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AS - N929 Pharmacology II > Cardiovascular II > Flashcards

Cardiovascular II Flashcards

1
Q

Nitrovasodilators

A

NO donors:

  • Nitroglycerin NTG
  • Sodium nitroprusside
  • Nitric oxide
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2
Q

Nitric Oxide NO

A

Endogenous gas messenger formed from L-arginine
NOT stored
Lipophilic - easily crosses membranes
Reactive & labile free radical

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3
Q

Nitric Oxide PK

A

Oxidation to NO (nitrate or nitrite) → Hgb nitrosylation

Half-life SECONDS

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4
Q

Nitric Oxide

Protective Biological Roles

A 
Vasodilator - smooth muscle relaxant
Neurotransmitter
Immune cytotoxicity
Inhibits platelet aggregation
Cytoprotection 
↓cell adhesion & proliferation
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5
Q

Nitric Oxide

Pathogenic Biological Roles

A

Neuronal injury NMDA
Cell proliferation
HoTN → shock
Inflammatory tissue injury

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6
Q

Organic Nitrates

A

Nitroglycerin NTG

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7
Q

Nitrovasodilators

Organic Nitrates & Sodium Nitroprusside MOA

A

NO release results in GC activation in vascular smooth muscle → cGMP formation → vascular smooth muscle relaxation & vasodilation

Organic nitrates require metabolism to release NO
NTG tolerance effect r/t metabolism

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8
Q

Sodium Nitroprusside

A

Nitrovasodilator (NO donor)
Direct-acting & non-selective peripheral vasodilator
Unstable - light & temperature sensitive
Deterioration results in change to bluish color (normal color faint brownish tint)
IV infusion via pump

Diluted in dextrose 5%
Admin shortest duration possible to avoid toxicity*
*Discontinue after 10 minutes at max infusion rate no ↓BP d/t cyanide toxicity risk

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9
Q

Sodium Nitroprusside

MOA

A

Relaxes arterial AND venous vascular smooth muscle
Limited effect on non-vascular smooth muscle & cardiomyocytes

SNP interacts w/ oxyhemoglobin to dissociate & form methemoglobin →
Methemoglobin releases NO & cyanide →
NO activates guanylate cyclase in the vascular muscle ↑cGMP →
cGMP inhibits Ca2+ entry into vascular smooth muscle & INCREASES ↑Ca2+ uptake into the smooth endoplasmic reticulum
Vasodilation via NO

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10
Q

Sodium Nitroprusside PK

A

1 Fe+, 5 cyanide, & 1 NO group
Direct-acting peripheral vasodilator → arterial & venous smooth muscle relaxation

Spontaneous breakdown to NO + cyanide (LIGHT SENSITIVE)
Metabolism - cyanide combines w/ sulfur groups to form thiocyanate & renal excretion

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11
Q

Sodium Nitroprusside

Dose

A

0.3-10 mcg/kg/min IV
DO NOT INFUSE MAX DOSE > 10 MINUTES

  • Requires continuous IV admin to maintain therapeutic effects
  • Extremely potent
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12
Q

Sodium Nitroprusside

Onset

A

< 2 minutes

Immediate

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13
Q

Sodium Nitroprusside

DOA

A

1-10 minutes SHORT
Half-life 2 minutes

Thiocyanate half-life 2-7 days (prolonged w/ impaired renal function)

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14
Q

Sodium Nitroprusside

Metabolism

A

Renal excretion as metabolites 1° thiocyanate
Also exhaled & excreted via feces

Transfer an electron from oxyhemoglobin Fe+ to SNP → MetHgb + unstable SNP radical
SNP radical breaks down → all 5 cyanide ions are released
Cyanide ion reacts w/ MetHgb to form cyano-methemoglobin (non-toxic)
Remainder metabolized in liver & kidneys → converted to thiocyanate

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15
Q

Sodium Nitroprusside

Clinical Indications

A

HTN crisis ↓BP to prevent/limit end-organ damage 1-2 mcg/kg bolus
Controlled HoTN during surgery → reduce bleeding when indicated
Acute and/or decompensated CHF 0.3-0.5 mcg/kg/min (do not exceed 2 mcg/kg/min)
Cardiac disease ↓LV atfterload
Acute MI → improve CO w/ LV failure present & low CO post-MI *Limited use d/t coronary steal effect - altered blood flow results in diversion away from ischemic areas

USE A-LINE TO MONITOR RESPONSE

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16
Q

Sodium Nitroprusside

Drug Interactions/Contraindications

A

Antihypertensive drugs d/t additive effects
ABSOLUTE CONTRAINDICATION - selective PDE 5 inhibitors (Sildenafil) → profound potentiation, potential life-threatening HoTN and/or hemodynamic compromise, cGMP accumulation d/t inhibiting breakdown
Guanylate cyclase stimulating drugs ↑cGMP

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17
Q

Sodium Nitroprusside PD

A

CNS ↑CBF/ICP caution w/ carotid disease
CV - direct venous & arterial vasodilation
↓arterial/venous pressure, SVR, afterload (CHF or acute MI potential ↑CO d/t ↓afterload), ↓venous capacitance ↓VR, ↓BP (SBP/DBP) ↓coronary perfusion, ↑HR (baroreceptor-mediated response), ↑contractility (↑intracoronary steal in damaged areas associated w/ MI), no significant effects on non-vascular smooth muscle & cardiac muscle
Pulm - HPV attenuation
Heme - NO inhibits platelet aggregation ↑bleeding time
Renal - vasodilation w/o significant Δ GFR

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18
Q

Sodium Nitroprusside

SIDE EFFECTS

A

Profound HoTN - potential to impair end-organ perfusion
Cyanide toxicity
Methemoglobinemia
Thiocyanate accumulation
↑serum creatinine (transient)
↑ICP, headache, dizziness, restlessness, palpitations, flushing, GI upset/nausea

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19
Q

Cyanide Toxicity

A

Adverse effect r/t sodium nitroprusside administration
Occurs d/t high plasma thiocyanate concentrations

Dose/duration related >2 mcg/kg/min
*Consider when patient demonstrates resistance to HoTN effects or previous responsive now unresponsive (tachyphylaxis) at 2-10 mcg/kg/min
Tissue anoxia & anerobic metabolism
Venous hyperoxemia - tissues cannot extract O2
Lactic acidosis
Confusion & death

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20
Q

Cyanide Toxicity

Treatment

A

Immediately discontinue SNP
FiO2 100% (regardless SpO2)
Admin Na+ bicarbonate to correct metabolic acidosis
Sodium thiosulfate 150 mg/kg over 15 minutes (sulfur donor to convert cyanide to thiocyanate)

Severe toxicity Na+ nitrate 5 mg/kg
→ converts Hgb to MetHgb then converts cyanide → cyanometHemoglobin

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21
Q

Methemoglobinemia

A

RARE adverse effect r/t sodium nitroprusside administration

Hgb Fe2+ (ferrous) oxidized to Fe3+ (ferric) → impaired oxygen affinity → reduced O2 delivery to tissues → hypoxia

Reversal agent = Methylene blue 1-2 mg/kg

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22
Q

When to consider methemoglobinemia as differential diagnosis?

A

Patients w/ impaired oxygenation despite adequate CO & arterial oxygenation

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23
Q

Thiocyanate

A

Cleared via kidneys in 3-7 days

Less toxic than cyanide

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24
Q

Thiocyanate Toxicity

A

Accumulation adverse effect r/t sodium nitroprusside administration

↑risk associated w/ prolonged infusion
Renal impairment
Neurotoxicity - tinnitus, miosis, & hyperreflexia
Hypothyroidism d/t impaired iodine uptake

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25
Q

Thiocyanate Toxicity

S/S

A

CNS hyperreflexia, confusion, & psychosis
Fatigue & tinnitus
Nausea/vomiting
Miosis seizures → coma

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26
Q

Phototoxicity

A

Mix SNP w/ 5% glucose to protect from light exposure
Continuous light exposure → SNP converted to aquapentacyanoferrate

Prevention - wrap the solution & tubing in foil or dark plastic bag

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27
Q

Nitroglycerin

MOA

A

Organic nitrate

NO released via cellular metabolism - glutathione-dependent pathway
*Requires thiols (sulfur group)
NO release stimulates GC → cGMP formation → vascular smooth muscle relaxation & peripheral vasodilation
1° action site = VENOUS capacitance vessels
Mildly dilates arteriolar resistance vessels

Admin IV, sublingual, translingual spray, transdermal patch, OR ointment

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28
Q

Nitroglycerin PK

A

Extensive hepatic 1st pass effect 90% after PO admin
Sublingual route to avoid 1st pass

Hepatic metabolism - denitrate via glutathione-organic nitrate reductase to glyceryl dinitrate → mononitrate

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29
Q

Nitroglycerin

Dose

A

125-500 mcg/kg/min IV

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30
Q

Nitroglycerin Onset/DOA

  • IV
  • Sublingual
  • Translingual Spray
  • PO XR
  • Topical
  • Transdermal
A 
IV immediate/3-5min
Sublingual 1-3min/>25min
Translingual 1-3min/>25min
PO extended release 60min/4-8hrs
Topical 15-30min/7hrs
Transdermal 30min/10-12hrs
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31
Q

Nitroglycerin

Clinical Indications

A

Angina

  • Acute angina SL
  • Prevention long-acting PO, transdermal, or ointment
  • Venodilation ↓VR ↓RV & LVEDP ↓MVO2
HTN - periop, HTN emergencies, postop HTN (after coronary bypass)
Controlled HTN intraop
Non-STEMI
Acute MI (limits damage)
Heart failure/low-output syndromes
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32
Q

Nitroglycerin

Relative Contraindications

A

Volume depletion, HoTN, brady/tachycardia, constrictive pericarditis, aortic/mitral stenosis, inferior wall MI & RV involvement

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33
Q

Nitroglycerin PD

A

1° action site at venous capacitance vessels = ↓preload & MVO2

Arterial resistance vessels - minimal ↓afterload & MVO2

Myocardial arteries ↑MVO2 supply d/t vasodilation

CV ↓VR ↓RV & LVEDP ↓CO
Ø SVR
↑coronary blood flow to ischemic subendocardial areas

Bronchial smooth muscle relaxation → bronchial dilation
Impairs HPV
Inhibits platelet aggregation

*Tolerance after 8-10 hours results in diminished effectiveness

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34
Q

Nitroglycerin

SIDE EFFECTS

A 
Throbbing headache
↑ICP
Orthostatic HoTN, dizziness, syncope
Reflex tachycardia (baroreceptor reflex)
Flushing, vasodilation, & venous pooling
↓CO
Methemoglobinemia (rare)
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35
Q

Phosphodiesterase

A

Enzymes that breakdown cyclic nucleotides
Regulate intracellular levels cAMP & cGMP (2nd messengers - endogenous pathways)
Numerous sub-families x11 differ in localization & potential therapeutic targets
Inhibitors boost cyclic nucleotide levels via preventing breakdown
Older non-selective drugs that inhibit PDE include Caffeine & Theophylline

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36
Q

PDE 3 Inhibitor

A

-rinone
Broad distribution
cAMP & cGMP substrate
Action site = heart & vascular smooth muscle
Cardiac contractility & platelet aggregation
Inotrope + peripheral vasodilation
↑contractility

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37
Q

PDE 3 Inhibitor

MOA

A

Milrinone - inhibits PDE3
Prevents cAMP breakdown to AMP (inactive form)
↑2nd messenger cAMP

38
Q

cAMP

A

Enhances the biological effect
Ca2+ channel activation ↑cytosolic Ca2+ → actin-myosin-troponin interaction → + INOTROPY
cAMP-dependent protein kinase ↑phosphorylated phospholamban → augmented Ca2+ SR uptake → VASODILATION

39
Q

Milrinone

A

PDE 3 inhibitor

40
Q

Milrinone

MOA

A

Inhibits cAMP breakdown

↑intracellular Ca2+

41
Q

Milrinone

Onset

A

IV 5-15 minutes
Half-life 3-6 hours

*Only parenteral

42
Q

Milrinone

Metabolism

A

> 80% excreted renally unchanged

43
Q

Milrinone

Clinical Indications

A

Acute heart failure or severe CHF
Cardiogenic shock (off-label)
Heart transplant bridge or post-op (off-label)

44
Q

Milrinone PD

A 
\+ inotrope
↑cardiac contractility
Vasodilation
Minimal chronotropic activity
Dilates pulmonary vasculature
45
Q

Milrinone

SIDE EFFECTS

A

Arrhythmias

HoTN

46
Q

PDE 4 Inhibitor

A

Broad distribution
CV, neural, immune & inflammatory function
cAMP substrate
Indications include ↓inflammation & remodeling associated w/ COPD

47
Q

PDE 5 Inhibitor

A

-afil
Broad distribution
cGMP substrate
Action site = vascular smooth muscle (erectile tissue, lung, retina)
Vascular smooth muscle relaxation at lungs
Pulmonary HTN & erectile dysfunction

48
Q

PDE 5 Inhibitor MOA

A

Sildenafil - inhibits PDE5
Prevents cGMP breakdown to GMP (inactive form)
↑2nd messenger cGMP

49
Q

RAAS

A

Renin-Angiotensin-Aldosterone system
Angiotensinogen + renin → angiotensin I + converting enzyme (ACE) → angiotensin II → aldosterone ↑preload OR vascular smooth muscle constriction ↑afterload
Aldosterone causes ↑H2O + Na+ retention

50
Q

What secretes renin?

A

The JG cells in the renal afferent tubules

Secretion stimulated via ↓BP or Na+ load

51
Q

ACE

A

Angiotensin converting enzyme

Converts angiotensin I → angiotensin II

52
Q

Angiotensin II

A

Causes vasoconstriction at angiotensin II type 1 GPCRs receptor
Aldosterone secretion
↑ADH ↑proximal tubule Na+ reabsorption

53
Q

Angiotensin II PD

Type 1 vs. 2 Receptors

A

AT1R

  • Blood pressure regulation
  • Body-fluid balance regulation
  • Vasoconstriction
  • Inflammation
  • Platelet aggregation/adhesion
  • Reactive oxygen species production
  • Proliferative
  • Hypertrophy
  • Fibrosis

AT2R

  • Natriuresis
  • Neuronal activity
  • Vasodilation
  • Anti-inflammation
  • Pro-apoptotic
  • Anti-oxidative
  • Anti-hypertrophic
  • Anti-fibrotic
54
Q

Aldosterone

A

Steroid hormone secreted via adrenal cortex
Regulates gene expression
↑Na+ reabsorption
H2O retention & K+ excretion

55
Q

RAAS Pathways Inhibition

A 
β1 adrenergic antagonist - Metoprolol
Renin inhibitor
ACEi -pril
Angiotensin II receptor antagonist ARBs -sartan
Aldosterone antagonist - Spironolactone
56
Q

ACE Inhibitors

A

-pril
↓angiotensin II → vasodilation, ↓remodeling (heart failure), ↓aldosterone (↓Na+/H2O ↑K+ retention), ↑sympathetic output, ↑natriuresis

↑bradykinin → vasodilation, cough, angioedema

57
Q

Bradykinin

A

Endogenous peptide

Stimulates NO & prostacyclin formation
Vasodilation (heart, kidney, microvascular beds)
Inflammatory actions ↑capillary permeability → angioedema

58
Q

Bradykinin

DOA

A

Elimination 1/2 time 16 seconds

59
Q

ACEi

A

Angiotensin converting enzyme inhibitors
-pril
Lisinopril, Enalapril, Benazapril
Captopril (prototype)

60
Q

ACE Inhibitors

MOA

A

Block angiotensin I → angiotensin II
Prevents vasoconstriction
Prevents aldosterone secretion ↓Na+ & H2O retention

61
Q

ACE Inhibitors PK

A

Commonly pro-drugs (Enalapril & Ramipril) inactive when administered & require metabolism → active form
1° renal excretion
Commonly combination drugs + diuretic ↑UOP

62
Q

ACE Inhibitors

Clinical Indications

A

HTN, CHF (systolic dysfunction), & mitral regurgitation
Post-MI
More effective in diabetes mellitus patients - diabetic neuropathy
Delay renal disease progression

63
Q

ACE Inhibitors

Drug Interactions

A

K+ sparing diuretics & supplements

K+ retention → hyperkalemia

64
Q

ACE Inhibitors

Contraindications

A

Renal artery stenosis - potential to develop renal failure d/t efferent arteriole constriction

Pregnancy - teratogenic

65
Q

ACE Inhibitors PD

A

↓BP → HoTN, syncope, & possible 1st dose effect
↓GFR ↑BUN/creatinine & renal dysfunction

Dry cough (reversible) bradykinin-related
Angioedema 1%

Teratongenic - causes fetal malformations & contraindicated in pregnancy

66
Q

ACE Inhibitors

SIDE EFFECTS

A 
Cough C1 esterase deficiency - contraindication 
Angioedema/agranulocytosis
Proteinurea/potassium excess 
Taste change
Orthostatic HoTN
Pregnancy CONTRAINDICATION (fetal renal damage)
Renal artery stenosis CONTRAINDICATION
Increases renin
Leukopenia/liver toxicity
67
Q

ARBs

A

Angiotensin receptor blocker
-sartan
Losartan (prototype)
Similar PK/PD to ACEi

68
Q

ARBs MOA

A

Competitive antagonist at AT1 receptor
Blocks angiotensin II effects mediated at AT1 receptor
Does NOT block bradykinin breakdown → no bradykinin accumulation

69
Q

ARBs

Metabolism

A

Hepatic via CYP2C9

70
Q

ARBs

Clinical Indications

A

Same as ACEi

71
Q

ARBs Drug Interactions

A

Interactions w/ K+ sparing diuretics & supplements

K+ retention → hyperkalemia

72
Q

ARBs Contraindications

A

Renal artery stenosis

Pregnancy

73
Q

ARBs PD

A

Similar effects to ACEi

Less frequent cough & angioedema (rare)

74
Q

ACEi vs. ARBs

A

No difference in HTN efficacy
ARBs less likely to be discontinued (main reason ↓dry cough 1% vs. 4%)
Longer history available w/ ACEi
ARBs no comparison vs. placebo

75
Q

Aldosterone Antagonist MOA

A

Spironolactone
Competitive antagonist at mineralocorticoid receptors (1° renal + heart, blood vessels, & brain)
Blocks gene transcription - coding Na+ channels

76
Q

Spironolactone MOA

A

Aldosterone antagonist

Off-target effects include blocking androgen & progesterone receptors

77
Q

Aldosterone Antagonist PK

A

Hepatic metabolism

Spironolactone - active metabolites w/ elimination 1/2 life 12-20 hours

78
Q

Aldosterone Antagonist

Clinical Indications

A

HTN & heart failure
K+ sparing diuresis
1° hypoaldosteronism

Spironolactone off-label uses acne, hirsutism, & PCOS

79
Q

Aldosterone Antagonist

Drug Interactions

A

Other K+ sparing drugs (ACEi or ARBs)
K+ supplements
NSAIDs ↑renal risks

80
Q

Aldosterone Antagonist PD

A

↑Na+ & H2O excretion → mild diuresis

↑K+ reabsorption

81
Q

Aldosterone Antagonist

SIDE EFFECTS

A

Hyperkalemia

Spironolactone - hepatic, renal, Steven-Johnson, toxic epidermal necrolysis, GI, gynecomastia, menstrual irregularities

82
Q

Hydralazine MOA

A

Direct vasodilator
Release NO from endothelial cells
Inhibits Ca2+ release from sarcoplasmic reticulum

83
Q

Hydralazine PK

A

Extensive 1st pass effect
25% bioavailability
Half-life 1.5-3 hours

84
Q

Hydralazine

Clinical Indications

A

↓BP

HTN - combination therapy + β-blocker & diuretic to limit SNS effects
Heart failure ↓ejection fraction

85
Q

Hydralazine

Contraindications

A

Coronary artery disease

Mitral valve disease

86
Q

Hydralazine PD

A 
Arteriole vasodilation
Minimal venous effects 
↓SVR
↓↓DBP > ↓SBP 
↑HR reflex tachycardia
↑SV/CO
87
Q

Hydralazine

Side Effects

A 
Headache
Palpitations, sweating, flushing
Reflex tachycardia & tolerance/tachyphylaxis
Angina w/ EKG changes
Nausea
Na+ & H2O retention
Lupus erythematous (reversible)
88
Q

Hydralazine

Contraindications

A

Coronary artery disease

Mitral valve disease

89
Q

Minoxidil

A

Direct arterial vasodilator

↑K+ efflux from vascular smooth muscle → hyperpolarization & vasodilation

90
Q

Nitric Oxide PK

A

AS - N929 Pharmacology II (10 decks)

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