Drugs for the vasculature

Question 1

What is the main factor determining BP

Answer 1

Peripheral resistance mostly is the target for HTN

to reduce arteriolar contraction

Question 2

Which vessels contribute to BP

What can sympathetic nerves release onto VSMC

Answer 2

Arterioles

Sympathetic nerves release noradrenaline, neuropeptide Y and ATP

Question 3

What is the effect of contracting and relaxing vessels on BP

Answer 3

Contract reduces radius, increasing resistance, reducing flow…

Question 4

What is vascular tone

Answer 4

Arteriolar S.M. normally displays a state of partial constriction

Question 5

Why is HTN important

Answer 5

Single most important risk factor for stroke, causing about 50% of ischaemic strokes

Question 6

What percentage of HF cases does HTN acount for

Answer 6

Accounts for ~25% of heart failure (HF) cases, this increases to ~70% in the elderly

Question 7

What is HTN a risk factor for

Answer 7

myocardial infarction (MI) & chronic kidney disease (CKD)

Question 8

What is the treatment for HTN

Answer 8

Combinations of

ACEi/ARB; CCB and thiazide like diurectic

Last stage is spironolactone or b/blocker or a blocker

note that ARB is angiotensin II receptor blocker WHEREAS

spironolactone (a K+ sparing diuretic) blocks the aldosterone receptor

Question 9

What increases renin secretin

Answer 9

↓renal Na+ reabsorption (i.e. if sodium in the filtrate reaching the DCT is low)
↓ renal perfusion pressure
↑ sympathetic NS

Question 10

Outline RAAS

Answer 10

Angiotensinogen –> Angiotensin 1 by renin

Angiotensin 1 –> angiotensin 2 by ACE
`

Question 11

What is the effect of Angiotentin 2

Answer 11

Vasoconstriction via AT1 receptor

Stimulates aldosterone release promotong sodium reabsorption

angiotensin II can also promote sodium reabsorption

acts on the brain to increase thirst

Question 12

MAO of ACEi

Answer 12

Inhibit the somatic form of angiotensin converting enzyme (ACE)
Prevent the conversion of angiotensin I to angiotensin II by ACE

Question 13

Use of ACEi

Answer 13

• hypertension
• heart failure
• post-myocardial infarction
• diabetic nephropathy
• progressive renal insufficiency (BUT NOT RENAL ARTERY STENOSIS!)
• patients at high risk of cardiovascular disease

Question 14

ACE inhiitor names

Answer 14

end in -pril

Question 15

How does ACEi work in HTN and HF

Answer 15

HTN: reduce vasoconstriction due to less AT1 activation (reduce TPR) and salt and water retnetion (reduce CO)
trying to reduce pressure in vasc.

HF: trying to reduce work for heart

reduce afterload due to vasodilation, reduce venous return (reduce congestion from right sided heart failure, and reduce stress on heart)

Question 16

What is the effect of Angiotensin II binding to VSMC

Answer 16

ACTIVATES AT 1

activated receptor in turn couples to Gq/11 and thus activates phospholipase C. This increases IP3 which increases the cytosolic Ca2+ concentrations, which works with CaM to activate MLCK

Also links to Gi receptor, so inhibits AC, so there is less cAMP. cAMP inhibits MLCK so less of this will mean more contraction

ARB blocks this (indirectly reduces calcium concentration)

CCB directly reduce calcium entry

Question 17

Effect of ARBs

name

Answer 17

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

-artan

Question 18

Use of ARB

Answer 18

hypertension, heart failure

Question 19

2 actions of ACE

Answer 19

Breaks down bradykinin

Convert angiotensin 1 to angiotensin 2

Question 20

Side effects of ACEi/ARB

Answer 20

Generally well tolerated (particularly ARB)

Cough (ACEI)

Both:
Hypotension

Hyperkalaemia (care with K supplements or K sparing diuretics)

Renal failure in patients with renal artery stenosis (both)

Question 21

Why do ACEi cause cough

Answer 21

Increasing levels of bradykinin

Question 22

What is the effect of Angiotensin II on VSMC

Answer 22

It inreases Ca2+ into the cell, so ARB blocks this

Angiotensin II is coupled to both a Gq protein, which acts via IP3 to increase intracellular [Ca2+], and also a Gi protein, which reduces cAMP mediated inhibition of MLCK. The increased [Ca2+] associated with calmodulin, as a Ca2+-CaM complex, to activate MLCK.

Question 23

Why does do ARB/ACEi cuase hyperkalaemia.

Care mist be taken when prescribing ACEi or ARBs with which other drugs

Answer 23

They reduce aldosterone release….

Thus less secretion of insertion of Na+/K+ATPase into basolateral membrane AND Na+ channels for influx into apical membrane AND K+ channels for efflux across apical membrane….

thus fewer of these channels in these drugs

so less Na+ in the cell, so less movement of K+ into the cell too

and less mvoement of K+ out of the cell

Thus you can’t excrete potassium

TAKE CARE WITH POTASSIUM SPARING DIURECTICS

Question 24

Why sholdn’t ARB/ACEi be used in renal artery stenosis

Answer 24

In renal artery stenosis, poor blood flow into the aferent arteriole so there is poor GFR.

In response, increases renin etc. which then causes Angiotensin II to come and constrict the efferent arteriole to increase pressure in teh glomerulus

Giving ARB/ACEi will then reduce this efferent arteriole vasoconstriction….. this will then lower the GFR and allow renal failure to continue

Question 25

Why are CCB used in HTN, and which would be used in HTN and why

Answer 25

Effects on smooth muscle contraction

Non-rate limiting …

• More selective for blood vessels
• Amlodipine -does not cause any negative inotropy
• Also licensed for prophylaxis of angina

Dihydropyridines inhibit Ca2+ entry into vascular smooth muscle cells

(* Calcium entry makes up 25% of the calcium required for contraction

• This stimulates the sarcoplasmic reticulum to release even more calcium (makes up 75%)
• This calcium is utilised by myosin light chain kinase to precipitate contraction)

↓ T.P.R. = ↓ B.P.

Question 26

What happens in normal VSMC contraction.

What happens when CCB used

Answer 26

Membrane depolarisation opens voltage-gated calcium (Ca2+) channels (VGCCs)
Ca2+ enters & binds to calmodulin (CaM)

Ca2+-CaM complex binds to & activates myosin light chain kinase (MLCK)

MLCK mediated phosphorylation  smooth muscle contraction

Less calcium entry with CBB so less contaction

Question 27

What is the problem with CCB in HTN

Answer 27

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

in non rate limiting CCBs (see heart lecture for why)

Question 28

Why are ACEi/ARB given in preference to CCB/thiazide type diuretics in people under 55 and non afro-caribbean people

Answer 28

Side effect profile normally determines (how adherent)

These people usually have low plasma renin HTN

But in afrocaribbeans then have LOW PLASMA RENIN ACTIVITY….. so renin isn’t coupled in the same way to angiotensin II and aldosterone…..

thus you need too high a dose of ACEi/ARB in afrocaribbean patients

In elderly people, it’s less to do with renin and more to do with atherosclerosis

Question 29

Which drugs are people most and least likely to take

Answer 29

Most- ACEi/ARBs

Least: Beta blockers/CCB/diuretics

Question 30

How are alpha blockers used in HTN

Answer 30

Only in resistant hypertensin

Reduces vasoconstriction

a1+a2 blockers –>phentolamine

a1 selective blocker –> prazosin

Question 31

Comapare effectiveness of drugs affecting Renin Angiotensin System (RAS) and CCB

Answer 31

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 32

Compare effectiveness of drugs affecting RAS and thiazides

Answer 32

hiazides seem more effective for BOTH heart failure AND stroke

• Thiazides also have a more profound effect on systolic BP