L10: ACE inhibitors

Question 1

What are the actions of ACE inhibitors

Answer 1

1. Inhibits breakdown of bradykinin:
   - mediate increased NO and prostacycline activity to increase endothelial function and vasorelaxation
2. Shunts the pathway to increase other vasoactive peptides: Ang 1-7
   - promote vasodilation
3. Inhibits conversion of Ang 1 –> Ang 2 by ACE.
   - Leads to reduction in Ang2 and Aldosterone

Question 2

What receptor does Angiotensin 2 antagonists act on- what is that activity.
and what is the other receptor that it doesn’t work on

Answer 2

1. Inhibit angiotensin 2 activity via type 1 receptors non competitively

(Type 2 Angiotensin receptor counterbalances some Type 1 effects: antiproliferative effects, vasodilation)

Question 3

What is 4 activities of Ang 2 activity via type 1 receptor (Kidney, Heart, VSM..)

Answer 3

1. Increase Endothelin ==> Vasoconstriction
2. Vascular SM hypertrophy
   and vascular fibrosis
3. Increase Aldosterone:
   ==> Na+ retention / K+ wasting
4. Increase sympathetic tone

Question 4

What 3 diseases does the RAAS System help and what 3 adverse CVS effects does it have

Answer 4

Involved in
- Congestive heart failure and hypertension progression (mortality/morbidity)

• VSM fibrosis which can lead to Atherosclerosis and thrombosis.
• new diabetes: promote impaired insulin signaling and pancreatic function

Adverse CVS effects:
- Cardiac hypertrophy (adverse remodelling)

• Pro-inflammatory/pro-oxidant
• increase Symp activity

Question 5

How does the effects of ACEi change over time

Answer 5

1. In first few weeks
   Leads to reduction in Ang2 and Aldosterone

Over months
2. Plasma Aldosterone and Ang2 rise to pretreatment levels due to chymase activity

3. However there is overall increase in Ang1-7 and Bradykinin which leads to vasodilation and therefore positive health benefits

Question 6

What are the beneficial effects of Acei/Ang 2 antagonists (5)

Answer 6

1. Vasodilation
   - decrease in arterial and venous pressure
   - decrease in ventricular preload and afterload (cardiac work)
2. Decrease in blood volume (due to reducing aldosterone)
   - decrease in Na+ retention in blood
   - increased diuresis
3. Decreased symp activity
4. Decreased cardiac and vascular hypertrophy
5. Reduce incidence of developing new diabetes

Question 7

Give an example of ACE i and Ang 2 antagonist and what is half life, excretion and cautions

Answer 7

ACEi: ~pril

(eg. Cilazapril, Perindopril)
- Prodrugs

A2a: ~sartan

(eg. Candesartan, Losartan-good 4 gout)
- Some have active metabolites

Both have variable half lifes.
- Caution is taken with Renal impairment due to renal excretion (esp ACEi which all renally excreted

Question 8

What are the indications for using ACEi as treatment

Answer 8

1. Hypertension: as monotherapy or combo if not effective
   - (Acei + diuretic+ vasodilator)
2. Congestive HF
   - used in combo to reduce ejection fraction, symptoms and prognosis

• (diuretic +Acei +BB + spironolactone (aldosterone antagonist)

Question 9

What are the indications for using Ang2 antagonist as treatment and what should never be used in combo

Answer 9

1. Patients that are intolerant to ACEi
   - Candesartan

ACEi + A2a get synergestic SE so NO

Question 10

What are the side effects of ACEi and A2a (5)

Answer 10

Both similar - but worse in Acei mostly

• Dry cough due to bradykinin irritating lungs - not dose dependent and can take months
• Hyperkalaemia: messing w aldosterone
• sudden Renal function deterioration -> reduce perfusion pressure
• Volume depletion
• Angio-oedema (lifethreatening in URT)

Question 11

What are the contra-indications of ACEi and A2a and why

Answer 11

1. Pregnancy
   because they cross the placenta and in 2nd & 3rd trimester they can cause fetal renal defects, oligohydramnios and fetal death through hypotension.
2. Bilateral renal artery stenosis:
   because RAAS is maintaining the perfusion pressure of the kidney (increasing efferent arteriole tone)