Adrenergic Receptors and Agonists

• The notes cover sympathetic pharmacology

Norepinephrine and Epinephrine Synthesis and Release

• Tyrosine converts to DOPA then to Dopamine, which enters the presynaptic vesicle.
• Norepinephrine waits for an action potential for release.
• Some norepinephrine converts to epinephrine, but it is not the primary source.
• Epinephrine's main origin is the adrenal medulla (80% adrenaline, 20% norepinephrine).
• Dopamine, norepinephrine & epinephrine are catecholamines possessing a catechol group connected to an amine group.
• The catechol group presence makes the molecule water-soluble, lipid-insoluble, unable to cross the blood-brain barrier and short acting as it gets destroyed by MAO, COMT.

Adrenergic Receptors (Sympathetic Receptors)

• α1 receptors activate Gq proteins, increasing inositol triphosphate (IP3) and diacylglycerol (DAG), leading to increased intracellular calcium and contraction.
• α2 receptors inhibit Gi proteins, decreasing cAMP levels, which decreases the release of certain hormones or neurotransmitters.
• β1 receptors (cardiogenic) activation increases the contraction in cardiac muscle.
• β2 receptors activation causes smooth muscle relaxation.
• Stimulation of α1 receptors leads to contraction.
• Stimulation of β receptors increases cAMP, which induces relaxation in smooth muscles.
• α1 receptors are found in blood vessels, sphincters of the body and dilator pupillae muscles of eye
• α2 receptors are located in presynaptic nerve terminals causing decreased norepinephrine release.
• β1 receptors are found in the heart and kidneys.
• Receptor distribution includes presynaptic nerve endings that increase noradrenaline release, increased central sympathetic outflow, VD of skeletal muscle BV and coronary artery.
• β receptor distribution also facilitates neurotransmission, elevation in plasma K+, and increased liver glycogenolysis. it also causes bronchodilation, relaxation of GIT & urinary bladder walls and relaxation of the uterus.
• α1 receptor stimulation causes smooth muscle contraction.
• β1 receptor stimulation increases contractility and cardiac output
• ↑ Stimulation of α2 receptors decreases norepinephrine release.
• β2 receptor stimulation causes relaxation in the wall of the bladder and lipolysis in adipose tissue.
• Β2 adrenoceptors are more sensitive and stimulated by low concentration of adrenaline

Fate of Norepinephrine

• 80% undergoes reuptake into presynaptic vesicles for recycling.
• 20% is destroyed by monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) enzymes.
• All adrenergic receptors are G-protein coupled receptors.

Adrenergic Agonists (Sympathomimetics)

• Drugs that produce similar pharmacological actions to sympathetic stimulation are adrenergic agonists (sympathomimetics).
• Direct acting agonists directly affect receptors.
• Indirect acting agonists enhance release or inhibit reuptake of norepinephrine.
• Mixed agonists act both directly and indirectly.
• Catecholamine drugs are adrenaline, noradrenaline, dopamine, and dobutamine.
• The rest of sympathomimetics are non-catecholamines

Adrenaline (Epinephrine)

• Adrenaline is a natural alkaloid synthesized by the adrenal medulla.
• It is ineffective orally.
• Absorption involves injection (SC & IM) and topical inhalation
• It cannot cross the BBB due to being highly polar.
• Rapidly destroyed by MAO & COMT leading to very short action.
• Adrenaline directly stimulates α1, α2, β1,2,3 adrenoceptors (β more sensitive). Intracellular pathways: increases IP3 and DAG via Gq for al, increasing cAMP via Gs for B, decreasing cAMP via Gi for a2.

Adrenaline Pharmacological Effects

• For the heart, β1 stimulation increases all properties, including rate and force of contraction, as well as cardiac output and conduction.
• For blood vessels, α1 stimulation causes vasoconstriction in skin and MM, while β2 stimulation causes vasodilation of skeletal muscle vessels.
• At therapeutic doses, increases blood pressure.
• Β2 stimulation causes Bronchodilation.
• Bronchial decongestion due to VC of bronchial BV through a1 receptors.
• β2 triggers GIT Wall relaxation, a1 causes Sphincters contraction.
• Mydriasis (α1), reducing intraocular pressure (IOP).
• Β2 causes Uterus relaxation.
• α1 causes Sweat glands stimulation, leading to sympathetic sweating (forehead and palms). Liver stimulation through β2 raises glycogenolysis.
• β3 triggers Fat cells to ↑ lipolysis.
• β1 Causes ↑ renin secretion.
• Skeletal muscle stimulation through β2 involves facilitation of neuromuscular transmission and vasodilation of skeletal blood vessels.

Adrenaline Therapeutic Uses

• For anaphylactic shock, acute bronchial asthma, and cardiac arrest the best use is systemic application.
• When used with local anesthetics, it prolongs the duration of action.
• It is used as a local hemostatic to stop nasal bleeding.

Adrenaline Side Effects

– ↑↑↑ blood pressure → cerebral hemorrhage. – Anxiety, restlessness, headache, tremor. – Palpitations, Cardiac arrhythmias (if given IV). – Injection with local anesthesia in end arterial supply (fingers, toes, pinna, nose) may cause tissue damage.

Norepinephrine (Noradrenaline)

• Administered through IV infusion slowly.
• Not given SC or IM due to its strong VC effect, so only useful for producing necrosis and sloughing
• Pharmacodynamics: Non-selective sympathomimetic predominantly α1 (alpha 1, alpha 2, beta 1).
• Causes reflex bradycardia.
• Used as hypertensive agent in acute hypotensive states.

Dopamine

• Given by IV infusion due to its very short half-life.
• D1 > β1 > α1 is its effect
• Indication: Shock state with impaired tissue perfusion.

Dobutamine

• Dobutamine is a synthetic catecholamine, related to dopamine.
• Kinetically administered through I.V. infusion because of its short duration (2 min).
• Dobutamine activates mainly cardiac β1-receptor.
• Heart (β1) stimulation : ↑↑ force of contraction→↑COP (inotropic); ↑ impulse conduction → ↑ HR → ↑ COP (cardiac output).
• For short term use in patients with decreased contractility due to acute decompensated heart failure or cardiogenic shock or cardiac procedure resulting in cardiac decompensation
• Adverse effects: Tachycardia & Tachyarrhythmia, Hypertension and Angina in predisposed patients.

Selective α-Agonists

• Phenylephrine, Oxymetazoline.
• Clonidine.
• Dobutamine.
• Formoterol, Salbutamol, Ritodrine.
• Mirabegron.
• Epinephrine (a1, a2, β1, β2).
• Norepinephrine (a1, a2, β1).
• Dopamine (D1, β1, α1).
• Amphetamine, Cocaine.
• Ephedrine, Pseudoephedrine.
• Phenylephrine are direct acting selective α1 agonists that induces blood vessels vasoconstriction (VC) as an effect, are used locally as decongestant and systemically to increase BP. The side effects are Elevation of BP, Atrophic rhinitis and Rebound nasal congestion
• Clonidine are Centrally-acting pre-synaptic α2 agonists that induces ↓NE release from presynaptic neuron & ↓ BP as an effect, are used as Antihypertensive drug, Treatment of opioid withdrawal symptoms and Treatment of ADHD. The side effects are Dry mouth, Sedation and Hypotension

Selective B2 Agonists

• Examples salbutamol, formoterol, ritodrine
• Pharmacodynamics: Direct acting selective β2 agonists (Gs ↑ CAMP).
• Effects bronchial smooth muscles → bronchodilation, uterine smooth muscles → uterine relaxation and blood vessels of skeletal MS → vasodilation
• Uses for bronchial asthma (aerosol) (salbutamol, formoterol) and delays premature labor (ritodrine).
• Side effects tachycardia & arrhythmias, tremors, tolerance and hypokalemia because lack of selectivity in high doses.

Selective B3 Agonists

• Mirabegron.
• Selective potent beta-3 agonist → relax detrusor smooth muscle→↑ bladder storage capacity decreasing the feeling of urgency and frequency.
• Used for Treatment of overactive bladder syndrome with and symptoms of urge urinary incontinence.
• Side effects are Hypertension, tachycardia and Urinary tract infection.

Test your knowledge of adrenergic receptors and their agonists. This quiz covers alpha-1, alpha-2, beta-1, and beta-2 receptors, as well as the effects of adrenergic receptor stimulation and the mechanisms of norepinephrine removal. Review the effects of adrenergic drugs.