Fenoldopam

Article Author:
Michael Szymanski
Article Editor:
John Richards
Updated:
1/26/2019 9:30:10 PM
PubMed Link:
Fenoldopam

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 are directly correlated 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 are mediated by cAMP, the major 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 be phosphorylated by MLCK, the cross-bridge formation between myosin and actin does not occur, rendering the arterial smooth muscle cell unable to contract. The end 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 is administered as a continuous intravenous (IV) infusion via infusion pump.

Available Forms

  • Corlopam: 10 mcg/mL (1 mL); 20 mg/2 mL (2 mL)
  • 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 every 15 minutes 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 every 20 to 30 minutes 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 every 20 to 30 minutes 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. It is metabolized by the liver and excreted 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 analogues
  • Quinagolide
  • Yohimbe

Decreased Antihypertensive Effects

  • Amphetamines
  • Brigatinib
  • Methylphenidate

Risk D: Consider 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 prior to 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 should be monitored 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 be used in combination with a beta-blocker for fear of inducing severe hypotension.

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)


References

[1] 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 PMID: 29133356]
[2] 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 PMID: 30089032]
[3] 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 PMID: 29582666]
[4] Vanhoutte PM,Shimokawa H,Feletou M,Tang EH, Endothelial dysfunction and vascular disease - a 30th anniversary update. Acta physiologica (Oxford, England). 2017 Jan     [PubMed PMID: 26706498]
[5] 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 PMID: 25977313]
[6] 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 PMID: 27452198]
[7] The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004 Aug     [PubMed PMID: 15286277]
[8] 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 PMID: 26763106]
[9] "Inactive" ingredients in pharmaceutical products: update (subject review). American Academy of Pediatrics Committee on Drugs. Pediatrics. 1997 Feb     [PubMed PMID: 9024461]
[10] Mårtensson J,Bellomo R, Prevention of renal dysfunction in postoperative elderly patients. Current opinion in critical care. 2014 Aug     [PubMed PMID: 24999794]
[11] 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 PMID: 28819767]
[12] 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 PMID: 28190602]