Fenoldopam

Mechanism of Action

Fenoldopam has a unique mechanism of action compared to other antihypertensive 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 either 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 documented mechanisms by which this can take place: reduced entry or decreased release of Ca++ from the sarcoplasmic reticulum and inhibition of MLCK by increased cyclic guanosine monophosphate (cGMP).[4]

Two mechanisms achieve the removal of Ca++ ions from the cytoplasm. 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 are the mechanisms 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 involves 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 via a continuous intravenous (IV) infusion using an 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 reaching a max of 0.8 mcg/kg/minute.

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. Metabolization 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 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 an interprofessional 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 collaborative interprofessional communication necessary for successful fenoldopam therapy to optimize patient outcomes. [Level 5]

Following the stabilization of the patient, other healthcare personnel outside the emergency department will have involvement 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 the continuation of the patient's care.[10]

Evidence-Based Outcomes

Fenoldopam has been demonstrated 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 2]