Continuing Education Activity

Clonidine is an antihypertensive medication that acts on alpha-adrenergic and imidazoline receptor agonists. Clonidine is an antihypertensive drug that lowers blood pressure and heart rate by relaxing the arteries and increasing the blood supply to the heart; it has other FDA-approved indications such as treatment of attention deficit hyperactivity disorder (ADHD) in children (FDA approval 2010); management of tics commonly found with Tourette syndrome; and adjunct therapy for severing cancer-related pain. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of clonidine, pertinent for interprofessional team members when indicated for therapy.

Objectives:

• Review the indications of clonidine.
• Explain the mechanism of action of clonidine.
• Describe the potential adverse reaction of clonidine.
• Summarize the importance of improving care coordination among interprofessional team members to improve outcomes for patients receiving therapy with clonidine.

Indications

Clonidine is a 40-year-old antihypertensive medication that acts as an agonist on alpha-adrenergic and imidazoline receptors. Clonidine is an antihypertensive drug that lowers blood pressure and heart rate by relaxing the arteries and increasing the blood supply to the heart; it has the following FDA-approved indications:

• Hypertension, as mentioned above; pediatric use for hypertension is off-label
• Treatment of attention deficit hyperactivity disorder (ADHD) in children (FDA approval 2010 for the extended-release dose form)[1][2]
• Management of tics commonly found with Tourette syndrome
• Adjunct therapy for severing cancer-related pain[3]
• As an adjunct in neonatal opioid withdrawal syndrome[4]

Clonidine has multiple off-label uses, such as managing withdrawal symptoms from opioids, benzodiazepines, and alcohol and treating anxiety, insomnia, and post-traumatic stress disorder (PTSD).[5]

Because of the effect of clonidine on the sympathetic nervous system, specifically, the reduction of circulating epinephrine, it has been used in many other aspects of medicine, for example, control of hot flashes in menopause, restless leg syndrome, and prophylaxis of vascular migraine headaches. Also, there is a test for phaeochromocytoma called the clonidine suppression test; in the lab, they measure the catecholamine levels before and after a dose of oral clonidine, which, in healthy people, should cause a decrease in the level of catecholamines in circulation.[3][5]

Mechanism of Action

Clonidine hydrochloride is an imidazoline derivative that acts centrally on alpha-2 adrenergic as an agonist. The chemical name for clonidine is 2-((2,6-dichlorophenyl) amino)-2-imidazoline hydrochloride.

As an alpha-adrenergic agonist in the nucleus tractus solitarii (NTS), clonidine excites a pathway that inhibits excitatory cardiovascular neurons. Clonidine has an alpha-antagonist effect in the posterior hypothalamus and medulla. The final response is reduced sympathetic outflow from the central nervous system (CNS), which clinically causes a decrease in arterial blood pressure.

One of the theories about the mechanism of action of clonidine in the management of pain in the CNS is that many pain signals occur in the dorsal horn of the spinal cord and are sent to higher centers of the CNS. There is a release of norepinephrine from the descending inhibitory bulbospinal neurons that binds to alpha-2-receptors in the dorsal horn to decrease afferent pain transmission and produce analgesia. Therefore, drugs like clonidine that target alpha-2 receptors can influence the transmission of pain.

Epidural clonidine used as an adjunct to local anesthetics has three different mechanisms of action. First, the stimulation of alpha-2-receptors in the dorsal horn reduces pain transmission. Secondly, clonidine can cause local vasoconstriction that limits vascular removal of local epidural anesthetics. Lastly, clonidine enhances neuraxial opioids and, in combination with fentanyl, interacts in an additive manner, which can reduce the dose of each component by 60% for postoperative analgesia.

The exact mechanism of action of clonidine in the management of attention-deficit hyperactivity disorder (ADHD) is not clear, but it is possible prefrontal cortex brain activity is involved.

Clonidine has a half-life of between 6 and 20 hours (17 to 40 hours in cases of renal impairment.)

Administration

Clonidine Forms and Dosages

Transdermal Patch (extended-release)

• Dosage: 0.1 mg/day, 0.2 mg/day, 0.3 mg/day. Change the patch every seven days
• Indications: hypertension, smoking cessation, cyclosporine nephrotoxicity, menopausal flushing, and opioid withdrawal

Tablet (immediate-release)

• Dosage: 0.1 mg, 0.2 mg, 0.3 mg
• Indications: hypertension, acute hypertension, opioid withdrawal, and pheochromocytoma

Tablet (extended-release)

• Dosage: 0.1 mg
• Indications: alcohol withdrawal, smoking cessation, restless-leg syndrome, ADHD, Tourette syndrome, menopausal flushing, dysmenorrhea, postherpetic neuralgia, and psychosis

Injectable Solution

• Dosage: 100 mcg/ml, 500 mcg/ml
• Indications: epidural infusion form in cancer pain not controlled by opioid analgesics and as an adjunct in anesthesia
• The initial dose of 30 mcg/hr and titration is necessary for pain management or potential side effects.

Dosing Considerations

Extended-release and immediate-release types of clonidine are not interchangeable.

In cases of conversion from oral to transdermal clonidine, the recommendation is:

• On day one: place a transdermal clonidine patch, and administer 100% of the oral dose.
• On day two: Administer only 50% of the oral dose.
• On day three: Administer 25% of the oral dose.
• On day four: Use of the transdermal patch continues without any further oral supplement.

Renal Impairment Dosing Modification

For renal impairment, the recommendation is to start a low dose and titrate the dose up with caution. The initial dose should consider the amount of renal impairment. Monitor carefully for hypotension and bradycardia.[6]

Hepatic dosing is undefined.

Adverse Effects

Like any other medication, clonidine has the potential for short-term and long-term side effects. Some of the common side effects based on FDA reports include:

Common Reactions (tend to resolve with continued therapy)

• Abdominal pain
• Headache
• Hypotension
• Fatigue
• Nausea
• Emotional instability
• Constipation
• Xerostomia
• Diarrhea
• Sexual dysfunction
• Dizziness
• Sedation

Serious Reactions

• Angioedema
• Depression
• Hypersensitivity
• Atrioventricular (AV) block
• Bradycardia
• Syncope
• Severe hypotension

Note rebound hypertension and withdrawal symptoms if the medication is discontinued abruptly.[7][7]

Other Symptoms

• Fever, headache
• Fatigue
• Bradycardia
• Congestive heart failure
• Decreased sexual activity
• Thrombocytopenia
• Agitation
• Depression is one of the rarely reported side effects that can occur with the chronic use of clonidine; however, because of the variety of applications for this medication and also because of its slowly progressive onset, clinicians should monitor patients for signs of depression.

Contraindications

Hypersensitivity to medication, class of alpha-2-agonist. For epidural use: administration above C4 dermatome. Do not suddenly discontinue the drug; otherwise, there is a risk of rebound hypertension and withdrawal symptoms. Dose adjustment is necessary for renal impairment, cardiovascular, bradycardia, hypotension, and severe coronary artery disease (CAD) patients. Also, caution is necessary when treating patients with a history of depression, recent myocardial infarction (MI), and syncope.

Pregnant patients should enroll or be encouraged to enroll in the National Pregnancy Registry for ADHD Medications. Clinicians should weigh the risk vs. benefit of giving clonidine to breastfeeding patients; while there is little adequate human data on risks, there is a chance for infant sedation hypotonia and apnea. The drug could also theoretically impair breast milk production because of decreased prolactin levels.[8]

There are no absolute drug interaction contraindications listed for clonidine; however, there are numerous agents that require caution, and the clinician is recommended to perform thorough medication reconciliation and enlist the services of a pharmacist if necessary.[9]

Monitoring

Clonidine has a black box warning for appropriate use:

• Prior to use, dilute 500 mcg/ml strength product in an appropriate solution.

Obstetrical, Postpartum, or Perioperative Use

• Weigh risk versus benefit
• Epidural clonidine is not recommended for obstetrical and postpartum perioperative pain control because of the increased risk of hemodynamic instabilities like hypotension and bradycardia.

Clonidine Addiction

Even though clonidine is a medication commonly used for withdrawal symptoms of opioid addiction, it has the potential to be a substance of misuse and needs monitoring in that regard.[10]

Clonidine use, in many cases, does not typically fit the category of addiction stereotype, especially because most of the abusers do not feel like they are doing anything wrong as it is a prescription medication. Clonidine is not in a category of high potential for abuse medication by the United States government. As a result, it has fewer restrictions, and it is less risky to take it for abuse. Unfortunately, much of clonidine abuse starts in rehabilitation centers as it is a common medication for opioid and alcohol withdrawal treatment. Since it helps reduce withdrawal symptoms and cravings, clinicians should evaluate their concerns about the potential of trading addictions.[11]

Also, the synergistic potential of clonidine, when mixed with other benzodiazepines, opioids, or alcohol, can give the individual more potent drowsiness and further detachment from reality. It is essential to notify the patients and try to screen for signs of dependency on clonidine as listed below:

• Feeling an intense urge for clonidine[10]
• Feeling the need for the use of clonidine regularly
• Finding that one is taking more clonidine to achieve the same effect
• A patient who always wants to ensure that there is always a backup supply of clonidine
• Spending more on clonidine than one can afford
• The patient cannot picture quitting clonidine
• Experience withdrawal symptoms such as nausea, vomiting, dizziness, headache, insomnia, restlessness, or anxiety when trying to stop taking clonidine[2]

Toxicity

There is a case report recommending using naloxone to counter the sedative effects of clonidine.[12]

Enhancing Healthcare Team Outcomes

Clonidine is prescribed by various clinicians, including primary care providers, cardiologists, psychiatrists, and internists; this can also include NPs and PAs. Besides hypertension, clonidine has multiple off-label uses, such as managing withdrawal symptoms from opioids, benzodiazepines, and alcohol, analgesia, and treatment of anxiety, insomnia, and post-traumatic stress disorder (PTSD).

While the drug is relatively safe, it is essential to discuss any potential contraindications and adverse effects with the pharmacist. The drug is also known to cause physical and psychological dependence.[13] This, in addition to the drug's clinical implications, are why an interprofessional team approach is necessary. Clinicians will prescribe the drug as they deem appropriate. Nursing can review administration and dosing with the patient and answer any questions the patient might have. The pharmacist will perform medication reconciliation, reinforce dosing counsel, and advise the patient regarding potential adverse events to be addressed promptly. If any member of the team, be it the nurses, pharmacist, or a clinician (including those who may not have prescribed the drug), becomes aware of an adverse event, therapeutic failure, or potential misuse of the drug, they must immediately alert all members of the interprofessional team so that appropriate corrective action can take place.

This interprofessional approach to medication therapy that includes the coordinated efforts of physicians (MDs and DOs), mid-level practitioners (PAs and NPs), nurses, and pharmacists will optimize clinical results with clonidine while reducing potential adverse events. [Level 5]