Arteriosclerosis= hardening of the arteries.
• ↑Serum cholesterol (above 4mmol/L) ↑risk of coronary heart disease• <4mmol/L level of plasma cholesterol is considered to be safe• ↑LDL ↑risk of coronary heart disease while,• ↑HDL ↓risk of coronary heart disease
• ↑Serum cholesterol (above 4mmol/L) ↑risk of coronary heart disease• <4mmol/L level of plasma cholesterol is considered to be safe• ↑LDL ↑risk of coronary heart disease while,• ↑HDL ↓risk of coronary heart disease
Dyslipidemia vs. hyperlipidemiaDyslipidemia: increase or decrease in specific types of lipoproteins. Hyperlipidemia: increase in level of plasma lipid in general.
Classification of lipoproteinsFraction%ProteincholesterolTriacylglycerol
(TG)PL
HDL, α-lipoproteins
4521826
LDL, β-lipoproteins
2151)cholesterol
carrier(
1018
VLDL,pre β-lipoproteins
12154)TG carrier(
9
Chylomicron2685)TG carrier(
7
If a drug acts on TAG then it affects
VLDL
Drugs acts on cholesterol it affects
LDL
If a drug acts on TAG then it affects
VLDL
Drugs acts on cholesterol it affects
LDL
Lipids & cholesterol are transported in the plasma as lipoproteins.
Lipophilic components (cholesterol ester and TG) inside the core of
lipoprotein
Hydrophilic components are on
the lipoprotein’s surface
Chylomicron:- transport of exogenous dietary TG
VLDL:- transport of endogenous dietary TG from liver to tissue
LDL:- transport of cholesterol to tissues
HDL:- transport of cholesterol out of the tissues to the liver.
• Type I has no pharmacologic treatment (only dietetic treatment).
• The most severe type is type II (whether IIa or IIb).
• Type IIb is mixed or combined (VLDL& LDL).
• Type III has abnormal elevated lipid (β VLDL)
• Both types IV&V have modest risk for atherosclerosis.
1-HypertriglyceridemiaDiabetes mellitus, obesity ,alcoholism (release VLDL), estrogens
(e.g.oral contraceptives), chronic renal & liver failure
2-Hypertriglyceridemia with hypercholesterolemia
Diabetes mellitus, renal transplantation, nephrotic syndrome
3-Hypertriglyceridemia with reduced HDLDrug-induced like: Non- selective β-blockers,
isoretinoin(derivative of Vit A) and norgestrel (contraceptive).
Classification of Cholesterol levels
Total Cholesterol mmol/l
LDL cholesterol mmol/l
Desirable<5.2<3.4
Borderline high
>5.2< 6.2>3.4<4.1
High>6.2>4.1
For managing patients with no need for pharmacologic therapy.
Cholesterol, saturated fats and trans fats→↑ LDL and (decrease HDL trans particularly)
Acute ↑ in carbohydrates intake →↑ VLDL.
Alcohol ↑triglycerides by inducing the secretion of VLDL from the liver.
Some forms of dietary fiber reduce LDL modestly.
Cis bond can converted to trans bond by increasing temperature
cistrans
Omega-3 fatty acids found in fish oils ↓triglycerides in
patients with endogenous or mixed lipidemia.
Supplementation with antioxidant vitamins such as
ascorbic acid (250 mg) and vit.E (50 IU on alternate
days) may be beneficial.
↓Calories & loss of weight →↓LDL & VLDL.
Cigarette smoking is a major risk factor for coronary disease.
It is associated with reduced levels of HDL,
impairment of cholesterol retrieval, Cytotoxic effects on the endothelium,
Increased oxidation of lipoproteins,
Stimulation of thrombogenesis.
Before getting to drugs, here’s a revision about lipoprotein and lipid metabolism
Lipids are digested and absorbed in the small intestine to simple fats
carried as chylomicron
Lipids are digested and absorbed in the small intestine to simple fats
carried as chylomicron
Peripheral tissues take up fats from chylomicron via the enzyme
lipoprotein lipase which converts TAGs to fatty acids leaving cholesterol
in chylomicron
Peripheral tissues take up fats from chylomicron via the enzyme
lipoprotein lipase which converts TAGs to fatty acids leaving cholesterol
in chylomicron
Chylomicron now is called chylomicron remnant is absorbed by
the liver
Chylomicron now is called chylomicron remnant is absorbed by
the liver
Cont’d
The liver distributes TAGs to different tissues in the form of VLDL
The liver distributes TAGs to different tissues in the form of VLDL
VLDL is digested by tissues with the help of lipoprotein lipase
VLDL is digested by tissues with the help of lipoprotein lipase
Then it’s called LDL which transports cholesterol to the tissues and liver
(bad cholesterol)
Then it’s called LDL which transports cholesterol to the tissues and liver
(bad cholesterol)
IDL
Enterohepatic circulation
The liver synthesizes bile from cholestrol
Bile is secreted in the duodenum to help fat
digestion
85-95% of the bile returns to the liver to be modified and released
again
85-95% of the bile returns to the liver to be modified and released
again
Nicotinic acid is not related to nicotine, yet it was first synthesized from it.
Nicotinic acid(niacin) is vit.B3
Ni ac in
nicotin acid vitamin
Mechanism of action:-Niacin inhibits VLDL’s secretion from the liver, thus concomitantly decreasing circulating LDL & hence ↑ HDL.Converted in the body to nicotinamide. Excreted in the urine as nicotinamide.
Nicotinamide has no antihyperlipidimic activity, yet it retains its vitamin’s physiologic
activity .
Has a slow onset of action
)2 months(
Harmless cutaneous flush due to vasodilatation resulting from the release of PG.
Pruritus, rash, and dry skin.
Impairment of glucose tolerance in patients with latent diabetes. Thus, niacin is used with caution in diabetic patients.
This manifestation
can be alleviated by taking aspirin.
This phenomenon is less seen in long-term
use of niacin .
Cont’d Nausea & abdominal discomfort.Reversible elevations in aminotransferases (liver toxicity).
Hyperuricemia, thus contraindicated in gout patients.
Supplied as the free acid form Undergoes enterohepatic circulationTightly bound to plasma albuminReadily passes the placenta
(thus contraindicated in pregnant women)
70% is excreted unchanged in the urine
T1/2 = 1.5 hr
Is a methylethyl ester that is hydrolyzed completely in the intestine.
T1/2 = 20 hr
60% is excreted in the urine as a glucuronide conjugate and about 25% in feces.
Fenofibrate is uricosuric (decreases uric acid in the blood by increasing the excretion of uric acid in the urine) used with gout
patients accompanied with dyslipidemia.
So it stimulate gene expression of lipoprotein lipase.Effect on chylomicron & VLDL
chylomicron remnant LDL
They potentiate the action of coumarins (e.g. warfarin)
They have toxic effect on
the liver
The risk of myopathy increases when fibrates are given along with statins.
↑ risk of cholesterol gallstone formation taken carfully in patients with biliary tract
diseases.
This group is not first line treatment.
They are polymers.
They bind bile acids in the intestine preventing their absorption.
In hypercholesterolemia it →↓LDL cholesterol,
If used to ↓ LDL in patients with combined (mixed) hyperlipidemia →↑VLDL .
They increase bile acid excretion
Little bile goes back to the liver
The liver needs more
cholesterol for bile synthesis
The liver increases LDL receptors in order
to get more cholesterol from the
plasma
↓LDL in plasma
Resins should be taken in two or three doses with meals, where they are
ineffective when taken between meals.
Resins should be taken in two or three doses with meals, where they are
ineffective when taken between meals.
Toxicity
They are devoid of systemic side effects.
Common complaints are constipation & bloating sensation.
Heart burn
Malabsorption of vit. A,D,E,K (lipid soluble vitamins)
Dry flaking skin
Lead to ↓ Absorption of thiazides, tetracyclines, & folic acid
Formation of gallstone (less than fibrates)
They are structural analogs of HMG-CoA reductase enzyme.
e.g. Lovastatin, atorvastatin, fluvastatin, pravastatin,simvastatin, & rosuvastatin.
HMG-CoA reductase mediates the first step in steroid genesis.
They are most effective in reducing LDL.
They decrease oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions.
Lovastatin and simvastatin are prodrugs, due to the inactive closed lactone ring.
The closed ring is opened, becoming active, when drugs are passing through the GIT.
Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing congeners that are active as given (due to the already open lactone ring).
Abosorption of statins is 40% to 75% with the exception of fluvastatin 100%.
Absorption of statins are enhanced when taken with food with the exception of pravastatin.
All have high first-pass metabolism in the liver.
Most of the absorbed dose is excreted in the bile; about 5–20% is excreted in the urine.
T1/2 range from 1 hour to 3 hours except for atorvastatin, which has a t1/2 of 14 hours, and rosuvastatin, 19 hours.
Because cholesterol occurs predominantly at night, reductase inhibitors-except atorvastatin and rosuvastatin- should be given in the evening.
catabolism of lovastatin, simvastatin, and atorvastatin → cytochrome P450 3A4
fluvastatin and rosuvastatin → CYP2C9.
Pravastatin is catabolized through other pathways, including sulfation.
Drug interactions:-Plasma levels of lovastatin, simvastatin, and atorvastatin may be elevated in patients ingesting more than 1 liter of grapefruit juice daily. inhibit P450 3A4
Adverse effect ↑level of serum transaminase, may produce liver toxicity in patient with liver disease or a history of alcohol abuse.Minor increases in creatine kinase activity in plasma.Myopathy may occur when used in combination with fibrates.Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy.↑Lenticular opacity
Ezetimibe inhibits intestinal absorption of cholesterol and phytosterols (plant sterols).
Reduces LDL
Ezetimibe is readily absorbed and conjugated in the intestine to an active glucuronide, reaching peak blood levels in 12–14 hours.
It undergoes enterohepatic circulation.
t1/2 = 22 hours
80% excreted in feces
Plasma ezetimibe concentrations are substantially increased when it is administered with fibrates and reduced when it is given with cholestyramine.
Therapeutic Uses
Primary hypercholesterolemia, effective in patients with phytosterolemia.
ADR
Reversible impaired hepatic function
Up regulation of LDL receptor
VLDL)VLDL(
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