Use of Drugs for the Treatment of Hypertension

Angiotensin Converting Enzyme Inhibitors

Angiotensin Converting Enzyme Inhibitors or “ACE Inhibitors” are a group of drugs which treat hypertension by inhibiting the Angiotensin Converting Enzyme. This enzyme is responsible for converting the inactive protein Angiotensin I into the active Angiotensin II. This has a large and complex range of effects in the regulation of blood pressure via the renin-angiotensin system - Angiotensin II effects changes in salt and water retention via the release of aldosterone and vasopressin and vasoconstriction (particularly in the kidneys). 

ACE Inhibitors are a commonly prescribed drug in the treatment of hypertension. They are often used because they are quite well tolerated by patients who take them. There are a variety of common side effects but they are rare. For this reason, ACE inhibitors are alongside Calcium-Channel blockers and Thiazide-Type Diuretics as a first choice for treating patients who are newly diagnosed with hypertension.

 

Many of the common ACE inhibitors use are:

Perindopril, Trandolapril, Captopril, Lisinopril, Ramipril, Quinapril, Enalapril, Fosinopril.

 

Mechanism of Action

By inhibiting Angiotensin Converting Enzyme, it decreases levels of Angiotensin II in the blood plasma.

See table 1 for a breakdown of the different effects.

This causes a variety of effects:

  • Angiotensin II causes Aldosterone release from the adrenal cortex. Aldosterone is a steroid hormone.  This acts on the kidneys and increases water and sodium reabsorption from the distal convoluted tubule and collecting duct. At the same time, potassium re-absorption is reduced. This acts to concentrate the urine more and increase blood volume.
  • Angiotensin II causes generalised vasoconstriction throughout the body. This acts to increase blood pressure. It also causes efferent arterioles of the juxtaglomerular apparatus to constrict, and this reduces the rate of blood flow to the kidneys (the resistance to the fluid in the arteriole is proportional to the radius of the arteriole to the power of four – increased resistance causes the flow of blood to slow). Since flow is lower, renal output drops and more fluid is retained, increasing blood volume.
  • It also caused Vasopressin release from the posterior pituitary gland. This also increases the sodium and water permeability of the collecting duct, and causes increased water reabsorption through a different mechanism to aldosterone.
  • Angiotensin II also generally increases sympathetic transmission – the state of sympathetic activity increases, and this results in a series of changes that increase blood pressure including an increase in vasoconstriction and changes in heart rate.
  • For a more in-depth discussion of the sympathetic NS, see Thiazide Diuretics

 

Do ACE inhibitors completely block Angiotensin II formation?

No! By blocking ACE, they don’t completely stop the formation of Angiotensin II. There are still other pathways in place which create Angiotensin II, for example Angiotensin Converting Enzyme 2!

To an extent, this is one of the reasons ACE is a useful drug – were it to completely block such a large-scale homeostatic mechanism such as the Renin-Angiotensin system, it would probably cause a greater range of side effects.Image courtesy of Wikipedia, chemical structure of Lotarsan

There are drugs which can be used to block Angiotensin II signalling – Angiotensin II receptor Antagonists. They block the AT1 receptor for Angiotensin II (again, they don’t block all Angiotensin II signalling). These are often used in place of ACE inhibitors where a patient does not tolerate ACE inhibitors well (for example, where a patient experiences a dry cough –see below)

The image to the left shows the chemical structure for Lotarsan, one of the first Angiotensin II receptor Antagonists.

 

 

 

 

ACE Inhibitors and Low-Renin Essential Hypertension

  • There is a common form of essential hypertension where low levels of renin in the blood plasma are present. Since there is low renin, this means there is little activity of the Renin-Angiotensin system.
  • As such it is often the case in these individuals that the renin-angiotensin system is making little contribution to their high blood pressure.
  • This form of hypertension is commonly seen in people of Afro-Caribbean descent.  For this reason, where an Afro-Carribean patient is first diagnosed with hypertension, doctors avoid prescribing ACE inhibitors, and used Thiazide-like diuretics.
  • Young people who are not of Afro-Caribbean origin often respond better to ACE inhibitors – in these patients the kidneys are often more of a contributing factor. This makes sense if you think about it - in patients over 55 there are often a lot more factors involved in their essential hypertension (for example, changes in vasculature associated with aging, increased obesity, increased sedenteriness), so other drugs like Thiazides are often preferred by medics.

 

Adverse reactions and problems

  • Rarely, an increase in bradykinin caused by the effects of ACE inhibitors can cause a dry cough. As well as converting Angiotensin I to Angiotensin II, it also has a secondary function in degrading bradykinin. Bradykinin is involved in the immune response, and for this reason causes the dry cough when levels increase in the lung parenchyma.                                                Man coughing
  • As well as resulting in a dry cough, much less commonly increased levels of bradykinin can also cause angioedema – this is a swelling of the dermis and associated tissues, which can in some cases be fatal – it is an again an allergic response.
  • Where these type of inflammatory responses are present, this is the reason that Angiotensin II receptor antagononists are used, because they do not affect bradykinin levels and so these symptoms are not seen.
  • It can cause hyperkalaemia (high serum potassium levels) in some individuals, especially if they have reduced kidney function. This is because aldosterone is one of the main factors responsible for directly regulating the plasma concentration of potassium. Aldosterone increases the rate of potassium excretion, so where its levels are inhibited, more potassium is retained.
  • Since it effectively reduces the function of the kidneys, in patients who already have reduced renal function it is not widely recommended for use. This is true for many antihypertensive drugs, and doctors take special care when treating these patients.


References

 

 Top image created by Martin Le Breuilly. Middle image courtesy of Wikipedia under the Creative Commons License. Bottom image couresy of Flickr under the Creative Commons License.