Adrenal medulla
A sympathetic ganglion that never grew axons: its cells dump adrenaline straight into the blood instead of onto a synapse, so when a tumour forms here the problem is never local — it is a whole-body adrenergic storm, and almost every drug you give aims at receptors somewhere else.
What it normally does
The medulla is the core of the adrenal gland and is not really a gland at all — it is a sympathetic ganglion whose cells never grew axons. Preganglionic sympathetic fibres from the lower thoracic cord (greater splanchnic nerve, T5-T9, with a contribution from the lesser splanchnic, T10-T11) run through the cortex and synapse directly on chromaffin cells. Acetylcholine on nicotinic receptors depolarises the cell, calcium enters, and the granules empty into the venous blood [neuroendocrine transducer]. About 80% of what comes out is adrenaline, the rest noradrenaline.
Explains why the whole body responds at once and for minutes rather than milliseconds, why the medulla can be removed with no replacement therapy while losing the cortex is fatal, and why a tumour of these cells secretes in unpredictable bursts — nothing is telling it when to stop.
The assembly line: tyrosine to DOPA by tyrosine hydroxylase (the rate-limiting step), then dopamine, then noradrenaline inside the granule (dopamine beta-hydroxylase), then adrenaline in the cytosol by PNMT before being repackaged. PNMT is switched on by the very high cortisol arriving from the cortex in the blood that drains inward, so only chromaffin cells sitting inside an adrenal gland make much adrenaline. Breakdown has two arms: COMT is the one that makes the metanephrines — adrenaline to metanephrine, noradrenaline to normetanephrine — while MAO takes those on to VMA. The critical point is that chromaffin cells carry their own membrane-bound COMT, so a tumour metabolises its stored catecholamines to metanephrines continuously inside itself, whether or not it is having a surge.
Explains why plasma free metanephrines, not catecholamines, are the screening test and why a sample taken in a quiet hour still rules the diagnosis out; and why a tumour outside the adrenal (paraganglioma, on the sympathetic chain) makes noradrenaline but almost never adrenaline.
Where the hormones land: alpha-1 on vascular smooth muscle (Gq, calcium up, vessels constrict); alpha-2 presynaptically on nerve terminals and on pancreatic beta cells (brakes noradrenaline release and insulin release); beta-1 on the heart (Gs, cAMP up, faster and harder); beta-2 on bronchi and on skeletal muscle arterioles (Gs — airways open, those vessels dilate, muscle tremors, potassium moves into cells). Adrenaline hits alpha and beta. Noradrenaline hits alpha and beta-1 with almost no beta-2 effect.
Explains that the beta-2 arm is a vasodilator brake sitting on top of alpha-1 constriction — take the brake off first with a beta blocker and pressure has nowhere to go but up — and why noradrenaline-secreting tumours tend to give steady hypertension with relatively little tachycardia (baroreflex slowing can even leave the rate normal or low) while adrenaline-secreting ones give palpitations, tremor and pallor in spells.
Adrenaline raises glucose from three directions at once: glycogen breakdown and new glucose production in the liver (beta-2 in humans), fat breakdown (beta-1/beta-2/beta-3 on adipocytes), and suppression of insulin release from the pancreatic beta cell (alpha-2). Beta-2 also drives potassium into cells. Meanwhile a circulation soaked in noradrenaline sits permanently constricted: the pressure reads high, but the actual circulating volume has been squeezed down and the receptors themselves have downregulated.
Explains the high glucose and weight loss of phaeochromocytoma, why adrenaline is what generates the warning symptoms of a hypo, and why blood pressure and glucose both fall through the floor the moment the tumour's vein is clamped.
What goes wrong
- Phaeochromocytoma (and paraganglioma)← from “The medulla is the core of the adrenal gland a…”
A tumour of chromaffin cells. It keeps the whole synthetic assembly line but loses the nerve that normally gates release, so catecholamines pour out in unregulated bursts — set off by palpating the abdomen, induction of anaesthesia, IV contrast, or nothing at all. Sustained alpha-1 stimulation clamps the arterioles and squeezes the plasma volume down; beta-1 stimulation drives the heart. Roughly 10-15% sit outside the adrenal along the sympathetic chain (paraganglioma) and, having no cortisol bathing them, secrete predominantly noradrenaline (some only dopamine) rather than adrenaline.
Headache, sweating, palpitations and hypertension in a young person: plasma free metanephrines. Pallor, not flushing. Alpha block, then beta block, then operate.
You would find: Spells of pounding headache, drenching sweat and palpitations lasting minutes, leaving the patient wrung out. Pallor during the attack, not flushing — the skin vessels are clamped shut. About half have sustained hypertension, a third paroxysmal, often resistant to three agents and in someone young; a minority are normotensive. Postural drop between spells because the volume is contracted. Fasting glucose up, weight down. Screen with plasma free metanephrines. Rare in Australia — roughly 2 to 8 cases per million per year — but about 5% of adrenal incidentalomas on CT turn out to be one, and up to 40% of patients carry a germline mutation (SDHB, VHL, RET in MEN2, NF1), so everyone diagnosed is referred for genetic testing.
- Hypertensive crisis from unopposed alpha stimulation← from “Where the hormones land: alpha-1 on vascular s…”
Give a beta blocker first — for the 'anxiety', the tachycardia or the high pressure — and you remove the beta-2 vasodilation in skeletal muscle vessels that was partly offsetting alpha-1 constriction. The circulating catecholamines now act on alpha-1 with nothing opposing them and systemic vascular resistance jumps. At the same time beta-1 blockade stops the ventricle raising its rate or force, so it meets an enormous afterload it cannot outrun.
Unopposed alpha. A beta blocker before alpha blockade in an undiagnosed phaeochromocytoma can kill — this single fact is the reason for the sequence.
You would find: Minutes to hours after a beta blocker — or after abdominal palpation, anaesthetic induction, contrast, or a drug that provokes catecholamine release such as metoclopramide: systolic above 200, tearing headache, chest pain, flash pulmonary oedema in a normal-sized heart, sometimes stroke.
- Catecholamine cardiomyopathy← from “Where the hormones land: alpha-1 on vascular s…”
Relentless beta-1 stimulation floods myocytes with calcium. Calcium overload, plus the oxygen demand of a fast hypertensive heart, plus alpha-1 driven coronary spasm, produces patchy myocyte death (contraction band necrosis) and stunning of muscle that is not infarcted.
Troponin up, coronaries clean, ventricle stunned — think catecholamines, and ask what the blood pressure has been doing.
You would find: Chest pain, troponin rise and ischaemic ECG changes in a young patient whose coronary angiogram is clean; echo shows regional ballooning (takotsubo pattern) or a globally poor ventricle. Usually recovers over weeks once the tumour is out.
- Circulatory collapse and hypoglycaemia after resection← from “Adrenaline raises glucose from three direction…”
Clamp the tumour's vein and plasma catecholamines fall to nothing within a couple of minutes. What is left is a dilated circulation whose volume was chronically squeezed down, adrenoceptors that have downregulated, and — if phenoxybenzamine was used — receptors still covalently blocked. Simultaneously the alpha-2 brake on the pancreatic beta cell lifts, insulin surges and glucose falls.
The dangerous part of the operation is the ten minutes after the tumour comes out: pressure crashes and sugar crashes together.
You would find: Profound hypotension in recovery needing fluid and vasopressor, and a sweaty, drowsy or confused patient with a capillary glucose of 2. Regular glucose monitoring after these operations exists for exactly this reason.
- Loss of the adrenaline warning system in diabetes← from “Adrenaline raises glucose from three direction…”
In long-standing type 1 diabetes, and in insulin-treated type 2, repeated hypos blunt the sympathoadrenal response. Glucagon goes first; then the medulla's adrenaline surge fails to arrive until glucose is already dangerously low [hypoglycaemia-associated autonomic failure], so the warning symptoms that adrenaline produces never happen.
Sweating with no tremor or palpitations during a hypo means the adrenaline signal has gone. Beta blockade imitates it.
You would find: The patient goes from feeling fine to confused or unconscious with no tremor or palpitations first. Sweating may persist, because sweat glands are driven by cholinergic sympathetic nerves rather than by the medulla. Non-selective beta blockers reproduce much of the same silence pharmacologically. In Australia type 2 diabetes is around three to four times more prevalent among Aboriginal and Torres Strait Islander people and is diagnosed a decade or more younger, so more people spend more years on insulin and severe hypoglycaemia is correspondingly more common — worth weighing when choosing a beta blocker or a glucose target, particularly where the nearest emergency department is hours away.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- Alpha-1 and alpha-2 adrenoceptors. Phenoxybenzamine binds covalently and irreversibly; prazosin and doxazosin are competitive and selective for alpha-1 only.
- Which does
- Alpha-1 is Gq-coupled, so blocking it means phospholipase C is not activated, IP3 does not release stored calcium, and the vascular smooth muscle cell cannot contract. Because phenoxybenzamine's bond is covalent, even a massive catecholamine surge cannot compete it off the receptor — which is the point in a tumour that surges without warning.
- So you see
- Vessels dilate, blood pressure falls, and over several days the squeezed-down plasma volume refills as the venous bed relaxes. That refilling is what makes the operation survivable. Adequate blockade looks like a normal-to-low pressure with a deliberate postural drop and a slightly blocked nose.
- And the same mechanism causes
- Every unwanted effect is the same blockade in a different bed or on the other receptor. Alpha-1 blockade in nasal mucosal vessels gives a stuffy nose, in resistance vessels gives postural dizziness and syncope, and at the bladder neck and vas deferens gives failure of ejaculation. Alpha-2 blockade (phenoxybenzamine, not prazosin) removes the presynaptic brake on noradrenaline release, so noradrenaline floods onto still-unblocked beta-1 receptors and the patient becomes tachycardic — that tachycardia is the reason a beta blocker is added, second.
- Handling
- The clinical effect of phenoxybenzamine outlives the drug in plasma by days, because recovery requires the cell to make new receptors. That is precisely why the hypotension runs on into the postoperative period.
Catches people out: Alpha first, always. And do not chase the reflex tachycardia by bringing the beta blocker forward — that is the trap the next entry describes.
- Binds
- Beta-1 adrenoceptors (Gs-coupled). Propranolol is non-selective and blocks beta-2 in every tissue as well; the 'cardioselectivity' of atenolol and metoprolol is relative and is lost at higher doses.
- Which does
- Less Gs signalling means less adenylate cyclase and less cAMP — cAMP gates the pacemaker funny current directly, and via protein kinase A it phosphorylates L-type calcium channels. The node depolarises more slowly and each contraction is weaker.
- So you see
- Rate falls, palpitations settle, ectopy and arrhythmia become less likely, and myocardial oxygen demand drops.
- And the same mechanism causes
- Given before alpha blockade it produces the crisis above: the beta-2 vasodilator brake disappears, alpha-1 constriction runs unopposed, and the pressure spikes into a ventricle that can no longer speed up — pulmonary oedema. The same beta-2 blockade with propranolol constricts airways (bronchospasm in asthma), blunts the hepatic glycogen breakdown that rescues a hypo, and strips out the tremor and palpitations that warn of one, leaving only the sweating. Cold hands and fatigue follow straight from the lower cardiac output.
- Handling
- Once started, it is not stopped abruptly — upregulated beta receptors plus circulating catecholamines make rebound tachycardia and hypertension worse than the starting point.
Catches people out: Never first, never alone. A young patient with 'anxiety and palpitations' who is handed a beta blocker before anyone has thought of metanephrines is the classic disaster.
- Binds
- Phentolamine: alpha-1 and alpha-2 adrenoceptors, competitive and reversible. Magnesium: presynaptic catecholamine release and L-type calcium channels. Nitroprusside and glyceryl trinitrate: nitric oxide donation, guanylate cyclase and cGMP in smooth muscle.
- Which does
- Phentolamine gives the same block of the Gq-calcium pathway in vascular smooth muscle as phenoxybenzamine, but reversible — so as the surge passes, the block passes with it and pressure is not left unsupported. The nitrovasodilators relax vessels through a pathway catecholamines cannot overcome at all.
- So you see
- Systemic vascular resistance falls within a minute or two and the pressure comes down; stopping the infusion undoes it just as fast.
- And the same mechanism causes
- Phentolamine's alpha-2 blockade releases more noradrenaline from nerve terminals, so tachycardia and sometimes arrhythmia follow — the same mechanism that makes phenoxybenzamine tachycardic. Push any of them too far and the pressure collapses, because you are removing vasoconstriction from a circulation whose volume is already contracted. Prolonged or high-dose nitroprusside accumulates cyanide, so it is used briefly and with an arterial line.
- Handling
- All are titrated by infusion against invasive arterial pressure in theatre or ICU, never by intermittent boluses on a ward.
Catches people out: Have fluid running before you dilate. A phaeochromocytoma crisis is a vasoconstricted, volume-deplete state wearing the disguise of a full circulation.
- Binds
- Noradrenaline binds alpha-1 (and beta-1) adrenoceptors; vasopressin binds V1a receptors on vascular smooth muscle.
- Which does
- Both raise intracellular calcium in vascular smooth muscle through Gq — noradrenaline at the alpha-1 receptor, vasopressin at V1a — so the vessels constrict. Fluid does the other half of the job by refilling a vascular space that was chronically underfilled.
- So you see
- Perfusing pressure is restored while the patient's own receptors re-emerge over the next day or two.
- And the same mechanism causes
- Noradrenaline often needs unusually large amounts because its receptors are blocked or downregulated, and the alpha-1 constriction that raises the pressure also shuts down gut, kidney and digital perfusion — ischaemic toes and a rising lactate are the same mechanism at the far end of the circulation. Vasopressin at high dose does the same through V1a.
- Handling
- Glucose is checked regularly alongside the pressure: the same operation lifted the alpha-2 suppression of insulin, and the hypoglycaemia that follows is easy to mistake for slow anaesthetic recovery. Both vasopressors run through a central line — extravasated noradrenaline causes local necrosis by the same alpha-1 constriction that raises the pressure.
Catches people out: The reflex is to turn the vasopressor up; the answer is usually more volume. And a drowsy patient here is hypoglycaemic until the glucometer says otherwise — not simply slow to wake.
Alpha before beta — that is the whole page in three words. A young person with resistant hypertension and spells of headache, sweating and palpitations gets plasma free metanephrines, not a beta blocker; pallor during the spell, postural drop between spells. Once confirmed: alpha blockade plus salt and fluid for a fortnight, beta blocker added last for the reflex tachycardia, then surgery. Then expect both the blood pressure and the glucose to fall through the floor the minute the tumour is out.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.