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Therapeutics Exam 2 Kwon
Therapeutics Exam 2 Kwon
96
Pharmacology
Graduate
08/20/2010

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Term
chronic coronary artery disease (stable angina is the prototypical manifestation)
acute coronary symptoms (constitute a series, not necessarily a linear progression, or clinical presentations including unstable angina, non-ST elevated myocardial infarction, and ST elevated myocardial infarction
[image]
1) normal 2) ST depressed 3) ST elevated
Definition
ischemic heart disease can be divided into two broad categories:
Term
stable angina
Definition
atherosclerotic plaque and inappropriate vasoconstriction (caused by endothelial damage) reduce the vessel lumen diameter, and hence decrease coronary blood flow
When resting, the blood supply is fine. When exercising the heart needs more oxygen and this cannot be supplied.
Term
unstable angina
Definition
Rupture of the plaque triggers platelet aggregation, thrombus formation, and vasoconstriction.
Depending on the anatomical site of the plaque rupture, this process can progress to non-Q wave (non-ST elevated) or Q wave (ST elevated) MI.
O2 imbalance can happen anytime, even when the person is resting.
Term
variant angina
Definition
artherosclerotic plaques are absent and ischemia is caused by intense vasospasm
Term
stents
angioplasty
bypass surgery
Definition
mechanical interventions that increase O2 supply
Term
amyl nitrite
nitroglycerin
isosorbide dinitrate
Definition
organic nitrates and nitrites
antianginal drugs
Term
Organic nitrates react with tissue thiols (L-Arg) to generate NO (via NO synthase). NO diffuses into vascular smooth muscle cells and activates guanylate cyclase. This converts GTP to cGMP. cGMP stimulates protein kinase that decrease Ca influx and increases Ca storage in SR. This leads to relaxation of the muscle
Definition
mechanism of action of NO muscle relaxation
Term
dilation of venous capacitance vessels, reduced venous return, lower ventricular filling pressure (preload), decreases ventricular wall tension, reduces myocardial O2 demand
arterial dilation, reduced resistance to ventricular emptying (afterload), decrease cardiac work, reduced myocardial O2 demand
blood flow through collateral vessels improved, increased blood supply to ischemic areas of myocardium
Definition
mechanism of action of organic nitrites and nitrates
Term
due to excessive vasodilation: headache, hypotension, dizziness, reflex tachycardia
Definition
adverse effects of organic nitrites and nitrates
Term
phosphodiesterase 5 (PDE5) inhibitors: sildenafil
in the presence of a PDE5 inhibitor, nitrates cause profound increases in cGMP and can cause dramatic reduction in blood pressure
Definition
organic nitrites and nitrates drug interactions
Term
tolerance develops rapidly if there is a sustained high plasma nitrate concentration
possible mechanisms include reduced capacity of the smooth muscle to convert nitroglycerin to NO, depletion of vascular thiol groups, reflex activation of sympathetic nervous system, and superoxide generation
to prevent nitrate tolerance, skin patch should be removed for at least 12-14 hours each day
Definition
mechanism of tolerance to organic nitrites and nitrates
Term
[image]
Definition
Where to DHP CCB, diliazem and verapamil bind to L type Ca channels? Intracellularly or extracellularly?
Term
arterial dilation; reduced resistance to ventricular emptying (afterload), decreased cardiac work, reduced myocardial O2 demand (requires higher concentrations), little effect on most venous beds
actions in cardiac cells; verapamil and diltiazem depress the rate of SA node pacemaker and AV node conduction (delay the recovery of the channel)
increase coronary blood flow; nifedipine, diltiazem, verapamil
Definition
mechanism of action of Ca channel blockers
Term
dihydropyridines: headache, dizziness, flushing, nausea, hypotension
nifedipine (immediate-releasing formula): worsening of angina due to coronary steal and/or reflex tachycardia (drop BP so rapidly, causes increased sympathetic output and leads to tachycardia)
verapamil and diltiazem: bradycardia, transient asystole (flatline)
Definition
adverse effects of Ca channel blockers
Term
verapamil and a B blocker can cause AV block and/or severe depression of ventricular function
the use of verapamil to treat digitalis toxicity is contraindicated; AV nodal conduction disturbances may be exacerbated
Definition
Ca Channel Blocker drug interactions
Term
ranolazine
Definition
antianginal drugs
fatty acid oxidation inhibitor
Term
thought to block the transcellular late Na current
by altering the intracellular Na level, ranolazine blocks Na-dependent Ca channels, thus preventing the Ca overload
does not significantly alter heart rate or blood pressure
used in combination with other antianginal drugs
decrease anginal episodes and increase exercise tolerance
Definition
mechanism of action of fatty acid oxidation inhibitor
Term
known to increase the QT interval on the EKG
dizziness
headache
constipation
nausea/vomiting
Definition
adverse effects of fatty acid oxidation inhibitor
Term
CYP3A inhibitors: diltiazem, verapamil, grapefruit juice
inhibitors of p-glycoprotein: amiodarone, clarithromycin, cyclosporin
risk of additive QT prolongation: quinidine (class 1a), dofetilide, sotalol, amiodarone (class III)
Definition
fatty acid oxidation inhibitor drug interactions
Term
systolic heart failure
Definition
left ventricular contractile dysfunction
Term
coronary artery disease (70%)
systemic arterial hypertension (pressure loading)
valvular heart disease (valvular loading from mitral regurgitation, or aortic regurgitation, pressure loading from aortic stenosis)
extrinsic cardiomyopathy (diabetes, alcoholism)
intrinsic cardiomyopathy
Definition
causes of systolic heart failure
Term
diastolic heart failure
impaired relaxation -> increased LV diastolic pressure -> increased left atrial and pulmonary capillary pressure -> fluid overload in the lungs
Definition
abnormalities of left ventricular relaxation and/or filling
causes: acute myocardial ischemia
Term
peripheral edema
Definition
impaired relaxation of the right ventricle leads to...
Term
upward
Definition
treatment of heart failure with a positive inotrope, such as a digitalis, shifts the Frank-Startling curve ( ), and cardiac output increases.
Term
concentric hypertrophy
Definition
aortic stenosis
systemic hypertension
chronic pressure overload
new sarcomeres are added in parallel to the existing myofilaments
increase wall thickness
decrease cavity size
Term
eccentric hypertrophy
Definition
mitral or aortic regurgitation
chronic volume overload
new sarcomeres are added in series to the existing myofilaments
wall thickness increases in proportion to cavity size
Term
digoxin
Definition
drugs for heart failure
positive inotropic drugs
digitalis glycosides
Term
inhibits Na/K/ATPase
Na concentration inside cell increases
Ca influx increases
contractility increases
[image]
indirectly increase parasympathetic tone, decrease HR, decrease conduction velocity
digoxin is unique in its ability to strengthen cardiac contraction while decreasing HR
Definition
mechanism of action of digitalis glycosides
Term
consequences of intracellular Ca overload: increased automaticity, tachycardia, ventricular ectopic beats
consequences of increased vagal activity: atrial tachycardia (due to increased automaticity) with 2:1 AV block
GI disturbances: anorexia, nausea, vomiting, diarrhea
neuronal disturbances: fatigue, confusion, vertigo, color vision
gynecomastia: breast enlargement (estrogenic activity)
Definition
adverse effects of digitalis glycosides
Term
1) PR
2) QT
Digoxin also causes ST segment depression, which gives rise to the hockey stick configuration.
[image]
Toxic concentrations of digoxin may cause afterdepolarizations throughout the heart and thereby cause extra systoles and tachycardia.
Definition
Digoxin causes increased parasympathetic tone and decreased sympathetic tone.
Heart rate is slowed by decreasing SA node automaticity.
AV node conduction velocity is slowed, this increases the ( ) interval on an EKG.
AV node refractory period is increased.
In ventricular tissue, digoxin shortens the action potential duration and this decreases the ( ) interval.
Term
antacids and cholestyramine; reduce the absorption of digoxin
diltiazem, quinidine, verapamil; reduce digoxin clearance, can cause digitalis toxicity
diuretics; hypokalemia can precipitate digitalis toxicity (hypokalemia increases digoxin binding to the sodium pump)
Definition
drug interactions of digitalis glycosides
Term
digoxin immune fab
Definition
antidote for serious digoxin toxicity
Term
dobutamine
isoproterenol
Definition
drugs for heart failure
positively inotropic drugs
adrenergic B-receptor agonists
Term
bind to B-adrenoceptor (GPCR)
activate AC
ATP -> cAMP
cAMP activates protein kinase
increased influx of Ca across cell membrane, increased affinity for myofilaments for Ca -> positive inotropy
increased reuptake of Ca into SR -> shortens systole, aids relaxation in diastole
Definition
mechanism of action of B agonists
Term
drug for HF
positively inotropic
a synthetic dopamine analogue
racemic mixture (a agonist activity by one isoform is cancelled out by another isoform)
has B1-adrenergic agonist effect
Definition
mechanism of action of dobutamine
Term
drug for HF
positively inotropic
non selective B-adrenergic agonist
increases both myocardial contractility (B1) and heart rate (B1)
produces peripheral arterial vasodilation (B2)
Definition
mechanism of action of isoproterenol
Term
predicted from agonist activity at adrenoceptors
excessive cardiac stimulation; tachycardia, palpitations, arrhythmias
Definition
adverse effects of B agonists
Term
dopamine
Definition
drugs for HF
positively inotropic drug
Term
positively inotropic
at low doses: causes vasodilation by stimulating dopaminergic receptors on smooth muscle and stimulating presynaptic D2 receptors (decrease NE release)
at intermediate doses: stimulates B1 receptors in the heart
at high doses: stimulates a1 receptors
Definition
mechanism of action of dopamine
Term
milrinone
enoximone
Definition
drugs for HF
positively inotropic drugs
phosphodiesterase inhibitors
Term
inhibit type III phosphodiesterase (convert cAMP to 5'-AMP)
increase the concentration of cAMP in cardiac tissue and smooth muscle
increase cardiac contractility and relax vascular smooth muscle
desensitization does not occur (doesn't touch a receptor)
additive effects with B agonists
Definition
mechanism of action of phosphodiesterase inhibitors
Term
tachycardia
palpitations
potentially serious arrhythmias
Definition
adverse effects of phosphodiesterase inhibitors
Term
ACEi
Definition
cause venous and arterial dilation
decrease secretion of aldosterone and ADH
reduce plasma volume, venous pressure, and level of edema
increase cardiac output by reducing arterial pressure and cardiac afterload
counteract the adverse effects of angiotensin II on cardiac (ventricular) remodeling in patients with heart failure
Term
ARB
Definition
selectively reduce the binding of angiotensin II to AT1 receptors
have pharmacological and clinical effects that are similar to that of ACEi
do no produce chronic cough
appear to be as effective as ACEi in treating HF
Term
isosorbide dinitrate
hydralazine
Definition
( ) primarily relaxes venous smooth muscle, whereas ( ) preferentially relaxes arterial smooth muscle
the combined use of these two drugs reduces cardiac preload and afterload, leading to reduced venous pressure and edema and to increased cardiac output, respectively
this drug combination reduces mortality more than placebo but less than enalapril
combination is sometimes used to treat patients with HF who cannot tolerate an ACEi
Term
spironolactone and eplerenone
HF causes increased sympathetic output and can stimulate the renin-angiotensin-aldosterone axis. these drugs can decrease some of this sympathetic activity
Definition
compete with aldosterone for the mineralocorticoid receptor in renal tubules and other tissues
increase Na excretion, decrease K excretion, and exert a moderate diuretic effect
prevent the adverse effects of excessive aldosterone levels
additive effects with ACEi and B blockers
Term
B-adrenergic receptor antagonists such as carvedilol
Definition
used to be contraindicated in HF because of the negative inotropic effect
emerged as one of the newer therapies for HF
the benefits of therapy are caused by the ability of these drugs to reduce excessive sympathetic stimulation of the heart and circulation in patients with HF
several clinical trials have shown that these drugs benefit patients with mild to moderate HF caused by left ventricular systolic dysfunction
Term

furosemide and thiazides

loop diruetics have more natriuretic activity than other types of diuretics

thiazide diuretics can be used when a lesser degree of diuresis is required in the treatment of HF

Definition

used to reduce plasma volume and edema

must be used carefully to avoid excessive diuresis, dehydration, and electrolyte imbalances

hypokalemia predisposes patients to digoxin toxicity and patients with HF should be closely monitored for this condition

Term
nesiritid, BNP
Definition
drugs for HF
natriuretic peptide
Term
1) atrial natriuretic peptide (ANP)
2) brain natriuretic peptide (BNP)
2) C-type natriuretic peptide (CNP)
Definition
1) released from the atria
2) released from brain and cardiac ventricles; plasma level goes up in patients with HF
3) released from vascular endothelial cells; no effect on natriuresis
Term
drug for HF
mimics the action of natriuretic peptide
arterial and venous dilation
increases CO and stroke volume without increasing HR
cause natriuresis and diuresis
binds to NP receptors, increases intracellular levels of cGMP, and causes smooth muscle relaxation
no effect on cardiac contractility or cardiac electrophysiology
Definition
mechanism of action of nesiritide
Term
hypotension
ventricular tachycardia
headache
nausea
Definition
adverse effects of nesiritide
Term
hyperlipidemia
Definition
major cause of atherosclerosis and atherosclerosis-associated conditions including: coronary artery disease, ischemic cerebrovascular disease, peripheral vascular disease.
Term
cholesterol
Definition
a vital structural component of cell membranes
a precursor of steroids, bile salts, and steroid hormones
mainly synthesized in the liver
also obtained in the diet
its synthesis in the liver involves HMG-CoA reductase
Term
triglycerides
Definition

the major dietary fat

composed of three fatty acids and glycerol

main storage form of fuel

fatty acids are released in periods of reduced calorie intake

fatty acids provide energy for muscle contraction and metabolic reactions

Term
emulsification of fat by bile salts -> breakdown of triglyceride by lipase into monoglyceride and fatty acids -> formation of micelle which is composed of bile salts, monoglycerides, fatty acids, phospholipids, and cholesterol -> absorption into enterocyte -> lymphatic capillaries, thoracic duct, subclavian veins, superior vena cava
Definition
absorption of lipids
Term
glucose and amino acids are absorbed from the small intestine and transported to the liver via hepatic portal vein
many drugs are also taken to the liver via hepatic portal vein and detoxified (first pass metabolism)
Definition
absorption of glucose, amino acids, and some drug molecules
Term
core: cholsteryl esters and some triacylglycerols
monolayer of phopholipid and cholesterol
apoprotein
[image]
Definition
structure of lipoproteins
Term
chylomicrons
very low density lipoprotein (VLDL)
intermediate density lipoprotein (IDL)
low density lipoprotein (LDL)
high density lipoprotein (HDL)
Definition
5 types of lipoproteins (from largest to smallest)
Term
core lipids: dietary triglycerides and cholesteryl esters (10:1)
apoproteins: B-48, C, E, and A
Definition
composition of chylomicrons
core lipids and apoproteins
Term
core lipids: endogenous triglycerides and cholesteryl esters (5:1)
apoproteins: C, B-100, and E
Definition
composition of VLDL
core lipids and apoproteins
Term
core lipids: cholesteryl esters
apoprotein: B-100
Definition
composition of LDL
core lipids and apoproteins
Term
core lipids: cholesteryl esters
apoproteins: A-I, A-II, C, E, and D
Definition
composition of HDL
core lipids and apoproteins
Term
chylomicrons
Definition
primarily involved in the transport of dietary lipids from the gut to the adipose tissue and liver
formed in the gut wall through emulsified lipids by bile acids combining with proteins
secreted into circulation
receive apoproteins C and E from HDL (apoC is a substrate for LPL)
deliver TG to adipose tissue via the actions of lipoprotein lipase (LPL) located in the vascular endothelial cells
transports cholesterol to the liver after being converted into cholesterol rich remnants
Term
VLDL
Definition
formed by golgi bodies in the liver from TG, cholesterol, and protein
secreted into circulation
receives apoproteins C and E from HDL
deliver TG to adipose tissue
transformed into IDL and LDL that contains a high percentage of cholesterol
Term
LDL
Definition
transports cholesterol to peripheral tissues for incorporation into cell membranes and steroids
undergoes endocytosis and incorporated into lysosomes
can deliver cholesterol to nascent atheromas
Term
HDL
their high density is caused by the large ratio of protein to lipid
Definition
small lipoproteins that are secreted by the gut and liver
new molecules contain protein and a small quantity of phospholipid, with relatively little cholesterol or TG
exchange apoproteins C and E with chylomicrons and VLDL
acquire cholesterol from peripheral tissues and atheromas
cholesteryl esters either are transported by HDL to the liver or are transferred to LDL for transport to the liver
Term
1) biosynthesis from acetyl-CoA
2) delivery of dietary cholesterol by chylomicron remnants
3) endocytosis by LDL cholesterol by LDL receptors
Definition
cholesterol is derived from 3 sources:
Term
genetic or environmental factors:
biochemical defects in lipoprotein metabolism
excessive dietary intake of lipids
endocrine abnormalities
drugs that perturb lipoprotein formation or catabolism (B blocker, thiazides)
Definition
causes of dyslipidemia
Term
familial hypercholesterolemia: defects in LDL receptor
familial defective apoB100: mutations in the apoB100 protein lead to decreased affinity of the LDL particles to the LDL receptors
polygenic hypercholesterolemia: a general term used to categorize the majority of patients (>85%) who have no defined genetic cause of the disorder
Definition
types of hypercholesterolemia
Term
familial hypertriglyceridemia of unknown genetic cause: increased hepatic TG synthesis, decreased lipolysis of chylomicrons and VLDL
familial LPL deficiency: elevated chylomicrons during infancy and impaired removal of VLDL later in life
apoCII deficiency: defect in apoCII which is an apolipoprotein responsible for the activation of LPL
Definition
types of hypertriglyceridemia
Term
combined hyperlipidemia
familial combined hyperlipidemia: present features of metabolic syndrome including abdominal obesity, glucose intolerance, and hypertension
Definition
hypercholesterolemia and hypertriglyceridemia characterized by increased LDL (cholesterol) and VLDL (triglycerides)
Term
decrease HDL
Definition

what will happen to HDL levels with the following defects?

ATP binding cassette protein A1 (ABCA1; a cholesterol efflux pump) defect

lecithin cholesterol acyltransferase (LCAT; converts cholesterol to cholestryl ester) deficiency

apoA1 (a cofactor for LCAT) deficiency

Term
increases HDL-C levels
Definition
what will happen to the levels of HDL-C with the following defect?
cholesterylester transfer protein (CETP; facilitates exchange of cholesteryl esters (from HDL to LDL and VLDL) and triglycerides (from LDL to HDL and VLDL)) deficiency
Term
torcetrapib
Definition
an inhibitor of CETP, reported to increase HDL levels but caused hypertension, no change in atherosclerosis, and increased cardiovascular events and mortality
Term
secondary hyperlipidemia
Definition
commonly caused by the presence of alcoholism, DM, or uremia or by the use of drugs such as B blockers, oral contraceptives, or thiazide diuretics
less commonly caused by hypothyroidism, nephrotic syndrome, or obstructive liver disease
Term
fluvastatin, lovastatin, atorvastatin, pravastatin, rosuvastatin, simvastatin
FLAPRS
Definition
HMG-CoA reductase inhibitors
Term
HMG-CoA reductase normally converts HMG-CoA to mevalonic acid which then becomes cholesterol
atorvastatin and other drugs reduce hepatic cholesterol biosynthesis by competitively inhibiting HMG-CoA reductase
this increases the number of hepatic LDL receptors and enables more LDL to be delivered to the liver
reduces the level of LDL in the plasma and the amount of cholesterol available for the formation of VLDL
the reductase inhibitors also reduce plasma triglyceride levels
Definition
mechanism of action of HMG-CoA reductase inhibitors
Term
well tolerated by most patients
may cause serious and life threatening toxicity in a small percentage of people (rhabdomyolysis)
myalgia: muscle ache or weakness (reversible)
myositis: muscle inflammation accompanied by muscle pain, elevated creatine kinase levels
rhabdomyolysis: muscle cells are destroyed, release myoglobin into the circulation, myoglobin accumulates in the kidney, can cause acute renal failure
GI upset, including nausea, vomiting, abdominal pain, diarrhea
lovastatin and simvastatin cross the BBB and can cause sleep disturbances
Definition
adverse effects of HMG-CoA reductase inhibitors
Term
can interact with other drugs metabolized by cytochrome P450
cause slight increase in plasma levels of warfarin
increase risk of myopathies when taken with erythromycin, gemfibrozil, or niacin
Definition
drug interactions of HMG-CoA reductase inhibitors
Term
cholestyramine, colestipol, colesevelam
Definition
bile acid binding resins
Term
bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid)
Definition
function:
eliminate cholesterol from the body
eliminate catabolites from the body
emulsify lipids and fat-soluble vitamins in the intestines
Term
after the resins (anion exchange) bind to bile acids, the bile acid resin complex is excreted
this action prevents the enterohepatic cycling of bile acids and facilitate the liver to synthesize bile acids from cholesterol
the liver increases the number of LDL receptors
reduction in the levels of LDL in the serum
the resins have relatively little effect on levels of HDL and TG
Definition
mechanism of action of bile acid binding resins
Term
few adverse effects
can cause constipation, fecal impaction, and other GI side effects
can cause irritation of the perianal area and a skin rash
Definition
adverse effects of bile acid binding resins
Term
in the gut, cholestyramine and colestipol can bind to digoxin, thyroxin, warfarin, and other drugs
for this reason, it is best to take these resins 2 hours before or after taking other medications
a newer resin, colesevelam (welchol), does not affect the oral availability of digoxin, warfarin, or lovastatin
colesevelam can be co-administered with most drugs including HMG-CoA reductase inhibitors
Definition
drug interactions of bile acid binding resins
Term
ezetimibe
Definition
cholesterol absorption inhibitor
Term
inhibits the absorption of dietary cholesterol by blocking cholesterol/sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1) at the brush border of the small intestine
cholesterol absorption is reduced by about 50%
it has no effect on the absorption of TG, bile acids, or fat soluble vitamins (absorbed by other transporters)
given alone, ezetimibe reduces plasma total cholesterol by about 15% and LDL cholesterol by about 18%
when taken with a low dose of statin, the combination is just as effective as the highest statin dose
Definition
mechanism of action of cholesterol absorption inhibitor
Term
diarrhea, headache, angioedema
Definition
adverse effects of cholesterol absorption inhibitor
Term
fenofibrate, gemfibrozil
Definition
fibric acid derivatives
Term
activate a gene transcription factor, peroxisome proliferator activated receptor alpha (PPAR-a):
increase expression of LPL; lower plasma TG levels
decrease expression of an inhibitor of LPL, apolipoprotein C-III
increase expression of enzymes that oxidize fatty acids
increase expression of apoproteins A-I and A-II; increase HDL levels
increase expression of a cholesterol transport protein, ABCA1; effluxes cholesterol from tissues
increased expression of hepatic LDL receptors
the fibrates reduce plasma levels of VLDL triglycerides and LDL-C, while raising levels of HDL-C
Definition
mechanism of action of fibric acid derivatives
Term
can cause blood cell deficiencies and other hypersensitivity reactions
can cause rhabdomyolysis and other myopathies
GI upset
rash or pruritis
dizziness, headache
Definition
adverse effects of fibric acid derivatives
Term
the combination of HMG-CoA reductase inhibitors and fibrates should be avoided or used with great caution
fibrates can be given with cholestyramine and colestipol but the doses must be separated by more than 2 hours, b/c these resins reduce fibrate absorption
Definition
drug interactions of fibric acid derivatives
Term
niacin
Definition
nicotinic acid derivative
Term
reduce lipolysis and free fatty acid mobilization from adipocytes to the liver
acting at a high affinity inhibitory GPCR, it decreases cAMP which decreases lipolysis in the adipocyte
decreased FFA availability reduces hepatic TG synthesis and VLDL secretion from the liver
Definition
mechanism of action of niacin
Term
the large doses of niacin that are required to lower serum lipid levels sometimes produce marked vasodilation and flushing of the skin (due to release of histamine and prostacyclins)
can elevate serum transaminase levels and cause hepatitis
also produces gastric distress and may activate a peptic ulcer
can cause glucose intolerance in some patients and can aggravate DM
niacin should be avoided in patients with hepatic disorders, peptic ulcers, or DM
Definition
adverse effects of niacin
Term
reduce TG in plasma, increase conversion of VLDL to LDL, increase HDL
reduction of plasma fibrinogen; decrease thrombogenesis
block platelet aggregation
retard atherosclerosis by reducing expression of endothelial adhesion molecules
promote NO-mediated vasodilation
reduce arrhythmia
Definition
potential cardioprotective effects of omega 3 fatty acids (fish oil)
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