Fenoldopam


Article Author:
Michael Szymanski


Article Editor:
John Richards


Editors In Chief:
Melissa Max
Danyae Lee
Manouchkathe Cassagnol


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Phillip Hynes
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Sandeep Sekhon


Updated:
10/3/2019 2:59:29 PM

Indications

Fenoldopam is used primarily for the lowering of blood pressure during episodes of severe hypertension.[1] 

Mechanism of Action

Fenoldopam has a unique mechanism of action compared to other anti-hypertensive medications: it is a dopamine (D1) receptor agonist that results in decreased peripheral vascular resistance primarily in renal capillary beds thus promoting increased renal blood flow, natriuresis, and diuresis. Fenoldopam has minimal adrenergic effects.[2]

It is important to understand the basics of vascular smooth muscle cell physiology and the role of D1 receptor agonism in severe hypertension. In arteries, the tunica media is composed of smooth muscle cells activated by various neurotransmitters, hormones, and mechanical perturbations. Examples of endogenous stimuli responsible for inducing arterial smooth muscle contraction include norepinephrine, angiotensin II, endothelin, and thromboxane-A2. Passive stretching also induces arterial smooth muscle contraction and can be of importance when describing the autoregulation of blood pressure. When an endogenous stimulus acts on a vascular smooth muscle cell, calcium (Ca++) is released from the sarcoplasmic reticulum or from an influx across the cell membrane and binds to cytoplasmic calmodulin. The Ca++/calmodulin complex subsequently activates myosin light chain kinase (MLCK). MLCK phosphorylates myosin heads in the presence of adenosine triphosphate (ATP) thus enabling actin-myosin cross-bridge formation and smooth muscle contraction.[2][3]

Relaxation of smooth muscle occurs when there is decreased phosphorylation of myosin. There are three documented mechanisms by which this can occur: reduced entry or decreased release of Ca++ from the sarcoplasmic reticulum, inhibition of MLCK by increased cyclic guanosine monophosphate (cGMP), or dephosphorylation of MLCK by myosin phosphatase.[4]

Removal of Ca++ ions from the cytoplasm is achieved by two mechanisms. The primary mechanism is a plasma membrane-bound sodium (Na+)/Ca++ antiporter that effluxes one Ca++ ion and influxes three Na+ ions by utilizing the electrochemical gradient created by the Na+/potassium (K+) ATPase. The second mechanism by which Ca++ is removed from the cytoplasm is by a Ca++/ATPase located on the sarcoplasmic reticulum.

The contraction and relaxation of vascular smooth muscle is the mechanism by which changes in systemic vascular resistance (SVR) occur. Contraction of vascular smooth muscle causes a decrease in the cross-sectional area of the arterial lumen, thus increasing SVR and afterload on the heart. Interpreting how changes in SVR affect blood pressure involve understanding the physiologic relationship between mean arterial pressure (MAP), cardiac output (CO), and SVR. MAP is equivalent to CO multiplied by SVR. Simply stated, this means that CO and SVR directly correlate with MAP such that increases in SVR cause a rise in MAP. This physiologic perturbation manifests clinically as high blood pressure. In contrast, by decreasing SVR, MAP decreases.

Dopamine D1 receptors are located in the tunica media of arteries and exert their effects through a G-alpha stimulatory second messenger system. Upon ligand binding to D1-receptors, the alpha subunit dissociates from the intracellular domain of the transmembrane receptor and activates adenylate cyclase (AC). AC subsequently converts ATP to cyclic adenosine monophosphate (cAMP). All downstream effects get mediated by cAMP, the chief second messenger in this pathway.[5]

Inside the cell, cAMP activates protein kinase A (PKA). PKA phosphorylates MLCK thus causing its inactivation. Since myosin cannot undergo phosphorylated by MLCK, the cross-bridge formation between myosin and actin does not occur, rendering the arterial smooth muscle cell unable to contract. The result is the dilation of arteries producing decreased SVR, increased renal blood flow, natriuresis, and diuresis. These pharmacologic effects result in a decrease in blood pressure.[6]

Administration

Fenoldopam administration is as a continuous intravenous (IV) infusion via infusion pump.

Available Formulations:

  • Generic: 10 mcg/mL (1 mL); 20 mg/2 mL (2 mL)

Adult Dosing

Severe/Malignant Hypertension

  • Initiate treatment at 0.01 to 0.3 mcg/kg/minute then increase by 0.05 to 0.1 mcg/kg/minute at 15 minute intervals until desired blood pressure is reached or a max of 1.6 mcg/kg/minute is reached.
  • Renal impairment dosing: No adjustments
  • Hepatic impairment dosing: No adjustments

Pediatric Dosing

Severe Hypertension

  • Initiate treatment at 0.2 mcg/kg/minute then increases by 0.3 to 0.5 mcg/kg/minute at 20 to 30 minute intervals until target blood pressure is reached or until a max of 0.8 mcg/kg/minute is reached.[7]
  • Pediatric renal impairment dosing: No adjustments
  • Pediatric hepatic impairment dosing: No adjustments

Neonatal Dosing (Full-term or at least 2 kg)

Severe Hypertension

  • Initiate treatment at 0.2 mcg/kg/minute then increases by 0.3 to 0.5 mcg/kg/minute at 20 to 30 minute intervals until target blood pressure is reached or until a max of 0.8 mcg/kg/minute is reached.

Pharmacokinetics

  • The onset of action is 10 minutes in adults and 5 minutes in children. The half-life of fenoldopam is 5 minutes in adults and 3 to 5 minutes in children. Metabolized is by the liver, and excretion is primarily in the urine. The volume of distribution is 0.6 L/kg, and the duration is 1 hour.[8]

Adverse Effects

Common

Cardiovascular

  • Flushing
  • Hypotension
  • Tachycardia

 Central Nervous System

  • Headache

 Gastrointestinal

  • Nausea

Uncommon

Cardiovascular

  • Chest pain
  • Bradycardia
  • ST-T abnormalities
  • Ectopic beats
  • Myocardial infarction
  • Orthostatic hypotension
  • Palpitations

Central Nervous System

  • Anxiety
  • Dizziness
  • Insomnia

Dermatologic

  • Diaphoresis

Endocrine and Metabolic

  • Hyperglycemia
  • Hypokalemia
  • Increased lactate dehydrogenase

Gastrointestinal

  • Abdominal pain
  • Constipation
  • Diarrhea
  • Vomiting

Genitourinary

  • Decreased urine output
  • Urinary tract infection

Hematologic and Oncologic

  • Hemorrhage
  • High white blood cell count

Hepatic

  • increased serum transaminases

Neuromuscular and Skeletal

  • Myalgias 

Ophthalmic

  • Increased intraocular pressure

 Renal

  • Increased BUN
  • Increased serum creatinine

Respiratory

  • Difficulty breathing
  • Nasal congestion

 Constitutional

  • Fever

Risk C: Monitor

Increased hypotensive effects

  • Alfuzosin
  • Second-generation antipsychotics (atypicals)
  • Barbituates
  • Benperidol
  • Brimonidine
  • Diazoxide
  • Duloxetine
  • Levodopa
  • Molsidomine
  • Naftopidil
  • Nicergoline
  • Nicorandil
  • Nitroprusside
  • Pentoxifylline
  • Pholcodine
  • Phosphodiesterase 5 inhibitors
  • Prostacyclin analogs
  • Quinagolide
  • Yohimbe

Decreased Antihypertensive Effects

  • Amphetamines
  • Brigatinib
  • Methylphenidate

Risk D: Consider an alternate

Amifostine: Increased hypotensive effects; withhold antihypertensive therapy for 24 hours following infusion of amifostine if possible

Obinutuzumab: Increased hypotensive effects; withhold antihypertensive include for 12 hours before and 1 hour after infusion of obinutuzumab.

Risk X: Avoid

Bromperidol: Decreased effects of fenoldopam

Pregnancy: Risk factor B

Safety and efficacy data for use in pregnancy has not been established; however, no fetal harm was evident in animal studies.

Contraindications

Allergy to propylene glycol and/or sulfites.[9]

Precautions

  • Hypokalemia (within 6 hours of infusion)
  • Tachycardia
  • Angina (due to tachycardia)
  • Glaucoma

Warnings

In pediatric patients, tachycardia may occur and may last up to 4 hours at doses greater than 0.8 mcg/kg/minute.

Monitoring

Routine vitals such as blood pressure and heart rate in addition to serial electrocardiograms (ECGs), renal/hepatic function tests, and serum potassium require monitoring during fenoldopam infusion.

Enhancing Healthcare Team Outcomes

A hypertensive crisis must be treated expeditiously and with the appropriate medications. Managing a hypertensive emergency requires a team-based approach starting in the emergency department or the intensive care unit, which includes the active participation of nurses and physicians from many specialties. During a hypertensive crisis, the healthcare team must coordinate patient care, which includes:

  • Serial blood pressure measurements
  • Monitoring the patient for end-organ damage (cerebrovascular accident, myocardial infarction, among others)
  • Vital signs 
  • Ensure Intravenous access
  • Appropriate labs (renal function tests, liver function tests, serum potassium)
  • Necessary tests (serial ECGs)
  • Administration of appropriate medication
  • Possible consultation with a cardiologist 

Besides the physicians, the nurse and pharmacist must be fully aware of the drug's adverse reactions and monitor the patient. The pharmacist should be fully aware that the drug is not administered to patients with glaucoma and asthma or used in combination with a beta-blocker for fear of inducing severe hypotension. Nurses must administer the drug according to appropriate dosing and protocol, and report any adverse reactions to the healthcare team.  All of the above represent examples of the type of collaborative interprofessional communication necessary for successful fenoldopam therapy to optimize patient outcomes. [Level V]

Once the patient has been stabilized, other healthcare personnel outside the emergency department will be involved in the patient's care. The type of providers involved in outpatient care differs based on etiology. However, a family practitioner or internist will always be responsible for initiating continuation of the patient's care.[10]

Evidence-Based Outcomes

Fenoldopam has been shown to have a renal protective effect in hypertensive patients with chronic kidney disease. However, a meta-analysis of many studies reveals that the drug can lower blood pressure effectively and decrease acute kidney injury, but in the long run, fenoldopam has no impact on renal replacement or the 30-day, in-patient mortality.[11][12] (Level II)


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Fenoldopam - Questions

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Which of the following about fenoldopam is true?



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An 81-year-old male presents to the emergency department with a chief complaint of a severe headache. He reports the onset of his headache occurred approximately 1 hour after dinner at a friend's house where he ate charcuterie, assorted cheeses, pasta with meatballs, and had one glass of red wine. The patient is alert and oriented to person, place, time, and situation. He denies loss of consciousness or shortness of breath. His past medical history is remarkable for myocardial infarction 3 years ago treated with emergent angioplasty and a history of depression on and off for the past 20 years. The patient appears well groomed, well nourished, and in distress. A Cincinnati stroke assessment is negative. His vitals are a heart rate of 52 beats/min, blood pressure 210/120 mmHg, respiratory rate 26, and SaO2 is 97% on room air. The patient takes low dose aspirin, clopidogrel, metoprolol, and phenelzine daily. The patient states that he was recently seen by a psychiatrist for the return of his depression prompting a discontinuation of sertraline and the initiation of phenelzine. While waiting for a CT of the brain, which of the following is the most beneficial medication to administer to the patient at this time?



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A 56-year-old male presents to the emergency department with a complaint of a severe headache. Vital signs reveal a heart rate of 64 bpm, blood pressure 190/118 mmHg, respiratory rate 16/minute, and pulse oximetry 95% on room air. After ruling out an acute cerebrovascular accident, the provider administers fenoldopam. Which of the following best describes the molecular mechanism of action of fenoldopam?



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A 7-year-old male with a past medical history of autosomal recessive, polycystic kidney disease presents to the pediatrician for a yearly physical. The patient reported that his vision appears "blurry" at times but usually goes away after several hours. Vitals revealed a blood pressure of 210/120 mmHg, heart rate 48 beats/min, respiratory rate 20, and SaO2 98% on room air. The clinician arranged for transport to the nearest emergency department where the patient was successfully treated with fenoldopam. Which of the following is a common adverse effect of fenoldopam administration seen in children?



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A 52-year-old female is administered fenoldopam to treat severe hypertension. The patient's past medical history is significant for atherosclerosis, major depressive disorder, myocardial infarction, and transient ischemic attack. Which of the patient's medications could increase the hypotensive effects of fenoldopam?



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A 66-year-old man with a history of hypertensive cardiomyopathy presents to the emergency department feeling dizzy. Upon initial evaluation, the emergency clinician finds the patient's blood pressure to be 217/120 mmHg. Before confirming current medications, the clinician decides to administer fenoldopam. After 45 minutes, the patient's blood pressure is 100/66 mmHg with a heart rate of 48/min. Which of the following medications most likely interacted with fenoldopam?



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Fenoldopam - References

References

Effect of Fenoldopam Continuous Infusion on Glomerular Filtration Rate and Fractional Excretion of Sodium in Healthy Dogs., Kelly KL,Drobatz KJ,Foster JD,, Journal of veterinary internal medicine, 2016 Sep     [PubMed]
The pharmacokinetics of intravenous fenoldopam in healthy, awake cats., O'Neill KE,Labato MA,Court MH,, Journal of veterinary pharmacology and therapeutics, 2016 Apr     [PubMed]
The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans., Natarajan AR,Eisner GM,Armando I,Browning S,Pezzullo JC,Rhee L,Dajani M,Carey RM,Jose PA,, Journal of the American Society of Nephrology : JASN, 2016 Jan     [PubMed]
Whelton PK,Carey RM,Aronow WS,Casey DE Jr,Collins KJ,Dennison Himmelfarb C,DePalma SM,Gidding S,Jamerson KA,Jones DW,MacLaughlin EJ,Muntner P,Ovbiagele B,Smith SC Jr,Spencer CC,Stafford RS,Taler SJ,Thomas RJ,Williams KA Sr,Williamson JD,Wright JT Jr, 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension (Dallas, Tex. : 1979). 2018 Jun     [PubMed]
"Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics Committee on Drugs. Pediatrics. 1997 Feb     [PubMed]
The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004 Aug     [PubMed]
Yip KP,Balasubramanian L,Kan C,Wang L,Liu R,Ribeiro-Silva L,Sham JSK, Intraluminal Pressure Triggers Myogenic Response via Activation of Calcium Spark and Calcium-Activated Chloride Channel in Rat Renal Afferent Arteriole. American journal of physiology. Renal physiology. 2018 Aug 8     [PubMed]
Vanhoutte PM,Shimokawa H,Feletou M,Tang EH, Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta physiologica (Oxford, England). 2017 Jan     [PubMed]
Bissell BD,Browder K,McKenzie M,Flannery AH, A Blast From the Past: Revival of Angiotensin II for Vasodilatory Shock. The Annals of pharmacotherapy. 2018 Sep     [PubMed]
Mårtensson J,Bellomo R, Prevention of renal dysfunction in postoperative elderly patients. Current opinion in critical care. 2014 Aug     [PubMed]
Chen X,Huang T,Cao X,Xu G, Comparative Efficacy of Drugs for Preventing Acute Kidney Injury after Cardiac Surgery: A Network Meta-Analysis. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2018 Feb     [PubMed]
Mas-Font S,Ros-Martinez J,Pérez-Calvo C,Villa-Díaz P,Aldunate-Calvo S,Moreno-Clari E, Prevention of acute kidney injury in Intensive Care Units. Medicina intensiva. 2017 Mar     [PubMed]

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