Sympathomimetics (Adrenergic Agonists)

Sympathomimetics (Adrenergic Agonists)

I. Introduction & Review of Autonomic Nervous System (ANS)

• Previous topics: Arachidonic acid pathway, asthma/COPD meds, Heparin/Warfarin, anti-platelets, thrombolytics, anti-seizure meds.

• Today's topic: Sympathomimetics (drugs that mimic the sympathetic nervous system).

• Sympathetic fibers secrete noradrenaline (norepinephrine).

• Sympathomimetics are agonists on adrenergic receptors.

• Parasympathetic NS: Nicotinic & Muscarinic receptors.

• Sympathetic NS: Alpha (α) & Beta (β) receptors.

• Next topic: Sympatholytics (adrenergic antagonists).

II. Autonomic Nervous System (ANS) Review

• ANS Divisions:

  • Parasympathetic: Rest & Digest

  • Sympathetic: Fight or Flight

  • Enteric

• Anatomy (Spinal Cord):

  • Anterior (Ventral) Horn: Motor (efferent).

  • Posterior (Dorsal) Horn: Sensory (afferent).

  • Lateral Horn: Origin of autonomic motor fibers.

• Sympathetic NS (Thoracolumbar):

  • Post-ganglionic fibers secrete noradrenaline → Adrenergic fibers.

  • Act on α and β receptors.

• Parasympathetic NS (Craniosacral):

  • Post-ganglionic fibers secrete Acetylcholine (ACh) → Cholinergic fibers.

  • Act on nicotinic and muscarinic receptors.

III. Sympathetic "Fight or Flight" Effects

• Eyes: Pupil dilation (mydriasis), eyelid elevation.

• Skin: Vasoconstriction, sweating.

• Lungs: Bronchodilation (β₂).

• Heart: ↑ Heart rate (HR), ↑ stroke volume (SV), ↑ contractility (β₁).

• Metabolism:

  • Catabolic state (vs. insulin's anabolic state).

  • Glycogen → Glucose (Glycogenolysis).

  • Triglycerides → Free Fatty Acids (Lipolysis).

  • ↓ Insulin secretion, ↑ Glucagon secretion.

• Vasculature:

  • Vasoconstriction (α₁) in skin & GI tract.

  • Vasodilation (β₂) in brain, heart, skeletal muscle.

• Bladder:

  • Bladder wall relaxation (β).

  • Sphincter contraction (α).

IV. Hemodynamics & Receptors

• Cardiac Output (CO) = Heart Rate (HR) x Stroke Volume (SV)

• Blood Pressure (BP) = Cardiac Output (CO) x Total Peripheral Resistance (TPR)

• β₁ Agonism: ↑ HR & ↑ SV → ↑ CO → ↑ BP.

• α₁ Agonism: Vasoconstriction → ↑ TPR → ↑ BP.

• β₂ Agonism: Vasodilation → ↓ TPR → ↓ BP.

V. Neurotransmitter Synthesis & Breakdown

• Synthesis Pathway: Phenylalanine → Tyrosine → DOPA → Dopamine → Norepinephrine (NE) → Epinephrine (Epi).

• Key Enzymes:

  • COMT (Catechol-O-Methyltransferase): Degrades catecholamines in synapse.

  • MAO (Monoamine Oxidase): Degrades catecholamines in presynaptic terminal.

• Reuptake: Norepinephrine transporter (NET) brings NE back into the presynaptic neuron.

VI. Adrenergic Receptor Types & Functions

• α₁ Receptors (Gq-coupled):

  • Effects: Vasoconstriction, pupil dilation, sphincter contraction, ↓ renin release.

  • Agonist: Phenylephrine.

  • Antagonist: Phentolamine.

• α₂ Receptors (Gi-coupled):

  • Effect: Presynaptic; inhibits further NE release (anti-sympathetic).

  • Effect: ↓ Insulin secretion.

  • Agonist: Clonidine.

• β₁ Receptors (Gs-coupled):

  • Effect: ↑ Heart rate, contractility, conduction velocity (↑ CO), ↑ renin release.

  • Location: Heart.

• β₂ Receptors (Gs-coupled):

  • Effects: Bronchodilation, uterine relaxation (tocolytic), vasodilation, ↑ K+ uptake into cells (can cause hypokalemia), glycogenolysis.

  • Location: Lungs, uterus, vasculature.

• β₃ Receptors:

  • Effect: Lipolysis (fat breakdown).

• D₁ Receptors (Gs-coupled):

  • Effect: Vasodilation (renal, mesenteric, coronary).

  • Agonist: Fenoldopam.

VII. Baroreceptor Reflex

• Hypotension → Baroreceptors sense drop → ↑ Sympathetic output → Reflex Tachycardia.

• Hypertension → Baroreceptors sense rise → ↑ Parasympathetic (Vagus) output → Reflex Bradycardia.

VIII. Classification of Sympathomimetics
A. Endogenous Catecholamines:

• Epinephrine (α1, α2, β1, β2)

• Norepinephrine (α1, α2, β1)

• Dopamine (D1, β1, α1 - dose-dependent)

B. Synthetic Catecholamines:

• Isoproterenol (β1, β2)

• Dobutamine (β1)

C. Synthetic Non-Catecholamines:

• Direct-Acting:

  • α1 Agonists: Phenylephrine, Methoxamine, Midodrine

  • α2 Agonists: Clonidine, α-Methyldopa

  • β2 Agonists: Albuterol (Salbutamol), Terbutaline, Salmeterol, Formoterol

• Indirect-Acting (Releasers/Reuptake Inhibitors):

  • Increase synaptic NE: Amphetamine, Tyramine, Ephedrine

  • Reuptake Inhibitors: Cocaine, TCAs

• Mixed-Action:

  • Ephedrine (direct & indirect)

IX. Key Drugs & Their Uses

• Norepinephrine (α1 > β1):

  • Use: Hypotension (septic shock, post-CABG), distributive shock.

  • Effects: Potent vasoconstriction → ↑ BP. No β2 effect.

  • Caution: Extravasation causes tissue necrosis (use central line); can cause renal ischemia.

• Epinephrine (α1, α2, β1, β2):

  • Uses:

    • Anaphylactic shock (for BP support + bronchodilation).

    • Cardiac arrest.

    • Adjunct to local anesthetics (vasoconstriction keeps drug local).

    • Asthma (status asthmaticus).

  • Effects: Dose-dependent. Low dose = β effects dominate; High dose = α effects dominate.

  • Metabolic: ↑ Glycogenolysis, ↑ Lipolysis, ↓ Insulin → Hyperglycemia.

  • No tachyphylaxis.

• Dopamine (Dose-Dependent):

  • Low dose: D1 agonism → renal vasodilation.

  • Medium dose: β1 agonism ↑ cardiac output.

  • High dose: α1 agonism → vasoconstriction.

• Phenylephrine (α1 Agonist):

  • Use: Hypotension (esp. during anesthesia), nasal decongestant, pupil dilation.

  • Effect: Vasoconstriction → ↑ BP → can cause reflex bradycardia.

• β2 Agonists (Albuterol, Terbutaline, Salmeterol):

  • Use: Asthma/COPD (bronchodilation), tocolytic (relax uterus).

• Dobutamine (β1 Agonist):

  • Use: Acute heart failure (increases contractility).

• Isoproterenol (β1, β2 Agonist):

  • Use: Bradycardia, heart block.

• Ephedrine:

  • Mixed-action (direct/indirect). Longer duration. Oral administration possible.

  • Uses: Bronchodilation, decongestant, hypotension.

  • Shows tachyphylaxis.

X. Electrolyte Effect

• β₂-Agonists: Stimulate Na+/K+ ATPase → K+ moves into cells → Hypokalemia.

• β-Blockers: Opposite effect → Hyperkalemia.

XI. Related Mechanisms: Phosphodiesterase (PDE) Inhibitors

• Mechanism: Inhibit PDE → ↑ cAMP (and/or cGMP) → enhanced effects of β-receptor stimulation.

• Effects: ↑ Cardiac contractility (inotropy), vasodilation, bronchodilation.

• Examples:

  • Milrinone, Inamrinone (PDE3 inhibitors): Used in acute heart failure.

  • Theophylline (non-selective PDE inhibitor): Bronchodilator.

  • Sildenafil (PDE5 inhibitor): ↑ cGMP → vasodilation.

• Warning: Never combine a nitrate (↑ cGMP) with a PDE5 inhibitor (sildenafil) → severe hypotension.