DRUGS AFFECTING

LIPID METABOLISM

MODERATOR:
DR.J.G.BUCH SIR
 INTRODUCTION
 Lipoproteins

 Dyslipidemia

Hyperlipoprote Decreased
inemia level of HDL

Hypercholeste Hyperlitriglycer
rolemia idemia
Classification of Lipoproteins
 Depending upon density, diameter and TAG
and Cholesterol ester content,
 Chylomicrons (CM)
 VLDL
 IDL
 LDL
 HDL
 Lp(a)
STRUCTURE OF LIPOPROTEIN
 COMPARISON OF VARIOUS
LIPOPROTEINS
 CE CONTENT: Lp(a)=LDL>IDL>HDL>VLDL>CM

 TAG CONTENT: CM>VLDL>IDL>LDL>Lp(a)=HDL

 ATHEROGENICITY: Lp(a)>LDL>VLDL=IDL=CM>HDL

RISK OF ATHEROSCLEROSIS IS
RELATED TO THE CHOLESTEROL
CONTENT OF LIPOPROTEIN
 APOPROTEINS
What is it’s role

LIPOPROTEINS APOPROTEINS (apo)

CM A-l, A-lV, B-48, C-l, C-ll, C-lll, E
VLDL B-100, C-l, C-ll, C-lll, E
IDL B-100, C-l, C-ll, C-lll, E
LDL B-100
A-l, A-ll, A-lV, C-l, C-ll, C-lll, E
HDL

Lp(a) B-100, A
 PLASMA LIPID LEVELS (mg/dl)
TOTAL CHOLESTEROL TAG
<200 Desirable < 150 Normal
200 – 239 Borderline high 150 – 199 Borderline high
≥ 240 High 200 – 499 High
≥ 500 Very high

LDL-C HDL-C
Optimal for high risk
< 70 <40 Low for men
patients
< 100 Optimal <50 Low for women
100 – 129 Near optimal >60 High
130 – 159 Borderline high
160 – 189 High
≥ 190 Very high
 RISK FACTORS FOR
CORONARY HEART DISEASE
AGE Male > 45 yrs
Female > 55 yrs
FAMILY HISTORY OF In first degree relative, male < 55 yrs or female <
PREMATURE CHD 65 yrs at first clinical CHD event
CURRENT CIGARETTE In last 30 days
SMOKING
HYPERTENSION BP ≥ 140/90
Use of anti-HT agents irrespective of BP
LOW HDL-C < 40 mg/dl for male
< 50 mg/dl for female
OBESITY BMI > 25 kg/m2
Waist cicumference > 40 inch for male and > 35
inch for female
TYPE-2 DM Independent risk factor for CHD
 Lipoprotein metabolism
1- Chylomicrons
 Synthesized from fatty acids from dietary TAG,
cholesterol, fat soluble vitamins.
 TAG : CH > 10

Triglycerides cholesterol

Diacyl gycerol trasnsferase NPC1L1 (Neimann pick

C1 like 1 protein)
Microsomal triglyceride transfer protein (MTP)
ABCG5 & ABCG8

ACAT-2

Form chylomicrons after combination with apo B-48, A-l, A-ll

Cont….
Chylomicrons in lymphatics from intestine

Thoracic duct

Systemic circulation

Combine with apo E, apo C-l, C-ll,C-lll

apo C-ll mediated interaction with LPL (lipoprotein lipase)

Chylomicron remnant

apo E – heparan sulfate interaction on surface of Hepatocyte

Hepatic lipase mediated lipolysis

apo E mediated endocytosis by LRP (LDL receptor related protein)

Cont…..
 Mutations

 Chylomicrons
 LPL
 apo C-ll
 Chylomicron remnant
 HL
 LRP
VLDL
Synthesized in liver when there is increase in FFA level
TAG > CH

MTP

Combines with apo B-100 to form VLDL

Secretion in cicrculation

Combines with apo E, C-l, C-ll, C-lll

LPL

IDL (VLDL remnant)

Cont…
IDL

50% apo E mediated 50% acted upon by HL

endocytosis in hepatocytes
via LDL receptors or LRP LDL

Non receptor mediated

Most part taken up by
clearance
hepatocytes
apo B mediated endocytosis
by LDL receptor
Cont……

LDL receptor regulation

Whenever there is decrease in intracellular cholesterol

Activates SREBP cleavage activating protein (Scap)

Cleavage of SREBP (sterol regulatory element binding protein)

Translocation of its amino terminal domain along with Importin β

inside nucleus

Transcription of LDL receptor gene

Expression of LDl receptors

Cont…..
 Mutations:

 VLDL
 MTP
 apo E2

 LDL
 LDL receptor
 apo B-100
 PCSK-9
Cont……..
HDL metabolism
Formation of pre-β HDL from apo A-l, phospholipids

ABCA 1, ABCG 1

LCAT (Lecithin cholesterol acyl trasnferase)

Reverse
HDL-3 cholesterol
transport
HDL-2

Cholesterol exchange with TAG by CETP (cholesterol ester

transfer protein)

HL mediated lipolysis

HDL-3
Cont……

 Mutations
 HDL
 ABCA-1 (Tangiers disease)
 apo A-l
 Frederickson’s / WHO classification of Primary hyperlipoproteinemias

Elevation in lipids
Elevation in
Type Name Defect
lipoprotein/s TAG CH

l Familial CM LPL +++ +/N

hyperchylomicronemia

lla Familial LDL LDL receptor N ++

hypercholesterolemia
LDL receptor +
llb Familial combined VLDL & LDL overproduction of ++ ++
hypercholesterolemia
VLDL
Familial IDL, CM
lll dysbetalipoproteinemia remnant apo E ++ ++

Overproduction &/or
Familial
lV hypertriglyceridemia VLDL decresed removal of ++ +/N
VLDL
Overproduction &/or
V Familial combined VLDL & CM decresed removal of ++ +/N
hypertriglyceridemia
VLDL& CM
Secondary causes of Hyperlipoproteinemias
 Hypertrigyceidemia:  Hypercholestrolemia:

 Corticosteroid excess  Corticosteroid excess

 Hypopituitarism  Hypopituitarism

 Myxedema  Hypothyrodism

 Severe nephrosis  Early nephrosis

 Ig-lipoprotein complex disorder  Ig-lipoprotein complex disorder
 Diabetes mellitus  Resolving lipemia
 Alcohol  Anorexia nervosa

 Estrogen  cholestatsis

 Uremia
 Acromegaly
Before starting treatment for dyslipidemia
 Lipodystrophy
secondary causes must be ruled out / treated
 Isoterinoin accordingly
 PIs
TREATMENT MODALITIES FOR DYSLIPIDEMIAS

 Primordial prevention:
 Population based approach to prevent development of risk factors
 Smoking cessation
 Weight management
 Physical activity
 Healthy and regular eating habits
 Regular check up of BP, Glucose, cholesterol

 Primary prevention:
 In high risk patients to prevent first ever CHD event

 Secondary prevention:
 Person had prior CHD event, prevents further CHD events
PHARMACOTHERAPY OF DYSLIPIDEMIAS

HYPERCHOLESTEROLEMIA HYPERTRIGLYCERIDEMIA

HMG Co-A Inhibitor of Fibric acid

reductase intestinal derivatives Niacin
Bile acid
inhibotors sequestrants cholesterol
(statins) absorptiion
 1- HMG co-A reductase inhibitors
(STATINS)

 Drugs in the group are,

 Lovastatin
 Simvastatin
Lovastatin
 Pravastatin derivatives
 Atorvastatin
 Rosuvastatin
Synthetic
 Fluvastatin derivatives
 pitavastatin
Mechanism of action of statins
Rate limiting step
in cholesterol
syntheis
HMG co-A
reductase
HMG co-A Mevalonate Cholestrol

Inhibited by
statins

↓ in cholesterol content in hepatocytes

↑ LDL receptor gene expression & up regulation of LDL receptors

↑ clearance of plasma LDL and ↓ LDL-C level

Cont……
 Other mechanisms of ↓ LDL-C
 ↑ removal of LDL precursors (VLDL & IDL)
 ↓hepatic VLDL production

Dose (mg) of statins to produce various reduction in LDL-C from baseline

20-25% 26-30% 31-35% 36-40% 41-50% 51-55%

Atorvastatin - - 10 20 40 80

Fluvastatin 20 40 80

Lovastatin 10 20 40 80

Pitavastatin 1 2 4

Pravastatin 10 20 40

Rosuvastatin 5 10 20

Simvastatin 10 20 40 80
Cont……
 Statins ↓ TAG with same magnitude as it
↓LDL by,
 ↓ VLDL production
 ↑ clearance of IDL

 Most Statins ↑ HDL-C by 5-10% but

Rosuvastatin causes 15-20%

 No effects on Lp(a) levels.

 Other cardioprotective / pleiotropic
effects

 Improve endothelial function

 Improves plaque stability
 ↓ vascular inflammation
 ↓ CRP levels
 ↑ neovascularisation of ischemic tissue
 ↓ LDL oxidation
 ↓ platelet aggregation
 ↓ fibrinogen level

But Importance of these pleiotropic effects in

clinical utility is not exactly defined
 Pharmacokinetics
 Variable absorption: 30-85%

 All statins are active except Simvastatin, Lovastatin (Prodrugs)

 Converted to their respective β-hydroxy acid active forms in liver,

Simvastatin acid & Lovastatin acid.

 Extensive first pass metabolism. BA is 5-30%

 Most statins have active metabolites (less active) except

fluvastatin, Pravastatin.

 > 95% PPB except Pravastatin - 50%

 Cont……
 Statins are taken up by the liver by specific tansporter
OATP1B1 and then metabolized,

 Atrovastatin, simvastatin, lovastatin CYP3A4 (mainly),

CYP3A5
 Fluvastatin CYP2C9 (>50%), CYP3A4/2C8
 Rosuvastatin non CYP enzymes

 Excretion as metabolites – 70% in feces

- 30% in urine
 Rosuvastatin not metabolized & excreted unchanged in urine.
 T1/2 for most statins is 1-4 hrs except,
 Simvastatin – 12 hrs
 Atorvastatin – 14 hrs
 Rosuvstatin – 20 hrs
Clinical use:
Statins are effective in all patients with ↑ LDL-C except
“Homozygous Familial Hypercholesterolemia”

Dysfunctional LDL receptors

Partial response is d/t ↓ VLDL production.

 Single daily dose – in evening or bedtime

 Atorvastatin, Rosuvastatin can be given at any time
 Dose depend upon the % reduction of LDL-C required.

 Pregnancy and lactation – relative contraindications

 Children – pravastatin >8yrs & atorvastatin, lovastatatin,
simvastatin >11yrs
Adverse drug reations:
 Common – myalgia, myopathy
 Rare but serious side effects are,
 Hepatotoxicity – 1/million person year
 Rhabdomyolysis – 1/million prescriptions (30 days)

 Serious ADRs are dose & plasma conc related.

 Risk ↑ in presence of following risk factors
 Age > 80 yrs
 Hepatic / renal dysfunction
 Multisystem disorder (esp. DM)
 Small body size
 Hypothyroidism
 Drug interactions
 Risk of serious adverse events in concurrent use of
following drugs

CYP3A4 inhibitors CYP2C9 inhibitors

Gemfibrozil Ketoconazole
Niacin Metronidazole
Cyclosporine Amiodarone
Itraconazole
Erythromycin
PIs

Gemfobrozil is the most common drug associated with drug interaction

induced myopathy (40%) because it also blocks OATP1B1
Laboratory monitoring:

ALT CK
Initiation of Not routinely
therapy necessary

Unpredictable
At 3-6 months nature

Every 6-12
monthly
2 – Bile acid sequestrants
 Drugs in this group are,
 Cholestyramine
 Colestipol
 Colesevelam

 Physiology,
Bile acids are synthesized in liver from cholesterol

Secreted in intestine for dietary fat absorption

Undergo enterohepatic circulation

Mechanism of action
Bile acid sequestrants / resins are insoluble, non-absorbable anion
exchange protein

Form complex with negatively charged bile acids and bile salts

This complex is non-absorbable

Excreted in feces as it is

↑ biosynthesis of bile acid from cholesterol

Partial depletion of intracellular cholesterol

 Upregulation of LDL receptors

↓ in LDL-C levels by ↑ clearance from plasma

As Monotherapy, at maximal therapeutic doses it ↓ LDL by 20-25%

Long term use partially offset this effect because of

compensatory increase in HMG Co-A reductase activity.

 It produces ↑ TAG level particularly if S.TAG>250mg/dl.

 Mechanism of action not clear but possibly ↑ in bile acid synthesis is

accompanied by ↑ TAG production as well.

 HDL-C ↑ 4-5% by undefined mechanism

Adverse drug reactions:
 Bloating Dose limiting side
 Dyspepsia effects, less likely
with colesevelam
 Constipation
 Exacerbation of pre-existing hemorrhoids

Drug interaction:
 It interefere with absorption of many drugs,
 Thiazide

 Furosemide
 Digoxin

 Propranolol
So its recommonded to give any drug
 Warfarin
1 hr before or 4 hrs after resin
 Statins

 Thyroxine
Clinical use:
 Cholestyramine (4g/dose) or colestipol (5g/day) initial dose BID
preferably taken just before breakfast & supper

 Dose increment as tolerated upto needed.

 Colesevelam: 3 tabs (0.625 gm/tab) BID or 6 tab at a time.

 These drugs have limited utility as monotherapy, used primarily as

adjunct to statins

 Pregnancy & lactation - avoided as its used in combination

 Children - >10 yrs

 Lab monitoring: S.TAG initially 1-2 weekly till S.TAG

stabilizes
3- Inhibitor of intestinal absorption
of cholesterol
 Drug in the group,
Ezetimibe

 Mechanism of action:
Inhibits NPC1L1

↓ TAG cholesterol absorption by 50-60% (no effect on

TAG absorption)

↓ cholesterol in chylomicrons
 ↓ cholesterol in chylomicron remnants

↓ atherogenesis directly ↓ cholesterol delivery to liver

↑ LDL receptor expression

↓ LDL-C level by ↑ plasma clearance

There is compensatory ↑ in HMG co-A activity, partially offsets its

LDL-C lowering effects

Monotherapy, clinical used doses it ↓ LDL-C by 15-20%

No effects on TAG, HDL levels

Pharmacokinetics:
 Highly water insoluble, Glucoronidation in intestinal
epithelia.

 Absorption

 Enterohepatic circulation.
70% - feces
 Excretion as gucoronide conjugates
10% - urine
 T1/2 – 20-22 hrs
 Adverse drug reaction:
 GIT discomfort
 Rarely allergic manifestations

 Drug interactions:
 Bile acid sequestrants - ↓ absorption

 Clinical use
 10 mg tab any time a day
 Limited use as monotherapy
 Used as adjuvant to statins

 Pregnancy, lactation, children: avoided

4-Niacin
 Vit-B3 but higher doses are used for its effects on lipid
metabolism

 Mechanism of action:
1. ↓ lipolysis by inhibiting hormone sensitive lipase in
adipose tissues.

↓ FFA, ↓ TAG synthesis by liver

This effect is mediated by specific GPCR for niacin on

adipose tissues (Gi) ↓ AC activity ↓ Lipase
activity
 Cont…..
2. Inhibits diacylglycerol acyltransferase-2 in liver (rate limiting
enzyme in TAG synthesis)

3. Inhibits esterification of FAs

4. ↑ LPL activity - ↑ clearance of VLDL, chlomicrons

Diacyglycerol
acyltransferas ↓ lipolysis
e
↓ VLDL
level

↓ esterification of ↑ LPL activity

FAs
↓ LDL-C
Cont……..
 ↓ hepatic clearance of apo A-l

↑ HDL-C levels

 In macrophages, ↑ expression of scavvanger receptors- CD36,

ABCA1

↓ cholesterol content of foam cells

 Overall,
 It’s best agent to ↑ HDL-C : 30-40% rise
 ↓ TAG : 35-45%
 ↓ LDL-C : 20-30%
 ↓ Lp(a): only agent ? mechanism
Pharmacokinetics
 Almost completely absorbed
 Low dose completely taken by liver

Nicotinuric acid (major metabolite) excreted in urine.

 High dose

Most part excreted unchanged in urine.

 T1/2 is 60 mins
 Adverse drug reactions
2 most common
 Flushing dose limiting side
 Dyspepsia effects

 Flushing PG mediated NSAIDs prophylaxis

 Others cutaneous side effects,
 Pruritus
 Skin rash
 Dry skin
 Acanthosis nigricans
 Rarely GIT side effects
 Nausea
 Vomitting D
 Diarrhoea
 Cont……..
 Rare but serious side effects,
 Hepatotoxicity
 Hypergycemia
 Hyperuricemia & acute gout
 Toxic amblyopia & maculopathy
 Atrial tachyarrhythmia & fibrillation

 Clinical use:
1. Crystalline niacin tab (50-500 mg):
 Initial dose is 100 mg BID Increment of 100-200 mg
weekly upto 2 gm

2. Sustained release preparation: Less chances of

hepatotixicity
Cont…….
 Use avoided in,
 Pregnancy
 Lactation
 H/o peptic ulcer disease
 H/o gout

 Lab monitoring:
S.Transaminase, FBS, Urate initially

At 2-4 weeks

Every 3-6 monthly

Fibric acid derivatives: PPAR Activators
 Drugs in this group,
 1st generation: Gemfibrozil, Clofibrate
 2nd generation: Fenofibrate, Ciprofibrate, Bezafibrate

 Mechanism of action: By stimulating PPAR-

↑ LPL activity ↓ apo C-lll ↑ apo A-l,ll

apo C-lll is inhibotor

of lipolysis by LPL
↑ clearance of CM,
VLDL ↑ clearance of CM, ↑ HDL-C level
VLDL