ACE Inhibitors and ARBs

Question 1

List common ACE inhibitors and ARB

Answer 1

ACE Inhibitors

Captopril
Enalapril
Lisinopril
Perindopril
Ramipril

ARBs

Losartan
Valsartan
Irbesartan
Candesartan
Telmisartan

Question 2

Which ACE Inhibitor is available for IV administration. How is IV therapy converted to oral therapy

Answer 2

Enalapril.

The IV drug is called enalaprilat

The dose of enalaprilat is 1.25 mg per dose given over 5 minutes every 6 hours. up to 5mg per dose every 6 hours

Conversion from IV enalaprilat to oral enalapril

• No concurrent diuretics give enealpril 5mg daily
• Concurrent diuretics give enalapril 2.5 mg daily
• -> thereafter titrate to response

Question 3

Which are the only ACE Inhibitors that are not Prodrugs that require some metabolism for activation

Answer 3

Captopril

Lisinopril

Question 4

Are ACE I water or fat solubility? Are there exceptions

Answer 4

Water soluble

Exception: Fosinopril

Question 5

Which ACE I undergo hepatic metabolism

Answer 5

All except lisinopril (0%)

Question 6

Which ARB undergo some renal elimination

Answer 6

All of them except telmisartan

Question 7

What is the mechanism of action of ACE:I

Answer 7

Bind to Zinc moeity of ACE and inhibit conversion of ANG1 to ANG 2

Question 8

What is the mechanism of action of ARB

Answer 8

Block AT 1 receptors, the main receptors which mediate the effects of ANG2

Question 9

List the physiological effects of ACE:I and ARBs

Answer 9

1. Reduce catecholamine sensitivity
2. Reduce aldosterone release
3. Reduced vasopressin release
4. Reduced Na/H exchange in the proximal tubules –> increased sodium excretion
5. Reduced sensation of thirst
6. Reduced myocardial remodelling and vascular smooth muscle hyperplasia

Question 10

What are the clinical effects of ARBs and ACE:I

Answer 10

1. Reduce BP
2. Reduce cardiac and vascular remodelling
3. Improve long term CVS mortality
4. Negative effects on renal function in at risk patients (shock)

Question 11

What is the benefit of ARB vs ACE:I

Answer 11

1. No chronic cough
2. Angioedema

This is related to the fact that ACE also degrades bradykinin. ACE:I therefore increase bradykinin where as ARBs do not

Question 12

Which ACE: I comes in a syrup

Answer 12

Captopril

Question 13

Which of the ACE:I have short half life and require regular (6 hourly) dosing

Answer 13

Captopril

Question 14

How do ACE:I and ARBs block the physiological response to their own hypotensive effect (i.e. tachycardia)

Answer 14

Normal haemodynamic responses to hypotension (tachycardia) are blunted. This may be closely tied to the RAAS increasing SNS sensitivity. As the drugs reduce sensitivity to catacholamines, there are reduced SNS effects such as tachycardia. These drugs appear to ablate the efferent arcs of these reflexes

Question 15

Describe the ‘nephrotoxicity’ of ARBs and ACE:I

Answer 15

Vulnerable kidneys (with reduced perfusion pressure) rely on ANG 2 via AT 1 receptors for postglomerular vasoconstriction to maintain some glomerular filtration.

ACE:I and ARB remove this physiological compensation and produce a ‘functional’ renal impairment in the at risk kidney.

There is a much higher risk of AKI if patients get septic whilst on ACE:I or ARBS

Question 16

How do ACE:I and ARBs improve cardiovascularmortality

Answer 16

In an apparently unrelated manner to the action on blood pressure, the ACE:I and ARBs seem to prevent long term myocardial and vascular remodelling

Question 17

Describe Angioedema observed with ACE:I use

Answer 17

Patients may have been taking ACE:I for years and then one day they have a completely unpredictable idiosyncratic reaction which results in life threatening airway swelling and haemodynamic collapse.

Question 18

What is the incidence, mechanism and treatment of ACE:I angioedema

Answer 18

Incidence 0.1 - 0.2 %
Mechanism: blockade of bradykinin breakdown

Treatment:
- Supportive, withdrawal of drug, adrenalin and potentially replacement of ACE with FFPs.

Question 19

What are the clinical effects in CCF from the blockade of ANG 2 and its receptors?

Answer 19

Reduced Afterload

• Reduced CAT sensitivity and decreased vasopressin release
• Reduced SVr –> reduced afterload –> reduced O2 demand

Reduced Preload

• Decreased vasopressin release
• Decreased aldosterone release
• Decreased Na/H exchange in the PCT
• -> Increased Na excretion and reduced H2O retention

Long term non-antihypertensive effects

• Reduced ANG 2 –>
  1. Anti-inflammatory effect on VSM
  2. Anti-fibroproliferative effect on VSM
• -> decreased hyperplasia VSM + reduced rate atherosclerosis
  3. Decreased cardiac myocyte hypertrophy (indirectly by suppression aldosterone)