Exam 2: CV Drugs 3 - VASODILATORS

Question 1

Nitrovasodilator Drugs - NO background

Answer 1

• Endogenous, gas messenger
• Lipophilic, highly reactive & labile free radical
• Formation – from L-arginine (aa)
• Elimination – oxidation to form NOx (NO2 or NO3); nitrosylation of hemoglobin
• t ½ ~ few seconds

Question 2

EDRF

Answer 2

• EDRF is identified as NO
  
  • Endothelium Mediated Vascular Smooth Muscle Relaxation
  • EDRF: Endothelium-derived relaxing factor
  • NO Release accounts for the biological activity of endothelium-derived relaxing factor
  • Endothelium-derived relaxing factor produced and released from artery and vein is NO
  • EDRF → ↑ cGMP, which acts on smooth muscle
• • cGMP = relaxes smooth muscle, vasodilation

Question 3

NO formation picture

Answer 3

Question 4

NOS: Nitric Oxide synthase enzyme

What are the 3 types? Occur in various tissues)

Answer 4

• nNOS – neuronal, found in neurons first
• iNOS – inducible, found in macrophages
• eNOS – endothelium ** one that we’re concerned with most
• NO: Nitric Oxide
• NO formed in the body on the spot

Question 5

NO: Multiple Biological Roles

Answer 5

• Protective (bolded) & Pathogenic (regular)
  
  • Nt
  • Inhibit Plt aggregation
  • Cytoprotection
  • Vasodilator smooth muscle relaxant***
  • ↓ cell adhesion, proliferation
  • Inflammatory tissue injury
  • Shock – hypotension
  • Cell proliferation
  • Neuronal injury, NMDA
  • Immune cytotoxicity

Question 6

Nitric oxide mediated vasodilation

Answer 6

• ACh activates muscarinic receptors
• Ca++ influx that activates NOS
• Resultant NO will activate GC – guanylyl cyclase – forms cGMP → relaxation occurs

Question 7

Nitrovasodilator (NO-donor) Drugs

Answer 7

• Organic nitrates
  
  • Nitroglycerin
  • Isosorbide dinitrate
  • Isosorbide mononitrate
• Sodium nitroprusside
• Amyl nitrite (not really used therapeutically)
• Nitric oxide gas – used in neonates, pHTN

Question 8

Organic nitrates & sodium nitroprusside

Answer 8

• Mechanism of action:
• NO release resulting in activation of GC in vascular sm muscle, formation of cGMP, vascular smooth muscle relaxation and vasodilation
• Organic nitrates – require metabolism to release NO
• Organic nitrates have to go thru a metabolism step – with nitrosothiol needed – eventually releases NO
• This is how NTG has a tolerance effect – need a break where they’re off of it. As opposed to SNP that doesn’t need this, spontaneous release of NO.
• Organic nitrates like NTG

Question 9

Sodium nitroprusside: mechanism of action

Answer 9

• Structure – complex of 1 iron, 5 cyanide and 1 NO group
• Spontaneous breakdown to NO & cyanide
• Direct acting peripheral vasodilator
• Relaxation of arterial & venous smooth muscle
• Metabolism
  
  • Cyanide combines with sulfur groups to form thiocyanate (eg, thiosulfate, cysteine, etc.); undergoes renal excretion

Question 10

Sodium nitroprusside: PK

Answer 10

• Onset < 2 minutes
• Duration 1-10 minutes
• Half-life ~ 2 minutes
• Half-life thiocyanate ~2-7 days
  
  • increased with impaired renal fxn
• Renal excretion as metabolites (mostly thiocyanate); some exhaled air, feces

Question 11

Sodium Nitroprusside clinical effects

Answer 11

• Cardiovascular
  
  • ↓ arterial/venous pressure
  • ↓ peripheral vascular resistance
  • ↓ afterload
    
    • In HF or acute MI – CO may increase due to ↓ afterload
  • Slight incr HR
  • Lacks significant effects on nonvascular smooth muscle and cardiac muscle
• Renal • vasodilation without significant change in GFR
• CNS • ↑ cerebral blood flow and intracranial pressure
• Blood
• NO - Inhibits platelet aggregation

Question 12

Sodium Nitroprusside Clinical Uses

Answer 12

• Hypertensive crisis
• BP reduction to prevent/limit target organ damage
• Controlled hypotension during surgery • During anesthesia, to reduce bleeding when indicated
• Congestive heart failure • Acute, decompensated
• Acute myocardial infarction
  
  • To improve cardiac output in LV failure & low CO post-MI
  • Limited use due to coronary steal- altered blood flow results in diversion of blood away from ischemic areas

Question 13

Sodium Nitroprusside: Adverse Effects

Answer 13

• Profound hypotension- possible impaired organ perfusion
• Cyanide toxicity
  
  • often dose/duration related, but may occur at recommended doses
  • Tissue anoxia
  • Venous hyperoxemia – tissues cannot extract oxygen
  • Lactic acidosis
  • Confusion, death
• Methemoglobinemia
  
  • Some iron in hemoglobin is oxidized to ferric (+3) state with impaired oxygen affinity; reduced O2 delivery to tissues (hypoxia); metHb >10% symptomatic
  • Measured by how much Hbg is affected by this
  • Should be considered as a differential diagnosis in patients with impaired oxygenation despite adequate cardiac output and arterial oxygenation
  • Reversal agent - Methylene blue
• Thiocyanate accumulation
  
  • ↑ risk with prolonged infusion; renal impairment
  • Neurotoxicity, including… tinnitus, miosis, hyperreflexia
  • Hypothyroidism – due to impaired iodine uptake
• Renal • Incr serum creatinine (transient)
• Others include… • Incr intracranial pressure; GI (nausea); headache; restlessness; flushing; dizziness; palpitation

Question 14

Sodium Nitroprusside Drug Interactions

Answer 14

• Hypotensive drugs including…
  
  • Negative inotropes
  • General anesthetics
  • Circulatory depressants
• Phosphodiesterase Type 5 inhibitors (eg., sildenafil, tadalafil – for ED) - also causes hypotension
• Soluble guanylate cyclase stimulators (eg., riociguat) – (role of cGMP in vasodilation) – also hypotension

Question 15

Sodium Nitroprusside Stability & Administration

Answer 15

• Stability
  
  • Unstable
  • Light & temperature sensitive
    
    • Protect from light and store at 20–25°C
    • deterioration results in change to bluish color
    • wrap the container with aluminum foil or other opaque material
• Administration
  
  • IV infusion via infusion pump
  • Diluted in 5% dextrose
  • Shortest infusion duration possible to avoid toxicity; if reduction in BP not obtained within 10 minutes @ max infusion rate, discontinue (cyanide toxicity)
  • Solution has faint brownish tint; if discolored (eg., blue, green, red) discard

Question 16

Organic Nitrates

Answer 16

• nitroglycerin (glyceryl trinitrate)
• isosorbide dinitrate
• isosorbide mononitrate
• amyl nitrite (rarely used)

Question 17

Nitroglycerin mechanism of action

Answer 17

• GC: guanylyl cyclase enzyme
• NO: nitric oxide
• NO release through cellular metabolism – glutathione-dependent pathway
• Requires thiols
• NO released—stimulates GC and formation of cGMP
• Vascular smooth muscle relaxation and peripheral vasodilation
• Primary action: venous capacitance vessels
• mildly dilate arteriolar resistance vessels
• dilation of large coronary arteries
• Administered IV, SL, translingual spray, transdermal, ointment
• These require that metabolism step, compared to SNP

Question 18

NTG - effects on venous capacitance vessels, arteriolar resistance and myocardial arteries

Answer 18

• Venous capacitance vessels
  
  • Decreased preload
  • Decreased myocardial O2 demand
• Arteriolar resistance vessels (mild)
  
  • Modest decreased afterload
  • Decreased myocardial O2 demand
• Myocardial arteries
  
  • Increased myocardial O2 supply
  • ↓ MVO2 is how NTG is good for MI’s, used to think that the dilation of the large epicardial arteries was the primary mechanism

Question 19

NTG effects on CV, other, pulm

Answer 19

• Cardiovascular
  
  • ↓ VR; decrease L and R ventricular end diastolic pressure
  • decrease Cardiac Output
  • No change in SVR
  • Increase in coronary blood flow to ischemic subendocardial areas (opposite of SNP)
  • Sodium Nitroprusside = Steal
• Other
  
  • Smooth muscle relaxation in bronchi, GI tract –small effects, but it’s still a possibility
  • Inhibits platelet aggregation
• Pulmonary
  
  • bronchial dilation
  • Inhibits Hypoxic pulmonary vasoconstriction

Question 20

NTG tolerance, cautions, clinical uses

Answer 20

• Tolerance – after 8-10 h, results in diminishing effectiveness
  
  • Nitrosothoil
  • Need to take the patch off for some time to get back that effect – double check this
• Cautions – volume depletion, hypotension, bradycardia or tachycardia, constrictive pericarditis, aortic/mitral stenosis, inferior wall MI and Rt ventricular involvement
• Clinical uses
  
  • Angina
    
    • Acute angina pectoris (sublingual) & prevention (longr-acting oral, transdermal, ointment, etc.)
      
      • → Venodilation decreases venous return to the heart which reduces RVEDP and LVEDP
      • → Reduces myocardial oxygen requirements
  • Hypertension
    
    • Perioperative hypertension
    • Hypertensive emergencies
    • Postoperative hypertension (eg., following coronary bypass surgery)
  • Controlled hypotension during surgery
  • Non-ST-Segment-Elevation
  • Acute Coronary Syndrome
  • Acute Myocardial Infarction – limits damage
  • Heart Failure, Low-output syndromes
    
    • decreases preload; relieves pulmonary edema

Question 21

NTG adverse effects

Answer 21

• CNS
  
  • Throbbing headache
  • Increased ICP
• Cardiovascular
  
  • Orthostatic hypotension, dizziness, syncope
  • Reflex tachycardia (baroreceptor)
  • Flushing
  • Vasodilation, venous pooling, decreased cardiac output
• Hematologic
  
  • Methemoglobinemia (rare)
• Tolerance
  
  • limitation of the use of nitrates

Question 22

NTG PK

Answer 22

• Large first-pass effect (90%) following oral admin – why we give it SL or IV
• Metabolism
  
  • Liver– denitrated by glutathione-organic nitrate reductase to glyceryl dinitrate and then mononitrate

Question 23

NTG onset & duration for each route

Answer 23

• IV
  
  • onset: immediate
  • DOA: 3-5 min
• SL
  
  • onset: 1-3 min
  • DOA: >25 min
• translingual spray
  
  • onset: 1-3 min
  • DOA: >25 min
• PO, extended release
  
  • onset: 60 min
  • DOA: 4-8 hrs
• Topical
  
  • onset: 15-30 min
  • DOA: 7 hrs
• Transdermal
  
  • onset: 30 min
  • DOA: 10-12 hrs

Question 24

Isosorbide Dinitrate onset & duration for each route

Answer 24

• SL
  
  • onset: 2-5 min
  • DOA: 1-2 hrs
• PO
  
  • onset: 60 min
  • DOA: up to 8 hrs

Question 25

Isosorbide Mononitrate onset & duration for each route

Answer 25

• PO
  
  • onset: 30-45 min
  • DOA: >6 hrs
• PO, extended release
  
  • onset: 30-45 min also
  • DOA: >12-24 hrs

Question 26

NTG Drug Interactions

Answer 26

• Antihypertensive drugs –additive effects
• Selective PDE-5 inhibitor drugs (avanafil, tadalafil, vardenafil, sildenafil)
  
  • Absolute contraindication
  • Profound potentiation
  • Possible life-threatening hypotension and/or hemodynamic compromise
  • Accumulation of cGMP by inhibiting its breakdown
• Guanylate cyclase stimulating drugs (riociguat) – increase the production of cGMP
• Other –see text
• Anything that causes ↑ cGMP will be contraindicated
• cGMP = vasodilation/relaxation

Question 27

Other organic nitrates - Isosorbide mononitrate, dinitrate

PO use and metabolism

Answer 27

• Oral nitrate forms – used for the prophylaxis of angina pectoris
  
  • Additional- heart failure in Black patients in combination with hydralazine (direct-acting vasodilator)
• Orally - Well absorbed from the GI tract duration of action 6 hours
• Metabolism
  
  • Dinitrate metabolized to mononitrate form (t1/2=5 hrs) – active metabolite
  • Mononitrate metabolized (by denitration) to isosorbide to sorbitol - inactive
  • Regular and extended-release forms
  • Need appropriate dosing intervals, to allow for nitrate-free period, to avoid tolerance
  • Disease concerns: similar to NTG
  • Avoid concomitant use with PDE5 inhibitor drugs
  • Toxicity similar to NTG

Question 28

Phosphodiesterase Inhibitor Drugs: Phosphodiesterase enzymes

Answer 28

• Family of enzymes that breakdown cyclic nucleotides
• Regulate intracellular levels of 2nd messengers cAMP & cGMP
• 11 major subfamilies (eg., PDE-3, PDE-4, PDE-5, etc); differ in localization, potential therapeutic targets
• Inhibitors – boost levels of cyclic nucleotides by preventing breakdown
• Older, non-selective drugs that inhibit PDE: caffeine, theophylline

Boost both cAMP and cGMP

Question 29

PDE3:

brand, distribution, substrate, fn, inhibitor clinical use

Answer 29

• PDE3 breaks down cAMP. So by inhibiting it you have MORE cAMP - more inotropy/chronotropy/vasodilation
• drug
  
  • amrinone
  • milrinone
• distribution
  
  • broad
  • includes heart and VSMC
• substrate
  
  • cAMP
  • cGMP
• fn
  
  • cardiac contractility, plt aggregation
• inhbiitor clinical use
  
  • inotrope + peripheral vasodilator
  • limited for acute HF
• cliastazol is used for intermittent claudication

Question 30

PDE4:

brand, distribution, substrate, fn, inhibitor clinical use

Answer 30

• drug
  
  • roflumilast
• distribution
  
  • broad
  • includes CV, neural, immune/inflammatory
• substrate - cAMP
• fn
  
  • immune, inflammatory
• inhibitor clinical use
  
  • COPD - decreases inflammation & remodeling

Question 31

PDE5:

brand, distribution, substrate, fn, inhibitor clinical use

Answer 31

• remember that PDE5 breaks down cGMP, so by inhibiting this enzyme, you have MORE cGMP
• drug
  
  • sildenafil
  • tadalafil
  • vardanafil
• distribution
  
  • broad
  • VSMC, esp erectile tissue, retina, & lung
• substrate - cGMP (relaxer!)
• fn
  
  • VSMC relaxation (esp erectile tissue, lung)
• inhibitor clinical use
  
  • ED
  • pHTN

Question 32

What does cAMP enhance/do?

Answer 32

• Ca++-channel activation
  
  • ↑ cytosolic Ca++
  • actin-myosin-troponin interaction
  • positive inotropy and chronotropy
• cAMP-dependent protein kinase
  
  • ↑ phosphorylated phospholamban
  • augmented Ca++ uptake by SR
  • vasodilation

PDE3 inhbitors prevent the breakdown of cAMP

“I went to cAMP when I was 3 (PDE3), no one knows why”

Question 33

PDE3 inhibitor - Milrinone

clinical uses, PK

Answer 33

• Clinical Uses
  
  • Acute heart failure or severe chronic HF
  • cardiogenic shock (off-label)
  • heart transplant bridge or post-op (off-label)
• PK
  
  • Onset (IV) 5-15 minutes
  • Half-life ~3-6 hrs
  • Parenteral only
  • Majority not metabolized; >80% excreted renally unchanged
• Note: amrinone another PDE3 inhibitor was withdrawn from market in US

Question 34

PDE3 inhibitor - Milrinone

Effects, Adverse Effects

Answer 34

• Effects
  
  • Inotropic, ↑ cardiac contractility
  • Vasodilation
  • Little chronotropic activity
• Adverse effects
  
  • Arrhythmias
  • Hypotension

Question 35

RAAS: Renin info

Answer 35

• Is an enzyme, not named like most are named -ase
• Secreted by the JG Apparatus
• Vasoconstriction and sodium retention
• Goal - maintain tissue perfusion through increase extracellular fluid volume
• RAAS is synergistic with SNS by increasing the release of noradrenaline from the sympathetic nerve terminals
• SNS: sympathetic nervous system
• ACE think -ase – enzyme that converts ANGI to ANG II

Question 36

RAAS - key components

Answer 36

• Regulates tissue perfusion, blood pressure, electrolytes & fluid
• Remember the B1 action of renin in the kidney!! SO metop would block this
• Remember that ACE = kininase II !
  
  • Also breaks down bradykinin, which causes vasodilation
  • Prevents vasodilation → increases vasoconstriction
  • ACE located in membrane of endothelial cells

Question 37

Info on:

Renin

ANG I

ACE

ANG II

Aldosterone

Answer 37

• Renin
  
  • formed/secreted from JG cells
  • rel stimulated by decrease BP or Na+, B1 rec activation
  • protease - cleaves angiotensinogen to form…
• Angiotensin I
  
  • inert
• ACE (kininase II)
  
  • broad protease action - forms ANG II from ANG I
  • metabolism of BKN to inactive form
  • located in the membrane of EC cells (??)
• ANG II
  
  • vasoconstriction (AT1 receptor)
  • aldosterone secretion (AT1 receptor)
  • other: increases ADH, increases proximal tubule Na+ reabsorption
• Aldosterone
  
  • steroid; adrenal cortex
  • regulates gene expression, increases Na+ reabsorption
  • H2O retention, K+ excreted (??? what)

Question 38

ANG II receptors

Answer 38

• GPCR
• subtypes: AT1 R, AT2 R
• Current antagonist drugs block AT1 R
• AT1R
  
  • reg of BP
  • reg of body fluid balance
  • vasoconstriction
  • inflammation
  • plt aggregation/adhesion
  • ROS production
  • proliferative
  • hypertrophy
  • fibrosis
• AT2R
  
  • natriuresis
  • neuronal activity
  • vasodilation
  • anti-inflammation
  • pro-apoptotic
  • antioxidative
  • anti-hypertrophic
  • anti-fibrotic

Question 39

Drugs that inhibit the RAAS pathways:

B1AR antagonists (metop)

Renin inhibitor

ACE inhibitor

ANG II Receptor Antagonists (ARB)

Aldosterone Antagonists

Answer 39

• B1AR antagonists (metop)
  
  • block SNS stimulation at renal JGC
• Renin inhibitor
  
  • prevent Renin from converting Angiotensinogen to ANG I
• ACE inhibitor (enalapril, lisinopril …)
  
  • prevents ACE from converting ANG I to ANG II
• ANG II Receptor Antagonists (ARB) (Losartan, valsartan)
  
  • prevents ANG II from binding to AT1 subtype of ANG II receptor
• Aldosterone Antagonists (spironolactone, eplerenone)
  
  • prevents increase in aldosterone
  • AT1 can be blocked by ARBs also!

Question 40

ACE inhibitor mechanism of action and effects

Answer 40

• MOA
  
  • prevents ACE from converting ANG I to ANG II
  • prevents ACE from converting bradykinin (BKN) to its inactive form
• Effects
  
  • decrease in ANG II
    
    • vasodilation
    • ↓ remodeling
    • ↓ aldosterone (↓ Na/H2O retention, ↑ K+ retention)
    • ↓ SNS output
    • ↑ natriuresis
  • increase in bradykinin
    
    • vasodilation
    • cough
    • angioedema
• The blocking of BKN breakdown is what contributes to the bad SEs of ACE inhibitors
• d/c the drug if they have angioedema/cough

Question 41

Bradykinin picture

Answer 41

Question 42

BKN: Bradykinin

Answer 42

• Endogenous peptide
• T1/2 = 17 sec
• Constitutive actions:
  
  • Stimulates NO & prostacyclin formation
  • Vasodilation (heart, kidney, microvascular beds)
• Inflammatory actions:
  
  • ­ capillary permeability

Question 43

ACE inhibitor brands

Answer 43

• generic name (Brand)
• Captopril (Capoten)
• Benazepril (Lotensin)
• Enalapril (Vasotec)
• Fosinopril (Monopril)
• Lisinopril (Zestril, Prinivil)
• Moexipril (Univasc)
• Perindopril (Aceon)
• Quinapril (Accupril)
• Ramipril (Altace)
• Trandorapril (Mavik)

Question 44

ACE inhibitor MOA & uses as 1st-line therapy

Answer 44

• Mechanism of Action
  
  • Block the conversion of Angiotensin I to Angiotensin II
  • Prevent vasoconstriction
  • Prevent aldosterone secretion, decreasing sodium and water retention
• First-line therapy
  
  • HTN
  • CHF
  • Mitral Regurgitation
• More effective in diabetes mellitus pts
• Delay progression of renal disease

Question 45

ACE inhibitor Clinical effects and common clinical uses

Answer 45

• Clinical effects
  
  • ¯ BP, peripheral vascular resistance
  • ¯ preload, afterload
  • ¯ cardiac workload
  • Do not result in reflex tachycardia (compared to the direct vasodilators
  • improves/prevents LV hypertrophy, remodeling
  • improves morbidity/mortality HF
  • diabetic nephropathy-delays progression (improves renal hemodynamics)
• Common Clinical Uses
  
  • *HTN - most commonly used for
  • Post MI
  • *HF (systolic dysfxn)
  • Diabetic nephropathy

Question 46

ACE inhibitor PK & drug interactions

Answer 46

• Metabolism & Elimination
  
  • Many are pro-drugs → Enalapril & ramipril – ester prodrugs (plasma conversion)
  • Usually renal
  • Oral dosage forms
    
    • Exception: enalaprilat (IV)
  • Lots of combo (+ diuretic, etc.)
• Drug Interactions
  
  • K+ sparing diuretic
  • K+ supplements

Question 47

ACE inhib common adverse effects: CV, electrolyte, renal, inflammatory

Answer 47

• CV
  
  • Hypotensive sx’s, syncope
  • “1^st dose effect” possible – more significant hypotensive effect initially
• Electrolyte
  
  • • HYPERkalemia
  • Caution with K+ sparing diuretics & K+ supplements
• Renal
  
  • ¯ GFR, ­ BUN & serum Cr, renal dysfxn
  • Contraindicated – bilateral renal artery stenosis (they have↑ ANGII to promote BF, so if you block that it might be bad)
• Inflammatory
  
  • Dry cough (~5-20%), reversible if d/c’d; BKN-related
    
    • Not self-limiting
  • Angioedema (~1%); BKN-related – they would be taken off this if this happened
    
    • Ex of pt who had stopped ACE inhibitor before surgery, and got the angioedema when they restarted it
• In surgery/anesthesia–can result in prolonged hypotension
• Neutropenia/agranulocytosis (captopril)
• Proteinuria

Question 48

ACE inhib common adverse effects: fetal dev’t

Answer 48

• Fetal malformations - teratogenic
• Contraindicated in pregnancy
  
  • Seen effects in 1^st trimester, but more profound effects during 2^nd and 3^rd trimester
• Any drug that works on the RAAS system – ACE inhibitor, ARB
• Neonatal
  
  • Skull hypoplasia
  • Anuria
  • Hypotension, death

Question 49

ACE inhibitor contraindications

Answer 49

• renal artery stenosis
• Renal artery stenosis patients may develop renal failure due to efferent arteriole constriction

Question 50

Captopril SEs

Answer 50

• C A P T O P R I L
• Cough/C1 esterase deficiency (contraindication)
• Angioedema/Agranulocytosis
• Proteinuria/Potassium excess (hyperK+)
• Taste change
• Ortho hypoTN
• Pregnancy (contraindication – fetal renal damage)
• Renal artery stenosis (contraindication)
• Increases Renin
• Leukopenia/Liver toxicity

Question 51

ARB brands

Answer 51

• generic name (Brand)
• Azilsartan (Edarbi)
• Candesartan (Atacand)
• Eprosartan (Teveten)
• Irbesartan (Avapro)
• Losartan (Cozaar)
• Olmesartan (Benicar)
• Telmisartan (Micardis)
• Valsartan (Diovan, Prexxatran)

Question 52

ARB prototype: Losartan

MOA, PK

Answer 52

Again, have extensive T1/2

• Mechanism
  
  • Competitive antagonist @ AT1 rec
  • Blocks effects of Ang II mediated by AT1 rec
  • Does not block breakdown of BKN – thus BKN does not accumulate
• Clinical Effects & Uses • Similar to ACEi
• PK
  
  • Varies with various agents
  • Metabolism - CYP 450 enzymes
    
    • CYP2C9 - losartan, irbesartan

Question 53

ARB prototype: Losartan

Adverse Effects, Interactions, Contraindication

Answer 53

• Adverse effects
  
  • similar to ACEi (see ACEi list)
  • Less frequent …
    
    • Cough (~30% rate of ACEi)
    • Angioedema (rare)
• Interactions
  
  • K+ sparing diuretics
  • K+ supplements
• Contraindication
  
  • renal artery stenosis
  • pregnancy

Question 54

ACEi vs ARB - So what’s the difference?

Answer 54

• Efficacy in HTN - No differences
  
  • Total mortality
  • CV morbidity, mortality (cardiac, stroke)
• ARBs slightly more tolerable, less likely to be discontinued
  
  • Main reason: ¯ dry cough (~1% vs 4%)
• ACEi – higher quality of data
  
  • ARBs no comparison vs placebo (ARBs compared to ACE inhibitors, but never really against the placebo)

Question 55

Aldosterone antagonists (spironolactone, eplerenone)

MOA, Effects, Uses

Answer 55

• Mechanism
  
  • Competitive antagonist at mineralocorticoid rec (kidney, but also heart, blood vessels, brain)
  • Prevent nuclear translocation of rec
  • Blocks transcription of genes coding for Na+ channels
  • Spironolactone – Off-target effects include androgen, progesterone rec blocking
  • Often combined with non-K-sparing drugs to offset the K+ excretion
• Effects
  
  • ­ Na+ , H20 excretion, mild diuresis
  • ­ K+ reabsorption
• Uses
  
  • HTN, HF
  • K+ sparing diuresis
  • 1° hyperaldosteronism
  • Spironolactone, off-label
  • Acne, hirsutism, PCOS

Question 56

Aldosterone antagonists (spironolactone, eplerenone)

PK, AEs, Drug Interactions

Answer 56

• PK - Metabolism (both hepatic, just different enzymes)
  
  • Spironolactone
    
    • Hepatic
    • active metabolites-canrenone & 7- alpha-spironolactone (t1/2 : 12-20 hrs)
    • P-gp inhibitor
  • Eplerenone • CYP3A4
• AEs include…
  
  • Hyperkalemia
  • Spironolactone—broad; includes hepatic, renal, serious derm (S-J, TEN, etc), GI, gynecomastia, menstrual irregularities, tumorigenic in animals
    
    • Blocking androgen and progesterone
• Drug Interactions
  
  • Other K+ sparing (e.g., ACEi, ARBs, etc.)
  • K+ supplements
  • NSAID (­ renal risks)
  • Eplerenone - CYP3A4 inhibitors

Question 57

Direct Arterial Vasodilators - minoxidil, hydralazine

• Hydralazine: Mechanism of action, Effects, PK

Answer 57

• Mechanism of action
  
  • Release of NO from endothelial cells
  • Inhibition of Ca release from SR?
• Effects
  
  • Vasodilates arterioles
  • Minimal venous effect
  • Decreased SVR
  • DBP reduced >SBP
  • Increase HR, SV, CO
• PK
  
  • Extensive first-pass
  • Bioavailability ~25%
  • Half-life 1.5 – 3 hours

Question 58

Hydralazine Clinical Uses, AEs, contraindications

Answer 58

• Clinical uses
  
  • Hypertension
  • Usually in combination with beta blocker & diuretic (to limit SNS effects)
  • HF – reduced ejection fraction (off-label)
• Adverse effects
  
  • Headache, nausea, palpitations, sweating, flushing
  • Reflex tachycardia, tolerance/tachyphylaxis
  • Sodium and H20 retention
  • Angina with EKG changes – r/t reflex responses in response to vasodilation
  • Lupus erythematosus (reversible)
  • Rash, arthralgias/myalgias, fever – reversible
  • Used in combo with _______ isosorbide?
  • Particularly effective in Black patients
  • Not a lot of orthostatic hypotension
• Contraindication
  
  • CAD, mitral valve RH disease

Question 59

Direct Arterial Vasodilators - minoxidil, hydralazine

Minoxidil: MOA, Effects, PK

Answer 59

• Mechanism of action
  
  • Directly relaxes the arteriolar smooth muscle little effect on venous capacitance
  • increases the efflux of potassium from vascular smooth muscle resulting in hyperpolarization and vasodilation
• Effects
  
  • Dilates arterioles, not veins
  • Use in hypertension (limited to later-line therapy due to risk-benefit profile)
• PK
  
  • 90% oral dose absorbed from the GI tract
  • Peak effects 2-3 hours
  • Half-life ~ 4 hours
  • 10% of drug is recovered unchanged in the urine

Question 60

Minoxidil: Clinical Uses, AEs, Warnings

Answer 60

• Clinical uses
  
  • Hypertension—later line therapy
  • Usually in combination with beta blocker & diuretic (to limit SNS effects)
• Adverse effects
  
  • Tachycardia, increased myocardial workload
  • Palpitations, angina
  • Sodium/fluid retention, edema
  • Weight gain
  • hypertrichosis = excessive hair growth , vasodilation/stimulation of resting hair follicles
• Warnings
  
  • Fluid retention
  • Pericardial effusion/tamponade
  • Rapid BP response
  • Sinus tachycardia
  • Elderly

Question 61

Peripheral Vasodilators: SNP

MOA, metab

Answer 61

• Direct acting , nonselective peripheral vasodilator
• Relaxation of arterial and venous vascular smooth muscle
• Lacks significant effects on nonvascular smooth muscle and cardiac muscle
• Mechanism of action
  
  • SNP interacts with oxyhemoglobin
  • dissociates immediately to form
    
    • Methemoglobin
    • Releasing Nitric Oxide (NO) and cyanide
  • Nitric Oxide activates guanylate cyclase (in the vascular muscle) thus increasing cGMP
  • cGMP inhibits calcium entry into vascular smooth muscle but increases uptake of Ca into the smooth Endoplasmic Recticulum.
  • Results in vasodilation via NO
• Metabolism
  
  • Transfer of an electron from the Iron (Fe) of oxyhemoglobin to SNP yields → metHGb and an unstable SNP radical
  • Unstable SNP radical breaks down → all 5 cyanide ions are released.
  • One of these cyanide ions reacts with metHGb to form cyanomethemoglobin (nontoxic)
  • Remainder are metabolized in the liver and kidney → converted to thiocyanate

Question 62

SNP toxicity & treatment

Answer 62

• Toxicity: occurs due to the effects of high plasma concentrations of thiocyanate
  
  • Cyanide Toxicity
    
    • Can occur at rates >2ug/kg/min for long periods
    • Suspect when the pt starts demonstrating resistance to hypotensive effects or a previous responsive patient who is unresponsive (tachyphylaxis) at rates >2-10 ug/kg/min
    • May precipitate tissue anoxia, anaerobic metabolism, and lactic acidosis
  • Treatment of Cyanide Toxicity
    
    • Immediate discontinuation of SNP
    • 100% 02 administration despite normal oxygen saturation
    • Sodium bicarbonate to correct metabolic acidosis
    • Sodium thiosulfate 150mg/kg over 15 minutes
    • Sodium thiosulfate Acts as a sulfur donor to convert cyanide to thiocyanate
  • Sodium nitrate 5mg/kg if severe toxicity
    
    • Converts hemoglobin to metHgb which coverts cyanide to cyanometHemoglobin
  • Thiocyanate Toxicity
    
    • Rare as thiocyanate is cleared by the kidney in 3-7 days
    • Less toxic than cyanide
    • Symptoms include:
      
      • N/V, tinnutis, fatigue, CNS hyperreflexia, confusion, psychosis, miosis seizure and coma
    • Methemoglobinemia
      
      • Rare
  • Should be considered as a differential diagnosis in patients with impaired oxygenation despite adequate cardiac output and arterial oxygenation
• Phototoxicity
  
  • SNP should be mixed with 5% glucose in water and be protected from exposure to light.
  • With continuous exposure to light SNP is converted to aquapentacyanoferrate in the presence of light and the release of hydrogen cyanide
  • Wrap the solution and tubing in foil or dark plastic bag.

Question 63

SNP dosage

Answer 63

• 0.3ug/kg/min - 10ug/kg/min IV
• Max dose: should not be infused for greater that 10 minutes
• Immediate onset
• Short duration of action
• Requires continuous IV administration to maintain therapeutic effect
• Extremely potent: use A-line

Question 64

SNP effects

Answer 64

• CV:
  
  • Direct venous and arterial vasodilation, decreased venous capacitance due to venous return Baroreceptor mediated reflex responses increased HR
  • ↓ SBP, ↓ SVR,↓ PVR, ­contractility, causes an intracoronary steal in areas of damage associated with MI; decreased diastolic BPàdecrease coronary perfusion
• CNS:
  
  • ↑ ­CBF, and ICP with modest decrease in MAP or with greater decrease in MAP can reduce cerebral blood flow (caution with carotid disease)
• Pulmonary:
  
  • Attenuation of hypoxic vasoconstriction.
• Blood: Increases in intracellular GMP → inhibit platelet aggregation and increase bleeding time

Question 65

SNP clinical uses & associated dosages

Answer 65

• Controlled hypotension: 0.3-0.5ug/kg/min not to exceed 2 ug/kg/min
• Hypertensive crises: infusion 1-2ug/kg IV can be given as bolus
• Cardiac disease:
  
  • decreases LV afterload, benefits management of MR or AR, CHF, and heart failure.
  • Consider coronary steal

Question 66

D/C B-blockers preop?

Answer 66

NO

BB therapy reduces perioperative MI

Question 67

D/C CC blockers preop?

Answer 67

NO

Benefits outweigh risks, UNLESS severe LV dysfn

-no good evidence one way or the other

Question 68

D/C ACE inhibitors preop?

Answer 68

YES

Withholding for 1 dosing interval (best if they don’t take the night before)

Dr. Walker: Give them back their RAAS! They need some compensatory mechanism

Question 69

D/C centrally acting agent?

Answer 69

NO

risk for rebound HTN if you hold it

Question 70

Ca-channel blockers

Answer 70

Ca-channel blockers – reduced inotropy

Inhalational agents will cause myocardial depression

Potential that it can improve outcomes?

Prolongs paralytics

Question 71

Deliberate Controlled Hypotension

Answer 71

• Indications: Minimize blood loss, fluid replacement and electrolyte disturbances
  
  • Think of surgery that has high expected blood loss, and someone who you don’t want to/can’t transfuse
    
    • Antibodies
    • Jehovah’s witness
    • Pre-transplant
    • Severe CAD – avoid losing blood
    • Pt Refuses
• Not used as much today
  
  • Stroke
  • POVL
  • Keep them within 20% of their b/l range
  • Still use – jaw/dental surgery on young pts (16-21 yo) – their SNS system works!
• Reduce MAP to pre-determined level
  
  • 50-60 mm Hg; may need higher MAP
• Maintain cerebral and renal blood flow and autoregulation
• Arterial line is REQUIRED
• Ways to do it
  
  • Increase inhalational agent
  • SNP

Question 72

Controlled hypotension dosages:

SNP

NTG

Nicardipine

Dexmedetomidine

Propofol

Labetalol (no dosage, just info for this one)

Answer 72

• Sodium Nitroprusside: 0.3-0.5mcg/kg/min not to exceed 2 mcg/kg/min (really high dose, usually ≅ 1 mcg/kg/min – and that’s for a carotid case)
  
  • More Arterial
• Hypertensive crises: infusion 1-2mcg/kg IV can be given as bolus
• Nitroglycerin: 125-500 mcg/Kg/min
  
  • More venous
• Nicardipine: 5mcg/kg/min
• Dexmedetomidine: 0.2-0.7mcg/kg/hr
  
  • Decreases release of NE
  • No amnesia
• Propofol infusion – vasodilation
• Labetalol/B-blockers IVP
  
  • Alpha and beta
  • 15-1 hr? Will get you thru the surgery, but be careful bc it will stick around
  • Will often see asthma in young ppl – bronchoconstriction B2 blockade
  • Esmolol – higher doses = non-selective, and so short acting that you’ll have to keep re-dosing it
    
    • <10 minutes