Cardiac Pharm - Bush Lecture Flashcards
what is nitric oxide
its an endogenous gas messenger
lipophillic, highly reactive, labile free radical
how is nitric oxide eliminated
oxidation to form NO2 or NO3
nitrosylation of hgb
what is the half life of nitric oxide
just a few seconds
what is nitric oxide also called
endothelium-derived relaxing factor
this is because it is released from endothelium and acts on VSMCs to increase cGMP and cause relaxation
what are the three types of nitric oxide synthase
nNOS - neuronal
iNOS - inducible - involved in infection response and is triggered by cytokines
eNOS - endothelial
what are the protective roles of nitric oxide
NT immune cytotoxicity inhibit platelet aggregation/ decreased cell adhesion cyto-protection vasodilator smooth muscle relaxant
what are the pathogenic roles of NO
neuronal injury
cell proliferation
shock - hypotension
inflammatory tissue injury
describe the pathway of NO mediated vasodilation
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
what are the nitrovasodilators?
aka NO donor drugs
organic nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate)
sodium nitroprusside
amyl nitrite
nitric oxide gas
MOA of organic nitrates
oranic nitrates undergo metabolism to form NO which then acts to activate guanylyl cyclase to form GMP and cause vasodilation
how is sodium nitroprusside metabolized
the cyanide that is left after breakdown combines with sulfur groups to form thiocyanate which then undergoes renal excretion
MOA of sodium nitroprusside
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)
onset of sodium nitroprusside
<2 minutes
duration of sodium nitroprusside
1-10 minutes
half life of sodium nitroprusside
less than 2 minutes
half life of thiocyanate
2-7 days - increased with impaired renal excretion
CV effects of sodium nitroprusside
decreased arterial and venous pressure
decreased peripheral VR
decreased afterload
slight increase in HR
doesn’t really effect cardiac muscle
sodium nitroprusside renal effects
vasodilation without significant change in GFR
sodium nitroprusside CNS effects
increased cerebral blood flow and ICP
effects on blood from sodium nitroprusside
inhibits platelet aggregation
what do we use sodium nitroprusside for?
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
sodium nitroprusside adverse effects
profound hypotension cyanide toxicity methemoglobinemia thiocyanate accumulation increased serum creatinine (transient) increased ICP nausea HA restlessness flushing dizzy palpitation
sodium nitroprusside and cyanide toxicity
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
methemoglobinemia
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
when does metHb become symptomatic
> 10%
what is the reveral agent for metHb
methylene blue
sodium nitroprusside and thiocyanate accumulation
increased risk with prolonged infusion, renal impairment
causes neurotoxicity - ears ringing, miosis, hyperreflexia
hypothyroidism - d/t impaired idodine uptake
drug interaction with sodium nitroprusside
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
sodium nitroprusside stability
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
administration of sodium nitroprusside
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
MOA nitroglycerin
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
what vasculature does nitroglycerin act on and what does that buy you?
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
what are the ways that you can administer nitroglycerin
IV, SL, translingual spray, transdermal ointment
nitroglycerin effects
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
how long until you develop nitroglycerin tolerance
after 8-10h you will start to see diminishing effects
when should you use caution with nitroglycerin
volume depletion
hypotension
bradycardia or tachycardia
constrictive pericarditis, aortic/mitral stensosis, inferior wall MI, and RV involvement
clinical uses for nitroglycerin
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)
angina and nitroglycerin
acute angina pectoris - give sublingual
prevention of angina - longer acting PO, transdermal, ointment
venodilation decreases VR to heart which reduces R&Lvedp
reduces mvo2
adverse effects of nitroglycerin
throbbing headache
orthostatic hypotension, dizziness, syncope
increase ICP reflex tachy (baroreceptor) flushing vasodilation, venous pooling, decreased CO methemoglobinemia tolerance
nitroglycerin metabolism
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
IV nitroglycerin onset and duration
immediate onset, lasts 3-5 minutes
sublingual and translingual spray nitroglycerin onset and duration
1-3 minutes onset
duration = >25 minutes
topical nitroglycerin onset and doa
onset = 15-30 minutes doa = 7 hours
transdermal nitroglycerin onset and doa
onset around 30 minutes
duration 10-12 hours
oral, extended release nitroglycerin onset and doa
onset about one hour
doa = 10-12 hours
how long should you have a nitrate free interval to avoid tolerance to organic nitrates?
8-12 hours
isosorbide dinitrate sublingual onset and doa
onset about 2-5 minutes
doa up to 8hours
isosorbide dinatrate oral onset and duration
onset about 60 minutes
doa up to 8 hours
isosorbide mononitrate oral onset and duration
onset 30-45 minutes and duration >6h
isosorbide mononitrate oral ER onset and duration
onset = 30-45 minutes and duration = >12-24 hours
nitroglycerin drug interaction
antihypertensives = additive effect
selective pde5 inhibitors = absolute contraindication d/t life threatening hypotension/hemodynamic compromise d/t accumulation of cGMP
guanylate cyclase stimulating drugs
isosorbide mononitrate and dinatrate uses
oral nitrate forms used for the prophylaxis of angina pectoris
additionally, used for heart failure in black patients in combo with hydralazine
isosorbide mononitrate and dinatrate absorption and metabolism
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
Phosphodiesterase enzymes - what are they
Family of enzymes that break down cyclic nucleotides
PDE inhibitors - MOA
Boost levels of cyclic nucleotides by preventing breakdowns
PDE3 distribution, substrate broken down and substrate function
Why would you want to inhibit PDE3 clinically?
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
PDE4 distribution, substrate broken down and substrate function
Why would you want to inhibit PDE4 clinically?
Distribution: broad, CV, neural, immune/inflammatory
Target substrate: cAMP
Substrate function: immune, inflammatory
Clinical use? COPD to decrease inflammation and remodeling
PDE5 distribution, substrate broken down and substrate function
Why would you want to inhibit PDE5 clinically?
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
Milrinone MOA
PDE3 inhibitor - inhibits breakdown of cAMP causing increased inotropy and vasodilation
Clinical uses of milrinone
Acute heart failure or severe chronic heart failure
Cardiogenic shock (off-label)
Heart transplant bridge or post op
Adverse effects of milrinone
Arrhythmias and hypotension
Onset of milrinone
5-15 minutes
Half life of milrinone
3-6h
Milrinone metabolism and excretion
Only given parenterally
Majority not metabolized - >80% excreted renally unchanged
What PDE3 inhibitor do we use for intermittent claudication
Cilastazol
What PDE4 inhibitor do we give to decrease inflammation and remodeling in patients with COPD
Roflumilast
What are the three PDE5 inhibitors listed on Bush’s chart - they are used for pulmonary hypertension and/or erectile dysfunction
Sildenafil
Tadalafil
Vardenafil
When was renin identified in extract of renal cortex, pressors activity demonstrated
1898
When did they discover that Renin has proteolytic action on plasma substrate (angiotensinogen) forming a pressor peptide (angiotensin/hypertensin ->angiotensin)
1930s
When was it identified that there were two forms of angiotensin, discovered ACE, and that ang ii stimulates release of aldosterone
1950s
Where is renin secreted from
JG apparatus
What does renin cause
Vasoconstriction and sodium retention (indirectly) by stimulating RAAS - aka converts angiotensinogen to ang i
What stimulates the release of renin
Low BP or sodium load, beta one receptor activation
What is the goal of renin release
Maintain tissue perfusion through increase in extra cellular fluid volume
Why is RAAS synergistic with SNS
It increases the release of norepi from the sympathetic nerve terminals
ACE (kinase ii)
Located in membrane of EC cells
Has broad protease action
- forms ang ii from ang i
- metabolized BKN to inactive form
What does Angiotensin ii cause
Vasoconstriction
Aldosterone secretion
ADH secretion increase, increase proximal tubule sodium reabsorption
What receptor does ang ii act on to cause vasoconstriction and aldosterone secretion
AT1 receptor
What is aldosterone, where is it located, and what does it do/cause
It is a mineralcorticoid secreted from the adrenal cortex
Regulates gene expression and increases sodium reabsorption
H20 retained and K excreted
What responses are mediated by activation of the AT1 receptor by angiotensin 2?
Regulation of BP and body fluid balance Vasoconstriction Inflammation Platelet aggregation/adhesion ROS production Proliferative Hypertrophy Fibrosis
What are the effects of decreased angiotensin ii specifically as seen when giving an ACE inhibitor?
Vasodilation Decreased remodeling Decreased aldosterone leading to decreased sodium and water retention and increased potassium retention Decreased sympathetic output Increased naturesis
What is an ACE inhibitor’s effect on bradykinin and what effects would could you see
ACE breaks down bradykinin to its inactive form - therefore with and ACEi you would see increased bradykinin which could cause vasodilation, cough, and angioedema
What is the half life of bradykinin
17 seconds
What are bradykinin’s constitutive actions
Stimulates NO and prostacyclin formation causing vasodilation in the heart, kidney and micro vascular beds and increases capillary permeability as an inflammatory response
What is the MOA of ACEi’s?
They block the conversion of ang i to ang ii, preventing vasoconstriction and aldosterone secretion which means decreased sodium and water retention
When would you use an ACE inhibitor
As a first line therapy against HTN, CHF, mitral regurgitation
In what patient population is diabetes more effective
Diabetes mellitus
For patients with kidney disease, is an ace inhibitor a good choice?
Yes! ACEi’s can delay progression of renal disease
What are the cardiovascular clinical effects of ACE inhibitors
Decreased BP, peripheral vascular resistance, preload, afterload, and cardiac workload
Improves/prevents LV hypertrophy and remodeling
Improves morbidity and mortality for HF patients
Do ACEi’s cause reflex tachycardia?
No
ACEi’s and diabetic neuropathy
Delays progression
How are ACE inhibitors metabolized and eliminated?
Most are pro drugs
Usually eliminated renally
Most are pro drugs
Usually eliminated renally
How are ACE inhibitors metabolized and eliminated?
Most are pro drugs
Usually eliminated renally
Which ace inhibitor has an IV form?
Enalaprilat
What drugs should you use caution with in combo with ace inhibitors
Potassium sparking diuretics and potassium supplements
Does benazopril have a metabolite and what is the doa?
Yes - benazepralit
24 hours doa
Does captopril have a prodrug and what is the doa
No
6 hours
Does enalopril have a metabolite and what is the doa
Enalopril = 12-24 hours and metabolite enalaprilat = 6 hours
Does lisinopril have a metabolite and what is the doa
No, 24 hours
What ace inhibitor has the longest duration of action
Trandolapril - 72 hours
What are the cv adverse effects of ace inhibitors
Hypotension, syncope, first dose effect possible
What are the electrolyte adverse effects of ace inhibitors
Hyperkalemia
What are the renal adverse effects of ace inhibitors
Decreased GFR, increased BUN and creatinine, renal dysfxn
What renal disease is an ace inhibitor contraindicated in
Bilateral renal artery stenosis
What are the inflammatory adverse effects of ace inhibitors
Dry cough and angioedema - both BKN related
What are the adverse effects on fetal development caused by ACEi’s?
Fetal malformations -teratogenic
Contraindicated in pregnancy
What are the surgical/anesthesia implications for ace inhibitors
Can result in prolongs hypotension
Captopril can cause neutropenia/agranulocytosis
Proteinuria
Ace inhibitor pneumonic for side effects
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
Lesarten (ARB) mechanism of action
Competitive antagonist at AT1 receptor blocking effects of angiotensin 2 mediated by AT1 agonism
Does not effect BKN so less extreme SE
How are ARBs metabolized
Varies
Losartan - CYP2C9
What drugs should you use caution with when giving an ARB
Potassium sparing diuretics
Potassium supplements
Contraindications of ARBs
Renal artery stenosis and pregnancy
MOA spironolactone aka aldosterone antagonist
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
Effects of aldosterone antagonists (spironolactone)
Increased sodium and water excretion, mild diuresis
Increased potassium reabsorption
What is spironolactone used for
HTN, HF, k-sparing diuresis, primary hyperaldosteronism,
Off label - acne, hirsutism, PCOS
Metabolism of spironolactone
Hepatic
Active metabolites - canrenone & 7-alpha-spironolactone - half life 12-20 hours
PGP inhibitor
Adverse effects of aldosterone antagonists
Hyperkalemia
Spironolactone - broad including hepatic, renal, derm (SJS), GI, gynecomastia, menstrual irregularities, tumorigenic
Drug interaction of aldosterone antagonists
Other potassium sparing drugs
Potassium supplements
NSAID - increased renal risks
What is the “cleaner, newer” version of aldosterone antagonist?
Eplerenone
It’s a cyp3a4 inhibitor though so be careful
how do you treat cyanide toxicity d/t SNP
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
Dose of SNP
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
