HTN/Dilators (Cardiovascular Part III) Flashcards
Nitric Oxide pharmacokinetics/background
endogenous, gas messenger lipophilic, highly reactive formed from L-arginine 1/2 life - few seconds elimination - oxidation to form NOx, nitrosylation of hemoglobin
3 types of Nitric Oxide Synthase enzymes
nNOS - neuronal, iNOS- induceable (macrophage), eNOS (endothelium)
Protective biological roles of Nitric Oxide
neurotransmitter, immune cytotoxicity, inhibit platelet aggregation, cytoprotection, vasodilator smooth muscle relaxant, decrease cell adhesion, proliferation
Pathogenic biological roles of Nitric Oxide
inflammatory tissue injury, shock, hypotension, cell proliferation, neuronal injury
Nitric Oxide mediated vasodilation MOA
ACh stimulates formation of NO by increasing Ca++ influx and activating NOS, that converts L-arginine to NO that will go to the VSMC and increase cGMP causing relaxation/vasodilation of the smooth muscle
What are the organic nitrates?
nitroglycerin
isosorbide dinitrate
isosorbide mononitrate
mechanism of action of sodium nitroprusside
release NO spontaneously which increases cGMP and leads to vascular smooth muscle relaxation and dilation
mechanism of action of organic nitrates
go through metabolism to release NO, need thiols to convert to NO which will then increase cGMP and cause relaxation and dilation of VSMC
metabolism of sodium nitroprusside
spontaneous breakdown to NO and cyanide, the cyanide combines with sulfur groups to form thiocyanate and undergoes renal excretion
if builds up or have impaired renal function = cyanide toxicity
sodium nitroprusside pharmacokinetics
onset <2 mins
duration 1-10mins
half life 2 mins but half life of thiocyanate about 2-7 days
renal excretion but some as exhaled air or feces
sodium nitroprusside effects on cardiovascular
decrease arterial/venous pressure, decrease PVR, decrease afterload, slight increase in HR
sodium nitroprusside effects on renal, cns, and blood
renal: vasodilation w/o significant change in GFR
CNS: increase cerebral blood flow and intracranial pressure
blood: inhibits platelet aggregation
sodium nitroprusside uses
hypertensive crisis, controlled hypotension during surgery, congestive HF, acute MI
why does sodium nitroprusside have a limited use in acute MI treatment?
d/t coronary steal which alters blood flow resulting in diversion of blood away from the ischemic areas
sodium nitroprusside adverse effects
profound hypotension, cyanide toxicity, methemoglobinemia, thiocyanate accumulation, increased serum creatinine, HA, increased intracranial pressure, restlessness, flushing, dizziness, palpitation, nausea
s/s of cyanide toxicity
tissue anoxia, venous hyperoxemia, lactic acidosis, confusion, death
explain methemoglobinemia
some iron in hemoglobin is oxidized to ferric state with impaired oxygen affinity so there is a reduced o2 delivery to the tissues
what do we use to reverse methemoglobinemia?
methylene blue
what are drug interactions with sodium nitroprusside?
negative inotropes, general anesthetics, circulatory depressants, PDE-5 inhibitors (sildenafil), soluble guanylate cyclase stimulators (riociguat)
pearls about sodium nitroprusside
light and temperature sensitive (store at 20-25 degrees C, wrap aluminum around container)
deterioration = bluish color (normally brown tint)
diluted in D5%
primary action of nitroglycerin
venous capacitance vessel dilation (decreased preload, myocardial o2 demand)
mildly dilates arteriolar resistance vessels (modest decreased afterload)
large coronary artery dilation (increased supply)
nitroglycerin cardiovascular and pulmonary effects
decrease VR, decrease LVEDP/RVEDP, decrease CO, increase coronary blood flow to ischemic areas, bronchial dilation, inhibits HPV
what is something we need to be mindful of with nitroglycerin?
can build tolerance, after about 8 hours = diminishing effectiveness
clinical uses of nitroglycerin
angina (acute and prevention), hypertension, controlled hypotension during surgery, ACS, acute MI, heart failure
nitroglycerin adverse effects
throbbing HA, increased ICP, orthostatic hypotension, dizziness, syncope, reflex tachycardia, flushing, vasodilation, venous pooling, decreased CO, methemoglobinemia (rare)
nitroglycerin pharmacokinetics
large first pass effect after oral admin
metabolized in the liver
IV - immediate onset, 3-5 min duration
Spray or Sublingual - 1-3min onset, >25min duration
Oral ER- 60 min onset, 4-8hr duration
Topical - 15-30min onset, 7 hour duration
Transdermal- 30 min onset, 10-12hr duration
drug interactions with nitroglycerin
antihypertensives (additive effect), PDE-5 inhibitors (ABSOLUTE CONTRAINDICATION- profound potentiation/hypotension), guanylate cyclase stimulating drugs
what are isosorbide mononitrate and dinitrate used for?
prophylaxis angina pectoris, heart failure in Black patients in combo w/ hydralazine
what do phosphodiesterase enzymes do?
regulate intracellular levels of 2nd messengers cAMP and cGMP
what do PDE 5 Inhibitors do? (MOA)
blocks cGMP from breaking down to inactive GMP so it increases cGMP which leads to vasodilation/relaxation
MOA of PDE 3 inhibitors?
increase cAMP by preventing cAMP converting to AMP
Milrinone (PDE 3 inhibitor) pharmacokinetics and adverse effects
onset 5-15mins
half life 3-6 hours
majority not metabolized, >80% excreted renally unchanged
adverse effects: arrhythmias, hypotension
Milrinone effects and clinical uses
increase contractility, vasodilation, little chronotropic activity
clinical uses: acute HF or severe chronic HF, cardiogenic shock, heart transplant bridge or post op
Describe the renin angiotensin aldosterone system :-)
decreased BP is sensed and renin is released where it meets up with angiotensinogen and converts it to angiotensin I where that is converted into angiotensin II by angiotensin converting enzyme, angiotensin II will increase blood pressure and stimulate aldosterone release which will cause salt and water retention to also increase blood pressure
If you block aldosterone what electrolyte abnormality would we be concerned about?
potassium
What are AT1 receptors?
GPCRs/ang II receptors
lead to vasoconstriction, decrease renal blood flow and GFR, increase aldosterone, remodeling
What drugs can inhibit the RAAS?
renin inhibitors, beta-1 adrenergic antagonists, angII antagonists (ARBs), ACE inhibitors, aldosterone antagonists
how do ACE inhibitors work in terms of angiotensin?
block conversion of angI to angII (so decreased angII)
leading to vasodilation, decreased remodeling, decreased aldosterone, decreased sympathetic output, and increased natiuresis
Another mechanism of ACE inhibitors
blocks bradykinin from breaking down (increased bradykinin)
can lead to vasodilation, cough, angioedema
Bradykinin
endogenous peptide
1/2 life: 17 sec
stimulates NO and prostacyclin formation, vasodilation and increased capillary permeability
What are ACE inhibitors first line therapy for ?
HTN, CHF, mitral regurgitation, more effective in patients with diabetes and delay progression of renal disease
clinical effects of ACE inhibitors
decrease BP, PVR, preload, afterload, workload, improves/prevents hypertrophy
*does not result in reflex tachycardia
ACE inhibitors pharmacokinetics
many are prodrugs and usually renally eliminated, usually used in combo with diuretics, interacts with K+ sparing diuretics and supplements, longer duration of action
what do we worry about with ACE inhibitors? and common adverse effects
hypotension! (long duration of action)
hyperkalemia, renal dysfunction, dry cough, angioedema, fetal malformations
why are ACE inhibitors contraindicated in patients with renal artery stenosis?
may develop renal failure d/t efferent arteriole vasoconstriction
angiotensin blockers (ARBs) MOA
competitive antagonist at AT1 receptors, blocks effects of angII , does not block the breakdown of bradykinin
similar uses as ace inhibitors
angiotensin blockers pharmacokinetics
avoid in sever renal and hepatic dysfunction, highly protein bound, some metabolized through CYP system
Spironolactone (aldosterone antagonist) MOA and uses
competitive antagonist at mineralocorticoid receptors and prevent nuclear translocation and blocks transcription of genes coding for Na+ channels
increase Na and H2O excretion, diuresis, increase K+ reabsorption (HTN, HF, K+ sparing diuresis, hyperaldosteronism, acne, hirsutiusm)
hydralazine (direct vasodilator) MOA, effects and uses
release of NO and inhibit Ca++ release from SR
vasodilates arterioles, minimal venous effect
decreased SVR and DBP, increase HR, SV, CO
used in HTN and HF
hydralazine pharmacokinetics and adverse effects
extensive first pass, half life 1.5-3 hrs
A/E: HA, nausea, palpitations, sweating, flushing, reflex tachycardia, Na+ and H2O retention, angina
dont give in CAD and mitral valve disease
Why is hydralazine given with a beta blocker and/or diuretic
because it can cause reflex tachycardia (beta blocker will prevent that) and Na+ and H2O retention (which the diuretic will prevent)
minoxidil (direct vasodilator) MOA, effects, uses
directly relaxes the arteriolar smooth muscle, little effect on venous, increases efflux of K+ = hyperpolarization and vasodilation
dilates arterioles not veins
use in HTN usually in combo with diuretic and beta blocker
minoxidil pharmacokinetics and adverse effects
peak 2-3 hours, half life 4 hours
A/E: tachycardia, increased workload, palpitations, angina, Na/H2O retention, edema, weight gain, hypertrichosis
drugs commonly used for controlled hypotension
sodium nitroprusside (0.3-0.5 mcg/kg/min; dont exceed 2)
nitroglycerin (125-500 mcg/kg/min)
nicardipine (5 mcg/kg/min)
dexmeditomidine (0.2-0.7 mcg/kg/hr)
