Beta Blockers in Cardiology

Overview

• Beta-blockers have been used since the 1960s.
• Used for hypertension, heart failure, arrhythmias, angina, and heart stroke.
• Also used for non-cardiovascular pathologies (details provided later).

Beta-Adrenergic Receptors Physiology

• Target of beta-blockers.
• Composed of 7 transmembrane patterns, linked to a G protein.
• Stimulates adenylate cyclase, transforming ATP to cAMP.
• Agonists/activators: adrenaline, noradrenaline, dopamine, dobutamine, salbutamol.
• cAMP, a second messenger, activates Protein Kinase A (PKA), phosphorylating various proteins.

Types of Beta-Adrenergic Receptors

• Beta 1: Located in heart and kidney's juxtaglomerular apparatus.
• Beta 2: Located in blood vessels and lungs.
• Beta 3: Located in adipocytes, increasing lipolysis upon stimulation.

Beta 1 Receptor Stimulation Effects

• Positive inotropic effect: increases contraction strength.
• Positive chronotropic effect: increases heart rate.
• Positive dromotropic effect: increases atrioventricular conduction speed.
• Positive bathmotropic effect: increases ventricular excitability.
• Increases renin secretion from kidney's juxtaglomerular apparatus.

Beta 2 Receptor Activation Effects

• Cardiac stimulation (not predominant).
• Relaxation of smooth muscle fibers in various organs.
  • Vasodilation, intestinal relaxation, bronchodilation (used in asthma).
  • Uterine relaxation (used in premature deliveries).

Beta Blockers Mechanism of Action

• Block beta receptors, countering the effects of adrenaline/noradrenaline.
• Catecholamine competitive antagonists.
• Only the levorotatory isomer has beta-blocker activity.
• Beta-blockers can also block alpha receptors (e.g., labetolol).
• Two groups: cardioselective and non-cardioselective, with/without intrinsic sympathomimetic activity (ASI).

Cardioselective Beta-Blockers

• Selective for Beta 1 receptors: fewer side effects from Beta 2 receptor blockade.
• Reduce cardiac work, oxygen consumption: negative inotropic, chronotropic, dromotropic, bathmotropic effects.
• Decrease cardiac output, blood pressure, peripheral resistance.
• Inhibit renin-angiotensin-aldosterone system: prevents water/solute retention and hypotension.

Non-Cardioselective Beta-Blockers

• Block Beta 1 and 2 receptors: more side effects from Beta 2 blockade.
• Side effects: hypoglycemia, masking hypoglycemia signs, vasoconstriction, Raynaud's syndrome, bronchoconstriction, decreased intraocular pressure (used in glaucoma).
• Forbidden for patients with asthma or COPD).

Intrinsic Sympathomimetic Activity (ASI)

• Partial agonist activity limiting bradycardic effects and Raynaud's syndrome aggravation.

Pharmacokinetics

Lipophilic Beta-Blockers

• Good digestive absorption; strong tissue distribution; pass blood-brain and fetal-placental barriers.
• Short half-life; taken 2-3 times/day.
• High hepatic first-pass effect; strong interindividual variability.
• Urinary elimination as inactive metabolite; dosage adjustment needed for kidney failure.
• Examples: propranolol, metoprolol.

Hydrophilic Beta-Blockers

• Poor digestive absorption; limited tissue distribution.
• Longer half-life; taken once/day.
• Little metabolism; less interindividual variability.
• Unchanged renal elimination.
• Examples: sotalol, labetolol.

Side Effects of Lipophilic Beta-Blockers

• Nightmares, insomnia, hallucinations, fatigue.
• To avoid: take in the morning or switch to hydrophilic beta-blockers.

Clinical Uses

• Hypertension: anti-hypertensive effects.
• Heart failure, angina, arrhythmia (second-class except sotalol is third-class).
• Migraine: propranolol as background treatment.
• Glaucoma: timolol reduces intraocular pressure.
• Essential tremors, hyperthyroid.
• Asthma: use Beta 2 mimetics (opposite of beta-blockers).

Mnemonics

• Cardioselective Beta-Blockers: "New Exclusive Beta Blockers Act in Majority As Cardioselective"
  • Each capital letter stands for a beta-blocker.
• With ASI Activity: "Contains Partial Agonist Like Properties"
  • Each capital letter stands for a beta-blocker.