Cardiovascular II Flashcards
Nitrovasodilators
NO donors:
- Nitroglycerin NTG
- Sodium nitroprusside
- Nitric oxide
Nitric Oxide NO
Endogenous gas messenger formed from L-arginine
NOT stored
Lipophilic - easily crosses membranes
Reactive & labile free radical
Nitric Oxide PK
Oxidation to NO (nitrate or nitrite) → Hgb nitrosylation
Half-life SECONDS
Nitric Oxide
Protective Biological Roles
Vasodilator - smooth muscle relaxant Neurotransmitter Immune cytotoxicity Inhibits platelet aggregation Cytoprotection ↓cell adhesion & proliferation
Nitric Oxide
Pathogenic Biological Roles
Neuronal injury NMDA
Cell proliferation
HoTN → shock
Inflammatory tissue injury
Organic Nitrates
Nitroglycerin NTG
Nitrovasodilators
Organic Nitrates & Sodium Nitroprusside MOA
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
Sodium Nitroprusside
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
Sodium Nitroprusside
MOA
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
Sodium Nitroprusside PK
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
Sodium Nitroprusside
Dose
0.3-10 mcg/kg/min IV
DO NOT INFUSE MAX DOSE > 10 MINUTES
- Requires continuous IV admin to maintain therapeutic effects
- Extremely potent
Sodium Nitroprusside
Onset
< 2 minutes
Immediate
Sodium Nitroprusside
DOA
1-10 minutes SHORT
Half-life 2 minutes
Thiocyanate half-life 2-7 days (prolonged w/ impaired renal function)
Sodium Nitroprusside
Metabolism
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
Sodium Nitroprusside
Clinical Indications
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
Sodium Nitroprusside
Drug Interactions/Contraindications
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
Sodium Nitroprusside PD
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
Sodium Nitroprusside
SIDE EFFECTS
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
Cyanide Toxicity
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
Cyanide Toxicity
Treatment
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
Methemoglobinemia
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
When to consider methemoglobinemia as differential diagnosis?
Patients w/ impaired oxygenation despite adequate CO & arterial oxygenation
Thiocyanate
Cleared via kidneys in 3-7 days
Less toxic than cyanide
Thiocyanate Toxicity
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
Thiocyanate Toxicity
S/S
CNS hyperreflexia, confusion, & psychosis
Fatigue & tinnitus
Nausea/vomiting
Miosis seizures → coma
Phototoxicity
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
Nitroglycerin
MOA
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
Nitroglycerin PK
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
Nitroglycerin
Dose
125-500 mcg/kg/min IV
Nitroglycerin Onset/DOA
- IV
- Sublingual
- Translingual Spray
- PO XR
- Topical
- Transdermal
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
Nitroglycerin
Clinical Indications
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
Nitroglycerin
Relative Contraindications
Volume depletion, HoTN, brady/tachycardia, constrictive pericarditis, aortic/mitral stenosis, inferior wall MI & RV involvement
Nitroglycerin PD
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
Nitroglycerin
SIDE EFFECTS
Throbbing headache ↑ICP Orthostatic HoTN, dizziness, syncope Reflex tachycardia (baroreceptor reflex) Flushing, vasodilation, & venous pooling ↓CO Methemoglobinemia (rare)
Phosphodiesterase
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
PDE 3 Inhibitor
-rinone
Broad distribution
cAMP & cGMP substrate
Action site = heart & vascular smooth muscle
Cardiac contractility & platelet aggregation
Inotrope + peripheral vasodilation
↑contractility
PDE 3 Inhibitor
MOA
Milrinone - inhibits PDE3
Prevents cAMP breakdown to AMP (inactive form)
↑2nd messenger cAMP
cAMP
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
Milrinone
PDE 3 inhibitor
Milrinone
MOA
Inhibits cAMP breakdown
↑intracellular Ca2+
Milrinone
Onset
IV 5-15 minutes
Half-life 3-6 hours
*Only parenteral
Milrinone
Metabolism
> 80% excreted renally unchanged
Milrinone
Clinical Indications
Acute heart failure or severe CHF
Cardiogenic shock (off-label)
Heart transplant bridge or post-op (off-label)
Milrinone PD
\+ inotrope ↑cardiac contractility Vasodilation Minimal chronotropic activity Dilates pulmonary vasculature
Milrinone
SIDE EFFECTS
Arrhythmias
HoTN
PDE 4 Inhibitor
Broad distribution
CV, neural, immune & inflammatory function
cAMP substrate
Indications include ↓inflammation & remodeling associated w/ COPD
PDE 5 Inhibitor
-afil
Broad distribution
cGMP substrate
Action site = vascular smooth muscle (erectile tissue, lung, retina)
Vascular smooth muscle relaxation at lungs
Pulmonary HTN & erectile dysfunction
PDE 5 Inhibitor MOA
Sildenafil - inhibits PDE5
Prevents cGMP breakdown to GMP (inactive form)
↑2nd messenger cGMP
RAAS
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
What secretes renin?
The JG cells in the renal afferent tubules
Secretion stimulated via ↓BP or Na+ load
ACE
Angiotensin converting enzyme
Converts angiotensin I → angiotensin II
Angiotensin II
Causes vasoconstriction at angiotensin II type 1 GPCRs receptor
Aldosterone secretion
↑ADH ↑proximal tubule Na+ reabsorption
Angiotensin II PD
Type 1 vs. 2 Receptors
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
Aldosterone
Steroid hormone secreted via adrenal cortex
Regulates gene expression
↑Na+ reabsorption
H2O retention & K+ excretion
RAAS Pathways Inhibition
β1 adrenergic antagonist - Metoprolol Renin inhibitor ACEi -pril Angiotensin II receptor antagonist ARBs -sartan Aldosterone antagonist - Spironolactone
ACE Inhibitors
-pril
↓angiotensin II → vasodilation, ↓remodeling (heart failure), ↓aldosterone (↓Na+/H2O ↑K+ retention), ↑sympathetic output, ↑natriuresis
↑bradykinin → vasodilation, cough, angioedema
Bradykinin
Endogenous peptide
Stimulates NO & prostacyclin formation
Vasodilation (heart, kidney, microvascular beds)
Inflammatory actions ↑capillary permeability → angioedema
Bradykinin
DOA
Elimination 1/2 time 16 seconds
ACEi
Angiotensin converting enzyme inhibitors
-pril
Lisinopril, Enalapril, Benazapril
Captopril (prototype)
ACE Inhibitors
MOA
Block angiotensin I → angiotensin II
Prevents vasoconstriction
Prevents aldosterone secretion ↓Na+ & H2O retention
ACE Inhibitors PK
Commonly pro-drugs (Enalapril & Ramipril) inactive when administered & require metabolism → active form
1° renal excretion
Commonly combination drugs + diuretic ↑UOP
ACE Inhibitors
Clinical Indications
HTN, CHF (systolic dysfunction), & mitral regurgitation
Post-MI
More effective in diabetes mellitus patients - diabetic neuropathy
Delay renal disease progression
ACE Inhibitors
Drug Interactions
K+ sparing diuretics & supplements
K+ retention → hyperkalemia
ACE Inhibitors
Contraindications
Renal artery stenosis - potential to develop renal failure d/t efferent arteriole constriction
Pregnancy - teratogenic
ACE Inhibitors PD
↓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
ACE Inhibitors
SIDE EFFECTS
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
ARBs
Angiotensin receptor blocker
-sartan
Losartan (prototype)
Similar PK/PD to ACEi
ARBs MOA
Competitive antagonist at AT1 receptor
Blocks angiotensin II effects mediated at AT1 receptor
Does NOT block bradykinin breakdown → no bradykinin accumulation
ARBs
Metabolism
Hepatic via CYP2C9
ARBs
Clinical Indications
Same as ACEi
ARBs Drug Interactions
Interactions w/ K+ sparing diuretics & supplements
K+ retention → hyperkalemia
ARBs Contraindications
Renal artery stenosis
Pregnancy
ARBs PD
Similar effects to ACEi
Less frequent cough & angioedema (rare)
ACEi vs. ARBs
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
Aldosterone Antagonist MOA
Spironolactone
Competitive antagonist at mineralocorticoid receptors (1° renal + heart, blood vessels, & brain)
Blocks gene transcription - coding Na+ channels
Spironolactone MOA
Aldosterone antagonist
Off-target effects include blocking androgen & progesterone receptors
Aldosterone Antagonist PK
Hepatic metabolism
Spironolactone - active metabolites w/ elimination 1/2 life 12-20 hours
Aldosterone Antagonist
Clinical Indications
HTN & heart failure
K+ sparing diuresis
1° hypoaldosteronism
Spironolactone off-label uses acne, hirsutism, & PCOS
Aldosterone Antagonist
Drug Interactions
Other K+ sparing drugs (ACEi or ARBs)
K+ supplements
NSAIDs ↑renal risks
Aldosterone Antagonist PD
↑Na+ & H2O excretion → mild diuresis
↑K+ reabsorption
Aldosterone Antagonist
SIDE EFFECTS
Hyperkalemia
Spironolactone - hepatic, renal, Steven-Johnson, toxic epidermal necrolysis, GI, gynecomastia, menstrual irregularities
Hydralazine MOA
Direct vasodilator
Release NO from endothelial cells
Inhibits Ca2+ release from sarcoplasmic reticulum
Hydralazine PK
Extensive 1st pass effect
25% bioavailability
Half-life 1.5-3 hours
Hydralazine
Clinical Indications
↓BP
HTN - combination therapy + β-blocker & diuretic to limit SNS effects
Heart failure ↓ejection fraction
Hydralazine
Contraindications
Coronary artery disease
Mitral valve disease
Hydralazine PD
Arteriole vasodilation Minimal venous effects ↓SVR ↓↓DBP > ↓SBP ↑HR reflex tachycardia ↑SV/CO
Hydralazine
Side Effects
Headache Palpitations, sweating, flushing Reflex tachycardia & tolerance/tachyphylaxis Angina w/ EKG changes Nausea Na+ & H2O retention Lupus erythematous (reversible)
Hydralazine
Contraindications
Coronary artery disease
Mitral valve disease
Minoxidil
Direct arterial vasodilator
↑K+ efflux from vascular smooth muscle → hyperpolarization & vasodilation
Nitric Oxide PK
