HTN PHARM_ RAAS_beta_CCB Flashcards
Renin
What stimulates release
Renin
- released by juxtaglomerular cells
- located between afferent and efferent arterioles
- sensation low BP, low blood volume, hyponatremia
Release stimulated by
- beta 1 adrenergic stimulation (E, NE)
- low BP
- low BV
- hyponatremia
Rate limiting step in RAAS Pathway
Renin conversion of angiotensinogen (inactive, produced by liver) to angiotensin I
ACE
Function and location
Angiotensin converting enzyme
- produced by cells lining blood vessels
- large concentration in lungs
Function
- conversion angiotensin I (weak vasoconstriction) to angiotensin II (strong vasoconstriction, responsible for HTN)
Non-specific enzyme
- mutiple substrates
- Kinase II (if not converting angiotensin I)
- degrades bradykinin
Functions of Angiotensin II
- STRONG vasoconstriction
- responsible for maintenance of BP
- fast response
A. Direct
- vasoconstriction vascular smooth muscles (arteries, veins)
- vasoconstriction afferent arteriole (decrease GFR, retain water)
B. Indirect
- Secretion E/NE from adrenal cortex
- stimulation beta adrenergic receptors
- 1. vasoconstriction 2. increase HR, conduction, cardiac output and BP 3. renin release
- Release Aldosterone
- aldosterone released from adrenal medulla
- aldosterone binds principle cell receptors in the distal tubules (kidney)
- Na/K pump synthesis
- reabsorption NA, water and excretion potassium - REMODELLING cardiac and vascular smooth muscle
- migration, proliferation, hypertrophy VSM cells
- increased ECM production by myofibroblasts
- hypertrophy cardiac cells
- increase BP (atheroscelerosis, decreased compliance heart, heart failure)
Functions
Aldosterone
- Maintain blood volume and blood pressure
- slow response
- takes weeks to months
- Angiotensin II stimulates release of aldosterone from adrenal medulla
- aldosterone binds receptors on PRINCIPLE CELLS in the distal tubules (kidney)
- synthesis of Na/K pumps
- reabsorption sodium, water, excretion potassium - CARDIAC remodelling
- causes cardiac remodelling, hypertrophy and fibrosis - Inhibits NE re-uptake
- increases stimuli heart, dysrhythmias - Increases BARORECEPTOR set point
Drugs that act on the RAAS System
- ACE inhibitors
- angiotensin converting enzyme inhibitors
- IPRIL
- block conversion angiotensin I to angiotensin II
- ARB
- angiotensin II receptor blockers
- SARTANS
- block effect of angiotensin II (1. vasoconstriction 2. cardiac remodelling 3. release of NE 4. release of aldosterone)
- DRI
- direct renin inhibitors
- Ex. aliskiren
- block release of renin from juxtaglomerular cells
- Aldosterone antagonist
- Ex. spironolactone, eplerenone
- Block aldosterone receptors (block Na/K pump synthesis at the distal tubules, block cardiac remodelling, block changes to baroreceptor reflex, and NE uptake)
Can ACE inhibitors block all angiotensin II formation?
NO
- tissues produce angiotensin II without ACE involvement
Special considerations
Life span
RAAS Drugs
Infants
- IPRILS (ACE inhibitors) safe
Children
- IPRILS safe (ACE inhibitors) safe
- SARTANS safe > 6 years old
Pregnancy and breastfeeding
- TERATOGENIC
- NOT SAFE
Old people
- SAFE
ACEi
MOA
Inhibit angiotensin converting enzyme
prevent formation of angiotensin II
1. decrease BP
2. decrease blood volume, sodium
3. decrease remodelling cardiac, vasculature
4. increase GFR
- Block vasoconstriction arteries, veins (decrease BP, increase GFR)
- Block release of epinephrine from adrenal cortex (decrease HR, CO and BP)
- Block release of aldosterone from adrenal medulla (increase na/water excretion, potassium absorption)
- Block remodelling cardiac and vasculature
- Block aldosterone effect on NE (decrease acccumulation NE)
- block aldosterone effect on baroreceptor setpoint
ACEi
Indications
- hypertension
- heart failure
- myocardial infarction
- stroke
- nephropathy
- retinopathy
- prevention MI, stroke, death (CVE mortality) in high risk cardiovascular populations (Ramipril)
- MI or HF
- ACEi + beta blocker - TIA
- ACEi + diuretic - Nephropathy
- ACEi + CCB dihydropyridine (diabetic)
- ACEi + diuretic (non diabetic) - Retinopathy Prevention (type I DM)
- ACEi
*ARB can be used instead of ACEi (if not tolerated)
SE and AE
ACEi
- first dose hypotension
- hyperkalemia
- cough/angioedema
- renal failiure
- neutropenia
- first dose hypotension
- proportional to angiotensin II level
- related to impaired baroreceptor setpoint (chronically high aldosterone)
- lie down, notify MD - Hyperkalemia
- if taking potassium supplements or potassium sparing diruetics
- D/C potassium sparing diuretic 2-3 days before starting ACEi - Cough (10%), Angioedema (1%)
- inhibition bradykinin breakdown (kinase II)
- vasodilation, permeability, edema
- most common older, asian, female
- Cough resolves with D/C in 3 days
- D/C if life threatening angioedema, Rx. epinephrine - Neutropenia / fatal aplastic anemia
- Monitor sore throat, fever - Renal failure
- contraindicated bilateral renal stenosis
- inhibition angiotensin II (vasoconstriction efferent arteriole to maintain GFR) -> precipitous drop in GFR -> oligouria -> renal failure
Prescriber considerations
Baseline/monitoring BLOODWORK
ACEi
BEFORE START
BASELINE BLOOD WORK
- CBC and diff (neutropenia)
- angiotensin II level (severity of first dose hypotension)
- risk factors for angioedema (asian, female, older)
- D/C potassium supplements, diuretics 2-3 days before (hyperkalemia)
- baseline BP
- Pregnancy status (teratogenic)
MONITORING BLOOD WORK
(2-4 weeks after starting)
- BP
- SE: angioedema, hyperkalemia, neutropenia, kidney failure
- repeat CBC and diff
- BUN, CrCl, proteinuri
- potassium levels
Combination drugs
ACEi
Combination Drugs
- contain both ACEi + thiazide diuretic
- contain both ACEi + CCB (dihydropyridine)
First line indications:
ACEi + Diuretic (post TIA)
ACEi + Diuretic (nephroprotective, non diabetic)
Thiazide Diuretics
- block Na/K/Cl reabsorption at the early distal convoluted tubule (10%)
- Examples: Hydrochlorothiazide, indapamide
- SE: hypotension, dehydration, hyperglycemia, hyperuricemia, hyponatremia, hypokalemia,
Drug interactions
ACEi
- Synergistic effect with other BP lowering agents
- beta blockers, diuretics
- DO NOT combine with any other RAAS drug (ACEi and ARBs)
- Lithium toxicity
- Potassium toxicity - salts, potassium sparing diuretics
- NSAIDS - vasoconstriction, decreased renal blood flow, increase risk MI, nephrotoxic
ARBs
MOA
ARB
- angiotensin II recetor blocker
- blocks angiotensin II binding receptors (1. vascular smooth muscle 2. cardiac 3. kidney (adrenal cortex, medulla)
Actions
- Block vasoconstriction (arteries, veins, afferent/efferent arterioles kidney; decrease BP, increase GFR)
- block release of aldosterone (sodium, water excretion; potassium retention)
- block VSM and cardiac remodelling
- block aldosterone effect on NE and baroreceptor set point
Angiotensin II Receptor blocker (ARB)
Indications
- hypertension
- MI (prevention mortality, HF post MI)
- HF
- TIA
- nephropathy
- retinopathy
Post-MI
- ACEi/ARB + beta blocker
HF
- ACEi/ARB + beta blocker
TIA
- ACEi/ARB + Diuretic (thiazide)
Nephropathy (diabetic)
- ACEi/ARB + CCB dihydropyridine
Nephropathy (non diabetic)
- ACEi/ARB + Diuretic (thiazide)
Prevention Cardiovascular mortality (stroke, MI, HF)
- ACEi/ARB + Diuretic
Retinopathy (type 1 DM, no evidence disease)
- ACEi/ARB
Are ACEi and ARBs interchangable?
NO
ARBs are 2nd LINE
- decreased evidence of prevention of cardiovascular morbidity and mortality
*angiotensin II is still produced
Angiotensin II Receptor Blocker (ARB)
SE/AE
- Angioedema
- Renal Failure
- Teratogenic
Angioedema
- 8% cross reactivity with ACEi
- causes increase synthesis of bradykinin*
- does not block kinase II
Hyperkalemia
- only at risk if taking potassium sparing diuretic (D/C) or potassium supplements/salts
Renal failure
- contraindicated in bilateral renal stenosis
- vasodilation efferent arteriole (cannot maintain GF pressure)
Teratogenic
- D/C immediately
- teratogenic in 2nd trimester onwards
(lung, kidneys, skull)
Patient Monitoring
ARBs
BASELINE
- blood pressure
- second line drug (ACEi intolerant)
- Hx. angioedema ACEi (8% cross reactivity)
- baseline kidney function (reduce dosage, can accumulate)
- pregnancy status (teratogenic)
MONITORING (2-4 week)
- blood pressure
- SE: angioedema, renal failure, hyperkalemia
- BUN, CrCl (kidney function), proteinuria
- potassium levels
Benefit ARB over ACEi
- less risk cough
- does not cause bradykinin to increase
- less risk hyperkalemia
- no neutropenia / fatal aplastic anemia
ARB
Drug interactions
- Hypotension when combined with other BP drugs and diuretics
- Hyperkalemia if combined with potassium salts, supplements or potassium sparing diuretics
- angioedema cross reactivity with ACEi
When do you bring the client back after starting ACEi or ARBs
2-4 weeks
- assess CBC & Diff (neutropenia)
- electrolytes (sodium, potassium)
- urinalysis (proteinuria)
- Kidney function (BUN, CrCl)
- Blood pressure trends (indication effective?)
Direct Renin Inhibitors
MOA
Binds tightly to renin reducing its action 50-80%
Inhibits downstream RAAS pathway
Aliskiren
AE
- hypotension and stroke
- teratogenic
- Kidney disease (type 2 DM)
Aliskiren
SE
- GI
- angioedema
- hyperkalemia
- Toxicity with CYP3A4 Blockers
GI
- Diarrhea, dyspepsia
- dose dependent
- women > men
Cough and angioedema
- 1% vs. ACEi 10%
Hyperkalemia
- if combined with potassium salts, potassium sparing diuretics, or ACEi
Aldosterone antagonists
MOA
Block aldosterone receptors
Prevent synthesis of Na/K pump in the distal tubules of the kidney
Prevent reabsorption water and sodium
Promote excretion potassium
Prevent aldosterone cardiac remodelling
