PHAR 6: Hypertension

Question 1

Observe the learning outcomes of this session

Answer 1

Question 2

What is hypertension?

Answer 2

• Hypertension refers to the condition in which your blood pressure is considered too high.
• Specifically, this refers to the pressure on your arterial vessels that carry blood from your heart to the rest of your body.
• When blood travels through the arteries, it pushes against the arterial wall.
• This force is exerted over the surface area of the artery.
• As pressure is defined as force over area, blood pressure is defined as the force applied by blood over the surface area of the blood vessel.

Question 3

Where in the body is blood pressure usually measured?

Answer 3

• When it comes to medicine, blood pressure is usually measured using the brachial artery (major blood vessel in the upper arm).
• The force at which blood is pushed through the artery will depend on the force at which this blood is pumped from the heart.
• As you can imagine, the surface area will be different depending on which vessel you are looking at.

Question 4

Use this diagram to describe blood flow and how this affects blood pressure on the brachial artery during a single heartbeat

Answer 4

• When the ventricles of the heart contracts, blood is pumped from the heart through the aorta (main artery leaving the heart) to the arteries that deliver blood to the rest of the body.
• One of the branches leaving the aorta carries blood to the brachial artery located in the upper arm.
• As the heart is contracting and the blood being pumped from the heart travels through the arteries, the force the blood exerts on the arterial wall increases until the heart is fully contracted.
• This period where the heart is contracting and consequently squeezing blood into the arteries is referred to as systole.
• Systolic blood pressure defines the point at which the force the blood exerts against the arterial wall is at its maximum (heart is fully contracted).
• After this point, the heart begins to relax and refill.
• The force the blood exerts on the arterial wall declines as a result until the heart is fully relaxed.
• It is as this point in which the pressure on the arterial wall be at its minimum (diastolic blood pressure).
• This period where the heart is relaxing is referred to as diastole.
• From this, you can see that your blood pressure is constantly changing within a range depending on whether your heart is contracting or relaxing and the systolic and diastolic blood pressure defines the lowest and highest points of blood pressure within that range.
• This pressure is measured in millimeters of mercury (mmHg).
• Looking at the pressure in the arteries during a single cardiac cycle, you can see that there is always force exerted on the arteries (blood pressure is always above zero) even when the heart is completely relaxed.

Question 5

Observe the ventricular and arterial pressure during cardiac cycles

Answer 5

• Looking at the pressure in the arteries during a single cardiac cycle, you can see that there is always force exerted on the arteries (blood pressure is always above zero) even when the heart is completely relaxed.

Question 6

If we compare arterial pressure to pressure in the ventricles of the heart (ventricular pressure), you can see that the arterial pressure does not go below 80 mmHg even when there is no/very little ventricular pressure. Why do you think this is?

Answer 6

• due to elastic recoil of arteries

Question 7

What is elastic recoil?

Answer 7

• When the heart pumps blood into the artery, the artery expands in response due to the abundance of elastic fibres along the arterial wall.
• As soon as the pressure to expand is no longer there (when the heart is relaxed), the arteries recoil back to the original shape.
• This is a result of the inherent ability of the arteries to change shape and is referred to as elastic recoil.
• This recoil maintains pressure exerted on the arterial wall when the heart is completely relaxed.
• This is what governs diastolic pressure and why there is always pressure in the arteries even when there is 0 mmHg pressure in the ventricles.
• This ensures that even during diastole blood continues to move around the circulatory system.

Question 8

What is blood pressure measured with?

Answer 8

• a sphygmomanometer.
• This consists of an arm cuff, pump and dial to exert pressure on the arm.
• A stethoscope is used alongside this to measure the points at which the blood flow is disturbed.

Question 9

Describe how blood pressure is measured using a sphygmomanometer and stethoscope

Answer 9

-

• a sphygmomanometer (or simply blood pressure monitor) works by disturbing the regular blood flow in the brachial artery by applying sufficient pressure to the arm.
• For this, the pump is used to inflate the cuff and apply enough pressure to disrupt blood flow through the brachial artery.
• This pressure in the cuff is then slowly released and at some point blood will start to flow through the brachial artery again

– this is when the pressure exerted by the heart is sufficient to force blood through the slowly widening brachial artery.

• The point at which this occurs is the systolic pressure i.e. the maximum pressure the heart can exert.
• With the stethoscope, this is identified as the point at which rhythmic noises can be heard in the artery which is due to turbulent blood flow through the partially compressed brachial artery (referred to as Korotkoff sounds).
• The pressure is then continually released and until the artery is completely relaxed, you will continue to hear the turbulent flow.
• At the point where there are no longer rhythmic sounds due to turbulent flow, this indicates there is no longer any resistance to blood flow (diastolic pressure).
• Nowadays, blood pressure monitors are largely automated with an auto-inflatable cuff and digital reading.

Question 10

What factors influence blood pressure?

Answer 10

• Cardiac output:
• The amount of blood the hearts pumps through the circulatory system in a minute.
• This will depend on the stroke volume (amount of blood pumped out during a single contraction) and the heart rate.
• Total peripheral resistance:
• This is also referred to as systemic vascular resistance (SVR) and describes the resistance the blood vessels have to the flow of blood.
• Volume of circulating blood:
• This is the volume of blood that is being carried along the blood vessels and is determined by the production of red blood cells and plasma.
• Viscosity of blood:
• This refers to the consistency of blood in relation to its thickness and stickiness.
• Elasticity of vessel walls:
• Blood vessel walls contain collagen and elastic fibres that allow the tissue to expand in response to an increase in force during a pulse.

Question 11

Which two of these five factors listed above do you think could be rapidly controlled to regulate blood pressure?

Answer 11

• cardiac output and total peripheral resistance
• Both the cardiac output and total peripheral resistance are controlled by the autonomic nervous system.
• These factors can therefore be easily regulated via pharmacological intervention by methods such as lowering the heart rate to decrease the cardiac output or increasing the diameter of blood vessels to lower the total peripheral resistance.
• While the other factors do influence blood pressure, they are not things that can be changed quickly and are therefore unhelpful in mediating rapid changes in blood pressure.

Question 12

Generally, what is a healthy blood pressure reading?

However, what factors varies what is considered normal?

Answer 12

• Generally speaking, a blood pressure reading of < 120/80 mmHg is considered healthy.
• The exact values that are considered normal however varies depending on factors such as height, age and weight

Question 13

How do height and weight influence blood pressure?

Answer 13

• these affect the metabolic demand of the circulatory system.
• In general, the taller you are, the harder your heart needs to work to pump blood around the body.
• This is shown by the fact that our blood pressure increases during childhood
• approximately 100/60 mmHg in a toddler versus 120/80 mmHg in a healthy adult.
• An increase in cardiac output is therefore required to increase blood pressure to ensure adequate perfusion of a larger surface area.
• This is also true as body mass increases which would again relate to a larger surface area for perfusion requiring a greater overall blood pressure.
• However, this is complicated in adulthood by the fact that an increase in body mass is most commonly due to overweight and obesity.
• Obesity is a risk factor for increased blood pressure, due to a variety of pathophysiological processes.

Question 14

Why does blood pressure tend to increase with age?

Answer 14

• This in part is due to the general aging process where there is a loss of elasticity in the arterial wall but also can be pathophysiological.
• Examples of this include atherosclerosis where fatty deposits build up on the arterial wall restricting blood flow and increasing resistance.
• Interestingly, when you are old, height appears to be associated with lower blood pressure (in contrast to young adults).
• The reasons for this are unclear and current research is attempting to explain this phenomenon.

Question 15

What are the blood pressure classifications?

Answer 15

• Although the exact blood pressure classifications may vary depending on the individual, a healthy cut off is <120/80 mmHg, and anything above this is considered either elevated or hypertensive depending on the degree of severity.

Question 16

Why is it important to monitor blood pressure, especially for those who are high risk?

Answer 16

• High blood pressure is often called the “silent killer” as there are no symptoms for an individual with hypertension.
• For this reason, it is important to monitor blood pressure, especially those who are high risk.
• When hypertension has been diagnosed, the treatment will vary depending on the degree of severity, the age of an individual, whether the individual is at risk of or has cardiovascular disease, whether there is any target organ damage or any other underlying medical condition.

Question 17

What are the two classes of hypertension?

Answer 17

• primary hypertension (or essential hypertension) where there is no known medical cause to the condition
• secondary hypertension where changes in blood pressure are the result of a known underlying medical condition.
• Most people who are diagnosed have primary hypertension where the cause is not known.
• Despite the causes of hypertension not being fully understood, there are many factors that are known to increase one’s risk of being hypertensive.
• These risk factors can be related to hereditary and physical attributes that are not modifiable.
• In addition to this, there are also an array of modifiable risk factors that one can manage to significantly reduce the risk of being hypertensive.

Question 18

Describe some non-modifiable risk factors for hypertension

Answer 18

These mostly include factors determined by genetics:

• Race:
• It has been found that African Americans are at much higher risk of developing high blood pressure than any other race and tend to have more severe cases.
• In addition to this, medication is generally less effective (covered in more detail later).
• It is not clear why this is the case but there are some theories that African Americans may have genes that make them more sensitive to salt.
• Family History:
• Like many other conditions with a hereditary component, hypertension tends to run in the family.
• While there are some common genetic variants associated more with people with primary hypertension than unaffected individuals, there is no known common genetic variants that cause hypertension.
• It is important to note that families tend to share a similar environment which may explain this commonality in some families.
• Gender: Men under the age of 65 are more at risk of being hypertensive than women <65.
• It has been found that men have higher levels of hypertension compared to woman of the same age group, particularly in early adulthood.
• This is particularly evident with those who have low testosterone levels.
• After 65 however, women are more at risk of developing hypertension.
• Hormonal changes during menopause is often associated with a rise in systolic blood pressure.

Question 19

What are some modifiable risk factors for hypertension?

Answer 19

These include factors associated with lifestyle:

• Unhealthy diet with excess sodium:
• High salt intake presents a big challenge to your kidneys to excrete the excess salt.
• The prevailing theory is that high salt intake leads to an expansion of circulating blood volume.
• This increases the stroke volume (one component of your cardiac output) thereby increasing the force the blood exerts on the arteries when the heart is contracting.
• The kidney cannot excrete the sodium quickly enough to restore the blood volume.
• Being overweight or obese:
• The mechanism of obesity induced hypertension is also complex.
• One theory suggests that inflammation associated with obesity contributes to changes in the kidney, heart and vasculature that can contribute to the development of hypertension.
• Excess alcohol consumption:
• Excessive alcohol levels have been shown to increase blood pressure.
• The higher the consumption, the higher the risk of developing hypertension.
• The exact causes of this are not fully understood but there are a number of proposed mechanisms.
• This includes enhanced sympathetic activity, stimulation of the renin-angiotensin-aldosterone system, increased vascular activity and increased cortisol levels.
• Stress:
• Too much stress can lead to excess cortisol levels.
• This induces sodium retention and blood volume expansion via mineralocorticoid activity.
• Additionally, increased cortisol levels inhibit nitric oxide induced vasodilation.
• Physical inactivity:
• Continuous physical activity improves cardiovascular health by improving blood flow (particularly through the skeletal muscle), reducing peripheral vascular resistance (partly due to vasodilation in the skeletal muscle) and reducing the resting heart rate.
• There is a higher prevalence of hypertension with people who are not physically active.
• Smoking:
• As you will have seen in the session on stimulants nicotine has multiple actions to increase blood pressure including activating the sympathetic nervous system, increasing heart rate, vasoconstriction and ultimately an increase in blood pressure.
• The chemicals in tobacco has also been shown to damage the lining of the arterial walls causing blood vessel narrowing.
• High cholesterol:
• High cholesterol levels leads to a build-up of plaque (fatty deposits) in the arterial walls, causing hardening and narrowing of the arteries.
• This narrowing will increase peripheral resistance in addition to contributing to the risk of stroke.

Question 20

What is secondary hypertension caused by?

Answer 20

• Secondary hypertension is often caused by conditions such as chronic kidney disease or diabetes.
• Secondary hypertension can occur in any individual with a condition that affects the kidneys, heart, arteries or endocrine system.
• The underlying condition must be treated in this case.

Question 21

How is treatment for hypertension chosen?

Answer 21

• When an individual is diagnosed with hypertension, the choice of antihypertensive treatment greatly depends on whether the individual has diabetes, their age, whether they are of black African or African Caribbean family origin and whether they have already had any previous treatment for hypertension.

Question 22

What are the three main classes of drugs used to treat hypertension?

Answer 22

1. Angiotensin-converting enzyme (ACE) inhibitors and Angiotensin II receptor blockers
2. Calcium Channel Blockers
3. Thiazide-like diuretics

Question 23

What is the renin-angiotensin system?

Answer 23

• The renin-angiotensin system is an endocrine system which exerts some control over blood pressure via the regulation of peripheral vascular resistance and blood volume.

Question 24

What detects a change in blood pressure within the renin-angiotensin system?

Answer 24

• When there is a change in blood pressure, this is detected in the kidney via baroreceptors in the afferent arterioles that detect changes in renal perfusion (blood flow to the kidney)

Question 25

What detects sodium concentration of the kidney filtrate in the renin-angiotensin system?

Answer 25

• the macula densa cells in the distal convoluted tubule can also detect the sodium concentration of the kidney filtrate.

Question 26

Describe renin and angiotensin release when blood pressure is low

Answer 26

• When blood pressure is low this leads to a decrease in renal perfusion and/or a decrease in sodium reabsorption in the kidney tubules (recognised by the macula densa cells).
• Both of these changes can act to stimulate renin release from the juxtaglomerular apparatus located in the distal convoluted tubule of the kidney.
• Renin circulating in the blood then cleaves the precursor protein angiotensinogen produced in the liver, converting it to angiotensin I, an inactive peptide hormone.
• Angiotensin I is then converted to the active version angiotensin II by the angiotensin converting enzyme (ACE) produced predominantly in the lungs.
• Some angiotensin II is also broken down into angiotensin III and IV by aminopeptidase A and N via the removal of a single amino acid.
• Angiotensin II and III both stimulate aldosterone release from the adrenal gland.
• Angiotensin IV has its own actions including plasminogen activator inhibitor-1 release involved in the breakdown of blood clots.

Question 27

Which chemical is mostly responsible for the physiological response that is initiated through the renin-angiotensin system?

• what is its receptor?
• what are the effects of this receptor?

Answer 27

• Angiotensin II is mostly responsible for the physiological response that is initiated through this system.
• The peptide is an agonist to the angiotensin II type 1 receptor (AT1) and type 2 receptor (AT2).
• AT1 and AT2 are members of the G-protein coupled receptor family and are coupled to Gq (AT1 and AT2) or Gi (AT2).
• Most effects within the renin-angiotensin system are mediated via AT1 receptor activation.
• AT1 stimulation activates Gq proteins and subsequently Phospholipase C and IP3 mediated calcium release.
• These receptors are expressed throughout the circulatory system, increasing blood pressure via different mechanisms.

Question 28

How does AT1 receptor activation in the vascular smooth muscle increase blood pressure?

Answer 28

• AT1 receptor activation on the vascular smooth muscle causes vasoconstriction, increasing blood pressure through an increase total peripheral resistance.

Question 29

How does AT1 receptor activation in the kidney increase blood pressure?

Answer 29

• AT1 receptor activation on the kidney increases water and sodium reabsorption through its action on the Na+/H+ exchange proteins in the proximal tubules of the kidney, increasing blood pressure through an increase in the volume of circulating blood by increasing water retention.

Question 30

What do AT1 receptors located on the posterior pituitary and adrenal cortex do?

Answer 30

• Activation on the posterior pituitary induces antidiuretic hormone (ADH or vasopressin).
• This activates vasopressin 2 receptors on the collecting tubules and ducts of the kidney leading to an increase in aquaporin (water channels) expression via adenyl cyclase activation.
• This in turn increases the kidney’s permeability to water, increasing the level of water reabsorption and ultimately the volume of circulating blood.
• Activation of Vasopressin 1 receptors also causes vasoconstriction, thereby further increasing blood pressure through an increase in total peripheral resistance.

Question 31

Describe how AT1 receptor activation stimulates the release of aldosterone

Answer 31

• AT1 receptor activation also stimulates the release of aldosterone through its action on the adrenal cortex.
• Aldosterone is a mineralocorticosteriod hormone that activates cystolic receptors in the epithelial cells of the renal collecting ducts.
• Aldosterone receptor activation increases the sodium reabsorption by initiating the transcription and translation of important proteins involved in sodium transport including components that make up the Na+/K+-ATPase pump.
• There is also a rapid increase in Na+ influx through its action on the Na+/H+ exchanger proteins.
• This increase in Na+ reabsorption increases the water that is reabsorbed and ultimately the volume of circulating blood.

Question 32

Compare the effects of AT2 receptors to AT1 receptors

Where are AT2 receptors predominantly expressed?

Answer 32

• activation of AT2 receptors has opposing effects to AT1 receptors.
• AT2 receptors are predominantly expressed during fetal development and in specific areas of the brain.

Question 33

What is the function of the renin-angiotensin system as a whole?

Answer 33

• Looking at the renin-angiotensin system as a whole, we can see there are a myriad of ways in which the total peripheral resistance and volume of circulating blood is increased via vasoconstriction of vascular smooth muscle and an increase of sodium and water reabsorption in the kidney, ultimately increasing blood pressure.
• With the use of angiotensin II type receptors (AT1) and ACE inhibitors, we can see that the physiological output of the system will be completely inhibited, thereby preventing any increase in blood pressure caused by renin release and the production of angiotensin II.

Question 34

What are the most commonly prescribed medications for hypertension?

Who are they prescribed to?

Answer 34

• ACE inhibitors and angiotensin II type blockers (ARBs)
• They are prescribed to those who are under 55 and are not of black-African and African-Caribbean origin.

Question 35

What are some common ACE inhibitors?

Answer 35

• Enalapril, Lisinopril, Perindopril and Ramipril.

Question 36

What do ACE inhibitors do?

Answer 36

• Along with the inhibition of sodium and water reabsorption and their vasodilative properties, ACE inhibitors also increase levels of bradykinin due to ACE’s role in breaking down bradykinin, leading to an accumulation in the upper and lower respiratory tract.
• Bradykinin promotes inflammation through prostaglandin release.
• Increased levels can therefore be associated with complications related to the lungs.
• A dry and irritating cough is one of the common side effects of ACE inhibitor use.
• This is not caused by all ACE inhibitors however so it is unclear whether this is caused by increased levels of bradykinin.
• Other possible side effects include kidney problems and hypotension.
• Individuals on this medication should be monitored.
• In general, ACE inhibitors are very effective at decreasing blood pressure in those who are hypertensive, especially those who have increased renin release.
• For healthy individuals who do not have excessive amounts of salt in their diet, the effect of ACE inhibitors on blood pressure is fairly minimal.

Question 37

How do ARBs work?

What are some common ARBs?

Answer 37

• ARBs work similarly to ACE inhibitors in that they also reduce sodium and water reabsorption and inhibit vasoconstriction caused by angiotensin II.
• ARBs are used as an alternative to ACE inhibitors and are not associated with the same respiratory complications.
• Common ARBs include candesartan, losartan, telmisartan, and valsartan.

Question 38

What are some side effects of ARBs and ACE inhibitors?

Answer 38

• Due to the direct effect that AT1 receptor activation has on K+ excretion
• (e.g. through an increase in Na+/K+ ATPase activity at the collecting ducts of the kidney), the use of ARBs can be associated with hyperkalemia (high potassium levels in the blood).
• This side effect can be caused by ACE inhibitors also and must be monitored with those on this medication, especially those who are taking multiple drugs.

Question 39

Who are calcium channel blockers prescribed to and why?

Answer 39

• Calcium channel blockers are prescribed as a first line of treatment for hypertensive patients who are over 55 years of age or of Black African or African-Caribbean family origin.
• For those of African origin, they are prescribed instead of ACE inhibitors and ARBs as the effects of inhibiting the renin-angiotensin system tends to be more attenuated when it comes to lowering blood pressure.
• Additionally, those of African origin are more at risk of developing drug-induced angioedema from taking ACE inhibitors and ARBs causing swelling in certain areas like the lips or around the eyes.
• This also applies to older people of all other ethnic origin as the risk of developing an allergic-type reaction to this medication is increased.

Question 40

What are voltage-gated calcium channels?

How many subtypes are there?

Answer 40

• Many calcium channels are voltage-gated, meaning they are activated when the membrane is sufficiently depolarized.
• There are five distinct subtypes of voltage-gated calcium channels with different gating and kinetic properties

Question 41

Describe L-type calcium channels

• its functions

Answer 41

• L-type calcium channels (L- meaning long-lasting as these channels have much longer opening times compared to other ion channels) are widely expressed throughout the body including the heart, smooth muscle and skeletal muscle.
• L-type channels are crucial for excitation-contraction coupling and thus important in regulating the contraction of cardiac and smooth muscle.
• In cardiac muscle cells, Ca2+ entry through L-type calcium channels initiates calcium release from intracellular stores to initiate contraction.

Question 42

How do you think a calcium channel blocker could lower blood pressure?

Answer 42

• On the vascular smooth muscle, L-voltage gated induced contraction causes vasoconstriction.
• By blocking this event, the vascular smooth muscle relaxes (vasodilation), reducing the total peripheral resistance.
• systemic vasodilation also reduces the ventricular afterload which is the pressure the heart must work against to inject blood into the blood vessels during contraction.
• By reducing the afterload, the oxygen demand of the heart is also reduced.
• Some calcium channel blockers also decrease the force at which the heart contracts by acting on the L-type calcium channels that are located on the cardiac myocytes.
• Here, calcium entry stimulates the heart to contract more forcefully.
• By inhibiting these calcium channels, the force of contraction is reduced.
• This decreases the stroke volume (volume of blood per beat), thereby decreasing the cardiac output and blood pressure.
• Calcium channel inhibition on the sinoatrial node and atrioventricular node also decreases the heart rate, further reducing the cardiac output.

Question 43

Give some examples of calcium channel blockers or antagonists that are prescribed for hypertension

Answer 43

• examples of calcium channels blockers or antagonists that are prescribed for hypertension include
• amlodipine, felodipine and nifedipine.
• Effects on vascular tone, heart rate and contractility are very much dependent on the choice of calcium channel blocker given.
• Amlodipine (a dihyrdopyridine type calcium channel blocker) for example is more selective for the calcium channels on the vascular smooth muscle causing systemic vasodilation.
• Other calcium channel blockers such as verapamil and diltiazem are more cardio-selective, decreasing heart rate and contractility.
• these are normally prescribed to treat angina pectoris where there is restricted blood flow to the heart causing the heart to become hypoxic (often characterized by chest pain).
• Decreasing contractility and heart rate will decrease the myocardial oxygen demand, thereby relieving any associated chest pain.

Question 44

Briefly explain what diuretics are and how they work for hypertension

Answer 44

• diuretics work by targeting a specific site on the kidney to increase urine production
• In the case of hypertension, this increase in urine will result in a decrease in blood volume which in turn will reduce blood pressure

Question 45

Describe the structure and function of the kidney

Relate this to how diuretics work

Answer 45

• the main function of the kidney is to maintain the interior environment of the body by eliminating waste products and regulating the volume, electrolytes and pH of the extracellular fluid.
• From previous modules, you may remember that the kidneys are also the main site in which drugs and their metabolites are eliminated from the body.
• Each kidney is made up of an outer cortex, medulla, and renal pelvis which empties urine into the ureter.
• The functional unit of the kidney is the nephron. It consists of a cluster of capillaries called a glomerulus.
• This projects into the Bowman’s capsule which is a cup-like sack that drains into the proximal tubule.
• This then extends to the loop of Henle and then to the distal tubule and collecting duct.
• Throughout the renal tubular network, there are transporter systems that control the level of ions that are absorbed back into the blood stream or excreted via the renal tubules into the ureter.
• It is this ionic balance between the capillary network and renal tubules which govern the degree of water reabsorption and consequently the amount of water in the urine.
• Specifically, this is often in relation to sodium as the more sodium that is excreted, the more water is excreted.
• Diuretics work by targeting these transport systems and consequently affecting the amount of sodium (and water) that is reabsorbed back into the bloodstream.
• This decrease in reabsorption decreases blood volume and consequently blood pressure.

Question 46

Looking at the different segments along the renal tubules, you can see the amount of sodium reabsorbed by the different transport system varies greatly. The majority of sodium reabsorption occurs at the proximal tubule whereas the transport systems at the distal tubule are responsible for 5% or less.

What transport systems do you think are targeted by the diuretics that are used to treat hypertension?

Answer 46

• Thiazide-like diuretics target the sodium-chloride co-transporter located on the distal tubule of the kidney.

Question 47

Why do thiazide-like diuretics target the sodium-chloride co-transporter when it is only responsible for 5% of sodium reabsorption?

Why not target a transporter system that will be more efficacious?

Answer 47

• Too much fluid loss can certainly be a bad thing.
• Loop diuretics which inhibit the sodium-potassium-chloride cotransporter located on the thick ascending limb of the Loop of Henle (responsible for up to 25% of sodium reabsorption) has been described to cause “torrential urine flow”.
• Excessive sodium and water loss can result in hypovolemia (abnormally low extracellular fluid) and hypotension (abnormally low blood pressure), hypokalemia (low plasma K+) and metabolic alkalosis.
• For this reason, loop diuretics are only prescribed to treat hypertension for those who have renal impairment.

Question 48

When are thiazide-like diuretics prescribed under current treatment guidelines?

Give some examples of medications

Answer 48

• Under current treatment guidelines, thiazide-like diuretics are only prescribed as a step 2 treatment.
• This means they are only are prescribed to hypertensive patients who have already been prescribed ACE inhibitors or ARBs but their blood pressure is still not under control.
• Examples of Thiazide-like diuretics include chlortalidone, indapamide and metolazone.
• Classical thiazides are also prescribed that not surprisingly work in the exact same way.
• Examples include hydrochlorothiazide and Bendroflumethiazide.

Question 49

How do thiazide-like diuretics work?

Answer 49

• Thiazide-like diuretics inhibit the Na+/Cl- co-transporter by competing with Cl- for the chloride binding site.
• As the protein is a co-transporter, reducing the likelihood that chloride will bind will also reduce the likelihood that both Cl- and Na+ will be transported from the distal tubule back into the bloodstream as the protein can only transport the two ions together.
• This decrease in Na+ reabsorption decreases the amount of water that is reabsorbed causing an increase in Na+ and water excretion through the collecting ducts and urethra.
• The end result is that less fluid is present within the bloodstream.
• A lower blood volume means less blood returning to the heart in the venous system – lower venous return. Venous return has a direct influence on heart contractility.
• If you think about it, this makes sense.
• If less blood is returned to the heart, then it doesn’t need to contract as forcefully to eject the blood from the ventricles.
• A lower heart contractility leads to a lower cardiac output which leads to a lower blood pressure.

Question 50

Can you see a potential problem there may be with decreasing blood volume and sodium levels that thiazide-like diuretics do?

Answer 50

• Remember the kidney can detect a reduction in blood volume and sodium concentration via the baroreceptors in the afferent arterioles and cells in the macula densa.
• A decrease in renal perfusion and sodium concentration triggers the release of renin from the juxtaglomerular cells.
• This ultimately triggers the Renin-Angiotensin system leading to an increase in blood pressure, thereby counteracting the effect of the thiazides.

Question 51

What are some other side effects of thiazide-like diuretics?

Answer 51

• Another important point to consider is drug tolerance.
• Overtime, thiazides can lose their diuretic effects.
• When this occurs, they can still be effective at lowering blood pressure. Continued
• Thiazide diuretics can also cause vasodilation independent of their diuretic effects.
• The mechanism of this is not fully understood as investigations using classical thiazides or thiazide-like diuretics have found significant differences in how these effects are induced.
• Some classical thiazides such as hydrochlorothiazide have been shown to induce vasodilation via calcium activated potassium channel activation for example whereas thiazide-like diuretics like indapamide have been shown to cause vasodilation via calcium channel antagonism.

Question 52

What is drug adherence?

Apply it to hypertension

Answer 52

• An often overlooked aspect of treatment is drug adherence i.e. is the patient actually taking the drug.
• At the start of this eModule we referred to hypertension as the ‘silent killer’.
• This relates to the fact that there are no specific symptoms associated with being hypertensive i.e. you wouldn’t know you were hypertensive unless someone measured your blood pressure.

Now imagine, you are a hypertensive patient who has just been prescribed an anti-hypertensive drug.

• You were given an ACE inhibitor and now you have a cough or you were given a calcium channel blocker and now you keep suffering dizzy spells (due to low blood pressure) or you were given a thiazide-like diuretic and now you keep needing to go to the bathroom.
• Would you keep taking the drug?

Question 53

Consider the data in the table below (derived from several studies comparing efficacy and adherence to common anti-hypertensives)

Suggest three take home messages

Answer 53

1. Adherence is not great for all of these drugs – even the most adherent drug class (ARBs) could still have nearly 40% of patients regularly choosing not to take them.
2. Efficacy for all of these drugs is pretty modest – between 10-15 mmHg.
3. If you had to choose, you would probably select the ARBs since they have the highest rate of adherence and the greatest impact on blood pressure.
4. Perhaps the reason why thiazide-like diuretics are not first line treatments is because of their rate of adherence.

Overall, if we simply look at efficacy (mean blood pressure reduction), then it may come as no surprise that most people require multiple anti-hypertensive medications to reduce their blood pressure sufficiently.

• However, as we increase the number of drugs, so the likelihood that patients will remain adherent decreases.