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antihyperlipidemia agents

ANTIHYPERLIPIDEMIA AGENTS

Plasma lipids
Transported in bloodstream in form of macromolecular complexes of lipid and known as lipoproteins
Two major clinical importance/sequelae of high lipid
Acute pancreatitis
atherosclerosis

Hyperlipoproteinemia
Hyperlipidemia
Lipoprotein disorders
Primary hypertriglyceridemias
Primary chylomicronemia
Familial hypertriglyceridemia
Familial combined hyperlipoproteinemia
Familial dysbetalipoproteinemia
Primary hypercholesterolemias
Famimial hypercholesterolemia
Familial ligan-defective apolipoprotein B
Familial combine hyperlipoproteinemia
Lp(a) hyperlipoproteinemia
Secondary hyperlipoproteinemia

Lipid-lowering drugs
Several drugs are used
To decrease plasma LDL-cholesterol
Drug therapy is only one approach
Dietary measures are the first choice
Unless the patient has evident coronary or peripheral vascular disease
It is used in addition to
dietary management and
correction of other modifiable cardiovascular risk factors.
The selection of pts to be treated with drugs
Remains controversial.

Classes of lipid-lowering drugs
Statins
HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) Reductase inhibitors
Fibrates
Bile acid-binding resins
Other –
nicotinic acid
Ezetimibe

Cholesterol synthesis:
HMG-CoA is the precursor for cholesterol synthesis. 
HMG-CoA is also an intermediate on the pathway for synthesis of ketone bodies from acetyl-CoA.
The enzymes are located in the mitochondrial matrix.
HMG-CoA in cholesterol synthesis is made by equivalent, but different, enzymes in the cytosol.
HMG-CoA is formed by condensation of acetyl-CoA and acetoacetyl-CoA, catalyzed by
HMG-CoA Synthase.

Statins - chemistry
Competitive inhibitors of HMG CoA reductase
Structural analogs of HMH-CoA
Lovastatin ) Inactive lactone
Simvastatin ) prodrugs
Atorvastatin )
Fluvastatin )
Mevastatin ) active as given
Pitavastatin )
Pravastatin )
Rosuvastatin )

Statins - pharmacokinetics
Absorption
40% to 75%
Exception of fluvastatin – almost completely absorbed
High first-pass extraction by the liver
Excretion
In the bile
5-20% in urine
Plasma half-lives
1 – 3 hrs
Exp
atorvastatin – 14 hrs
Rosuvastatin – 19 hrs

Statins - mechanism of action
HMG-Co A reductase mediates the first commited step in sterol biosynthesis
Statins cause partial inhibition /competitive inhibitors of HMG CoA reductase
induce an increase in high-affinity LDL receptors
Lead to increase
Fractional catabolic rate of LDL
Liver’s extraction of LDL precursors from the blood
Thus reducing LDL

Decrease in cholesterol concentration activates
a cellular signaling cascade culminating in the activation of sterol regulatory element binding protein (SREBP),

SREBP is a transcription factor
up-regulates expression of the gene encoding the LDL receptor.

Increased LDL receptor causes
increased uptake of plasma LDL, and
Leading to decreases plasma LDL-cholesterol concentration.

LDL receptors are expressed by
Approximately 70% are hepatocytes,
remaining expressed by a variety of cell types in the body.

Statin – therapeutic uses and dosage
One regime only
Combination regime
Resins
Niacin
Ezetimbie
Generally given at evening, cholesterol synthesis occurs at night
Except atorvastatin and rosuvastatin
Absorption is enhanced by food
Exception pravastatin
Dose: varies 5 – 80 mg/day

Adverse effects and contraindications
HMG-CoA inhibitors are contraindicated in pregnancy.
Liver disfunction:
Elevations of serum aminotransferase activity (up to three times normal)
intermittent and usually not associated with other evidence of hepatic toxicity.
Pt with underlying liver disease or a history of alcohol abuse, levels may exceed three times normal.
A relatively common side effect of the statins is myositis,
infammation of skeletal muscle accompanied by pain,weakness,and high levels of serum creatine kinase.
Rhabdomyolysis,
disintegration of muscle with urinary excretion of myoglobin and kidney damage

Fibric acid derivatives (Fibrates)
Several fibric acid derivatives
Gemfibrozil,
fenofibrate,
bezafibrate,
ciprofibrate and
clofibrate
Fibrates reduce plasma levels of triglycerides by 30-50% and typically increase levels of HDL-C by 5-15%

Fibrates - pharmacokinetics
Gembfibrozil
Absorption
From intestine and tightly bound to plasma proteins
Undergoes enterohepatic circulation and readily passes placenta
Half-life – 1.5 hrs
Elimination –
70% kidney (mostly unmodified)
Liver- modifies to hydroxymethyl, carboxyl or quinol derivatives
Fenofibrate
An isopropyl ester
Hydrolyzed completely in intestine
Half-life – 20 hrs
Elimination
60% Excreted in urine as glucuronide
25% excreted in feces

Mechanism of action
Act as ligands.

activation of the nuclear transcription factor PPARα, predominantly expressed in tissues that metabolise fatty acids, such as the liver, kidney, heart and muscle.

PPARα recognises and binds to specific PPARαresponse elements leading to modulation of expression of the target genes

Therapeutic uses and dosage
Hypertriglyceridemias
VLDL predominate
Dysbetalipoproteinemia

Gemfibrozil – 600 mg orally dly/ bd
Fenofibrate 48mg – 1-3 tab dly

Bile acid – binding resins (Bile Acid Sequestrants)
Example: Cholestyramine, Colestipol and colesevelam
Useful only for isolated increases in LDL
In hypertriglyceridemia, VLDL may increased during treatment with resins.

Resins - pharmacokinetics
Polymeric cationic exchangeresins
Insoluble in water
not absorbed from the GI tract
Bind to bile acids in the intestinal lumen and prevent reabsorption
will lower circulating levels of LDLs. 
A slight increase in VLDL may be seen early, but these levels will generally fall to pre-treatment levels soon (2-3 months) after the initiation of therapy. 
no effect on HDLs. 
if pre-treatment levels of VLDL and IDL TG is high, then they are generally NOT effective.

Resins - Mechanism of Action
bind to bile acids in the intestine. 
prevents the absorption of dietary fats
effectively removing the exogenous pathway of lipid transport. 
liver will detects in decreasing cholesterol and
up-regulates the LDL receptors, thus removing LDLs from the systemic circulation

Adverse Effects
GI in nature 
steatorrhoea (fatty diarrhoea, due to dietary fats remaining in the gut),
constipation, and nausea. 
decrease the absorption of drugs which will bind to the resin, including fat soluble vitamins (A, D, E, K), digoxin, phenobarbitone, and oral anticoagulants. 

Nicotinic Acid (Niacin)
reduce circulating levels of VLDL and LDL (slower response that VLDL) and Lp (a).
It will increase circulating levels of HDL.
It is converted to amide in body
Which is incorporated into niacinamide adenine dinucleotide (NAD)
Excreted in the urine (2 form)
Unmodified
Several metabolites

Niacin- Mechanism of Action
exact mechanism of action of niacin is not known. 
it may decrease synthesis of VLDL by either inhibition of lipolysis in adipose (reducing lipid mobilisation) or decreased esterification of TG. 

Therapeutic uses and dosage
In combination with
Resin
Reductase inhibitor
Used in
heterozygous familial hypercholesterolemia and
other form of hypercholesterolemia.
Severe mixed lipemia
Useful
Combined hyperlipidemia
dysbetalipoproteinemia
Effective agent
Increasing HDL
Only agent to reduce Lp(a)
Dose : 1.5 – 6 g daily

Inhibitors of intestinal sterol absorption
Ezetimibe (Zetia) is distinct from agents
it does not inhibit cholesterol synthesis in the liver or increase bile acid excretion.
selectively inhibits the intestinal absorption of cholesterol and related phytosterols.

Ezetimibe – pharmacokinetics
water insoluble,
absorbed and extensively conjugated to an active phenolic glucuronide (ezetimibe-glucuronide) after oral intake.
ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
metabolized mainly in the small intestine and liver via glucuronide conjugation,
Then biliary and renal excretion.
half-life of about 22 hours

Ezetimibe Mechanism of action
inhibits the absorption of cholesterol in the small intestine.
Unlike other cholesterol-reducing agents,
act at the brush border of the small intestine
leading to a decrease cholesterol absorption to the liver.
leads to a reduction of hepatic cholesterol stores and
an increase in clearance of cholesterol from the blood.
has no significant effect on the plasma concentrations of the fat-soluble vitamins A, D, and E

Therapeutic uses and dosage
Dose range- 5 –20 mg/d
Hypercholesterolemia
Phytosterolemia

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