ANTI-HYPERLIPIDEMICS

HYPERLIPIDEMIA
CVS

disorders:

Atheroschelorsis:

Hyperlipidemia
Atheroschelorosis: degenerative

changes in intima of arteries.

Degeneration:

Accumulation

of

lipids, complex carbohydrates, blood accompanied by formation of fibrous

tissue and calcium deposition

Deposits/ Plaques: hardening of blood vessel and occlusion.

LIPOPROTEINS
Made up of lipids with proteins, carbohydrates

Non polar core Monolayer of phospholipids (PL)

PL: contains cholesterol, apoproteins

Apoproteins: Solubilize lipids

CLASSIFICATION OF LIPOPROTEINS

COMPOSITION OF LIPOPROTEINS
Lipoprotein Protein Cholesterol PPL 3-7% 3-8% TG 90-95%

Chylomicrons 1-2% (CM)

VLDL IDL
LDL HDL

10% 18%
25% 49%

19% 11%
50% 22%

15% 22%
21% 28%

53% 31%
4% 2%

LDL: Major cholesterol carrying protein 65% plasma cholesterol

Major concern in hyperlipidemic disease states

LIPOPROTEIN METABOLISM

LIPOPROTEIN METABOLISM (Contd) EXOGENOUS PATHWAY

Dietary fat

Intestines

CM

Remnants

Liver

ENDOGENOUS PATHWAY Liver VLDL IDL

Extrahepatic tissue

LDL Receptor

LDL

HDL

HYPERLIPOPROTEINEMIA
Lipid disorders related to abnormal lipid metabolism.

DISEASES/ DISORDERS RESULTING FROM HYPERLIPOPROTEINEMIA

Coronary heart disease (CHD):

angina+ MI + ischemic heart disease Atherosclerosis: Leading cause for CHD

Lowers Plasma LDL levels Bile acid sequestrants Increases level of LDL clearance Lowers plasma cholesterol levels Lowers plasma TG, VLDL levels Fibrates Increases HDL levels Inhibition of lipolysis in adipose tissue Inhibition of absorption of cholesterol

HMG CoA Reductase Inhibitors

Hyperlipidemia Drug therapy

Niacin Cholesterol absorption inhibitor

FIBRATES
CH3 HO

O Aryl

Aryloxyisobutyric acid

Lowers plasma cholesterol and total lipid levels

H3C

CH3

O O OH

Cl

Ethyl-pchlorophenoxy isobutyrate

CLOFIBRATE Prodrug of p-chlorophenoxy isobutyric acid Approved for therapeutic use in 1967 Drawback: no effect on CVS disorders despite cholesterol lowering effect, increase in mortality

Gemfibrozil

Approved for use in 1981 (G) and 1998 (F) Safer, more effective at lowering plasma TG and raising HDL levels

Fenofibrate

BIOACTIVATION OF FIBRATES

bioactivation

Clofibrate (prodrug)

Clofibric acid

bioactivation Cl

O H H3C CH3

Fenofibrate (Prodrug)

Fenofibric acid

EFFECTS MEDIATED THROUGH ACTIVATION OF PPAR

MOA OF FIBRATES

Decrease TG levels more than plasma cholesterol

VLDL decreased, HDL increased

LDL: variable effects Effects mediated through activation of PPAR Decrease in VLDL: Stimulation of lipoprotein lipase, reduced TG synthesis, reduced expression of ApoC III Reduced expression of ApoC III: stimulates lipoprotein lipase Increased HDL: Increased expression of ApoA I and ApoA II

STRUCTURE ACTIVITY RELATIONSHIP OF FIBRATES

N-propyl Spacer resulted in active drug

p-chloro substituent increased half-life

Essential for activity

Analogues of phenoxyisobutyric acids

PHYSICOCHEMICAL PROPERTIES OF FIBRATES All fibrates: carboxylic acid-containing. Ionized at physiological pH.
Clofibrate, fenofibrate: prodrugs: non electrolytes
Gemfibrozil: acidic drug Gemfibrozil: good lipophilicity owing to spacer and 2,5-dimethylphenyl aromatic group Fenofibrate: good lipid solubility due to ester group and additional aromatic ring

PHARMACOKINETIC PROPERTIES OF FIBRATES

Fibrates: Good oral B.A Gemfibrozil lesser half life due to dimethyl substituent on aromatic ring being susceptible to oxidation

High PPB
Route of excretion: majorly renal; partly fecal

METABOLISM OF FIBRATES Prodrugs clofibrate and fenofibrate undergo hydrolysis. Further metabolism: oxidative, conjugative pathways. Gemfibrozil: oxidation of aromatic methyl to hydroxymethyl and carboxy groups lead to inactive metabolites. Fibrates and oxidized analogs excreted as glucuronide complexes.

CH2OH or COOH

THERAPEUTIC APPLICATIONS OF FIBRATES

Hypertriglycidemia
Familial hyperlipidemia (Type IIa, Iib, III, IV & V) Monotherapy or combination therapy ADVERSE EFFECTS OF FIBRATES Clofibrate: more toxic: 1978: mortality

CI in patients with cholelitiasis (increases

cholesterol content of bile) Myopathy, myositis, rhabdomylosis which may

lead to renal failure especially in combination

with statins

HMG-CoA REDUCTASE INHIBITORS (HMGRIs)

Extremely important class of antihyperlipidemic drugs Drugs in this class: inhibit enzyme HMG CoA reductase

Currently: 6 HMGRIs approved in US

Chemically two groups: (a) Natural products

(b) Synthetic agents

Differ in their indications, potencies and PK properties

Also referred to as statins/ vastatins

Natural products

Lovastatin

Simvastatin Synthetic products

Pravastatin

Atorvastatin

Fluvastatin

Rosuvastatin

DEVELOPMENT OF STATINS (HMGRIs)

Mevastatin

Fungal metabolite isolated from Penicillium species Potent competitive inhibitor of HMG-CoA reductase Affinity for enzyme: 10,000 times> substrate HMG-CoA Withdrawn from clinical trials: altered intestinal morphology in dogs

Lovastatin

Isolated from Monascus ruber, Aspergillus terrius Two-fold greater activity as compared to mevastatin Differed only in additional methyl at 6 position of bicyclic ring FDA approval: 1987

BINDING OF STATINS (HMGRIs) TO ENZYME

Both bind strongly to HMG-CoA owing to: (a) Hydrolyzed by enzyme (b) Bicyclic portions: Bind to CoA site of enzyme lactones: Mimic

tetrahedral intermediate produced

STRUCTURE ACTIVITY RELATIONSHIP OF STATINS (HMGRIs)

Mevastatin, lovastatin: lead compounds
Alterations of lactone ring (1), bicyclic ring (2) and ethylene bridge (3) led to following conclusions: Stereochemistry of lactone ring important

Lactone ring has to be hydrolyzed to exert activity

Length of bridge connecting ring systems important Bicyclic rings may be replaced with other lipophilic rings

Pravastatin: lactone ring opened

Advantages: i. ii. Minimal penetration into lipophilic membranes of peripheral cells Better selectivity for hepatic tissues

iii. Reduction in incidence of s.e

STRUCTURE ACTIVITY RELATIONSHIP OF STATINS (contd)

Replacement of bicyclic rings: fluvastatin, atorvastatin, rosuvastatin Compound A: 2,4-dichlorophenyl substitution:

less active
Compound B: Substituted pyrrole: more active 4-fluorophenyl and isopropyl substitutions common in pyrrole (atorvastatin), indole (fluvastatin) and pyrimidine (rosuvastatin) All these synthetic molecules have lactone ring opened. More specific activity

STRUCTURE ACTIVITY RELATIONSHIP OF STATINS (contd)

COMMON FOR ALL HMGRIs

2
HO

1
COOH

Essential for inhibitory activity

Lactone prodrugs: bioactivation.

OH H

Stereochemistry of hydroxy groups: important

Ehtyl group: optimum for compounds with

bicyclic ring systems

Ethenyl group: optimum for compounds with

RING SYSTEM 7-substitied-3,5-dihydroxyheptanoic acid

substituted ring system

STRUCTURE ACTIVITY RELATIONSHIP OF STATINS (contd)

Ester group: if converted to ether

decreased activity observed Stereochemistry: Irrelevant
O

Decalin
RING A
O C7 H CH3

ring:

achors
decreased

compound to enzyme Cyclohexane: activity

H3C R2 CH3

R1

-hydroxyl substitution: increased hydrophilicity

STRUCTURE ACTIVITY RELATIONSHIP OF STATINS (contd)

Cannot be co-planar with central aromatic ring
F

W X

W, X, Y: C or N
n: 0 or 1 (5 or 6 membered heterocycle)

Substitution
sulfonamides

with

aryl,

hydrocarbon chain, amides,

R n
RING B

increase

lipophilicity and inhibition

MECHANISM OF ACTION OF STATINS

Role of HMG-CoA reductase: Conversion of HMG CoA to mevalonate during cholesterol biosynthesis HMG-CoA reductase: rate-limiting catalyst in cholesterol synthesis Elevated plasma cholestserol levels: increased in cardiac disease

MECHANISM OF ACTION OF STATINS (contd)

MOA: (a) Reduction in de novo

cholesterol synthesis
(b) Increase in number of LDL receptors (c) Decreased synthesis of VLDL Atorvastatin, rosuvastain: additional

abilility to lower plasma TG levels

PHYSICOCHEMICAL PROPERTIES OF STATINS

HMGRIs: carboxylic acids pKa 2.5-3.5: ionized at physiological pH. Lovastatin, simvastain: neutral due to lactone ring Nitrogen in atorvastatin p: part of aromatic ring (non-ionizable) Atorvastain, lovastatin higher lipid solubility than pravastain, rosuvastatin

Hydrolysis of prodrugs: ring opening: 3,5-dihydroxycarboxylate

METABOLISM OF STATINS
Lovastatin, simvastatin : bioactivation/ in-vivo hydrolysis All drugs: extensive first pass metabolism. CYP3A4 isozyme: oxidative metabolism of atorva, simva, lova

Atorva: o, p hydroxylated active metabolites

PHARMACOKINETIC PROPERTIES OF STATINS

HMGRIs: 2 weeks to demonstrate lowering of plasma cholesterol
Peak reduction: 4-6 weeks after initiating therapy. Atorva: 2 weeks sufficient for peak effect HMGRIs: Absorbed well but low oral B.A due to high first-pass metabolism. HMGRIs generally taken during late evening Drug Atorvastatin Oral B.A (%) 12-14 PPB (%) 98 Peak Plasma Conc (h) 1-2 Elimination Half life (h) 14-19 Route of excretion Biliary/ fecal

Lovastatin

>95

3-4

Fecal

THERAPEUTIC APPLICATIONS OF STATINS

Primary hypercholesterolemia Hyperlipoproteinemia (Type IIa/IIb) Alone or in combination therapy. In combination with bile acid sequesterants , HMGRIs should be taken 1 h

before or 4-6 h after Bile acid sequestarants.

Atorva: Primary dysbetalipoproteinemia, hypertriglyceridemia

ADVERSE EFFECTS OF STATINS

GI disturbances Elevated hepatic transaminases

DRUG INTERACTIONS OF STATINS

Drug

Interaction

Amiodarone Antacids
Azole antifungals Bile acid sequesterants Ethanol Fibrates Isradipine

Myopathy (increased creatinine kinase) Decreased absorption of statins

Myopathy (CYP3A4 inhibited) Decreased B.A of HMGRIs Hepatotoxicity Increased risk of myopathy Increased clearance of lovastatin and metabolites

NIACIN (NICOTINIC ACID/ VITAMIN B3)

Water soluble vitamin (Vit B3)

Anti-pellagra
In the body conveterted to nicotinamide which is incorporated into NAD/ NADP

MECHANISM OF ACTION OF NIACIN

Inhibition of lipolysis Lowers free fatty acids

Inhibition of triacylglycerol synthesis

PHYSICOCHEMICAL PROPERTIES OF NIACIN

Non-hygroscopic crystalline powder. pKa 4.76: ionized at physiological pH. Pyridine Nitrogen: Weak base (unionized)

METABOLISM OF NIACIN
Dietary nicotinic acid: converted to nicotinamide. Inactive metabolites: Nicotinuric acid, N-methylated derivatives excreted by kidney

PHARMACOKINETICPROPERTIES OF NIACIN
Readily absorbed. Peripheral vasodilation: 20 min. Peak Plasma conc: 45 min Elimination half life: 1 hr

THERAPEUTIC APPLICATIONS OF NIACIN

Hypercholesterolemia Hypertriglyceridemia. Hyperlipoproteinemia (Types IIa/ Iib/ IV, V) Anti pellagra

ADVERSE EFFECTS OF NIACIN

Flushing of skin, pruritis. GI side effects. Hepatic dysfunction Hyperglycemia

DRUG INTERACTIONS OF NIACIN

Drug
Adrenergic agents, Vasodilators Bile acid sequesterants Ethanol HMGRIs

Interaction
Enhanced vasodilation, postural hypotension Reduced B.A of niacin Hepatotoxicity Myopathy