PHARMACOLOGY

Lectures 9,10:
Drugs for Hyperlipidemia
OBJECTIVES:
By the end of those 2 lectures the student will be able to:
• Define hyperlipidemia vs normal lipid levels
• Discuss the non-pharmacological treatment of hyperlipidemia
• Classify lipid lowering agents targeting exogenous &
endogenous pathways
• Expand on the pharmacology of drugs related to each group
• Hint on adjuvant drugs that can help in lipid lowering

Before studying this lecture, we advise

you to study biochemistry lectures of
cholesterol metabolism & lipoproteins

Abbreviations:
C = cholesterol
CM = cylomicrons  Important.
LPL= lipoprotein lipase enzyme
 Extra notes.
 Introduction to lipids

Origin of lipids
e.g. Cholesterol (C) & Triglycerides (TG)

endogenous lipids: de novo exogenous lipids: ingested and

synthesized in the liver processed in the intestine (dietary)

Lipid profile blood tests: detected in serum after a 12-hour fast.

Lipid Normal Lipid levels

Cholesterol < 200 mg/dl

Triglycerides < 220 mg/dl

LDL < 130 mg/dl (Bad C)

HDL > 50 mg/dl (Good C, non-atherogenic)

 Introduction to Hyperlipidemia

Hyperlipidemia is the most common form of dyslipidemia,

It denotes abnormally increased levels of any or all LIPIDS and/or
LIPOPROTEINS [LP] in blood.
Hyperlipidemia is a major cause of atherosclerosis which may lead to CAD
and ischemic cerebrovascular disease.

Types of hyperlipidemia :
1- Familial Hyperlipoproteinemia
Which caused by elevated level of one
lipid or lipoproteins as the following :
Lipoproteinemia LP Lipids Risk
Type I CM TGs -
Type IIa LDL C 
Type IIb VLDL & LDL TG & C 
Type III IDL TGs & C 
Type IV VLDL TGs 
Type V VLDL & CM TGs & C _
2- Secondary hyperlipidemia
Risk factors:
smoking (reduced levels of HDL, cytotoxic effects on the endothelium, increased oxidation
of lipoproteins, and stimulation of thrombogenesis)

family history of CVD, Hypertension, obesity, inactivity / lack of exercise, alcohol

intake (increases TGs)

DM (increased generation of VLDL and free fatty acids presented to the liver)
 Therapeutic strategies for treatment of hyperlipidemia

1-Therapeutic lifestyle changes :

1. Healthy diet; optimal Quantitative & Qualitative fat content:
• Diet has <30% of calories as fat, <7% as saturated fat and <200mg cholesterol/day
• Avoid trans-fatty acids & acute increase in C intake
• Use vegetable oils rich in unsaturated fatty acids: oleic acid, linoleic acid & linolenic
acids. Diet should also contain plant stanols (which interfere with the formation of
micellar* cholesterol) & soluble fibers
* Micelles are lipid molecules that arrange themselves in a spherical form in aqueous solutions.
• Eat food high in antioxidants vitamins
2. Regular exercise
3. Cessation of hazards habits; smoking, alcohol, …etc
4. Losing weight
Can achieve a fall in LDL-C of 8-15% … but long-term compliance is a
problem. Only recommended for patients with non-familial low grade
hyperlipidemia

2-Antihyperlipidemic agents :
According to the mechanism of According to the site of action
action
1- Inhibits cholesterol absorption in the I-Agents targeting exogenous
intestine: Ezetimibe cholesterol
2-Sequester bile acids in the intestine: • Ezetimibe
Exchange resins (AKA bile acid • bile acid sequestrants: Colestipol
sequestrants) & cholestyramine
3- Inhibits de novo synthesis of II-Agents targeting endogenous
cholesterol by Inhibition of HMG cholesterol
CoA reductase (key enzyme for • Statins
cholesterol synthesis) • Fibrates
Statins (1st drug choice) • Nicotinic acid
4- Alter relative levels of different Adjuvant agents
plasma LPs • Omega-3-Fatty Acids
Fibrates, Nicotinic acids • Stanols
Statins, Fibrates, Niacin, etc. - Easy Pharm for USMLE Step 1
 I- agents targeting exogenous pathways

1. BILE ACID SEQUESTRANTS (Are polymeric anion exchange resins)

Cholestyramine Colesevelam Colestipol
• Moderately effective, with excellent safety record
• Large MW polymers
• can raise triglycerides modestly
Overview • Decrease levels of plasma LDL by decreasing intracellular cholesterol
concentration.
• The concentration of HDL-c is unchanged.

1. Bind to bile acids and bile salts in the small intestine

2. They form resin/bile acid complex which is excreted in the feces (10 fold),
thus lowering the bile acid concentration.
3. By doing so, they prevent enterohepatic cycling of bile acids
4. This obligates the liver to synthesize replacement bile acids, causing
Mechanism of hepatocytes to increase conversion of cholesterol to bile acids, which are
action essential components of the bile.
5. Consequently, intracellular cholesterol concentrations decrease, which
activates an increased hepatic uptake of cholesterol- containing LDL particles
(by an up-regulation of cell surface LDL receptors), leading to a fall in plasma
LDL-C.

Indication • Excellent choice for people who cannot tolerate other types of drugs

• They are clinically safe as they are not systemically absorbed

ADRs •  GIT bloating, diarrhea, constipation, dyspepsia, abdominal discomfort
•  absorption of fat soluble vitamins ( A, D, E, K)

• Complete Biliary obstruction (because bile is not secreted into the intestine,
and thus resins would be of no use)
• Chronic constipation
Contra- • Severe hypertriglyceridemia (TG >400 mg/dL), because the bile acid binding
indications resins can raise triglycerides modestly ( about 5%) and thus cannot be used if
the triglycerides are elevated.

•  absorption of some drugs : Statins, Ezetimibe, Chlorothiazides,

Digoxin, Warfarin. Therefore, these drugs should be taken at least 1 to
Interactions 2 hours before, or 4 to 6 hours after taking resins.
• Colesevelam hasn’t been shown to interfere with other drugs (best
choice for patient on multiple drug regimens)
 I- agents targeting exogenous pathways (cont.)
1. Inhibition of Cholesterol Absorption in the Intestine by Selective C
Transporter Inhibitors; Ezetimibe

2. Sequester Bile Acids in Intestine by Sequestrants:

Colestipol & Cholestyramine

2. Ezetimibe
Selectively inhibits absorption
of dietary and biliary cholesterol
in the small intestine, leading to a
Decrease in the delivery of
Mechanism intestinal cholesterol to the liver.
of action This causes a reduction of hepatic
cholesterol stores and lowers LDL by
reducing its precursor (VLDL)
* This mechanism is distinct from that
of statins, which inhibits de novo synthesis of LDL principally in the liver.
Pharmacolo LDL 20%,  TG 8% ,  HDL 1-4%
gical action no effect on steroids, lipid-soluble vitamins, bile acid. (unlike resins)

Absorbed & conjugated in intestine to active glucuronide (> potent )

Pharmaco- -Reaches peak blood level in 12–14 hours
-Its half-life is 22 hours
kinetics -Undergoes enterohepatic circulation (prolong action of drug)
-80% of the drug is excreted in feces
N.B. Drug level will  if with statins &  if with cholystyramine
As Monotherapy: Primary prevention of low risk of CHD. (if LDL is very high,
statins should be used. Ezetimibe isn’t used alone except in modest of LDL)
Indications As Combination Therapy; it’s safe With: (statins; synergistic In
moderate/severe  LDL ) Or ( If must  statin dose because of side effects)
Or (With other lipid lowering drugs As fibrates ).

Not common:
ADRs & • GIT disturbance ( the main symptoms for most of antihyperlipidemics)
Interactions • headache, fatigue, arthralgia and myalgia.
• Seldom reversible impairment of hepatic function
 II-Agents targeting endogenous cholesterol
Statins (HMG-Co A Reductase Inhibitors)
Simvastatin Lovastatin Atorvastatin Pravastatin Rosuvastatin
• the most effective & best-tolerated agents for treating hyperlipidemia
• first-line drugs when LDL-lowering drugs are indicated
• they cause modest decrease in plasma TG and slight ↑ LDL 18-55%
Overview in HDL-C)
  HDL 5-10%

  TG & VLDL 10-30%

1. potent competitive inhibitors of HMG-CoA reductase, which catalyzes a rate-

limiting step in de novo hepatic cholesterol synthesis. Thus, HMG-Co A is not
converted to mevalonic acid, reducing cholesterol. And Because C is required for
Mechanism the synthesis of VLDL (the precursor of LDL-C), production of VLDL & LDL will
of action : decrease.
2. The liver compensates for this decrease in cholesterol by ↑ the number of LDL
receptors on the surface of hepatocytes (upregulation of LDL- R), This results in ↑
removal of LDL from the blood and lowering of serum LDL- C levels.
Pleiotropic effects of statins (Beyond cholesterol lowering):
• improvement of endothelial function,
• increased nitric oxide bioavailability & antioxidant properties,
Advantages • inhibition of inflammatory & thrombogenic responses,
• stabilization of atherosclerotic plaques
• Furthermore, statins have beneficial extrahepatic effects on the immune system,
CNS, and bone.

 Monotherapy :
Primary Prevention :
1- Patients with hyperlipidemia and with other risks for ischemic insults.
2. Type IIa Hyperlipoprotinemia. If there is no control, combine ( bile acid sequestrants /
ezetimibe, niacin,.. ) to decrease cholesterol .
Secondary Prevention :
In all ischemic insults : [ stroke, ACSs up to AMI, …..etc.]
So given from 1st day of ischemic attack (stabilize plaques)

indication  Combination therapy

1. Mixed dyslipidemias; Added to fibrates or niacin if necessary.
(because the use of a statin alone may be insufficient for the treatment of mixed
dyslipidemia, which is characterized by low levels of HDL-C and elevated levels of TG
with or without ↑ LDL-C.)
2. In diabetics and patients with insulin resistance [metabolic syndrome]. Because these
patients will possess small dense LDL (severely atherogenic) with evident endothelial
dysfunction & increased thrombotic profile. (due to its Pleiotropic effects)
 statins (cont.)

• Most statins have a high first-pass clearance by the liver

• Greater than 95% of most of these drugs are bound to plasma proteins with short
half-life
Pharmaco- • Drug-drug interactions involve specific interactions with the cytochrome P-450 drug
kinetics metabolizing system, especially CYP3A4
• All statins are taken orally at bedtime because hepatic cholesterol synthesis is
maximal between midnight and 2:00 a.m. , except atorvastatin taken at any time
because of its long half-life (14 hours)

• Common: Headache , myalgia, fatigue, GI intolerance, and flu-like symptoms

• Hepatotoxicity, raised concentrations of liver enzymes (serum aminotransferases)
• Teratogenicity, statins should be avoided during pregnancy

ADVERSE
 Myopathy:
EFFECTS • Muscle aches, or weakness associated with an elevation of creatine kinase (CK)
released from muscles, are the best indicator of statin-induced myopathy.
• Failure to recognize myopathy and to discontinue drug therapy can lead to
rhabdomyolysis (the destruction of striated muscle cells), myoglobinuria, and acute
renal necrosis.
It is important to check CK & liver enzymes regularly upon administration of statins.

lab 1.  Creatine kinase activity (index of muscle injury) :

Measured only if myalgia or myositis develops. if CK increases 3-5 folds, we decrease
investigati statin doses / omit combination with fibrates…..
2. Serum aminotransaminase, can progress to evident hepatotoxicity. So lab
ons investigations are recommended every 6 month. if levels increase up to 3 folds at
any time, statin must be stopped then dose adjusted.

 Statins potentiate the action of oral anticoagulant and anti-diabetic drugs (by
displacement from plasma protein binding sites (activation) )
 Drugs that increase the risk of statin-induced myopathy include:
Inter- • Other antihyperlipidemics ( fibrates )
• Drugs metabolized by 3A4 isoform of cytochrome P450: erythromycin, verapamil,
actions cyclosporin, ketoconazole.
Pravastatin and fluvastatin are the statins of choice in patients taking other drugs
metabolized by cytochrome 3A4 system.

Main ADRs
& contraindication:
 II-Agents targeting endogenous cholesterol

Niacin (Nicotinic Acid):

Definition - Water soluble B-complex vitamin with multiple actions

- most effective medication for increasing HDL cholesterol levels and it has positive
effects on the complete lipid profile
- In adipose tissue: it binds to adipose nicotinic acid receptors, this will lead to
decrease in free fatty acids mobilization from adipocyte to the liver resulting in ↓
Mechanism TG and thus ↓ VLDL synthesis
- In liver: Niacin ( Nicotinic acid ) inhibits hepatocyte diacylglycerol acyltransferase-2
(a key enzyme for TG synthesis) → it decrease VLDL production (by decreasing TG
synthesis & esterification)
- In plasma : it increase LPL activity that increase clearance of VLDL & chylomicron
- Niacin also promotes hepatic apoA-I production and slows hepatic clearance of
apoA-I and HDL (most favorable effect)

Pharmaco- - Effect on VLDL : ↓ VLDL by :

1- ↓ synthesis in liver
logical 2- increased clearance in plasma
Actions 3-↓ mobilization of free fatty acids from adipose tissue
- Effect on LDL : ↓ LDL due to reduction in its precursor (VLDL)
- Effect on HDL : induces a large increase in HDL-C (The catabolism of HDL can be
inhibited by nicotinic acid through a mechanism that is largely unknown)

Indications - Monotherapy or in combination with fibrate, resin or statin

- Niacin exerts greatest beneficial effects on wide range of lipoprotein abnormalities:
• Type llA hypercholestrolemia - Type llB hypercholesterolemia & any combined
hyperlipidemia
• Patient with hypertriglyceridemia & low HDL-C.
• Hyperchylomicronemia.
• mixed dyslipidemia

Adverse - Most common: Sensation of warmth & cutaneous flushing (prostaglandin-induced

vasodilation) → (can be avoided by low dose of Aspirin half-an-hour before the use
effects of niacin, because it blocks prostaglandin).
N.B Slow release formulations→ ↓incidence of flushing
- Pruritus, rash, dry skin
- GIT disturbance: Dyspepsia: nausea, vomiting, reactivation of peptic ulcer (↓ if
taken after meal).
- High dose:
• Reversible ↑ liver enzymes → hepatotoxicity.
• Impairment of glucose tolerance → Hyperglycemia in diabetes patients (don’t give to
diabetes patient).
• ↑ uric acid. (thus contraindicated in patients with gout)
Contra-indications Gout – Peptic ulcer – Hepatotoxicity – Diabetes mellitus
 II-Agents targeting endogenous cholesterol

Fibrates They are Peroxisome proliferator activator receptor [PPARa] Agonists, which are
a class of intracellular receptors that modulate fat metabolism.

Mechanism They increase gene transcription for lipoprotein lipase (LPL) leading
to increased catabolism of TG in VLDL and chylomicrons

Drugs Clofibrate Fenofibrate Gemfibrozil

• ⬆ LPL activity → increases clearance of VLDL & chylomicron in plasma
• ⬆ HDL (by increasing the production of the apoprotein components of HDL)
Pharmacological •  LDL-C uptake by the liver (⬇ LDL in plasma)
action • ⬇ TG . due to ⬇ VLDL
• ⬆FFA uptake by the liver
• ⬇ Vascular inflammation
• Improve glucose tolerance
•  excretion of hepatic C in bile, thus endogenous hepatic C synthesis may
be decreased.

1st-line defense for:

• Mixed dyslipidemia (i.e. raised serum TG and C )
• Patients with low HDL and high risk of atheromatous disease ( often type 2
Indications diabetic patients )
• Patients with severe resistant dyslipidemia ( combination with other lipid
lowering drugs ).
• GIT (indigestion, abdominal pain, diarrhea)
• Rash, urticaria, hair loss
• Myositis : can occur resulting in weakness and tenderness of muscles,
Myalagia, Myositis, Rhabdomyolysis Acute renal failure  Occurs:
-In alcoholics,
Adverse effects -If combined with statins (each –ve metabolism of other )
-In impaired renal function
• Gallstones: fibrates, especially Clofibrate increases C content of bile,
predisposes to gallstones, and its use is therefore limited to patients who
have cholecystectomy

• Pregnant or nursing women (cause teratogenicity, but not as severe as statin)

• Renal impairment.
Contraindications • Gall-bladder disease.
• In alcoholics

- increase risk of myopathy when combined with statins . ( metabolism of

statins  toxicity  myalgia, myositis) . Give lower doses
Interactions - Displace drug from plasma proteins. e.g. oral anticoagulants (warfarin 
bleeding tendency  anticoagulant dose must be adjusted) and oral
hypoglycemic drugs )
 Combinations & adjuvants

Antihyperlipedemic combinations:
Indications:
1. Severe hypertriglycerdemia or severe
hypercholesterolemia
2. To take lower doses of each drug
3. High LDL or VLDL not normalized with a single drug
(failure of monotherapy)
Resins: decreases the absorption of statins and
ezetimibe, Therefore, these drugs should be taken at
least 1 to 2 hours before, or 4 to 6 hours after taking Ezatimibe
resins.
Statins & Fibrates
• Contraindicated (in full dose) because the incidence Statin & ezetimibe
of myopathy may increase (synergistic combination)
• So, use not more than ¼ maximum dose of statin - Statin blocks synthesis
and use pravastatin (Pravastatin and fluvastatin of endogenous cholesterol
are the statins of choice in patients taking other while ezetimibe blocks
drugs metabolized by cytochrome 3A4 system) exogenous cholesterol

Adjuvants in Hyperlipidemia
Omega -3-FA β--‐Sitosterol
The adjuvant (found in fish oils containing (found in plants with structure
highly unsaturated FA) similar to cholesterol)
• ↓ enzymes involved in TG They work by mimicking cholesterol
synthesis . and competing with it for dietary &
•  beta‐oxidation of FFA biliary Absorption, thereby ↓ LDL
Mechanism of Lead to decreases TG . levels up to 10%
action and • ↓ platelet function
Pharmacological • Prolongation of bleeding time
Effect • Reduction of plasma
fibrinogen
• Anti ‐inflammatory effects
it gives Some vascular protection

Adjunctive treatment of very Given as food supplement before

Indication
high TGs meal in Hypercholesterolemia
Summary

Drug Class Agents Effects Side Effects

(% change)
HMG CoA Lovastatin LDL (18-55), Myopathy, increased
reductase Pravastatin  HDL (5-15) liver enzymes
inhibitors  Triglycerides (7-30) (hepatotoxicity)

Cholesterol Ezetimibe  LDL( 14-18), Headache, GI distress

absorption  HDL (1-3)
inhibitor Triglyceride (2)
Nicotinic LDL (15-30), Flushing (+aspirin)
Acid (Niacin)  HDL (15-35) Hyperglycemia,
 Triglyceride (20-50) Hyperuricemia, GI
distress,
hepatotoxicity
Fibric Acids Gemfibrozil LDL (5-20), Dyspepsia,
Fenofibrate HDL (10-20) gallstones, myopathy
Triglyceride (20-50)
Bile Acid Cholestyra  LDL GI distress,
sequestrants mine no change in constipation,
(Resins) HDL(slight increase) decreased absorption
 Triglyceride of other drugs
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‫‪Quiz‬‬ ‫‪435 PHARMACOLOGY TEAM‬‬

‫عبدالرحمن السياري‬
‫أحمد اليحيى‬ ‫شماء السعد‬ ‫لولوه الصغير‬
‫خالد الزهراني‬
‫رهف بن عبّاد‬ ‫شادن العمران‬
‫عبدهللا الجنيدل‬
‫أحمد المصعبي‬ ‫سارة الخليفة‬ ‫لمى الزامل‬
‫عبدالرحمن الزامل‬ ‫ساره المطوع‬ ‫كوثر الموسى‬
‫عبدالرحمن الشمري‬ ‫فاطمة الدين‬ ‫ديمه الراجحي‬
‫معاذ باعشن‬
‫عبدالعزيز الشعالن‬ ‫آية غانم‬ ‫جواهر الحربي‬
‫محمد السحيباني‬ ‫أسرار باطرفي‬ ‫دالل الحزيمي‬
‫فارس المطيري‬ ‫نوف العبدالكريم‬ ‫رنيم الدبيخي‬
‫فوزان العتيبي‬
‫وضحى العتيبي‬ ‫نورة الصومالي‬
‫محمد ابونيان‬
‫عمر القحطاني‬ ‫ريما الحيدان‬ ‫منيرة السلولي‬
‫يوسف الصامل‬
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