Lipid Lowering Drugs

Dyslipidaemia

Primary
Common (polygenic)
Familial

Secondary

Disease

Hypothyroidism

DM

NS

CLD
Drugs

Isoretenoin

Thiazide

Alcohol

Anti psoriatic

Dyslipidaemia
Total Cholesterol (> 5.2 mmol)
TG (> 1.7 mmol)
LDL-cholesterol (> 4.2 mmol)
HDL-cholesterol (< 1.11 mmol)
Lipoproteins
Chylomicrons
Very low density lipoprotein (VLDL)
Low density lipoprotein (LDL)
Intermediate density lipoprotein (IDL)
High density lipoprotein (HDL)
Lipoprotein metabolism
Exogenous pathways
Starts with intestinal absorption

Dietary cholesterol

Fatty acids

Endogenous pathways
Begins with synthesis of VLDL
(by liver)

Sources of Cholesterol Liver, Intestinal

Mediterranean Diet
Risk of heart disease (CHD)
Diet
High
Low Moderate
Fruits
Fish
Vegetables
Poultry
Whole grains
Dairy products
Nuts
Red meat
Seeds
Olive oil
Effects
Subsequent cardiac events
Inflammatory markers, insulin resistance
LDL oxidation
DASH Diet (Dietary Approach to Stop Hypertension)
Diet
High
Moderate
Low
Fruits
Low-fat dairy products
Animal protein
Vegetables
Protein (plant source)

Legumes

Nuts
Effects
BP
LDL-cholesterol
Risk of Stroke, CHD
Lipid Lowering Drugs
HMG CoA reductase inhibitor
Fibrate
Resin
Nicotinic acid
Ezetimibe
Sites & Mechanisms Drugs for Hyperlipidaemia

Risk Factors CHD

Dyslipidaemia
Hypertension
Smoking
Treatment
Diet polymeal
Weight
Exercise
Smoking cessation
Alcohol cessation
Stress management
Lipid Lowering with Diet/ Dietary Supplements
Fish oil
Soy protein
Guggulipid
Garlic
Polyphenols
Products with trans fatty acids
Fiber
Nuts
Tea
Calcium

Lipid Lowering Drugs

HMG CoA Inhibitor (Statins)
Atorvastatin (Lipitor) ( t )
Rosuvastatin (Crestor)
Pravastatin (Pravachol)
Lovastatin (Mevacor)
Simvastatin (Zocor)
Fluvastatin (Lescol)
MOA
Competitive inhibitors of
hydroxymethylglutaryl coenzyme A reductase
(rate-limiting enzyme in cholesterol biosynthesis)
Inhibition of cholesterol biosynthesis
( Cholesterol concentration within hepatocyte)

Homeostatic event restore intrahepatic cholesterol lvl

Production of LDL receptors

Enhanced clearance of LDL (plasma hepatocyte)
Effects
LDL cholesterol
HDL cholesterol
Adverse Reactions (Common)
GIT Abdominal pain, constipation, flatulence, indigestion
Hepatic - Liver enzymes
Neurologic Headache
Musculoskeletal Myalgia, myopathy
Adverse Reactions (Serious)
Musculoskeletal Rhabdomyolysis, rupture of tendon
Avoid drugs assoc. w. rhabdomyolysis
(when taking statins)

Fibrates (esp. gemfibrazol)

Warfarin

Digoxin

Macrolide antibiotics

Niacin

Antifungals

Cyclosporine
Contraindications
Hypersensitivity to atorvastatin
Liver disease (active)
Pregnancy, lactation (fetal harm)
Serum transaminases (unexplained persistent elevation)
Drug Interactions
Effect with Colestipol, Antacids
Adsorption with Cholestyramine
Level with CYP3A4 inhibitors

Amiodarone

Macrolide antibiotics

Cyclosporine

Ketoconazole

HIV protease inhibitors

Fibrates

Niacin

Grapefruit

Exchange Resin (Bile Acid Sequestrants)

Cholestyramine
Colestipol
Colesevelam (better GIT tolerability)

Exetimibe

Ezetimibe

Gemfibrozil
Bezafibrate
Ciprofibrate
Fenofibrate

Fibrate (Fibric acid derivatives)

Effects
LDL clearance from plasma (LDL receptor pathway)
LDL receptors (due to Intrahepatic cholesterol)
Interruption of enterohepatic circulation of bile acids

Conversion of cholesterol to bile acids

Intrahepatic cholesterol

Activated 2 homeostatic responses

(return intrahepatic cholesterol to normal)
LDL receptor activity
Cholesterol biosynthesis

Effects
LDL cholesterol
Inhibitor of cholesterol absorption (well tolerated)
Bind to intestinal brush border protein
(cholesterol influx transporer)
Cholesterol concentration within hepatocytes
Enhance clearance of LDL from plasma
(via LDL receptor pathway)
Pharmacokinetics
Absorbed in intestine
Peak level 12-14h

Effects
Less effective in LDL cholesterol (compared to others)
HDL cholesterol (more than statins)

Adverse Effects (Common)

GIT Abdominal discomfort, constipation, flatulence,
nausea, vomiting
Hematologic Blood coagulation disorder
(due to hypoprothrombinemia)

Adverse Effects (Common)

GIT Diarrhoea
Musculoskeletal Arthralgia, Myalgia
Respiratory Nasopharyngitis, Sinusitis, URTI
Adverse Effects (Serious)
Hepatic Hepatitis, LFT
Immunology Anaphylaxis
Musculoskeletal Disorder of muscle, Rhabdomyolysis

Adverse Effects (Common)

Dermatologic Rash
GIT Abdominal pain, Diarrhoea, Flatulence, Indigestion,
Xerostomia
Musculoskeletal Myalgia
Adverse Effects (Serious)
Hepatic LFT abnormal
Musculoskelatal Rhabdomyolysis
(esp. coadministered with statin)

Contraindications
Complete biliary obstruction
Hyperlipidaemia (ypes III, IV, V)
Hypersensitivity to bile-sequestering resins

Contraindications
Concomitant use with statin in

Pregnant, nursing mothers

Active liver disease

Unexplained persistent hepatic transaminase

Hypersensitivity to ezetimibe
Precautions (Use not recommended)
Use with fibrates (other than fenofibrate)
Hepatic impairment (moderate severe)
Myopathy (inc. rhabdomyolysis)

Contraindications
Concomitant gemfibrozil, cerivastatin
Preexisting gallbladder disease
Hepatic dysfunction (inc. primary biliary cirrhosis)
Hypersensitivity to gemfibrozil
Severe renal impairment
Precautions
Cholelithiasis
Concomitant use of HMG-CoA reductase inhibitors (statin)
(risk for rhabdomyolysis)
Type IIa Hyperlipidaemia (not recommended)( LDL)

Precautions
Bleeding tendency
(due to hypoprothrombinemia Vitamin K deficiency)
Interfere fat absorption ( Vitamin A,D, E, K)
Pre-existing constipation
Absorption of other drugs

Other Lipid Lowering Drugs

Nicotinic acid group (nicotinic acid, acipimox)
Fish oils (omega-3 marine triglycerides)
Soluble fibre (ispaghula husk)
Nicotinic acid (Vitamin B3) (Niacin)
MOA
Do not involve LDL receptor pathway
Binds to a G-protein-coupled receptor in adipocytes

cAMP levels

Hormone-sensitive lipase in adipocytes

( Delivery of fatty acids to liver)
( Hepatic synthesis, secretion of VLDL)
(Hormone-sensitive lipase = enzyme for hydrolysis of TG in adipose tissue)
Effects
LDL
VLDL
Remnants of VLDL
Lipoprotein (a)
HDL (most effective available drug)
Contraindications
Active liver disease
Active peptic ulcer disease
Hypersensitivity to Niacin
Adverse Effects
Diarrhoea, nausea, vomiting, abdominal pain
Restlessness
Flushing, warmth sensation in face, neck, ears
Headache
Hypotension
Rash, tingling, itching, dry skin

Combination Therapy
No more effective than -dose statin monotherapy
Severe Hypercholesterolemia
Combination regimen for intensive of LDL level
Drugs must individually LDL
Must do so by different MOA
Bad HDL-cholesterol Responders
HDL-cholesterol (< 1.0 mmol/L or 30 mg/dL) during treatment
(despite higher HDL-cholesterol before treatment)
Bad HDL-cholesterol responders

Statins (higher)

Fibrates
Treatment for HDL-cholesterol levels
Maximize life habit changes

Cigarette smoking

Obesity

Physical inactivity
Favour fibrates over statins (patients with CHD, HDL-cholesterol)
Combine statins with fibrate/ nicotinic acid/ ezetimibe
(for risk patients with isolated HDL-cholesterol levels)
Drug Therapy for Dyslipidaemia