-
HMG CoA reductase
- converts HMG CoA to mevalonic acid
- rate limiting step in cholesterol biosynthesis
-
Low cholesterol may be a marker for
cancer presence
-
Lipoproteins consist of
- Triglycerides
- esterified cholesterol
-
Apolipoproteins
- characterized by weight
- solubilizors
- receptor recognition
- enzyme co-factors
-
Apo B's are in volved in transport of
-
Apo (a)
- transport
- inhibits thrombolysis
-
VLDL
carries TGs to peripheral cells from the liver
-
LDL
- bad cholesterol
- primary cholesterol carrying particle
-
HDL
removes cholesterol from cells
-
LP (a)
potential to obstruct endogenous anti-platelet enzymes
-
Triglycerides synthesized in the liver leave through
LDL
-
lipoprotein lipase acts on LDL particles to make them
smaller
-
Carry cholesterol back to the liver
-
Elevated homocysteine levels
- cytotoxic to endothelium (inhibit NO production)
- promote prothrombic activity
- increase LDL oxidation resulting in increased risk of stroke, CAD and PVD
-
Used to reduce homocysteine levels
- folic acid
- does not prevent elevation
-
C Reactive protein
- measured to asses CV risk
- accute phase reactant released in inflammatory situations
- increased when inflamation to vessel walls is present
-
Increased c-reactive protein levels are reduced by
- aspirin
- HMG-CoA reductase inhibitors
-
Measurements of CV risk
- homocysteine levels
- C-reactive protein levels
- walking speed
-
Secondary causes of dislipidemias
- hypotheyroidism
- protenuria
- DM
- liver disease
- alcohol
-
Drugs that can cause dislipidemias
- androgens
- beta blockers
- thiazides
-
Beta-blocker effect on lipid profiles
- inhibit lipoprotein lipase disrupting cholesterol cycle
- increases triglycerides
- increases total cholesterol
-
Alcohol effects on lipid profiles
- alcohol increases VLDL secretion from the liver
- results in higher triglyceride levels
-
NCEP screening guidelines say screening should be completed every
5 years for adults >20
-
Desired total cholesterol level
< 200 mg/dl
-
High total cholesterol
> 240 mg/dl
-
Optimal LDL cholesterol
< 100 mg/dl
-
Borderline high LDL
130 - 159 mg/dl
-
Very high LDL
> 190 mg/dl
-
Low HDL level
- < 40 mg/dl for men
- < 50 mg/dl for women
-
-
Calculation of LDL cholesterol
TC- [HDL + (TG/5)]
-
High triglycerides can contribute to
pancreatitis
-
calculation of non-HDL cholesterol and its use
- TC - HDL
- best used to asses risk in pt with hypertriglyceridemia
-
Low risk non-HDL level
<160 mg/dl
-
Moderate risk non-HDL level
190-219 mg/dl
-
high risk non-HDL level
> 220 mg/dl
-
Another good ratio to look at to asses CV risk
ApoB/ApoAI
-
Risk factors for CHD other than LDL
- Age
- Family history
- Smoking
- Hypertension
- HDL < 40 mg/dl
- DM
-
Male age at risk for CHD
> 45
-
Female age at risk for CHD
- > 55
- or premature menopause w/o estrogen replacement
-
Negative risk factors for CHD
- HDL > 60 mg/dl
- if present, subtract one risk factor (except smoking)
-
Small LDL particle vs Large LDL particles
Large LDL particles are better
-
Small HDL particles vs Large HDL particles
- large HDL good
- small HDL bad
-
High risk patient (# of risk factors, goal LDL, when to start lifestyle change, when to start drug therapy)
- pt has CHD or risk equivalents
- goal LDL < 100 mg/dl
- lifestyle change >100
- start drugs at > 100
-
Moderately high risk patient
- pt has two or more risk factors
- Goal LDL < 130 mg/dl
- start lifstyle change at >130
- start drugs at >130
-
Moderate risk patient
- two or more risk factors
- goal LDL < 130
- start lifestyle change >130
- start drugs at >160
-
Low risk patient
- < one risk factor
- Goal LDL <160 mg/dl
- start lifestyle change at > 160
- Start drugs at >190
-
Diet and exercise will lower LDL by
15 to 20%
-
Normal triglyceride levels
< 150 mg/dl
-
High triglyceride levels
200-499 mg/dl
-
Why LDL is bad
- attaches to walls of blood vessels and becomes oxidized releasing cholesterol
- macrophages & WBC are attracted to the area
- Foam cells form which lead to fatty streaks which leades to plaque
-
% of 20 y/o that have fatty streak formation
33%
-
Complications of untreated hyperlipidemia
- Coronary heart disease
- Peripheral vascular disease
- Carotid artery disease
-
Treatment options for hyperlipidemia
- diet therapy
- exercise
- drugs that reduce cholesterol absorption/reabsorption
-
Diet therapy
- diet and exercise should be tried for 6 mo
- may drop cholesterol up to 14%
-
Diet has the most effect on decreaseing
-
Exercise
- 3 sessions per week for 20 min each have an impact
- duration is better than intensity
-
Exercise changes triglycerides by
- raising HDL up to 1%
- drops VLDL
- drops triglycerides
-
Drug therapies for reducing cholesterol absorption/reabsorption
- bile acid binding resins
- cholesterol absorption inhibitors
- inhibitors of dietary fat absorption
- niacin
-
Bile acid resins usually decrease ____ & ____.
__, __, ___ may increase.
- decrease LDL by 15-20%
- decrease total cholesterol
- VLDLD, TG and HDL my increase
-
Bile acid resin agents
- cholestyramine
- colestipol
- colesevelam
-
Bile acid binding resins are indicated for
- familial hypercholesterolemia with normal TGs
- rarely used as mono therapy
- usually combined with reductase inhibitors
-
Mechanism of action for bile acid resins
- bind bile salts in the GI tract inhibiting them to be reabsorbed to hepatic circulation
- Hepatic LDL receptors upregulated
- cholesterol 7a hydroxylase upregulated
- HMG CoA reductase upregulated
- phosphatidit acid phosphatase upregulated
-
Adverse reactions with bile acid resins
- GI problems as drug is not absorbed
- Constipation (fecal impaction) 39% elderly
- Bloating and gas
- abdominal pain
- nausea
- vitamin deficiency?
-
Drug interactions with bile acid resins
- drug binds anions, cations and neutral compounds
- (warfarin, thyroid hormone, digoxin, niacin)
-
Bile acid resin that does not interfere with absorption of warfarin, digoxin or statins
colesevelam
-
cholesterol absorption inhibitors
ezetimibe
-
cholesterol absorption inhibitors (ezetimibe) are indicated for
- familial hypercholesterolemia + statin
- combined hyperlipidemia (cautiously with statins or fenofibrates)
- sitosterolemia + diet
-
ezetimibe drops GI cholesterol absorption by ___%, and drops total cholesterol by ___%
- 50%, however only 25% of cholesterol comes from diet
- 10%
-
Statins + ezetimibe
- synergistic
- lowers LDL
- no difference in carotid intima thickness
-
mechanism of action for ezetimibe
- inhibits abs. of cholesterol from the small intestine at ABCG5
- upregulation of LDL receptors on the liver occurs
- inhibition of NPC1L1 (increases cholesterol elimination through the bile acid mech.)
-
Ezetimibe effects on cholesterol levels
- decrease in total cholesterol
- LDL, apo B and TG decreased
- small increase in HDL
- does not decrease small LDL as much
-
Adverse drug reactions with ezetimibe
- very low incidence of:
- diarrhea
- arthralgia
- respiratory issues
-
Drug interactions with ezetimibe
- Eze levels decreased by bile acid resins
- fibric acids increase Eze level = not recommended may lead to cholelithiasis
- cyclosporin can increase eze levels
-
Any drugs that effect cholesterol should be avoided in
moderate-severe hepatic dysfunction
-
Inhibitors of dietary fat absorption
orlistat (alli)
-
Use of orlistat
- not used for hypercholesterolemia
- used with statins or eze (synergistic) to drop TC, LDL and increase HDL
- primarily used for obesity
- OTC
-
Mechanism of action for orlistat
- reversible lipase inhibitor
- decreases absorption of fats by 30%
- forms bond with pancreatic lipase to inactivate
- decreases TC hydrolysis in stomach and Sm. I.
- no effects on serum lipases
-
ADRs with orlistat
- GI issues (diarrhea do to fat in bowels)
- increased urinary oxalate = kidney stones
- DM pt may need to decrease dosage of insulin or hypoglycemics
- abuse potential: no additive effects above 120mg tid
-
Drug interactions with orlistat
- fat soluble vitamins 2hr before or after orlistat
- insulin (may need to decrease)
- cyclosporin
- warfarin (vit K levels may decrease)
-
orlistat + fenofibrate
reduced clotting risk
-
Niacin is indicated for
all lipid disorders
-
Niacin administration results in
- decreased VLDL, LDL, TG, Lp(a), apo B, TC
- increases HDL
-
Niacin is the only drug to
- decrease LP(a)
- increase HDL as much
-
Niacin can result in ____% increase in HDL
14-39%
-
Mechanism of action for niacin in the liver
- Decreased TG synthesis
- Decreased APO B formation
- Decreased VLDL secretion
- Decreased LPa
-
Mechanism of action for niacin in the systemic circulation
- decreased serum VLDL results in reduced lipolysis to LDL
- decreased serum LDL and ApoB
- increased HDL and Apo A-1
- decreased mobilization of fats from tissues
- increased reverse cholesterol transport
-
Key receptor for the action of niacin
GPR109a which mediates VLDL formation and secretion
-
Niacin kinetics
- well absorbed
- rapidly metabolized
- usually dosed in ER dosage forms
-
_____ causes the problem that leads to flushing and adverse effects associated with niacin.
nicotinuric acid
-
conversion of niacin to nicotinuric acid is
high capacity low affinity
-
ER tablets convert niacin to nicotinamide which results in
- low capacity, high affinity reactions
- some hepatotoxicity
-
Adverse reactions wtih niacin
- skin flushing 90% of pt experience
- pruritis
- abdominal pain
- activation of peptic ulcer
- increased liver enzymes
- hyperuricemia (caution in gout)
- glucose intolerance (DM pt can still take)
- myopathy
-
Mechanisms to avoid flushing with niacin
- gradual dose increase
- use prostaglandin inhibitor 30-60 min before dose (nsaids)
- take ER pills at bedtime
- tolerance will build up over time
- D2 antagonist laropiprant
-
Drug interactions with niacin
- vasodilators => postural hypotension
- HMG-CoA reductase inhibitors => increased risk of myopathy
- Anticoagulatns => decreased platelet count and increased prothrombin times
-
Niacin receptor agonists
- adiponectin
- increases leptin levels which has an anorexic effect
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