Pharm Section 4 Flashcards
functions of cholesterol
responsible for proper cell membrane synthesis and the formation of bile acids and steroid hormones
rate limiting step in cholesterol formation
mevalonate
formed by acetyl CoA and catalyzed to HMG-CoA reductase
cholesterol synthesis pathway
acetyl Coa > HMG CoA reductase > mevalonate > farnesyl pyrophosphate > squalene > cholesterol
cholesterol and transportation
hydrophobic, must be transported in blood by hydrophilic lipoproteins
most cholesterol in plasma normally carried in what form?
LDL; low density lipoproteins; “bad cholesterol” associated with increased risk of CAD
apoB
apolipoprotein B; apoB binds lipids to LDLs and acts as ligand to “unlock” cell membranes to allow LCL inside; it is responsible for carrying cholesterol to tissues
the more apoB, the more atherogenic
test for apoB amounts
“Berkeley” cholesterol test
HDL cholesterol
high density lipoprotein; “good cholesterol” because low HDL traditionally seen as strong risk factor for CAD. Recent data is challenging this.
triglycerides
carried in chylomicrons, VLDL (very low), and IDL (intermediate)
ATP IV guidelines (new 2013)
do away with specific goals (numbers) for LDL and instead categorize patients into four groups of primary and secondary prevention patients. Recommend “intensity” of tx for each prevention group in order to achieve desired LDL cholesterol reduction. No evidence to support specific target. May increase people on statins by 70 million in US (1/2 US pop 40-75).
ATP four new guideline documents include…
- tx of blood cholesterol in adults
- assessment of CV risk
- lifestyle management to reduce CV risk
- management of overweight and obesity in adults
ATP IV new risk categories for hyperlipidemia patients
- with CV disease; 40-75 years old; >=7.5% calculated risk for MI or stroke within 10 years
- with hx MI, stroke, angina, PAD, TIA, or revascularization
- 21 and older with LDL level of 190mg/dL or higher
- 40-75 years old with type 1 or 2 diabetes
ATP IV new guidelines for assessment of CV risk
focus on atherosclerosis as chronic disease that extends beyond the heart
ATP IV new guidelines for lightly management to reduce CV risk
recommendations cover evidence related to dietary patterns, nutrient intake, and levels/types of physical activity
ATP IV new guidelines for management of overweight/obese adults
BMI as quick, first screening step for wright loss counseling; waist circumference as indicator for T2 diabetes, CVD, all-cause mortality; new recommendations for BMI cutoff for treatment recommendations (was BMI30 or [25 +2comorbidities], now BMI25 and 1 comorbidity)
AACE response to ATP IV guidelines?
they reject the new guidelines and question their scientific basis. say certain at-risk populations will be underserved by new guidelines
Metabolic syndrome
–formerly syndrome X
–describes patients with three or more of: …obesity (waist circ >40in M/ >35in F)
…dyslipidemia (triglyceride >150; HDL <40 M/ <50 F)
…HTN (>135/85 mmHg)
…diabetes (FBG >110mg/dL)
HMG-CoA reductase inhibitors are also called…?
statins
most widely used drugs for dyslipidemia
first statin drug
lovastatin (Mevacor); 1987
how do statins work?
inhibit cholesterol synthesis
inhibit HMG-CoA reductase (rate-limiting step in cholesterol synthesis), which aids in removal of cholesterol from blood
how is ubiquinonse/coenzyme Q10 related to cholesterol? what might it be related to?
other side of the pathway for cholesterol production
deals with muscle properties, so may be related to myopathy side effects of statins
may be helpful to give statins with CoQ10 supplement
statin impact on LDL, HDL, total cholesterol and triglyceride concentrations
lower plasma concentration of LDL
lower total cholesterol
reduce levels of triglycerides
increase levels of HDL
statins must be taken for how long?
indefinitely. if stopped, cholesterol will return to baseline within a few weeks
statins may be beneficial for what non-CV conditions?
improved endothelial function
decreased platelet aggregation
reduced inflammation
seven statin drugs available include…?
lovastatin (Mevacor) simvastatin (Zocor) Pravastatin (Pravachol) Fluvastatin (Lescol) Atorvastatin (Lipitor) Rosuvastatin (Crestor) Pitavastatin (Livalo)
statin combo drugs include…?
Vytorin (simvastatin and ezetimibe)
Liptruzet (atorvastatin and ezetimibe)
Simcor (simvastatin and ER Niacin) no more
Caduet (atorvastatin and amlodipine)
comparison between statin drugs…
which to choose?
- -rosuvastatin a little more potent
- -simvastatin don’t use more than 40 mg
- -if fail to achieve cholesterol goals with less potent statin, switch to more potent drug
- -CAD pts with hard LDL goals, max dose of atorvastatin
- -pravastatin totally hydrophilic, not metabolized or excreted @liver (may have fewer interactions, side effects)
- -Asian descent, 2 fold inc in concentrations of rosuvastatin–use in lower dose in asians
effect of doubling dose of statin?
only increases LDL reduction by 5-7%, but probably doubles the side effects
statins and pediatrics
most statins approved in kids
recommended screening beginning at 2 and tx for kids over 8
statins and pregnancy
statins are contraindicated in pregnancy
which statins should you take in the evening?
those with shorter 1/2 lives
lovastatin (2hr 1/2 life); fluvastatin (<3hrs); simvastatin (<5hrs)
which statins should you take in the morning?
those with longer 1/2 lives
atorvastatin (14hrs); rosuvastatin (19 hrs); pravastatin (22hrs)
all statins except _______ can be taken without regard to meals
lovastatin (should be taken with dinner)
adverse effects of statins?
all are contraindicated in pregnancy
liver monitoring no longer required
primary concern: myopathy
other concerns: myalgia, myositis, rhabdomyolysis
statins and myopathy
considered in any pts with diffuse myalgia, muscle tenderness, weakness, increase in CPK/CK,
> 10 ULN levels indicate myopathy
symptoms usually resolve apron 2 mo after discontinuing statin, can restart same statin at lower dose or try new one
can also be due to hypothyroidism, low CoQ10 levels, vitamin D
FDA recommendations in relation to inc risk of muscle damage with statins?
providers should restrict prescribing max dose of a statin
drug interactions and myopathies related to statins
protease inhibitors for HIV and hep C and statins may cause renal failure assoc with rhabdo
greater risk if administered with P450 inhibitors like azole antifungals, amiodarone, and fabric acid derivatives
statins and rhabdomyolysis
breakdown of skeletal muscle protein myoglobin with leakage of muscle contents into the circulation. can infiltrate kidneys and cause toxic reaction, obstruction (block O2 supply).
characterized by tea-colored urine, flu-like symptoms, and muscle pain
15% acute renal failure
8% mortality
<0.001% cases annually with statins
also crush injuries, overexertion, alcohol abuse
statins and diabetes
statins may cause small inc in risk of raising blood glucose levels
ADA still recommends mod-high dose statins. Risk shouldn’t stop diabetics from taking statins.
statins and confusion (cognitive decline)
2012-statin use could affect memory, attention span, etc.
2015- meta-analysis says no significant worsening of cognitive capacity
2015-statin and non-statin LDL meds associated with acute memory loss within 30 days, but confounded by fact that they see MD more, more likely to detect memory loss
statins and cataracts
risk of developing cataracts increased by 27% in those taking statins (2013)
other studies did not find association
efficacy of statins
average about 1/3 reduction in incidence of cardiovascular events (coronary heart disease)
statins after heart surgery
anti-inflammatory effects of statins may mitigate inflammation and other risks (fib in CABG) associated with extended time under anesthesia
benefits outweigh risks
statins effect on serious vascular events
they reduce serious vascular events by 20% regardless of heart disease status
statin recommendations for elderly (esp men)
97% between 65 and 77 and 100% of men in that age group should consider taking statins to reduce risk of heart attack and stroke
statin recommendations for adults under 75 with risk factors
low-moderate dose statins for those 40-75 with CVD risks
no evidence to suggest whether or not those younger than 20 should be screened for lipid disorders
PCSK9 inhibitors
proprotein convertase subtilisin/kexin type 9 inhibitors
monoclonal antibodies that target specific protein (PCSK9), which works by reducing the number of receptors in liver that remove LDL from the blood. By blocking these receptors, increase the number of receptors available to remove LDL from blood…and thus lower LDL cholesterol in blood.
“promote modulation of a receptor that clears LDL in blood”
PCSK9 inhibitor drugs
alirocumab (Praluent): 1st approved. biweekly subQ injection of 75 or 150mg or monthly of 420mg
evolocumab (Repatha):biweekly 140 mg injection or monthly 420 mg subQ
PCSK9 inhibitors are approved for use in what populations
in addition to diet modification and statin therapy in people with heterozygous familial hypercholesterolemia (HeFH) OR in patients with clinical atherosclerotic CVD (MI, strokes) who need additional lowering of LDL
PCSK9 inhibitors and % LDL reduction
average reduction of 36-59%
side effects of PCSK9 inhibitors
no myopathies (yet)!
itching, swelling, pain, bruising at injection site, nasopharyngitis, cold/flu symptoms
bile acid resins (sequestering agents)…how do they work?
bind to and sequester bile acids, decreasing cholesterol return from intestines to liver and stimulating liver to produce more bile acids, “draining” liver of cholesterol and excreting it via GI tract
major side effect of bile acid resins/dequestering agents?
increase triglyceride levels.
contraindication for bile acid resins?
triglyceride levels >400mg/dL
bile acid resins and % reduction of LDL
bile acid resins reduce LDL by 20% and increase HDL by 8%
if patients can’t take statins, they should take these…next best.
bile acid resin agents
cholestyramine (Questran, Prevalite): many drug interactions, reduces their bioavailability, requires adjustment of other drugs; powder mix with liquid
colesevelam (Welchol): more potent, fewer side effects, used as absorbent in tx of c.diff
first and only medication approved for tx of diabetes AND hyperlipidemia?
bile acid resin, colesevelam (Welchol)
adverse side effects of bile acid resins
not absorbed systematically, no severe effects. mostly GI (constipation, heartburn, nausea)
cholesterol absorption inhibitor drug
Ezetimibe (Zetia)
available as combination therapy with simvastatin (Vytorin) or atorvastatin (Liptruzet), which 2014 study shows is beneficial for lowering LDL
cholesterol absorption inhibitor mechanism
inhibits intestinal absorption of cholesterol, does not affect absorption of fat soluble vitamins, triglycerides, or bile acids
different from bile acids that bind cholesterol in small intestine
makes it complementary to statins which work in the liver
how well does Ezetimibe (Zetia) work? (% dec in LCL)
reduces LDL levels by 15-25%
niacin (what it is and mechanism)
naturally occurring B vitamin (B3) that in large doses (100-300x the recommended daily dose as a vitamin) increases HDL and lowers LDL and triglyceride levels
mechanism unknown. thought to inhibit VLDL production, thus dec LDL
adverse effects of niacin?
“niacin flushes out toxins from the body”
“I feel like I’m on fire”
primary effects are flushing and pruritus (itching). others are: nausea, GI distress, glucose intolerance, hyperuricemia, hepatic toxicity (mostly with sustained release)
niacin and flushing (cause, management)
cause: mediated by prostaglandin PGD2 (vasodilation @ skin)
management: “start low and go slow; antiprostaglandins (NSAIDs) may help, avoid hot beverages and alcohol, pretreat with 325mg aspirin or 200mg ibuprofen.
niacin and liver damage
more damage with SR, and OTC niacin products
Niaspan ER may be better bc its ER and not SR formulation, but its costly.
niacin and diabetes
not contraindicated, but use caution! can cause a loss in glucose control, but helps lower triglycerides which are problematic in diabetic patients
Niaspan vs. others?
stick with Niaspan. slower than immediate release Niacor, but faster than long acting Slo-Niacin. Long acting niacins run risk of toxic buildup from slow metabolism. others not as effective or not effective at all.
niacin and illicit drug users
may try to take niacin to conceal illicit drug use. doesn’t work, but get flushing side effects and could end up with liver failure.
HDL controversy and niacin
framingham study and others suggest inc HDL to lower CV risk. HPS2-THRIVE and AIM-HIGH studies show no benefit and some harm to use niacin to inc HDL levels
so, niacin should not be used routinely, only in patients with very high CV risks with contraindications for taking statins. 4th line therapy after lifestyle modification, fabric acid derivatives, pharm fish oil preparations).
bottom line: reducing HDL in isolation probably not overly beneficial
niacin combinations, new FDA decisions?
in 2016, FDA pulled approval for combos of niacin ER and fenofibric acid with statins
Niaspan, Trilipix, Advicor, Simcor all affected
fibric acid derivatives
decrease triglycerides and increase HDL
esp beneficial for pts with atherogenic dyslipidemia
they enhance oxidation of fatty acids in the liver and muscle to reduce the rate of lipogenesis, thus reducing VLDL triglycerides
triglyceride levels in serum…normal/abnormal?
normal = 10-70mg/dL
abnormal = >150mg/dL
very high = >500mg/dL inc risk of pancreatitis
fibric acid derivatives…drugs?
gemfibrozil (Lopid): GI, liver side effects. interact w/ statins to inc risk of rhabdo
fenofibrate (Tricor): many different branded generics to improve absorption
fenofibric acid (TriLipix): active metabolite of fenofibrate in SR form, lower trigly, inc HDL, lower total cholesterol (not as well as statins tho)
omega 3 fatty acids “fish oil” (what are they used for?)
FDA has approved 3 of these meds to treat hypertriglyceridemia (levels >500mg/dL)
may also inc HDL and lower apoB. Lp-PLA2, and hs-CRP.
FDA approved formulations of omega3 FAs?
omega-3 acid ethyl ester (Lovaza, Omtryg): DHA and EPA
icosapent (Vascepa): EPA only
omega-3 carboxylic acids (Epanova): free fatty acid form
other tx for cholesterol?
- -high soluble fiber diet
- -garlic (0-6% dec in LDL)
- -Policosanol (waxy substance, unclear evidence)
- -red yeast rice/ cholestin (really works, but side effect is myopathies, if pt takes both statin and RYR, may inc chance of developing)
- -phytosterols (prevent cholesterol absorption @ gut, no sig pharm effectS)
how to determine if someone is in heart failure?
LVEF <40% is considered HF and assessment, tx should be initiated
BNP levels <100pg/ml can be used to rule out HF
who generally gets HF?
those 60 years and older (75%)
blacks more at risk than whites
first line therapy for HF?
minimum, both an ACEI and/or beta blocker (unless contraindicated). IF cannot tolerate ACEI, try ARB.
second line therapy for HF?
aldosterone agents and combo therapy with hydralazine and a nitrate (possibly digoxin too, see sub specialist)
drugs that exacerbate HF?
nondihydro CCBs, NSAIDs, thiazolidinediones
classifications and stages for HF?
Classes: I: asymptomatic II: symptomatic with moderate exertion III: symptomatic with minimal exertion IV: symptomatic at rest
Stages:
A: at risk because of CV probs
B: no symptoms but recent MI or heart damage
C:structural heart disease plus symptoms
D: refractory symptoms of HF, even @ rest
digoxin (Digitek, Lanoxin) for HF
used for both heart failure and a fib
avoid at first line therapy; don’t give more than 0.125mg/day for any indication
actions: cardio-tonic (more contraction), bradycardia, anti-arrhythmic, increased cardiac output
digoxin is a classic example of what?
NTI (narrow therapeutic index) drug
today’s recommendations: 0.5-0.8ug/L, don’t exceed 1.0 ug/L esp in women
side effects of digoxin
bradycardia
anorexia, nausea, vomiting
yellow/green halos around lights
EKG changes (arrhythmia)
hypokalemia (doesn’t cause it, but if have it, inc risk for digoxin toxicity)
dec cardiac output (fluid, dec. K+ levels)
how to treat digoxin toxicity?
hold, DC digoxin
supplement K+ if needed
treat arrhythmia
Digibind for acute toxicity (also possibly Question or Welchol)
ACEIs for HF
first line therapy
improve symptoms within days, 4-12 weeks
ARBs for HF
can be used alone or with Bblocker
use in patients with persistent problems even on ACEIs
Diuretics and HF
loop diuretics generally more effective than thiazides for HF patients
most HF patients have fluid retention, req these
Spironolactone (inc K+) and Eplerenone (SARA) for aldosterone inhibition
vasodilators for HF
concurrent use of hydralazine and ISDN (isosorbide dinitrate) improves EF
combo drug = BiDil for Af Am pop removed from market
Beta blockers for HF
1st line drugs, use with ACEI or ARB if not contraindications
metoprolol succinate ER, bisoprolol, carvedilol (Best)
antidysrhythmic agents for HF
arrhythmias common in HF pts
amiodarone = most positive results
antidysrhytmic drugs for HF?
ivabradine (Corlanor)niche drug, blocks pacemaker channel slows rate w/ no effect on vent depolarization or contractility
Sacubitril/Valsartan (Entresto) game changer combo neprilysin inhibitor and A-II agonist given FDA priority approval. neprilysin inhibition inc. conc. on natriuretic (sodium excretion) peptides (natriuretic and vasodilatory properties)
Entresto (sacubitril and valsartan)
game changer) combo drug inc. natriuretic peptides
new AHA guidelines list it as 1st line therapy instead of ACEIs and ARBs.
side effects: hypotension, hyperkalemia, renal impairment, angioedema
drugs used for acute cardiac failure and shock include…?
vasopressors (change muscle contractility) and inotropic drugs (alter contractility)
dopamine (Inotropin) first line tx hotn/shock
dobutamine (Dobutrex) no norepi release
norepinephrine (Levophed) septic shock
phenylephrine (Neo-Synephrine) anesthesia
epinephrine anaphylactic shock
atropine not for asystole
milrinone (Primarcor) danger low BP
vasopressin/ADH (Pitressin) severe septic shock or afib
hBNPs (Nesiritide) doesn’t hurt, doesn’t help
medications that worsen/exacerbate HF?
negative inotropics (dysarrhythmics)
cardiotoxic agents (CCBs)
Thiazolidinediones
Na/H2o retention (corticosteroids, NSAIDs)
antianginal drugs
low-dose aspirin (reduce MI risk by 1/3)
CCBs (if Bblockers don’t work, can’t use)
Bblockers (initial therapy unless contraindic)
nitrates (improve exercise tolerance)
cholesterol-lowering drugs (prevent MI)
Ranolazine (Ranexa) chronic angina, prolongs QT interval
all clients should have sublingual nitroglycerin for immediate relief
nitrate-type vasodilators
nitric oxide relaxes vascular smooth muscle, inhibits platelet aggregation
potent vasodilators, arterial dilators @ high doses, reduce LV wall stress, which dec. myocardial O2 demand
dosage forms: sublingual, ointment, patches, IV, aerosol, buccal
ISDN and ISMN
ISDN vs ISMN (isosorbide dinitrate vs mononitrate)
ISMN preferred for management of angina
ISDN more evidence for heart failure
side effects of nitrates?
flushing, headache, hypotension (monitor BP)
DONT TAKE WITH 5PDE inhibitors (viagra, cliais) b/c BP will bottom out.
tolerance and nitrates
can develop tolerance over time, so make sure to use in intervals. nitrate free intervals now recommended @ least 14 hours (only wear for 8 hours)
nitrates storage
they are volatile
store in close containers, check expiration dates often
newer tablets less volatile than old ones
how many nitro tablets to take before calling 911?
call 911 if don’t get relief within 5 minutes of taking 1 tablet. can take up to two more (total = 3) while EMS on the way if need to.
Ranolazine (Ranexa)
“metabolic modifier” for chronic angina tx
inhibits fatty acid oxidation, improves exercise performance/tolerance
prolongs QT interval
antiarrhythmic drugs
class I: Na2+ channel blockers class II: beta blockers-inhibit catecholamines class III: K+ channel blockers class IV: Ca2+ channel blockers misc: digoxin, adenosine
vaughn-williams classifications
class I: Na2+ channel blockers a--rarely used, frequent toxicity b-- c--proarryhthmics, no structural HD class II: beta blockers-inhibit catecholamines class III: K+ channel blockers class IV: Ca2+ channel blockers
arrhythmia should be called?
dysarrhythmia (connotes tachyarrhythmia)
most commonly encountered arrhythmia and common recommendation for it?
a fib
warfarin or NOAC daily to prevent complications of fib (clots, stroke)
initial therapy for a fib?
second-line therapy?
control ventricular rate with nodihydro CCB, BBlocker, or digoxin
restore sinus rhythm w/ electrical cardioversion
Class IA anthiarrhythmic agents
quinidine (Quinagulate, Quinidex)
Procainamide (Pronestyl)
disopyramide (Norpace)
Class IB anthiarrhythmic agents
lidocaine (Xylocaine) *losing to amiodarone, may cause seizures, short acting)
fosphenytoin (Cerebyx) prodrug to dilantin, mostly with digitalis-induced tachyarrhythmia
Mexiletine (Mexitil): “oral lidocaine”
Class IC anthiarrhythmic agents
proarrhythmic, only use in pts without structural heart disease
boxed warning: use only for life-threatening refractory arrhythmias
includes felcainide (Tambocor) and propafenone (rythmol)
Class II anthiarrhythmic agents
beta blockers
includes: propranolol (Inderal) acebutolol (Sectral) Timuolol (Blocadren) Esmolol (Brevibloc) *rapid Sotalol (Betapace) *rapid, also K+ blcoker*
Class III anthiarrhythmic agents
K+ channel blockers
sotalol
ibutilide
dofetilide
AMIODARONE complete VW classifications
Class IV anthiarrhythmic agents
verapamil
diltiazem
