CV Drugs III Flashcards
Nitric oxide
- endogenous gas messenger
- lipophilic, highly reactive, labile free radical
NO formation
from L-arginine with NOS (nitric oxide synthase enzyme)
NO elimination
oxidation to form either nitrate or nitrite; nitrosylation of hemoglobin
NO half-life
a few seconds
NO Protective biological roles
- NT
- immune cytotoxicity
- inhibit platelet aggregation
- cyto-protection
- vasodilator, smooth muscle relaxation
- decreased cell adhesion, proliferation
NO pathogenic biological roles
- neuronal injury (NMDA)
- cell proliferation
- shock, hypotension,
- inflammation, tissue injury
NO Donor Drugs
- Organic Nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate)
- sodium nitroprusside
- amyl nitrite
- nitric oxide gas
Sodium nitroprusside structure
complex of 1 iron, 5 cyanide, and 1 NO group
sodium nitroprusside MOA
- spontaneous breakdown to NO and cyanide
- NO release resulting in activation of guanylyl cyclase in vascular smooth muscle, formation of cGMP, VSMC relaxation and vasodilation
sodium nitroprusside PK/PD
- metabolism – cyanide combines with sulfur groups thiocyanate
- renal excretion; but some exhaled in air or excreted in feces
- onset < 2 min
- DOA 1-10 min
- half-life ~2 min
- half-life thiocyanate 2-7 days (increased with impaired renal fxn)
sodium nitroprusside administration parameters
- IV infusion via pump
- dilute in 5% dextrose
- shortest infusion possible to avoid toxicity, if reduction in BP not obtained within 10 min, d/c
sodium nitroprusside clinical uses
- HTN crisis – BP reduction to prevent/limit target organ damage
- controlled hypotension during surgery – to reduce bleeding when indicated
- CHF (acute, decompensated)
- acute MI – improve CO; limited use due to coronary steal effect
sodium nitroprusside effects
CV:
-decreased arterial/venous pressure
-decreased PVR
-decreased afterload (in HF or acute MI – CO may increase due to decreased afterload)
-slight increased HR
Renal – vasodilation without significant change in GFR
CNS – increase CBF and ICP
Blood – inhibits plt aggregation
-Stability – unstable, light and temp sensitive; protect from light and store at 20-25 C; deterioration = blue color
sodium nitroprusside adverse effects
- profound hypotension (potential for impaired organ perfusion)
- cyanide toxicity
- methemoglobinemia
- thiocyanate accumulation
- renal – transient increased serum Cr
- others – increased ICP, nausea, HA, restlessness, flushing, dizziness, palpitation
Cyanide toxicity
often dose/duration dependent, but may occur at recommended dose; tissue anoxia; venous hyperoxemia (tissues can’t extract oxygen); lactic acidosis; confusion; death
methemoglobinemia
iron becomes ferric (3+) and has reduced O2 affinity; decreased O2 to tissues; symptomatic metHb>10%; reversal = methylene blue
Thiocyanate accumulation
increased with prolonged infusion and renal impairment; neurotoxicity (tinnitus, miosis, hyperreflexia); hypothyroid d/t impaired iodine uptake
Sodium Nitroprusside drug interactions
- hypotensive drugs (negative inotropes, general anesthetics, circulatory depressants)
- PDE 5 inhibitors
- soluble guanylate cyclase stimulators
organic nitrates
- nitroglycerin
- isosorbide dinitrate
- isosorbide mononitrate
nitroglycerin MOA
- NO release through cellular metabolism – glutathione dependent pathway
- requires thiols
- NO release resulting in activation of guanylyl cyclase in vascular smooth muscle, formation of cGMP, VSMC relaxation and vasodilation
- PRIMARY ACTION – at venous capacitance vessels; venodilation –> decreased VR –> decreased RVEDP and LVEDP –> decreased MVO2
nitroglycerin PK/PD
- large first pass (90%) after oral admin
- metabolized in liver –> denitrated by glutathione-organic nitrate reductase to glyceryl dinitrate and then mononitrate
nitroglycerin administration notes
Route – IV, SL, translingual spray, transdermal ointment
-tolerance after 8-10 hours; diminishing effectiveness –> have to have an off period
nitroglycerin clinical uses
- angina – acute (sublingual) and prevention (longer acting oral, transdermal, or ointment)
- HTN – peri or postop; HTN emergencies
- controlled hypotension
- NSTEMI ACS
- acute MI (limits damage)
- HF, low output syndromes –> decreases preload and relieves pulmonary edema
nitroglycerin effects
CV:
-venous capacitance vessels – decreased preload and MVO2
-arteriolar resistance (mild) – modest decreased afterload and MVO2
-myocardial arteries – increased O2 supply
-no change in SVR
-decrease VR, and LVEDP/RVEDP
-decrease CO
-increase corrP to ischemic areas
Pulm – bronchial dilation; inhibit HPV
Other – smooth muscle relaxation in bronchi, GI tract; inhibit plt aggregation
nitroglycerin adverse effects
CNS:
-throbbing HA
-increased ICP
CV:
-orthostatic hypotension, dizziness, syncope
-reflex tachycardia (arterial barorecptors)
-flushing
-vasodilation, venous pooling, decreased CO
Heme – methemoglobinemia (rare)
Tolerance – limitation of use of nitrates
nitroglycerin cautions
volume depletion, hypotension, brady- or tachycardia, constrictive pericarditis, AS, MS, inferior wall MI, RV involvement
nitroglycerin drug interactions
- antihypertensive drugs
- selective PDE-5 inhibitor drugs
- guanylate cyclase stimulating drugs
nitroglycerin and PDE-5 inhibitors
- absolute contraindication
- will get profound potentiation
- possible life-threatening hypotension and/or hemodynamic compromise
- accumulation of cGMP by inhibiting its breakdown
isosorbide mononitrate or dinitrate PK/PD
- well absorbed orally from GI tract
- DOA 6 hrs
- dinitrate – metabolized to mononitrate (active)
- mononitrate – metabolized to isosorbide to sorbitol (inactive)
isosorbide mononitrate or dinitrate administration
- regular and extended release forms
- need nitrate-free period to prevent tolerance
isosorbide mononitrate or dinitrate clinical uses
- prophylaxis of angina
- HF in Black patients combined with hydralazine
isosorbide mononitrate or dinitrate considerations
-avoid concomitant use with PDE5 inhibitor drugs
Phosphodiesterase enzymes
- family of enzymes that breakdown cyclic nucleotides
- regulate intracellular levels of 2nd messengers (cAMP and cGMP)
- 11 subfamilies
- inhibitors - boost levels of cyclic nucleotides by preventing their breakdown
older non-selective drugs that inhibit PDE
caffeine
theophylline
PDE3
- broad distribution that includes heart and VSMC
- substrates include cAMP, cGMP
- function has to do with cardiac contractility and platelet aggregation
PDE 3 inhibitor drugs
amirone, milrinone, cilastazol
PDE 3 inhibitor clinical use #1
- positive inotrope (increase force of contraction)
- peripheral vasodilator
- limited for acute HF
- milrinone, amirone
PDE 3 inhibitor clinical use #2
- intermittent claudication
- cilastazol
PDE4
- broad distribution including CV, neural, and immune/inflammatory
- substrate includes cAMP
- immune, inflammatory function
PDE4 inhibitor clinical use/drugs
- COPD - decrease inflammation, decrease remodeling
- roflumilast
PDE5
- broad distribution in VSMC especially erectile tissue, retina, lungs
- substrate is cGMP
- causes vascular smooth muscle relaxation, especially erectile tissue and lung
PDE5 inhibitor clinical uses
- erectile dysfunction
- pulmonary hypertension
PDE5 inhibitor drugs
- sildenafil
- tadalafil
- vardenafil
milrinone class
PDE 3 inihibitor
milrinone MOA
inhibit breakdown of cAMP
milrinone PK/PD
- onset (IV) 5-15 min
- half-life ~3-6 hrs
- majority not metabolized
- renally excreted >80% unchanged
milrinone clinical uses
- acute HF or severe chronic HF
- cardiogenic shock
- heart transplant bridge or post-op
milrinone effects
- inotropic, increase cardiac contractility
- vasodilation
- little chronotropic activity
milrinone adverse effects
- arrhythmias
- hypotension
Key components of RAAS
- renin
- angiotensin I
- ACE (kinase II)
- angiotensin II
- aldosterone
Goal of RAAS
maintain tissue perfusion through increase in extracellular fluid volume
renin
- formed/secreted from JG cells
- release stimulated by decreased BP or Na+ load, beta 1 receptor activation
- protease - cleaves angiotensinogen to form ANGI
angiotensin I
inert, inactive form of ANGII
ACE (Kinase II)
- broad protease action –> forms ANGII from ANGI
- metabolism of bradykinin to inactive form
- located in membrane of EC cells
angiotensin II
- vasoconstriction (AT1 receptor)
- aldosterone secretion (AT1 receptor)
- other - increase ADH, increase proximal tubule Na reabsorption
aldosterone
- steroid formed in adrenal cortex
- regulates gene expression, increases Na+ reabsorption
- H2O retained
- K+ excreted
angiotensin II receptors
- GPCR
- subtypes are AT1R and AT2R
- current antagonist drugs block AT1R
normal functions of AT1 Receptor
- regulate BP
- regulate body fluid balance
- vasoconstriction
- inflammation
- platelet aggregation/adhesion
- reactive oxygen species
- proliferative
- hypertrophy
- fibrosis
ACE inhibitor drugs
-Captopril
-Enalapril
-Lisinopril
(ends in pril)
ACE inhibitor MOA
- decreases ANGII by preventing conversion of ANGI to ANGII
- prevent vasoconstriction
- prevent aldosterone secretion, decreasing sodium and water retention
- increases bradykinin by inhibiting the breakdown
ACE inhibitor PK/PD
- many are prodrugs
- usually renal metabolism and elimination
ACE inhibitor clinical uses
- HTN
- CHF
- mitral regurgitation
- post MI
- more effective in DM for diabetic nephropathy
- delay progression of renal disease
ACE inhibitor clinical effects
- decreased ANGII –> vasodilation, decreased remodeling, decreased aldosterone, (less Na/H2O retention, increased K+), decreased SNS output, increased natriuresis
- increased BKN –> vasodilation, cough, angioedema
- decreased BP, PVR
- decreased preload, afterload
- decreased cardiac workload
- no reflex tachycardia
- improve/prevent LV hypertrophy and remodeling
- improved morbidity/mortality in HF
- delays progression of diabetic nephropathy (improves renal hemodynamics)
ACE inhibitor adverse effects
- CV – hypotensive symptoms, syncope; 1st dose effect
- electrolyte – hyperkalemia; caution with K+ sparing diuretics or supplements
- renal – decreased GFR, increased BUN/Cr; renal dysfunction; contraindicated in bilateral renal artery stenosis
- inflammatory – dry cough (r/t BKN, reversible), angioedema (r/t BKN)
- fetal development – teratogenic; contraindicated in pregnancy bc can cause fetal anuria, RF, skull hypoplasia, death
ACE inhibitor surgical considerations
potential for prolonged hypotension, hold DOS
Captopril duration of BP lowering effects
~6 hours
Enalapril duration of BP lowering effects
12-24 hours
Lisinopril duration of BP lowering effects
24 hours
Angiotensin Receptor Blocker (ARB) Drugs
Losartan
ends in sartan
Angiotensin Receptor Blocker (ARB) MOA
- competitive antagonist at AT1 receptor
- blocks effects of ANGII mediated by AT1 receptor
- does not block breakdown of BKN, so no accumulation of BKN
Angiotensin Receptor Blocker (ARB) PK/PD
- varies
- metabolized in liver by CYP450
Angiotensin Receptor Blocker (ARB) clinical uses
uses similar to ACEi
Angiotensin Receptor Blocker (ARB) effects/considerations
- adverse effects similar to ACEi
- less incidence of cough/angioedema because no buildup of BKN
- contraindication –> renal artery stenosis, pregnancy
- more tolerable than ACEi
Differences between ACEi and ARB?
- efficacy in HTN
- ARBs slightly more tolerable, less likely to be d/c (main reason for d/c would be dry cough)
- ACEi - higher quality of data; ARBs don’t have a comparison vs placebo
Aldosterone Antagonist Drugs
Spironolactone
Eplerenone
Aldosterone Antagonist MOA
- competitive antagonist at mineralocorticoid receptor (kidney, heart, blood vessels, brain)
- prevent nuclear translocation of receptor
- block transcription of genes coding for Na+ Ch
Aldosterone Antagonist PK/PD
- Spironolactone = hepatic metabolism; active metabolites; P-gp inhibitor
- eplerenone = CYP3A4
Aldosterone Antagonist clinical uses
- HTN, HF
- K+ sparing diuresis
- primary hyperaldosteronism
- off label –> acne, hirsutism, PCOS
Aldosterone Antagonist effects
increased Na+/H2O excretion (mild diuresis); increased K+ reabsorption
Aldosterone Antagonist adverse effects
hyperkalemia; spironolactone has broad effects
Aldosterone Antagonist drug interactions
- other K+ sparing
- K+ supplements
- NSAIDs (increased renal risks)
- eplerenone - CYP3A4 inhibitors
Direct Arterial Vasodilators
- hydralazine
- minoxidil
hydralazine MOA
- release of NO from endothelial cells
- potential inhibition of calcium release from SR
hydralazine PK/PD
- extensive first pass
- bioavail ~25%
- half-life 1.5-3 hrs
hydralazine clinical uses
- HTN (in combo with beta blocker and diuretic to limit SNS effects)
- HF (reduced EF)
hydralazine effects
vasodilates arterioles, minimal venous effect, decreased SVR, DBP reduced > SBP, increased HR/SV/CO
hydralazine adverse effects
HA, nausea, palpitations, sweating, flushing, reflex tachy, tolerance/tachyphylaxis, Na/H2O retention, angina with EKG changes, lupus (reversible)
hydralazine contraindications
CAD, mitral valve RH disease
minoxidil MOA
- direct relaxation of arteriolar smooth muscle, little effect on venous capacitance
- increases efflux of K+ form VSMC resulting in hyperpolarization and vasodilation
minoxidil PK/PD
- 90% oral dose absorbed from GI tract
- peak 2-3 hrs
- half-life ~ 4 hrs
- 10% drug recovered unchanged in urine
minoxidil clinical uses
HTN (limited to later line)
minoxidil effects
vasodilation of arterioles, not veins
minoxidil adverse effects
tachycardia, increased MVO2, palpitations, angina, sodium/fluid retention, edema, weight gain, hypertrichosis
minoxidil warnings
fluid retention, pericardial effusion or tamponade, sinus tahcy, rapid BP response, elderly
