Transcript ANTIHYPERTENSIVES, DIURETICS, ANTICOAGULANTS AND …

ANTIHYPERTENSIVES,
DIURETICS,
ANTICOAGULANTS AND
DYSLIPIDEMICS
PHARMACOLOGY
NUR 3703
BY LINDA SELF
Hypertension
• Hypertension common in US, up to
60 million afflicted
• Leads to MI, heart failure, stroke and
renal disease
• Strong correlation with metabolic
syndrome
Blood Pressure
Classification according to
the JNC 7
• Normal SBP<120 and DBP <80
• Prehypertension SBP 120-139 and
DBP 80-89
• Stage 1 Hypertension SBP 140-159
or DBP 90-99
• Stage 2 Hypertension SBP > or
equal to 160 or DBP > or equal to
100
Types of Hypertension
• Essential or primary—etiology ?.
Contributors include: salt sensitivity,
insulin resistance, genetics, sleep
apnea, environmental factors,others
• Secondary—renal, adrenal,
coarctation of the aorta, steroids,
pregnancy
BP review
• Any condition that affects heart rate,
stroke volume or peripheral vascular
resistance affects arterial blood
pressure
• Compensatory mechanisms to
maintain balance between
hypotension and hypertension
BP review
• BP regulation operates in a negative
feedback system
• Baroreceptors and chemoreceptors in the
carotid arteries and aortic arch detect
changes in arterial blood pressure and in
pO2, pCO2 and H+.
• Increased BP results in increased stretch
of vessels; activation of vagus and
stimulation of medulla via sympathetic or
parasympathetic pathways.
BP review
Normally, when the arterial blood pressure
is elevated
1. Kidneys will excrete more fluid
2. Fluid loss will result in decreased ECF
volume and blood volume
3. Decreased blood flow to the heart will
reduce cardiac output
4. Decreased CO reduces arterial blood
pressure
BP review cont.
5. Vascular endothelium produces
vasodilating substances (nitric oxide,
prostacyclin) which reduce blood
pressure
Essential Hypertension
• Activation of sympathetic nervous system
causing prolonged vasoconstriction
• Activation of RAAS plays integral part as
well
• In combination, mechanisms cause
prolonged increased vascular resistance;
this in turn results in a thickening of
vessel walls, less production of nitric
oxide (vasodilator) and increased
endothelin (increased vascular tone)
Essential Hypertension
• Also felt that hyperinsulinemia and
insulin resistance cause endothelial
dysfunction by enhanced oxygen
free radical-mediated damage and
decreased nitric oxide bioavailability.
Also is an increased sympathetic
response; results in increased
vascular tone and constriction
Nonpharmacologic
Management of
Hypertension
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Weight reduction
Exercise
Salt restriction in diet
Stress reduction
DASH eating plan
Moderation in alcohol intake
If systolic BP cannot be maintained
<140 systolic, tx.
Antihypertensive Drugs
• Classes:
1. Angiotensin converting enzyme
inhibitors (ACEI)
2. Angiotensin II Receptor Blockers
3. Antiadrenergics
4. Calcium channel blockers
5. Diuretics
6. Direct vasodilators
7. Renin inhibitors
ACEIs
• Block the enzymes that convert
angiotensin I to angiotensin II
(potent vasoconstrictor)
• Have action of vasodilation and
decrease aldosterone production
• Inhibit breakdown of bradykinins
(vasodilator) prolonging effect
ACEIs
• Reverse remodeling of heart muscle
and blood vessels
• Reno-protective
• Excellent for heart failure and
hypertension
• Improve post-myocardial infarction
survival
• Used alone or in combination
ACEIs
• Useful in heart failure as decrease
peripheral vascular resistance,
cardiac workload and ventricular
remodeling
• Captopril is the prototype
• Low incidence of side effects
• Can cause cough or hypotension
when first started
ACEIs
• Can cause hyperkalemia
• Should never be used during
pregnancy
• May not be as effective in African
Americans—may add diuretic in this
population to increase efficacy
ACEIs
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Lotensin (benazepril)
Capoten (captopril)
Vasotec (enalapril)
Zestril (lisinopril)
Altace (ramipril)
Aceon (perindopril)
Angiotensin II Receptor
Blockers (ARBs)
• Block effects of angiotensin II,
compete with angiotensin II for
tissue binding sites
• Block the receptors in brain, kidneys,
heart, vessels and adrenal tissue
ARBs
• Similar end results as seen with
ACEIs
• Less likely to cause hyperkalemia
• Persistence of cough is rare
• Prototype is Cozaar (losartan)
Examples of ARBs
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Atacand (candesartan)
Cozaar (losartan)
Diovan (valsartan)
Micardia (telmisartan)
Benicar (olmesartan)
Antiadrenergics
• Inhibit activity of the sympathetic
nervous system
• Effective in decreasing heart rate,
force of myocardial contraction,
cardiac output, and blood pressure
Antiadrenergics
• Alpha 1 adrenergics receptor
blocking agents dilate vessels and
decrease peripheral vascular
resistance
• Can experience first dose
phenomenon with orthostatic
hypotension, dizziness, syncope,
possible sodium and fluid retention
Antiadrenergics-Alpha 1
• Cardura (doxazosin)
• Minipress (prazosin)
• Hytrin (terazosin)
Antiadrenergics
• Centrally acting sympatholytics
stimulate presynaptic alpha 2
receptors in the brain
• Less norepinephrine is released and
sympathetic outflow is reduced
• Results in decreased cardiac output,
heart rate, peripheral vascular
resistance and blood pressure
Antiadrenergics—Alpha 2
agonists
• Centrally acting agents also can
result in fluid and sodium retention
• Catapres (clonidine)—orally or by
patch
• Tenex (guanfacine)
• Aldomet (methyldopa)
Beta Adrenergic Blockers
• Decrease heart rate, force of myocardial
contraction, cardiac output, and renin
release from the kidneys
• Drugs of choice with patients with
tachycardia, angina, MI, left ventricular
hypertrophy and high renin hypertension
• Most are pregnancy category C and D
Beta Blockers
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Inderal (propranolol)
Corgard (nadolol)
Lopressor (metoprolol)
Tenormin (atenolol)
Kerlone (betaxolol) for glaucoma
(ophthalmic), hypertension (orally)
Calcium Channel Blocking
Agents
• Useful in hypertension as dilate
peripheral arteries and decrease
peripheral vascular resistance by
relaxing vascular smooth muscle
• Monotherapy or in combination
• Tolerated well in renal failure
Calcium Channel Blocking
Agents
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Norvasc (amlodipine)
Cardizem (diltiazem)
Plendil (felodipine)
Procardia (nifedipine)
Calan (verapamil)—may cause
gingival hyperplasia
• Note these are also Pregnancy
category C
Diuretics
• Useful in hypertension due to their
sodium and water depletion
• May be used as monotherapy
• Preferred in the elderly and in AfricanAmericans
• Should be included in any multi-drug
regimen
• Thiazide diuretics are most commonly
used diuretics for hypertension
Diuretics
• Hydrodiuril (HCTZ)
Vasodilators
• Relax smooth muscle in blood
vessels resulting in dilation and
decreased peripheral vascular
resistance
• Reduce afterload so helpful in heart
failure
• May cause sodium and water
retention
Vasodilators
• Limited effect when used alone.
Vasodilating action that lowers BP
also stimulates SNS. This, in turn,
triggers reflexive compensatory
mechanisms that raise BP
Vasodilators
• Corlopam (felodapam)—IV infusion,
in hypertensive emergencies, avoid
in patients with allergies to sulfites
• Apresoline (hydralazine)—IV, IM or
PO. Can cause orthostatic
hypotension.
• Rogaine (Minoxidil) po or topical
Ethnic Considerations
• Use calcium channel blockers,
diuretics and alpha blockers most
effective in African Americans; beta
blockers, ACEIs and some ARBs are
not as effective as in Caucasians
• Beta blockers have greater effects
on Asians than in Caucasians
Hypertensive Emergencies
• Is defined as having end organ
damage or diastolic BP of 120 torr or
higher
• With oral medications, use captopril
25-50mg po every 1 to 2 hours or
clonidine , 0.2mg initially then 0.1mg
every hour until diastolic blood
pressure falls below 110 torr or
0.7mg has been given
Hypertensive Emergencies
• Nitroglycerine—tolerance develops
over 24-48 hours
• Nitroprusside—intraarterial bood
pressure should be monitored;
metabolized to thiocyanate
(precursor to cyanide), a toxic
metabolite. Measure serum levels if
drug given over 72h. Is
photosensitive.
Hypertensive Emergencies
• Corlopam (felodopam)—IV infusion,
use short term.
Herbals that affect BP
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Ephedra (ma huang)
Gingseng
Yohimbe (for erectile dysfunction)
caffeine
• In regards to anti-hypertensives,
should not abruptly stop any of
them. May develop rebound
hypertension.
Diuretics
• Indicated for the treatment of
edematous and nonedematous
conditions
• May be useful in preventing renal
failure by sustaining urine flow
• A minimum daily urine output of
approx. 400ml is required to remove
normal amounts of metabolic end
products
Diuretics
• Act on kidneys to decrease
absorption of sodium, chloride, water
and other substances such as
calcium
• Major subclasses are: thiazides,
loop and potassium-sparing diuretics
• Each act at different sites of the
nephron
Diuretics
Used to manage:
• Edema and ascites
• Management of heart failure
• Hypertension
Thiazide Diuretics
• Chemically related to sulfonamides so
caution with sulfa allergies
• Used in long term management of heart
failure and hypertension
• Affect distal convoluted tubule
• Effectiveness decreases as the GFR
decreases. Ineffective when GFR is <
30mL/minute. As rising creatinine noted,
should use alternative such as loop
diuretic.
Thiazide Diuretics
• Diuril (chlorothiazide)
• Hygroton (chlorthalidone)
• HydroDIURIL (hydrochlorothiazide)
Loop Diuretics
• Inhibit sodium and chloride
reabsorption in the ascending limb of
the Loop of Henle
• Potent diuresis
• Need to restrict dietary sodium when
taking these meds
• Lasix (furosemide) is the prototype
Loop Diuretics
• Bumex (bumetamide) more potent
than Lasix
• Can give either as oral agents, IV or
IM
• Rapid administration can cause
deafness
• Must monitor potassium levels, I&0,
also weight would be optimum
Potassium Sparing
Diuretics
• Act at distal tubule to decrease
reabsorption of sodium and
potassium excretion
• Spironolactone (prototype) blocks
the sodium retaining effects of
aldosterone
• Weak diuretics when used alone,
often used in combination
• Contraindicated in renal failure
Osmotic Diuretics
• Produce rapid diuresis by increasing
the solute load of the glomerular
filtrate
• Water is pulled into the intravascular
space and excreted via kidneys
• Useful in managing oliguria or anuria
• Can prevent acute renal failure
during prolonged surgery, trauma or
during chemotherapy
Osmotic Diuretics
• Help reduce increased ICP,
reduction of intraocular pressure
before certain ophthalmic surgery
and for urinary excretion of toxic
substances
• Examples include: Osmitrol
(mannitol), Ismotic (isosorbide) and
Osmoglyn (glycerin)
Drugs that affect
Coagulation
• Thrombosis may occur in both arteries
and veins
• Arterial thrombi cause disease by
obstructing blood flow which can result in
tissue ischemia or death
• Venous thrombosis is associated with
venous stasis. A venous thrombus is less
cohesive than an arterial embolus so
venous emboli more prevalent
Hemostasis
• Hemostasis is the prevention or stoppage
of blood loss from an injured blood
vessel. Process involves
vasoconstriction, formation of a platelet
plug, activation of clotting factors and
growth of fibrous tissue into the blood clot
making it more stable.
Clot Lysis
• When clot is being formed,
plasminogen is bound to fibrin and
becomes a component of the clot
• After tear in blood vessel is repaired,
plasminogen is activated by
plasminogen activator to produce
plasmin. Plasmin (enzyme) breaks
down the fibrin mesh and dissolves
the clot.
Blood Coagulation Factors
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I fibrinogen
II prothrombin
Ill thromboplastin
IV calcium
V Labile factor
VII proconvertin or stable factor
VIII antihemophilic factor
IX Christmas factor
X Stuart factor
XI plasma thromboplastin antecedent
XII Hageman factor
XIII fibrin-stabilizing factor
Anticoagulants
• Given to prevent formation of new
clots and extension of clots already
present; do not dissolve clots
already present
• Prototype is Heparin
• Heparin may be used in pregnancy
• Weight based dosing per institutional
nomogram
Heparin
• Usually will give a loading dose then
calculated dosage per 24h; e.g. 1525units/kg/h for IV dosing
• Monitor aPTT, should be 1.5-2.5
control value—normal value is 35
sec.
• Can cause heparin induced
thrombocytopenia
• Reversal agent is protamine sulfate
Heparin
• Combines w/antithrombin III which
will inactivate clotting factors IX, X,
XI and XII, inhibits conversion of
prothrombin to thrombin and
prevents thrombus formation.
Further affects coagulation by
preventing conversion of fibrinogen
to fibrin, inhibiting factors V,VIII, XIII
and platelet aggregation.
Low Molecular Weight
Heparins
• Given subcutaneously in abdomen
and do not require close monitoring
of blood coagulation tests
• Still should follow platelet counts
• Fragmin (dalteparin)
• Lovenox (enoxaparin)
Coumadin (warfarin)
• Most commonly used oral
anticoagulant
• Drug acts in liver to prevent
synthesis of vitamin K-dependent
clotting factors (II,VII,IX, X). Acts as
a competitive antagonist to hepatic
use of vitamin K.
• Anticoagulant of choice for long-term
maintenance therapy.
Coumadin (warfarin)
• Anticoagulant effects do not occur
for 3-5 days after warfarin is started
• Has no effect on platelets or on
circulating clotting factors
• Regulated according to the INR
(international normalized ratio)
. Therapeutic values are generally 2 to
3.
Coumadin
• INR is based on prothrombin time.
Normal baseline or control PT is 12
seconds, therapeutic value is 1.5
times the control or 18 seconds.
• Use of INR has eliminated
disparities in different labs
Coumadin
• Dosage reduction in patients with biliary
tract disorders, liver disease,
malabsorption syndromes, and
hyperthyroidism. These conditions
increase anticoagulant drug effects by
reducing absorption of vitamin K or
decreasing hepatic synthesis of clotting
factors
• Has multiple, multiple drug interactions
• Counteract with vitamin K
Other anticoagulants
• Orgaran (danaparoid)—low
molecular weight, heparin-like drug.
Given subq. Used in management of
hip surgery, ischemic stroke or in
those who cannot take heparin.
Does not contain heparin.
• Refludan (lepirudin)—used as
heparin substitutes
• Arixtra (fondaparinux) –binds to clot
bound factor Xa, inhibits thrombon
productions
Other Anticoagulants cont.
Trade and generic names
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Refludan (lepirudin)
Argatroban (same generic name)
Arixtra (fondaparinux)
Angiomax (bivalirudin)
Antiplatelet Drugs
• Arterial thrombi are composed primarily of
platelets
• Antiplatelet drugs act by inhibiting platelet
activation, adhesion, aggregation, or
procoagulant activity.
• Include drugs that block platelet receptors
for thromboxane, ADP, glycoprotein
IIb/IIIa and phosphodiesterase inhibitors
Thromboxane A2 Inhibitors
• Work by inhibiting synthesis of
prostaglandins. TA inhibitors work by
acetylating cyclooxygensase, the enzyme
in platelets that synthesizes thromboxane
A2 (which causes platelet aggregation).
• ASA is example. It affects the platelets for
the life of the platelet.
• NSAIDs not so useful as action wears off
as drug wears off
Adenosine Diphosphate
Receptor Antagonists
• Ticlid (ticlopidine)
• Inhibit platelet aggregation by preventing
ADP-induced binding between platelets
and fibrinogen. This reaction inhibits
platelet aggregation irreversibly and
persist for the lifespan of the platelet (910 days)
• Indicated in TIAs
• Adverse effects-neutropenia, diarrhea,
skin rashes
Adenosine Diphosphate
Receptor Antagonists
• Plavix (clopidogrel)
• Fewer side effects than ASA or
Ticlid
• indicated for patients with
atherosclerosis for reduction of MI,
stroke and vascular death
• Does not need reduction in those
with renal problems
Glycoprotein IIb/IIIa
Receptor Antagonists
• Reopro (abciximab) is a monoclonal
antibody that prevents the binding of
fibrinogen, von Willebrand factor and
other molecules to GP IIb/IIIa receptors
on activated platelets. This action inhibits
platelet aggregation.
• Used with percutaneous transluminal
coronary angioplasty or removal of
atherosclerotic plaque to prevent
rethrombosis
Reopro cont.
• Used with aspirin and heparin and is
contraindicated in clients who have
recently received oral anticoagulants
or IV dextran.
• Other contraindications include
active bleeding, thrombocytopenia,
history of stroke, surgery or trauma
within past 6 weeks, uncontrolled
hypertension or hypersensitivity.
Other glycoprotein IIb/IIIa
Receptor antagonists
• Integrilin (Eptifibatide)
• Aggrastat (tirofiban)
• Similar mechanism of action as
Reopro
• Indicated for acute coronary
syndrome who are managed
medically or by angioplasty or
atherectomy
Glycoprotein IIb/IIIba
receptor antagonists cont.
• Contraindications include: recent
bleeding, history of thrombocytopenia,
history of stroke within 30 days, major
surgery or severe trauma within past
month, severe hypertension, hx of
intracranial hemorhage, neoplasm, AV
malformation, or aneurysm; platelet ct
less than 100,000 or creatinine greater
than 2 mg/dL
Phosphodiesterase
Inhibitors
• Pletal (cilostazol) increases cAMP which
then inhibits platelet aggregation and
produces vasodilation. Drug reversibly
inhibits platelet aggregation.
• Indicated for intermittent claudication.
• Contraindicated in patients with heart
failure
• Most common SE is diarrhea and
headache
Miscellaneous
• Persantine (dipyridamole) inhibits
platelet aggregation but mechanism
is unclear
• Used for prevention of
thromboembolism after cardiac valve
replacement and is given with
Coumadin
Thrombolytics
• Given to dissolve thrombi
• Stimulate conversion of plasminogen
to plasmin, an enzyme that breaks
down fibrin (the framework of a
thrombus)
• Used in severe thromboembolic
disease such as MI, PE and
ileofemoral thrombosis
Thrombolytics
• Goal is to re-establish blood flow
and prevent tissue damage
• Also used to dissolve clots in arterial
or venous cannulas or catheters
• Must obtain baseline INR, aPTT,
platelet count and fibrinogen
• Will monitor labs 2-3 hours after
thrombolytic tx is instituted to
determine efficacy
Thrombolytics
• Activase (alteplase), Retavase (reteplase)
and TNKase (tenecteplase) are tissue
plasminogen activators used mainly in
acute MI to dissolve clots.
• Eminase (anistreplase), Streptase
(streptokinase) and Abbokinase
(urokinase) are enzymes that break down
fibrin. Used to lyse coronary clots in acute
MI.
Thrombolytics cont.
• Xigris (drotrecogin alfa) is a
recombinant version of human
activated protein C. Is approved for
use in sepsis. Sepsis causes
inappropriate blood clot formation
and may lead to DIC. Xigris useful in
this situation.
Drugs Used to Control
Bleeding
• Amicar (aminocaproic acid) and
Cyklokapron (tranexamic acid) are
used to stop bleeding caused by
overdoses of thrombolytic agents
• Trasylol (aprotinin) indicated in
patients undergoing CABG . Inhibits
breakdown of blood clotting factors.
Important reminders
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Risk factors for thromboembolism
Obesity
MI
Atrial fibrillation
Prosthetic heart valves
ASHD
OCP or HRT
Hx of DVT or Pe
Cigarrette smoking
Immobility
Overview of cholesterol
panel
Total cholesterol
Desirable-less than 200
Borderline high—200-239
High—240 or greater
LDL
Desired <100
Above optimal—100-129
Borderline high—130-159
High-160-189
Very high190
Overview cont.
HDL
• High >60
• Low <40
Triglycerides
Normal—less than 150
Borderline high—150-199
High--200 to 499
Very high—500 or above
Dyslipidemia
• Associated with athersclerosis and
numerous pathophysiologic effects
• Elevated total cholesterol, high LDL
and low HDL are all risk factors for
CAD
• TG indicated excessive caloric
intake; excessive proteins and
carbohydrates are converted to TG
and obesity
Contributors to
dyslipidemia
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Hypothyroidism
Diabetes mellitus
Alcoholism
Obesity, beta blockers, oral
estrogens, gluccorticoids, sertraline,
thiazide diuretics, protease inhibitors
Dyslipidemia cont.
• High dietary intake also increases
the conversion of VLDL to LDL
cholesterol, and high dietary intake
of TG and saturated fat decreases
the activity of LDL receptors and
increases synthesis of cholesterol.
Types of Lipoproteins
• LDL—unfavorable type. Transports 75%
of serum cholesterol to peripheral tissues
and the liver. High levels are atherogenic
• VLDL—contains 75% TG and 25%
cholesterol. Transports endogenous TG
to fat and muscle cells.
• HDL—favorable type. This LP transports
cholesterol back to the liver for catabolism
and excretion.
Initial Management
• Treat conditions that contribute to elevated lipids
(DM, hypothyroidism)
• Start low fat diet
• Increase intake of fiber-lowers LDL
• Cholesterol lowering margarines
• Weight reduction
• Exercise—increases HDL
• Smoking cessation
• HRT
Drug Therapy
• Based on the type of dyslipidemia
and its severity
• Classes of agents include: HMBCoA reductase inhibitors or “statins”,
fibrates, bile acid sequestrants and
niacin in different forms
• Lovaza
• Zetia
HMG-CoA reductase
inhibitors or “statins”
• Inhibit an enzyme
(hydroxymethylglutaryl-coenzyme A
reductase) required for hepatic
synthesis of cholesterol
• Decrease serum cholesterol, LDL,
VLDL and TG
• Reach maximal effects within about
6 weeks
Statins cont.
• Drugs also reduce C reactive
protein, associated with
inflammation and development of
CAD
• Undergo extensive first pass
metabolism
• Metabolism occurs in liver
Statins cont.
• Adverse effects include:HA, diarrhea,
rashes, headaches, constipation,
hepatotoxicity and myopathy.
• Should obtain baseline LFTs and then at
6 and 12 weeks after starting then every 6
months
• If serum aminotranferases increase to
more than 3x normal, should be reduced
or DCed.
Statins cont.
• Do not take with grapefruit juice
• Pregnancy category X
• Examples: Lipitor (atorvastatin),
Pravachol (pravastatin), Zocor
(simvastatin), Lescol (fluvastatin)
Bile Acid Sequestrants
• Bind bile acids in the intestinal
lumen. This causes the bile acids to
be excreted in feces and prevents
their being recirculated to the liver.
Thus, the liver will use cholesterol to
produce bile acids thus decreasing
serum levels.
Bile Acid Sequestrants
• Especially lower LDL
• Examples are: Questran
(cholestyramine) and Welchol
(colesevelam)
• Often used with patients already on
a statin
• Long term use can affect absorption
of folate, Vitamins A,D,E,K
Fibrates
• Tricor (fenofibrate)
• Lopid (gemfibrozil)
• These drugs increase oxidation of
fatty acids in liver and muscle tissue
thus decreasing hepatic production
of TG, VLDL and increase HDL.
• Most effective drugs for reducing
TG.
Fibrates cont.
• Can cause hepatotoxicity
• Main side effects include: diarrhea,
GI discomfort, cause gallstones,
interact with Coumadin
Niacin (nicotinic acid)
• Decreases both cholesterol and
triglycerides
• Bottom line—decreases hepatic
synthesis of TG and secretion of
VLDL (which leads to decreased
production of LDL)
• Need high doses for efficacy
Niacin
• Side effects include: flushing,
pruritus, gastric irritation. May cause
hyperglycemia, hyperuricemia,
elevated hepatic aminotransferase
enzymes and hepatitis.
• Can reduce flushing by starting with
low doses, taking dose with meals,
and taking ASA 325mg thirty
minutes before taking dose
Niacin
• More effective in preventing heart
disease when used in combination
with another dyslipidemic such as a
bile acid sequestrant or a fibrate.
• Zetia (ezetimibe) Inhibits absorption
of cholesterol from small intestine
• Don’t give with Questran
(cholestyramine)
• Lovaza