Drugs Targeting The RAAS

Question 1

What are the actions of ACE inhibitors?

Answer 1

• peripheral vasodilatation, ↓ BP
– reduces AngII constrictor action in arteries and veins
– more pronounced in hypertensives than normal volunteers
– esp. when renin secretion enhanced due to salt/volume depletion
• lower aldosterone (and vasopressin) secretion
– lower Na+ /water retention, pre-load
• ↓ sympathetic activation
– ↓ facilitation of neuronal noradrenaline release by angiotensin II
• ↑ bradykinin / PG vasodilatation,
– prevent metabolism of bradykinin, helps ↓ BP
– improved endothelial function, ↓risk of cardiovascular events in atheromatous disease
• ↓ angiotensin mediated generation of ROS
– inhibition of NADPH oxidase, oxidative stress-related injury, improved NO bioavailability
• decr glomerular perfusion pressure
• ↓ hypertension-related remodelling – in vasculature, heart and kidney

Question 2

What is the chemical structure of ACE inhibitors

Answer 2

Similar actions and benefits - class effect
Differ in regard to chemical group which interacts with ACE active site

Question 3

The 3 chemical groups that interacts with ACE active site

Answer 3

Sulphydryl group - captopril
Carboxyl group - lisinopril, enalapril
Fosphitinic acid group - fosinopril

Question 4

Describe ADME and pharmacokinetics

Answer 4

• most are pro-drugs activated by liver metabolism
– suffix ‘at’ indicates active metabolite e.g. enalaprilat
– captopril and lisinopril active on absorption
• mainly cleared by renal excretion
• differ in potency, action duration, rate of excretion
– influences frequency and dose of administration

Question 5

ACE inhibitors: indications

Answer 5

Uncomplicated hypertension (step 1 or 2 in uk) especially if other classes are contra-indicated, not-tolerated or inadequate
=to other drug classes for lowering BP - CAPPP, ALLHAT, PROGRESS
Lower CV risk (death, MI, stroke etc) beyond reducing BP? HOPE (high risk pop)

Question 6

ACEI: variation with … and …

Answer 6

Age and ethnicity
Younger Caucasians respond better to ACEI mono therapy for BP reduction (high RAAS activity) than blacks />55 years
-volume expanded hypertension / low RAAS activity in blacks /elderly
-combine with thiazide diuretic or CCB for increased response
All benefit to some extent even if renin levels low or normal (additional mechanisms?)
-bradykinin antagonist blunts 20% of ACEI hypotension effect

Question 7

ACE inhibitors and metabolic syndrome

Answer 7

• ACEIs associated with ↓ incidence of new onset diabetes vs. other anti-hypertensive drug classes – beta blockers, diuretics ↑ incidence, CCBs neutral?
• attenuate vascular and organ damage – coronary arteries, heart, kidney
• good choice in South Asians – ↑prevalence of Type II diabetes?

Question 8

ACEI now recommended for …… regardless of ……

Answer 8

T2DM hypertensives regardless of age and ethnicity (NICE 2019)

Question 9

ACE inhibitors cardiac indicatons

Answer 9

• hypertension with recurrent atrial fibrillation (SOLVD)
– ↓ atrial fibrosis and remodelling, ↓ stroke
• hypertension with history of myocardial infarction or established coronary heart disease?
– reduce cardiac work, (↓BP), reduce remodelling post-MI, prophylaxis to prevent further cardiovascular events
• hypertension with asymptomatic LV dysfunction or symptomatic heart failure
– ↓ cardiac preload (↓ Na+ , water), ↓after-load (↓vasoconstriction)
– also regress LVH (AngII is a hypertrophic growth factor)
– prolong survival (CONSENSUS, SOLVD)

Question 10

ACE inhibitors: renal indications

Answer 10

• hypertension with Type I diabetic nephropathy
– esp. if proteinuria, microalbuminuria (>30 mg/24 h) present
– slow progression of renal damage, failure beyond ↓ BP per se?
– ↓renal arteriolar resistance, ↓renal perfusion pressure
• evidence less convincing in Type II diabetes?
• possibly beneficial (with caution) in non-diabetic chronic renal parenchyma disease?
• [also retard diabetic neuropathy and retinopathy?]

Question 11

I if >/3 positive tests…..

Answer 11

Initiate ACEI even if BP normal to minimise risk of renal deterioration

Question 12

Adverse effects of ACE inhibitors

Answer 12

• rapid initial ↓ BP
– especially in combination with thiazide diuretic, low Na+ diet, dehydrated, or renal dialysis (due to ↑ RAAS activity: ↑response to ACEI)
– give first dose at bedtime, start with low dose
– if possible consider temporary ↓ dose of diuretic if taken concurrently
• hyperkalaemia – due to reduced aldosterone secretion
• cough, angioedema (due to bradykinin)
• rarely GI disturbances, blood disorders, headache, dizziness, fatigue, sinusitus, rhinitis, sore throat?
• taste and skin disturbances – due to sulfhydryl group in captopril molecule?

Question 13

Contraindications/caution in ….

Answer 13

Renal impairment/renovascualr disease

Question 14

Contraindications and cautions to take in renal impairment and ACE inhibitors

Answer 14

• avoid in bilateral renal artery stenosis
– ↓↓ glomerular filtration rate (due to further↓ filtration pressure) can precipitate renal failure
– suggested by history of peripheral vascular disease /atherosclerosis
– indicated by ↓↓ BP and ↑↑ serum creatinine on initiating ACEI?
• caution in unilateral disease – risk of long-term damage to affected kidney?
• caution in elderly (↓ renal function)- reduce dose?
• monitor renal function and electrolytes (before/after) – risk of hyperkalaemia ↑ if renal function impaired

Question 15

(Other then renal) caution to take with ACE inhibitors

Answer 15

• if evidence of ↓ Na+ or hypotension
– > renin activation, > response to ACE ↑ risk of hypotension
• caution in severe symptomatic mitral/aortic stenosis
– ↑ risk of hypotension
• avoid in late stages of pregnancy
– foetal growth defects/renal failure in 2nd/3rd trimester

Question 16

ACE inhibitors:Drug interactions

Answer 16

• in combination with diuretics or high dose vasodilators
– risk of 1st dose hypotension esp. in volume –depleted
– consider temporary ↓ dose of diuretic
• in combination with potassium –sparing diuretics – ↑ risk of hyperkalaemia
• ↑ hypoglycaemic effect of insulin/oral anti-diabetic drugs – especially in renal impairment
• in combination with NSAIDS- ↑ risk of renal impairment – compromised glomerular haemodynamics (↓AngII and PGs)

Question 17

Limitations of ACE inhibitors

Answer 17

Inhibit metabolism of other peptides eg bradykinin
Characteristic cough <10% - dry, irritating, non-productive; due to bradykinin/PG accumulation in bronchial tissues?
<0.2% angio oedema - bradykinin?
-vascular reaction, localised oedema due to dilation and incr permeability of capillaries, development of giant wheals - avoid if history of idiopathic or hereditary angio-oedema
Formation of ang 2 by ACE independent route <40% - eg heart chymases incomplete blockade of synthesis

Question 18

AT1 receptor antagonists

Answer 18

• antagonise effects of AngII at AT1 receptors
– including that derived from other synthetic pathways such as heart cell chymase
• do not prevent metabolism of vasodilator mediators such as bradykinin
– avoid cough but also ↓ some benefits of ACE inhibitors?
• might also promote AT2 receptor signalling?
– due to surplus of angiotensin II? consequences?
• cleared by hepatic metabolism

Question 19

Indications for use of AT1 receptor antagonists

Answer 19

• less clinical trial data available than for ACEI
–ONTARGET: as effective in high cardiovascular risk patients, better tolerated
> reduction in cardiovascular outcomes (especially stroke) than other (non ACEI) classes for same ↓ BP
–LIFE, SCOPE, VALUE
–additional effect beyond BP lowering
–Class effect?
• Step 1 or 2 agent in uncomplicated hypertension – BHS/NICE 2011 (and 2019)- equal status to ACEI
• like ACE inhibitors, < effective ↓ BP in Afro- Caribbean, elderly than in younger Caucasian patients
• useful substitute if troublesome cough or risk of angio- oedema with ACE inhibitor – esp. for step 2 in Afro-Caribbean as better tolerated
• use if intolerant to other anti-hypertensive drugs
• generally similar indications to ACE inhibitors
– T2DM generally, regardless of age, ethnicity
– LV dysfunction post MI (OPTIMAAL)
– coexisting heart failure (Val-HeFT, ELITE, CHARM) if ACE inhibitor and/or -blocker not tolerated?
– attenuate progression of diabetic nephropathy < ACE Inhibitor for Type I, > for Type II? (IDNT, RENAAL)

Question 20

Contraindications / cautions for use of AT1 receptor antagonists

Answer 20

• generally similar to ACE inhibitors
• contra-indicated in bilateral renal artery stenosis
– caution in unilateral renal artery stenosis or history of renal impairment or peripheral vascular disease
– monitor renal function / serum K+
• avoid in aortic /mitral stenosis
• contra-indicated in pregnancy

Question 21

Adverse effects of AT1 receptor antagonists

Answer 21

• generally mild?
• 1st dose hypotension – esp. in volume-depleted /in combination with diuretics
• occasionally hyperkalaemia – especially with K+ sparing diuretics?
• rarely angio-oedema
• drug-specific side-effects?
– Losartan: dizziness, taste disturbance
– Candesartan: nausea, rhinitis, back pain
– Valsartan: fatigue

Question 22

Combination formulation ACEI+ARB

Answer 22

Not recommended, little increased efficacy BUT incr side effects (ONTARGET)
Incr renin secretion, aldosterone escape?

Question 23

Combination formulations: ACEI OR ARB + diuretic or CCB

Answer 23

First stabilise on individual components
– ACEI/Thiazide: capozide, innozide, accuretic
– ARB/Thiazide: co-aprovel, olmetec plus, co-diovan

– ACEI/CCB: triapin, tarka
– ARB/CCB: sevikar
superior to diuretic combinations (especially in diabetics?) ACCOMPLISH

Question 24

Dual NEP enzyme/angiotensin receptor inhibitors?

Answer 24

• EntrestoTM (sacubitril/valsartan, LCZ696)
− inhibition of neprilysin (prevents metabolism of natriuretic peptides- vasodilators)
− blockade of Angiotensin AT1 receptor (prevents actions of angiotensin II)
− clinical trials ongoing in hypertension (and other current indications for ACEI, ARB use)
- superior decr bp vs valsartan?
- greater influence on systolic than diastolic?
- longer term studies required / in specialised sub populations

Question 25

Describe 1st generation Renin Inhibitors

Answer 25

Enalkiren, Remikiren
High potency
Long duration of action
Poor oral bioavailability (1st pass effect, ,low plasma conc in humans)
Clinical trials??

Question 26

Describe renin inhibitors

Answer 26

Non-peptide given orally
Overcame some problems associated with 1st generation
Sub-optimal absorption but minimal metabolism
150mg Dalit for treatment of hypertension
-and associated organ damage (cardiac, renal)
-generally not 1st line therapy (not recommended in Scotland)

Question 27

Side effects and caution of renin inhibitors

Answer 27

Side effects - diarrhoea, rash - avoids ACEI cough, low incidence of hyperkalaemia
Caution in dehydrates, low sodium diet, concomitant diuretic use - risk of 1st dose hyPOtension
Causation in renal artery stenosis, renal impairment - monitor plasma K+ and renal function (especially in diabetes, HF)

Question 28

Describe the ALTITUDE study

Answer 28

• Type 2 diabetics with renal impairment at high risk of cardiovascular and renal events – aliskiren in addition to optimal treatment (including ACEI or ARB)
• stopped prematurely due to no benefit above existing treatment but > risk of stroke, renal complications, hyperkalaemia, hypotension
• wider implications?
– do NOT combine with ACEI or ARB in ANY hypertensive patient? (dual RAAS inhibition not useful strategy?)