Dopamine D2R Agonist-Induced Cardiovascular Effects in Healthy Male Subjects: Potential Implications in Clinical Settings

Abstract

Dopamine D2 receptor agonists represent a first line treatment option in young patients with signs and symptoms of idiopathic Parkinson's disease. An association between the use of D2 receptor agonists in Parkinson's disease patients and heart failure has been reported. The identification of the underlying mechanism is needed to minimize the resultant cardiovascular morbidity. In a phase I clinical trial, a D2 receptor agonist (pramipexole) was administered to 52 healthy male subjects following a dose escalation scheme. Serial measurements of resting blood pressure, heart rate, and derived parameters including pulse pressure, pulsatile stress, and rate pressure product were analysed. Statistically significant and clinically relevant increases in most of the assessed parameters were found. Ten subjects were removed prematurely from the trial because of clinically significant increases in blood pressure and/or heart rate requiring immediate intervention with IV rescue medications including a selective β-1 blocker. The observed drug-related changes in vital signs were of clinical relevance and might explain some of the cardiovascular morbidity reported in patients receiving D2 receptor agonist in clinical settings. We suggest that the additional use of a β-1 blocking agent might mitigate the risk of cardiovascular morbidity among patients receiving long-term D2 receptor agonists.

Novel Metabolites Are Associated With Augmentation Index and Pulse Wave Velocity: Findings From the Bogalusa Heart Study

“…In human, dopamine D2 receptor agonist can cause adverse cardiovascular morbidity. [31][32][33] Histidine is an essential amino acid. In a study among 1,898 female participants, although not significant, higher dietary intake of histidine resulted in lower PWV.…”

Associations Between Cardiovascular Events and Nonergot Dopamine Agonists in Parkinson's Disease

“…Moreover, authors suggest that nonphysiological increased chronic pulsatile stress (equal to pulse pressure * heart rate) may result in endothelial cell dysfunction through a variety of pathophysiological mechanisms. [33][34][35] Our findings that men and older individuals treated with pramipexole were more likely than those not receiving pramipexole to be diagnosed with HF have several possible explanations. HF is more prevalent in men than women at all ages, even after adjusting for common HF risk factors, such as obesity and diabetes.…”

“…Statistically significant increases in mean systolic blood pressure, heart rate, pulse pressure, and resting pulse pressure were observed in a dose‐dependent fashion. Moreover, authors suggest that nonphysiological increased chronic pulsatile stress (equal to pulse pressure * heart rate) may result in endothelial cell dysfunction through a variety of pathophysiological mechanisms …”

“…Although biological mechanisms by which pramipexole could potentially cause HF remain unclear, a recent phase I clinical trial suggests that drug-induced supraphysiologic increases in vital signs underlie the associations between D2 receptor agonists and HF. 33 In this trial, pramipexole was administered to 52 healthy male subjects in escalating doses over 13 days and serial measurements of blood pressure and heart rate were analyzed. Statistically significant increases in mean systolic blood pressure, heart rate, pulse pressure, and resting pulse pressure were observed in a dose-dependent fashion.…”

Pramipexole Extended-Release: A Review of Its Use in Patients with Parkinson’s Disease

“…III score was tested in order to meet the FDA's criteria for the approval of pramipexole ER in the USA [30]. [16,18,21] Lacks affinity for receptors of the dopamine D 1 subfamily a [22] Lacks affinity for a 1 -adrenergic, b-adrenergic, ACh, and serotonin 5-HT 1A and 5-HT 2 receptors [22] Demonstrated dopaminergic activity in animal models of PD [13,23] Demonstrated numerous potential neuroprotective actions in preclinical models of PD [24] ; Dopamine neuronal degeneration in pts with early PD c [25] ; Prolactin and : growth hormone levels in healthy volunteers [26] No effect on QT interval in healthy volunteers [27] Up-titration of PPX ER at faster than the recommended rate : BP and : HR in healthy volunteers d [8,10,28] Up-titration of PPX ER at the recommended rate did not : BP and : HR in pts with PD [8,10] Up-titration of PPX ER at the recommended rate occasionally caused symptomatic orthostatic hypotension in pts with PD e [10] ACh acetylcholine, BP blood pressure, HR heart rate, L-DOPA levodopa, PD Parkinson's disease, PL placebo, PPX ER pramipexole extended release, pts patients, ; decreased, : increased a D 1 subfamily includes D 1 and D 5 receptors; D 2 subfamily includes D 2 , D 3 and D 4 receptors b Binding affinity (K i ) of 3.9, 3.3, 0.5 and 3.9 nmol/L at D 2L , D 2S , D 3 and D 4 receptor subtypes, respectively [21] c p = 0.01 vs. L-DOPA; as assessed by dopamine transporter brain imaging d Albeit mean values remained within normal reference ranges e Reported in 3 % of pts with early or advanced PD who received PPX ER in two large PL-controlled trials [10] (see Sect. 4.2.2) Monotherapy with pramipexole ER administered once daily was noninferior to monotherapy with pramipexole IR administered three times daily and significantly more effective than placebo in improving activities of daily living and motor function in patients with early PD [11].…”