Transcript 7. antihyperlipidemics

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
Dyslipidemia vs. hyperlipidemia
Dyslipidemia: increase or decrease in specific types of lipoproteins.
Hyperlipidemia: increase in level of plasma lipid in general.
Classification of lipoproteins
Fraction
%Protein cholesterol
Triacylglycerol
(TG)
PL
HDL, αlipoproteins
45
21
8
26
LDL, βlipoproteins
21
51
10
18
VLDL,pre βlipoproteins
1
21
9
Chylomicron
2
6
54
(TG carrier)
85
(TG carrier)
(cholesterol
carrier)
7
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.
Lipoproteins are
oxidized by free
radicals
They bind to
scavenger
cells
Endocytosis
of oxidized
lipoproteins
Formation of foam
cells
Foam cells +
fibrin +
calcium =
atheroma
Dyslipidemia
Primary (genetic)
6 phenotypes
(according to the
type of lipoprotein
elevated)
Secondary
(caused by
acquired
conditions)
• 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-Hypertriglyceridemia
Diabetes 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 HDL
Drug-induced like: Non- selective β-blockers,
isoretinoin(derivative of Vit A) and norgestrel (contraceptive).
Classification of Cholesterol
levels
Desirable
Borderline
high
High
Total
Cholesterol
mmol/l
<5.2
LDL
cholesterol
mmol/l
<3.4
>5.2 <6.2
>3.4<4.1
>6.2
>4.1
drugs
Sequestering bile acid
in the intestine
Exchange Resins
(Polymeric&HMW)
Altering lipoproteins
levels
Inhibiting
cholesterol
synthesis
Ezetimibe
Nicotinic acid
HMG-CoA
reductase inhibitors
fibrates
Inhibiting cholesterol
absorption from the
intestine
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
trans
cis
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
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
Cont’d
The liver distributes TAGs to different
tissues in the form of VLDL
VLDL is digested by tissues with the
help of lipoprotein lipase
IDL
Then it’s called LDL which transports
cholesterol to the tissues and liver
(bad cholesterol)
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
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.
Therapeutic
uses of
niacin
In type
IIa↓LDL
In type IIb
↓TAG
Has a slow
onset of action
(2 months)
Harmless cutaneous flush due to vasodilatation
resulting from the release of PG.
This phenomenon is
less seen in long-term
use of niacin.
This
manifestation
can be
alleviated by
taking aspirin.
Pruritus, rash, and dry skin.
Impairment of glucose tolerance in patients with
latent diabetes. Thus, niacin is used with caution in
diabetic patients.
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 circulation
Tightly bound to plasma albumin
Readily 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.
Fibrates bind to
peroxisome proliferatoractivated receptor-alpha
(PPAR-α ) receptor
↑synthesis of
lipoprotein
lipase
↓ serum TAG
So it stimulate gene expression of lipoprotein lipase.
Effect on chylomicron & VLDL
chylomicron remnant
LDL
rash
↑aminotransferase
and alkaline
phosphatase
They have
toxic effect on
the liver
GI
symptoms
Toxic
effect
Myopathy
(most
important(
hypokalemia
arrhythmia
They potentiate the action of coumarins
(e.g. warfarin)
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.
uses
Those with mixed
dyslipidamia
Those with low
HDL and at risk of
atherma (e.g. type
II diabetes)
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
↓LDL in plasma
Little bile goes back to
the liver
The liver increases
LDL receptors in order
to get more
cholesterol from the
plasma
Resins should be taken in two or three
doses with meals, where they are
ineffective when taken between meals.
The liver
needs more
cholesterol for
bile synthesis
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)
As monotherapy
when statins are
contraindicated
(e.g.allergies to (
statins
In type IIa
with statin if
they are not
enough for
treatment
uses
Digitalis
poisoning
(As antidote)
Relieves
Pruritus
resulting
from partial
biliary
obstruction
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.
Decrease
hepatic synthesis
of cholesterol
Decrease
cholesterol in
liver
Increase
receptors
for LDL
↓release of
VLDL
↓LDL in
plasma
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
Secondary
prevention of
MI or stroke in
patient with
atherosclerosis
uses
Primary prevention
of arterial disease
in patient who have
high cholesterol
level
Atorvastatin is used in
homozygous familial
hypercholestrolemia
Resins are added with
statin in drug-induced
dyslipidemia
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(