Week 3 Pharmacology Flashcards
Background of Nitric Oxide
endogenous, gas messenger
lipophilic, highly reactive and labile free radical
forms from L-arginine
elimiated by oxidation to form Nox, nitrosylation of hemoglobin
half life is a few seconds
Pathogenic Biological Roles of Nitric Oxide
Neuronal Injury (NMDA)
Cell proliferation
shock (hypotension)
inflammatory tissue injury
Protective Biological Roles of Nitric Oxide
NT Immune Cytotoxicity Inhibit Platelet agreggation Cyto-protection Vasodilator Smooth muscle relaxant Decreases cell adhesion and proliferation
Nitrovasodilator Drugs
NO- Donor organic nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate) sodium nitroprusside amyl nitrite nitric oxide gas
Mechanism of Action of Sodium Nitroprusside & Organic Nitrates
NO release resulting in activation GC in vascular smooth muscle, formation of cGMP, vascular smooth muscle relaxation and vasodilation
What do organic nitrates require to release NO
metabolism
Sodium Nitroprusside
complex of 1 iron, 5 cyanide and 1 NO group
spontaneous breakdown to NO and cynaide
Direct acting peripheral vasodilator
relaxation of arterial and venous smooth muscle
Metabolism of Sodium Nitroprusside
cyanide combines with sulfur groups to form thiocyanate undergoes renal excretion
Onset of Sodium Nitroprusside
less then 2 minutes
Duration of Sodium Nitroprusside
1-10 minutes
Half life of Nitroprusside
about 2 minutes
Half life of thiocyanate
2-7 days
Increased with impaired renal function
Excretion of Sodium Nitroprusside
renal excretion as metabolites (thiocyanate) some exhaled air, feces
Cardiovascular Clinical Effects of Sodium Nitroprusside
decrease arterial and venous pressure decreases peripheral vascular resistance decrease in afterload slight increase in HR lacks significant effects on nonvascular smooth muscle and cardiac muscle
Renal Clinical Effects of Sodium Nitroprusside
vasodilation without significant change in GFR
CNS Clinical effects of Sodium Nitroprusside
increase in CBF and intracranial pressure
Blood Clinical effects of Sodium Nitroprusside
Decreases platelet aggregation (NO)
Clinical Uses of Sodium Nitroprusside
Hypertensive Crisis
Controlled Hypotension during surgery
Congestive Heart Failure (Acute and decompensated)
Acute Myocardial MI
During surgery how does sodium nitroprusside help?
reduces bleeding when inidicated
What does SNP do during acute myocardial MI?
improves cardiac output in LV failure & low CO post MI
limited use due to coronary steal- altered BF results in diversion of blood away from ischemic areas
Adverse effects of SNP?
profound hypotension cyanide toxicity methemoglobinemia thiocyanate accumulation renal increase in intracranial pressure, GI, headache, restlessness, flushing, dizziness, palpitation
Drug interactions of SNP
negative inotropes GA Circualtory depressants Phosphodiesterase type 5 inhibitors soluble guanylate cyclase stimulators
Stability of SNP
unstable
light and temperature sensitive
protect from light and store at 20-25C
deterioration results in change to blueish color
wrap container with aluminium foil or other opaque material
Administration of SNP
IV infusion
Diluted in 5% Dextrose
shortest infusion duration possible to avoid toxicity- if not reduced within 10 mintues @ max infusion move on
solution has faint brownish tint, if discolored discard
Cyanide toxicity
often dose/duration related tissue anoxia venous hyperoxemia (tissue cannot extract O2) lactic acidosis confusion death
Thiocyanate accumulation
increase risk with prolonged infusion; renal impairment
neurotoxicity, including… tinnitus, miosis, hyperreflexia
hypothyroidism (d/t impaired iodine uptake)
Organic Nitrates
Nitroglycerin (glyceryl trinitrate)
isosorbide dinitrate
isosorbide mononitrate
amyl nitrite (not used)
MOA of Nitroglycerin
No release through cellular metabolism (Glutathione-depedent pathway)
requires thiols
NO released, stimulates GC and formation of cGMP
vascular smooth msucle relaxation and peripheral vasodilation
Actions of Nitroglycerin
venous capacitance vessles
mildly dilate arteriolar resistance vessels
dilation of large coronary arteries
administered IV SL translingual spray transdermal ointment
Major Effects of Nitroglycerin
dilation of venous capacitance vessels that decreases preloand and MVO2 demand
arteriolar resistance vessels (mild) causes small decrease in afterload, decrease MVO2 demand
Myocardial arteries (increases MVO2 supply)
Cardiovascular application of nitroglycerin
decreases venous return, decrease L and R ventricular end diastolic pressure
decreases CO
no change in SVR
increase in coronary BF to ischemic subendocardial areas (opposite SNP)
Other applications of Nitroglycerin
smooth muscle relaxation in bronchi, GI tract- small
inhibits platelet aggregation
Pulmonary application of Nitroglycerin
bronchial dilation
inhibits HPV
Tolerance of Nitroglycerin
after 8-10 hours, results in diminishing effects
Cautions of Nitroglycerin
volume depletion, hypotension, bradycardia or tachycardia, constrictive pericarditis, aortic/mitral stenosis, inferior wall MI and RT ventricular involvement
Clinical Uses of Nitroglycerin
angina hypertension (peri-op, HTN emergencies, post operative HTN) controlled hypotension during surgery Non-ST segment elevation ACD Acute MI HF, Low output syndromes
Why use nitroglycerin in Low Output Syndromes
decreases preload, relieves pulmonary edema
Adverse Effects of Nitroglycerin
throbbing headache, increased ICP, orthostatic hypotension, dizziness, syncope, reflex tachycardia, flushing, vasodilation, venous pooling, decreased CO, methemoglobinemia, limitation of the use of nitrates
Pharmacokinetics of Nitroglycerin
large first pass following oral administration
metabolized in the liver
Duration of IV Nitroglycerin
3-5 minutes
Onset of sublingual Nitroglycerin
1-3 minutes
Duration of sublingual Nitroglycerin
> 25 minutes
Onset of topical Nitroglycerin
15-30 minutes
Duration of topical Nitroglycerin
7 hours
Onset of transdermal Nitroglycerin
about 30 minutes
Duration of Nitroglycerin
10-12 hours
Onset of Oral Isosorbide Dinitrate
about 60 minutes
Duration of Oral Isosorbide Dinitrate
up to 8 hours
Onset of Oral Isosorbide mononitrate (reg + extended)
30-45 minutes
Duration of Oral Isosorbide Mononitrate
greater then 6 hours
Duration of Extended release Oral Isosorbide mononitrate
12 to 24 hours
Drug Interactions with Nitroglycerinn
antihypertensive drugs (additive effects) selective PDE5 inihibitor drugs guanylate cyclase stimulating drugs
Phosphodiesterase Enzymes
family of enzymes that breakdown cyclic nucleotides
regulate intracellular levels of 2nd messanger cAMP and cGMP
11 major subfamilies that differ in localization, potential therapeutic targets
Inhibitors
boost levels of cyclic nucleotides by preventing breakdown
Older non-selective drugs that INHIBIT PDE
caffeine, theophylline
Body Distribution of PDE3
broad includes heart and vascular smooth muscle
Body Distribution of PDE4
broad includes CV, neural, immune/inflammatory
Body Distribution of PDE5
broad
vascular smooth muscle, especially erectile tissue, retina, lung
Substrate of PDE3
cAMP
cGMP
Substrate of PDE4
cAMP
Substrate of PDE5
cGMP
Function of PDE3
cardiac contractility
platelet aggregation
Function of PDE4
Immune, inflammatory
Function of PDE5
vascular smooth muscle relax (erectile tissue, lung)
Inhibitor Clinical Use of PDE3 (milrinone, amrinone)
intotrope, peripheral vasodilator
limited for acute HF
Inhibitor Clinical Use of PDE3 (cilastazol)
intermittent claudication
helps with exercise
Inhibitor Clinical Use of PDE4
roflumilast
COPD- decreases inflammation, decreases remodeling
inhibitor of clinical Use of PDE5
Sildenafil
tadalafil
vardenafil
erectile dysfunction, pulmonary hypertension
MOA of Milrnone
inhibits breakdown of cAMP
Effects of Milrnone
inotropic increases cardiac contractility
vasodilation
little chronotropic activity
Clinical uses of Milrnone
acute heart failure or severe chronic HF
cardiogenic shock
heart transplant bridge or post-op
Adverse effects of Milrnone
arrhythmias
hypotension
PK of Milrnone (Onset, 1/2 life, administration, metabolism)
5-15 minutes
3-6hours
parental only
majority not metabolized > 80% excreted renally unchanged
Angiotensin 2
stimualtion of aldosterone secretion
constriction of Vascular smooth muscle
Aldosterone
increased water and sodium retention
Renin
secreted by JG apparatus
vasoconstriction and sodium retention
formed/secreted from JG cells
release stimulated decrease BP or Na, B1 receptor activation
goal of renin
maintain tissue perfusion through increase extracellular fluid volume
RAAS is synergistic with
SNS by increasing the release of NE from SN terminals
Renin activates what to cleave angiotensinogen to angiotensin 1
protease
ACE
broad protease action forms ang2 from ang1
metabolism of BKN to inactive form
located in membrane of EC cells
Angiotensin 2
vasoconstriction (AT1 receptor) aldosterone secretion (AT1 receptors) increase ADH, increase proximal tubule Na resorbption
Aldosterone
steroid, adrenal cortex
regulates gene expression, increase Na reabsorption
H20 retained, K excreted
ATI1 Receptor
regulation of blood pressure regulation of body fluid balance vasoconstriction inflammation platelet aggregation/adhesion reactive oxygen species production proliferation hypertropy fibrosis
B1 adrenegric receptor antagonist (metoprolol)
antagonize sympathetic stimulation of beta 1 receptor JGC
Bradykinin
endogenous substance 1/2 life is 17 seconds stimulates NO and prostacyclin formation vasodilation (heart, kidney, microvascular beds) increases capillary permeability
ACE inhibitor Drug list
captopril benazepril enalapril fosinopril lisinopril moexipril perindopril quinapril ramipril trandorapril
MOA of ACE inhibitors
block conversion of angiotensin 1 to angiotensin 2
prevent vasoconstriction
prevent aldosterone secretion, decrease sodium and water retention
First line therapy of ACE Inhibitors
HTN, CHF, Mitral regurgitation
ACE inhibitors are
more effective in DM patients
delay progression of renal disease
Clinical Effects of ACE Inhibitors
decrease BP, peripheral vascular resistance
decrease preload, afterload
decrease cardiac workload
do not result in reflex tachycardia
improves/presents LV hypertropy, remodeling
improves morbidity/mortality HF
diabetic nephropathy-delays progression (improves renal hemodynamics)
Common clinical uses for ACE inhibitors
HTN post MI Systolic HF diabetic nephropathy
Drug interactions of ACE inhibitors
K sparing diuretcis
K supplements
Cardiovascular AE’s of ACE Inhibitors
hypotensive symptoms (syncope) 1st dose effect
Electrolyte AE’s of ACE Inhibitors
increase K
Renal AE’s of ACE Inhibitors
decrease GFR adn increase BUN and serum Cr, renal dysfunction
contraindicated in bilateral renal artery stenosis
inflammatory AE’s of ACE Inhibitors
vasodilation
cough
angioedema
Fetal Development AE’s of ACE Inhibitors
contraindicated
fetal malformations- teratogenic
Mnemonic for AE’s of ACE Inhibitors
CAPTOPRIL cough/ c1 esterase deficiency angioedema/agranulocytosis proteinuria/potassium excess taste change orthrostatic hypotension pregnancy contraindication renal artery stenosis contraindications increases renin leuopenia/liver toxicity
Angiotensin receptor blockers
azilsartan candesartan eprosartan irbesartan losartan olmesartan telmisartan valsartan
MOA of Angiotensin Receptor Blockers
competitive antagonist @ AT1 receptor
blocks effects of Ang 2 mediated by AT1 receptor
does not block breakdown of BKN
PK of ARbs
metabolism CYP2C9- losartan, irbesartan
Drug INteractions with ARBs
K sparing diuretics
K supplements
Contraindications of ARBS
renal artery stenosis
pregnancy
ARBs vs ACEis
no difference in HTN, total mortality, CV morbidity, mortality
ARBs slightly more tolerable d/t less cough
Higher quality data in ACEi
Aldosterone Antagonist
spironolactone
eplernone
Mechanism of action for Aldosterone Antagonist
competitive antagonist at mineralocorticoid rec
prevent nuclear translocation of receptor
blocks transcription of genes coding for Na channels
MOA of spirolactone
off target effects include androgen, progesterone receptor blocking
Effects of Aldosterone Antagonist
increase Na, H20 excretion, mild diuresis
increase K reabsorption
Uses of Aldosterone Antagonist
HTN, HF
K sparing hyperaldosterism
PK of Spirolactone
hepatic
active metabolites
Pk of eplernone
CYP3A4
AE of Aldosterone Antagonist
hyperkalemia
AE of Spirolactone
hepatic, renal, serious derm (SJ, TEN) GI gynecomastia, menstral irregularities
Drug interactions of Aldosterone Antagonist
other K sparing drugs (ACEi, ARBs)
K supplements
NSAID increase renal risk
MOA of hydralazine
release NO from endothelial cells
inhibition of calcium release from SR?
Effects of hydralazine
vasodilates arterioles minimal venous effect decreased SVR DBP reduced > SBP increase HR, stroke volume, cardiac output
PK of hydralazine
extensive first pass
bioavailability ~25%
half life 1.5-3hours
Clinical Uses of hydralazine
HTN- used with BB and diuretic
HF- reduced EF
AE of hydralazine
headache, nausea, palpitations, sweating, flushing, reflex tachycardia tolerance,
sodium/h20 retention
angina wiht EKG changes
lupus erythematosus (reversible)
Contraindications of hydralazine
CAD, mitral valve RH disease
MOA of Minoxidil
directly relaxes the arteriolar smooth muscle, no venous effect
increases the efflux of potassium from vascular smooth muscle resulting in hyperpolarization and vasodilation
Effects of Minoxidil
dilates arterioles, not veins
used in hypertension
PK of Minoxidil
90% oral dose absorbed from GI tract
peak effect 2-3 hours
half life- 4 hours
10% of drug recovered unchanged in urine
Clinical uses of Minoxidil
HTN
Adverse effects of Minoxidil
tachycardia, increase MVO2, palpitations, angina, sodium fluid retention edema
weight gain
hypertrichosis
Warnings of Minoxidil
fluid retention pericardial effusion/tamponade rapid BP response sinus tachycardia elderly
