Drugs and the CVS: Vasculature

Question 1

How do the arterioles contribute to blood pressure?

Answer 1

Key:

• r = radius
• R = resistance
• F = flow

Think of it like like this

• Resistance is higher → flow is slower
• Slower flow means blood remains in the arteries for longer
• Therefore, you have increased blood volume in the arteries
• Increased blood volume → increased hydrostatic pressure → increased MAP
• Therefore:
  
  • Vasoconstriction → increased TPR → increased MAP
    
    • ​Arteriolar vasoconstriction

IMPORTANT:

• Arteriolar smooth muscle normally displays a state of partial constriction
  
  • This is known as vascular tone

Question 2

What is step 1 in hypertension treatment?

Answer 2

Under 55s

• Angiotensin converting ezyme (ACE) inhibitor
• Angiotensin receptor blocker (ARB)

Over 55s or Afro-Caribbeans (at any age)

• Calcium channel blocker (CCB)
• Thiazide-like diuretic

Question 3

What is step 2 in hypertension treatment?

Answer 3

A combination of either…

• Calcium channel blocker (CCB)
• Thiazide-like diuretic

with either…

• ACE inhibitor - generally this
• Angiotensin receptor blocker (ARB)

NOTE: For Afro-Caribbeans, ARB is preferred over ACE inhibitor

Question 4

What is step 3 in hypertension treatment?

Answer 4

Combination of:

• ACE inhibitor OR angiotensin receptor blocker (ARB)
  
  • Generally ACE inhibitor
• Calcium channel blocker
• Thiazide-like diuretic

Question 5

What is step 4 in hypertension treatment?

Answer 5

You get to step 4 when the body has become resistant to the treatment already given → resistant hypertension

• Resistant hypertension = high blood pressure that remains uncontrolled despite treatment with at least three antihypertensive agents, one of which is a diuretic, at best tolerated doses

Treatment - consider:

• Low dose spironolactone
  
  • This is further diuretic therapy
• Beta-blocker or alpha-blocker

Question 6

Which of the drugs used to treat hypertension have an impact on vascular tone?

Answer 6

• ACE inhibitor
• Angiotensin receptor blocker
• Calcium channel blocker
• Alpha-blocker

Question 7

Describe the renin-angiotensin-aldosterone system (RAAS).

Answer 7

Renin production in the kidneys is stimulated by:

• Reduced renal Na⁺ reabsorption
• Reduced renal perfusion pressure
• Increased sympathetic activation

Renin is an enzyme - catalyses:

• Angiotensinogen → angiotensin I

ACE produced in lungs - catalyses:

• Angiotensin 1 → angiotensin II

Effects of angiotensin II:

• SNS activation
• Stimulates thirst
• Vasoconstriction
• Salt and water retention - DIRECTLY
• Salt and water retention - indirectly by stimulating aldosterone secretion from the adrenal gland
  
  • Salt and water retention → increased blood volume

Angiotensin II acts on its targets via the AT₁ receptor and acts to increase blood pressure

REMEMBER:

• ACE also breaks down bradykinin into inactive metabolites

Question 8

What are the drug actions on the RAAS?

Answer 8

ACE inhibitor

• Inhibits ACE
• Prevents conversion of angiotensin → angiotensin II
• Also prevents breakdown of bradykinin - less important

Angiotensin receptor blocker

• Blocks the AT₁ receptor to prevent angiotensin II binding to its target tissues and exerting its effect on them

Question 9

What are ACE inhibitors used to treat?

Answer 9

• Hypertension
• Heart failure
• Post-myocardial infarction
• Diabetic nephropathy
• Progressive renal insufficiency
• Patients at high risk of cardiovascular disease

In all these conditions, it is useful to reduce blood pressure, therefore ACE inhibitors are used

Question 10

Explain in more detail how ACE inhibitors are useful in treating hypertension and heart failure.

Answer 10

ACE inhibitors prevent the formation of angiotensin II

Effects of angiotensin II

In relation to hypertension:

• BP = CO x TPR
  
  • BP - arterial pressure
• ​Angiotensin II stimulates vasoconstriction which inreases TPR
• Increased TPR leads to increased venous return to the heart
  
  • Vasoconstriction of all blood vessels, including veins will mean less blood pools in veins and therefore returns to the heart faster
• ​Angiontesin II also stimulates salt and water retention
  
  • This leads to increased blood volume which also leads to increased venous return
• Increased venous return = increased preload → increased contractility (via Starling’s law) → increased CO
• As per the equation: both increased TPR and increased CO lead to an increase in BP

In relation to heart failure:

• Angiotensin II stimulates vasoconstriction
• Vasoconstriction → increased afterload → increased cardiac work
  
  • i.e. The heart has to work harder which exacerbates the problem as the heart is already failing - insufficient CO to meet demand
• Angiotensin II also increases venous return
  
  • Since the heart is not working properly, you have reduced SV and therefore:
    
    • Long term fluid retention and congestion in the circulatory system → oedema

Question 11

Give an example of an ACE inhibitor.

Answer 11

Enalapril

Question 12

What are angiotensin receptor blockers used to treat?

Answer 12

• Hypertension
• Heart failure

REMINDER - how it works:

• These drugs are ntagonists of type 1 (AT₁) receptors for angiotensin II
• Therefore they act to prevent the renal and vascular actions of angiotensin II
  
  • Vascular - vasoconstriction
  • Renal
    
    • Salt and water retention
    • Aldosterone secretion - aldosterone acts on renal tubules
• ​NOTE: Angiotensin II also blocks AT₁ receptors in the brain to prevent SNS activation and stimulation of thirst - less important than the other effects

Question 13

Give an example of an angiotensin receptor blocker.

Answer 13

Losartan

Question 14

What are some side effects of ACE inhibitors and angiotensin receptor blockers?

Answer 14

Both are generally well tolerated - especially angiotensin receptor blocker

Side effects on both drugs:

• Hypotension
• Hyperkalaemia
  
  • So the patient has to be careful if they are also taking K⁺ supplements or K⁺ sparing diuretics
    
    • Potassium sparing diuretics prevent sodium reabsorption via the Na⁺/K⁺ pump, thereby preventing water reabsorption
    • By doing this, it also prevents renal K⁺ excretion, increasing blood K⁺ levels
• Renal failure in patients with renal artery stenosis

Explanation of the last point (extra)

In general:

• ​Renal artery stenosis = narrowing of the renal arteries
• Therefore you get reduced blood flow through kidneys → reduced GFR
• Significantly reduced GFR → kidney failure
  
  • ​This means that you are no longer sufficiently filter your blood to remove waste products

Why ACE inhibitor or ARB is contraindicated:

• Renal artery stenosis → reduced blood flow through kidneys → reduced GFR
• Renal artery stenosis results in decreased renal perfusion pressure (BP in the afferent arteriole)
• This stimulates renin secretion which leads to angiotensin II production
• Angiotensin II is a vasoconstrictor → vasoconstriction of the efferent arteriole
• This increases the hydrostatic pressure in the glomerular capillaries → increased ultrafiltration and GFR
• IMPORTANT:
  
  • Therefore, by using ACE inhibitor or ARB, you prevent the GFR-increasing effects of angiotensin II
  • This leads to a significantly reduced GFR → renal failure

Question 15

What is a side effect of ACE inhibitors which is NOT a side effect of angiotensin receptor blockers?

Answer 15

ACE inhibitors can result in a cough

• This is because by inhibiting ACE, you are also preventing the breakdown of bradykinin
• Bradykinin is pro-cough
  
  • The may be due to bradykinin causing sensitisation of airway sensory nerve fibres
  • So the nerve fibres are more easily stimulated which leads to an enhancement of the cough reflex

Therefore, even though both ACE inhibitors and ARBs are well tolerated, ARBs are especially well tolerated

Question 16

Describe the process of excitation-contraction coupling in smooth muscle.

Answer 16

• Membrane depolarisation opens VGCCs
• Ca²⁺ enters & binds to calmodulin (CaM)
• Ca2+-CaM complex binds to & activates myosin light chain kinase (MLCK)
• MLCK phosphorylates myosin light chains allowing them to form cross-bridges with actin filaments → smooth muscle contraction

NOTE: Membrane depolarisation is due to AP generation and propagation across entire membrane

Question 17

How do calcium channel blockers work?

Answer 17

• They block the VGCCs in both smooth muscle cells and cardiomyocytes
• However, there are two types of CCBs because the VGCC is sligtly different depending on what muscle type it is present in
• Therefore each type of CCB is more selective to one of the muscle types

REMEMBER:

• Depolarisation of the cardiomyocyte membrane causes opening of VGCCs
• This allows calcium inflx into the cell → calcium-induced calcium release from SR
• Most of the Ca²⁺ which binds to troponin comes from the SR
• So the VGCC is very important for allowing Ca²⁺ release from the SR

Question 18

What are the two types of calcium channel blockers? Give an example of each type.

Answer 18

Dihydropiridines (DHPs) = rate-limiting

• More selective for blood vessels
• EXAMPLE: amlodipine
  
  • ​Does not cause any negative inotropy (i.e. reduced contractility)
    
    • ​This is due to its lack of an effect on the heart
  • Also licensed for the prophylaxis of angina
    
    • Prophylaxis = treatment given or action taken to prevent disease

Non-DHPs = rate-limiting

• More selective for the heart
• EXAMPLE: verapamil
  
  • ​Large negative ionotropic effect

Question 19

Which type of calcium channel blocker should be used to treat hypertension?

Answer 19

You would use dihydropiridines

• Altering the resistance within the vasculature (TPR) would be more effective at controlling blood pressure
• DHPs cause vasodilation → reduced TPR → reduced BP
• PROBLEM:
  
  • Powerful vasodilation can lead to stimulate the baroreceptor reflex → tachycardia and increased ionotropy (contractiity)
  • This leads to increased myocardial oxygen demand which could be a problem
  • BUT still effective in reducing BP
    
    • CO doesn’t increase as much as TPR decreases

NOTE: For angina you would use the rate-limiting CCBs as they have a direct effect on the heart which is more effective

Question 20

Why do you not use ACE inhibitors or angiotensin receptor blockers as a first line treatment in over 55s or Afro-Caribbeans?

Answer 20

Both these groups of people have a low plasma renin activity

• Over 55s - natural decrease in activity with ageing
• Afro-Caribbeans - genetic

NOTE: Low plasma renin acticity means reduced renin production - indicates that RAAS is less active (less active means there is not much point targeting it)

Question 21

Which drugs are the most preferred for hypertension and why?

Answer 21

RAS inhibitors…

• ↑ - increased incidence found in RAS inhibitors compared with the other drug
• ↓ - decreased incidence found in RAS inhibitors compared with the other drug

The reason we don’t really use beta blockers as an antihypertensive (definitely not first choice) is due to evidence showing that other drugs (i.e. RAS inhibitors) are more effective in lowering the incidence of cardiovascular events

Question 22

Give two examples of alpha-blockers.

Answer 22

Phentolamine - non-selective

Prazosin - alpha-1 selective

Question 23

Why might alpha-blockers be used in hypertension treatment?

Answer 23

• Alpha-1 activation → vasoconstriction
• Therefore, if you block the alpha-1 receptor you get:
  
  • vasodilation → reduced TPR → reduced BP