Drugs and vasculature

Question 1

Where is ACE found?

Answer 1

in endothelial cells, lung capillaries, kidney epithelial cells

Question 2

Where does angiotensin 2 act?

Answer 2

AT1 receptor

Question 3

What are some VSM mediators that stimulate VSM contraction?

Answer 3

• Ang2
• PGG2, PGH2
• ET1

Question 4

What are some endothelial cell agonists that cause relaxation?

Answer 4

• NO
• CNP –C-Type Naturietic Peptide
• PGI2
• EDHF –Endothelial Hypopolarising Factor

Question 5

What are the vessels with the greatest influence on BP?

Answer 5

arterioles - they have partial tone normally

Question 6

What is hypertension?

Answer 6

more than 140/90

Question 7

What is the single most important risk factor for stroke and important in MI and CKD?

Answer 7

hypertension

Question 8

What is the treatment overview for hypertension?

Answer 8

1. Single therapy - for under 55s give ACEi or ARB, over 55 or afro caribbean give CCB or thiazide diuretic
2. Dual therapy - ACEi and CCB or ACEi and thiazide diuretic
3. Triple therapy - ACEi, CCB and thiazide diuretic
4. Symptomatic relief - low dose spironolactone (aldosterone receptor antagonist so diuretic effects) and B blocker or alpha blocker

Question 9

What should first be considered for hypertensive patients?

Answer 9

lifestyle modifications, then pharmacology

Question 10

Why are patients over 55 not given RAS targetting drugs?

Answer 10

Low renin/low renin sensitivity over that age so less responsive to the drugs hence other drugs are needed

Question 11

What stimulates the RAS?

Answer 11

• low renal sodium reabsorption
• low renal perfusion
• high sns activation

Question 12

What do ACEi do?

Answer 12

Decrease Ang2 production and increase bradykinin

Question 13

What are the uses of ACEi?

Answer 13

• hypertension
• heart failure
• post MI
• diabetic nephropathy
• progressive renal insufficiency
• high CVS disease risk patients

Question 14

How do ACEi work in treating hypertension?

Answer 14

• Reduce TPR–more bradykinin & less AngII -> reduces TPR via less AT1R-mediated vasoconstriction so less BP and more bradykinin vasodilation
• Sodium retention –less Na+retention in the kidneys via blocked actions of AngII on the AT1R in the kidneys and less aldosterone secretion as blocked AT1R in the adrenal medulla
• Thirst drive –less SNS activation of thirst in the brain via AT1R

Question 15

How do ACEi work in heart failure?

Answer 15

• Reduce TPR –less vasoconstriction via AT1R in the peripheral vasculature so less TPR so less afterloadon the heartso ionotropic effects of the heart decrease.
• Reduce preload –venodilation (bradykinin?) means less preload

Question 16

What do ACEi end in?

Answer 16

-ipril

Question 17

What are ARBs and their uses?

Answer 17

• angiotensin receptor blockers

- used in hypertension and heart failure

Question 18

Give an example of an ARB

Answer 18

losartan

Question 19

What are the side effects of ARBs and ACEi?

Answer 19

Cough –ACEi

Urticaria/angioedema –ACEi rarely

Hypotension –ACEi, ARBs

Hyperkalaemia – ACEi, ARBs
Care with K+ supplements or K+-sparing diuretics. Aldosterone promotes K+loss so aldosterone inhibitors (ACEi, ARBs) produce a hyperkalaemia

Foetal injury –ACEi, ARBs

Renal failure (in patients with renal artery stenosis) –ACEi, ARBs
Glomerular filtration is maintained by AngII so you need to be careful in renal failure patients

Question 20

Give examples of calcium channel blockers

Answer 20

amlodipine, verapamil

Question 21

What normally happens in smooth muscle contraction?

Answer 21

Membrane depolarisation opens VGCC -> Ca2+enters and binds calmodulin (CaM) -> Ca2+-CaM complex activates MLCK -> MLCK mediated phosphorylation -> VSM contraction

Question 22

Why is amlodipine used to treat hypertension?

Answer 22

Doesn’t have an inotropic effect on the heart

Question 23

What do dihydropyridines act on and what are they used for??

Answer 23

• Affect smooth muscle only
• More selective for blood vessels
• Amlodipine does not cause any negative inotropy
• Also licensed for prophylaxis of angina
• These are the drugs used to treat hypertension, because they are effective on the vasculature

Question 24

What do non-DHPs act on?

Answer 24

• Cardiac and smooth muscle

- Verapamil has a large negative chronotropic effect

Question 25

How do dihydropyridines work?

Answer 25

Inhibit Ca2+ entry into vascular smooth muscle cells so ↓ T.P.R. = ↓ B.P.

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

Question 26

Why are ACEi and ARBs first line for under 55s?

Answer 26

good patient adherence which means few side effects

Question 27

Why are over 55s and afrocaribbeans given CCB or thiazide duiretics?

Answer 27

This group of people have a different drug schedule due to low plasma renin activity and so ACEi doesn’t work as well –the studies into this are not confirmed

Question 28

Compare the use of CCBs and RAS inhibitors

Answer 28

ACE inhibitors seem to be more effective for heart failure patients

• CCBs seem to be more effective if you are likely to develop stroke

Question 29

Compare the effectiveness of thiazides and RAS inhibitors

Answer 29

Thiazides seem more effective for BOTH heart failure AND stroke

Thiazides also have a more profound effect on systolic BP

Question 30

How do alpha 1 receptor inhibitors work?

Answer 30

• Alpha 1 adrenoreceptor antagonists are used as a last resort as antihypertensive treatment
• The alpha 1 receptor is the predominant vasoconstricting receptor in the vasculature
• Blocking alpha 1 receptors reduces vasoconstriction -> reduce TPR -> decrease BP

Question 31

Give an example of an alpha blocker

Answer 31

Prazosin (1), Phentolamine (1/2)