Adrenergic Agonists & Neurotransmission

• Adrenergic agonists mimic norepinephrine and epinephrine, which occur naturally
• Norepinephrine is also known as noradrenaline
• Epinephrine is also known as adrenaline
• Sympathomimetics activate adrenergic receptors
• Sympatholytics block adrenergic receptors

Process of Neurotransmission in Adrenergic Neurons

• Tyrosine is transported into the neuron via sodium-dependent transport
• Tyrosine is converted by tyrosine hydroxylase into L-3,4-dihydroxyphenylalanine (L-dopa or levodopa)
• L-dopa is converted into dopamine by aromatic amino acid decarboxylase
• Dopamine is transported into a synaptic vesicle, where dopamine beta-hydroxylase converts it to norepinephrine
• Action potential triggers the opening of calcium channels, allowing calcium to flow into the neuron
• Increase in calcium causes synaptic vesicles to fuse with the membrane and release norepinephrine into the synapse
• Norepinephrine binds to postsynaptic receptors on the target organ, triggering a cellular response
• Norepinephrine also binds to presynaptic receptors, reducing further norepinephrine release via negative feedback
• Norepinephrine is removed from the synaptic space through diffusion into systemic circulation, enzymatic inactivation by catechol-o-methyltransferase (COMT), and reuptake into the neuron by the norepinephrine transporter (NET)
• Once inside the neuron, norepinephrine can be transported back into synaptic vesicles for future use, or broken down into inactive metabolites by monoamine oxidase (MAO)

Adrenergic Receptors

• These receptors can be activated by norepinephrine, adrenaline, and adrenergic drugs
• Preganglionic sympathetic neurons release acetylcholine, which binds to nicotinic receptors on postganglionic adrenergic neurons or the adrenal medulla

Release Dynamics

• Adrenergic neurons release norepinephrine, while the adrenal gland releases approximately 20% norepinephrine and 80% epinephrine
• Norepinephrine and epinephrine bind to alpha and beta receptors on target organs

Alpha Receptors

• Alpha receptors are divided into alpha-1 and alpha-2 subtypes

Alpha-1 Receptors

• Alpha-1 receptors are Gq protein-coupled receptors
• Activation generally causes an excitatory response mediated by an increase in intracellular calcium
• Alpha-1 receptors are primarily located on vascular smooth muscle throughout the body, causing vasoconstriction
• They are also found on the iris dilator muscle, leading to mydriasis (pupil dilation) when activated
• Alpha-1 receptors on the urinary sphincter cause contraction and urinary retention
• In the liver, alpha-1 receptor activation leads to glycogenolysis (breakdown of glycogen into glucose)
• Alpha-1 receptors in the kidney inhibit renin release, which is involved in blood pressure regulation
• Activation of alpha-1 receptors leads to a sympathetic response, useful in fight-or-flight situations to constrict blood vessels, retain urine, and provide extra glucose

Alpha-2 Receptors

• Alpha-2 receptors are Gi protein-coupled receptors
• Located primarily on presynaptic nerve endings, activation decreases cAMP production
• Inhibition of further norepinephrine release
• Alpha-2 receptors on pancreatic islet cells reduce insulin secretion upon activation

Beta Receptors

• Beta receptors are divided into beta-1, beta-2, and beta-3 subtypes
• Unlike alpha receptors, beta receptors are coupled with Gs proteins

Beta-1 Receptors

• Beta-1 receptors are mainly located on the heart, activation lead to increased heart rate, increased contractility, and increased AV node conduction
• Beta-1 receptors on juxtaglomerular cells in the kidney, cause increased renin release, leading to increased blood pressure

Beta-2 Receptors

• Beta-2 receptors are mainly located in the lungs on bronchial smooth muscles, increased activation leads to bronchodilation
• Located on vascular smooth muscle of skeletal muscle arterioles, activation leads to vasodilation
• Beta-2 receptors on smooth muscle in the gastrointestinal tract and uterus, activation leads to smooth muscle relaxation
• Beta-2 receptors in the pancreas increase insulin secretion when activated

Beta-3 Receptors

• Beta-3 receptors primarily located in adipose tissue, increased activation leads to lipolysis (breakdown of stored fat)
• Beta-3 receptors in the bladder cause bladder relaxation and prevent urination

Adrenergic Agonists

• Adrenergic agonists are divided into two main chemical classes: catecholamines and noncatecholamines

Catecholamines

• Catecholamines are organic compounds with a catechol ring (benzene ring with two hydroxyl groups), an ethyl side chain, and a terminal amine group

Noncatecholamines

• Noncatecholamines have a similar backbone structure but lack the two hydroxyl groups on the benzene ring

Differences Due to Structural Variations

• Oral Use: Catecholamines are ineffective due to rapid metabolism by COMT and MAO in the digestive system, liver, and even within neurons
• Duration of Action: Noncatecholamines lack catechol hydroxyl groups and are poor substrates for COMT; they are metabolized slowly by MAO, allowing for a longer duration of action
• CNS Penetration: Hydroxyl groups make catecholamines polar, resulting in poor CNS penetration, noncatecholamines are less polar and penetrate the CNS more easily

Types of Adrenergic Agonists

• Direct-Acting Agonists: These agents produce effects by binding to alpha or beta receptors and mimicking the actions of naturally occurring epinephrine, norepinephrine, and dopamine
• Indirect-Acting Agonists: These drugs do not directly interact with postsynaptic receptors; they enhance the effects of epinephrine or norepinephrine by inhibiting their reuptake or degradation
• Mixed-Acting Agonists: These agents both directly bind to receptors and enhance the release of norepinephrine from presynaptic terminals

Examples of Direct-Acting Agonists

• Epinephrine - Epinephrine can activate almost all adrenergic receptors, treatment for anaphylaxis
• Activation of alpha-1 receptors by epinephrine causes vasoconstriction, which reduces mucosal edema, relieves airway obstruction, and increases blood pressure, alleviating shock
• Activation of beta-1 receptors increases cardiac output, which is why epinephrine is also used to restore cardiac function in patients with cardiac arrest due to asystole
• Activation of beta-2 receptors in the lungs leads to bronchodilation, which is why epinephrine is sometimes used as an emergency treatment for respiratory conditions
• Norepinephrine - Norepinephrine primarily stimulates alpha-1 receptors, leading to profound vasoconstriction and increased blood pressure
• Lacks beta-2 activity, it has more limited clinical use compared to epinephrine, useful in cardiac arrest and hypotensive shock
• Dopamine: Dopamine is unique as it stimulates alpha, beta, and dopamine receptors in a dose-dependent manner
• At low doses, dopamine acts on dopamine receptors only, as the dosage increases dopamine activates cardiac beta-1 receptors, at high doses that include alpha-1 receptors
• Activates cardiac beta-1, alpha-1, and dopamine receptors on vascular smooth muscle, is useful in treating severe acute heart failure and hypotensive shock

Selective Agonists

• Alpha-1 Selective Drugs: Oxymetazoline and Phenylephrine are found in products used to treat nasal congestion

• Oxymetazoline - Also be found in eye drops to treat eye redness

• Phenylephrine - Ability to raise systolic and diastolic blood pressure, sometimes used in hospital patients to treat hypotension

• Alpha-2 Selective Drugs: Clonidine the most common medication, stimulation of alpha-2 receptors leads to a decrease in sympathetic tone

• Clonidine - Commonly used to treat hypertension, also has other indications such as ADHD, withdrawal symptoms from alcohol and opioids

• Beta-1 Selective Agonists: Dobutamine - Increases heart rate and cardiac output, used to treat acute heart failure

• Beta-2 Selective Agonists: Albuterol and Terbutaline, used to relieve acute asthma symptoms and Salmeterol and Formoterol used to prevent asthma attacks

• Beta-3 Selective Agonist: Mirabegron - Mimics beta-3 receptors on the bladder detrusor muscle, for overactive bladder

Indirect Acting Adrenergic Agonists

• Cocaine and Amphetamine - Act by blocking the reuptake of norepinephrine and also dopamine, particularly in the brain region that controls the reward system

Mixed-acting Adrenergic Agonists

• Both Directly and Indirectly Acting
• Ephedrine and Pseudoephedrine - Cause activation of adrenergic receptors by both directly binding and releasing stored norepinephrine from presynaptic terminals, long duration of action because they are not catecholamines
• Pseudoephedrine - Also causes vasoconstriction and bronchial smooth muscle relaxation
• Pseudoephedrine - Activates receptors in nasal passages, used as a decongestant