lecture 5- ACEi, AARBs, CCB

what are the four major things angiotensin II influences

• vasoconstriction- increased SVR

• aldosterone- increase volume

• ADH- increase water retention

• remodeling- HF, CKD progression

ACEi MOA

• inhibit ACE to block conversion of angiotensin I to angiotensin II

  • decreased angiotensin II formation

  • increased levels of bradykinin

• result: VASODILAITON

  • removes major vasoconstrictor

  • prevents breakdown of vasodilator bradykinin

  • vasodilation→ decreased SVR→ decreased BP

ex of ACEi

lisinopril

ACEi therapeutic use

• heart protection

• kidney protection

• blood pressure control

ACEi uses- heart protection

• HFrEF

• left ventricular dysfunction

• post MI remodeling

• high CV risk

ACEi uses- kidney protection

• CKD

• diabetic nephropathy

• proteinuria/albuminuria

  • allow for decrease pressure and filter more consistently

when to avoid ACEi

• pregnancy

• hx angioedema (due to increased bradykinin)

• pts with BILATERAL renal artery stenosis

why avoid ACEi in renal artery stenosis?

• can cause acute renal failure

  • afferent arteriole already constricted due to stenosis; if add ACEi → now constrict efferent also → acute renal failure

ACEi ADE

• dry cough- due to increased bradykinin (MC)

• angioedema - due to increased bradykinin

• HYPERkalemia (decreased aldosterone)

• first dose hypotension

• AKI

  • small increase in Cr or drop i nGFR is normal

concerning findings after initiating ACEi

• >30% increase creatinine

• major decrease in eGFR

things to consider with increased creatinine

• bilateral renal artery stenosis

• vol depletion

• NSAID use

• advanced CKD or severe heart failure

how to proceed if creatinine increased <30%

• cont ACEi

• recheck labs

• no need fro changes

how to proceed if creatinine increased >30%

• ask pt:

  • dehydration

  • hypotensive

  • NSAID use

  • recently started diuretic

  • vol depleted

• correct reversibel causes

• repeat labs

• withhold or d/c

when to temporarily hold ACEi

acute reversible problem- treat underlying problem and restart once stable

• dehydration

• vomiting

• diarrhea

• hypotension

• acute illness

• contrast nephropathy

• AKI

• severe HYPERkalemia

when to d/c ACEi

• bilateral renal artery stenosis

• recurrent severe HYPERkalemia depsite mgmt

• severe allergy or angioedema

• persistent, sign decline in kidney function clearly attributed to med despite correcting reversible causes

what to monitor- ACEi

• K- check 1 week after starting/changing dose

• Cr- check one week after starting/changing dose

role of ACEi in HF

• heart failure→ body activates RAAS→ more Na and water retained→ heart works harder (increased preload)→ cardiac remodeling

• ACEI INTERRUPTS this cycle

  • decreased vol overload

  • decreased cardiac workload

  • improved remodeling

how do ACEi protect kidney

normally:

• ang II constricts EFFERENT arteriole → increased glomerular pressure→ increased kidney damage over time

ACEi

• DILATES efferent arteriole→ decreased intraglomerular pressure→ slows CKD progression→ reduces proteinuria

why are ACEi so important?

• HTN- decrease SVR
  HFrEF- decrease preload/afterload + remodeling

• post mi- prevent remodeling

• diabetic nephropathy- protect kidneys

• high CV risk- reduce events

ACEi DDI- K supp

• increased hyperkalemia via decreased aldosterone

• clinical action: avoid unless indicated; monitor K

ACEi DDI- K -sparing diuretics

• increased hyperkalemia via additive LK retention

• clinical action: monitor K adn renal function

ACEi DDI- NSAIDs

• decrease antihypertensive effect

• increased AKI risk

• reduced renal prostaglandins

• clinical action:

  • limit use

  • monitor renal function

ACEi DDI- diuretics

• increased first dose hypotension via volume depletion

• clinical action: consider lower ACEi starting dose

ACEi DDI- lithium

• increased lithium toxicity via reduced renal lithium clearance

• clinical action: monitor lithium levels or avoid

ACEi DDI- aliskiern

• increased hyperkalemia, renal impairment, and hypotension via dual RAAS blockade

• clinical action: avoid combo

lisinopril dosage

• 10-40mg daily (MC adult dose)

ACEi summary

• agents: lisinopril

• site of action: ACE enzyme

• MOA: bloack conversion ang i → ang II

  • decrease vasoconstriction, decrease aldosterone, increase bradykinin

• indications: HTN, HFrEF, MI/LV dysfunction, diabetic nephropathy

• common ADR: dry cough, hyperkalemia, angioedema, increased SCr, first dose hypotension

• monitor: BP, K, creatinine/eGFR

ARB MOA

• block AT1 receptor→ vasodilation

ex of ARB

losartan

ARB therapeutic use

• heart protection

• kidney protection

• blood pressure control

ARB uses- heart protection

• HFrEF

• left ventricular dysfunction

• post MI remodeling

• high CV risk

ARB uses- kidney protection

• CKD

• diabetic nephropathy

• proteinuria/albuminuria

when to avoid ARBs

• pregnancy

• bilateral artery stenosis

ARB ADE

• hyperkalemia (decreased aldosterone)

• AKI

• first dose hypotension

• rare angioedma

what to monitor when using an ARB

• K- check levels 1 week after starting/changing dose

• Cr- check 1 week after starting/changing dose

ARB interactions- K supp

• increased hyperkalemia via decreased aldosterone

• clinical acton: monitor K

ARB interactions- K sparing diuretics

• increased hyperkalemia via additive effect

• clinical action: monitor K

ARB interaction- NSAIDs

• decrease BP effect and increased AKI via renal vasoconstriction

• clinical action: monitor renal function

ARB interaction- lithium

• increased lithium toxicity via reduced clearance

• clinical action: monitor levels

ARB interaction- ACEi

• increased hyperkalemia, AKI, hypotension via dual RAAS blockade

• clinical action: do not combine

losartan dosage

• 25-100mg daily

• prototype ARB, lowers uric acid slightly

ARB summary

• agents: losartan

• site of action: AT1 receptor

• MOA: blocks Ang II form activating the AT1 receptor

  • decreased vasoconstriction, decreased aldosterone secretion

• indications: HTN, HFrEF, MI/LV dysfunction, diabetic nephropathy

• common ADRs: hyperkalemia, increased SCr, first dose hypotension

• monitoring: BP, K, SCr/eGFR

when to choose ARB instead of ACEi

• persistent ACEi cough

• ACE inhibitor intolerance

• similar cardiovascular and renal benefits

direct renin inhibitor- agent and MOA

• aliskiren

• MOA: inhibit conversion of angiotensinogen to ang I

  • vasodilation→ decreased SVR

  • reduced aldosterone secretion→ decreased SV

direct renin inhibitor- indications

• not widely used

• not a key drug in HTN but used as an alternative

  • ACE/ARB intolerance but RAAS targeting agent desired

direct renin inhibitor- avoid and/or caution in:

• pregnancy

• pts with bilateral renal artery stenosis

direct renin inhibitor- disadvantages

• lack of evidence of benefit in reducing CV events in HTN

• CANNOT be combined with ACE/ARB

direct renin inhibitor- ADR

• generally well tolerated

• diarrhea

• hyperkalemia

• angioedema

• AKI

direct renin inhibitor- monitoring

• K and creatinine

two subclasses of CCB

• dihydropyridine calcium channel blocker

• non-dihydropyridine calcium channel blockers

DHP CCB agents

• amlodapine; “-dipines”

DHP CCB- MOA

• block L type calcium channel in vascular smooth muscle

  • decrease calcium influx → vasodilation→ decreased SVR → decreased BP

DHP CCB- site of action

• primarily arteriolar smooth muscle

• minimal effects on nodal cells

DHP CCB- indications

• HTN (first line)

  • chronic stable angina

  • vasospastic angina

  • soem agents used iV for HTN emergencies (nicardipinem clevidipine)

DHP CCB- common ADR

• peripheral edema

• HA

• flushing

• dizziness

• gingival hyperplasia (esp nifedipine)

DHP CCB- monitoring

• BP

• peripheral edema

• HR

DHP CCB interactions- grapefruit juice

• increased drug concentration via CYP3A4 inhibition

• clinical action: avoid large amnts

DHP CCB interactions- CYP3A4 inhib (azoles)

• increased hypotension and edema via decreased metabolism

• clinical action: consider dose adjustments

DHP CCB interactions- CYP3A4 inducers (rifampin, carbamasepine)

• decrease effectiveness due to increased metabolism

• clinical action: monitor BP

DHP CCB interactions- simvistatin

• increased statin toxicity via CYP3A4 inhib

• clinical action: limit sim dose (20mg) or use alt statin

non DHP CCB- agents

• verapamil

• diltiazem

non DHP CCB- MOA

• block L type calcium channels in the heart- nodal cells

  • decrease HR, decrease AV conduction, decrease contractility

  • mild vasodilation

non DHP CCB- indications

• HTN

• chronic stabel angina

• RATE CONTROL in AFIB/flutter

• SVT

• migraines- verapamil

no DHP CCB- common ADR

• bradycardia

• VA block

• hypotension

• constipation

• worsening heart failure (CONTRAINDICATED)

non DHP CCB- monitoring

• BP

• HR

• ECG/PR interval

• signs of HF

• sx improvement

non DHP CCB interactions- BB

• bradycardia, AV block via additive VA node suppression

• clinical action: avoid or monitor

non DHP CCB interactions- digoxin

• increased digoxin levels adn bradycardia via decreased digoxin clearance

• clinical action: monitor digoxin and HR

non DHP CCB interactions- grapefruit juice

• increased drug concentration via CYP3A4 inhib

• clinical action: avoid excess intake

non DHP CCB interactions- CYP3A4 inhib

• increased toxicity via decreased metabolism

• clinical action: consider dose reduction

non DHP CCB interactions- simvastatin

• increased statin toxicity (myopathy.rhabdo) via CYP3A4 inhib

• clinical action: limit dose or use alternate statin

DHP CCB- summary

• chemical family

• usually end in -dipine

• prefer blood vessels

• vasodilation

• used mainly fro HTN

non DHP CCB- summary

• everything else

• verapamil and diltiazem

• perfer the heart

• decrease HR, AV conduction, and contractility

• used fro AFIB, angina, HTN