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
Example
Aldosterone antagonists
Spironolactone
Eplerenone
Indications
Aldosterone antagonists
- HTN
- HF (cardioprotective)
Sprionolactone
SE/AE
Non-selective aldosterone receptor blocker
Binds androgen receptors
- hirsituism
- deep voice
- impotence
- menstrual irregularities
- gynecomastia
Teratogenic
Tumorgenic
Hyperkalemia
- Caution: potassium salts, supplements, RAAS drugs
Spironolactone
Drug interactions
CYP3A4 inhibitors
- toxicity
- do not combine
Lithium toxicity
- reduce dosage of lithium
- increased reabsorption
ACEi and ARBs and potassium supplements
- hyperkalemia
Advantage of Eplerenone over Spironolactone
Selective aldosterone blocker
- does not bind and stimulate androgen receptors
- no hirsituism, impotence, dysmenorrhea, deep voice
Teratogenic RAAS Drugs
ACEi
ARBs
DRI (aliskiren)
Spironolactone
Baroreceptor Reflex
Pathophysiology
Carotid bodies and aortic arch sense change in BP
Signal to brain
Turn on ANS
Low BP –> Activation SNS
- 1. Vasoconstriction
- 2. Increase HR, contractility, conduction = increase CO and BP
High BP –> activation PNS
- 1. Vasodilation
- 2. Decrease HR, contractility, conduction = decrease CO and BP
Neurotransmitters of the Peripheral Nervous System
- Acetylcholine
- neuromuscular junctions
- Pre-ganglionic neurons of SNS
- Pre and post ganglionic neurons of PNS - Norepinephrine
- Post-ganglionic neurons SNS - Epinephrine
- Released by adrenal medulla
Functions of Adrenergic Receptor Subtypes
alpha 1, beta 1, beta 2
Alpha 1
*shunt blood to vital organs
- Eyes: pupil dilation (constriction iris)
- Arteries: constriction (skin, mucous membranes, viscera)
- Veins: constriction
- Sex organs: contraction prostate, vas deferens
Beta 1
*increase BP and blood volume
- Heart: increase HR, contractility, conduction
- Kidney: increase renin release
Beta 2
*increase BF to vital organs, increase energy, increase oxygen
- Lungs: vasodilation, bronchodilation
- Heart: vasodilation
- MSK: increased contraction, glycogenolysis
- Liver: glycogenolysis
Monoamine Neurotransmitters
matching receptors
Epinephrine
- binds alpha 1, 2, beta 1, 2
*Hepatic degredation
Norepinephrine
- binds alpha 1, 2, beta 1
*MAO degredation
Dopamine
- binds alpha 1, beta 1
Beta Blockers
Indication
- angina
- cardiac dysrhythmias
- HTN
- Beta blocker first line for CAD and HTN - MI
- beta blocker + ACEi - HF
- beta blocker + ACEi - reduce peri-operative and post-operative mortality in heart surgery
- prescribe 2-3 weeks before surgery
- HR 60-80bpm
- continue 1 month after surgery - glaucoma
- phenochromocytoma
- tumour secretes NE and E - hyperthyroidism
- migraines
- stage fright
Beta blocker Therapeutic Action
Beta 1 or Beta 2 receptors?
Beta 1 receptor antagonist = therapeutic effect
- Heart: decrease HR, conduction (SA, AV node), and contractility = Decrease CO and BP
- Contraindicated 2/3 degree heart blocks
- Contraindicated late stage HF
- Contraindicated sinus sickness
- Kidney: decrease renin and RAAS activation = decrease fluid and sodium retention = Decrease BP
Beta 2 receptor antagonists = SE
- Heart, Lungs, MSK = prevents vasodilation
- Lungs = prevents bronchodilation
- Contraindicated asthmatics - Glycogenolysis prevented in liver and MSK
- hypoglycemia
- impaired awareness hypoglycemia (beta 1 blockage)
- Caution diabetics
Beta blockers
SE/AE and Neonates
Beta 1 adrenergic block SE
- bradycardia (block SA node)
- decreased conduction, heart block (AV node)
- rebound tachycardia (wean over 1-2 weeks)
- Heart failure and FVO (decreased contractility)
Beta 2 adrenergic block SE
- hypoglycemia (block glycogenolysis liver and msk)
- bronchoconstriction (block lungs bronchodilation)
Lipophilic
- depression, insomnia, hallucinations, nightmares
Neonates
- beta blockers remain in system 3-5 days after birth
- 1. hypotension
- 2. respiratory distress (decreased BF to lungs)
- 3. hypoglycemia
Three classes of beta blockers
- first generation
- non-selective
- bind beta 1 and beta 2
- Ex. Propranolol - second generation
- cardioselective (at low dosages)
- bind beta 1
- Ex. metoprolol - third generation
- non-selective (bind beta 1, beta 2)
- bind alpha adrenergic receptors (alpha 1)
- Ex. Labetalol, carvedilol
beta blockers
Safe in pregnancy
Examples & risk to neonate
First choice: labetalol (third generation, non selective, alpha 1, beta 1, beta 2)
Others
- pindolol (non-selective)
- sotalol (non-selective, K+ channel blocker)
- acebutolol (cardioselective)
Neonatal monitoring 3-5 days after birth
- 1. hypotension
- 2. hypoglycemia
- 3. Respiratory depression (block beta 2 - blood flow to lung)
Beta Blocker
MOA
SA and AV Node and His-Purkinje system
- Block calcium channels
- prevent influx calcium
- prevents depolarization
- decrease HR (SA node)
- decrease conduction (AV node) and ventricule (His-purkinje system)
Myocardium
- Block calcium channels
- prevents influx of calcium
- prevents depolarization
- prevents myocardium force of contraction
Propranolol, Pindolol
SE/AE
Non-selective beta adrenergic blocker
SE beta 1 blockade
- bradycardia
- heart block
- heart failure exacerbated
- reflex tachycardia
- IAH
SE beta 2 bockade
- hypoglycemia
- bronchoconstriction
- impaired response to anaphylaxis treatment
Both
- CNS: depression, hallucinations, insomnia, nightmares
Metoprolol, acebutolol
SE / AE
Cardio-selective beta blocker
SE beta 1 blockade
- bradycardia
- heart block
- exacerbation HF
- rebound tachycardia
- IAH
- depression, hallucinations, insomnia, nightmares
Contraindications and Special Considerations
Beta Blockers
Contraindications
- Sinus sickness
- bradydysrhythmias
- 2nd or 3rd degree heart blocks
Caution
- heart failure (monitor S&S: coughing, SOB, edema, nocturnal dyspnea)
- diabetes (IAH, hypoglycemia, reduce insulin/insulin secretagogues)
- anaphylaxis patients
- asthmatics
Patient monitoring
Beta blockers
Patient monitoring
Baseline
- BP (orthostatic), HR
- ECG (investigation for heart block, sinus sickness, bradydysrhythmias)
- Hx. asthma, diabetes, anaphylaxis, depression (cardioselective)
Follow-Up
- HR, BP
- SE development
Patient Education
Beta Blockers
- Monitor for S&S heart failure
- SOB, dyspnea, nocturnal coughing, edema - Impaired awareness hypoglycemia
- Monitor BG more regularly
- S&S: fatigue, hunger, confusion - Hypoglycemia
- reduce insulin dosage - Report asthma exacerbations
Do we therapeutic blood monitor for beta blockers?
No
Different patients have different responses (sensitivity/number SNS receptors)
*Start low, go slow
How are beta blockers coupled to calcium channel blockers in the heart?
- beta 1 adrenergic receptors bind NE/E
- activation G-protein
- cAMP signal cascade
- protein kinase activation
- phosphorylation calcium channels
- open calcium channel
- influx calcium
*increase HR, conduction, contractility - influx calcium, depolarization, SA/AV node conduction, myocardial contraction
Calcium channel blockers
2 classes and site of action
- Diydropyridines
- Ex. AmloDIPINE, NifeDIPINE, NicarDIPINE
- Site of action: 1. VSM
- Indication: HTN, angina - Non-dihydropyridines
- Ex. Verapamil, diltiazem
- Site of action: 1. heart 2. VSM
- Indication: HTN, angina, dysrhythmias
*Diabetic HTN with nephropathy
ACEi + dihydropyridine CCB
Calcium channel blocker
MOA
Block calcium channels
Decrease HR, conduction, contractility
Vasodilation peripheral arteries, and coronary arteries
- Heart
- Vascular smooth muscle
Heart:
- SA node and AV node: block phase 0 of action potential, prevent influx calcium, prevent depolarization and action potential
- slow automaticity
- slow conduction
- Myocardial cells: block phase 2, prevent influx calcium, prevent depolarization for contraction
- decrease contractility
Vascular smooth muscle:
- block influx calcium
- prevent depolarization and contraction
- vasodilation results
- arteries > veins
Calcium channel blockers
Indication
- HTN
- Angina
- Dysrhythmias
- Decrease workload of heart
- Decrease conduction in heart
- Decrease CO and BP
Non-dihydropyridines
- HTN, angina, dysrhythmias
Dihydropyridines
- HTN, angina
Calcium Channel Blocker
Contraindications
*Same as beta blockers
- 2nd or 3rd degree AV blocks
- Sick sinus syndrome
- hypotension
- Caution in heart failure
_* do not combine with beta blockers
NifeDIPINE, amloDIPINE, nicarDIPINE
(Dihyrdopyridines)
MOA
Block calcium channels on the vascular smooth muscle, preventing depolarization and contraction
VASODILATION
peripheral arteries - decrease afterload of heart and BP
coronary arteries - increase blood flow to heart
NifeDIPINE, AmloDIPINE, nicarDIPINE
(dihydropyridines)
SE
- Baroreceptor reflex
- reflex tachycardia
- worsening angina
- vasodilation -> decreased BP -> baroreceptor reflex -> ANS/SNS -> increase HR, contractility, conduction
- PRN: beta blocker - flushing, edema, HA, dizziness, orthostatic hypotension
- Change positions slowly
- PRN: diuretic for FVO - Eczema
NifeDIPINE and/or Immediate release formulae
AE
Immediate release
increase mortality from MI or ACS (unstable angina)
- baroreceptor reflex
- reflex tachycardia
- increase demand on heart
- death
Prescriber considerations and monitoring
Dihydropyridines
Dihydropyridines = DIPINES
Site of action: VSM peripheral arteries and coronary arteries
Baseline
- BP, HR
- Hx. angina, peripheral edema
- liver and kidney function (metabolism and clearance of drug, dose adjustments)
Monitoring
- BP, HR
- SE: edema, reflex tachycardia, worsening angina
- PRN: diuretics, beta blockers, ER vs. IR
Benefits of Dihydropyridine
Caution (not contraindicated)
- AV blocks
- sick sinus syndrome (SA)
- hypotension
Can be prescribed with:
- Digoxin (doesn’t influence conduction, contractility)
- beta blockers (doesn’t potentiate effect)
Dihydropyridines and Pregnancy
Dihydropyridines can be used in pregnancy
Ex. NifeDIPINE
First line is labetalol (non-selective, beta 1,2, alpha 1 blocker)
Patient Education
Dihydropyridines
- Monitor worsening angina, reflex tachycardia/palpitations
- Monitor peripheral edema
Examples
non-dihydropyridines
- Verapamil
- Diltiazem
MOA
Non-dihydropyridines
Block calcium channels 1. heart 2. vascular smooth muscle
Heart
- decrease HR, conduction, contraction
Brain
- activate baroreceptor reflex
- increase HR, conduction, contraction
Vascular smooth muscle
- vasodilation (blocking contraction of VSM) of peripheral arteries (lower BP) and coronary arteries (increase cardiac perfusion)
NET EFFECT: Decrease BP (through VSM dilation arteries) and increase CA perfusion
Indication
Verapamil, Diltiazem
- HTN
- Angina
- Dysrhythmias
Verapamil, Diltiazem
SE/AE
CCB heart:
- Bradycardia (decrease SA node automaticity)
- AV block (decrease AV node conduction)
- HF (decrease contractility)
CCB VSM:
- vasodilation: flushing, HA, dizziness, orthostatic hypotension, edema
- Constipation (less with diltiazem)
- PRN: bulk forming laxative
Eczema (diltiazem)
Verapamil, Diltiazem
Contraindications & Drug interactions
- Digoxin (AV block if combined)
- Beta blockers (toxic cardiosupression if given together)
- grapefruit juice (increase level)
- Drugs that require CYP3A4 for metabolism (macrolides, spironolactone, eplerenone)
- AV block, sinus sickness syndrome, caution heart failure
Verapamil, Diltiazem
Prescriber considerations
Baseline
- Heart rate, BP
- liver and kidney function (metabolism and clearance)
- ECG (r/o AV block, sinus sickness syndrome)
Monitoring
- HR, BP
- worsening angina, edema
Patient education
verapamil, diltiazem
- Avoid grapefruit juice
- inform pharmacist CYP3A4 inhibitor (Abx., diuretic interactions)
- report edema or worsening angina or constipation
