DRUGS AFFECTING LIPID METABOLISM

MODERATOR:

DR.J.G.BUCH SIR

INTRODUCTION

Lipoproteins

Dyslipidemia

Hyperlipoproteinemia

Hyperlitriglyceridemia

Hypercholesterolemia

Decreased level of HDL

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

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

HDLA-l, A-ll, A-lV, C-l, C-ll, C-lll, E

Lp(a) B-100, A

What is it’s role

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

< 70Optimal for high risk patients

<40 Low for men

< 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 yrsFemale > 55 yrs

FAMILY HISTORY OF PREMATURE CHD

In first degree relative, male < 55 yrs or female < 65 yrs at first clinical CHD event

CURRENT CIGARETTE SMOKING

In last 30 days

HYPERTENSION BP ≥ 140/90Use of anti-HT agents irrespective of BP

LOW HDL-C < 40 mg/dl for male< 50 mg/dl for female

OBESITY BMI > 25 kg/m2Waist cicumference > 40 inch for male and > 35 inch for female

TYPE-2 DM Independent risk factor for CHD

Lipoprotein metabolism

Synthesized from fatty acids from dietary TAG, cholesterol, fat soluble vitamins.

TAG : CH > 10

1- Chylomicrons

Triglycerides

Diacyl gycerol trasnsferase

Microsomal triglyceride transfer protein (MTP)

cholesterol

NPC1L1 (Neimann pick C1 like 1 protein)

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

VLDLSynthesized in liver when there is increase in FFA levelTAG > 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 endocytosis in hepatocytes via LDL receptors or LRP

50% acted upon by HL

LDL

Most part taken up by hepatocytesapo B mediated endocytosis by LDL receptor

Non receptor mediated clearance

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 metabolismFormation of pre-β HDL from apo A-l, phospholipids

ABCA 1, ABCG 1

LCAT (Lecithin cholesterol acyl trasnferase)

HDL-3

HDL-2

Cholesterol exchange with TAG by CETP (cholesterol ester transfer protein)

HL mediated lipolysis

HDL-3

Reverse cholesterol transport

Cont……

Mutations HDL

ABCA-1 (Tangiers disease) apo A-l

Frederickson’s / WHO classification of Primary hyperlipoproteinemias

Type Name Elevation in lipoprotein/s Defect

Elevation in lipids

TAG CH

l Familial hyperchylomicronemia CM LPL +++ +/N

lla Familial hypercholesterolemia LDL LDL receptor N ++

llb Familial combined hypercholesterolemia VLDL & LDL

LDL receptor + overproduction of VLDL

++ ++

lll Familial dysbetalipoproteinemia

IDL, CM remnant apo E ++ ++

lV Familial hypertriglyceridemia VLDL

Overproduction &/or decresed removal of VLDL

++ +/N

V Familial combined hypertriglyceridemia VLDL & CM

Overproduction &/or decresed removal of VLDL& CM

++ +/N

Secondary causes of Hyperlipoproteinemias

Hypertrigyceidemia:

Corticosteroid excess Hypopituitarism Myxedema Severe nephrosis Ig-lipoprotein complex disorder Diabetes mellitus Alcohol Estrogen Uremia Acromegaly Lipodystrophy Isoterinoin PIs

Hypercholestrolemia:

Corticosteroid excess Hypopituitarism Hypothyrodism Early nephrosis Ig-lipoprotein complex disorder Resolving lipemia Anorexia nervosa cholestatsis

Before starting treatment for dyslipidemia secondary causes must be ruled out / treated

accordingly

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

HMG Co-A reductase inhibotors (statins)

Bile acid sequestrants

Inhibitor of intestinal

cholesterol absorptiion

HYPERTRIGLYCERIDEMIA

Fibric acid derivatives

Niacin

1- HMG co-A reductase inhibitors (STATINS)

Drugs in the group are, Lovastatin Simvastatin Pravastatin Atorvastatin Rosuvastatin Fluvastatin pitavastatin

Lovastatin derivatives

Synthetic derivatives

Mechanism of action of statins

HMG co-A Mevalonate Cholestrol

HMG co-Areductase

Inhibited by statins

Rate limiting step in cholesterol

syntheis

↓ 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

GemfibrozilNiacinCyclosporineItraconazoleErythromycinPIs

KetoconazoleMetronidazoleAmiodarone

CYP2C9 inhibitors

Gemfobrozil is the most common drug associated with drug interaction induced myopathy (40%) because it also blocks OATP1B1

Laboratory monitoring:

ALT

Initiation of therapy

At 3-6 months

Every 6-12 monthly

Not routinely necessary

Unpredictable nature

CK

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 Dyspepsia Constipation Exacerbation of pre-existing hemorrhoids

Drug interaction:

It interefere with absorption of many drugs, Thiazide Furosemide Digoxin Propranolol Warfarin Statins Thyroxine

Dose limiting side effects, less likely with colesevelam

So its recommonded to give any drug 1 hr before or 4 hrs after resin

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.

Excretion as gucoronide conjugates

T1/2 – 20-22 hrs

70% - feces

10% - urine

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

↓ VLDL level

↓ lipolysis

↑ LPL activity↓ esterification of FAs

Diacyglycerol acyltransferase

↓ 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 Flushing Dyspepsia

Flushing PG mediated NSAIDs prophylaxis

Others cutaneous side effects, Pruritus Skin rash Dry skin Acanthosis nigricans

Rarely GIT side effects Nausea Vomitting D Diarrhoea

2 most common dose limiting side

effects

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 A-l,ll

↓ apo C-lll

apo C-lll is inhibotor of

lipolysis by LPL

↑ clearance of CM, VLDL

↑ clearance of CM, VLDL ↑ HDL-C level