Adrenergic Drugs: Clinical Pharmacology

• Adrenergic drugs are discussed as part of clinical pharmacology, focusing on sympathomimetics.
• The learning outcomes include understanding the sympathetic nervous system and the classification of sympathomimetic drugs.
• Pharmaco-kinetics, dynamics, and uses of epinephrine (adrenaline) and norepinephrine (noradrenaline) are also learning outcomes.
• The autonomic nervous system controls involuntary body activities.
• The sympathetic nervous system is associated with stress and the "fight or flight" response.
• The parasympathetic nervous system is associated with peace, rest, and digest functions.
• Sympathetic neurotransmitters include epinephrine and norepinephrine, which are catecholamines.
• Parasympathetic neurotransmitters include Acetylcholine.
• The sympathetic nervous system involves postganglionic release of norepinephrine (NE).
• It results in effects like mydriasis, decreased salivation, bronchodilation (mainly by epinephrine), and tachycardia.
• It also decreases digestion and urination.
• Catecholamines' action is terminated through re-uptake (80%) and metabolism (20%).
• Biosynthesis, storage, and release are initial processes, followed by action on receptors.

Adrenergic Receptors

• Adrenergic receptors include alpha (α) and beta (β) types, with subtypes like α1, α2, β1, β2, and β3.
• Αlpha 1: Gq coupled receptors that increase calcium release and cause smooth muscle contraction
• Alpha 2: Gi coupled receptors that decrease cyclic AMP(cAMP) levels and are inhibitory
• Beta 1: Gs coupled receptors that increase cAMP
• Beta 2: Gs coupled receptors that increase cAMP and smooth muscle relaxation
• Beta 3:Gs coupled receptors that increase cAMP
• Stimulation of α1 receptors leads to increased calcium and smooth muscle contraction.
• Stimulation of α2 receptors decreases cAMP and inhibits further norepinephrine release.
• Stimulation of β1 receptors increases cAMP in JG cells, leading to renin release.
• Stimulation of β2 receptors increases cAMP, causing smooth muscle relaxation and promoting bronchodilation.
• Stimulation of β3 receptors increases it which results in the regulation of lipolysis and thermogenesis and is expressed in the urinary bladder muscles that allow for bladder relaxation and filling
• Sympathomimetics mimic sympathetic stimulation, while sympatholytics have opposite effects.
• Sympathomimetics can be direct, mixed, or indirect in their action.
• Direct-acting drugs bind directly to receptors
• Nonselective direct acting drugs include: adrenaline (all a & β), noradrenaline (α & β1), dopamine (D1, β1, α1), xylometazoline (a1, a2) and Isoprenaline: all β
• Selective direct acting drugs include: Dobutamine (ẞ1), Salbutamol (ẞ2), Mirabegron (ẞ3), Phenylephrine( a1), Clonidine( a2) and Fenoldopam (D1)
• Ephedrine is a mixed acting drug and it results in the release of noradrenaline and acts on all a & β receptors
• Indirect acting drugs are releasing agents (Amphetamine & its derivatives), uptake inhibitors (Cocaine), MAO Inhibitors (Selegiline) and COMT Inhibitors (Entacapone)

Epinephrine (Adrenaline)

• Epinephrine is a catecholamine and unstable in alkaline solutions; oxidizes when exposed to air or light.
• It is given parenterally due to poor oral absorption.
• It has a rapid onset and short duration of action.
• It does not cross the blood-brain barrier.
• It is inactivated in the liver by MAO & COMT
• It is excreted renally.
• Administration can be subcutaneous, intramuscular, or via inhalation through a nebulizer.
• Intravenous administration can be dangerous and can precipitate ventricular fibrillation.
• Therapeutic uses include acute anaphylactic shock, cardiac arrest (in I.C.U during cardiopulmonary resuscitation), and post-intubation infectious are all therapeutic uses
• Pharmacodynamics involves activation of all α and β adrenergic receptors.
• Cardiovascular effects include increased heart rate and contractility, and increased cardiac output.
• It causes relaxation of bronchial smooth muscle and decreases bronchial secretion.
• It also causes mydriasis.
• It creates a metabolic effect as a result of stimulation of hepatic glycogenolysis (β2).

Side effects and contraindications of epinephrine:

• Side effects include cerebral hemorrhage, anginal pain, cardiac arrhythmia, and acute pulmonary edema.
• Contraindications include hypertension, ischemic heart disease, cardiac arrhythmia, cardiac outflow obstruction, and thyrotoxicosis.

Norepinephrine (Noradrenaline)

• It activates all α (mainly) and β1 receptors, with little activity on β2 receptors.
• Increases systolic and diastolic blood pressure.
• Used as a vasoconstrictor in acute hypotensive states (septic shock).
• Given by slow intravenous infusion.

Practice questions:

• Norepinephrine is therapeutically used for acute hypotensive states.
• Dobutamine activates the β1 receptor.
• Adrenaline is therapeutically used for acute anaphylactic shock.