Pramipexole

BRAND NAMES

Mirapex 1.5mg ER: Mirapex 1.5 mg Tablet Extended-release (pramipexole) works by imitating the function of dopamine, a chemical messenger required to govern movement in the brain.

Mirapexin: Mirapexin contains pramipexol and is used in adults to treat moderate to severe idiopathic restless legs syndrome.

MECHANISM OF ACTION

Pramipexole is a selective dopaminergic agonist with only modest agonistic action at other receptors. The lower its dissociation constant (Km in nmol/L), the stronger it has an affinity for a receptor. Pramipexole has the lowest Km value for the D3 dopaminergic receptor and somewhat higher for the D2 receptor. As a result, pramipexole is highly selective to D3 and D2 receptors, with an affinity for D3 that is about eight times that of D2. Affinity for D1 receptors is negligible, approximately 200000 times lower than D3. Aside from dopaminergic action, pramipexole has a limited affinity for several serotonergic and adrenergic receptors. Pramipexole's efficacy in PD is due to its D3 selectivity. It binds to presynaptic dopamine autoreceptors, which provide negative feedback on endogenous dopamine production. This procedure reduces oxidative stress, which protects the nigrostriatal circuits.

PHARMACOKINETICS

Absorption

Pramipexole is rapidly absorbed, reaching plasma peak concentrations in around 2 hours. Food does not affect pramipexole absorption; nevertheless, taking the medicine with a meal delays the time of maximum plasma concentration (T max) by around one hour. Pramipexole has an absolute bioavailability of higher than 90%, indicating that it is effectively absorbed with minimal first-pass metabolism.

Distribution

It is widely spread and has a total distribution volume of around 500 L. Approximately 15% of pramipexole connects to plasma proteins.

Metabolism

Pramipexole is minimally metabolized (less than 10%). As a result, no particular active metabolite has been detected in human urine or plasma.

Elimination

Pramipexole is mainly eliminated through the kidneys, with 90% of a given dosage recovered in urine, virtually entirely unmodified. Pramipexole has a renal clearance of around 400 mL/min, which is almost three times the glomerular filtration rate.

PHARMACODYNAMICS

Parkinson's disease:

Pramipexole is hypothesized to treat Parkinson's disease symptoms via stimulating dopamine receptors. Parkinson's disease motor symptoms are caused in part by a decline in dopamine levels in the brain's substantia nigra. Dopamine is an important neurotransmitter that has a significant impact on motor actions in humans.

Restless Legs Syndrome:

Pramipexole most likely restores equilibrium to the dopaminergic system, hence alleviating the symptoms of this illness. Restless legs syndrome is hypothesized to arise, in part, due to malfunction of the dopaminergic system, which results in unpleasant lower extremities symptoms.

DOSAGE AND ADMINISTRATION

Pramipexole is taken orally and comes in the shape of pills. As soon as it was licensed for Parkinson's disease therapy, the instant release (IR) tablet form became available in 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, and 1.5 mg dosages. The simplest method to administer pramipexole is with a single daily dosage because of the availability of larger doses in 2010 (0.575, 0.375, 1.5, 2.25, 3 mg, 3.75 mg, and 4.5 mg) in extended-release (ER) form. Both Immediate Release and Extended-Release have the same mechanism of action and effectiveness. For example, 4.5 mg ER given once a day is physiologically comparable to 1.5 mg IR given three times each day.

In Parkinson's disease, pramipexole is started at 0.125 mg thrice a day and subsequently raised week by week to a maximum dose of 1.5 mg thrice daily, depending on the clinical response. The gradual titration is intended to reduce the drug's harmful effects. Pramipexole must be titrated according to its degree in individuals with renal insufficiency, as it is virtually eliminated unmodified by the kidneys.

CONTRAINDICATION

There are no absolute contraindications stated on the product label. However, key warnings and precautions are listed below. 

• Special notifications for dopamine agonist withdrawal syndrome (DAWS). Panic attacks, sleeplessness, irritability, anxiety, and sadness are some of the symptoms of dopamine agonist withdrawal syndrome (DAWS). 
• The risk of hallucinations and psychotic behavior rises with age. 
• Pramipexole dihydrochloride pills can induce or aggravate dyskinesia. 
• Patients experiencing a sudden onset of sleep should report their symptoms. 
• If pramipexole dihydrochloride pills cause postural deformity, reduce the dose or discontinue use.
• Monitor for symptomatic orthostatic hypotension when increasing dosage. 
• Patients may exhibit compulsive behaviors such as gambling, shopping, and hypersexuality. 

DRUG INTERACTIONS

Pramipexole's moderate interactions include:

• Cimetidine
• Clobazam
• Memantine
• Ropinirole
• Cabergoline
• Diltiazem
• Methylclothiazide
• Levodopa
• Apomorphine
• Lurasidone
• methyldopa

SIDE EFFECTS                                   

The most common side effects of pramipexole include

• Nausea
• Restlessness
• Stomach pain
• weakness
• constipation
• insomnia
• abnormal muscle movements
• Dizziness
• Abnormal thoughts or dreams
• Dry mouth
• Urinary frequency
• Vomiting

Severe side effects of pramipexole include

• Sweating
• Hallucinations
• Muscle spasms
• Extreme drowsiness
• Tremors
• cough
• fast heartbeat
• Loss of appetite

TOXICITY

According to the labeling, there is no recognized antidote for dopamine agonist overdose. If symptoms of CNS activation are evident, a neuroleptic medication may be suggested; however, the utility of such medicines in reversing the consequences of over-dosage has not been shown. Overdose management may need supportive treatments, such as gastric lavage, intravenous fluids, and EKG monitoring.