ACEIs, ANG 2 receptor antagonists and Renin Inhibitors

Question 1

Goal of antihypertensive therapy

Answer 1

reduce cardiovascular/renal morbidity and mortality

e.g. MI & strokes & damage to kidneys

Question 2

Drugs used to treat hypertension

Answer 2

1) Agents affecting RAAS
- ACEIs
- ANG 2 antagonists
2) Thiazide diuretics (used alongside 1)
3) Calcium Channel Blockers (BAME population)
4) Beta adrenoreceptor antagonists - last choice

Question 3

AT1 receptor

Answer 3

Gq receptor in smooth muscle
ANG II binds to receptor - causes hypertension by =
Vasoconstriction of afferent arterioles
Reduces synthesis of NO - vasodilator
Stimulates the release of aldosterone - Na+ and water reabsorption

Receptor action =

1) IP3 acts on sarcoplasmic reticulum to release Ca2+ - increases cardiac inotropy + stroke volume - O2 demand of respiring skeletal muscle
2) results in normal ( can happen in pathology too) remodelling of cardiac muscle = increased physiological demand

Question 4

MOA of ACE inhibitors

Answer 4

PRILS
Competively antagonise ACE enzyme - stop conversion of ANG 1 to ANG II
Reduction of ANG II stops receptor activation in tissues
- reduces vascular tone
- increased production of bradykinin - contributes to vasodilation via increased NO/ Na+ excretion + inflammation of tissues
- decreases aldestrone release + sodium reabsorption

Question 5

MOA of ANG II receptor antagonists

Answer 5

SARTANS
Competively antagonise the AT1 receptor to stop ANGII from binding
- block receptors in vasculature/adrenal/neuronal tissues
Reduction of ANG II =
- reduced vascular resistance
- decreased aldosterone release + sodium reabsorption
- decreased sympathetic activity - decreased cardiac output

Question 6

MOA of renin inhibitor

Answer 6

Competitive antagonist of enzyme renin - stops conversion of angiotension to angiotension 1

• reduces vascular tone
• increases production of bradykinin
• decreases aldestreone release + Na+ reabsorption

Question 7

Side effects of Ace Inhibitors

Answer 7

Dry cough - most common - caused by increased bradykinins - bronchospasm
Hyperkalemia - decreased aldestrone = K+ retention -> can cause renal failure
Skin rash
Hypotension - all vasculature is relaxed

Contraindications

• pregnancy
• renal artery stenosis
• renal disease - drugs may cause reduction in renal function

Question 8

Side Effects of ANG II antagonists

Answer 8

Hyperkalemia
Hypotension
Allergic reactions - rare but serious

Contraindications 
Pregnancy 
Renal artery stenosis 
Renal disease
Severe hepatic imparement - drug is metabolised by the liver

Caution
Breast feeding
Mild to moderate hepatic imparement
Elderly with postural hypotension/hyperkalaemia

Question 9

Side Effects of Renin Inhibitors

Answer 9

Diarrhoea - dehydration!
Cough - less often than ACEis

Subject to drug interactions - metabolised by CYP3A4 - grapefruit

Contraindictaions
do not combine with ACEis/ARBs
pregnancy

Question 10

Hypotension side effect

Answer 10

Augmented (extension of mechanism of action) adverse effect - especially when first used/when used with diurectics

Question 11

Pharmacokinetics of ACEis

Answer 11

Administration: oral - Enalaprilat = IV (active metabolite)
- given as a prodrug - active forms are polar/poorly absorbed from the gut
Absorption: good and rapid - absorbed by gut wall
Metabolism: all prodrugs require hepatic metabolism
- active = “prilat”
Execretion = Kidneys except for fosinopril

Question 12

Pharmacokinetics of ARBS

Answer 12

Candesartan - prodrug
Losartan - parent drug
Valsartan - parent drug
Administration: oral
Metabolism: Candesartan and Losartan - partially metabolised in liver to active metabolites
Excretion: Valsartan - unchanged as parent drug in bile
Canesartan/Losartan - excreted by kidney = more polar

Question 13

ACE inhibitors in heart failure

Answer 13

Decrease in ANG II = vasodilation and decreased TPR
Protective effect - decreases futher hypertrophy in cardiac muscle in ventricles
Cardiac output becomes sufficient for perfusion - CO X TPR = BP

Question 14

Impared diastolic filling

Answer 14

• impared myocardial relaxation
• increased stiffness in the ventricular wall
• decreased left ventricular compliance

Question 15

Hypertension - heart failure

Answer 15

- increased wall stress stimulates myocyte hypertrophy + ventricular hypertrophy 
CARDIAC 
- decreased SV and CO
- increased ED pressure
VASCULAR 
- increased systemic resistance - increased afterload and TPR
-decreased arterial pressure
-decreased venous compliance
-increased venous pressure
-increased blood volume