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N929 - Anesthesia Pharmacology > CV Drugs III > Flashcards

CV Drugs III Flashcards

1
Q

Nitric oxide

A
  • endogenous gas messenger

- lipophilic, highly reactive, labile free radical

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2
Q

NO formation

A

from L-arginine with NOS (nitric oxide synthase enzyme)

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3
Q

NO elimination

A

oxidation to form either nitrate or nitrite; nitrosylation of hemoglobin

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4
Q

NO half-life

A

a few seconds

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5
Q

NO Protective biological roles

A
  • NT
  • immune cytotoxicity
  • inhibit platelet aggregation
  • cyto-protection
  • vasodilator, smooth muscle relaxation
  • decreased cell adhesion, proliferation
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6
Q

NO pathogenic biological roles

A
  • neuronal injury (NMDA)
  • cell proliferation
  • shock, hypotension,
  • inflammation, tissue injury
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7
Q

NO Donor Drugs

A
  • Organic Nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate)
  • sodium nitroprusside
  • amyl nitrite
  • nitric oxide gas
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8
Q

Sodium nitroprusside structure

A

complex of 1 iron, 5 cyanide, and 1 NO group

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9
Q

sodium nitroprusside MOA

A
  • spontaneous breakdown to NO and cyanide
  • NO release resulting in activation of guanylyl cyclase in vascular smooth muscle, formation of cGMP, VSMC relaxation and vasodilation
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10
Q

sodium nitroprusside PK/PD

A
  • metabolism – cyanide combines with sulfur groups  thiocyanate
  • renal excretion; but some exhaled in air or excreted in feces
  • onset < 2 min
  • DOA 1-10 min
  • half-life ~2 min
  • half-life thiocyanate 2-7 days (increased with impaired renal fxn)
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11
Q

sodium nitroprusside administration parameters

A
  • IV infusion via pump
  • dilute in 5% dextrose
  • shortest infusion possible to avoid toxicity, if reduction in BP not obtained within 10 min, d/c
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12
Q

sodium nitroprusside clinical uses

A
  • HTN crisis – BP reduction to prevent/limit target organ damage
  • controlled hypotension during surgery – to reduce bleeding when indicated
  • CHF (acute, decompensated)
  • acute MI – improve CO; limited use due to coronary steal effect
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13
Q

sodium nitroprusside effects

A

CV:
-decreased arterial/venous pressure
-decreased PVR
-decreased afterload (in HF or acute MI – CO may increase due to decreased afterload)
-slight increased HR
Renal – vasodilation without significant change in GFR
CNS – increase CBF and ICP
Blood – inhibits plt aggregation
-Stability – unstable, light and temp sensitive; protect from light and store at 20-25 C; deterioration = blue color

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14
Q

sodium nitroprusside adverse effects

A
  • profound hypotension (potential for impaired organ perfusion)
  • cyanide toxicity
  • methemoglobinemia
  • thiocyanate accumulation
  • renal – transient increased serum Cr
  • others – increased ICP, nausea, HA, restlessness, flushing, dizziness, palpitation
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15
Q

Cyanide toxicity

A

often dose/duration dependent, but may occur at recommended dose; tissue anoxia; venous hyperoxemia (tissues can’t extract oxygen); lactic acidosis; confusion; death

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16
Q

methemoglobinemia

A

iron becomes ferric (3+) and has reduced O2 affinity; decreased O2 to tissues; symptomatic metHb>10%; reversal = methylene blue

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17
Q

Thiocyanate accumulation

A

increased with prolonged infusion and renal impairment; neurotoxicity (tinnitus, miosis, hyperreflexia); hypothyroid d/t impaired iodine uptake

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18
Q

Sodium Nitroprusside drug interactions

A
  • hypotensive drugs (negative inotropes, general anesthetics, circulatory depressants)
  • PDE 5 inhibitors
  • soluble guanylate cyclase stimulators
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19
Q

organic nitrates

A
  • nitroglycerin
  • isosorbide dinitrate
  • isosorbide mononitrate
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20
Q

nitroglycerin MOA

A
  • NO release through cellular metabolism – glutathione dependent pathway
  • requires thiols
  • NO release resulting in activation of guanylyl cyclase in vascular smooth muscle, formation of cGMP, VSMC relaxation and vasodilation
  • PRIMARY ACTION – at venous capacitance vessels; venodilation –> decreased VR –> decreased RVEDP and LVEDP –> decreased MVO2
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21
Q

nitroglycerin PK/PD

A
  • large first pass (90%) after oral admin
  • metabolized in liver –> denitrated by glutathione-organic nitrate reductase to glyceryl dinitrate and then mononitrate
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22
Q

nitroglycerin administration notes

A

Route – IV, SL, translingual spray, transdermal ointment

-tolerance after 8-10 hours; diminishing effectiveness –> have to have an off period

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23
Q

nitroglycerin clinical uses

A
  • angina – acute (sublingual) and prevention (longer acting oral, transdermal, or ointment)
  • HTN – peri or postop; HTN emergencies
  • controlled hypotension
  • NSTEMI ACS
  • acute MI (limits damage)
  • HF, low output syndromes –> decreases preload and relieves pulmonary edema
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24
Q

nitroglycerin effects

A

CV:
-venous capacitance vessels – decreased preload and MVO2
-arteriolar resistance (mild) – modest decreased afterload and MVO2
-myocardial arteries – increased O2 supply
-no change in SVR
-decrease VR, and LVEDP/RVEDP
-decrease CO
-increase corrP to ischemic areas
Pulm – bronchial dilation; inhibit HPV
Other – smooth muscle relaxation in bronchi, GI tract; inhibit plt aggregation

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25
Q

nitroglycerin adverse effects

A

CNS:
-throbbing HA
-increased ICP
CV:
-orthostatic hypotension, dizziness, syncope
-reflex tachycardia (arterial barorecptors)
-flushing
-vasodilation, venous pooling, decreased CO
Heme – methemoglobinemia (rare)
Tolerance – limitation of use of nitrates

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26
Q

nitroglycerin cautions

A

volume depletion, hypotension, brady- or tachycardia, constrictive pericarditis, AS, MS, inferior wall MI, RV involvement

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27
Q

nitroglycerin drug interactions

A
  • antihypertensive drugs
  • selective PDE-5 inhibitor drugs
  • guanylate cyclase stimulating drugs
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28
Q

nitroglycerin and PDE-5 inhibitors

A
  • absolute contraindication
  • will get profound potentiation
  • possible life-threatening hypotension and/or hemodynamic compromise
  • accumulation of cGMP by inhibiting its breakdown
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29
Q

isosorbide mononitrate or dinitrate PK/PD

A
  • well absorbed orally from GI tract
  • DOA 6 hrs
  • dinitrate – metabolized to mononitrate (active)
  • mononitrate – metabolized to isosorbide to sorbitol (inactive)
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30
Q

isosorbide mononitrate or dinitrate administration

A
  • regular and extended release forms

- need nitrate-free period to prevent tolerance

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31
Q

isosorbide mononitrate or dinitrate clinical uses

A
  • prophylaxis of angina

- HF in Black patients combined with hydralazine

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32
Q

isosorbide mononitrate or dinitrate considerations

A

-avoid concomitant use with PDE5 inhibitor drugs

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33
Q

Phosphodiesterase enzymes

A
  • family of enzymes that breakdown cyclic nucleotides
  • regulate intracellular levels of 2nd messengers (cAMP and cGMP)
  • 11 subfamilies
  • inhibitors - boost levels of cyclic nucleotides by preventing their breakdown
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34
Q

older non-selective drugs that inhibit PDE

A

caffeine

theophylline

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35
Q

PDE3

A
  • broad distribution that includes heart and VSMC
  • substrates include cAMP, cGMP
  • function has to do with cardiac contractility and platelet aggregation
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36
Q

PDE 3 inhibitor drugs

A

amirone, milrinone, cilastazol

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37
Q

PDE 3 inhibitor clinical use #1

A
  • positive inotrope (increase force of contraction)
  • peripheral vasodilator
  • limited for acute HF
  • milrinone, amirone
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38
Q

PDE 3 inhibitor clinical use #2

A
  • intermittent claudication

- cilastazol

39
Q

PDE4

A
  • broad distribution including CV, neural, and immune/inflammatory
  • substrate includes cAMP
  • immune, inflammatory function
40
Q

PDE4 inhibitor clinical use/drugs

A
  • COPD - decrease inflammation, decrease remodeling

- roflumilast

41
Q

PDE5

A
  • broad distribution in VSMC especially erectile tissue, retina, lungs
  • substrate is cGMP
  • causes vascular smooth muscle relaxation, especially erectile tissue and lung
42
Q

PDE5 inhibitor clinical uses

A
  • erectile dysfunction

- pulmonary hypertension

43
Q

PDE5 inhibitor drugs

A
  • sildenafil
  • tadalafil
  • vardenafil
44
Q

milrinone class

A

PDE 3 inihibitor

45
Q

milrinone MOA

A

inhibit breakdown of cAMP

46
Q

milrinone PK/PD

A
  • onset (IV) 5-15 min
  • half-life ~3-6 hrs
  • majority not metabolized
  • renally excreted >80% unchanged
47
Q

milrinone clinical uses

A
  • acute HF or severe chronic HF
  • cardiogenic shock
  • heart transplant bridge or post-op
48
Q

milrinone effects

A
  • inotropic, increase cardiac contractility
  • vasodilation
  • little chronotropic activity
49
Q

milrinone adverse effects

A
  • arrhythmias

- hypotension

50
Q

Key components of RAAS

A
  • renin
  • angiotensin I
  • ACE (kinase II)
  • angiotensin II
  • aldosterone
51
Q

Goal of RAAS

A

maintain tissue perfusion through increase in extracellular fluid volume

52
Q

renin

A
  • formed/secreted from JG cells
  • release stimulated by decreased BP or Na+ load, beta 1 receptor activation
  • protease - cleaves angiotensinogen to form ANGI
53
Q

angiotensin I

A

inert, inactive form of ANGII

54
Q

ACE (Kinase II)

A
  • broad protease action –> forms ANGII from ANGI
  • metabolism of bradykinin to inactive form
  • located in membrane of EC cells
55
Q

angiotensin II

A
  • vasoconstriction (AT1 receptor)
  • aldosterone secretion (AT1 receptor)
  • other - increase ADH, increase proximal tubule Na reabsorption
56
Q

aldosterone

A
  • steroid formed in adrenal cortex
  • regulates gene expression, increases Na+ reabsorption
  • H2O retained
  • K+ excreted
57
Q

angiotensin II receptors

A
  • GPCR
  • subtypes are AT1R and AT2R
  • current antagonist drugs block AT1R
58
Q

normal functions of AT1 Receptor

A
  • regulate BP
  • regulate body fluid balance
  • vasoconstriction
  • inflammation
  • platelet aggregation/adhesion
  • reactive oxygen species
  • proliferative
  • hypertrophy
  • fibrosis
59
Q

ACE inhibitor drugs

A

-Captopril
-Enalapril
-Lisinopril
(ends in pril)

60
Q

ACE inhibitor MOA

A
  • decreases ANGII by preventing conversion of ANGI to ANGII
  • prevent vasoconstriction
  • prevent aldosterone secretion, decreasing sodium and water retention
  • increases bradykinin by inhibiting the breakdown
61
Q

ACE inhibitor PK/PD

A
  • many are prodrugs

- usually renal metabolism and elimination

62
Q

ACE inhibitor clinical uses

A
  • HTN
  • CHF
  • mitral regurgitation
  • post MI
  • more effective in DM for diabetic nephropathy
  • delay progression of renal disease
63
Q

ACE inhibitor clinical effects

A
  • decreased ANGII –> vasodilation, decreased remodeling, decreased aldosterone, (less Na/H2O retention, increased K+), decreased SNS output, increased natriuresis
  • increased BKN –> vasodilation, cough, angioedema
  • decreased BP, PVR
  • decreased preload, afterload
  • decreased cardiac workload
  • no reflex tachycardia
  • improve/prevent LV hypertrophy and remodeling
  • improved morbidity/mortality in HF
  • delays progression of diabetic nephropathy (improves renal hemodynamics)
64
Q

ACE inhibitor adverse effects

A
  • CV – hypotensive symptoms, syncope; 1st dose effect
  • electrolyte – hyperkalemia; caution with K+ sparing diuretics or supplements
  • renal – decreased GFR, increased BUN/Cr; renal dysfunction; contraindicated in bilateral renal artery stenosis
  • inflammatory – dry cough (r/t BKN, reversible), angioedema (r/t BKN)
  • fetal development – teratogenic; contraindicated in pregnancy bc can cause fetal anuria, RF, skull hypoplasia, death
65
Q

ACE inhibitor surgical considerations

A

potential for prolonged hypotension, hold DOS

66
Q

Captopril duration of BP lowering effects

A

~6 hours

67
Q

Enalapril duration of BP lowering effects

A

12-24 hours

68
Q

Lisinopril duration of BP lowering effects

A

24 hours

69
Q

Angiotensin Receptor Blocker (ARB) Drugs

A

Losartan

ends in sartan

70
Q

Angiotensin Receptor Blocker (ARB) MOA

A
  • competitive antagonist at AT1 receptor
  • blocks effects of ANGII mediated by AT1 receptor
  • does not block breakdown of BKN, so no accumulation of BKN
71
Q

Angiotensin Receptor Blocker (ARB) PK/PD

A
  • varies

- metabolized in liver by CYP450

72
Q

Angiotensin Receptor Blocker (ARB) clinical uses

A

uses similar to ACEi

73
Q

Angiotensin Receptor Blocker (ARB) effects/considerations

A
  • adverse effects similar to ACEi
  • less incidence of cough/angioedema because no buildup of BKN
  • contraindication –> renal artery stenosis, pregnancy
  • more tolerable than ACEi
74
Q

Differences between ACEi and ARB?

A
  • efficacy in HTN
  • ARBs slightly more tolerable, less likely to be d/c (main reason for d/c would be dry cough)
  • ACEi - higher quality of data; ARBs don’t have a comparison vs placebo
75
Q

Aldosterone Antagonist Drugs

A

Spironolactone

Eplerenone

76
Q

Aldosterone Antagonist MOA

A
  • competitive antagonist at mineralocorticoid receptor (kidney, heart, blood vessels, brain)
  • prevent nuclear translocation of receptor
  • block transcription of genes coding for Na+ Ch
77
Q

Aldosterone Antagonist PK/PD

A
  • Spironolactone = hepatic metabolism; active metabolites; P-gp inhibitor
  • eplerenone = CYP3A4
78
Q

Aldosterone Antagonist clinical uses

A
  • HTN, HF
  • K+ sparing diuresis
  • primary hyperaldosteronism
  • off label –> acne, hirsutism, PCOS
79
Q

Aldosterone Antagonist effects

A

increased Na+/H2O excretion (mild diuresis); increased K+ reabsorption

80
Q

Aldosterone Antagonist adverse effects

A

hyperkalemia; spironolactone has broad effects

81
Q

Aldosterone Antagonist drug interactions

A
  • other K+ sparing
  • K+ supplements
  • NSAIDs (increased renal risks)
  • eplerenone - CYP3A4 inhibitors
82
Q

Direct Arterial Vasodilators

A
  • hydralazine

- minoxidil

83
Q

hydralazine MOA

A
  • release of NO from endothelial cells

- potential inhibition of calcium release from SR

84
Q

hydralazine PK/PD

A
  • extensive first pass
  • bioavail ~25%
  • half-life 1.5-3 hrs
85
Q

hydralazine clinical uses

A
  • HTN (in combo with beta blocker and diuretic to limit SNS effects)
  • HF (reduced EF)
86
Q

hydralazine effects

A

vasodilates arterioles, minimal venous effect, decreased SVR, DBP reduced > SBP, increased HR/SV/CO

87
Q

hydralazine adverse effects

A

HA, nausea, palpitations, sweating, flushing, reflex tachy, tolerance/tachyphylaxis, Na/H2O retention, angina with EKG changes, lupus (reversible)

88
Q

hydralazine contraindications

A

CAD, mitral valve RH disease

89
Q

minoxidil MOA

A
  • direct relaxation of arteriolar smooth muscle, little effect on venous capacitance
  • increases efflux of K+ form VSMC resulting in hyperpolarization and vasodilation
90
Q

minoxidil PK/PD

A
  • 90% oral dose absorbed from GI tract
  • peak 2-3 hrs
  • half-life ~ 4 hrs
  • 10% drug recovered unchanged in urine
91
Q

minoxidil clinical uses

A

HTN (limited to later line)

92
Q

minoxidil effects

A

vasodilation of arterioles, not veins

93
Q

minoxidil adverse effects

A

tachycardia, increased MVO2, palpitations, angina, sodium/fluid retention, edema, weight gain, hypertrichosis

94
Q

minoxidil warnings

A

fluid retention, pericardial effusion or tamponade, sinus tahcy, rapid BP response, elderly

N929 - Anesthesia Pharmacology (12 decks)

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