Fenoldopam

Article Author:
Michael Szymanski
Article Editor:
Steve Bhimji
Updated:
9/23/2018 2:04:11 PM
PubMed Link:
Fenoldopam

Indications

Fenoldopam is used primarily for the lowering of blood pressure during episodes of severe hypertension.[1] The drug is unique and that unlike many other antihypertensives, it is a selective D1 receptor partial agonist.

Mechanism of Action

Fenoldopam is a dopamine (D1) receptor agonist that results in decreased peripheral vasculature 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 to understand the role of D1 receptor agonism in severe hypertension. In systemic arteries, the tunica media is composed of smooth muscle cells. Smooth muscle cells may be activated by various neurotransmitters, hormones, and mechanical perturbations. Examples of endogenous stimuli responsible for inducing systemic arterial vascular smooth muscle contraction include norepinephrine, angiotensin II, endothelin, and thromboxane-A2. Passive stretching also induces arterial vascular 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 is released from the sarcoplasmic reticulum or from an influx across the cell membrane. Once in the cytoplasm, calcium binds to an intracellular protein called calmodulin. The calcium-calmodulin complex subsequently activates an enzyme called myosin light chain kinase (MLCK). MLCK phosphorylates myosin heads in the presence of ATP thus enabling actin-myosin cross-bridge formation and smooth muscle contraction.[2][3][2]

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 calcium from the sarcoplasmic reticulum, inhibition of MLCK by increased cGMP, or dephosphorylation of MLCK by myosin phosphatase.[4]

Removal of calcium ions from the cytoplasm is achieved by two mechanisms. The primary mechanism is a plasma membrane-bound Na+/Ca++ antiporter effluxes one Ca++ ion and influxes three Na+ ions by utilizing the electrochemical gradient created by the Na+/K+ ATPase. The second mechanism by which calcium 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 occur. Contraction of vascular smooth muscle causes a decrease in the cross-sectional area of the arterial lumen thus increasing systemic vascular resistance and afterload on the heart. Interpreting how changes in systemic vascular resistance affect blood pressure involve understanding the physiologic relationship between mean arterial pressure (MAP), cardiac output (CO), and systemic vascular resistance (SVR). Mean arterial pressure is equivalent to cardiac output multiplied by systemic vascular resistance. Simply stated, this means that cardiac output and systemic vascular resistance are directly correlated with MAP such that increases in systemic vascular resistance cause a rise in mean arterial pressure. This physiologic perturbation manifests clinically as high blood pressure. In contrast, by decreasing systemic vascular resistance, mean arterial pressure decreases.

Dopamine D1 receptors are located in the tunica media of systemic arteries. D1 receptors 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 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 myosin light chain kinase (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 peripheral vasculature resistance, 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 per minute then increase by 0.05 to 0.1 mcg/kg per minute every 15 minutes until desired blood pressure is reached or a max of 1.6 mcg/kg per minute is reached.
  • Renal impairment dosing: No adjustments
  • Hepatic impairment dosing: No adjustments

Pediatric Dosing

Severe Hypertension

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

 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 per minute.

Monitoring

Routine vitals such as blood pressure and heart rate in addition to serial 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 (CVA, MI, 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)