To be able to describe: Cholesterol synthesis, source & metabolism Hyperlipidemia – definition & normal values. Anti hyperlipidemic drugs: its classification, mechanism of action & side effects. The natural history of atherosclerosis might involve coronary  plaque rupture / erosion, thrombus formation and vessel lumen occlusion, clinically recognized as acute coronary syndrome (ACS). International guidelines strongly recommend early statin administration in patients admitted for ACS. In addition to lowering circulating levels of low-density lipoprotein cholesterol (LDL-c), statin treatment was shown to promote plaque stabilization or regression in several ways, including reduction in necrotic lipid core, anti-inflammatory effects and improvement in endothelial function. Update on the efficacy of statin treatment in acute coronary syndromes by Rosa, Gian Marco; Carbone, Federico; Parodi, Antonello; Massimelli, Elena A; Brunelli, Claudio; Mach, François (more...) European journal of clinical investigation, 05/2014, Volume 44, Issue 5, 501 - 515

1. PHARMACOTHERAPY OF
HYPERLIPIDEMIA
YEAR 3 “CVS & RESPIRATION MODULE”
DR AWAIS IRSHAD
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 1

2. OBJECTIVES
To be able to describe:
Cholesterol synthesis, source & metabolism
Hyperlipidemia – definition & normal values.
Anti hyperlipidemic drugs: its classification,
mechanism of action & side effects.
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 2

3. Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 3
INTRODUCTION
HYPERLIPIDEMIA - Hyper lipoproteinemia –
abnormally increased plasma lipoproteins
HYPERLIPEMIA - increased levels of
triglycerides
Lipids are insoluble in plasma and are transported in protein capsule
known as LIPOPROTEIN
Plasma lipids include: cholesterols, triglycerides and phospholipids.

4. Apolipoprotein
(apo) B-100
Apolipoprotein
(apo) B-48
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 4
Intermediate -density
lipoprotein (IDL)
Low-density lipoprotein
(LDL)
Very low-density lipoprotein
(VLDL)
Lipoprotein(a)
(Lp[a]).
Convey lipids into
artery wall
Remnant lipoproteins -
catabolism of chylomicrons
transport triglycerides from liver to the plasma.
Primary carrier of cholesterol to the tissues 50%.
cholesterol rich
High density lipoproteins (HDL) - 20 % cholesterol, removes cholesterol
from cells & transport it to liver where it is converted to bile acids

5. Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 5

6. Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 6

7. ANTIHYPERLIPIDEMIC
DRUGS.
HMG CoA
reductase
inhibitor
Atorvastatin
Fluvastatin
Simvastatin
Fibrates
Fenofibrate
Gemfebrozil
Niacin
PCSK9
Inhibition
Bile acid
sequestrants
Colestipol
Cholystyramine
Cholesterol
absorption
inhibitorss
Ezetimibe
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 7
Alirocumab
&
Evolocumab
Inhibitors of Microsomal
triglyceride transfer protein (MTP)
Lomitapide
Mipomersen

8. STATINS
The natural history of atherosclerosis might involve coronary plaque rupture / erosion,
thrombus formation and vessel lumen occlusion, clinically recognized as acute coronary
syndrome (ACS). International guidelines strongly recommend early statin
administration in patients admitted for ACS. In addition to lowering
circulating levels of low-density lipoprotein cholesterol (LDL-c), statin
treatment was shown to promote plaque stabilization or regression in several
ways, including reduction in necrotic lipid core, anti-inflammatory effects and
improvement in endothelial function.
Update on the efficacy of statin treatment in acute coronary syndromes by Rosa, Gian Marco; Carbone, Federico; Parodi, Antonello; Massimelli, Elena A; Brunelli,
Claudio; Mach, François (more...) European journal of clinical investigation, 05/2014, Volume 44, Issue 5, 501 - 515
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 8

9. Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 9

10. HMG-COA REDUCTASE INHIBITORS.
LOVASTATIN, SIMVASTATIN, FLUVASTATIN, PRAVASTATIN.
.
Decrease in cholesterol synthesis
Statins are the analogs of 3-
hydroxy-3-methylglutarate,
precursor of cholesterol and because
of their strong affinity for enzyme,
all compete effectively to inhibit
HMG-CoA reductase, the rate
limiting step in cholesterol synthesis.
INCREASES IN LDL RCEPTOR:
Decrease of intracellular cholesterol causes
the cell to increase cell-surface LDL
receptors that can bind and internalize
circulating LDLs.
Decreases secretion of VLDL from liver
into blood
Also increases HDL levels.
Small decrease in triacylglycerol can occur.
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 10
Mechanism of
action
PCSK9
inhibitors

11. Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 11

12. STATINS POSSESS PLEIOTROPIC
EFFECTS
Besides cholesterol-lowering effects, statins possess PLEIOTROPIC anti-
inflammatory, anti-oxidant, anti-platelet and anti-fibrotic properties,
which may additionally play imperative roles in statins-mediated cardiovascular
protection.
Intriguingly, a considerable number of studies demonstrated the potential
modulatory role of statins on endothelial nitric oxide synthase (NOS), a
key enzyme involved in the regulation of cardiovascular function by generating
endothelium-derived relaxing factor (often represented 'nitric oxide'). Worthy
of note is that vascular generation of nitric oxide has beneficial anti-
inflammatory, anti-platelet and vasodilatory actions.
Is targeting enos a key mechanistic insight of cardiovascular defensive potentials of statins? By balakumar, pitchai; kathuria,
sonam; taneja, gaurav; kalra, sanjeev; mahadevan, nanjaian. Journal of molecular and cellular cardiology, 01/2012, volume 52
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 12

13. Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 13
FENOFIBRATE AND GEMFIBROZIL.
• Mechanism of action: agonists at PPAR (peroxisome
proliferator - activated receptor) → expression of genes
responsible for up regulation of plasma lipoprotein lipase
enzyme → hydrolysis of VLDL and chylomicrons → ↓
serum triglyceridess
• Increase clearance of LDL by liver & ↑ HDL.
Therapeutic uses:
• Hypertriglyceridemia (effective in ↓ triglycerides) - combined
hyperlipidemia (type III) if statins are contraindicated.

14. D- NIACIN; NICOTINIC ACID (INHIBITOR OF
LIPOLYSIS)
Decrease both VLDL & LDL
Mechanism of action:
It is a potent inhibitor of lipolysis in adipose tissues
→ ↓ mobilization of Free Fatty acids (major
precursor of TG) to the liver → ↓ VLDL (after few
hours).
Since LDL is derived from VLDL so ↓ VLDL → ↓
LDL (after few hours).
↑ HDL levels
↓ endothelial dysfunction →↓ thrombosis.
Department of Pharmacology 14

15. BILE ACID BINDING AGENTS.
CHOLESTYRAMINE & COLESTIPOL.
MECHANISM OF ACTION.
These drugs are anion exchange resins that bind negatively charged bile
acids and bile salts in the small intestine. The resin/bile complex are then excreted
in the feces, thus preventing the bile acids from returning to the liver by the
enterohepatic circulation.
Consequently, the intracellular cholesterol also decreases, which activates an
increased hepatic uptake of cholesterol containing LDL particles, leading to fall in
plasma LDL
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 15

16. Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 16

17. EZETIMIBE (CHOLESTEROL ABSORPTION
INHIBITORS)
Inhibits intestinal cholesterol absorption → ↓
concentration of intrahepatic cholesterol→
compensatory ↑ in LDL receptors →↑ uptake
of circulating LDL →↓ serum LDL cholesterol
levels.
Used in hypercholesterolemia together with
statins & diet regulation.
20% extra LDL reduction & ↑ of HDL
Adverse effects: diarrhea and abdominal pain.
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 17

18. Department of Pharmacology
FAZAIA RUTH PFAU
MEDICAL COLLEGE
18
(A) (1) LDLR binds to LDL particle at the liver cell
surface.PCSK9 can also bind to the LDLR.
(2) The LDL particle‒LDLR complexes with or without
PCSK9 bound are internalized in the liver cell by
endocytosis.
(3) LDLR not bound to PCSK9 release the LDL particle,
which goes to a lysosome for digestion, whereas LDLR
is recycled to cell surface.
(4) LDLR bound to PCSK9 is digested in the lysosome
along with LDL particle.
LDL : low-density
lipoprotein
LDLR, low-density
lipoprotein
receptor; mAb,
monoclonal
antibody
PCSK9, proprotein
convertase
subtilisin/kexin
type 9.
(B) (1) PCSK9 mAb binds PCSK9 in circulation,
preventing it from binding the LDLR.
(2) The LDL particle‒LDLR complexes are internalized
in the liver cell.
(3) In the absence of PCSK9 binding, increased LDLR
receptor recycling & more LDLR on liver cell surface
to bind result.
(4) Circulating LDL particle levels are reduced.
Gissette Reyes-soffer, Marianna Pavlyha, Colleen Ngai, Etal, Effects of PCSK9 inhibition with Alirocumab on
lipoprotein metabolism in healthy humans, Circulation. 2017;135:352–362. DOI:
PCSK9 Inhibitors - ALIROCUMAB
Alirocumab
reduced
LDL-C by
55.1%, LDL-
apoB by
56.3%, &
plasma
Lp(a) by
18.7%.

19. 19
a. Hepatocytes express LDL-R
that bind LDL & remove it from
the plasma. Upon internalization,
vesicles containing LDL–LDL-R
complex fuse with endosomes.
LDL-R cycles back to the
hepatocyte surface to bind
additional LDL. Free LDL in
endosomes is degraded into
lipids, free fatty acids, and amino
acids.
b PCSK9 is a protein that regulates expression of
LDL-R in liver. Hepatocytes produce a precursor of PCSK9
that undergoes self cleavage in endoplasmic reticulum &
ultimately is secreted into plasma as functional PCSK9.
Extracellular PCSK9 binds to LDL-Rs on surface of
hepatocyte & is internalized with LDL–LDL-R complex
which is routed to lysosome for degradation, thereby
preventing cycling of LDL-R back to the hepatocyte surface.
The reduced concentration of LDL-R on surface of
hepatocytes results in a lower rate of plasma LDL elimination.
c A monoclonal antibody directed
against PCSK9 could lower LDL if
binding to circulating PCSK9 blocks
interaction of PCSK9 with cell surface
LDL-R. Internalized LDL-R could cycle
back to cell surface instead of being
degraded in lysosomes, leading to
increased concentrations of LDL-R on
cell surface.
This could result in a higher LDL
elimination rate by hepatocytes & an
overall reduction in plasma LDL.
Evolocumab reduced LDL-C by approximately 55–75% compared with placebo at the mean of
weeks 10 and 12 LDL-C low-density lipoprotein cholesterol, LDL-R low-density lipoprotein receptor, PCSK9 proprotein
convertase subtilisin/kexin type 9..
Liver is responsible for
catabolism of plasma LDL
PCSK9 Inhibitors – Evolocumab (S/C administration)
Sreeneeranj Kasichayanula, Anita Grover, Etal, Clinical Pharmacokinetics and Pharmacodynamics of Evolocumab, a PCSK9 Inhibitor, Clin Pharmacokinet
(2018) 57:769–779 https://doi.org/10.1007/s40262-017-0620-7
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE

20. Department of Pharmacology
FAZAIA RUTH PFAU MEDICAL
COLLEGE
20
Lomitapide lowers cholesterol by inhibition of the microsomal
triglyceride transfer protein (MTP). MTP is involved in
loading of triglyceride onto apolipoprotein B100, which is a part of
assembly process of very low density lipoprotein (VLDL). After
excretion by hepatocytes, VLDL is converted to LDL. By blocking the
assembly of VLDL, lomitapide reduces VLDL release and VLDL-
mediated triglyceride secretion. This leads to a reduction of LDL
concentrations in plasma
Homozygous familial hyper cholesterolaemia (HoFH) is
an inherited disease which causes accelerated
atherosclerosis.
HoFH commonly arises from a loss-of-function
mutation in both alleles of the low density lipoprotein
(LDL) receptor.
This mutation inhibits LDL uptake from the circulation,
thus resulting in increased plasma concentrations of
total cholesterol and LDL.
Lomitapide
Lomitapide, Sebastiaan C Goulooze, Adam F Cohen, Robert Rissmann, Br J Clin Pharmacol. 2015 Aug; 80(2): 179–181

21. Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE 21
DRUG COMMON ADVERSE EFFECTS COMMON DRUG INTERACTIONS
HMG-CoA
reductase
inhibitors
Elevated serum levels of hepatic
enzymes; hepatitis; and myalgia,
rhabdomyolysis, and other
myopathies
Cause slight increase in serum levels of
warfarin. Increase risk of myopathies
when taken with erythromycin,
gemfibrozil, or niacin. *
Bile acid–binding
resins
Constipation, fecal impaction, and
rash
Decrease absorption of digoxin,
thyroxin, warfarin, and other drugs.
Fibric acid
derivatives
Allergic reactions; blood cell
deficiencies; and myalgia,
rhabdomyolysis, and other
myopathies
Increase risk of myopathy when taken
with HMG-CoA reductase inhibitors or
niacin.
Ezetimibe Headache, myalgia Absorption decreased by cholestyramine.
Niacin
PCSK9 inhibitors
MTP inhibitors
Gastric irritation; glucose
intolerance; myalgia,
rhabdomyolysis, and other
myopathies; and vasodilation,
flushing, and pruritus
Myalgias, Delerium Dementia, other
neurocognitive disorders
Increases risk of myopathy when taken
with gemfibrozil or HMG-CoA reductase
inhibitors
Increases risk of myopathy when taken
with gemfibrozil or HMG-CoA reductase
inhibitors
Summary: Adverse Effects and Interactions of Drugs for Hyperlipidemia

22. REFERENCE
S:
Gissette Reyes-soffer, Marianna Pavlyha, Colleen Ngai,
Etal, Effects of PCSK9 inhibition with Alirocumab on
lipoprotein metabolism in healthy humans, Circulation.
2017;135:352–362. DOI:
10.1161/CIRCULATIONAHA.116.025253
Sreeneeranj Kasichayanula, Anita Grover, Etal, Clinical
Pharmacokinetics and Pharmacodynamics of Evolocumab, a
PCSK9 Inhibitor, Clin Pharmacokinet (2018) 57:769–779
https://doi.org/10.1007/s40262-017-0620-7
Basic & Clinical Pharmacology : 14th edition by Katzung
Rang & Dale Pharmacology; 8TH EDITION
Lippincott's Pharmacology: 6TH EDITION
For queries: a.mehdi@frpmc.edu.pk
22
THANK
YOU
Department of Pharmacology FAZAIA RUTH PFAU MEDICAL COLLEGE