Transcript Atherosclerosis, Management and Medications

Management & Medications
 Diet, weight loss and drug therapy are the
mainstay of treatment, while exercise
training is used as adjunctive therapy
 Lipid-lowering medications
 Nicotinic acid – niacin suppresses VLDL synthesis
 Bile acid-binding resins – lowers LDL (Lipitor,
Metaprol, Cholestyramine)
 Fibric acid derivatives – increase enzyme activity
(Gemfibrozil)
Management & Medications
 Lipid-lowering medications:
 HMG CoA inhibitors – inhibit cholesterol synthesis
(Lovostatin, Provostatin)
 Other medications to be aware of
 Beta blockers – increase TG, decrease HDL
 Diuretics – increase Chol, VLDL, LDL & TG
 Insulin therapy – decrease TG and increase HDL
 Estrogens – increase HDL, VLDL, TG
Mechanisms of action of drugs
 bind to bile acids/cholesterol
 inhibit absorption/reabsorption
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increase peroxisomal FA oxidation
stimulate lipoprotein lipase
inhibit triglyceride lipase
inhibit HMG CoA reductase
stimulates microsomal 7-alpha hydroxylase
Drug Classification
 systemic/non-sytemic
 cholesterol lowering agents
 bile acid sequestrants
 sitosterols*
 probucol*
 d-thyroxin*
 HMG Co-A reductase inhibitors
* No longer available commercially in the U.S
Drug Classification
 mixed activity (nicotinic acid)
 triglyceride lowering
 clofibrate (Atromid-S)
 gemfibrosil (Lopid)
 fenofibrate (Tricor)
Mechanism of Action of
Statins,
acetyl CoA
Cholesterol Synthesis Pathway
HMG-CoA synthase
HMG-CoA reductase
HMG-CoA
X Statins
mevalonic acid
mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
ubiquinones
Squalene synthase
farnesyl pyrophosphate
squalene
cholesterol
dolichols
Pharmacokinetics of Statins
Statin
Metabolised
by CYP450
Protein
binding (%)
Lipophilic
Halflife (h)
lovastatin
Yes
>95%
Yes
~2
pravastatin
No
~50%
No
~2
simvastatin
Yes
95–8%
Yes
~3
atorvastatin
Yes
>98%
Yes
~15
cerivastatin
Yes
>99%
Yes
~3
fluvastatin
Yes
>98%
No
~3
(Adapted from Horsmans 1999, Vaughan et al, 2000)
HMG CoA reductase inhibitors
 Precautions:
 mild elevation of serum aminotransferase (should
be measured at 2 to 4 month intervals)
 minor increases in creatine kinase (myopathy,
muscle pain and tenderness)
 do not give during pregnancy
CLOFIBRATE
 Primary activity on triglycerides
 MOA:
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increases lipoprotein lipase
lowers VLDL
increases peroxisomal FFA oxidation
inhibits cholesterol biosynthesis
increases biliary secretion of cholesterol
 ancillary:
 decreases platelet adhesiveness/fibrinogen
Clofibrate (Atromid-S)
 Precautions
 enhances coumarin activity
 renal/hepatic injury contraindication
 pregnancy/nursing
 cholelithiasis
 most commonly reported ADR are GI related
 liver malignancies (not very common; but has led to
scant usage)
Fenofibrate (Tricor)
 a relatively new fibric acid derivative (micronized
form of the drug)
 lowers plasma TG
 inhibits TG synthesis
 stimulates catabolism of VLDL
 indicated primarily for hypertriglyceridemia
 same side effects and precaution as in other fibric
acid compounds
 half-life: 20 hours
 Dose: 67-201 mg/day with meals
Gemfibrosil (Lopid)
 MOA
 stimulates lipoprotein lipase
 interact with PPARa (peroxisome proliferator-activated
receptors)
 inhibits triglyceride lipolysis in adipose tissue
 decreases FFA uptake by the liver
 decreases hepatic VLDL/TG synthesis
 slight cholesterol lowering effect
 precautions
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similar to clofibrate
myositis (voluntary muscle inflammation)
GI (indigestion, abdominal pain, diarrhea)
cholelithiasis (increased cholesterol biliary secretion)
 half life: 1.1 hours
NICOTINIC ACID (Niacin)
COOH
N
NICOTINIC ACID (NIACIN)
A water soluble vitamin of the B family;
nicotinamide is not active
Once converted to the amide, it is
incorporated into NAD
In order to be effective, it has to be dosed at the rate of 1.5 to
3.5 gm daily.
A sustained release dosage form is available
adverse effects: GI disturbances (erosion and ulceration)
red flush especially in the face and neck area
caused by vasodilation of capillaries
Nicotinic acid
(Niacin)
 MOA
 dual plasma triglyceride and cholesterol lowering
 decreases VLDL and LDL
 decreases TG lipase in adipose tissue
 increases lipoprotein lipase in adipose tissue
 precaution
 transient cutaneous flush
 histamine release
 potentiates BP effect of antihypertensives
Advicor®
 niacin-extended-release and lovastatin tablets
 reduces LDL-C, TC, TG and increases HDL-C
 available as 500/20, 750/20 and 100/20 mg
tablets
Lipid Management Pharmacotherapy
TC
LDL
HDL
TG
Patient
tolerability
 19-37%
 25-50%
4-12%
 14-29%
Good
 13%
 18%
1%
 9%
Good
Bile acid
sequestrants
 7-10%
 10-18%
3%
Neutral or
Poor
Nicotinic acid
 10-20%
 10-20%
14-35%
 30-70%
Reasonable to
Poor
 19%
 4-21%
11-13%
 30%
Good
Therapy
Statins*
Ezetimibe
Fibrates
HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol,
TC=Total cholesterol, TG=Triglycerides
*Daily dose of 40mg of each drug, excluding rosuvastatin.
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Investigational drugs
 acylCoA: cholesterol acyltransferase
inhibitors
 Orphan nuclear receptors:
 LXR – “oxycholesterol receptor” --- enhanced
cholesterol efflux
 FXR – “bile acid receptor” ---- decreased cholesterol
conversion to bile salts
Squalene synthase inhibitors
 squalestin 1, a fermentation product derived
from Phloma species (Coelomycetes)
 a potent inhibitor of squalene synthase
 produces a marked decrease in serum
cholesterol and apoB levels
 may represent an alternative clinical therapy
to hypercholesterolemia