Antiadrenergic Drugs

Antiadrenergic agents are drugs that block the activity of catecholamines, primarily norepinephrine (NE). There are 2 major types of adrenergic receptors–alpha and beta receptors—and there are several subtypes of each. Antiadrenergic drugs can be classified according to their specificity for the different receptors, with the major classes including selective beta-1 receptor blockers, nonselective beta-blockers, mixed alpha- and beta-blockers, selective alpha-1 receptor blockers, and nonselective alpha-blockers. There are many beta receptors in the heart, so these medications are primarily used for cardiac indications, including MI, angina, heart failure (HF) (stable), and hypertension (as an alternative agent). Alpha receptors are prominent in smooth muscle, especially in the vasculature. Alpha-blockers cause significant vasodilation and are indicated in hypertension and benign prostatic hyperplasia (BPH). Significant adverse effects are possible.

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Overview

Overview of the ANS

The ANS is subdivided into the sympathetic and parasympathetic pathways. Both pathways contain 2 efferent neurons in series known as the preganglionic and postganglionic neurons.

Preganglionic neuron:

  • 1st neuron in the series 
  • The cell body originates in the CNS.
  • Release acetylcholine onto nicotinic cholinergic receptors in the autonomic ganglia
  • In the adrenal gland, preganglionic neurons synapse directly with chromaffin cells in the adrenal medulla (instead of the sympathetic ganglia).

Postganglionic neuron: 

  • Second neuron in the series 
  • The cell body originates in the ganglion.
  • May release:
    • Norepinephrine (NE) onto alpha- or beta-adrenergic receptors in target tissues:
      • Cardiac and smooth muscle
      • Gland cells
      • Nerve terminals
    • Acetylcholine onto muscarinic receptors in sweat glands
    • Dopamine onto dopaminergic receptors in renal vascular smooth muscle
  • In the adrenal gland, chromaffin cells act as modified postganglionic neurons and release epinephrine (80%) and NE (20%) directly into the bloodstream.
Overview of the ans

Overview of the ANS
ACh: acetylcholine
N: nicotinic receptor
M: muscarinic receptor
α and β: α and β adrenergic receptors
NE: norepinephrine
D: dopamine
D1: dopamine receptor
Epi: Epinpehrine

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Chemistry and Pharmacodynamics

Chemistry

  • Catecholamines are derived from the amino acid tyrosine (a.a. Tyr).
  • Most beta-blockers are structurally similar to the catecholamines.

Mechanisms of action

Antiadrenergic drugs work by inhibiting the postganglionic adrenergic receptors. These are G-protein-coupled receptors.

Alpha receptors: 

  • Alpha-1 receptors:
    • Alpha-1 stimulation: 
      • Activates the enzyme phospholipase C → 
      • Generates inositol triphosphate (IP3) and diacylglycerol (DAG) as secondary messengers → 
      • Causes ↑ calcium ion (Ca2+) levels intracellularly → 
      • Smooth muscle contraction
    • Alpha-1 receptor antagonists: inhibit release of IP3 and DAG → ↓ Ca2+ release → smooth muscle relaxation
  • Alpha-2 receptors (primarily located at peripheral nerve endings):
    • Alpha-2- receptor stimulation: 
      • Inhibits the enzyme adenylyl cyclase → 
      • ↓ Levels of the secondary messenger cAMP → 
      • Ultimately blocks the presynaptic release of NE → 
      • ↓ Adrenergic stimulation
    • Alpha-2 receptor antagonists: block reduction in cAMP → ↑ NE release → ↑ adrenergic stimulation
  • Alpha receptor inhibitor binding may be:
    • Selective or nonselective for alpha-1 vs. alpha-2 receptors 
    • Reversible or irreversible

Beta receptors: beta-1, beta-2, and beta-3 

  • Beta receptor stimulation: stimulates adenylyl cyclase → ↑ cAMP → triggers target cell effects
  • Beta receptor antagonists: 
    • Competitively inhibit catecholamines at the beta-adrenergic receptors 
    • ↓ Activation of adenylyl cyclase → inhibits target cell effects
    • Have minimal impact on patients who are at rest
  • Beta receptor partial agonists:
    • Partially activate the beta receptors, though not as strongly as true catecholamines
    • Results in decreased effects when NE is ↑ and increased effects when NE is ↓

Physiologic effects

Adrenergic receptors are located throughout the body and trigger a wide variety of effects. The physiologic effects of antiadrenergic agents are to block whatever the typical response is of that particular receptor. 

  • Alpha-1 receptors: 
    • Found in smooth muscle throughout the body (e.g., bronchial, vascular, intestinal, and bladder walls)
    • Play a major role in determining vascular tone
    • Alpha-1 receptor antagonists cause: 
      • Vasodilation
      • Relaxation of bladder muscles → improved micturition 
  • Beta-1 receptors: 
    • Primarily located in the heart 
    • Play a major role in determining heart rate (HR) and contractility
    • Beta-1 antagonists:
      • ↓ HR and contractility 
      • ↓ Myocardial O2 demand
  • Beta-2 receptors: 
    • Located throughout the body, including heart, lungs, and smooth muscle
    • Usually has effects opposite those of alpha-1 receptors 
    • Beta-2 antagonists:
      • ↓ HR, contractility, and myocardial O2 demand
      • Bronchoconstriction (adverse effect)
      • Vasoconstriction
      • ↓ Intraocular pressure (IOP)
      • Metabolic effects 
Table: Physiologic effects of antiadrenergic medications
System Organ Receptors Physiologic actions from receptor stimulation (agonism) Physiologic effects from receptor blockade (antagonism)
Eye Iris radial muscle α1 Contraction → pupil dilation Relaxation → pupil constriction
Ciliary muscle β Relaxes → flattens lens → better for long-range focus ↓ Relaxation → rounder lens → short range focus
Ciliary epithelium β ↑ Production of aqueous humor ↓ Secretion of aqueous humor → ↓ IOP
Cardiovascular system SA β1, β2 Acceleration (↑ HR) ↓ HR
Ectopic pacemakers β1, β2 Acceleration (↑ HR) ↓ HR
Contractility of atria and ventricles β1, β2 ↑ Contractility ↓ Contractility
Vascular wall smooth muscle α1 Vasoconstriction Vasodilation → may cause orthostatic hypotension and reflex tachycardia
β2 Vasodilation Vasoconstriction → ↑ peripheral resistance
Pulmonary smooth muscle Bronchiolar smooth muscle β2 Bronchodilation Bronchoconstriction (especially with asthma)
GI tract smooth muscle Intestinal walls α2, β2 Relaxation (↓ motility) ↑ Motility → may lead to diarrhea
Sphincter muscles α1 Contracts (prevents chyme from passing through) Sphincter relaxation → ↑ risk of heartburn
Genitourinary smooth muscle Bladder wall β2, β3 Relaxes ↓ Resistance to urine flow
Urethral sphincters α1 Contracts ↓ Resistance to urine flow → ↑ risk of incontinence
Pregnant uterus α Uterine contraction Uterine relaxation
β2 Uterine relaxation Uterine contractions → labor/preterm labor
Penis and seminal vesicles α Ejaculation Difficulty with ejaculation
Metabolic functions Liver α, β2 Gluconeogenesis, glycogenolysis ↓ Glycogenolysis → may impair recovery from hypoglycemia
Adipose tissue β3 Lipolysis Inhibition of lipolysis
Kidney β1 Renin release Suppression of renin release
IOP: Intraoccular pressure
SA: Sinoatrial node
HR: heart rate

Classification

Alpha-blockers

  • Alpha-1-selective blockers:
    • Prazosin
    • Doxazosin
    • Terazosin
    • Tamsulosin
  • Alpha-2-selective blocker: yohimbine (currently not FDA approved) 
  • Nonselective alpha-1 and alpha-2 blockers:
    • Phenoxybenzamine
    • Phentolamine

Beta-blockers

  • Beta-1-selective blockers:
    • Atenolol 
    • Metoprolol
    • Esmolol
    • Nebivolol
  • Beta-2-selective blocker: butaxamine (used only experimentally)
  • Nonselective beta-blockers:
    • Propranolol
    • Nadolol
    • Timolol
  • Beta-blockers with partial agonist activity: 
    • Pindolol
    • Acebutolol

Mixed Alpha- and Beta-blockers

These drugs have inhibitory effects at both the beta and alpha-1 receptors 

  • Carvedilol
  • Labetalol

Pharmacokinetics

Differences in pharmacokinetics can help determine which medication in a particular class is optimal for a given clinical scenario.

Table: Pharmacokinetics of antiadrenergic drugs
Drug Absorption Distribution Metabolism Excretion
Prazosin (selective α1-blocker) Onset: 2‒4 hrs
  • VD: 0.5 L/kg
  • Protein binding: 97%
Extensive hepatic via demethylation and conjugation
  • Fecal
  • Half-life: 2‒3 hrs
Phentolamine (nonselective α-blocker
  • Poor oral absorption
  • Onset:
    • IM: 15‒20 min
    • IV: 1‒2 min
Widely distributed Hepatic
  • Urine
  • Half-life: approximately 20 min
Propranolol (nonselective β-blocker)
  • Rapid complete oral absorption
  • Onset:
    • By mouth: 1‒2 hrs
    • IV: < 5 min
  • VD 4 L/kg
  • Cross BBB
  • Protein binding: approximately 90%
Extensive 1st-pass hepatic metabolism
  • Urine (as metabolites)
  • Half-life: 3‒6 hrs
Atenolol1-selective β-blocker)
  • Rapid incomplete oral absorption (approximately 50%)
  • Onset (by mouth): < 1 hr
  • VD: approximately 75 L
  • Does not cross BBB
  • Protein binding: approximately 10%
Minimal hepatic metabolism
  • Feces: 50%
  • Urine: 40%
  • Half-life: 6‒7 hrs (up to 35 hrs in ESRD)
Metoprolol1-selective β-blocker)
  • Rapid complete oral absorption
  • Onset:
    • By mouth: 1‒2 hrs
    • IV: 20 min
  • VD: approximately 4 L/kg
  • Crosses BBB
  • Protein binding: approximately 10%
Extensive 1st-pass hepatic metabolism
  • Urine
  • Half-life: 3‒4 hrs (↑ in hepatic impairment)
Carvedilol (mixed α and β blockade)
  • Rapid complete oral absorption
  • Onset (by mouth):
    • α blockade: 30 min
    • β blockade: 1 hr
  • VD: 115 L (distributes in extravascular space)
  • Protein binding: 98%
Extensive 1st-pass hepatic metabolism
  • Feces
  • Half-life: 7‒10 hrs
IM: intramuscular
IV: intravenous
BBB: blood–brain barrier
ESRD: end-stage renal disease
VD: volume of distribution

Drug interactions

Drug interactions are also important for several medications within this class.

  • Alpha-blockers + medications for erectile dysfunction (e.g., sildenafil) → may cause significant hypotension
  • Beta-blockers + loop diuretics → may result in hypotension
  • NSAIDs may ↓ the efficacy of beta-blockers.

Indications

Alpha antagonists

While Alpha-2 antagonists have few clinical uses, alpha-1 and nonselective alpha antagonists are used for their ability to cause vasodilation and smooth muscle relaxation. They are frequently used in the treatment of:

  • Prazosin:
    • Hypertension 
    • Benign prostatic hyperplasia (BPH, enlargement of the prostate resulting in urinary retention)
    • Off-label use: nightmares in PTSD
  • Phenoxybenzamine: pheochromocytoma (catecholamine-secreting tumors of the adrenal medulla)
  • Phentolamine: 
    • Erectile dysfunction (ED)
    • Prevention or treatment of extravasation of IV NE 
    • Reversal of soft-tissue anesthesia from local anesthetics containing a vasoconstrictor

Beta antagonists

Beta-blockers have a variety of indications. They are frequently used for their negative inotropic and chronotropic effects in the heart. 

  • Cardiovascular indications: 
    • Atrial fibrillation (AFib)
    • Congestive heart failure (CHF)
    • Post-MI
    • Angina
    • Hypertension
  • Other indications for propranolol:
    • Neuropsychiatric
      • Essential tremor
      • Migraine headache
      • Anxiety (especially performance anxiety)
    • GI: bleeding from esophageal varices (beta blockade ↓ portal vein pressure in cirrhosis) 
    • Endocrine: hyperthyroidism
  • Specialized indications for other beta-blockers:
    • Labetalol: hypertension in pregnancy
    • Timolol (good ocular penetration): glaucoma
    • Esmolol (very short half-life): when steady-state infusions are required
    • Butoxamine (beta-2-selective antagonist): used for research purposes 

Adverse Effects and Contraindications

Antiadrenergic medications must be used with caution and titrated slowly to avoid side effects.

Table: Adverse effects and contraindications of anti-adrenergic medications
Drug Adverse effects Contraindications
Beta-blockers
  • Bradycardia
  • Bronchospasm (due to beta-2 blockade with nonselective beta-blockers)
  • HF
  • Hypotension
  • Syncope and/or dizziness
  • Impotence/ejaculatory failure
  • Diarrhea
  • Heartburn
  • Fatigue
  • Hyperglycemia
  • Mask signs of hypoglycemia in diabetics
  • Blurred vision
  • Absolute contraindications:
    • Asthma
    • Uncompensated HF and/or cardiogenic shock
    • 2nd- or 3rd-degree heart block
  • Relative contraindications:
    • Individuals prone to hypoglycemia
    • Diabetes
    • Hypotension
    • PVD
    • Liver or kidney disease
    • Pheochromocytoma (untreated with alpha blockade)
    • MG
    • Hyperthyroidism
Alpha-1 blockers (prazosin)
  • Orthostatic hypotension
  • Syncope and/or dizziness
  • Headache
  • Fatigue
  • Nasal congestion
  • GI distress
  • Edema
  • Priapism (prolonged erection)
Known hypersensitivity to the drug
Nonselective alpha antagonists (phenoxybenzamine, phentolamine)
  • Same as alpha-1 antagonists, especially orthostatic hypotension
  • Reflex tachycardia (due to additional alpha-2 blockade, which causes ↑ NE release)
  • Breastfeeding
  • Cardiovascular conditions that cannot tolerate hypotension:
    • CHD
    • Angina
    • MI
    • HF
HF: Heart failure
PVD: Peripheral vascular disease
MG: Myasthenia gravis
CHD: Coronary heart disease

Overdose

Presentation of beta-blocker toxicity

Although beta-blockers are generally safe, overdose can produce symptoms of toxicity, typically within 2 hours (almost always within 6). Symptoms include:

  • Bradycardia
  • Hypotension
  • Myocardial depression and cardiogenic shock
  • Ventricular dysrhythmias
  • Mental status changes (e.g., delirium, coma, seizures)
  • Bronchospasm
  • Hypoglycemia

Management

  • Acute stabilization of the airway, breathing, and circulation (ABC):
    • Intubate if needed.
    • Isotonic fluid to treat hypotension 
  • Reverse the cardiotoxic effects:
    • Atropine to treat symptomatic bradycardia
    • Glucagon
    • Calcium salts
    • Vasopressors
  • Avoid hypoglycemia: IV dextrose
  • Treat seizures: benzodiazepines

Comparison of Medications

Table: Comparison of medications
Medication Mechanism Physiologic effects Indication
Metoprolol Selective β1-blocker
  • ↓ HR
  • ↓ Contractility
  • Less effect on bronchial smooth muscle
  • MI
  • HF with ↓ EF (stable)
  • Angina
  • Hypertension (not 1st line)
  • AFib
Propranolol Nonselective β-blocker
  • ↓ HR
  • ↓ Contractility
  • ↓ Blood pressure
  • Higher risk of bronchospasm
  • MI
  • AP
  • Hypertension (not 1st line)
  • Migraine prophylaxis
  • Essential tremor
  • Performance anxiety
  • PTSD
  • Thyrotoxicosis
Carvedilol Nonselective α- and β-blocker
  • ↓ HR
  • ↓ Contractility
  • Vasodilation
  • ↓ Renin release
  • HF with ↓ EF (stable)
  • Angina
  • AFib
Prazosin Selective α1-blocker
  • Vasodilation of arteries and veins
  • ↓ Blood pressure
  • Relaxation of bladder muscles
  • Hypertension (not 1st line)
  • BPH
  • PTSD (off-label use)
Phentolamine Nonselective α-adrenergic antagonist
  • Vasodilation
  • ↓ Blood pressure
  • ↑ HR
  • Pheochromocytoma
  • Prevention or treatment of extravasation of IV NE
  • Reversal of soft-tissue anesthesia from local anesthetics containing a vasoconstrictor
HF: heart failure
AFib: atrial fibrillation
AP: angina pectoris
BPH: benign prostatic hyperplasia
NE: norepinephrine

References

  1. Katzung, BG. (2012). Introduction to autonomic pharmacology. In Katzung, BG, Masters, SB, & Trevor, AJ. (Eds.), Basic and Clinical Pharmacology. 12th Ed. pp. 79–95. McGraw-Hill.
  2. Robertson, D, & Biaggioni, I. (2012). Adrenoceptor antagonist drugs. In Katzung, BG, Masters, SB, & Trevor, AJ. (Eds.), Basic and Clinical Pharmacology. 12th Ed. pp. 151–165. McGraw-Hill.
  3. Podrid, PJ. (2020). Major side effects of beta blockers. UpToDate. Retrieved September 1, 2021, from https://www.uptodate.com/contents/major-side-effects-of-beta-blockers
  4. Farzam, K, & Jan, A. (2021). Beta blockers. StatPearls. Retrieved August 31, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/18241/ 
  5. Nachawati, D, & Patel, J. (2021). Alpha blockers. StatPearls. Retrieved August 31, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/17401/ 
  6. Lexicomp Drug Information Sheets (2021). In UpToDate. Retrieved August 31, 2021:
  7. Wang, J, Gareri, C, & Rockman, HA. (2018). G-protein-coupled receptors in heart disease. Circ Res. 123(6), 716–735. https://doi.org/10.1161/CIRCRESAHA.118.311403 
  8. Westfall, TC, Macarthur, H, & Westfall, DP. (2018). Neurotransmission: The autonomic and somatic motor nervous systems. Adrenergic Agonists and Antagonists. In Brunton, LL, et al. (Eds.). Goodman & Gilman’s: The Pharmacological Basis of Therapeutics 13e. New York, NY: McGraw-Hill. 
  9. Gorodetzky, CW, et al. (2017). A phase III, randomized, multi-center, double-blind, placebo-controlled study of safety and efficacy of lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal. Drug Alcohol Depend. 176, 79–88. https://doi.org/10.1016/j.drugalcdep.2017.02.020 
  10. Sarma, AV, Wei, JT. (2012). Benign prostatic hyperplasia and lower urinary tract symptoms. N Engl J Med. 367(3), 248–57. https://doi.org/10.1056/NEJMcp1106637 
  11. Wolraich, ML, et al. (2019). Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 144(4), e20192528. https://doi.org/10.1542/peds.2019-2528 
  12. Campbell, RJ, et al. (2019). Evolution in the risk of cataract surgical complications among patients exposed to tamsulosin: A population-based study. Ophthalmology. 126(4), 490–496. https://doi.org/10.1016/j.ophtha.2018.11.028 
  13. The definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. (1996). J Auton Nerv Syst. 58(1–2), 123–4. https://doi.org/10.1016/0165-1838(96)90001-6 
  14. Griebenow, R, et al. (1997). Low-dose reserpine/thiazide combination in first-line treatment of hypertension: efficacy and safety compared to an ACE inhibitor. Blood Press. 6(5), 299–306. https://pubmed.ncbi.nlm.nih.gov/9360001/
  15. Li, S, Liu, X, & Li, L. (2020). A Multicenter retrospective analysis on clinical effectiveness and economic assessment of compound reserpine and hydrochlorothiazide tablets (CRH) for hypertension. Clinicoecon Outcomes Res. 12, 107–114. https://www.ncbi.nlm.nih.gov/pubmed/32104022
  16. Shamon, SD, Perez, MI. (2016). Blood pressure–lowering efficacy of reserpine for primary hypertension. Cochrane Database Syst Rev. 12, CD007655. https://www.ncbi.nlm.nih.gov/pubmed/27997978
  17. Khakurel, S, Sapkota, S, & Karki, AJ. (2019). Analgesic effect of caudal bupivacaine with or without clonidine in pediatric patient. J Nepal Health Res Counc. 16(41), 428–433. https://www.ncbi.nlm.nih.gov/pubmed/30739935
  18. Bello, M, et al. (2019). Effect of opioid-free anesthesia on postoperative epidural ropivacaine requirement after thoracic surgery: A retrospective unmatched case-control study. Anaesth Crit Care Pain Med. 38(5), 499–505. https://pubmed.ncbi.nlm.nih.gov/30731138/
  19. Pelayo, R, & Yuen, K. (2012). Pediatric sleep pharmacology. Child Adolesc Psychiatr Clin N Am. 21(4), 861–83. https://pubmed.ncbi.nlm.nih.gov/23040905/
  20. Drugs for ADHD. (2020). Med Lett Drugs Ther. 62(1590), 9–15. https://pubmed.ncbi.nlm.nih.gov/31999670/

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