity occurs.

• Special alerts dopamine agonist withdrawal syndrome (DAWS): DAWS may occur after decreasing or discontinuing dopamine agonists and includes symptoms such as panic attacks, insomnia, irritability, anxiety, and depression.[16]

Monitoring

The therapeutic plasma concentration of pramipexole is around 0.2 to 7 ng/ml.[17] According to a study, most PD patients in remission had a 2.47 +/- 3.27 ng/mL plasma concentration. Clinicians should cautiously monitor this concentration in patients with renal impairment to prevent pramipexole toxicity. The elimination half-life of 8 to 12 hours in individuals with normal renal function increases to 36 hours in moderate to severe renal function patients.[11]

Toxicity

As per product labeling, there is no known antidote for overdosage of a dopamine agonist. If signs of CNS stimulation are present, a neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been evaluated. Management of overdose may require supportive measures and gastric lavage, intravenous fluids, and EKG monitoring.

A case report has been published in the literature describing attempted suicide with various medications. However, the overdose manifestations were more suggestive of pramipexole toxicity than that of other drugs. A 59-year-old male was brought to the hospital 5 hours after ingesting 3 mg pramipexole, 2250 mg venlafaxine SR, and 360 mg mirtazapine. His vitals were stable, and his neurological examination, including muscle tone and power, was normal. He was mildly agitated and had visual hallucinations. Nine hours later, he developed severe myoclonus to the extent he feared falling from bed. He consistently reported spiders crawling in the room and an alien man sitting on a chair next to him. He had some degree of urinary retention, was jittery and hypervigilant, and could not move due to postural dizziness. His routine blood reports were normal, with mild elevation in lactate. The serum concentration of pramipexole was significantly elevated at 34.2 ng/ml, around five times the upper limit of the therapeutic range. It decreased progressively, and the patient was then discharged after his symptoms subsided.

The combination of the above symptoms was very suggestive of pramipexole toxicity. The patient did not meet the Hunter Serotonin Toxicity Criteria, eliminating venlafaxine toxicity. Moreover, mirtazapine overdose is known to cause hypersomnolence. The patient received no specific antidote. Only 5 mg of diazepam was given to control his agitation.[17]

Enhancing Healthcare Team Outcomes

The role of transdermal administration of dopamine agonists (DA) is under investigation to improve treatment outcomes in patients with PD. In many patients, switching from oral DA such as pramipexole to transdermal DA such as rotigotine proved beneficial. These include ones with swallowing difficulties and gastrointestinal symptoms. Gastroparesis significantly reduces the absorption of oral medicines, minimizing its therapeutic benefit. Transdermal rotigotine bypasses GI reducing the incidence of nausea and vomiting and preventing the problem of absorption due to gastroparesis. Transdermal patches are an effective alternative in patients on pramipexole undergoing surgery. Many patients had switched to rotigotine before surgery and restarted pramipexole post-operatively. Neurologists and anesthesiologists agree that the transdermal route can be as effective as oral DA in controlling PD symptoms preoperatively.

In patients with renal impairment, transdermal rotigotine can be used instead of pramipexole and other renally excreted oral DA. Evidence suggests that the route of administration and formulation of the DA influences the occurrence of impulse control disorder (ICD). Studies show that the incidence of ICD in patients treated with transdermal rotigotine is lower than in patients treated with oral PD agents like pramipexole. ICDs are attributed to the D3 selectivity of oral DA. Rotigotine being less selective to D3 poses a smaller risk of ICD.[18]

Pramipexole is well known to improve depressive symptoms in patients with PD through direct dopaminergic stimulation. Its efficacy has been recently explored in the cases of bipolar depression and treatment-resistant depression (TRD). A case report from France suggested that a combination of selegiline and pramipexole effectively treated TRD. One study indicated that pramipexole could effectively treat depression resistant to electroconvulsive therapy.[19] More studies are necessary in this regard. However, such promising results can offer a few more options for healthcare professionals to treat depression resistant to first-line agents.[4]

Given the evolving information regarding therapy with pramipexole, therapy requires the efforts of an interprofessional team that includes clinicians, specialists, nurses, and pharmacists, each contributing from their areas of expertise and working collaboratively with other disciplines. Clinicians should prescribe pramipexole and titrate the dose as per the patient's clinical needs. Before administration, nurses can verify the dose and counsel the patients on potential adverse drug reactions. Pharmacists should perform medication reconciliation and check for any potential dosing errors. All health care team members need to communicate openly to contribute to optimized therapeutic outcomes and minimize adverse events.[Level 5]