Autonomic & Cardiovascular Pharmacology

1. What this chapter covers, and how NEET PG actually tests it

Autonomic pharmacology has a reputation for requiring vast memorisation of drug effects. It does not.

Every effect of every autonomic drug is the sum of two things: which receptors it acts on, and where in the body those receptors happen to be.

Learn the receptor distribution once and you can derive the effects of any agonist or antagonist, including drugs you have never seen.

The cardiovascular drugs follow the same logic applied to the circulation: identify where in the loop a drug acts and its effects and side effects both follow.

2. Receptor distribution: the foundation

2.1 The adrenergic receptors

Alpha-2 receptors are presynaptic and inhibitory, which is why an alpha-2 agonist lowers blood pressure rather than raising it.

Clonidine and methyldopa work this way, reducing central sympathetic outflow, and abrupt clonidine withdrawal causes rebound hypertension because that suppression is suddenly removed.

Beta-1 selectivity matters clinically because beta-2 blockade causes bronchospasm, which is why metoprolol, atenolol and bisoprolol are preferred in airways disease.

2.2 The cholinergic receptors

Muscarinic receptors are G protein-coupled and mediate parasympathetic effects at smooth muscle, cardiac muscle and glands.

Nicotinic receptors are ligand-gated ion channels at the neuromuscular junction and autonomic ganglia.

The muscarinic effects are worth learning as a single list, because atropine blocks all of them and organophosphates stimulate all of them.

Stimulation gives salivation, lacrimation, urination, defecation, gastrointestinal upset, emesis, bradycardia, bronchoconstriction and miosis.

Blockade gives the opposite, and produces the anticholinergic toxidrome: dry as a bone, hot as a hare, red as a beet, blind as a bat, mad as a hatter.

2.3 The sympathomimetics compared

Adrenaline is the drug of choice in anaphylaxis because it covers every element of the emergency at once: alpha-1 vasoconstriction reverses hypotension, beta-1 support maintains cardiac output, beta-2 bronchodilatation relieves the airway obstruction, and mast cell stabilisation limits further mediator release.

No other single agent does all four, which is why antihistamines and steroids are adjuncts rather than alternatives.

2.4 Cholinergic drugs and the anticholinesterases

Direct muscarinic agonists such as pilocarpine and bethanechol act on the receptor itself.

Anticholinesterases act indirectly by preventing acetylcholine breakdown, so their effects appear wherever acetylcholine is already being released.

Whether an anticholinesterase crosses the blood-brain barrier determines what it is used for.

Neostigmine and pyridostigmine carry a quaternary nitrogen and are charged, so they stay peripheral and are used in myasthenia gravis and to reverse neuromuscular blockade.

Physostigmine is tertiary and uncharged, crosses into the brain, and is therefore the antidote for central anticholinergic toxicity.

Donepezil, rivastigmine and galantamine are central agents used in Alzheimer disease for the same reason.

Organophosphates bind irreversibly, and after some hours the complex undergoes ageing and can no longer be reactivated, which is why pralidoxime must be given early.

The edrophonium test historically separated myasthenic from cholinergic crisis, since a short-acting anticholinesterase improves the former and worsens the latter.

2.5 Neuromuscular blockers

Depolarising and non-depolarising blockers differ in mechanism and therefore in almost everything else.

Suxamethonium is a depolarising agonist that holds the endplate depolarised, producing fasciculations before paralysis.

Because it depolarises muscle, it releases potassium, which is why it is dangerous in burns, crush injury, prolonged immobility and denervation, where receptors are upregulated.

It also triggers malignant hyperthermia in susceptible individuals, treated with dantrolene, and its effect is prolonged by pseudocholinesterase deficiency.

Non-depolarising agents such as vecuronium and rocuronium are competitive antagonists, produce no fasciculations, and are reversed by neostigmine or, for rocuronium, by sugammadex.

Anticholinesterases reverse non-depolarising blockade but prolong suxamethonium, which follows directly from the difference in mechanism.

3. Antihypertensives

3.1 Choosing by comorbidity

Antihypertensive questions are rarely about which drug lowers pressure best. They are about which drug suits the patient.

ACE inhibitors are contraindicated in bilateral renal artery stenosis because the stenosed kidney depends on angiotensin II-mediated efferent arteriolar constriction to maintain filtration pressure. Removing it collapses the filtration gradient and precipitates acute kidney injury.

The same mechanism explains why a modest creatinine rise after starting an ACE inhibitor is expected and acceptable, while a steep rise demands investigation.

3.2 The mechanisms and their side effects

ACE inhibitors block conversion of angiotensin I to angiotensin II and also prevent bradykinin breakdown.

The accumulated bradykinin causes the dry cough and the angioedema, which is precisely why angiotensin receptor blockers, acting downstream at the receptor, avoid both.

Both classes cause hyperkalaemia by reducing aldosterone, and both are teratogenic.

Calcium channel blockers divide into dihydropyridines acting on vessels, causing ankle oedema and flushing, and non-dihydropyridines acting on the heart, causing bradycardia and constipation.

Thiazides cause hypokalaemia, hyponatraemia, hyperuricaemia, hyperglycaemia and hypercalcaemia; loop diuretics do the same but lower calcium instead.

That single difference in calcium handling is the cleanest way to separate the two diuretic classes.

3.3 Beta blockers are not interchangeable

Beta blockers differ enough that the exam treats the choice between them as a separate question.

Cardioselective agents — metoprolol, atenolol, bisoprolol, nebivolol — spare beta-2 and are preferred in airways disease, though selectivity is relative and lost at high dose.

Carvedilol and labetalol also block alpha-1, adding vasodilatation, which is why labetalol is favoured in hypertensive emergencies and in pregnancy.

Nebivolol additionally releases nitric oxide.

Beta blockers mask the adrenergic warning signs of hypoglycaemia, notably tremor and palpitations, while leaving sweating intact, which matters in insulin-treated diabetes.

They are avoided in cocaine-associated chest pain, since blocking beta receptors leaves alpha-mediated coronary vasoconstriction unopposed.

Abrupt withdrawal after chronic use causes rebound tachycardia and angina from receptor upregulation, so they must be tapered.

4. Heart failure, angina and lipids

4.1 Survival versus symptoms

The most important distinction in heart failure pharmacology is between drugs that prolong life and drugs that relieve symptoms, because the exam asks about mortality far more often than about symptom control.

Mortality benefit is established for ACE inhibitors or ARBs, beta blockers, mineralocorticoid receptor antagonists, sacubitril-valsartan, and SGLT2 inhibitors.

Diuretics relieve congestion and improve symptoms without established mortality benefit.

Digoxin reduces hospitalisation but does not prolong life.

Beta blockers must be started at low dose in stable patients and titrated slowly, because the initial negative inotropy can worsen decompensated failure.

4.2 Digoxin

Digoxin inhibits the sodium-potassium ATPase, raising intracellular sodium, which reduces calcium extrusion through the sodium-calcium exchanger and so raises intracellular calcium.

Hypokalaemia potentiates digoxin toxicity because potassium and digoxin compete for the same binding site on the pump, so less potassium means more digoxin binding.

That is why diuretic-induced hypokalaemia so often unmasks toxicity in a patient whose dose has not changed.

Toxicity produces nausea, confusion, xanthopsia with yellow-green vision, and arrhythmias, classically atrial tachycardia with block.

4.3 The newer heart failure agents

Two classes have changed heart failure practice recently and both are now examinable.

Sacubitril inhibits neprilysin, the enzyme that degrades natriuretic peptides, so those peptides persist and promote natriuresis and vasodilatation.

Neprilysin also degrades bradykinin, which is why sacubitril must never be combined with an ACE inhibitor — the additive bradykinin accumulation causes angioedema, and a 36-hour washout is required when switching.

Sacubitril is therefore paired with valsartan rather than with an ACE inhibitor.

SGLT2 inhibitors reduce heart failure hospitalisation and mortality in patients with and without diabetes, which was unexpected and is why they now feature in heart failure guidance rather than only in diabetes.

Their characteristic adverse effects are genital mycotic infection, volume depletion and euglycaemic diabetic ketoacidosis.

Ivabradine slows the sinoatrial node by inhibiting the funny current, lowering rate without any negative inotropy, and causes transient visual brightness called phosphenes.

4.4 Antianginals and lipid-lowering drugs

Nitrates release nitric oxide, causing venodilatation that reduces preload; tolerance develops within 24 hours, requiring a nitrate-free interval.

Nitrates with phosphodiesterase-5 inhibitors cause profound hypotension, because both raise cyclic GMP.

Statins inhibit HMG-CoA reductase, the rate-limiting step of cholesterol synthesis, and the resulting upregulation of hepatic LDL receptors is what clears LDL from plasma.

Combining a statin with a fibrate multiplies myopathy risk, since both cause it independently.

5. Antiarrhythmics and anticoagulants

5.1 The Vaughan Williams classes

Class Ib agents act preferentially on ischaemic and depolarised tissue, which is why lidocaine is used in ventricular arrhythmia after infarction.

Amiodarone has properties of all four classes, which is why it is so broadly effective and also why its toxicity is so wide-ranging.

Its adverse effects follow its iodine content and its lipophilicity: thyroid dysfunction in both directions, pulmonary fibrosis, hepatitis, corneal microdeposits, blue-grey skin discolouration and photosensitivity.

Adenosine terminates supraventricular tachycardia by transient atrioventricular nodal block, has a half-life of seconds, and causes a brief sense of impending doom that should be warned about.

Its effect is antagonised by theophylline and potentiated by dipyridamole, both of which act on the same adenosine pathway.

Verapamil must be avoided in a wide-complex tachycardia of uncertain origin, because if the rhythm is ventricular it can precipitate cardiovascular collapse.

5.2 Anticoagulants and antiplatelets

Heparin acts by potentiating antithrombin, monitored by activated partial thromboplastin time, and reversed by protamine.

Low molecular weight heparin acts mainly on factor Xa, requires no routine monitoring, and is only partially reversed by protamine.

Warfarin inhibits vitamin K epoxide reductase, and its initial procoagulant effect occurs because protein C has a shorter half-life than the clotting factors, which is why heparin cover is needed at initiation and why warfarin-induced skin necrosis occurs.

Direct oral anticoagulants act on thrombin, as dabigatran does, or on factor Xa, as rivaroxaban and apixaban do; idarucizumab reverses dabigatran and andexanet alfa the factor Xa inhibitors.

Aspirin irreversibly acetylates cyclooxygenase-1, so its effect lasts the platelet lifespan of seven to ten days.

Clopidogrel blocks the P2Y12 receptor and is a prodrug requiring CYP2C19 activation, so poor metabolisers respond inadequately.

That activation requirement also explains the interaction with omeprazole, which inhibits CYP2C19 and blunts the antiplatelet effect; pantoprazole is preferred alongside it.

Ticagrelor and prasugrel act on the same receptor without needing activation, and ticagrelor characteristically causes dyspnoea.

Thrombolytics such as alteplase and tenecteplase convert plasminogen to plasmin, and their absolute contraindications turn on bleeding risk: previous intracranial haemorrhage, ischaemic stroke within three months, active bleeding, and suspected aortic dissection.

Tranexamic acid works in the opposite direction, inhibiting plasminogen activation, which is why it reduces bleeding in trauma and postpartum haemorrhage.

6. Worked examples

Example 1

A patient with anaphylaxis is given an antihistamine and hydrocortisone but deteriorates. Why is adrenaline the drug of choice?

The question is about breadth of action rather than potency at any one target.

Anaphylaxis simultaneously produces vasodilatation with hypotension, bronchoconstriction, and continuing mediator release.

Adrenaline addresses all three: alpha-1 vasoconstriction, beta-2 bronchodilatation, and mast cell stabilisation, with beta-1 support of cardiac output alongside.

Antihistamines block only histamine, and corticosteroids act through nuclear receptors with an onset of hours, so neither can substitute in the acute phase.

Example 2

A patient stable on digoxin develops nausea, confusion and yellow-green vision after starting furosemide.

The digoxin dose has not changed, so something must have altered its effect rather than its concentration.

Furosemide causes potassium loss, and potassium competes with digoxin for the binding site on the sodium-potassium ATPase.

Hypokalaemia therefore increases digoxin binding and precipitates toxicity at an unchanged plasma level.

Xanthopsia is the characteristic visual disturbance, and correcting potassium is part of management alongside stopping the drug.

Example 3

A hypertensive patient with bilateral renal artery stenosis is started on ramipril and the creatinine rises steeply within days.

The stenosed kidney is perfused at low pressure, so glomerular filtration depends on angiotensin II constricting the efferent arteriole to maintain the pressure gradient across the glomerulus.

Blocking angiotensin II removes that efferent constriction, the filtration gradient collapses, and filtration fails.

The drug must be stopped, and the episode is diagnostically useful because it points to the underlying stenosis.

A small creatinine rise on starting an ACE inhibitor is expected and acceptable; a steep rise is not.

7. Traps the exam sets repeatedly

Expecting an alpha-2 agonist to raise blood pressure. Alpha-2 receptors are presynaptic and inhibitory, so clonidine lowers pressure by reducing sympathetic outflow.

Assuming angiotensin receptor blockers cause cough. The cough is a bradykinin effect specific to ACE inhibition, which is exactly why ARBs avoid it.

Confusing thiazide and loop diuretic calcium handling. Thiazides raise serum calcium; loop diuretics lower it.

Treating digoxin as a mortality-reducing drug in heart failure. It reduces hospitalisation only.

Forgetting warfarin's initial procoagulant phase. Protein C falls before the clotting factors do, which is why heparin cover is required.

Combining sacubitril-valsartan with an ACE inhibitor. Neprilysin also degrades bradykinin, so the combination causes angioedema and a 36-hour washout is mandatory.

Giving an anticholinesterase to reverse suxamethonium. It reverses non-depolarising blockade but prolongs depolarising blockade, because the mechanisms are opposite.

Summary

Every autonomic drug effect is the sum of which receptors it hits and where those receptors are, so learning distribution replaces learning drug lists.

Alpha-2 receptors are presynaptic and inhibitory, which is why alpha-2 agonists lower blood pressure.

Adrenaline is the anaphylaxis drug of choice because it covers vasoconstriction, bronchodilatation, inotropy and mast cell stabilisation simultaneously.

Antihypertensive choice is driven by comorbidity, and ACE inhibitors fail in bilateral renal artery stenosis because filtration depends on efferent constriction.

Bradykinin accumulation causes the ACE inhibitor cough and angioedema, and ARBs avoid both by acting downstream.

In heart failure, ACE inhibitors, beta blockers, mineralocorticoid antagonists, sacubitril-valsartan and SGLT2 inhibitors prolong life while diuretics and digoxin do not.

Hypokalaemia precipitates digoxin toxicity because potassium and digoxin compete for the same pump binding site.

Statins act at the rate-limiting step of cholesterol synthesis and upregulate hepatic LDL receptors.

Amiodarone has properties of all four antiarrhythmic classes, which explains both its efficacy and its wide toxicity.

Warfarin has an initial procoagulant phase because protein C has the shortest half-life, requiring heparin cover at initiation.

Whether an anticholinesterase crosses the blood-brain barrier determines whether it treats myasthenia or central anticholinergic toxicity.

Suxamethonium releases potassium because it depolarises, which is what makes it dangerous in burns, crush injury and denervation.

Sacubitril cannot be combined with an ACE inhibitor because neprilysin also degrades bradykinin.