MED-203

Antihyperlipidemic drugs

Dr. Razia Khanam

2/7/21

www.gmu.ac.ae COLLEGE OF MEDICINE

 LEARNING OBJECTIVES
• At the end of the class student should be able to:

• Enumerate the antihyperlipidemic agents

• Describe the mechanism of action, pharmacological actions, uses and
adverse effects of
• HMG-CoA reductase inhibitors
• Bile acid binding resins
• Fibric acid derivatives
• Ezetimibe
• Nicotinic acid
• Outline the management of primary and secondary hyperlipidemias
 DYSLIPIDEMIA
• Disorders of the metabolism of lipoproteins, including lipoprotein over
production / deficiency

• Elevated cholesterol (CH) levels

• Elevated low density lipoprotein (LDL) CH levels
• Elevated triglyceride (TG) levels
• Decreased high density lipoprotein (HDL) CH levels

• Antihyperlipidemic drugs: Attracted considerable attention because of

their potential to prevent CV disease by retarding the accelerated
atherosclerosis in hyperlipidaemic individuals
 DYSLIPIDEMIA
• If the metabolic disorders of lipoproteins are due to genetic reasons :
Primary dyslipidemia
• If the disorders (↑LDL or ↓HDL) are secondary to some disease
(diabetes, myxoedema, nephrotic syndrome, chronic alcoholism, drugs):
Secondary dyslipidemia
• Risk factors: Diet, obesity, hypertension, smoking, alcohol, sedentary
lifestyle
• Metabolic disorders that involve elevations in lipoprotein species (LDL,
IDL, VLDL) are termed hyperlipidemias or hyperlipoproteinemias
• Hyperlipemia denotes increased levels of triglycerides
 Types of hyper-lipoproteinemia
Type Disorder Cause Occurrence Elevated Plasma lipids
plasma CH TG
lipoprotein

I Familial lipoprotein Genetic Very rare Chylomicron ↑↑ ↑ ↑↑

lipase deficiency
II a Familial hyper- Genetic Less common LDL ↑↑ N
cholesterolemia
II b Familial combined Multi Commonest LDL, VLDL ↑↑ ↑↑
hyperlipidemia factorial
III Familial dysbeta- Genetic Rare IDL, ↑ ↑
lipoproteinemia chylomicron
remnants
IV Hypertriglyceridemia Both Common VLDL ↑/N ↑↑
V Familial combined genetic Less common VLDL, ↑ ↑/N
hyperlipidemia Chylomicron
 LIPOPROTEINS
• Lipids: Simple, compound, neutral {TG, CH, cholesterol esters (CE)}
• Neutral lipids are transported into circulation in solubilized form, with
the help of lipoproteins
• Lipoproteins: Spherical particles of water soluble proteins, that transport
neutral lipids
Types of lipoproteins
 ANTI-HYPERLIPIDEMIC AGENTS
• HMG-CoA reductase inhibitors: Atorvastatin, Simvastatin,
Rosuvastatin, Pravastatin, Fluvastatin, Pitavastatin

• Bile acid binding Resins (Sequestrants): Cholestyramine,

Colistipol, Colesevelam

• Fibrates: Gemfibrozil, Clofibrate, Bezafibrate, Fenofibrate

• Inhibitor of VLDL secretion & lipolysis: Nicotinic acid (Niacin)

• Cholesterol Uptake Inhibitors: Ezetimibe

 HMG-CoA reductase inhibitors (Statins)
• Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin, Fluvastatin,
Pitavastatin
• Most efficacious, best tolerated

• Mechanism: They competitively inhibit HMG-CoA reductase enzyme,

which converts HMG-CoA to mevalonic acid (Rate-limiting step in
cholesterol synthesis)

• Hence depletes the intracellular supply of CH by inhibiting its biosynthesis

• HMG-CoA: 3-Hydroxy-3-methyl Glutaryl coenzyme A

 HMG-CoA reductase inhibitors / (Statins)
• Reduces CH synthesis by 20-50%
• This results in compensatory increase in LDL receptor expression on liver
cells (Upregulation)
• Results in increased receptor mediated uptake and catabolism of LDL and
IDL, thus desired reduction in LDL is achieved
• Low intracellular levels of CH also decreases secretion of VLDL, remnants
of IDL and VLDL are also taken up by LDL receptors, also produce
moderate lowering of TG
• Overall: ↓ LDL (up to 30%), ↓ TG (10-35%), ↓ total cholesterol
• ↑ HDL (5-10%)
• Potency : rosuvastatin > atorvastatin > simvastatin > pravastatin &
lovastatin
 HMG-CoA reductase inhibitors (Statins)

• Combined with Bile acid sequestrants / Nicotinic acid to achieve

maximum results
• HMG-CoA reductase activity is maximum at midnight, all statins are
administered at bedtime to obtain maximum effectiveness
• Atorvastatin, Rosuvastatin- long plasma t1/2 (18-24h)
• Uses: First choice of drugs for primary hyperlipidemias and in secondary
hyperlipidemias (Type IIa, IIb)
• Lower the risk of atherosclerotic vascular disease, Coronary artery
disease
• Efficacy of statins in reducing raised LDL-CH associated mortality and
morbidity is now well established
HMG-CoA reductase inhibitors (Statins)
 HMG-CoA reductase inhibitors
• Also exert Pleotropic effect:
Improvement of endothelial
dysfunction, antioxidant property,
inhibition of inflammatory
responses, immune suppression,
reduced platelet aggregation,
stabilization of atherosclerotic
plaque etc.
• lower the risk of stroke,
Dementia, Alzheimer's disease,
improve bone density etc
 HMG-CoA reductase inhibitors: Adverse effects
• Generally well tolerated
• Headache, Nausea, GI disturbance, sleep disturbances (lovastatin,
simvastatin can cross BBB)
• Rise in serum transaminase can occur (hepatitis): 1-2%
• Muscle pain and tenderness / myositis (inflammation of SKM with pain,
weakness) → rhabdomyolysis (disintegration of muscles)
• Myopathy more common when combined with gemfibrozil / nicotinic
acid / CYP3A4 inhibitor
 HMG-CoA reductase inhibitors: Drug
interactions
• All statins (except Rosuvastatin) are metabolized by CYP3A4
• Inhibitors and inducers of this isoenzyme respectively increase and
decrease statin blood levels)
• Drugs which inhibit CYP3A4 (cyclosporin, erythromycin, itraconazole)
can vastly increase plasma levels of statins, thus risk of toxicity

• Drug that induce CYP3A4 (phenytoin) can accelerate the metabolism,

suppress the blood levels
• Rosuvastatin, Fluvastatin: metabolized by CYP2C9, drugs like
ketoconazole, amiodarone, metronidazole can increase their toxicity
 Bile acid (B.A) binding resins
• Cholestyramine, Colestipol, Colesevelam
• Bile acids (B.A) are synthesized in liver from CH, secreted into the
duodenum to aid absorption of dietary fat, then reabsorbed and
returned to the liver through portal circulation
• B.A binding resins: non-absorbable anion exchange resins that
complex with B.A in the small intestine
• Complex = Non-absorbable, gets excreted, thus preventing B.A from
returning to the liver
• To make up the loss of B.A, the biosynthesis of B.A from CH
increases, leading to partial depletion of CH pool →up-regulation of
LDL receptors →LDL-CH levels from the blood stream is cleared
 Bile acid (B.A) binding resins

• Small rise in HDL-CH and TGs

level (B.A suppress hepatic
TG production)
• Uses: Familial
hypercholesterolemia (IIa)
• For the treatment of type
IIb, (VLDL raised); used with
niacin
• Relieving of pruritus in
patients suffering from
cholestasis and bile salt
accumulation
 Bile acid (B.A) binding resins
• Adverse effects: Unpalatable, large amount needed, poor
patient acceptability, Constipation, GI distress, interfere with
the absorption of many drugs
• Long term use increases TGs levels, induce HMG-CoA reductase,
hence unsuitable as monotherapy
• Drug interactions: Absorption of fat soluble vitamins and folic
acid can be impaired. Cholestyramine and colestipol bind to
digoxin, tetracycline, thiazide diuretics, hence interval of 3-4 hrs
is required.
• Colesevelam is devoid of such interactions
 Fibric acid derivatives / Fibrates

• Gemfibrozil, Bezafibrate, Clofibrate, Fenofibrate, Ciprofibrate

• Mechanism: They activate a nuclear receptor PPAR-α. Activation of

PPAR-α leads to:
• Increased peripheral lipolysis and decrease hepatic TG production
• Enhance lipoprotein lipase activity (Also called as Activators of
lipoproteins lipase activity)
• Facilitates reverse CH transport to HDL

• PPAR-α: Peroxisomal proliferation activated receptor- α

 Fibric acid derivatives / fibrates
• USES: Drug of choice for treating hypertriglyceridemia (particularly Type
III and IV); Also used along with niacin to treat type IIb
• Fenofibrate is uricosuric, used where hyper-uricemia coexist
• Adverse effects: Epigastric distress, diarrhoea, dyspepsia, Myopathy,
Increases liver enzymes and risk of gall stones, impotence (Lower
testosterone levels)
• Drug Interactions: Increase action of oral anticoagulants (coumarin);
Increase the risk of myopathy, rhabdomyolysis (along with statins)
• Contraindications: Hepatic disease with persistently elevated serum
transaminase; Pregnancy and lactation
Inhibitor of intestinal absorption of CH: EZETIMIBE

• Mechanism: It is a novel drug that acts by inhibiting intestinal absorption

of cholesterol and phytosterols
• It interferes with a specific CH transport protein NPC1L1 in the intestinal
mucosa and reduces absorption of both dietary and biliary CH.
• Also inhibits enterohepatic reabsorption of CH excreted in the bile
• Net loss of CH, in turn, accelerates the uptake of LDL from the plasma via
LDL receptors upregulation
• It reduces total CH, LDL-CH, TGs, while increases HLD-CH

• NPC1L1 : Niemann-Pick C1-Like 1

 EZETIMIBE
• Uses:
• Used orally, as monotherapy / with statins to treat type IIb and type
IIa hyper-lipoproteinemia
• Adverse effects: rare
• GIT discomfort, avoided in patients with liver dysfunction
 Nicotinic acid / Niacin
• Mechanism: Inhibitor of VLDL secretion and lipolysis in adipose tissue,
thus reduces the levels of free fatty acids
• Liver uses free fatty acids for TG synthesis (then VLDL production)
• Decrease in liver TGs synthesis leads to a reduction in plasma VLDL, and
LDL
• Also increases HDL-CH
• Inexpensive; Used alone, it decrease TG 40%, VLDL 35%, LDL 25%,
increase HDL-CH by 25-30%
• Numerous acute and chronic side effects
 Nicotinic acid / Niacin/ Vit B3
• Uses: Useful in treating IIb and IV hyper-lipoproteinemia (both LDL and
VLDL are elevated)
• Useful in patients at increased risk for coronary heart diseases
• Can also reverse some of the endothelial cell dysfunction contributing to
thrombosis associated with hypercholesterolaemia
• Adverse effects: cutaneous flush and pruritus initially (used with low
dose aspirin), GI distress, dry skin, hyperuricemia, hepatic dysfunction,
hyperglycemia
• Contraindicated in hepatic impairment, diabetes, hyperuricemia, ulcer
 Treatment of Dyslipidemias
• Hypercholesterolemia: to lower LDL-CH, the primary drugs are statins
(at low dose). In case of inadequate response, dose should be
doubled at 6 weeks intervals (till max dose reached)
OR
• Another drug (Ezetimibe) should be added

• If statins combined with fibrates for high risk patients, patients must
be carefully watched for myopathy (2%)
 Treatment
• Treatment of low HDL-CH level
• Observed in patients with premature coronary artery diseases
• Nicotinic acid has the highest efficacy, followed by fibrates
• May be usefully combined with statins, watching for signs of myositis

• Treatment of raised TG levels

• Diet and weight reduction
• Fibrates and nicotinic acid (may be added carefully with statin)
 Review questions
1. A 31-year-old woman recently diagnosed with familial combined hyperlipidemia star ted a treatment with
lovastatin. Which of the following molecular actions most likely mediated the therapeutic efficacy of the drug in
the patient’s disease?
• A. Downregulation of hepatic LDL receptors B. Increased synthesis of lipoprotein lipase
• C. Decreased synthesis of mevalonic acid D. Decreased storage of LDL in hepatic endosomes
• E. Increased plasma levels of hepatic aminotransferases F. Increased plasma levels of creatine phosphokinase

2. A 55-year-old obese woman was found to have a total cholesterol level of 360 mg/dL (normal < 200 mg/dL),
despite many months of lovastatin treatment. The physician decided to add ezetimibe to the therapeutic
regimen. Which of the following cells represents the main site of action of the added drug?
• A. Adipocytes B. Capillary endothelial cells
• C. Platelets D. Hepatocytes
• E. Intestinal epithelial cells
 Review questions
• 3. A woman taking a drug for high LDL-cholesterol levels experiences muscle
tenderness and pain with no apparent cause. Which agent is least likely to cause this
adverse effect?
(A) atorvastatin (B) niacin
(C) fenofibrate (D) rosuvastatin
• 4. Stimulation of lipoprotein lipase by a fenofibrate results in lowered serum levels of
which substance?
(A) triglycerides (B) HDL-cholesterol
(C) LDL-cholesterol (D) apolipoprotein B
(E) phospholipids
• 5. Which drug increases utilization of cholesterol to synthesize bile acids?
(A) niacin (B) rosuvastatin
(C) gemfibrozil (D) ezetimibe
(E) Colesevelam
 References
• Essential reading
• Medical Pharmacology and therapeutics. 5th edition. Waller Derek G., Sampson
and Anthony P.
https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780702071676000488
• Additional
• Basic and clinical pharmacology, 13th Edition, Katzung B.G
• Rang and Dale Pharmacology. 9th Edition
• https://www.clinicalkey.com/#!/content/book/3-s2.0-B978070207448600024X
• http://www.if-pan.krakow.pl/pjp/pdf/2011/4_859.pdf . Statin-induced
myopathies