Beta-Adrenergic Receptors and Beta-Blockers

Beta-Adrenergic Receptors

• Beta 1 receptors are primarily located in the heart and cause increased inotropy and chronotropy when stimulated.
• They're also found in juxtaglomerular cells, increasing renin secretion, and in pancreatic islet cells, increasing insulin release.
• Beta 2 receptors are found in smooth muscle (vascular, bronchial, gastrointestinal, and genitourinary), leading to vasodilation and bronchodilation, as well as relaxation of the detrusor muscle and uterine relaxation.
• They are also present in skeletal muscle, causing relaxation.

Beta-Blocker Classifications

• Beta-blockers are classified based on their receptor selectivity.
• Cardioselective agents (beta-1 selective) such as atenolol, metoprolol, esmolol, acebutolol, betaxolol, bisoprolol, celiprolol, and nebivolol prefer beta-1 receptors at therapeutic dosages.
• Beta-1 receptor activation results in increased inotropy and chronotropy in the heart.
• Beta-2 receptor activation causes smooth muscle relaxation (vasodilation, bronchodilation), glycogenolysis, and potassium uptake in skeletal muscle, and glycogenolysis and gluconeogenesis in the liver.
• Non-selective agents block both beta-1 and beta-2 receptors at therapeutic dosage, including propranolol, sotalol, labetalol, nadolol, pindolol, carvedilol, timolol, bucindolol, carteolol, levobunolol, metipranolol, oxprenolol, and penbutolol.
• Other classifications comprise lipophilic qualities, membrane-stabilizing activity, potassium channel blockade, intrinsic sympathomimetic properties, and vasodilating properties.

Beta-Blocker Toxicity Clinical Aspects

• Toxicity is more probable at supratherapeutic dosages (accidental or intentional overdose).
• It can occur at therapeutic dosages due to drug interactions or renal failure.
• General toxicity depends on the drug's propreties, dosage, formulation, interactions, and pre-existing health conditions.
• Beta-blocker toxicity typically causes bradycardia and hypotension from decreased cardiac output; severe toxicity leads to central nervous system depression, convulsions, shock, arrhythmia and death.

Causes of Beta-Blocker Intoxication

• Primary drug characteristics impact clinical toxicity.
• Receptor selectivity can influence toxicity, but it diminishes during overdose.
• Beta-1 receptor blockade slows down heart rate by affecting pacemaker cells and contractility, decreasing cardiac output.
• Beta-2 receptor blockade causes peripheral vasoconstriction, bronchospasm, hyperkalemia, and usually hypoglycemia.

Liposolubility

• Highly lipid-soluble drugs like propranolol enter the central nervous system easily and cause more central nervous system effects.
• High liposolubility drug need liver biotransformation before elimination and may accumulate with hepatic insufficiency.
• High water-soluble drugs are excreted renally and may accumulate with renal insufficiency.

Membrane Stabilizing Activity

• Sodium channel-blocking medicines (propranolol, acebutolol) have a greater risk of arrhythmia from QRS prolongation.

Potassium Channel Blockade

• Sotalol blocks potassium channels, causing QT prolongation and ventricular arrhythmias (e.g., torsades de pointes).
• Acebutolol has same effect.

Clinical Toxicity - Time Course

• Patients show reactions between 20 minutes to hours, reliant on taken chemical agent, individual tolerance, cardiovascular status.
• Extended-release formulation symptoms may take over two hours in development
• Symptoms manifest within six hours of ingestion in a significant overdose, except for sotalol which may present later (up to 9 hours).

Beta Blocker Intoxication Symptoms

• Lightheadedness and syncope
• Overall weakness
• Diaphoresis
• Nausea and Vomiting
• Dyspnea and cough
• Hypotension, bradycardia, poor perfusion
• Possibly secondary to pulmonary edema or bronchospasm.
• Respiratory illness is more frequent in individuals with existing breathing problems.
• CNS depression and confusion may emerge with lipophilic agents that easily cross the blood-brain barrier.
• Convulsions frequently occur after propranolol digestion.
• Cardiac condition indicators can appear; there is a decline in cardiac output.
• Pulmonary crackles are present, with or without more breathing effort.
• Jugular venous distention
• Peripheral edema
• Hepatomegaly

Beta Blockers: Unique Toxicity Profiles

• Propranolol is severely lethal in overdose due to high lipid solubility, membrane-stabilizing activity, and a lack of intrinsic sympathomimetic activity.
• It crosses the blood-brain barrier, leading to centrally mediated respiratory depression and central nervous system symptoms.
• Sotalol is particularly lethal in excess owing to the effect of obstructing potassium channels and delaying repolarization, furthering malignant ventricular arrhythmia.

Other Risk Factors

• Coingestion of other cardioactive medicines (e.g., digoxin, calcium channel blockers, tricyclic antidepressants) increases the risk of cardiovascular instability.

Management of Beta-Blocker Intoxication

• Prevention of absorption involves gastrointestinal decontamination.
• Activated Charcoal is administered as single dose orally either for kids (25-50g) every 4-6 hrs or Adults (50g)
• Whole Bowel Irrigation employs polyethylene glycol solution orally or via nasogastric tube which needs to be clear. Children get doses of 25mL/kg/hr until a max of (500mL/hr). Adults/adolescents get between (1.5-2L/hr) or nasogastric until elimination of 15L is achieved.
• Provide supportive care for bradycardia and hypotension, and preventing terminal organ damage/ death.
• Pharmacotherapy addresses absorption effects

Pharmacotherapy for Treating Absorption Effects

• Atropine acts for short duration where injectable solution is needed ( minimum dose is 0.1mg). Max is 0.5mg dose. Adults have small IV solution over 3-5 minutes every 3mg

Glucagon

• Glucagon administration with prior antiemetics (ondansetron) can diminish ill effects
• The effects onset at nine minutes and last for around 15 minutes
• Doses can build up fast for response desired of injectable solution
• Infants/kids dosage: 0.03–0.15 mg/kg intravenously to a max of 10mg to repeat every 3-5 mins.
• Adolescents dosage: Initial dose consists of 5-10mg through IV; should be replicated every 3–5 mins
• Adults dosage: Administer via IV for 3-10mg, along infusion rate of 1–10 mg/hour afterward

Calcium

• Administer calcium chloride preferably through a central vein or large vein with secure infusion due to reduce extravasation risk.
• Calcium gluconate is administered through IV safely

Gluconate

• Pediatric dosage: 60mg/kg dose and max of 3g dose via IV
• Adult dosage: 3g in IV ( 30 mL of solution) and may repeat every 10-20 mins for a total of 3 doses.
• Catecholamines include norepinephrine, epinephrine, and dobutamine such as epinephrine for adults with 0.01-2mcg/kg via infusion

Bicarbonate

• Indicated for wide QRS from Sodium channels
• Solution injectable has children:1mEq/kg via IV slowly or Adults 2mEq/kg via IV slowly

Magnesium Sulfate

• Indicated to treat torsades de pointes from potassium channel cause by Sotalol, to consider for prophylactic QT prolongation
• Pediatric dosage: Between 25-50mg/kg to max of 2g dose via IV
• Adult dosage is 1-2g mg via IV

Calcium Channel Antagonists

• Calcium Channel Blockers (CCB) have variety therapeutic uses and a chance for serious toxicity particularly with verapamil, nifedipine and diltiazem

Pathophysiology

• Calcium channel blocker blocks type L calcium channel to suppress calcium with heart muscle and myocardium
• Verapamil works to resist Inotrope and chronotrope, also has effects on systemic vascular resistance where the dihydropyridinenes reduces systemic vascular resistance
• Verapamil and dilitiazem has potential to decrease rate of heart conduction
• BCC, blocking calcium produces hyperglycemia.
• BCC overdoses are followed by bradycardia, hypotension, with either high or low heart rate. Rhythm abnormalities are there including AV block or junction rhythms during QT delay.
• Normal BCC characteristic includes, Patient with well awareness during severe hypotension

Treatments

• Initial phase, gastrointestinal purification to begin along with corresponding activated charcoal.
• Smooth muscle can cause motility to decrease because of contamination during gastrointestinal needs for exams.
• Patients administered gluconate or calcium chloride during blockage
• Hypotension treated, but needs to consider the chance for potential edema
• Hypotension, requires intravenous Calcium every 5 mins as needed

High doses of insulin

• High doses of insulin treats BCC, along with Isoproterenol and glucagon
• Euglycemia is the primary way of restoring metabolic efficiency for carbohydrates and energy in the area that needs for extra blood to be circulating
• Blood glucose/potassium needs checked with extra dextrose for euglycemia needed.
• Hypopotasemia tolerated to reflect potassium intracellular from body
• Additional measures involved include fluids by IV and vasopressors (high doses), and heart Stimulation needs be saved for any vital need.
• Lipids save the ones with verapamil and diltiazem and extra care needs to be taken from hospital intake.

Digitalis Intoxication - Cardioactive Steroids

• Cardiac glycosides, also commonly referred to as cardioactive steroids, exist as phytochemicals typically in nature that connect to potassium (Na+/K+) in the cellular membrane
• Most cardiac use commonly contains digoxin/digitoxin
• The intoxication stems when derivatives are excessive
• Poisoning originates via a non chronic/acute usage.

Acute Toxicity

• Rapid symptoms are seen in minutes/hours