ACE Inhibitors, AngII Receptor Antagonists, Renin Inhibitors

Question 1

What are the main antagonists used to treat hypertension?

Answer 1

• Agents affecting RAAS
• Thiazide diuretics
• Calcium channel antagonists
• β-adrenoceptor antagonists

Question 2

What are ACEIs (‘prils’) also used to manage?

Answer 2

• Cardiac failure
• Following MI

Question 3

What can ANGII Antagonists also be used to manage?

Answer 3

• Cardiac failure (when ACEI contraindicated)
• Diabetic nephropathy in Type II Diabetes

Question 4

Describe what stimulates renin release.

Answer 4

• Baroreceptor responses to reduced renal arterial pressure and sympathetic stimulation of β1-adrenoceptors (by renal sympathetic nerves)
• Reduced sodium intake and increased sodium loss
• Decrease in renal tubular fluid Na+ concentration

Question 4

Describe the effects of Angiotensin II and what mediates its effects.

Answer 4

• Vasoconstriction of efferent arterioles of glomerulus - increased glomerular filtration
• Aldosterone secretion - increased renal sodium reabsorption/increased blood volume
• Mediated by stimulation of angiotensin II type 1 (AT1) receptors.

Question 5

What are the 3 ways AngII causes hypertension via the AT1 receptor?

(b) What would be the effects for AT2 receptor stimulation?

Answer 5

• Vasoconstriction of afferent arterioles
• Reduction in NO synthesis
• Stimulation of aldosterone release from zona glomerulosa

(OPPOSITE TO THAT OF AT1)

Question 6

How does AngII cause cardiac muscle hypertrophy through the AT1 receptor?

Answer 6

• Release of IP3 - causes calcium release - increased inotropy and stroke volume
• Results in normal remodelling of cardiac muscle to meet physiological demands
• Can also occur due to failing to meet O2 demands

Question 7

What is the mechanism of action and effects of ACEIs and aliskiren?

Answer 7

• ACEIs - Competitive antagonism of ACE - inhibits conversion of ANGI to ANGII.
• ALISKIREN - Competitive antagonism of renin. Inhibits conversion of Angiotensinogen to ANGI

BOTH:
- Dampens AT1 receptor activation (because reduced ANGII production)
- Reduced vascular tone
- Decreased aldosterone release and sodium reabsorption
- Increased bradykinin production - vasodilation by NO

Question 8

Describe the mechanism of action and effects of AngII receptor antagonists.

Answer 8

• Competitive antagonism of AT1 receptor - prevent ANGII binding
• AT1 receptors in vasculature, adrenals and neuronal tissue are blocked
• Decreases sympathetic activity
• Reduced vascular resistance
• Decreased aldosterone release (and thus sodium reabsorption)

Question 9

What are the side effects and contraindications of renin inhibitors i.e aliskiren?

Answer 9

• SIDE EFFECTS - Diarrhoea (especially at high doses), cough (less frequent than with ACEIs), angioedema, metabolised by CYP344 - subject to multiple drug interactions
• CONTRAINDICATIONS - Pregnancy and don’t combine with ACEI/ANGII antagonists when treating HTN

Question 10

What are the side effects and contraindications of ACEIs?

Answer 10

• SIDE EFFECTS: Dry cough, hyperkalaemia, skin rash, hypotension and altered taste
• CONTRAINDICATIONS - Pregnancy, renal artery stenosis (may progress to renal failure), other renal diseases(may cause reduction in renal function - used cautiously with constant renal function monitoring)

Question 11

What are the side effects and contraindications of ANGII receptor antagonists?

When should it be used cautiously?

Answer 11

• SIDE EFFECTS: Rare but serious allergic reactions, hypotension, hyperkalaemia
• CONTRAINDICATIONS - Same as ACEIs but also contraindicated in severe hepatic impairment
• USED CAUTIOUSLY when breastfeeding, mild to moderate hepatic impairment, elderly with persistent hypotension and/or hyperkalaemia

Question 12

Describe the pharmacokinetics of ACEIs.

Answer 12

• ADMINISTRATION - usually oral apart from enalaprilat (active metabolite of enalapril - available IV)
• Many administered as prodrug - active forms polar, poor absorption in gut
• ABSORPTION - varies from 55-75% (good and rapid) as either a prodrug or drug (captopril and lisinopril)
• METABOLISM - All require hepatic metabolism bar captopril/lisinopril. t1/2: range from 1-5 hrs ramiprilat to 30-35 hrs enalaprilat
• EXCRETION - Primarily by kidneys except FOSINOPRIL

Question 13

Describe the pharmacokinetics of ANGII Receptor antagonists.
Use the following examples:
- Candesartan (prodrug)
- Losartan (parent drug)
- Valsartan (parent drug

Answer 13

• Administered orally.
• C and L partially metabolised in liver to active metabolites
• Usually renal excretion except valsartan

Question 14

Describe what can cause heart failure.

Answer 14

• Structural and functional cardiac disorders

Question 15

What element of heart failure can hypertension contribute to?

Answer 15

• Increased wall stress leading to ventricular hypertrophy

Question 16

How does ventricular hypertrophy lead to diastolic ventricular dysfunction?

Answer 16

Impaired diastolic filling due to:
- Impaired myocardial relaxation
- Increased stiffness in the ventricular wall
- Decreased left ventricular compliance
O2 DEMANDS OF TISSUES CANNOT BE MET BY HEART

Question 17

Describe how ACE inhibitors work in heart failure.

Answer 17

• Cause decreased ANGII production resulting in a vasodilation and decreased TPR
• Decreases further ventricular hypertrophy
• Cardiac output becomes sufficient for perfusion