Post on 02-Apr-2015
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