Vasodilator Drugs Flashcards
nitric oxide properties, formation from, elimination, t1/2
endogenous, gas and acts as messenger
lipophilic, highly reactive and labile free radical (will not stay around for long since its so highly reactive)
formation: from L argon
elimination: oxidation to form NO(x) or nitrosylation of HGB
t1/2: a few seconds
NO MOA
acts on endothelium to vasodilate (used to be called endothelium relaxing factor or EDRF). increases cGMP which is how NO acts on smooth muscle
How is NO formed in body
formed from L arginine via NOS or NO synthase to make NO and L citrulline
nNOS
neuronal
inos
inducible (macrophage)
enos
endothelium
NO biological roles
- inhibit platelet aggregation (beneficial)
- cyto protection
- can inhibit cell adhesion to endothelium (protective)
- serves as neurotransmitter
- does have role in neuronal injury (harmful)
- inflammatory tissue injury (r/t free radical)
- vasodilators smooth muscle
- shock and hypotension
- cell proliferation
- immune cytotoxicity
NO intracellular**
acts on Ach, increase in intracellular Ca, activates eNOS–>L arginine–>NO which acts on ca channel then guanylate cyclase (which makes cGMP) to cause relaxation
Nitrovascular (NO donor) drugs
organic nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate)
sodium nitroprusside
amyl nitrite
nitric oxide gas
Na Nitroprusside MOA
No release (spontaneously) resulting in activation of guanylate cyclase in vascular smooth muscle, formation of cGMP, vascular smooth muscle relaxation and vasodilation
Organic Nitrates MOA
require metabolism to release NO (S nitrosothiol and RNO2 involvement)
Sodium Nitroprusside Structure, metabolism
1 iron, 5 cyanide, 1 NO group
spontaneous breakdown to NO and cyanide (cyanide is direct acting peripheral vasodilator)
relaxation of arterial and venous smooth muscle
metabolism: cyanide combines with sulfur groups to form thiocyanate, undergoes renal excretion. so careful in impaired renal function
Sodium Nitroprusside onset, duration, t1/2, t1/2 of the metabolite, metabolism, excretion
onset <2 minutes duration 1-10 minutes t1/2 2 minutes t1/2 thiocyanate 2-7d metabolism: renal excretion excretion: some exhaled air, feces
Sodium nitroprusside Clinical Effects: CV, Renal, CNS, blood
CV: decrease arterial/venous pressure, decrease PVR, decrease after load, slight increase in HR. no significant effects on cardiac muscle
renal: vasodilation without significant change in GFR
CNS: increased CBF and ICP
blood: NO inhibits platelet aggregation
Sodium Nitroprusside Clinical Uses
- HTN crisis: BP reduction to prevent/limit target organ damage
- controlled hypotension during surgery: during anesthesia, to reduce bleeding when indicated
- CHF: acute, decompensated
- acute MI: to improve CO in LV failure, and low CO post MI. limited use due to coronary steal, altered BF results in division of blood away from ischemic areas
Sodium Nitroprusside Adverse Effects
- profound hypotension
- cyanide toxicity: often dose/duration related, but may occur at recommended doses. tissue anoxia, venous hyperoxemia, lactic acidosis, confusion, death,
- metheglobinemia (>10% symptomatic)
- thiocyanate accumulation (increased risk with prolonged infusion, neurotoxicity, hypothyroidism)
- renal (increased creatinine)
- high ICP, GI (nausea), HA, restlessness, flushing, dizziness, palpation
methemoglobinemia reversal agent
methylene blue
Sodium Nitroprusside: Drug Interactions
hypotensive drugs (negative inotropes, general anesthetics, circulatory depressants)
- PDE5 inhibitors
- soluble guanylate cyclase stimulators
Sodium Nitroprusside Stability
unstable
light and temperature sensitive
protect from light and store at 20-25c
deterioration results in change to bluish color
wrap container with aluminum foil or other opaque material
Sodium Nitroprusside Administration and considerations
IV infusion via infusion pump
diluted in 5% dextrose
shortest infusion duration possible to avoid toxicity, if reduction in BP not obtained within 10 minutes of max infusion rate, discontinue (r/t cyanide toxicity)
solution has faint brownish tint, if discolored then discard
Organic Nitrrates
nitroglycerin (glyceryl trinitrate)
isosorbide dinitrate
isosorbide mononitrate
amyl nitrite (rarely used)
Nitroglycerin MOA
NO release through cellular metabolism via glutathione dependent pathway
requires thiols
NO released, stimulates guanylyl cyclase enzyme and forms cGMP
vascular smooth muscle relaxation and peripheral dilation
nitroglycerin primary action, other actions, routes of administration
primary action: venous capacitance vessel dilation (versus arterial)
other actions: mildly dilate arteriolar resistance vessels, dilation of large coronary arteries
administered IV, SL, translingual spray, transdermal ointment
Nitroglycerin preload and after load considerations
decreased preload, decreased MVO2 demand, modest decreased after load (related to arteriolar vessels), increased myocardial O2 supply in arteries.
Nitroglycerin CV, pulmonary, and other effects
decreased venous return, decreased end diastolic pressure, decreased CO, no change in SVR, increase in coronary BF to ischemic subendocardial areas (opposite of sodium nitroprusside).
smooth muscle relaxation in bronchi, inhibits HPV
inhibits platelet aggregation, smooth muscle relaxation to small GI tract
Nitroglycerin tolerance
after 8-10 hours, results in diminishing effectiveness. for PO and patch, have “off” period to recover metabolism enzymes
Nitroglycerin clinical uses
angina pectoris or prevention, SL (most commonly)
HTN
controlled hypotension during surgery
NSTEMI
acute MI
HF, low output syndromes (decreases preload, relieves pulmonary edema)
Nitroglycerin Adverse Effects CNS, CV, hematologic, tolerance
CNS: throbbing HA and increased ICP
CV: orthostatic hypotension, dizziness, syncope, reflex baroreceptor mediated tachycardia, flushing, vasodilation, venous pooling, decreased CO
Hematologic: methemoglobinemia (rare and more unusual than for sodium nitroprusside)
tolerance limits the use of nitrates
Nitroglycerin PK administration considerations, metabolism
large 1st pass (90%) following oral admin, give SL to avoid this. (isosorbide mononitrate and dinitrate avoid this as well)
metabolized via liver through denigrated glutathione organic nitrate reductase to glyceryl denigrate and then mononitrate. “take nitrates off by glutathione”
Which organic nitrate can be given topical or transdermal
nitroglycerin
Nitroglycerin Drug Interactions
antihypertensive drugs-additive
selective PDE5 inhibitors (adanafil, tadalafil, vardenafil, sildenafil) are an absolute contraindication. accumulation of cGMP via inhibiting breakdown
guanylate cyclase stimulating drugs (stimulates enzyme that makes cGMP
Non Nitroglycerin Isosorbide Mononitrate, Dinitrate uses, absorption, DOA, metabolism, forms, dosing, contraindications
uses: for the prophylaxis of angina pectoris. alternative uses: heart failure in AA patients in combination with hydralazine
absorption: well absorbed from GI tract
duration of action: 6 hours
metabolism: dinitrate metabolized to mononitrate form (t1/2 5 hours active metabolite), mononitrate metabolized by denigration to isosorbide to sorbitol-inactive
-regular and ER forms
need appropriate dosing intervals to allow for nitrate free periods and avoid tolerance
avoid concomitant use with PDE5 inhibitor drugs
toxicity similar to nitroglycerin
Phosphodiasterase Enzymes, role, classification
family of enzymes that break down cyclic nucleotides
- regulate intracellular levels of 2nd messengers cAMP and cGMP
- 11 major subfamilies that differ in localization and therapeutic targets
PDE inhibitors action and “older examples”
boost levels of cyclic nucleotides by preventing breakdown
older, nonselective PDE inhibitor drugs include caffeine and theophylline
PDE3 distribution, substrate it breaks down, function, clinical use of the inhibitor, drug example
distribution: broad, includes heart and vascular smooth muscle
substrate: cAMP and cGMP
function: cardiac contractility, platelet aggregation
inhibitor clinical use: inotrope (+), peripheral vasodilator, limited for acute HF
drug: amrinone, milrinone, (cilastazol for intermittent claudication)
PDE4 distribution, substrate it breaks down, function, clinical use of the inhibitor, drug example
distribution: broad, includes CV, neural, immune/inflammatory
substrate: cAMP
function: immune, inflammatory
inhibitor clinical use: COPD, decreased inflammation and remodeling
drug: roflumilast
PDE5 distribution, substrate it breaks down, function, clinical use of the inhibitor, drug example
broad, vascular smooth muscle especially erectile tissue, retina, lung
substrate: cGMP
function: vascular smooth muscle relaxation, esp erectile tissue, lung
inhibitor clinical use: ED, pHTN
drug: sildenafil, tadalafil, vardenafil
PDE5 Inhibitor MOA
nitric oxide reacts with guanylate cyclase to form cGMP which is usually broken down by PDE5
PDE3 Inhibitor MOA beta receptor example
beta receptor activation increases adenyl cyclase, cAMP. inhibiting PDE3 inhibits the breakdown of cAMP
milrinone MOA, effects, clinical uses, adverse effects, onset, t1/2, route of administration, metabolism, excretion
MOA: inhibits breakdown of cAMP
effects: increases inotropy and cardiac contractility, vasodilation, little chronotropic activity
clinical uses: acute HF, severe chronic HF, cardiogenic shock, heart transplant bridge or postop
adverse effects: arrhythmias or hypotension
onset IV: 5-15 minutes
half life 3-6h
route: IV only
metabolism: >80%
excretion: renal
role of aldosterone
increased sodium and water retention, potassium excretion. stimulated by AII
how is renin release stimulated
low blood pressure, low sodium, B1 receptor activation
what happens when AII acts on AT1 receptor
vasoconstriction, decreased renal BF and GFR, increased aldosterone secretion, remodeling
bradykinin and ACEI
ACEI inhibits breakdown of bradykinin, which is responsible for vasodilation, cough, angioedema
bradykinin t1/2, constitutive actions, inflammatory actions
endogenous peptide, t1/2 17 seconds
constitutive actions: stimulates NO and prostacyclin formation to increase vasodilation
vasodilation of heart, kidney, microvascular beds
inflammatory actions: increases cap permeability
ACEI MOA, uses, clinical effects
MOA: block conversion of AI to AII, prevent vasoconstriction, aldosterone secretion, and Na/H2O retention
used: HTN, CHF, mitral regurgitation, post MI, systolic HF, more effective in DM patients, delays progression of renal disease (diabetic neprhopathy)
clinical effects: decreases BP, PVR, preload, after load, cardiac workload. does not result in reflex tachycardia. improves/prevents LV hypertrophy, remodeling. improves HF morbidity/mortality.
ACEI metabolism, elimination, route of administration, drug interactions, duration, 2 drugs for route 1, one drug for route 2
elanapril and ramipril are prodrugs
metabolism: usually renal
route of admin: usually PO except enalaprilat (IV)
drug interactions: K sparing diuretics or K supplements
DOA: long duration of decreased BP for the most part
ACEI SE’s, CV, electrolyte, renal, inflammatory, fetal development, etc, contraindication
CV: hypotensive symptoms, syncope, first dose effect possible
electrolyte: hyperkalemia, caution with potassium sparing diuretics and potassium supplements
renal: decreased GFR, increased BUN and serum creatinine, renal dysfunction. contraindicated in bilateral renal artery stenosis
inflammatory: dry cough r/t BKN, angioedema
fetal development: teratogenic, contraindicated in pregnancy
-neutropenia, agranylocytosis (captopril), proteinuria
contraindications: renal artery stenosis
Angiotensin Receptor Antagonist (ARB) MOA, clinical effects, uses, metabolism, adverse effects, interactions, contraindication
MOA: competitive antagonist at AT1 receptor. blocks effects of angio mediated AT1 receptor. does not block breakdown of BKN, therefore do not have the cough and angioedema problem as often
clinical effects and uses: HTN, CHF, mitral regurgitation, post MI, systolic HF, more effective in DM patients, delays progression of renal disease (diabetic neprhopathy)
clinical effects: decreases BP, PVR, preload, after load, cardiac workload. does not result in reflex tachycardia. improves/prevents LV hypertrophy, remodeling. improves HF morbidity/mortality.
metabolism: liver (CYP?)
adverse effects: similar to ACEI
interactions: K sparing diuretics and K supplements
contraindication: renal artery stenosis, pregnancy
aldosterone antagonist MOA, effects, uses, metabolism, side effects, drug interactions, drug examples
MOA: competitive antagonist at mineralocorticoid receptor, blocks transcription of genes coding for Na+ channels. spironolactone off target effects include androgen, progesterone, receptor blocking
effects: increased Na, H2O excretion, mild diuresis, increased K reabsorption
uses: HTN, HF, K sparing diuresis, primary hyperaldosteronism, spironolactone off label includes acne, hirsutism, PCOS
metabolism: spironolactone: hepatic. active metabolites canrenone and 7 alpha spironolactone. p-gp inhibitor. eplerenone: CYP3A4
se: hyperkalemia. spironolactone: broad, includes hepatic, renal, serious derm problems, GI, gynecomastia, menstrual irregularities, tumorigenic in animals
drug interactions: other K sparing, K supplements, NSAID, eplerenone is a CYP3A4 inhibitor
hydralazine MOA, effects, first pass, bioavailability, t1/2, clinical uses, adverse effects, contraindication
MOA: release of NO from endothelial cells.
effects: vasodilators arterioles, minimal venous effect, decreased SVR, DBP reduced more than SBP, increased HR SV CO
extensive first pass
bioavailability about 25%
half life 1.5-3h
clinical uses: HTN (usually with BB or diuretic), HF with reduced EF
adverse effects: HA, nausea, palpitations, sweating, flushing, reflex tachycardia, tolerance, sodium and water retention, angina with EKG changes, lupus erythematous
contraindication: CAD, mitral valve RH disease
minoxidil MOA, effects, oral absorption, peak effects, t1/2, clinical uses, adverse effects, warnings
MOA: directly relaxes arteriolar smooth muscle little effect on venous capacitance. increases efflux of K from vascular smooth muscle resulting in hyper polarization and vasodilation
effects: dilates arterioles, not veins. use in hypertension (limited to later line therapy)
90% oral dose absorbed from GI tract
peak effects 2-3h
t1/2 4 hours
10% of drug recovered unchanged in urine
clinical uses: HTN, later line therapy. usually in combo with BB or diuretic
adverse effects: tachycardia, increased myocardial workload, palpitations, angina, na/fluid retention, edema, weight gain, hypertrichosis
warnings: fluid retention, pericardial effusion/tamponade, rapid BP response, sinus tachycardia, elderly
