Sympathomimetics/Adrenergic agonists

1 · Introduction

Sympathomimetic agents—or adrenergic agonists—comprise a pharmacological super-family that mimics or amplifies the actions of endogenous catecholamines (noradrenaline, adrenaline and dopamine) at α₁, α₂, β₁, β₂, β₃ and dopaminergic receptors. Their capacity to modulate cardiovascular tone, airway calibre, intra-ocular pressure, central arousal and metabolic flux renders them indispensable across emergency medicine, anaesthesia, respiratory care, ophthalmology, psychiatry and urology. The same potency, however, carries risk—arrhythmias, hypertensive crises, substance misuse—necessitating nuanced understanding of receptor pharmacodynamics, pharmacokinetics and clinical context.

2 · Adrenergic Receptors: Distribution & Signalling

Knowledge of receptor location is the Rosetta stone for predicting the therapeutic scope and adverse-effect spectrum of each sympathomimetic.

3 · Chemical Taxonomy

Structurally, sympathomimetics diverge along two axes: (i) presence or absence of the catechol nucleus; (ii) substitution at the α- and β-carbon and amine nitrogen.

• Catecholamines (adrenaline, noradrenaline, isoprenaline, dopamine, dobutamine) rapidly degrade via COMT and MAO, are polar (poor oral bioavailability) and have short plasma half-lives (minutes).
• Non-catecholamines (phenylephrine, salbutamol, ephedrine, amphetamine, clonidine, mirabegron) evade COMT, are more lipophilic, orally active and longer-lasting.

Strategic alkyl substitutions confer receptor selectivity: bulky -C(CH₃)₂ groups enhance β-affinity (isoprenaline), while ω-chloro substitutions heighten α₂ selectivity (clonidine).

4 · Mechanistic Classes

1. Direct-acting agonists—bind and activate adrenoceptors (e.g., phenylephrine, salmeterol).
2. Indirect-acting agents—increase synaptic noradrenaline/ dopamine through:
   • Promotion of release (tyramine, amphetamine)
   • Re‐uptake inhibition (cocaine, atomoxetine)
   • MAO/COMT inhibition (selegiline, entacapone)
3. Mixed-acting drugs—both direct binding and NE release (ephedrine, pseudoephedrine).

5 · Pharmacokinetics in Brief

5.1 Catecholamines

Administered IV or via inhaled/nebulised routes (adrenaline for croup). Distribution is extracellular; they do not cross the blood–brain barrier. Hydroxyl groups render them susceptible to COMT (cytosolic) and MAO (mitochondrial) metabolism, yielding vanillylmandelic acid (VMA) excreted renally.

5.2 Non-catecholamines

Resistant to COMT; lipophilicity allows oral, transdermal or inhalational delivery and CNS penetration (basis for psychostimulant effect of amphetamine). Renal elimination may involve active secretion; urinary acidification accelerates clearance of basic amines.

6 · Drug Profiles & Therapeutic Applications

6.1 Catecholamines

1. Adrenaline (Epinephrine)—non-selective α/β agonist.
   • Uses: anaphylaxis (β₂ bronchodilation + α₁ vasoconstriction), cardiac arrest (β₁), added to local anaesthetic (α₁) to prolong action.
   • Adverse: tachyarrhythmias, hyperglycaemia, digital ischaemia if extravasated.
2. Noradrenaline (Norepinephrine)—α₁≈α₂ >> β₁.
   • First-line vasopressor in septic shock—restores MAP without excessive tachycardia.
   • Reflex bradycardia may offset direct β₁ chronotropy.
3. Dopamine—dose-dependent receptor hierarchy: D₁ (1–3 µg/kg/min) → β₁ (3–10 µg/kg/min) → α₁ (>10 µg/kg/min).
   • Former renal-protective myth debunked; now rarely used except in cardiogenic shock with low output and preserved SVR.
4. Dobutamine—β₁ selective with modest β₂; racemic mixture (-) agonist α₁, (+) antagonist α₁.
   • Inotrope of choice in acute decompensated heart failure, stress echocardiography.
5. Isoprenaline (Isoproterenol)—potent β₁/β₂.
   • Historic use in AV block and asthma; supplanted by safer β₂-selectives.

6.2 α₁-Selective Agonists

• Phenylephrine—systemic vasopressor for neurogenic shock; topical decongestant; mydriatic without cycloplegia. Avoid with MAO inhibitors.
• Midodrine (prodrug): chronic orthostatic hypotension. Caution: supine hypertension.
• Oxymetazoline, Xylometazoline: intranasal decongestants—risk of rhinitis medicamentosa (tachyphylaxis, rebound congestion).

6.3 α₂-Selective Agonists (Central Sympatholytics)

• Clonidine: resistant hypertension, opioid/alcohol withdrawal, ADHD adjunct. Abrupt cessation → rebound hypertensive crisis.
• Dexmedetomidine: ICU sedation—“co-operative sedation,” minimal respiratory depression.
• α-Methyldopa: prodrug converted in CNS; safe in pregnancy-induced hypertension.
• Tizanidine: spasticity due to spinal injury or MS.

6.4 β₂-Selective Agonists

Class adverse effects: tremor, tachycardia, hypokalaemia, lactic acidosis (high dose).

6.5 β₃ Agonist

• Mirabegron: overactive bladder; relaxes detrusor, increases capacity. CYP2D6 inhibition—interacts with metoprolol, desipramine. Monitor BP (mild HTN).

6.6 Mixed & Indirect Agents

• Ephedrine/Pseudoephedrine—nasal decongestant, intra-operative hypotension bolus; CNS stimulation, urinary retention in BPH.
• Amphetamine, D-Methamphetamine, MDMA—potent releasers; ADHD, narcolepsy vs. high abuse liability, neurotoxicity.
• Methylphenidate—dopamine-NE reuptake blockade; first-line ADHD in paediatrics.
• Tyramine—dietary amine (aged cheese, wine); hypertensive crisis with non-selective MAO inhibitors.
• Cocaine—DAT/NET inhibitor; ENT anaesthesia (topical vasoconstriction); cardiotoxic, arrhythmogenic.

7 · System-Wise Pharmacology

7.1 Cardiovascular

α₁ agonism raises systemic vascular resistance (SVR); β₁ increases HR and contractility; β₂ dilates skeletal muscle beds; D₁ dilates renal/ splanchnic vessels. Clinical permutations allow tailored haemodynamic goals:

• Septic shock: noradrenaline preferred (α₁ + β₁) to maintain MAP without tachydysrhythmia.
• Anaphylactic hypotension: adrenaline counters vasodilation and supports β₁ output.
• Cardiogenic shock: dobutamine augments CO; add noradrenaline if vasodilatory.
• Orthostatic hypotension: midodrine day-time α₁ boost.

7.2 Respiratory

β₂ agonists remain cornerstone of obstructive airway therapy. LABA monotherapy is contraindicated in asthma (risk of death without steroid). Epinephrine nebulisation useful in upper-airway obstruction (croup) due to α-mediated mucosal vasoconstriction.

7.3 Obstetrics

Terbutaline and ritodrine delay pre-term contractions but increase maternal tachycardia, pulmonary oedema; limited to 48 h to facilitate corticosteroid lung maturation.

7.4 Ophthalmology

α₁ agonists (phenylephrine 2.5 % drops) dilate pupil pre-operatively. α₂ agonist brimonidine reduces aqueous humour production in glaucoma.

7.5 Metabolic & Endocrine

β₂ activation stimulates glycogenolysis, gluconeogenesis; α₂ inhibits insulin secretion. Hence systemic adrenaline spikes may transiently raise glucose and lactate. β₃ agonists in trials for obesity augment thermogenesis via uncoupling protein-1 in brown fat.

7.6 Central Nervous System

Lipophilic non-catecholamines energise cognition (locus coeruleus firing) or euphoria. Atomoxetine and modafinil harness NE overflow with lower addiction risk compared with classical amphetamines.

8 · Adverse Effects & Toxicity

Drug–drug interactions: Non-selective β-blockers blunt salbutamol effect; MAOIs prolong catecholamine action; linezolid (reversible MAO-A blockade) potentiates pressors; halogenated anaesthetics sensitize myocardium to catecholamines → arrhythmia risk.

9 · Contra-indications & Cautions

• Phaeochromocytoma—avoid indirect agonists.
• Severe CAD—β₁ agonists may precipitate infarction.
• Hyperthyroidism—enhanced catecholamine sensitivity.
• Angle-closure glaucoma—α₁ mydriasis obstructs drainage.
• Pregnancy—β₂ inhalers acceptable; stimulants risk foetal growth restriction.

10 · Laboratory & Point-of-Care Pearls

• Urinary VMA & metanephrines measure endogenous catechol excess; not altered substantially by inhaled β₂ agonists.
• High-dose nebulised salbutamol (10–20 mg) for hyperkalaemia may drop serum K⁺ 0.5–1 mmol/L within 30 min—watch for tachycardia.
• Bedside dopamine test: low-dose challenge no longer recommended for renal protection; evidence neutral.

11 · Emerging & Investigational Agents

• Odanacatib-β₃ conjugates: targeted bone anabolism without cardiovascular stimulation.
• Selective α_2B agonists for sickle-cell vaso-occlusive crisis pain modulation.
• D₁/β₃ “renal-selective” agonists (e.g., fenoldopam analogues): postoperative AKI prevention trials.
• Optogenetic sympathetic neuromodulation (pre-clinical): light-activated adrenergic cells circumvent systemic side-effects.

12 · Clinical Vignettes

12.1 Anaphylaxis in the ED

25-year-old with peanut exposure; hypotensive, wheezing. IM adrenaline 0.5 mg (1 mg/mL) into vastus lateralis → improved BP, SpO₂. Adjunct H₁/H₂ blockers, corticosteroid. Second dose after 5 min due to persistent stridor. Key learning: prompt IM route superior to IV push for safety.

12.2 Septic Shock

ICU patient with MAP 50 mmHg after fluid resuscitation. Noradrenaline infusion titrated 0.05–0.4 µg/kg/min; lactate clears, urine output rises. Vasopressin added when noradrenaline >0.3 µg/kg/min to spare catechol dose and preserve mesenteric perfusion.

12.3 Asthma Exacerbation

8-year-old receives salbutamol MDI (4 puffs via spacer) every 20 min × 3, plus ipratropium. Develops 120 bpm tachycardia and tremor—acceptable trade-off vs. respiratory distress. Serum K⁺ drops from 4.5 to 3.7 mmol/L.

13 · Key Take-Home Points

1. Sympathomimetics can be parsed by receptor selectivity, mechanism (direct vs. indirect), and chemical structure; each domain predicts clinical utility and toxicity.
2. Half-life hinges on catechol nucleus; non-catecholamines achieve oral/CNS bioavailability but carry abuse risk.
3. Choice of vasopressor/inotrope should align with targeted haemodynamic deficit (SVR vs. cardiac output) and patient comorbidities.
4. β₂ agonists are lifesaving in asthma yet can mask worsening hypercapnia; always co-administer inhaled steroids for maintenance.
5. Central α₂ agonists provide antihypertensive and sedative benefit but require slow taper to avoid rebound sympathetic surge.
6. Extravasation of potent catechols demands immediate local α-blockade to prevent ischaemic necrosis.
7. Catecholamine surge states (MAO-I interaction, phaeochromocytoma) pose hypertensive emergency—treat with α-blocker first, then β-blocker if needed.

14 · Conclusion

From the fight-or-flight cascade of evolutionary biology to bedside resuscitation and chronic disease modulation, sympathomimetics remain among medicine’s most versatile tools. Mastery of receptor pharmacology, drug-specific kinetics and patient-centred tailoring allows clinicians to harness these agents’ life-saving potential while averting harm. As synthetic chemistry and molecular modelling progress, upcoming generations of agonists promise ever greater selectivity, oral activity and safety—yet the bedrock principles outlined in this chapter will continue to guide their judicious use.

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