Effects of dopamine receptor antagonist antipsychotic therapy on blood pressure
2017; Wiley; Volume: 43; Issue: 1 Linguagem: Inglês
10.1111/jcpt.12649
ISSN1365-2710
AutoresN. H. Gonsai, Vishrant Amin, C. G. Mendpara, Robert C. Speth, Genevieve M Hale,
Tópico(s)Electroconvulsive Therapy Studies
ResumoJournal of Clinical Pharmacy and TherapeuticsVolume 43, Issue 1 p. 1-7 REVIEW ARTICLEFree Access Effects of dopamine receptor antagonist antipsychotic therapy on blood pressure N. H. Gonsai PharmD Candidate, N. H. Gonsai PharmD Candidate Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USASearch for more papers by this authorV. H. Amin PharmD Candidate, V. H. Amin PharmD Candidate Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USASearch for more papers by this authorC. G. Mendpara PharmD Candidate, C. G. Mendpara PharmD Candidate Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USASearch for more papers by this authorR. Speth MA, PhD, R. Speth MA, PhD Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USASearch for more papers by this authorG. M. Hale PharmD, BCPS, Corresponding Author G. M. Hale PharmD, BCPS gh341@nova.edu orcid.org/0000-0002-2161-1543 Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USA Correspondence Genevieve Marie Hale, Nova Southeastern University College of Pharmacy, Palm Beach Gardens, FL, USA. Email: gh341@nova.eduSearch for more papers by this author N. H. Gonsai PharmD Candidate, N. H. Gonsai PharmD Candidate Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USASearch for more papers by this authorV. H. Amin PharmD Candidate, V. H. Amin PharmD Candidate Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USASearch for more papers by this authorC. G. Mendpara PharmD Candidate, C. G. Mendpara PharmD Candidate Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USASearch for more papers by this authorR. Speth MA, PhD, R. Speth MA, PhD Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USASearch for more papers by this authorG. M. Hale PharmD, BCPS, Corresponding Author G. M. Hale PharmD, BCPS gh341@nova.edu orcid.org/0000-0002-2161-1543 Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USA Correspondence Genevieve Marie Hale, Nova Southeastern University College of Pharmacy, Palm Beach Gardens, FL, USA. Email: gh341@nova.eduSearch for more papers by this author First published: 08 November 2017 https://doi.org/10.1111/jcpt.12649Citations: 18AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Summary What is known and Objective Hypertension, a major risk factor for adverse cardiovascular events, such as stroke and myocardial infarction, affects 80 million American adults. The aetiology of hypertension is multifaceted and difficult to identify. Dopamine receptors, especially those in the kidneys, play a role in blood pressure regulation, and alterations in their function can cause hypertension. The objective of this review was to investigate the association between the use of dopamine antagonists with hypertension focusing especially on second-generation antipsychotics, like clozapine that is D4 receptor antagonist. Methods A literature review was conducted using MEDLINE, Ovid, Science Direct, Web of Science and Cochrane Database of Systematic Reviews databases with keywords:hypertension, hypotension, renin-angiotensin-aldosterone system, dopaminergic receptors, blood pressure, antipsychotics. Inclusion criteria were human or animal studies, systematic reviews, meta-analyses, randomized controlled trials, case report/series, published in selected for inclusion. Results and Discussion All 5 dopamine receptor subtypes (ie D1, D2, D3, D4 and D5) regulate sodium excretion and BP. The D1, D3 and D4 receptors interact directly with the renin-angiotensin-aldosterone system, whereas D2 and D5 receptors directly interact with the sympathetic nervous system to regulate BP. Use of dopaminergic agonists or antagonists could therefore disturb the regulation of BP by dopamine receptors. What is new and Conclusion Based upon this review, individuals on antipsychotic agents, particularly clozapine, should be routinely monitored for hypertension, and addition of antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) is indicated if hypertension occurs. 1 WHAT IS KNOWN AND OBJECTIVE Hypertension (HTN), the leading cause of major adverse cardiovascular events such as stroke, aneurysms and myocardial infarction, afflicts 80 million adults aged 20 years or older in the United States.1-3 The aetiology of HTN can be difficult to identify as it is multifaceted and highly complex. Causal factors include genetic predispositions, epigenetic alterations, environmental influences, diet and other lifestyle characteristics. Dopamine influences BP primarily by its action on renal hemodynamics as well as ion and water transport. It acts in concert with, or in opposition to, hormonal regulators, including aldosterone, norepinephrine, epinephrine, endothelin, prolactin, renin and vasopressin. Dopamine receptors, especially those in the kidneys, play a direct role in BP regulation. Dopamine exerts its effect via a family of cell surface G protein–coupled receptors (GPCRs), classified as D1-like (ie, D1 and D5) and D2-like (ie, D2, D3 and D4). Among these receptors, D1, D3 and D4 receptors interact with the renin-angiotensin-aldosterone system (RAAS), whereas the D2 and D5 receptors interact with the sympathetic nervous system to regulate BP.4, 5 It has also been shown that stimulation of both D1 and D5 receptors directly inhibits renal tubular Na+ reabsorption.6, 7 Therefore, the clinical use of dopaminergic agonists or antagonists could disturb the regulation of BP leading to either hypo- or hypertension, respectively. Most antipsychotic agents utilized in the treatment of schizophrenia, bipolar disorder and other psychoses are dopaminergic antagonists of the D2-like family, primarily D2 antagonists, and some are D4 antagonists (eg, clozapine).8 Older antipsychotic agents (ie, phenothiazine and haloperidol) target D2 receptors, whereas newer antipsychotics (ie, clozapine, olanzapine) target D4 receptors. Fenoldopam is a peripherally acting D1 dopamine receptor agonist used clinically to lower blood pressure in hypertensive emergencies.9 Non-selective dopaminergic agonists are also used to treat Parkinson's disease and attention deficit hyperactivity disorder (ADHD) for improvement of motor and cognitive activities, respectively.8 Dopamine receptor affinities for commonly used antipsychotics are described in Table 1.10 However, to our knowledge, systematic studies investigating the effect of selective dopamine receptor agonists and antagonists on BP do not exist. The primary objective of this systematic review is to investigate the association between the use of dopaminergic agonists or antagonists and HTN to improve the patient safety outcome and to facilitate clinical decision-making in pharmacotherapy. Table 1. Dopamine receptor affinities of commonly used antipsychotics10 Antipsychotic drug Affinity for dopamine receptor D1 D2 D3 D4 D5 Clozapine ++++ ++ + +++++ +++ Risperidone + +++++ +++ ++++ ++ Olanzapine ++++ ++ +++ +++++ + Quetiapine +++ ++++ +++++ + ++ Ziprasidone +++ +++++ ++++ + ++ Aripiprazole +++ +++++ ++++ ++ + Haloperidol ++ +++++ +++ ++++ + 2 METHODS A literature review was conducted at Nova Southeastern University's electronic library using MEDLINE, Ovid, Science Direct, Web of Science and Cochrane Database of Systematic Reviews databases with keywords:dopamine receptors, blood pressure, renin-angiotensin system, antipsychotics, hypertension, hypotension. Inclusion criteria consisted of human and animal studies conducted as either a systematic review, meta-analysis, randomized controlled trial, observational study or case report/series, and published between January 1997 and December 2016. Exclusion criteria were non-English articles discussing agents other than dopaminergic agonists and/or antagonists. 3 RESULTS AND DISCUSSION Based on the prespecified criteria, 11 articles were included in our analysis. Out of these studies, 5 studies were conducted on animal models (rats/mice) and 6 were human trials. Main results and implications of these studies are discussed in Table 2. Table 2. Overview of current literature Article Human or animal trial Study objectives Main results Study implications Jose et al4 Animal trial (rat) Determine the role of dopamine receptors in kidney along with BP regulation Impaired transduction of dopamine signals leads to HTN by D1-like receptors. D2-like receptors act synergistically with D1 to increase the renal sodium excretion. D4 receptors may also regulate BP by interacting with ARBs Treatment of essential HTN can be tailored based on the individual's dopamine receptor dysfunction Sen et al16 Animal trial (mice) Determine which dopamine receptor subtype would alter sodium and water metabolism thereby affecting BP An association was found between the “long” and “short” dopamine receptor allele (DRD4) and systolic (P = .031) and diastolic BP (P = .034). Interaction between D4 receptor and BP with increasing age was found The effects of genes on the level of BP differ over time, either because they are active during a critical period in the evolution of HTN or because they contribute to age-related target organ effects caused by HTN Zhang et al17 Animal trial (rat) Determine the role of the intrarenal dopaminergic system in renin expression Low salt–induced renal cortical renin synthesis and secretion are attenuated in COMT-/- mice which have increased renal dopamine. However, Intrarenal dopamine stimulates renal renin expression in high salt–treated animals. Activation of renal D1-like receptors both stimulates and inhibits renal renin expression in a salt diet–dependent manner These studies elucidated multiple effects of dopamine acting at D1 receptors to inhibit renin secretion indirectly by inhibiting COX-2 activity, or to stimulate renin secretion in a high salt environment by direct stimulation of D1 receptors Bek et al18 Animal trial (mice) Assess the interaction of dopamine receptors with AT1 receptor expression in male and female mice from 6th to 10th generation BP was obtained in mice of both genders from the sixth and tenth generation (P < .05). BP was unaffected by an acute sodium load in D4 mice. Decreased BP was noted in both D4 receptor–deficient and D4 wild-type littermates after injection of AT1 receptor antagonist (P < .05), but was more sustained in D4−/− mice Disruption of D4 dopamine receptor results in increased BP and is related to the activation of AT1 receptor in the brain. D4 receptor gene locus is linked to variants that are associated with HTN. The relevance of the D4 receptor in the pathogenesis of the human essential HTN needs to be evaluated Asico et al19 Animal trial (mice) To examine the role of dopamine receptors in relation to renin-dependent HTN Inhibition of D1-like receptor function may lead to sodium retention and simultaneously produce low renin state. D2-like receptors inhibit renin release. D2-like receptors also negatively regulate renin secretion possibly by D3 receptor as this is expressed in juxtaglomerular cells unlike D2 receptors Disruption of the D3 receptor, a member of the family of D2- like receptors, increases systolic BP and produces diastolic HTN in both heterozygous and homozygous D3 dopamine receptor mutant mice. The increased BP is associated with increased renal renin activity De Fazio et al20 Human trial Describe the rare adverse effects of clozapine treatment Rare adverse effects include bowel obstruction, ischaemia, perforation, aspiration, hematemesis, oesophageal reflux, Ogilvie's syndrome, priapism, urinary incontinence, angioedema, acute generalized exanthematous reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, pulmonary thromboembolism, parotitis, pseudopheochromocytoma, periorbital oedema Monitoring both common and rare adverse effects could significantly reduce the disability and mortality associated with clozapine treatment Visscher et al21 Human trial Determine rare side effects associated with clozapine Periorbital oedema was observed on rare occasions Periorbital oedema and HTN were both induced by clozapine Henderson et al22 Human trial To examine the change in cardiovascular risk factors and estimate mortality from cardiovascular disease with clozapine treatment 10-y mortality from cardiovascular disease was 9%. African Americans and Hispanics exhibited a higher risk compared to Caucasian patients (odds ratio=7.2 and 11.3; P = .09 and P = .04, respectively). New onset diabetes mellitus was approximately 43%. African Americans showed a higher risk of developing diabetes compared to Caucasian patients (P = .0001) Clozapine-treated patients appear to be at increased risk of death from cardiovascular disease secondary to clozapine-associated medical disorders such as obesity, diabetes, HTN and hyperlipidemia Henderson et al23 Human trial Assess changes in systolic and diastolic BP and treatment of HTN in patients treated with clozapine Significant increase in both systolic and diastolic BP with clozapine treatment Long-term clozapine treatment is associated with increased rates of HTN, which may have a significant impact on medical morbidity and mortality Woo et al24 Human trial BP changes in Korean schizophrenic inpatients treated with clozapine and olanzapine Significantly lower prevalence of HTN with olanzapine vs clozapine treatment Clozapine treatment may be associated with increased BP and higher prevalence of HTN, which may have significant impact on morbidity and mortality Hoorn et al25 Human trial Evaluate the relation between HTN and hypokalemia associated with the use of clozapine Treatment with antihypertensive drugs and potassium supplementation resulted in partial correction of HTN and hypokalemia in clozapine-treated patients Clozapine likely caused hypokalemic through renal potassium loss in a patient with schizophrenia ARBs, Angiotensin receptor blockers; AT1, angiotensin II type 1; BP, blood pressure; COMT, catechol-O-methyl transferase; COX, cyclooxygenase; HTN, hypertension. 3.1 RAAS and the kidneys The RAAS is critical for body homeostasis. It works to retain fluids and electrolytes in a variety of ways, many of which involve renal handling of fluids and electrolytes, which are opposed by other systems in the body, in particular, the dopaminergic system. As recently reviewed by Sparks and colleagues, detection of low BP in afferent arterioles of the kidneys or the presence of hyponatremia causes the juxtaglomerular (JG) cells of the kidneys to secrete renin.11 This in turn regulates blood flow to the kidneys by promoting angiotensin II (Ang II) formation. Renin cleaves angiotensinogen, a protein secreted from the liver into the bloodstream, forming angiotensin I (Ang I). Circulating Ang I is converted to Ang II by angiotensin-converting enzyme (ACE), a luminal enzyme in the blood vessels. While Ang II has multiple actions, 2 of its primary mechanisms are as follows: (i) as a potent vasoconstrictor, it increases the peripheral resistance in arterioles that have Ang II type 1 receptors (AT1) leading to HTN, and (ii) stimulates aldosterone synthesis and secretion from the adrenal gland, which increases the reabsorption of sodium (Na+) from the distal tubule and cortical collecting duct. The resulting rise in Na+ reabsorption increases the amount of water reabsorption from the kidneys and can also stimulate thirst osmotically. These changes can in turn increase blood volume, which can then increase BP. The increased BP will increase blood flow to the kidneys thereby inhibiting renin secretion from the JG cells, subsequently restoring a homeostatic condition. 3.2 Dopaminergic receptors and blood pressure As aforementioned, dopamine is produced locally in the kidneys and takes part in the regulation of renal tubular Na+ transport.4 Of note, dopamine also regulates jejunal Na+ transport from the gut.4 Under conditions of normal Na+ intake, dopamine decreases renal Na+ transport and retention in the body opposite of the RAAS function.5 A deficient dopaminergic response to increased Na+ intake plays a major role in HTN, which can be explained by a failure to decrease renal or jejunal Na+ transport.5 If the dopamine receptor is uncoupled from its G protein complex, transduction of the dopaminergic signal to decrease Na+ transport is impaired.5 As dopamine receptors belong to the GPCR family, they are further divided into 2 subfamilies, the D1-like and D2-like receptors.4 The D1-like receptors include D1 and D5 receptors, which primarily activate the Gs protein to stimulate adenylyl cyclase and its downstream pathways. There is some G protein promiscuity among dopamine receptors. For instance, in the presence of the adaptor protein calcyon, phospholipase C, calcium channels are also stimulated by the D1 family of dopamine receptors.4 In contrast, D2-like receptors, which include D2, D3 and D4 receptor subtypes, primarily interact with the Gi protein to inhibit adenylyl cyclase and open potassium (K+) channels.4 The impaired transduction of the dopamine signal in some organs in HTN is mainly caused by diminished D1-like receptor function.4 In this situation, function is impaired in the proximal tubule and ascending limb of Henle, but not in cortical collecting duct or the distal tubule (Figure 1). Figure 1Open in figure viewerPowerPoint Dopamine receptors and blood pressure D1 and D2 receptors both affect kidney function. D1 receptors inhibit renal tubular basolateral Na+/K+ ATPase and luminal Na+/H antiporter, and decrease tubular Na+ reabsorption. In contrast, activation of D2 receptors stimulates Na+/K+ ATPase.8 However, when co-expressed, D1 and D2 receptors can work synergistically to decrease tubular Na+ reuptake.12 The D1-like receptors decrease renal tubular Na+ transport, thereby increasing Na+ excretion. Impaired D1-like receptor functionality in genetic HTN is mediated by decreased production of cyclic AMP and decreased inhibition of transporters leading to increased renal Na+ retention, which can increase BP.4 In one study examining the role of dopamine receptors in the kidneys, interaction with the RAAS is well defined.4 With the administration of an AT1 receptor antagonist known as an angiotensin receptor blocker (ARB), such as losartan, valsartan, olmesartan, telmisartan or azilsartan, there is a decrease in arterial BP for a longer duration in non-functional D3 knockout mice (which are hypertensive) than in wild-type mice. D3 receptors are present in rat renal juxtaglomerular cells and may inhibit renin secretion.4 Another D2-like receptor, the D4 receptor, may also regulate BP. Mice in which the D4 receptor is knocked out are also hypertensive, and both kidney and brain AT1 receptors are increased in the D4 receptor knockout mouse.13 Interestingly, AT1 receptor activation increases D4 receptor expression in rat kidney proximal tubule cells in culture and increases D4 receptor-mediated natriuresis.14 In contrast, activation of the D4 receptor downregulates AT1 receptor expression in the mouse kidney.13 D1 receptor activation also decreases AT1 receptor expression in the renal proximal tubules, but in contrast to D3 receptor stimulation, D1 receptors increase renin secretion likely by removing the negative feedback on renin release mediated by AT1 receptors.4 Hence, an abnormal D3 receptor or its inhibition could be a cause of increased renin release leading to HTN, whereas an abnormal D4 receptor could be a cause of renin-independent essential HTN. Both hypertensive conditions can be corrected by inhibition of renin release, reduction in Ang II formation via inhibition of ACE, or AT1 receptor blockade. In the presence of D4 receptor blockade with clozapine or olanzapine, it is likely that the natriuretic effects of ARBs will be increased, further supporting the concept of treating hypertension associated with antipsychotic dopamine receptor antagonists. Of note, a recent review suggest that inhibition of the brain angiotensin system can reduce psychosis, thus complementing the antipsychotic actions of D2-like receptor antagonists.15 The mutant mouse with a non-functional D2 receptor mutation also has increased BP due to increased vasoconstrictor effects of sympathetic nervous system activation and endothelin type B receptor activation.4 A study by Sen and colleagues showed the association between a D4 receptor polymorphism for repeats of a 16-amino acid sequence that interacts with G proteins and BP.16 D4 receptors, which are located on the juxtaglomerular and cortical collecting duct cells, alter blood pressure by changing Na+ and water balance. An association was found between the “long” (7, 8 or 10 repeats of the 16-amino acid sequence) and “short” (less than 7 of the repeat sequences) dopamine receptor allele on blood pressure. Systolic BP (P = .031) and diastolic BP (P = .034) were significantly elevated with the “long” allele in a Caucasian population. They also found an association between the “long” D4 receptor polymorphism and elevated BP with increasing age.16 Zhang and colleagues investigated dopamine regulation of renal renin release and the potential role of macula densa COX-2 in dopaminergic regulation of renal renin synthesis and release in vivo.17 This study showed that dopamine acting at D1 receptors inhibits COX-2 activity, which indirectly inhibits renin secretion by increasing the delivery of Na+ to the macula densa. To study the importance of the D4 receptor on BP regulation, a comparison of the effect of anaesthesia, normal saline load and acute drug infusion on mean arterial pressure (MAP) in D4 knockout (D4−/−) and wild-type (D4+/+) mice was made.18 A bolus intravenous injection of the AT1 receptor antagonist, losartan, reduced MAP quickly in both strains, but the effect was prolonged (> 45 min) in D4−/− mice. By contrast, bolus injections of Ang II increased MAP in a dose-dependent manner in both strains with higher increases in D4−/− at all doses.18 The study showed that the increase in BP due to activation of AT1 receptor in the brain was greater when the D4 dopamine receptors were non-functional.18 This suggests that further evaluation of D4 receptor function in the pathogenesis of the human essential HTN is warranted. 3.3 Clozapine and dopamine receptors The use of antipsychotic medications that block D2 and D4 receptors, such as clozapine, is associated with increased risk of HTN and cardiovascular morbidity.19 The potentially adverse cardiovascular effects of these antipsychotic drugs may warrant concurrent use of antihypertensive drugs. Clozapine is a drug used for the treatment of schizophrenia. Its primary mechanism of action is thought to be as an antagonist of D4 receptors, but it also blocks D2 and the 5-HT2A serotonin receptor subtype. It has many adverse effects and black box warnings, including agranulocytosis, myocarditis, orthostatic hypotension, hypertension, seizures, dementia, sialorrhea, weight gain and sedation. Uncommon adverse effects of clozapine are primarily gastrointestinal leading to bowel obstruction, ischaemia, colonic perforation, aspiration or hematemesis, oesophageal reflux, Ogilvie's syndrome, as well as priapism, urinary incontinence, angioedema, acute generalized exanthematous reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, pulmonary thromboembolism, parotitis, pseudopheochromocytoma and periorbital oedema.20, 21 Monitoring both common and rare adverse effects could significantly reduce the morbidity and mortality associated with clozapine treatment. The incidence of hypotension and HTN among clozapine users is 9% and 4%, respectively, regardless of the duration of treatment.22 Furthermore, it has been demonstrated that patients on clozapine are at an increased risk for 10-year mortality from cardiovascular disease secondary to clozapine-associated medical disorders such as obesity, diabetes, HTN and hyperlipidemia.22 This risk appears higher in African Americans and Hispanics compared to Caucasian patients. In addition to causing both hypotension and HTN, clozapine also causes substantial increases in heart rate unrelated to dose.22 This may indicate that individuals with the normally functioning D4 receptor polymorphism become hypertensive when the D4 receptor is blocked, while individuals with the D4 receptor polymorphism associated with functional impairment do not show this effect of clozapine blockade. Other off-target effects of clozapine, such as blockade of 5-HT2 receptors on vascular smooth muscle, may cause hypotensive effects.22 Henderson and colleagues studied case reports to assess changes in systolic and diastolic BP and treatment of HTN in patients treated with clozapine.23 Systolic BP and diastolic BP were examined for up to 5 years in 82 patients (91% Caucasian) treated with clozapine with a mean age of 36.4 years. A significant increase in systolic BP (P = .0004) and diastolic BP (P = .0001) occurred with clozapine therapy.23 Thus, long-term treatment with clozapine in this population has a significant adverse impact on cardiovascular morbidity and mortality. In a retrospective study, BP changes in Korean schizophrenic inpatients treated with clozapine and olanzapine were investigated over 8 weeks.24 In this study, patients received clozapine (n = 70) or olanzapine (n = 97). BP was measured before the start of medication and after 8 weeks. For the clozapine group, there was a significant increase in systolic (3.0 mm Hg, P = .031) and diastolic (3.7 mm Hg, P = .001) BP. Interestingly, no significant changes were found in the olanzapine-treated patients. The authors stated that the increase in BP could not be attributed to weight gain, as the clozapine-treated group had less weight gain than the olanzapine-treated group, and that the weight gain in the clozapine-treated group did not correlate with the increase in BP.24 A case report assessing the relationship between HTN and hypokalemia in a patient on varying doses of clozapine showed that HTN and hypokalemia increased while up-titrating clozapine.25 Treatment with metoprolol succinate and K+ supplementation along with decreasing the dose of clozapine resulted in partial correction of HTN and hypokalemia. Of note, the normal ratio of plasma aldosterone to renin concentration ruled out primary aldosteronism and renal artery stenosis as possible causes of the hypokalemic HTN. It was concluded that clozapine likely caused hypokalemia through renal K+ loss in exchange for Na+ reabsorption.25 4 LIMITATIONS All studies included in this review suggest a causal relationship between dopaminergic drugs and blood pressure. However, this review has some limitations. First, several of the studies included in this review were performed on experimental animals, which limits the direct application to human populations. Second, all studies included in our research have different study designs and were not directed to assessment of the same outcomes. Despite these limitations, a role of the dopaminergic system in human BP regulation should not escape the attention. 5 CONCLUSION This review suggests that the use of dopaminergic antagonists and agonists can lead to HTN or hypotension. Based on the current literature, individuals on antipsychotic agents, particularly clozapine, should have their vitals, especially BP, routinely monitored. If HTN occurs, addition of antihypertensive agents such as ACE inhibitors or ARBs is strongly indicated based upon the contrasting effects of dopamine receptors and AT1 receptors in the kidneys and possible complementary effects on psychoses. Further research regarding the concomitant antihypertensive therapy with dopaminergic agonist or antagonist use and stringent BP monitoring is warranted. Additionally, for better patient safety outcome larger prospective studies are warranted to further assess the risk of HTN or hypotension with the use of dopaminergic agonists and antagonists. ACKNOWLEDGEMENTS The authors would like to acknowledge the reviewers for ensuring the quality of this review. REFERENCES 1 American Heart Association. 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