Drugs and the vasculature

Question 1

What is hypertension defined as?

Answer 1

BP = CO x TPR

Defined as blood pressure being consistently above 140/90mmHg

Hypertension causes:

• 50% of ischaemic stroke
• 25% of HF –> 70% in the elderly
• risk factor for MI and KD

Question 2

What are the steps to hypertension treatment?

Answer 2

Step 1

• Under 55s - Angiotensin converting enzyme (ACE) inhibitor OR angiotensin receptor blocker (ARB)
• Over 55s or afro-Caribbeans - Calcium channel blocker (CCB) or thiazide-like diuretic

Step 2
CCB or thiazide-like diuretic and ACEi or ARB
ARBs preferred to ACEi for AfroCaribbean’s

Step 3
Combination of ACEi/ ARB with CCB and thiazide-like diuretic is recommended

Step 4 - resistant hypertension
Consider low-dose spironolactone
Consider beta-blocker or alpha blocker

See slides

Question 3

What stimulates the production of renin?

Answer 3

From the juxtoglomerular cells in the kidneys, renin is produced when there is:

• decreased Na+ reabsorption
• decreased renal perfusion pressure
• increased sympathetic NS stimulation (Beta 1)

Question 4

What does ACE inhibitors do?

Answer 4

Prevent the conversion of angiotensin I to angiotensin II

Prevent the break down of bradykinin

Question 5

What does bradykinin do?

Answer 5

Causes vasodilaiton

Question 6

What does Angiotensin receptor blockers do?

Answer 6

They block AT1 receptors that causes:

• SNS activation –> thirst
• Vasocontriction
• Aldosterone secretion
• Salt and water retention (AGII has aldosterone like effect)

Question 7

What are the uses of ACE i?

Give an example

Answer 7

Uses:
•	hypertension
•	heart failure
•	post-myocardial infarction
•	diabetic nephropathy
•	progressive renal insufficiency
•	patients at high risk of cardiovascular disease

Enalapril - ends in -pril probably an ACEi

Question 8

In terms of BP = CO x TPR what causes hypertension? Why use ACEi?

Answer 8

Increased TPR directly contributes to increased BP and increased venous return leads to increased cardiac contractility (via Starling’s Law) and thus CO.

Decreases TPR (reduce vasoconstriction) and decrease salt and water retention (reduced venous return = less fluid in the system)

Question 9

In terms of BP = CO x TPR what causes heart failure? Why use ACEi?

Answer 9

Increased vasoconstriction increases the afterload and increases cardiac work. Increased venous return leads to long term fluid retention and congestion, leading to oedema.

vasodilation - means the after load decreases
Decreasing venous return - decreases how hard the heart needs to work.

Question 10

What are the uses of ARB

Give an example?

Answer 10

Uses:

• Hypertension
• Heart failure

Antagonists of type 1 (AT1) receptors for Ang II, preventing the renal and vascular actions of Ang II,

Losartan

Question 11

What is a problem with ACEi?

Answer 11

Bradykinin - causes cough

Hypotension

Question 12

Give an example of an ARB?

Answer 12

Losartan - Antagonists of type 1 (AT1) receptors for Ang II, preventing the renal and vascular actions of Ang II.

Question 13

What is Losartan used for?

Answer 13

Hypertension and Heart failure

Angiotensin Receptor Blocker

Question 14

Describe normal smooth muscle contraction?

Answer 14

1) Membrane depolarisation opens voltage-gated calcium (Ca2+) channels (VGCCs)
2) Ca2+ enters and binds to calmodulin (CaM)
3) Ca2+-CaM complex binds to and activates myosin light chain kinase (MLCK)
4) MLCK mediated phosphorylation –> smooth muscle contraction

Angiotensin II promotes contraction

Question 15

What are the two types of calcium channel blockers?

Answer 15

Dihydropyridines (DHPs) Non-rate limiting - Amlodipine (selective for blood vessels and does not cause negative intropy)

Non-DHPs rate limiting - Verapamil (large negative inotropic effect)

Question 16

Describe the mechanism of action of DHPs?

Answer 16

Hypertension: Go for a calcium channel blocker that target smooth muscle - so the non-rate limiting one.

Dihydropyridines inhibit Ca2+ entry into vascular smooth muscle cells

↓ T.P.R. = ↓ B.P.

N.B. Powerful vasodilation can lead to reflex tachycardia and increased inotropy thus increased myocardial oxygen demand

Question 17

Compare RASi vs CCBs

Answer 17

CCBs ↓ SBP more than RAS inhibitors
RAS inhibitors ↓ heart failure
RAS inhibitors ↑ stroke
No difference for all-cause death (mortality)

Question 18

Compare RASi vs thiazides

Answer 18

Thiazides ↓ SBP more than RAS inhibitors
RAS inhibitors ↑ heart failure
RAS inhibitors ↑ stroke
No difference for all-cause death

Question 19

Compare RASi vs beta-blockers

Answer 19

No difference in SBP reduction
RAS inhibitors ↓ CV events
RAS inhibitors ↓ stroke
No difference for all-cause death

Question 20

Why are alpha-blockers used as anti-hypertensives

Answer 20

a(1)-receptor blocker- decreases vasoconstriction = promotes vasodilation

[a(2)-receptor - decreased sympathetic simulation]

Used when you have resistant hypertension

a1 = prazosin
a1+2 = phentolamine

Question 21

Why do you get hyperkalaemia with ACEi and ARBs?

Answer 21

Aldosterone causes the insertion of Na+ channels and Na/K+ ATPases into the cells.
These drugs cause fewer channels in the membrane. As a result the potassium can not be excreted in the urine. Sodium cannot be reabsorbed into the cell = K+ build up in the blood as it cannot be exchanged in the ATPase.

See diagram

Question 22

Why do you get renal failure with ACEi and ARBs?

Answer 22

Renal failure in patients with renal artery stenosis. There is poor flow into the glomerulus = low GFR. Angiotensin II will constrict the efferent artiole to increase the the pressure in the glomerulus = to increase the GFR. If you give ACEi or ARB you remove the mechanism to increase the GFR leading to renal failure.

Question 23

Describe how treatment changes when dealing with low renin levels?

Answer 23

If plasma renin levels are low relatively to Angiotensin II, ACEi will have less of an effect.
Use other methods.

This affects Afro Caribbean and old people. blood pressure becomes uncoupled –> atheroscleroiss