Adrenergic drugs

Synthesis and release of catecholamines

• Tyrosine is hydroxylated to DOPA (rate-limiting, tyrosine hydroxylase), then dopamine, then noradrenaline inside vesicles (dopamine β-hydroxylase).
• Adrenaline is made from noradrenaline by PNMT in the chromaffin cells of the adrenal medulla; PNMT is induced by cortisol arriving in portal blood from the cortex. The medulla secretes about 80% adrenaline and 20% noradrenaline.
• Noradrenaline is released by postganglionic sympathetic neurons (except those to sweat glands, which release ACh). It is removed mainly by reuptake (uptake 1, blocked by cocaine and tricyclics) and then metabolised by MAO and COMT.
• Reserpine blocks the vesicular monoamine transporter (VMAT), so noradrenaline, dopamine and serotonin leak out and are destroyed; stores deplete, blood pressure falls and severe depression follows. Tetrabenazine, used for chorea, shares this action.

Adrenergic receptors

• Salbutamol stimulates β2 receptors, raising cAMP, which activates protein kinase A, lowers intracellular calcium and inactivates myosin light-chain kinase: the bronchial muscle relaxes. It also stimulates Na+/K+-ATPase, so overuse causes hypokalaemia and nebulised salbutamol treats hyperkalaemia.
• Adrenaline and glucagon both raise blood glucose through cAMP: hepatic glycogenolysis and gluconeogenesis. Adrenaline also suppresses insulin (α2) and stimulates lipolysis.

Adrenaline: effects depend on dose

• Anaphylaxis: 0.5 mg IM (1 mg/mL) into the anterolateral thigh. It works by α1 vasoconstriction, β1 cardiac support, β2 bronchodilatation and a β2-mediated rise in mast cell cAMP that limits further histamine release. Patients on β-blockers respond poorly; glucagon can help.
• Cardiac arrest: 1 mg IV (0.1 mg/mL).
• Croup: nebulised adrenaline gives rapid relief by α1 vasoconstriction of the subglottic mucosa, shrinking oedema. The effect wears off in 2 hours, so observe before discharge.
• With local anaesthetic: vasoconstriction slows absorption, prolongs the block, reduces bleeding and allows a higher maximum dose (lidocaine about 3 mg/kg plain, 7 mg/kg with adrenaline).
• Halothane sensitises the myocardium to catecholamines; infiltrating large volumes of adrenaline under halothane causes ventricular ectopics and tachycardia. Lidocaine itself is not the culprit.
• Lactate rise on adrenaline in sepsis, with improving perfusion, is caused by β2-driven aerobic glycolysis in skeletal muscle (with hyperglycaemia), not by hypoperfusion.

Other sympathomimetics

• Phenylephrine raises blood pressure and the baroreceptor reflex slows the heart. Ephedrine raises both pressure and heart rate because it also acts on β1.
• Ephedrine with an MAO inhibitor (phenelzine): nerve endings are loaded with noradrenaline that MAO has not destroyed, so the indirect agent releases an excess of stored noradrenaline, causing a hypertensive crisis. Use a direct agent in small doses.
• Methyldopa induces IgG red cell autoantibodies in up to 20% of users: a positive direct antiglobulin test, usually without haemolysis. Change it after delivery because it can worsen postnatal depression.
• Apraclonidine test for Horner syndrome: the sympathetically denervated dilator pupillae and Müller muscle develop α1 denervation supersensitivity, so the weak α1 action of apraclonidine dilates the small pupil and lifts the ptosis. It may be negative in very recent Horner syndrome.

Inotropes and vasopressors in shock

• Vasopressin works when catecholamines fail because septic shock produces a relative vasopressin deficiency and V1 receptors still respond in acidosis. It is a catecholamine-sparing add-on, not first line.
• Vasopressors are given through a central line where possible.

α-blockers

Exam trap Do not give atropine for the sweating and salivation of a scorpion sting; it worsens the tachycardia and hypertension.

β-blockers

• Side effects: bronchospasm, bradycardia, prolonged PR interval (slowed AV nodal conduction), heart block, cold peripheries, fatigue, nightmares, erectile dysfunction.
• In an insulin-treated diabetic, propranolol masks the warning signs of hypoglycaemia (tremor, palpitations; sweating is cholinergic and persists) and delays recovery by blocking glycogenolysis.
• Contraindications: asthma, second- or third-degree block, acute decompensated heart failure, IV verapamil, cocaine toxicity.
• β-blocker overdose with bradycardia and hypotension resistant to atropine and fluids: glucagon. It acts on its own Gs-coupled receptor in the myocardium, raising cAMP independently of β-receptors. High-dose insulin euglycaemia therapy is also used.

Remember Glucagon and milrinone both raise cardiac cAMP by bypassing the blocked β-receptor.

The cholinergic side at a glance

This chapter shares questions with the cholinergic chapter; the key facts are:

Exam trap In phaeochromocytoma, give α-blockade first; β-blockade alone leaves α1 vasoconstriction unopposed.

How FCPS asks about this

• Low-dose adrenaline in a volunteer: systolic up, diastolic down (β2 vasodilatation).
• Heart slows after phenylephrine: baroreceptor reflex; ephedrine raises both pressure and rate.
• β-blocker overdose resistant to atropine: glucagon, acting via its own Gs receptor.
• Milrinone mechanism: PDE3 inhibition raises cAMP; levosimendan sensitises troponin C.
• First vasopressor in septic shock and MAP target: noradrenaline, 65 mmHg; vasopressin works through relative deficiency.
• Why adrenaline is added to lidocaine: slows absorption, prolongs action, raises the maximum dose.
• Salbutamol and electrolytes: hypokalaemia; β2 raises cAMP to relax bronchi.