What systolic, diastolic, pulse and mean pressures are and how they are measured; the baroreceptor, chemoreceptor and CNS ischaemic reflexes; the renin–angiotensin–aldosterone and vasopressin systems that set long-term pressure; and how diuretics, sympatholytics, vasodilators and renin–angiotensin blockers act.
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Systolic pressure is the peak reached during ejection, about 120 mmHg in a young adult; diastolic pressure is the trough just before the next ejection, about 80 mmHg; pulse pressure is their difference. Because diastole lasts longer than systole, the mean arterial pressure is closer to the diastolic value and is estimated as diastolic pressure plus one third of pulse pressure, about 93 mmHg. Mean pressure is what drives flow, and it equals cardiac output times total peripheral resistance, so every regulator of pressure works through one of those two factors. Central venous pressure, measured in the right atrium, is about 0 mmHg and rises with volume overload and right heart failure; mean circulatory filling pressure, about 7 mmHg, is the pressure everywhere when the heart is stopped and blood has redistributed, and it measures how full the circulation is. Pressure is measured indirectly with a cuff and stethoscope: inflate above systolic, deflate slowly, and the first Korotkoff sound (turbulent flow through the partly compressed brachial artery) marks systolic pressure while the disappearance of sound marks diastolic; the cuff must be at heart level and wide enough for the arm. Gravity adds 0.77 mmHg for every centimetre below the heart and subtracts it above, so in a standing adult the arterial pressure in the feet is about 190 mmHg and in the head about 60 mmHg, and venous pressure in the feet reaches 90 mmHg unless the muscle pump is working.
The baroreceptors in the carotid sinus and the aortic arch are stretch receptors that fire in proportion to pressure and, above all, to its rate of change; they respond between about 60 and 180 mmHg and most steeply around 100 mmHg. Their signals reach the nucleus of the solitary tract, inhibit the vasoconstrictor area of the medulla and excite the vagal nucleus, so a rise in pressure produces bradycardia, reduced contractility, arteriolar dilatation and venodilatation within seconds. The reflex is a buffer: it minimises the swings caused by posture, exercise and emotion, but it resets to any pressure that persists for one to two days and therefore cannot set the long-term level. On standing, about 500 ml pools in the leg veins, venous return and stroke volume fall, the baroreceptors unload, and the reflex raises heart rate by 10 to 20 beats and constricts the resistance and capacitance vessels so that mean pressure barely changes; when the reflex fails (autonomic neuropathy, some drugs, prolonged bed rest) standing causes orthostatic hypotension and fainting. The peripheral chemoreceptors in the carotid and aortic bodies respond to a low oxygen tension, high carbon dioxide or acidity and raise pressure through sympathetic activation, mainly when pressure has fallen below about 80 mmHg. Low-pressure receptors in the atria and pulmonary vessels sense volume and adjust vasopressin release and renal sodium handling (the atrial reflex), and atrial stretch releases atrial natriuretic peptide. When cerebral flow falls far enough for the vasomotor centre itself to become ischaemic, the CNS ischaemic response fires the most powerful sympathetic discharge the body can produce, raising pressure to as much as 250 mmHg; it is a last-ditch mechanism active only below about 60 mmHg, and it underlies the Cushing reaction when raised intracranial pressure compresses the brain vessels.
The kidney decides the long-term level of arterial pressure. When pressure rises the kidney excretes more sodium and water (pressure natriuresis), blood volume and venous return fall, and output and pressure return to the point at which intake and output of salt and water balance; because this mechanism keeps acting until pressure is corrected, it has infinite gain over days and overrides the nervous reflexes, which reset. Any factor that shifts the renal function curve to a higher pressure, such as renal artery stenosis, reduced nephron number, excess aldosterone or a high salt intake in a salt-sensitive person, produces sustained hypertension. The renin–angiotensin system is the main hormonal arm. A fall in renal perfusion pressure, a fall in sodium delivery to the macula densa or sympathetic beta-1 stimulation releases renin from the juxtaglomerular cells; renin cleaves angiotensinogen to angiotensin I, and angiotensin-converting enzyme in the lung and elsewhere converts it to angiotensin II. Angiotensin II constricts arterioles (raising resistance within minutes), constricts the efferent arteriole to preserve filtration, stimulates aldosterone from the adrenal cortex, acts directly on the tubules to retain sodium, stimulates thirst and vasopressin release, and enhances sympathetic transmission; aldosterone then increases sodium reabsorption and potassium secretion in the collecting duct over hours to days. Vasopressin (antidiuretic hormone), released in response to raised plasma osmolality and to a large fall in volume or pressure, retains water and, at high concentrations, constricts vessels. Together these systems explain why haemorrhage is followed by thirst, oliguria and a gradual restoration of volume, and why blocking the system lowers pressure in most hypertensive patients.
Diuretics lower pressure first by reducing blood volume and cardiac output and, with continued use, by lowering peripheral resistance. Thiazides such as hydrochlorothiazide and chlorthalidone block the sodium–chloride cotransporter in the distal tubule, are first-line for uncomplicated hypertension, and cause hypokalaemia, hyponatraemia, hyperuricaemia (gout), hyperglycaemia and a rise in lipids; they lose effect when the glomerular filtration rate falls below about 30 ml/min. Loop diuretics such as furosemide block the sodium–potassium–chloride cotransporter in the thick ascending limb, are the choice in renal impairment and in volume overload, and cause hypokalaemia, hypocalcaemia and ototoxicity at high doses. Potassium-sparing drugs act in the collecting duct: spironolactone and eplerenone antagonise aldosterone and help in resistant hypertension and primary aldosteronism (spironolactone causes gynaecomastia); amiloride and triamterene block the epithelial sodium channel; all can cause hyperkalaemia, especially with ACE inhibitors. Sympathoplegic drugs reduce sympathetic drive at different sites. Clonidine and methyldopa stimulate central alpha-2 receptors and lower outflow; methyldopa is the traditional choice in pregnancy, clonidine causes sedation, dry mouth and rebound hypertension if stopped abruptly. Prazosin, doxazosin and terazosin block alpha-1 receptors on vessels, lower resistance, relieve prostatic symptoms, and cause first-dose orthostatic hypotension. Beta-blockers such as propranolol (non-selective), atenolol and metoprolol (beta-1 selective) lower heart rate, contractility and renin release; they are preferred when hypertension coexists with angina, previous infarction, heart failure or tachyarrhythmia, and they cause bradycardia, fatigue, bronchospasm in asthma (non-selective drugs), masking of hypoglycaemia, and worsening of peripheral vascular disease; they must not be stopped suddenly.
Calcium channel blockers reduce calcium entry through L-type channels. The dihydropyridines amlodipine and nifedipine act mainly on vascular smooth muscle, lower resistance and are first-line for hypertension, causing ankle oedema, flushing, headache and reflex tachycardia (with short-acting nifedipine); verapamil and diltiazem act also on the sinoatrial and atrioventricular nodes and the myocardium, so they are used when rate control is wanted and avoided in heart failure and with beta-blockers; verapamil causes constipation. Direct vasodilators relax arteriolar smooth muscle: hydralazine (used in pregnancy and with nitrates in heart failure, causes a lupus-like syndrome), minoxidil (opens potassium channels, causes hirsutism and fluid retention, reserved for severe cases) and sodium nitroprusside (intravenous, releases nitric oxide, dilates arteries and veins, used in hypertensive emergencies, cyanide toxicity with prolonged infusion); because they trigger reflex tachycardia and salt retention they are given with a beta-blocker and a diuretic. Angiotensin-converting enzyme inhibitors such as captopril, enalapril and lisinopril block the formation of angiotensin II and the breakdown of bradykinin; they lower resistance without reflex tachycardia, protect the kidney in diabetes and improve survival in heart failure and after infarction, and they cause dry cough (bradykinin), angio-oedema, hyperkalaemia, first-dose hypotension and acute renal failure in bilateral renal artery stenosis; they are teratogenic and contraindicated in pregnancy. Angiotensin receptor blockers such as losartan and valsartan block the AT1 receptor and share the benefits and the renal and pregnancy cautions without the cough. Aliskiren inhibits renin directly. For most patients therapy starts with one of three classes, a thiazide, an ACE inhibitor or ARB, or a dihydropyridine, and adds a second from a different class rather than pushing one to its maximum; beta-blockers are chosen when there is a cardiac indication, and hypertensive emergencies are treated intravenously with labetalol, nicardipine or nitroprusside while lowering pressure gradually to protect the brain.
The average pressure over the cycle, approximately diastolic pressure plus one third of pulse pressure; the product of cardiac output and total peripheral resistance.
Stretch receptors in the carotid sinus (glossopharyngeal nerve) and aortic arch (vagus) fire faster when pressure rises, inhibiting the vasomotor centre and exciting the vagal centre; it buffers pressure changes within seconds.
The rise in renal salt and water excretion when arterial pressure rises; because it has infinite gain over time, the kidney sets the long-term level of arterial pressure.
Renin from the juxtaglomerular cells converts angiotensinogen to angiotensin I; angiotensin-converting enzyme forms angiotensin II, a vasoconstrictor that also stimulates aldosterone, sodium retention and thirst.
A drug that lowers pressure by reducing sympathetic outflow or blocking its receptors: central alpha-2 agonists, alpha-1 blockers, beta-blockers.
A calcium channel blocker selective for vascular smooth muscle (amlodipine, nifedipine) that lowers resistance with little direct effect on the heart, unlike verapamil and diltiazem.
Explain why a thiazide diuretic continues to lower blood pressure after blood volume has returned toward normal.
The initial fall is from reduced volume and cardiac output. With continued use, volume is partly restored by the renin–angiotensin system, but peripheral resistance falls, probably because sodium depletion of vascular smooth muscle reduces its responsiveness to vasoconstrictors, so the antihypertensive effect persists.
Describe the sequence of events by which the body restores arterial pressure over the first hours and days after a moderate haemorrhage.
Seconds: baroreceptor and chemoreceptor reflexes raise rate, contractility and resistance and constrict veins. Minutes to hours: renin release, angiotensin II vasoconstriction, vasopressin release; capillary hydrostatic pressure falls and fluid moves in from the interstitium; thirst. Hours to days: aldosterone and vasopressin retain salt and water, pressure natriuresis is suppressed, plasma proteins and red cells are replaced over days to weeks.
A patient with bilateral renal artery stenosis is started on an ACE inhibitor and develops acute renal failure. Explain the mechanism.
With reduced perfusion pressure the glomerular filtration rate is maintained only because angiotensin II constricts the efferent arteriole. Removing angiotensin II dilates the efferent arteriole, glomerular capillary pressure falls and filtration collapses.
Compare the dihydropyridine and non-dihydropyridine calcium channel blockers under mechanism, effect on heart rate, main uses and a characteristic adverse effect.
Both block L-type channels. Dihydropyridines (amlodipine) are vascular-selective, may cause reflex tachycardia, are used for hypertension and angina, and cause ankle oedema. Verapamil and diltiazem act on the nodes and myocardium, slow the rate, are used for rate control and angina, and cause constipation (verapamil) and heart block, especially with beta-blockers.
Why are direct vasodilators such as hydralazine and minoxidil usually combined with a beta-blocker and a diuretic?
Arteriolar dilatation lowers pressure and unloads the baroreceptors, producing reflex tachycardia and increased renin, and the fall in pressure causes salt and water retention. The beta-blocker prevents the tachycardia and renin release, the diuretic removes the retained fluid, so the antihypertensive effect is preserved.
بطاقات مهمة
Diastolic pressure + one third of pulse pressure; also cardiac output × total peripheral resistance.
Turbulent flow through the partly compressed artery as cuff pressure falls just below systolic pressure; marks systolic pressure.
Carotid sinus via the glossopharyngeal nerve; aortic arch via the vagus; both project to the nucleus of the solitary tract.
About 500 ml pools in the leg veins; the baroreflex raises rate and resistance; failure of the reflex causes orthostatic hypotension.
The strongest sympathetic discharge, triggered when the vasomotor centre itself becomes ischaemic below about 60 mmHg; basis of the Cushing reaction.
Fall in renal perfusion pressure, reduced sodium at the macula densa, sympathetic beta-1 stimulation of juxtaglomerular cells.
Blocks the Na+/Cl- cotransporter in the distal tubule; first-line for hypertension; causes hypokalaemia, hyperuricaemia, hyperglycaemia.
Dry cough from bradykinin, plus hyperkalaemia, angio-oedema, first-dose hypotension; contraindicated in pregnancy.
Amlodipine, nifedipine: vascular-selective, lower resistance; cause ankle oedema, flushing, reflex tachycardia.
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