HTN PHARM_ RAAS_beta_CCB Flashcards
1
Q
Renin
What stimulates release
A
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
2
Q
Rate limiting step in RAAS Pathway
A
Renin conversion of angiotensinogen (inactive, produced by liver) to angiotensin I
3
Q
ACE
Function and location
A
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
4
Q
Functions of Angiotensin II
A
- 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)
5
Q
Functions
Aldosterone
A
- 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
6
Q
Drugs that act on the RAAS System
A
- 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)
7
Q
Can ACE inhibitors block all angiotensin II formation?
A
NO
- tissues produce angiotensin II without ACE involvement
8
Q
Special considerations
Life span
RAAS Drugs
A
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
9
Q
ACEi
MOA
A
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
10
Q
ACEi
Indications
A
- 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)
11
Q
SE and AE
ACEi
A
- 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
12
Q
Prescriber considerations
Baseline/monitoring BLOODWORK
ACEi
A
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
13
Q
Combination drugs
ACEi
A
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,
14
Q
Drug interactions
ACEi
A
- 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
15
Q
ARBs
MOA
A
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
16
Q
Angiotensin II Receptor blocker (ARB)
Indications
A
- 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
17
Q
Are ACEi and ARBs interchangable?
A
NO
ARBs are 2nd LINE
- decreased evidence of prevention of cardiovascular morbidity and mortality
*angiotensin II is still produced
18
Q
Angiotensin II Receptor Blocker (ARB)
SE/AE
A
- 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)
19
Q
Patient Monitoring
ARBs
A
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
20
Q
Benefit ARB over ACEi
A
- less risk cough
- does not cause bradykinin to increase
- less risk hyperkalemia
- no neutropenia / fatal aplastic anemia
21
Q
ARB
Drug interactions
A
- 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
22
Q
When do you bring the client back after starting ACEi or ARBs
A
2-4 weeks
- assess CBC & Diff (neutropenia)
- electrolytes (sodium, potassium)
- urinalysis (proteinuria)
- Kidney function (BUN, CrCl)
- Blood pressure trends (indication effective?)
23
Q
Direct Renin Inhibitors
MOA
A
Binds tightly to renin reducing its action 50-80%
Inhibits downstream RAAS pathway
24
Q
Aliskiren
AE
A
- hypotension and stroke
- teratogenic
- Kidney disease (type 2 DM)
25
Aliskiren
SE
1. GI
2. angioedema
3. hyperkalemia
4. 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
26
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
27
Example
Aldosterone antagonists
Spironolactone
Eplerenone
28
Indications
Aldosterone antagonists
- HTN
- HF (cardioprotective)
29
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
30
Spironolactone
Drug interactions
CYP3A4 inhibitors
- toxicity
- do not combine
Lithium toxicity
- reduce dosage of lithium
- increased reabsorption
ACEi and ARBs and potassium supplements
- hyperkalemia
31
Advantage of Eplerenone over Spironolactone
Selective aldosterone blocker
- does not bind and stimulate androgen receptors
- no hirsituism, impotence, dysmenorrhea, deep voice
32
Teratogenic RAAS Drugs
ACEi
ARBs
DRI (aliskiren)
Spironolactone
33
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
34
Neurotransmitters of the Peripheral Nervous System
1. Acetylcholine
- neuromuscular junctions
- Pre-ganglionic neurons of SNS
- Pre and post ganglionic neurons of PNS
2. Norepinephrine
- Post-ganglionic neurons SNS
3. Epinephrine
- Released by adrenal medulla
35
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
36
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
37
Beta Blockers
Indication
1. angina
2. cardiac dysrhythmias
3. HTN
- Beta blocker first line for CAD and HTN
4. MI
- beta blocker + ACEi
5. HF
- beta blocker + ACEi
6. reduce peri-operative and post-operative mortality in heart surgery
- prescribe 2-3 weeks before surgery
- HR 60-80bpm
- continue 1 month after surgery
6. glaucoma
7. phenochromocytoma
- tumour secretes NE and E
8. hyperthyroidism
9. migraines
10. stage fright
38
Beta blocker Therapeutic Action
Beta 1 or Beta 2 receptors?
Beta 1 receptor antagonist = therapeutic effect
1. 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
2. Kidney: decrease renin and RAAS activation = decrease fluid and sodium retention = Decrease BP
Beta 2 receptor antagonists = SE
1. Heart, Lungs, MSK = prevents vasodilation
2. Lungs = prevents bronchodilation
- Contraindicated asthmatics
3. Glycogenolysis prevented in liver and MSK
- hypoglycemia
- impaired awareness hypoglycemia (beta 1 blockage)
- Caution diabetics
39
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
40
Three classes of beta blockers
1. first generation
- non-selective
- bind beta 1 and beta 2
- Ex. Propranolol
2. second generation
- cardioselective (at low dosages)
- bind beta 1
- Ex. metoprolol
3. third generation
- non-selective (bind beta 1, beta 2)
- bind alpha adrenergic receptors (alpha 1)
- Ex. Labetalol, carvedilol
41
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)
42
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
43
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
44
Metoprolol, acebutolol
SE / AE
Cardio-selective beta blocker
SE beta 1 blockade
- bradycardia
- heart block
- exacerbation HF
- rebound tachycardia
- IAH
- depression, hallucinations, insomnia, nightmares
45
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
46
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
47
Patient Education
Beta Blockers
1. Monitor for S&S heart failure
- SOB, dyspnea, nocturnal coughing, edema
2. Impaired awareness hypoglycemia
- Monitor BG more regularly
- S&S: fatigue, hunger, confusion
3. Hypoglycemia
- reduce insulin dosage
4. Report asthma exacerbations
48
Do we therapeutic blood monitor for beta blockers?
No
Different patients have different responses (sensitivity/number SNS receptors)
*Start low, go slow
49
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
50
Calcium channel blockers
2 classes and site of action
1. Diydropyridines
- Ex. AmloDIPINE, NifeDIPINE, NicarDIPINE
- Site of action: 1. VSM
- Indication: HTN, angina
2. Non-dihydropyridines
- Ex. Verapamil, diltiazem
- Site of action: 1. heart 2. VSM
- Indication: HTN, angina, dysrhythmias
*Diabetic HTN with nephropathy
ACEi + dihydropyridine CCB
51
Calcium channel blocker
MOA
Block calcium channels
Decrease HR, conduction, contractility
Vasodilation peripheral arteries, and coronary arteries
1. Heart
2. 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
52
Calcium channel blockers
Indication
1. HTN
2. Angina
3. Dysrhythmias
- Decrease workload of heart
- Decrease conduction in heart
- Decrease CO and BP
Non-dihydropyridines
- HTN, angina, dysrhythmias
Dihydropyridines
- HTN, angina
53
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
54
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
55
NifeDIPINE, AmloDIPINE, nicarDIPINE
(dihydropyridines)
SE
1. Baroreceptor reflex
- reflex tachycardia
- worsening angina
- vasodilation -> decreased BP -> baroreceptor reflex -> ANS/SNS -> increase HR, contractility, conduction
- PRN: beta blocker
2. flushing, edema, HA, dizziness, orthostatic hypotension
- Change positions slowly
- PRN: diuretic for FVO
3. Eczema
56
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
57
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
58
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)
59
Dihydropyridines and Pregnancy
Dihydropyridines can be used in pregnancy
Ex. NifeDIPINE
First line is labetalol (non-selective, beta 1,2, alpha 1 blocker)
60
Patient Education
Dihydropyridines
1. Monitor worsening angina, reflex tachycardia/palpitations
2. Monitor peripheral edema
61
Examples
non-dihydropyridines
1. Verapamil
2. Diltiazem
62
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
63
Indication
Verapamil, Diltiazem
1. HTN
2. Angina
3. Dysrhythmias
64
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)
65
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
66
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
67
Patient education
verapamil, diltiazem
- Avoid grapefruit juice
- inform pharmacist CYP3A4 inhibitor (Abx., diuretic interactions)
- report edema or worsening angina or constipation
