Astra Stem

Hypertension: The Basics

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By Masooma Hyder Baig

Hypertension, more commonly referred to as high blood pressure, is a chronic condition determined by increased pressure within the vascular system. It is known to be a major risk factor for various diseases from cardiovascular (heart attack and heart failure) to non-cardiovascular (renal disease, diabetes.) This article delves into the pathophysiological mechanisms involved in sustaining hypertension, the therapeutic action of antihypertensive drugs, and how the management of hypertension differs between multiple ethnic groups.

Mechanisms of hypertension

Blood pressure can be defined as the product of CO (cardiac output) and TPvR (total peripheral vascular resistance) (1). In most cases of hypertension, patients often have normal cardiac output but increased TPvR (2), which haemodynamically alters pressure as blood flows through arterioles. Increased TPvR can occur in various ways, primarily through vasoconstriction (constriction of blood vessels), increased blood volume and, to a smaller extent, increased blood viscosity (3). 

Renin-Angiotensin-Aldosterone system (RAAS)

It can be argued that RAAS is an essential contributor (particularly in relation to target therapies) to increasing blood pressure through vasoconstriction and increased blood volume. Renin is a hormone released from juxtaglomerular cells located in the kidney, which converts circulating angiotensinogen (inactive) into angiotensin I. Angiotensin-converting enzyme (ACE) then converts angiotensin I to the more potent vasoconstrictor angiotensin II which also stimulates aldosterone release from the adrenal glands, resulting in sodium and water retention and thus, increased blood volume (4). 

Autonomic nervous system 

The autonomic nervous system, consisting of the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), is also involved in regulating blood pressure. The SNS increases heart rate and vasoconstriction (through the release of adrenaline and noradrenaline) thereby increasing blood pressure whereas the PNS decreases heart rate and causes vasodilation to lower blood pressure. Often in hypertension, SNS activity supersedes PNS activity instead of both systems working together in blood pressure regulation (5).

Baroreceptor response

Baroreceptors are receptors located in the carotid artery and aortic arch which are specialised in detecting even the slightest changes in blood pressure through the mechanical stretch of arterial walls. When high blood pressure is detected, baroreceptors increase their signal release to the cardiovascular centres of the brain which then decreases heart rate and cardiac output whilst increasing vasodilation to lower and restore blood pressure. This is achieved by suppressing the SNS while further stimulating PNS activity. Conversely (but also due to negative feedback), if blood pressure is too low, baroreceptors instead send signals to the brain to ensure SNS activity is promoted over PNS activity, allowing for increased heart rate, vasoconstriction, and cardiac output. This then allows for the restoration of blood pressure homeostatically (6). In hypertension, baroreceptors reset the threshold of pressure detection. A reduction in baroreceptor sensitivity enables the continuation of high blood pressure instead of suppression (7). 

Mechanisms of action in anti-hypertensives

Diuretics 

These medications promote sodium excretion (natureisis) and water excretion by urine which helps to lower blood volume and thus blood pressure. Different subclasses of diuretics have different sites of action on the nephron –the kidney’s filtering units– which dictate their potency in promoting natuerisis, as discussed below: 

  1. Loop Diuretics: furosemide, bumetanide, torsemide

These diuretics act on the thick, ascending column of the Loop of Henle in the kidney, binding to and inhibiting the Na+/K+/2Cl- co transporters. This prevents the reabsorption of sodium, water and chloride ions thus promoting natriuresis and diuresis (8). 

  1. Thiazide Diuretics: indapamide, hydrochlorothiazide, metolazone

Thiazides act on the early distal convoluted tubule (DCT) where they inhibit Na+/Cl- cotransporters, preventing the reabsorption of sodium and chloride ions and subsequently enabling them to be excreted as water through osmosis (8). Compared to loop diuretics, they are said to be moderately powerful (9). 

  1. Potassium-sparing diuretics and hypokalemia prevention
  • Aldosterone antagonists: eplerenone, spironolactone 

These drugs act on the late DCT and collecting duct. They directly bind to aldosterone receptors to prevent mRNA synthesis and further prevent the activation of sodium channels. As a result, sodium reabsorption decreases whilst potassium levels are preserved (8). 

  • Epithelial Na+ channel inhibitors: amiloride, triamterene

The channel inhibitors also act on the late DCT and collecting duct of the nephron. They directly bind to and inhibit Na+ channels thus averting sodium reabsorption and promoting natriuresis (8). 

Angiotensin-converting enzyme Inhibitors (ACE-i): lisinopril, ramipril, enalapril

ACE inhibitors block the conversion of angiotensin I into angiotensin II by, as their name suggests, inhibiting ACE. This results in lower levels of angiotensin II in circulation thus reducing vasoconstriction, sodium retention, and overall blood pressure. ACE inhibitors are also thought to increase levels of bradykinin, a potent vasodilator, further enhancing their antihypertensive effects (10). 

Angiotensin-receptor blockers (ARBs): candesartan, losartan, valsartan

ARBs are selective blockers of the AT1 receptor (angiotensin receptor) which affects angiotensin II located in blood vessels and other tissues. Directly blocking angiotensin II action prevents vasoconstriction and aldosterone secretion, which results in lowering blood pressure and limited sodium reabsorption. Additionally, ARBs do not increase bradykinin levels and as such, are a suitable option for patients who may experience dry coughs with ACE-i (11). 

Calcium-channel blockers (CCBs)

CCBs inhibit L-type calcium channels in order to prevent calcium ion entry into cardiomyocytes and smooth muscle cells. This results in vasodilation, decreased contractility of the myocardium, and decreased heart rate. CCBs are divided into two further subclasses: 

  1. Dihydropyridines: amlodipine, nifedipine, felodipine

CCBs that act peripherally on vascular tissue, exerting minor effects on the myocardium. 

  1. Non-dihydropyridines: Diltiazam, Verapamil 

Rate-limiting CCBs that directly affect the nodal tissue of the heart thus slowing cardiac conduction and cardiac contractility in addition to promoting vasodilation (12). 

Hypertension management 

The management of hypertension varies based on patient characteristics including  age, ethnicity, genetics, other illnesses, and socioeconomic status. In white patients under the age of 55, RAAS-induced hypertension is believed to be predominant and so ACE-i or ARBs are usually first-line treatment (13). In patients over 55 and in Black/Afro-Caribbean patients, the RAAS system is not dominant (2) and so CCBs are usually the first treatment used instead (13). Patients with comorbidities like diabetes, ACE-i or ARBs may be given first-line regardless of ethnic background due to renal and cardioprotective effects which are vital in slowing the progression of diabetes-related nephropathy and vascular damage (14). Overall, it is vital to consider the patient holistically and their circumstances to ensure effective, tailored patient care. 

References

  1. Mayet J. Cardiac and vascular pathophysiology in hypertension. Heart [Internet]. 2003 Sep 1 [cited 2025 Feb 14];89(9):1104–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1767863/
  2. Beevers G, Lip GYH, O’Brien E. ABC of hypertension: The pathophysiology of hypertension. BMJ [Internet]. 2021 Apr 14 [cited 2025 Feb 14];322(7291):912–6. Available from: https://www.bmj.com/content/322/7291/912.1
  3. Liu J, Wu J. The Pathogenesis and Impact of Arterial Stiffening in Hypertension: The 2023 John H. Laragh Research Award. American Journal of Hypertension. 2024 Jan 12;37(4):241–7.
  4. Fountain JH, Lappin SL, Kaur J. Physiology, renin angiotensin system [Internet]. National Library of Medicine. StatPearls Publishing; 2023 [cited 2024 Feb 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470410/
  5. Mancia G, Grassi G. The Autonomic Nervous System and Hypertension. Circulation Research [Internet]. 2014 May 23 [cited 2024 Feb 15];114(11):1804–14. Available from: https://www.ahajournals.org/doi/10.1161/circresaha.114.302524
  6. Armstrong M, Moore RA, Kerndt CC. Physiology, Baroreceptors [Internet]. National LIbrary of Medicine. StatPearls Publishing; 2023 [cited 2025 Feb 15]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538172/
  7. Kougias P, Weakley SM, Yao Q, Lin PH, Chen C. Arterial baroreceptors in the management of systemic hypertension. Medical science monitor : international medical journal of experimental and clinical research [Internet]. 2010 [cited 2025 Feb 15];16(1):RA1. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC2921195/
  8. Chakraverty R, Samanta K, Mandal P, Karmakar S. Chapter 16 – Mechanism of action of diuretic and anti-diuretic drugs [Internet]. Kazmi I, Karmakar S, Shaharyar MdA, Afzal M, Al-Abbasi FA, editors. ScienceDirect. Academic Press; 2023 [cited 2025 Feb 15]. p. 369–90. Available from: https://www.sciencedirect.com/science/article/pii/B9780323998550000166
  9. National Institute for Health and Care Excellence. Diuretics [Internet]. NICE. 2023 [cited 2025 Feb 15]. Available from: https://bnf.nice.org.uk/treatment-summaries/diuretics/
  10. Herman L, Bashir K. Angiotensin Converting Enzyme Inhibitors (ACEI) [Internet]. National Library of Medicine. StatPearls Publishing; 2023 [cited 2025 Feb 16]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431051/
  11. klabunde R. CV Pharmacology | Angiotensin Receptor Blockers (ARBs) [Internet]. Cvpharmacology.com. 2011 [cited 2025 Feb 16]. Available from: https://cvpharmacology.com/vasodilator/ARB
  12. McKeever RG, Hamilton RJ. Calcium channel blockers [Internet]. Nih.gov. StatPearls Publishing; 2022 [cited 2025 Feb 16]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482473/
  13. NICE. Recommendations | Hypertension in adults: diagnosis and management | Guidance | NICE [Internet]. Nice.org.uk. NICE; 2019 [cited 2025 Feb 16]. Available from: https://www.nice.org.uk/guidance/ng136/chapter/Recommendations#treating-and-monitoring-hypertension
  14. Whalen KL, Stewart RD. Pharmacologic Management of Hypertension in Patients with Diabetes. American Family Physician [Internet]. 2008 Dec 1 [cited 2025 Feb 16];78(11):1277–82. Available from: https://www.aafp.org/pubs/afp/issues/2008/1201/p1277.html

Edited by: Sofía Oural Martínez

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