Drugs for the treatment of lipid disorders Flashcards
energy stored in adipose tissue derived from FFA
triglycerides
formulated into transportable particles in liver and gut in the form of
lipoproteins
composition and origin of chylomicrons
Exogenous/dietary triglycerides, unesterified cholesterol, cholesteryl esters
origin is the intestine
Very-low density lipoproteins (VLDL)
composition and origin of this lipoprotein
Triglycerides; some cholesteryl esters
origin is the liver
Intermediate-density lipoproteins (IDL)
composition and origin
Cholesteryl esters and triglycerides
VLDL/HDL catabolism
whya re LDL the bad guys?
take the cholesterol out into the periphery
HDL
take cholesterol out of the cells into the liver fro making stuff
Large TG-rich particles formed in intestine
Carry dietary triglycerides, unesterified cholesterol, and cholesteryl esters from diet or synthesized in gut —>liver
Chylomicrons
Normally contain 15-20% of total cholesterol and most of total TG; cholesterol usually 1/5 of TG concentration
VLDL
VLDL is formed in the
liver
it is how we get TG to the peripheral tissue
if we have high VLDL and we give them something that enhances lipatic lipase what will the result be
more LDL
Apo B
takes into account both particles >
VLDL and LDL?
LDL bound to (a) protein
Lp(a) Lipoprotein
Contribute to coronary artery disease by inhibiting thrombolysis
lipoproteins that contain apolipoprotein (apo) B-100
Lipoproteins that contain apolipoprotein (apo) B-100 convey lipids into the artery wall. These are low-density (LDL), intermediate-density (IDL), very-low-density (VLDL), and lipoprotein( a) (Lp[ a]).
Chylomicrons are formed in the________ and carry triglycerides of _______ unesterified cholesterol, and cholesteryl esters.
Chylomicrons are formed in the intestine and carry triglycerides of dietary origin, unesterified cholesterol, and cholesteryl esters. They transit the thoracic duct to the bloodstream.
VLDL triglycerides are hydrolyzed by LPL, yielding free fatty acids for storage in adipose tissue and for oxidation in tissues such as cardiac and skeletal muscle.
VLDL triglycerides are hydrolyzed by LPL, yielding free fatty acids for storage in adipose tissue and for oxidation in tissues such as cardiac and skeletal muscle.
if someone has a TC 220
HDL of 30 and TG of 185 what is there total TG LDL
(TC)- (1/5th of TG + HDL )
220-67=153
calculate non HDL
TC 220
HDL 30
TG 185
220-20
TC-HDL
what measurement is most predictive of ASCVD risk
non-HDL
desirable LDL
<100
optimal TG
<150
why do you treat high TG
more than 500 b/c of acute pancreatitis
boderline TG
150-199
what is the tx for someone with TG at 180
emphasis weight reduction and increased physical activity as well as minimize
drugs that elevate LDL
some progestins anabolic steroids danazol isotetinoin immunosuppressive amiodarone thiazide diuretics glucocorticoids TZDS fibric acids long chain omega fatty acids
drugs that elevate TG
oral estrogens tamoxifen raloxifen retinoids immunosuppresives interferon Beta-blockers atypical antipsychotics protease inhibitors thiazide diuretics glucocorticoids rsoiglitazone bile acide sequestrants L-asparaginase cyclophosphamide
diet characteristics and dz that are associated with elevated LDL or TG
Anorexia nervosa ckd Nephrotic syndrome DM HIV autoimmune pregnancy PCOS menopause
drugs used for the tx of dyslipidemia
HMG CoA reductase inhibitors (statins Fibric Acid derivatives Niacin Bile Acid Binding Resins Intestinal Sterol Absorption Inhibitors Omega-3 Fatty Acids CETP Inhibitors PCSK-9 Inhibitors
These compounds are structural analogs of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme
statins
Lovastatin, atorvastatin, fluvastatin, pravastatin,
simvastatin, rosuvastatin, and pitavastatin
primary prevention
high risk (angina) without an MI or a stroke It has become standard practice to initiate reductase inhibitor therapy immediately after acute coronary syndromes, regardless of lipid levels.
when to treat
moderate to high dose with greater than 7.5% estimated 10 year risk age 40-75
transport dietary/synth fats to cells and to liver (to be made into VLDL and sent out again)
Chylomicrons
when do we see the elevation of chlomicrons
). Elevated for 10-12h after a meal.
a key enzyme used by cells to “pick” fats off the various “fat trucks” (chylomicrons, LDL, VLDL, etc) as they float by.
o LPL (lipoprotein lipase
. Effectively, the______ and ________ are important for getting LDL out of commission and back to liver.
. Effectively, the ApoB proteins and LDL receptors are important for getting LDL out of commission and back to liver.
fat-filled macrophages
foam cells
what would you need when considering statin in an individual with clinical ASCVD
fasting lipid panel
ALT
CK (if indicated)
consider evaluation for other secondary casues
MOA of bile acid sequesterants
Resin binds bile in intestine = insoluble complex → excreted in feces
LDL lowering we see with BAS
Resin binds bile in intestine = insoluble complex → excreted in feces
adverse effects of BAS
GI: constip, abd discomfort, bloating, flatulence, activation of diverticulitis. (high d/c rates)
Metabolic: INCREASE in TG by 10% in pts (esp if has high TG’s already)
not for pt with high TG
May reduce absoprtion of fat sol vitamins & folate → hypothrombinemia in chronic use
CI of BAS
if TG >400
what is the dosing issue with BAS
Binds other anionic agents (amiodarone, oral anticoag, digoxin, gemfibrozil, glipizide, phosphate supplements, piroxicam, propranolol, diuretics, thyroid hormone
therefore → wait 4-6h b4 taking other drugs
VERY hard to do since dosed 3x/d
BAS seen with LESS DDI
Colesevelam (Welchol®)
Tablets (3x/d)
Niacin MOA
Inhibits FA mobilization from peripheral tissue
reduces LDL 15-20% (at higher doses) and TG as well as increasing HDL (at lower doses) 20-35%
biggest ADE with Niacin
Flushing: more common w/ IR → vasodilate in 20 min; lasting 20-60 min
can take ibuprofen 30 mins before or titrate to avoid
other than flushing what are the ADE seen with Niacin
Eyes: conjunctivitis, blurred vision, dry eyes
Metabolic: ↑A1c (worst if fat, high A1c, hyperuricemia)
Hepatotoxic: reported mainly w/ SR preps, reversible w/ d/c
CI of Niacin
relative and absolute
Absolute: liver dz, PUD
Relative: DM, gout, renal dz
Therapeutic range of Niacin
Most effect w/ 1.5-2gm/d IR
Four major statin benefit groups:
- Clinical ASCVD
- Primary LDL-C >190
- DM aged 40-75 & LDL 70-189 & no clinical ASCVD
- No clinical ASCVD or DM but has LDL between 70-189 & ASCVD risk >7.5%.
What is clinical ASCD?
Acute coronary syndrome
Hx of MI or angina
Coronary or other arterial procedures to “revascularize”
Stroke or TIA
Peripheral artery disease
place in Tx for niacin
pt that can’t tolerate a stating (myopathy)
but cardiovascular benefit is not well studied
MOA of HMG CoA reductase inhibitors
competitive inhibition of HMG-CoA ( an early step in cholesterol synthesis)
Leads to upregulation of the LDL receptor and increased catabolism of LDL (LDL-C) and precursor particles ( TG).
Proprotein convertase subtilisin/kexin type 9 (PCSK9)
When PCSK9 binds to the LDL receptor, the receptor is broken down and can no longer remove LDL cholesterol from the blood.
blocking PCSK9 can lower blood cholesterol levels
; proprotein convertases is needed to make PCSK9 active
Calculated LDL-C not accurate if TG is greater than
400
how can you calculate LDL-C
Total cholesterol – (HDL + TG/5)
normal TG
<150
boderline high TG
150-199
high TG
200-499
If TG borderline recommended tx
emphasis on weight reduction, increased physical activity, alcohol intake
NLA very high risk pt
ASCVD or DM with 2 or more major ASCVD risk factors for end-organ damage
high risk NLA
DM with 0-1 other major ASCVD rf
- CKD stage 3b or 4
- LDL-C>190
metabolic syndrome
3 or more risk facotrs
abd obesity :wais circumfrence >102 in men >88 in women
TG>150
HDL
men <40
women<50
BP >130/>85
FBS>100
statin benefit groups
- ascvd
- primary LDL-c >190
- DM aged 40-75 with LDL-C 70-189 mg/fL and without clinical ASCVD
- without ASCVD or DM with LDL-C b/w 70-189 and estimated 10 year ascvd risk >7.5%
what you should assess for with suspected lipid disease
- Assess for secondary causes of high cholesterol level
- Assess for familial disorders
- Presence of Clinical ASCVD
- Lipid panel values
(3. , 4. and age determine treatment intensity)
indications of HMG-CoA Reductase Inhibitors
Various dyslipidemias
Have looked at effect on cancer
Oxidative stress & vascular inflammation → Atherosclerotic lesion stability For ALL: ↑ HDL 5-10%
what is clinical ascvd
● Acute coronary syndrome ● Hx of MI or angina ● Coronary or other arterial procedures to "revascularize" ● Stroke or TIA ● Peripheral artery disease
Lovastatin dosage
20-80mg
Pravastatin dosage
10-80
Simvastatin dosage
5-40mg
Rosuvastatin dosage
5-10mg (up to 40mg)
atorvastatin dosage dosage
10-80mg
ADE of HMG-CoA Reductase Inhibitors
” Myopathy/myositis = rhabdo (elevated CK, cola urine, weakness, ↓urine output, myalgia) 1:1250 pts
” Elevated A1c (NNH ranges from 300 - 500)
Elevated LFTs (<2%, toxicity?, obtain baseline LFTs)
CNS → insomnia, memory impairment, loss of
Neuropathy → paresthesia, hyperesthesia
Skin: eczematous rash (uncommon)
proteinuria with rosuvastatin doses greater
symptoms of rnhabdomylosis
dark red or cola-colored urine decreased urine output general weakness muscles stiffness muscle tenderness weakness of affected muscles
how to we measure muscle breakdown associated with Hmg Coa reductase inhibitors
Ck (creatine kinase)
risk factors for rhabdo
Hx of statin intolerance CYP-inhibition >75 yO Hx of CVA aSIAN High dose statin hypothyroidism reduce renal/hepatic fxn rheumatologic d/o steroid myopathy decreased vitamin D primary muscle disease
what do you do if pts are at risk for rhabdo
check CK before starting drug
if pt has myalgia of statin
d/c until sx have been evaluated check CK and urine myoglobin r/o other causes re challenge w/ los dose to determine cause try another atatin
DDI for statins
Gemfibrozil & Nelfinavir (fibric acid derivative) = ↑ risk of myositis
azole antifungals
EtOH - ↑ risk of myopathy
Warfarin - ↑ prothrombin time
BAS’s - reduced absorption
what ate the specific concerns we are worried about with rosuvastatin
Proteinuria when dosed >40 mg/d
Myopathy, rhabdo (esp w/ ↑ doses)
Altered metabolism in Asians: (2-fold ↑)
which HMG coa reductase inhibitors are metbaolised by cyp3a4 and what DDI are we concerned about
lovastatin
simvastatin and
atorvastatin
inhibited by azoles, macrolides, nefazodone, PIs, amiodarone, verapamil grapefruit juice.
which HMG coa reductase inhibitors are metabolizes by CYP29C, major DDI
fluvastatin
rosuvastatin
pitavastatin
CYP29C Nelfinavir ➔ ↑ risk of myositis
*If CrCl 30-60 how should you dose pivistatin (livalo)
*If CrCl 30-60 í initial 1mg
2mg max
if you’ve never had an event and you’re being treated for lipid disorder
primary
when you absorb from the gut what is the cholesterol formed
chylomicrons this is why we need to fast before a lipid panel
NLA ASCVD Criteria
evidence of vascular disease but NOT chest pain
Myocardial infarction or other acute coronary syndrome
Coronary or other revascularization procedure
Transient ischemic attack
Ischemic stroke
Atherosclerotic peripheral arterial disease
Included ankle/brachial
index < 0.90
Other documented atherosclerotic disease:
Coronary atherosclerosis
Renal atherosclerosis
Abdominal aortic aneurysm
secondary to atherschlerosis
Carotid artery plaque ≥
50% stenosis
mainstay of lipid tx
statins hmg-CoA
Lipid drug of choice for HIV pt
pravastatin
moderate lipid lowering
moderate 30-50%
high intesity therapy should decrease lipids by
> 50%
atorvostatin 40-80mg
rosuvastatin 20- 40mg
Main difference in LDL lowering is seen with initial dose
With subsequent doubling of statin dose, an additional ____ LDL lowering is seen
Main difference in LDL lowering is seen with initial dose
With subsequent doubling of statin dose, an additional 5-6% LDL lowering is seen
if you have someone on a statin and they get rhabdo on low doses
switch the BAS
BAS is contraindicated in
TG >400 mg/dl - dysbetalipoprotienemia
TG>200 (relative)
increased HDL more than any other drug but has very little cardio protective effect
niacin
how to avoid flushing with niacin
niaspan at night
or NSAIDS but that would have to be 3x a day
niascin is CI in (absolute and relative)
Absolute: liver dz, PUD
Relative: DM, gout, renal dz
gout (changing uric acid up or down causing the white blood cells to mobilize)
if used in a pt with attacks need to be given an anti-inflammatory to avoid attack
FIBRIC ACID DERIVATIVES MOA
Bind to and stimulate PPAR-a (peroxisome proliferator-activated receptor-alpha) í
↓ Apo C-III —> ↑ lipolysis of lipoprotein TG via LPL (lipoprotein lipase) —> ↓ TG
the higher the TG the more likely you are to see and increase in LDL
why do we are about high tG
pancreatitis over 500
CI of FIBRIC ACID derivatives
CI in pts with renal failure because of renal clearance
CrCl<30 –>Avoid
CrCl 30-60 –>Limit dose
ADE of fibric acids
> 10% Dyspepsia, abd pain, cholelithiasis
1-10% fatigue, vertigo, HA, rash, N/V/D, constipation
<1% atrial fibrillation, hyperesthesia, dizziness, drowsiness, depression, blurred vision, myalgia (rhabdo!)
Gemfibrozil (Lopid®)
Fenofibrate (Tricor®)
are both
fibric acids
Ezetimibe
(Zetia®)
10mg QD
” Inhibits absorption of cholesterol in small intestine
ADE Ezetimibe
Zetia®
” GI sx: abd pain, D
“ Fatigue
“ Arthralgia
“ Back pain
orphan drug used for
homozygous familial hypercholesterolemia (HoFH) w/ LDL-C > 500mg/dL
Lomitapide
(Juxtapid®)
and
Mipomersen
(Kynamro®)
” Manmade antibodies that target proteins in the body that prevent the elimination of LDL cholesterol
PCSK9 Inhibitors
Injectable drugs that can be used w/ statins
PCSK9 Inhibitors
PCSK9 Inhibitors
increase LDL receptor
Reduce LDL 59-66% in combo w/ moderate intensity statin
“ Proof of efficacy TBD
Ezetimibe
(Zetia®)
MOA
” Inhibits absorption of cholesterol in small intestine
Lomitapide
Juxtapid®
Microsomal triglyceride transfer protein (MTP) inhibitor - resides in lumen of the endoplasmic reticulum í thus prevents apo B-containing lipoprotein assembly
Mipomersen
(Kynamro®) . moa
SC injection q wk
” Inhibits apolipoprotein B-100 synthesis
non pharm tx for lowering lipids
omega 3 (lovaza) soluble fiber sitosanol (margarine) red yeast 600mg garlic
these lipoproteins are responsible for taking the lipids to the liver
chylomicrons
when food is absorbed in the liver it is absorbed into this
liver transforms chylomicrons and makes
VLDL
chylomicrons originate in the
intestine
as your going down in density you have _____ fat and more _______
you have less fat and more cholesterol as you are going down in density
APOE
protein on the VLDL that binds to the receptors on the liver and makes this lipoprotein into LDL
lipid lowering drugs that are CI in pts with high TG
BAS >400
Gemfibrozi l>500
Therapeutic range of nIacin
less than 2mg
doesn’t have cardio protective evidence that statins does
what drugs are we worried about pt getting DM
Niacin can increase A1C
high intensity statins has been shown to increase dm
Increase in gout attack seen with what lipid med
niacin
changing uric acid level in either direction causes wbc to mobilize
main reason we treat hyperlipidemia and what drug would be best for this
fibric acids
gemfibrozil
fenofibrate
fibric acid derivates are metabolized how?
hepatically metabolized
metabolites
excreted in the urine
avoid in CrCl<30 or CKD
cholilethiasis is a complication of what medication
fibric acid derivatives (10%)
MOA of PCSK9
man made antibodies that target proteins in the body that prevent the elimination of LDL increasing LDL receptor and inhibiting protein that destroys the receptor
indications of PCSK9
very high risk of another event
seen with LDL cholesterol fomr 59-66%
PSCK9 drug names
evolucumab
alirocumab
other non drug tx for lowering cholesterol
fiber omega 3 fatty acids garlic sitosanol (margarine) red yeast 600mg (statin)
lovaza
fish source that lowers TG
for someone that doesn’t tolerate fibric acid
can elevate liver enzymes
maybe some benefit in heart failure
