Drugs Targeting The RAAS Flashcards
(28 cards)
What are the actions of ACE inhibitors?
• 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
What is the chemical structure of ACE inhibitors
Similar actions and benefits - class effect
Differ in regard to chemical group which interacts with ACE active site
The 3 chemical groups that interacts with ACE active site
Sulphydryl group - captopril
Carboxyl group - lisinopril, enalapril
Fosphitinic acid group - fosinopril
Describe ADME and pharmacokinetics
• 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
ACE inhibitors: indications
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)
ACEI: variation with … and …
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
ACE inhibitors and metabolic syndrome
• 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?
ACEI now recommended for …… regardless of ……
T2DM hypertensives regardless of age and ethnicity (NICE 2019)
ACE inhibitors cardiac indicatons
• 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)
ACE inhibitors: renal indications
• 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?]
I if >/3 positive tests…..
Initiate ACEI even if BP normal to minimise risk of renal deterioration
Adverse effects of ACE inhibitors
• 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?
Contraindications/caution in ….
Renal impairment/renovascualr disease
Contraindications and cautions to take in renal impairment and ACE inhibitors
• 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
(Other then renal) caution to take with ACE inhibitors
• 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
ACE inhibitors:Drug interactions
• 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)
Limitations of ACE inhibitors
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
AT1 receptor antagonists
• 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
Indications for use of AT1 receptor antagonists
• 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)
Contraindications / cautions for use of AT1 receptor antagonists
• 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
Adverse effects of AT1 receptor antagonists
• 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
Combination formulation ACEI+ARB
Not recommended, little increased efficacy BUT incr side effects (ONTARGET)
Incr renin secretion, aldosterone escape?
Combination formulations: ACEI OR ARB + diuretic or CCB
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
Dual NEP enzyme/angiotensin receptor inhibitors?
• 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
