of dyslipidaemia-20-09-2015.pdf · @f55 f55%fe3; ;% @2e5 2e5%243 ;% o=5+ , o45+ , o45 # @245...

Dr Karuna Sree PAsst. ProfessorDept. Of Pharmacology

Newer drugs in pharmacotherapy of Dyslipidaemia

2016-1-19 Dr Karuna Sree, Dept. Of Pharmacology, KIMS

Contents

Introduction, history Hypolipidaemic drugs

▪ Classification▪ Mechanism of action▪ Uses and Adverse effects

Summary


Introduction

Two major consequences of hyperlipidaemias are acute pancreatitis and atherosclerosis

Globally atherosclerosis - major cause of death and premature disability.

Experimental & epidemiological evidence s/o atherosclerosis ∝ elevated plasma lipids (CH & TG)


History of Hypo-lipidaemic drugs


HistoryRudolf VirchowFound cholesterol in the arteries of people died from Occlusive vasc. diseases like MI

1950 - Framingham heart study� led by Dr. Dawber – ↑ blood CH levels ∝ CAD.1970 – Akira endo –

fermented product of Penicillium - block CH synthesis, named as compactin- withdrawn - high toxic effects in animal studies.

1978 - Alfred Alberts et al found fermented product from Aspergillus & named Mevinolin later called as Lovastatin

2016-1-19 Dr Karuna Sree, Dept. Of Pharmacology, KIMS 7

Risk factors of atherosclerosisCigarette smoking

Hypertension (BP -140/90 mmHg or on antihypertensive medication)

Low HDL cholesterol* [<1.0 mmol/L / <40 mg/dL]Diabetes mellitus

Family history of premature CHD

CHD ♂ - 1˚ relative <55 yrs

CHD ♀ - 1˚ relative <65 yrs

Age (♂ - 45 yrs; ♀ - 55 yrs)

Lifestyle risk factorsObesity (BMI 30 kg/m2)

Physical inactivityAtherogenic dietEmerging risk factorsLipoprotein(a)HomocysteineProthrombotic factorsProinflammatory factorsImpaired fasting glucoseSubclinical atherosclerosis


Lipoproteins


High density

Chylo-microns

Very low density

Low density

Apolipoproteins

Major core

proteins

Relative size


Lipid transport

Hepatic lipase


Types of Dyslipidaemia

Primary : Genetic (Monogenic / Polygenic)

Secondary : Diabetes, Chronic Renal Failure, Nephrotic Syndrome,

Hypothyroidism, Liver Disease, Alcoholism

or Drug Induced (ß-blockers, Corticosteroids, OC pills, Tamoxifen, Protease Inhibitors, Isotretinoin, Cyclosporine)


Frederickson’s classification : Primary Hyperlipoproteinaemia’s

Type Disorder Cause Occurrence Lp elevated

I Familial Lp lipase Def. G Very rare Chylomicron

IIa Familial hypercholesterolaemia

G Less common LDL

IIb Polygenic hypercholesterolaemia

MF Commonest LDL

III Dysbetalipoprotenaemia

G Rare LDL,CM remnants

IV Hypertriglyceridaemia G,MF Common VLDL

V Combined hyperlipidaemia

G Less common VLDL,LDL


Management of Dyslipidaemia

Non - pharmacological▪ Dietary modification▪ Increased physical activity▪ Elimination of associated risk factors

Pharmacological therapy

Treatment of causative disease in c/o secondary hyperlipidaemias


HMG CoA reductase inhibitors(Statins)

Simvastatin, Atorva, Rosuva

Bile acid sequestrants(Resins)

Colestipol, Cholestyramine

Fibric acid derivatives / activate LP lipase

Clofibrate, Gemfibrozil, Bizafibrate, Fenofibrate

Inhibit lipolysis and TG synthesis

Nicotinic acid

Inhibitors of CH intestinal absorption

Ezitimibe

Stanol esters

Others Gugulipid, Probucol

Classification :

Hypolipidaemic

Drugs


HMG CoA Reductase InhibitorsSTATINS


Statins

Most efficacious, best tolerated & introduced in 1980s.Chemistry : Simvastatin & pravastatin are structurally similar to Lovastatin. Lova & Simvastatin are prodrugs.

Atorvastatin, fluvastatin, rosuvastatin, and pitavastatin are fluorinated active compounds.

Statins possess a hydroxy acid side chain similar to that of HMGCoA intermediate metabolite.


Statins : MOA contd…. ↓ free CH in hepatocytes

SREBP gets cleaved by SCAP & translocates

to nucleus

Binds to SRE of LDL-R gene

Synthesis of LDL receptors

• Statins also ↑ removal of LDL precursors (VLDL & IDL) &↓ synthesis of VLDL, thereby ↓ TG & LDL-C


Statins : Pharmacokinetics

Absorption : well absorbed with BA of 40-90 %, fluvastatin- completely absorbed

Metabolism : Undergoes First pass metabolism Except Rosuva & Fluva (CYP2C9) and pravastatin(sulfate conjugation)

all are metabolized by CYP3A4. Excretion : Mostly in bile & 5-20% excreted in urine

Administered at bed time except for Atorva & Rosuva due to their long t1/2.

Dose dependent effect.


Statins : Pharmacological actions

Role of statins in cardioprotection other than ↓LDL-C

Improves endothelial function

Stabilises the atheroma plaque

Anti-inflammatory role - ↓ hsCRP

Prevents Lipoprotein oxidation

↓ Platelet aggregation


Drug Dose T1/2 Metabolism

Lovastatin 10-40mg 1-4 hrs

High 1st pass, CYP3A4

Simvastatin -Twice potent to lova, ↑HDL more

5-20mg 2-3 hrs

-do-

Pravastatin - hydrophilic ,less DI, ↓ fibrinogen

10-40mg 1-3 hrs

Sulfate conjugation

Atorvastatin - anti oxidant, No dose adjustment in renal failure

10-80mg 14hrs

CYP3A4

Rosuvastatin - Twice potent to atorva, ↑HDL more

5 - 40mg 19hrs

CYP2C9

Fluvastatin - No dose adjust in renal failure, less DI

20-80mg, Less efficacious

0.5-3hrs

CYP2C9


Statins : Uses

Hypercholesterolemia – Primary, secondary prophylaxis

In Combination : Statins + resins - ↓ 60% of Ch Statins + resins + NA – ↓ 70%


Statins : Adverse Reactions

Liver : Rise in serum transaminases but rarely liver damage

Muscle : Muscle tenderness, ↑ CPK, myopathy (<1/1000) ▪ ↑ Severity in combination with Fibrates/NA/ other CYP3A4 inhibitors Myositis, Rhabdomyolysis and renal shutdown.

GI disturbances : nausea, bowel upset CNS: insomnia, headache Hypersensitivity reactions : rashes

C/I : Pregnancy, Breast Feeding, Children, Severe Liver Disease


Bile acid sequestrants / BA binding resins

Cholestyramine, Colestipol, Colesevelam

These are insoluble, non absorbable anion exchange resins

Resins retard atherosclerosis but less compliant because of unpalatability, require large doses, GI Adverse reactions


↑ BA synthesis in liver, they also ↑ synthesis of TG, hence TG levels to be monitored every 1-2 weeks

while on therapy esp. in patients with hypertriglyceridaemia

MOA : Resins

Resins bind with Bile acids

Up regulation of LDL-R

Decreased LDL in blood

Depletion of CH pool in liver

↓BA in liver

Biosynthesis of BA from CH in liver↑

Resulting complex is excreted


BA binding resins : uses

Hyperlipidaemia

1-2 weeks is sufficient for ↓ in LDL-C High doses poorly tolerable, inspite of greater efficacy.

Cholestasis, Bile salt accumulation, Digitalis toxicity

↓ LDL-C ↑ HDL-CCholestyramine (8 - 12 g) /

colestipol (10 - 15 g) 12-18%

4-5% Colesevelam (3 - 3.75 g) 9-19 %

Resins With niacin / statins 40-60%


BA binding resins cont…

ADR : Constipation, exacerbation of pre existing hemorrhoids, GIT distress,

hyperchloremic acidosis (rarely)DI : Absorption of vitamins, FA may impair.

Binds to Digoxin, Tetracycline, Statins, Thiazides Diuretics & interfere with absorption/action.

Preparations : powder / tablet (colesevelam).


Fibric acid derivatives

1st generation fibrates : Clofibrate 2nd generation : Gemfibrozil, Fenofibrate, Bezafibrate, ciprofibrate

Lowers VLDL, TG by 50% & ↑ HDL-C by 15% & ↓ fibrinogen levels &

LDL-C by 15-20%

Effect mediated through PPAR∝ receptor expressed in liver, fat &

muscles.


Fibrates : MOA

Activates peroxisome proliferation activated receptor factor (PPAR-∝)

↓TG, VLDL & ↑ HDL

↑ fatty acid

oxidation

↑ LPL activity

↑ Apo A I & II, hepatic SREBP-1

production↓ Apo

CIII


Pk Dose uses

GemfibrozilT1/2 : 1-2hrs, High efficacy in Type III & ↓CH, Factor VII-PL complex & promotes fibrinolysis

Absorption : Oral - Complete

Metabolism: GlucuronidationExcretion:

urine

600mg BD before meals

Type IIIType

IV,V

And as adjuvant in Type II

200mg TDSBezafibrate

Dose reduction needed in elderly / renal insufficiency↑action of warfarin

200mg OD with meals

FenofibrateT1/2 : 20 hrsGreater ↓ in CH & ↑ HDLMost suitable combination with statins


Fibric acid derivatives cont…

Uses : Hypertriglyceridaemias. Fenofibrate is uricosuric - given in coexisting hyperuricaemia

ADR : GI, skin rashes, body ache, myalgia, reversible myopathy. Eosnophilia, Impotence, Blurred Vision, cholelithiasis with Gemfibrozil ↑ Aminotransferases & Alk. Phosphatase – Fenofibrate

DI : with statins increase myositis, potentiates affect of warfarin


Nicotinic acid / Niacin

It is a water-soluble B-complex vitamin (B3) ↓ TG by 35-45%, VLDL by 35%, LDL by 20-30% ↑ HDL by 30-40% The only agent to ↓ Lp(a)

Inexpensive but many acute & chronic side effects.


MOA Niacin / Nicotinic Acid

↓ TG lipolysis & free fatty acids

↓ TG

Adipose tissue Promotes

LPL activity

Clearance of CM &

VLDL

↓ hepatic clearance of Apo-A1

↑ Plasma Apo-A1

↑ HDL-C

Macrophages

↑ expression of the scavenger receptor CD36

& cholesterol exporter ABCA1 – ↓ CH in cell

Liver

↓ synthesis &

esterification of FFA

↓ TG

↓ VLDL & LDL-C


Nicotinic acid contd…

Pk : completely absorbed, t1/2 – 60min.

Dose : 2-8 g /day in 3 divided doses, starting with 100mg TID & escalating the dose every 2-3 wks.

Uses : highly efficacious in hypertriglyceridaemia (Type III, IV, V) Pancreatitis in Type IV & V


Nicotinic acid : ADR

Cutaneous vasodilator : Flushing, pruritis, skin rashes, acanthosis nigricans.

GI discomfort : Dyspepsia, vomiting, diarrhoea

Hyperglycaemia, Hyperuricaemia, gout, atrial arrhythmias

Hepatic dysfunction (> 2 G/day, Knopp et al., 2009).

Blurred vision- toxic maculopathyC/I : Pregnancy Preparations : Regular / extended release tablets.


Ezetimibe

Synthetic drugInhibits Niemann-Pick C1 Like 1 protein (NPC1L1) transporter on jejunum

↓ CH absorption & plant sterols

By ABCG5 and ABCG8 transporters – pumps back absorbed plant sterols into intestinal

lumen

Ezetimibe MOA

↑ LDL-receptors thus LDL-C ↓ by 15-20% in plasma

↓ CH in CM & its remnants – ↓CH in liver


Ezetimibe cont…

Pk: Readily absorbed, half life of 20 -22hrs

Dose : 10 mg/d ADR : GI discomfort, reversible hepatic dysfunction &

rarely myositis.

Liver Function Tests to be done before starting therapy.


Miscellaneous- Gugulipid

Developed by CDRI- Lucknow

Mixture of sterones, obtained from Gum guggul.

Inhibits CH biosynthesis and increases CH excretion

Dose : 25 mg TID

ADR : Loose stools


Probucol

Introduced in 1970s Powerful antioxidant, with marginal lowering in

HDL, LDL-C, no effect on TG.

Macrophages Oxidised LDL-C

Fatty streaks

Foam Cells

Atherosclerosis

Probucol LDL-C


Probucol cont…

Uses : type IIa & IIb hypercholesteraemia.

ADR : GIT discomfort (8% patients)

DI : prolongs QT interval, hence not combined with digoxin and quinidine.

C/I : Ventricular arryhthmias


Hypolipidaemic drugs : Site of

action


Hypolipidaemic drugs : Novel drug targets


Newer drugs

Cholesteryl ester transfer protein inhibitors – torcetrapib, Anacetrapib, dalcetrapib, evacetrapib

Cholesterol O-acyltransferase inhibitors (ACAT) – HL-004

Diacylglycerol acyltransferases inhibitors

Microsomal TG transfer protein inhibitors – Dirlotapide, lomitapide

Squalene synthase inhibitors – lapaquistat, EP2306, 2302

Thyroid hormone analogues –eprotirome

Other targets - lanosterol synthase inhibitors, CH metabolising CYP450, AMP activated protein

kinase, omega3fatty acids.


Cholesteryl ester transfer protein inhibitors

Torcetrapib, Anacetrapib, dalcetrapib, evacetrapib Torcetrapib – trials halted because of cardiovascular

adverse effects.

Anacetrapib in phase III trials – its safety and efficacy established in DEFINE, REVEAL trial in progress.

Dose/day Raises HDL by Anacetrapib + statins 100mg 140%

Dalcetrapib + statins 600mg 30%

Evacetrapib + statins 100mg 80%


Microsomal TG transfer protein inhibitors

MTTP is a heterodimeric lipid transfer protein that catalyzes the transport of TG, cholesteryl ester, and phosphatidylcholine between membranes.

Site : Intestine and liver tissues.

Role : Lipid assembly, transport, and secretion of lipoproteins, Chylomicrons (in enterocytes), and VLDL (in hepatocytes) and synthesis of nascent lipoprotein particles within the lumen and ER.

Inhibition of MTTP should decrease plasma TG & CH levels.

Dirlotapide – approved as anti-obesity drug for Dogs ADR - ↑hepatic transaminases, GI side effects.

Lomitapide - 60mg/day FDA approved in 2012.

Use : Homozygous familial hypercholesterolaemia.


Antisense oligonucleotide (ASO) inhibitor

Mipomersen is a first-in-class ASO inhibitor approved in Jan 2013, that targets apolipoprotein B-100 and reduces LDL-C, total cholesterol, and non-HDL-C.

Dose : once-weekly inj. SC, as an adjunct to other medications and diet

Indication : Homozygous familial hypercholesterolemia.


Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors


PCSK-9 inhbitors

Alirocumab, approved on july 25th 2015 - the first PCSK-9inhibitors.

These are monoclonal antibodies - that act by identifying and knocking out PCSK9 enzymes in the liver.

↓ low-density lipoprotein cholesterol (LDL-C), likely more potent than statins.

Other egs : Elocumab is expected shortly.

Use : hyperlipidemia


Thyroid hormone analogues

Thyroid hormone accelerates LDL-c clearance rate. T3 increases levels of both the hepatic LDL receptor and its mRNA. Increases the activity of lipoprotein lipase.

Eg. Eprotirome, in phase II trials that only interacts with the β-receptors found primarily in the liver.

No adverse effects on heart and bone

Given along with statins - significant in ↓LDL-C, TG, ApoB Dose : 25-100mcg/day oral


Acyl-CoA: Cholesterol O-acyltransferase inhibitors

ACAT is an important enzyme involved in re-esterification of absorbed cholesterol within enterocytes.

Functions : cholesterol metabolism in macrophages, liver, intestine and adrenal cortex Secretion of VLDL from liver and development of atherosclerotic lesion.

Two types of ACAT enzymes : ACAT1 : present in ER throughout the body – if inhibited prevent the transformation of

macrophages into foam cells. ACAT2 : present in ER of liver and intestinal tissues - if inhibited, ↓ synthesis of liipoproteins – ↓

serum lipid levels.

Eg. HL-004, fungal derivative – pyripyroneA are under trials


DGAT inhibitors

Diacylglycerolacyltransferases (DGATs) are enzymes involved in adipocyte lipid accumulation and catalyzes the final step reaction of triacylglycerol formation from diacylglycerol.

DGAT1 is expressed in skeletal muscle, skin, intestine (ileum, colon), and testis, with lower levels of expression in liver and adipose tissue.

DGAT2 is ubiquitous with high expression levels in hepatocytes and adipocytes.


Newer drugs contd…

Squalene synthase inhibitors – lapaquistat, EP2306, 2302

Lanosterol synthase inhibitors

CH metabolising CYP450

AMP activated protein kinase activators

Omega 3 fatty acids.


NCEP-ATPIII :Treatment Guidelines

Lifestyle modification Prescribe drugs depending on the lipid levels and risk factors associated. Risk factors for CAD

♂>45 yrs, ♀>55 yrs F h/o MI / sudden cardiac death before 55yrs in ♂ & before 65yrs in ♀

in 1st degree relatives HTN(>140/90 mmHg or use of Antihypertensives) Low HDL-CH(♂<40mg/dl, ♀<50mg/dl) High LDL-CH ≥160mg/dl or total CH ≥240mg/dl Obesity (BMI>25kg/m2 or waist Cf>40” ♂ and >35” in ♀)


Treatment guidelines

Lipids Desirable mg/dl Borderline mg/dl

Total CH <200 200-239

LDL-C <130 130-159

HDL-C >40 (♂),>50(♀) >50

TG <150 150-199

Risk category LDL-CH goal

LCL-CH level for initiation of Rx TG

Lifestyle modification

Drug Rx

Very high risk <70 All subjects All subjects >500, drug Rx

High risk(>20%) <100 All subjects All subjects 200-499, drug Rx

Moderately high risk(10-20%)

<130 ≥100 ≥130

Moderate risk(<10%)

<130 ≥130 ≥160

Low risk(≤1 ) <160 ≥160 ≥190


Choice of lipid lowering drugsDrug Hypercholester

olemia (↑LDL-C + TG<200mg/dl)

Combined hyperlipidaemia (↑LDL-C + TG: 200-400 mg/dl)

Hypertriglyceridaemia (TG>400mg/dl)

Statins DOC Effective ---

Fibrates ---- Effective in high doses

DOC

Nicotinic acid

Effective, usefulness limited by adverse effects

DOC Effective but poorly tolerated


Summary

Patients with any type of dyslipidemia are at risk of developing atherosclerosis - induced vascular disease.

Hypolipdemic drugs used - Statins, Fibrates, Bile acid binding resins, Nicotinic acid & ezitimibe.

In every type of dyslipidemia, statins are proven to ↓ the risk of subsequent CHD events and non-hemorrhagic stroke, hence first DOC and dose to be titrated according to the goals.


Than Q

of dyslipidaemia-20-09-2015.pdf · @f55 f55%fe3; ;% @2e5 2e5%243 ;% o=5+ , o45+ , o45 # @245...

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