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Alpha-Adrenergic Receptors
Indications
The indication for the use of an alpha-adrenergic receptor modifying medication depends on which receptor is the target: the alpha-1 receptor or the alpha-2 receptor. Alpha-1 receptors bind catecholamines including, both epinephrine and norepinephrine. In instances in which there is hypoperfusion secondary to decreased cardiac output or decreased systemic vasculature resistance, alpha-1 receptors become stimulated. It is worth noting that these compounds are not purely selective for the alpha receptor, and often engage beta-adrenergic receptors as well. The use of alpha-1 agonists is common in all types of shock, cardiopulmonary resuscitation, and heart failure decompensation.[1] Alpha-1 agonists, such as phenylephrine, are also used to treat upper airway congestion as stimulating the receptor leads to a decreased mucus secretion.[2] Alpha-antagonists, colloquially known as alpha-blockers, work in the peripheral vasculature and inhibit the uptake of catecholamines in smooth muscle cells resulting in vasodilation and blood pressure lowering. Alpha-antagonists, including doxazosin, prazosin, and phentolamine - are primarily used in the treatment of hypertension and urinary retention.[3]
Alpha-blockers have significant use in the setting of pre-operative pheochromocytoma care.[4] Alpha-blockers are also used off-label for the treatment of post-traumatic stress disorder (PTSD).[5] Alpha-2 stimulation reduces the sympathetic outflow from the vasomotor center centrally and increases vagal tone. Peripheral presynaptic alpha-2 receptors may also reduce sympathetic tone. Alpha-2 agonists, including clonidine and guanfacine - are used as anti-hypertensives, as well.[6] Both clonidine and guanfacine are used for behavior modification in children with attention deficit disorder, as well as in adults with PTSD as well.[7][8]
Alpha-1 Agonists
FDA Approved Indications
Oral Agents
- Midodrine
- Treatment of symptomatic orthostatic hypotension
Topical Agents
- Naphazoline/naphazoline-pheniramine
- Topical ocular vasoconstriction
- Use for the relief of redness in the eye/itching (pheniramine)
- Phenylephrine
- Dilate pupils (ophthalmic)
- Temporary relief of nasal congestion due to the common cold or allergic rhinitis (nasal)
- Used in the treatment of hemorrhoids (rectal/topical)
- Xylometazoline
- Temporary relief of nasal and nasopharyngeal mucosal congestion
Intravenous
- Phenylephrine
- Hypotension/shock/cardiogenic shock
- Hypotension during anesthesia: vasoconstrictor in regional analgesia
Off-label Uses
Oral Agents
- Midodrine
- Refractory ascites[9]
- Prevention of dialysis-induced hypotension
- Hepatorenal syndrome
- Vasovagal syndrome
Topical Agents
- Phenylephrine
- Topical vasoconstriction in nasal procedures
Intravenous
- Phenylephrine
- Hypotension in patients with obstructive hypertrophic cardiomyopathy
- Priapism
Alpha-1 Blockers
FDA Approved Indications
Oral Agents
- Treatment for signs and symptoms of benign prostatic hyperplasia (BPH)[10]
- Alfuzosin
- Tamsulosin
- Doxazosin
- Terazosin
- Silodosin
- Management of hypertension; alpha-blockers not recommended as the first-line agents[11]
- Prazosin
- Doxazosin
- Terazosin
Intravenous Agents
- Phentolamine
- Pheochromocytoma: Diagnosis of this condition via the phentolamine blocking test
- Extravasation management: prevention of dermal necrosis/sloughing after extravasation of norepinephrine
- Local anesthesia reversal: reversal of soft tissue anesthesia and the associated functional deficits resulting from intraoral submucosal injections of local anesthetics
- Phenoxybenzamine
- Pheochromocytoma: Treatment of sweating and hypertension associated with the condition
Off-label Uses
Specific Agents
- Tamsulosin:
- Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in males
- Lower urinary tract symptoms (LUTS) in males
- Ureteral calculi expulsion
- Ureteral stent-related urinary symptoms, treatment
- Prazosin
- Post-traumatic stress disorder PTSD related nightmares and sleep disruptions[12]
- Raynaud phenomenon
- Phentolamine
- Hypertensive crisis
- Extravasation of sympathomimetic vasopressors
- Phenoxybenzamine
- Hypertensive crisis caused by sympathomimetic amines
- Micturition problems associated with neurogenic bladder
- Functional outlet obstruction and partial prostate obstruction
Other Uses
- Ureteral calculi (distal)[13]
- Alfuzosin
- Doxazosin
- Terazosin
- Silodosin
Alpha-2 Agonists
FDA Approved Indications
Oral
- Clonidine
- Treatment of attention-deficit/hyperactivity disorder (ADHD) as monotherapy or as adjunctive therapy (extended-release tablet)[14]
- Management of hypertension, but not recommended as first-line treatment, should be avoided in heart failure patients with a reduced ejection fraction of ischemic origin[11][15]
- Guanfacine
- Methyldopa
- Management of hypertension, not recommended first line, particular use in pregnancy; may cause positive Coombs test[11]
- Lofexidine
- Mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults[16]
- Tizanidine
- Management of spasticity; reserve treatment with tizanidine for daily activities and times when relief of spasticity is most improtant[17]
Topical
- Brimonidine
- Topical treatment of persistent (non-transient) erythema of rosacea in adults
Intravenous
- Clonidine
- Continuous epidural administration as adjunctive therapy with opioids for the treatment of severe cancer pain in patients tolerant to or unresponsive to opioids alone; more effective for neuropathic pain and less effective (or possibly ineffective) for somatic or visceral pain[18] (epidural)
- Dexmedetomidine
- Intensive care unit sedation: Sedation of initially intubated and mechanically ventilated patients during treatment in intensive care settings
- Procedural sedation: Procedural sedation before and/or during awake fiberoptic intubation; sedation before and/or during surgical or other procedures of non-intubated patients
Off-label Uses
- Clonidine
- Clozapine-induced sialorrhea
- Diagnosis of pheochromocytoma
- Growth hormone stimulation test
- Opioid withdrawal
- Tourette syndrome
- Vasomotor symptoms associated with menopause
- Dexmedetomidine
- Sedation during awake craniotomy
- Treatment of shivering
Mechanism of Action
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Mechanism of Action
There are two types of alpha-adrenergic receptors; alpha-1 and alpha-2. Both are G-protein coupled receptors (GPCR); however, the downstream effects of the two are different. The alpha-1 receptor is of the Gq type, resulting in activation of phospholipase C, increasing IP3 and DAG, and ultimately increasing the intracellular calcium concentrations leading to smooth muscle contraction and glycogenolysis.[19] The alpha-2 receptor acts as an allosteric inhibitor through Gi function, leading to an inhibition of adenylyl cyclase, decreasing the formation of intracellular cAMP. It also leads to a reduced amount of cytoplasmic calcium, which decreases neurotransmitter release and central vasodilation.[20] Epinephrine and norepinephrine have relatively equal affinities for both types of alpha-receptors, with other drugs used in shock having a higher selectivity for the alpha-1 receptor.
Administration
Administration of alpha-1 receptor agonists is done intravenously through a central line for shock. In the setting of anaphylaxis, epinephrine administration should be either intramuscular or subcutaneous, not intravenous. Phenylephrine can be administered orally for congestion. Alpha-1 receptor antagonists can be administered orally for refractory hypertension, behavioral modification, and urinary hesitancy. In the emergent setting, the administration of alpha-1 blockade agents can be via the intravenous route. Alpha-1 antagonists are predominantly administered orally and in the outpatient setting. Alpha-2 agonists can be given orally or intravenously, depending on the setting and requirement.
Adverse Effects
The adverse effects can be related to autonomic response to the systemic changes induced by the agent or to other receptors being antagonized, often those in the beta-adrenergic receptor family. When ordering an alpha-1 blocker, it is important to be aware and inform the patient of a first-dose effect. With the initial administration of an alpha-1 blocker, systemic vasodilation can lead to a tachycardic response and orthostatic hypotension.[21] This same effect may also occur in the alpha-2 agonist family; however, this is generally less pronounced than in the alpha-1 blockade. The most common adverse effects of alpha-2 receptor agonists are sedation and fatigue.[22] The adverse effects of alpha-1 agonists include hypertension, tachycardia or other dysrhythmias, increased cardiac demand, and subcutaneous ischemia at the site of injection.[23][24]
Contraindications
As with all drugs, the prescriber should account for any previous history of hypersensitivity before the administration. Alpha-1 receptor agonists are contraindicated in patients with the Reynaud phenomenon or closed-angle glaucoma.[25] Epinephrine should not be given subcutaneously in the upper or lower digits, nose, or penis.[26] Alpha-1 agonists given for congestion are contraindicated in the setting of hypertension, tachycardia, or any cardiac history, causing increased demand on the heart. If prescribing an alpha-1 receptor agonist for vasoconstriction, the administration must be through a central line. The main contraindications for the use of an alpha-blocking agent are a history of orthostatic hypotension and concurrent use of phosphodiesterase inhibitors.[27] Contraindications for alpha-2 agonists include concurrent use of phosphodiesterase inhibitors, orthostatic hypotension, and any condition leading to autonomic instability.[28]
Monitoring
Monitoring depends on the setting of drug administration. If the clinician is giving the drug to increase systemic vascular resistance, then the patient should be maintained on continuous telemetry with ideally continuous monitoring of central venous pressure and arterial pressure. During a period of acute illness, the patient and will likely be under close monitoring in general; special consideration is necessary for cardiac rhythm and blood pressure. If being given for anaphylaxis, the patient should be monitored in a hospital setting for at least ten hours, as anaphylaxis can have a biphasic onset related to the metabolism of the epinephrine.[29] Patients receiving alpha-1 agonists require monitoring for tachyarrhythmias, blood pressure, and other adverse symptoms relative to taking the drug. In patients receiving either alpha-1 blocking agents or alpha-2 agonists, blood pressure and orthostatic hypotension warrant specific attention.
Toxicity
Alpha-1 receptor agonists taken at toxic doses lead to increased sympathetic tone, which results in tachycardia, early hypertension progressing to hypotension, mydriasis, anxiety, and increased glycogenolysis. Recent ingestion or asymptomatic patients require observation; if very recent, then activated charcoal may be an option to attempt to prevent the drug from absorbing if the drug was ingested orally. If symptomatic, the patient should be admitted, generally to the intensive care unit. Symptomatic treatment is the mainstay, with control of the airway, blood pressure, and heart rate. The alpha blockade may be attempted with caution, as well. Once symptoms abate, the patient is considered to have wholly metabolized the drug. The toxicity of alpha-1 blockers and alpha-2 agonists is an unopposed parasympathetic activity, with bradycardia, hypotension, miosis, and sedation. Observation is sufficient in asymptomatic patients. Supportive care is necessary for symptomatic patients. There is no single antidote for either type of toxicities.[6]
Enhancing Healthcare Team Outcomes
Alpha-1 agonists are used in the critical care setting to increase systemic vascular resistance are considered high alert drugs and can be very dangerous if used or dosed incorrectly. Clear and concise communication is necessary between the nurse, pharmacist, and ordering practitioner (physician, nurse, or physician assistant) in these instances to prevent mistakes that can cause morbidity and mortality. Very close continuous monitoring is also necessary for patients receiving these drugs, and many facilities assign these patients a one-to-one nurse staffing. Many local anesthetics are co-formulated with epinephrine as a hemostatic agent, and when injected subcutaneously, this can cause skin necrosis. Special care between physicians, pharmacists, and nurses is necessary to identify the local agents containing epinephrine clearly to prevent unnecessary complications. Many alpha-1 and alpha-2 drugs are used clinically in the emergency department, so clinical staff must be very thorough in medical and social history before ordering these medications. In patients that are in skilled nursing facilities that are likely fall risks, if given an alpha-1 blocker or alpha-2 agonist, it should be communicated that they should have close monitoring by nursing staff, as well as fall precautions including a bed alarm, bed rails, and a fall mat, due to the risk of orthostatic hypotension. Drugs that affect alpha-receptors, both antagonists and agonists, require an interprofessional team approach to include clinicians, specialists, nurses, and pharmacists, all working as a collaborative interprofessional team, to direct therapy optimally and derive successful results for patients. [Level V]
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