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Cardiac Pharm - Bush Lecture Flashcards

1
Q

what is nitric oxide

A

its an endogenous gas messenger

lipophillic, highly reactive, labile free radical

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2
Q

how is nitric oxide eliminated

A

oxidation to form NO2 or NO3

nitrosylation of hgb

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3
Q

what is the half life of nitric oxide

A

just a few seconds

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4
Q

what is nitric oxide also called

A

endothelium-derived relaxing factor

this is because it is released from endothelium and acts on VSMCs to increase cGMP and cause relaxation

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5
Q

what are the three types of nitric oxide synthase

A

nNOS - neuronal
iNOS - inducible - involved in infection response and is triggered by cytokines
eNOS - endothelial

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6
Q

what are the protective roles of nitric oxide

A 
NT
immune cytotoxicity
inhibit platelet aggregation/ decreased cell adhesion
cyto-protection
vasodilator smooth muscle relaxant
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7
Q

what are the pathogenic roles of NO

A

neuronal injury
cell proliferation
shock - hypotension
inflammatory tissue injury

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8
Q

describe the pathway of NO mediated vasodilation

A

an agonist triggers the GPCR on an endothelial cell, causing an increase in intracellular calcium that activates eNOS to convert L-arginine to NO

NO then acts at the VSMC on guanylyl cylcase to increase cGMP causing smooth muscle relaxation and therefore vasodilation of the VSMC

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9
Q

what are the nitrovasodilators?

A

aka NO donor drugs

organic nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate)
sodium nitroprusside
amyl nitrite
nitric oxide gas

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10
Q

MOA of organic nitrates

A

oranic nitrates undergo metabolism to form NO which then acts to activate guanylyl cyclase to form GMP and cause vasodilation

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11
Q

how is sodium nitroprusside metabolized

A

the cyanide that is left after breakdown combines with sulfur groups to form thiocyanate which then undergoes renal excretion

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12
Q

MOA of sodium nitroprusside

A

structure: 1 iron, 5 cyanide, 1 NO group

spontaneously breaks dow to NO and cyanide to act directly as a peripheral vasodilator on arteries and veins (aka nonselective)

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13
Q

onset of sodium nitroprusside

A

<2 minutes

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14
Q

duration of sodium nitroprusside

A

1-10 minutes

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15
Q

half life of sodium nitroprusside

A

less than 2 minutes

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16
Q

half life of thiocyanate

A

2-7 days - increased with impaired renal excretion

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17
Q

CV effects of sodium nitroprusside

A

decreased arterial and venous pressure
decreased peripheral VR
decreased afterload
slight increase in HR

doesn’t really effect cardiac muscle

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18
Q

sodium nitroprusside renal effects

A

vasodilation without significant change in GFR

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19
Q

sodium nitroprusside CNS effects

A

increased cerebral blood flow and ICP

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20
Q

effects on blood from sodium nitroprusside

A

inhibits platelet aggregation

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21
Q

what do we use sodium nitroprusside for?

A

hypertensive crisis - to reduce BP to prevent/limit target organ damage

controlled hypotension during surgery - to decrease bleeding

congestive heart failure - to improve CO

Acute MI - to improve CO in LV failure and low CO post-MI
** limited use d/t coronary steal - altered blood flow results in diversion away from ischemic stress

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22
Q

sodium nitroprusside adverse effects

A 
profound hypotension
cyanide toxicity
methemoglobinemia
thiocyanate accumulation
increased serum creatinine (transient)
increased ICP
nausea
HA
restlessness
flushing
dizzy
palpitation
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23
Q

sodium nitroprusside and cyanide toxicity

A

often dose/duration related (aka too much or too long), but may occur at recommended doses
tissue anoxia
venous hyperoxemia - tissues cannot extract oxygen
lactic acidosis
confusion
death

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24
Q

methemoglobinemia

A

some iron in hgb is oxidized to ferric state with impaired o2 affinity and reduced O2 delivery to tissues (hypoxia)

sign = impaired oxygenation despite adequate CO and arterial oxygenation

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25
Q

when does metHb become symptomatic

A

> 10%

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26
Q

what is the reveral agent for metHb

A

methylene blue

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27
Q

sodium nitroprusside and thiocyanate accumulation

A

increased risk with prolonged infusion, renal impairment

causes neurotoxicity - ears ringing, miosis, hyperreflexia
hypothyroidism - d/t impaired idodine uptake

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28
Q

drug interaction with sodium nitroprusside

A

hypotensive drugs - negative inotropes, GAs, circulatory depressants

phosphodiesterase type 5 inhibitors (sildenafil) - creates profound hypotension because these drugs will decrease the breakdown of cGMP

soluble guanylate cyclase stimulators (riociguat) - increased GC = more cGMP = more vasodilation

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29
Q

sodium nitroprusside stability

A

unstable
light and temp sensitive

protect from light and store at 20-25C
deterioration results in change to bluish color
wrap the container with aluminum foil or other opaque material

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30
Q

administration of sodium nitroprusside

A

IV infusion via pump
dilute in 5% dextrose
shortest infusion duration possible to avoid toxicity - if reduction in BP not obtained within 10 minutes @ max infusion rate you should DC

IF SOLUTION IS NOT A FAINTISH BROWN AND IS BLUE OR GREEN OR RED DO NOT GIVE THROW AWAY

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31
Q

MOA nitroglycerin

A

NO release through cell metabolism - glutathione dependent pathway
(requires thiols - sulfur molecules in body)

the NO stimulates GC and formation of cGMP and leads to VSMC relaxation and peripheral vasodilation

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32
Q

what vasculature does nitroglycerin act on and what does that buy you?

A

primary = venous capacitance vessels: decreased preload and decreased MVO2

they mildly dilate arteriolar resistance vessels: modest decreased afterload, decreased MVO2

dilation of larger coronary arteries: increased myocardial oxygen supply

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33
Q

what are the ways that you can administer nitroglycerin

A

IV, SL, translingual spray, transdermal ointment

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34
Q

nitroglycerin effects

A

decreased VR, R&LVEDP, CO
no change in SVR
increased coronary blood flow to ischemic areas (less coronary steal)

small smooth muscle relaxation in bronchi/GI tract

inhibits platelet aggregation

bronchial dilation
INHIBITS HPV

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35
Q

how long until you develop nitroglycerin tolerance

A

after 8-10h you will start to see diminishing effects

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36
Q

when should you use caution with nitroglycerin

A

volume depletion
hypotension
bradycardia or tachycardia
constrictive pericarditis, aortic/mitral stensosis, inferior wall MI, and RV involvement

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37
Q

clinical uses for nitroglycerin

A 
angina
hypertension (periop, htn emergency)
controlled  hypotension during surgery
non ST segment elevation
acute MI
heart failure, low output syndromes (decreases preload and relieves pulmonary edema)
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38
Q

angina and nitroglycerin

A

acute angina pectoris - give sublingual
prevention of angina - longer acting PO, transdermal, ointment

venodilation decreases VR to heart which reduces R&Lvedp
reduces mvo2

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39
Q

adverse effects of nitroglycerin

A

throbbing headache
orthostatic hypotension, dizziness, syncope

increase ICP
reflex tachy (baroreceptor)
flushing 
vasodilation, venous pooling, decreased CO
methemoglobinemia
tolerance
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40
Q

nitroglycerin metabolism

A

large first pass effect (90%) following oral admin
liver - denitrated by glutathione-organic nitrate reductase to glyceryl dinatrate and then mononitrate
- aka taking off nitrates

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41
Q

IV nitroglycerin onset and duration

A

immediate onset, lasts 3-5 minutes

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42
Q

sublingual and translingual spray nitroglycerin onset and duration

A

1-3 minutes onset

duration = >25 minutes

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43
Q

topical nitroglycerin onset and doa

A 
onset = 15-30 minutes
doa = 7 hours
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44
Q

transdermal nitroglycerin onset and doa

A

onset around 30 minutes

duration 10-12 hours

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45
Q

oral, extended release nitroglycerin onset and doa

A

onset about one hour

doa = 10-12 hours

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46
Q

how long should you have a nitrate free interval to avoid tolerance to organic nitrates?

A

8-12 hours

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47
Q

isosorbide dinitrate sublingual onset and doa

A

onset about 2-5 minutes

doa up to 8hours

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48
Q

isosorbide dinatrate oral onset and duration

A

onset about 60 minutes

doa up to 8 hours

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49
Q

isosorbide mononitrate oral onset and duration

A

onset 30-45 minutes and duration >6h

50
Q

isosorbide mononitrate oral ER onset and duration

A

onset = 30-45 minutes and duration = >12-24 hours

51
Q

nitroglycerin drug interaction

A

antihypertensives = additive effect
selective pde5 inhibitors = absolute contraindication d/t life threatening hypotension/hemodynamic compromise d/t accumulation of cGMP
guanylate cyclase stimulating drugs

52
Q

isosorbide mononitrate and dinatrate uses

A

oral nitrate forms used for the prophylaxis of angina pectoris
additionally, used for heart failure in black patients in combo with hydralazine

53
Q

isosorbide mononitrate and dinatrate absorption and metabolism

A

absorbed well in GI tract with a duration of 6 hours

metabolism
dinitrate metabolized to mononitrate = active metab
mononitrate metabolized to isosorbide and sorbitol = inactive

54
Q

Phosphodiesterase enzymes - what are they

A

Family of enzymes that break down cyclic nucleotides

55
Q

PDE inhibitors - MOA

A

Boost levels of cyclic nucleotides by preventing breakdowns

56
Q

PDE3 distribution, substrate broken down and substrate function

Why would you want to inhibit PDE3 clinically?

A

Distribution: broad, includes heart and vascular smooth muscle

Substrate it breaks down: cGMP, cAMP

Function of substrate: cardiac contractility and platelet aggregation

Inhibition = increased inotropy and peripheral vasodilation, can help with intermittent claudication

57
Q

PDE4 distribution, substrate broken down and substrate function

Why would you want to inhibit PDE4 clinically?

A

Distribution: broad, CV, neural, immune/inflammatory

Target substrate: cAMP

Substrate function: immune, inflammatory

Clinical use? COPD to decrease inflammation and remodeling

58
Q

PDE5 distribution, substrate broken down and substrate function

Why would you want to inhibit PDE5 clinically?

A

Distribution: broad, vascular smooth muscle especially erectile tissue, retina, lung

Target substrate: cGMP

Substrate function: VSMC relaxation (especially erectile tissue, lung)

Clinical use: erectile dysfunction, pulmonary hypertension

59
Q

Milrinone MOA

A

PDE3 inhibitor - inhibits breakdown of cAMP causing increased inotropy and vasodilation

60
Q

Clinical uses of milrinone

A

Acute heart failure or severe chronic heart failure

Cardiogenic shock (off-label)

Heart transplant bridge or post op

61
Q

Adverse effects of milrinone

A

Arrhythmias and hypotension

62
Q

Onset of milrinone

A

5-15 minutes

63
Q

Half life of milrinone

A

3-6h

64
Q

Milrinone metabolism and excretion

A

Only given parenterally

Majority not metabolized - >80% excreted renally unchanged

65
Q

What PDE3 inhibitor do we use for intermittent claudication

A

Cilastazol

66
Q

What PDE4 inhibitor do we give to decrease inflammation and remodeling in patients with COPD

A

Roflumilast

67
Q

What are the three PDE5 inhibitors listed on Bush’s chart - they are used for pulmonary hypertension and/or erectile dysfunction

A

Sildenafil
Tadalafil
Vardenafil

68
Q

When was renin identified in extract of renal cortex, pressors activity demonstrated

A

1898

69
Q

When did they discover that Renin has proteolytic action on plasma substrate (angiotensinogen) forming a pressor peptide (angiotensin/hypertensin ->angiotensin)

A

1930s

70
Q

When was it identified that there were two forms of angiotensin, discovered ACE, and that ang ii stimulates release of aldosterone

A

1950s

71
Q

Where is renin secreted from

A

JG apparatus

72
Q

What does renin cause

A

Vasoconstriction and sodium retention (indirectly) by stimulating RAAS - aka converts angiotensinogen to ang i

73
Q

What stimulates the release of renin

A

Low BP or sodium load, beta one receptor activation

74
Q

What is the goal of renin release

A

Maintain tissue perfusion through increase in extra cellular fluid volume

75
Q

Why is RAAS synergistic with SNS

A

It increases the release of norepi from the sympathetic nerve terminals

76
Q

ACE (kinase ii)

A

Located in membrane of EC cells

Has broad protease action

  • forms ang ii from ang i
  • metabolized BKN to inactive form
77
Q

What does Angiotensin ii cause

A

Vasoconstriction
Aldosterone secretion

ADH secretion increase, increase proximal tubule sodium reabsorption

78
Q

What receptor does ang ii act on to cause vasoconstriction and aldosterone secretion

A

AT1 receptor

79
Q

What is aldosterone, where is it located, and what does it do/cause

A

It is a mineralcorticoid secreted from the adrenal cortex

Regulates gene expression and increases sodium reabsorption

H20 retained and K excreted

80
Q

What responses are mediated by activation of the AT1 receptor by angiotensin 2?

A 
Regulation of BP and body fluid balance
Vasoconstriction
Inflammation
Platelet aggregation/adhesion
ROS production
Proliferative
Hypertrophy
Fibrosis
81
Q

What are the effects of decreased angiotensin ii specifically as seen when giving an ACE inhibitor?

A 
Vasodilation
Decreased remodeling
Decreased aldosterone leading to decreased sodium and water retention and increased potassium retention
Decreased sympathetic output 
Increased naturesis
82
Q

What is an ACE inhibitor’s effect on bradykinin and what effects would could you see

A

ACE breaks down bradykinin to its inactive form - therefore with and ACEi you would see increased bradykinin which could cause vasodilation, cough, and angioedema

83
Q

What is the half life of bradykinin

A

17 seconds

84
Q

What are bradykinin’s constitutive actions

A

Stimulates NO and prostacyclin formation causing vasodilation in the heart, kidney and micro vascular beds and increases capillary permeability as an inflammatory response

85
Q

What is the MOA of ACEi’s?

A

They block the conversion of ang i to ang ii, preventing vasoconstriction and aldosterone secretion which means decreased sodium and water retention

86
Q

When would you use an ACE inhibitor

A

As a first line therapy against HTN, CHF, mitral regurgitation

87
Q

In what patient population is diabetes more effective

A

Diabetes mellitus

88
Q

For patients with kidney disease, is an ace inhibitor a good choice?

A

Yes! ACEi’s can delay progression of renal disease

89
Q

What are the cardiovascular clinical effects of ACE inhibitors

A

Decreased BP, peripheral vascular resistance, preload, afterload, and cardiac workload

Improves/prevents LV hypertrophy and remodeling

Improves morbidity and mortality for HF patients

90
Q

Do ACEi’s cause reflex tachycardia?

A

No

91
Q

ACEi’s and diabetic neuropathy

A

Delays progression

92
Q

How are ACE inhibitors metabolized and eliminated?

Most are pro drugs

Usually eliminated renally

A

Most are pro drugs

Usually eliminated renally

93
Q

How are ACE inhibitors metabolized and eliminated?

A

Most are pro drugs

Usually eliminated renally

94
Q

Which ace inhibitor has an IV form?

A

Enalaprilat

95
Q

What drugs should you use caution with in combo with ace inhibitors

A

Potassium sparking diuretics and potassium supplements

96
Q

Does benazopril have a metabolite and what is the doa?

A

Yes - benazepralit

24 hours doa

97
Q

Does captopril have a prodrug and what is the doa

A

No

6 hours

98
Q

Does enalopril have a metabolite and what is the doa

A

Enalopril = 12-24 hours and metabolite enalaprilat = 6 hours

99
Q

Does lisinopril have a metabolite and what is the doa

A

No, 24 hours

100
Q

What ace inhibitor has the longest duration of action

A

Trandolapril - 72 hours

101
Q

What are the cv adverse effects of ace inhibitors

A

Hypotension, syncope, first dose effect possible

102
Q

What are the electrolyte adverse effects of ace inhibitors

A

Hyperkalemia

103
Q

What are the renal adverse effects of ace inhibitors

A

Decreased GFR, increased BUN and creatinine, renal dysfxn

104
Q

What renal disease is an ace inhibitor contraindicated in

A

Bilateral renal artery stenosis

105
Q

What are the inflammatory adverse effects of ace inhibitors

A

Dry cough and angioedema - both BKN related

106
Q

What are the adverse effects on fetal development caused by ACEi’s?

A

Fetal malformations -teratogenic

Contraindicated in pregnancy

107
Q

What are the surgical/anesthesia implications for ace inhibitors

A

Can result in prolongs hypotension

Captopril can cause neutropenia/agranulocytosis

Proteinuria

108
Q

Ace inhibitor pneumonic for side effects

A 
C - cough, c1 esterase deficiency contraindication
A - angioedema, agranulocytosis
P - proteinuria, potassium excess
T - taste change
O - orthostatic hypotension
P - pregnancy contraindication
R - renal artery stenosis contraindicatoin
I - increases renin
L - leukopenia/liver toxicity
109
Q

Lesarten (ARB) mechanism of action

A

Competitive antagonist at AT1 receptor blocking effects of angiotensin 2 mediated by AT1 agonism

Does not effect BKN so less extreme SE

110
Q

How are ARBs metabolized

A

Varies

Losartan - CYP2C9

111
Q

What drugs should you use caution with when giving an ARB

A

Potassium sparing diuretics

Potassium supplements

112
Q

Contraindications of ARBs

A

Renal artery stenosis and pregnancy

113
Q

MOA spironolactone aka aldosterone antagonist

A

Competitive antagonist at mineralcorticoid receptor, prevents nuclear translocation of receptor, blocks transcription of genes coding for sodium channels

Off target effects - androgen and progesterone receptor blockers

114
Q

Effects of aldosterone antagonists (spironolactone)

A

Increased sodium and water excretion, mild diuresis

Increased potassium reabsorption

115
Q

What is spironolactone used for

A

HTN, HF, k-sparing diuresis, primary hyperaldosteronism,

Off label - acne, hirsutism, PCOS

116
Q

Metabolism of spironolactone

A

Hepatic

Active metabolites - canrenone & 7-alpha-spironolactone - half life 12-20 hours

PGP inhibitor

117
Q

Adverse effects of aldosterone antagonists

A

Hyperkalemia

Spironolactone - broad including hepatic, renal, derm (SJS), GI, gynecomastia, menstrual irregularities, tumorigenic

118
Q

Drug interaction of aldosterone antagonists

A

Other potassium sparing drugs
Potassium supplements
NSAID - increased renal risks

119
Q

What is the “cleaner, newer” version of aldosterone antagonist?

A

Eplerenone

It’s a cyp3a4 inhibitor though so be careful

120
Q

how do you treat cyanide toxicity d/t SNP

A

Immediate discontinuation of SNP
100% o2 administration despite normal oxygen sat
Sodium bicarbonate to correct acidosis
Sodium thiosulfate 150 mg/kg over 15 minutes - acts as a sulfur donor to convert cyanide to thiocyanate

Sodium nitrate 5mg/kg if severe toxicity
Converts hgb to methgb which converts cyanide to cyanomethgb

121
Q

Dose of SNP

A

0.3 mcg/kg/min - 10 mcg/kg/min

Max dose: should not be infused for greater than 10 minutes

For controlled hypotension in OR
0.3-0.5 mcg/kg/min not to exceed 2 mcg/kg/min

Hypertensive crisis
1-2 mcg/kg can be given as bolus

**remember cyanide toxicity can occur at rates >2mcg/kg/min

Advanced Pharm (11 decks)

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