Download Anti Hyperlipidaemic Agents

Anti Hyperlipidaemic Agents
Basis of Anti Hyperlipidaemic Agents Usage
Decision in choosing Anti Hyperlipidaemic agents
1. Specific metabolic defect that causes hyperlipidaemia
2. The potential of the particular metabolic defect to cause
a. Artherosclerosis
b. Pancreatitis
3. Treatment in children
a. In heterozygous familial hypercholestrolaemia
i. Only be given Antihyperlipidaemic agents after 7-8
years old
1. Complete myelination of nervous system happens at
this particular age
ii. Can be treated with
1. Statin
2. Niacin
3. Resin
4. Ezetimibe
b. Decision should solely depends on
i. Level of LDL
ii. Family history
iii. Child’s age
iv. Other risk factors
c. Antihyperlipidaemic agents rarely be given in patient
below the age of 16
4. Antihyperlipidaemic agents should never be given to
a. Pregnant ladies
b. Woman who intends to get pregnant
c. Lactating mother
5. Dose should be adjusted in patient receiving
a. Warfarin
b. Indandione anticoagulant
Disorder
Manifestations
Familial Hyperchylomicronaemia
Famillial
Hypertriglyceridaemia
Moderate
Severe
Familial Combined Hyperlipidaemia
Broad Beta Band Disease




↑chylomicron
↑VLDL
↑chylomicron (maybe
increased)
↑VLDL
↑chylomicron
↑VLDL
↑↑VLDL

↑↑LDL

Both ↑


↑IDL
↑Chylomicron remnant

↑LDL

↑↑LDL

↑LDL



Heterozygous
Familial
Hypercholesterolaemia
Homozygous
Familial Ligand-defective apo B
Lp(a) Hyperlipoproteinaemia
 Lp(a)↑
*Single Therapy – only one drug is used out of the list
Single Therapy*
Combined Therapy
1. Niacin
2. Fibrate
1. Niacin (and)
2. Fibrate
1.
2.
3.
1.
2.
3.
1.
2.
1.
2.
1. Two or three of the single
therapy drugs
Niacin
Fibrate
Statins
Niacin
Statins
Ezetimibe
Niacin
Statins
Niacin
Fibrate
3. Statins
4. Resin
5. Niacin
6. Ezetimibe
7. Niacin
8. Atorvastatin
9. Rosuvastatin
10. Ezetimibe
11. Niacin
12. Statins
13. Ezetimibe
14. Niacin
1.
2.
1.
2.
3.
4.
Niacin + Statins (or)
Fibrate + Statins
Niacin + Fibrate (or)
Niacin + Statins (or)
Fibrate + Statins
Two or three of the single
therapy drugs
5. Niacin +Statins +
Ezetimibe
6. Niacin + Statins (or)
7. Niacin + Ezetimibe
8. NA
HMG-CoA Reductase Inhibitor (Statins)
Drug
Simvastatin
Drug drug interactions
1. Plasma level ↑ if
given with CYP450
inhibitors
a. Macrolides
b. Cyclosporine
c. Ketoconazole
d. Protease Inhibitor
in HAART
e. Tacrolimus
f. Fibrates
g. Nefazodone
2. Plasma level ↓ if
given with CYP450
inducers
a. Phenytoin
b. Griseofulvin
c. Barbiturates
d. Rifampicin
Pharmacokinetic
Absorption
 Given in inactive form
(lactone prodrug)
o Metabolized in the gut wall
into active B-hydroxyl
derivatives
 Readily absorp (lipophilic in
nature) through intestinal
mucosa
 Improve absorption when
taken with food
o Knowledge that it is absorp
together with lipid and
fatty acids of the food
Distribution
 Plasma half life is 12-24 hours
Metabolism
 Extensively undergoes 1st
metabolism
Excretion
 Bile
o 80%
 Urine
o 20%
1.
2.
3.
4.
Mechanism of Action
HMG-CoA Reductase is an enzyme
required for a commited step in
coverting HMG-CoA  Mevalonate
Simvastatin is an analogue of HMG-CoA
and therefore acts as competitve
partial inhibitor of HMG-CoA Reductase
enzyme
Consequences to the inhibition of the
HMG-CoA Reductase commited step
are
a. ↓in the synthesis of endogenous
cholesterol in the liver
b. As a part of compensatory
mechanism secondary to ↓heaptic
cholesterol level, liver will ↑the
expression of LDL receptors on its
surface so that
i. ↑internalization of plasma
1. IDL
2. LDL
ii. ↓level of LDL in the circulation
c. ↓in the level of the hepatic
cholesterol level will lead to
secondary ↓of TG as VLDL
(endogenous TG carrier) needs
cholesterol during its synthesis
Other therapeutical effects of statin are
a. ↓vascular inflammation
b. Stabilizes artheromatous plaque
i. ↓new coronary event
ii. ↓formation of thromboembolism
c. ↓oxidative stress levels
Adverse Effects
1. Myositis/Rhabdomyolisis
a. ↑CK level and
myoglobin in the
blood
i. ↑renal shut down
b. Need to be carefully
monitored and
might be
discontinued if CK
level persistently ↑
2. Hepatotoxicity
a. ↑plasma
aminotransferase
level (3 times higher
than that of normal
range)
b. Discontinued
immediately if
plasma
aminotransferase
↑persistently
Should be temporarily
discontinued in case of
1. Serious illness
2. Trauma
3. Major surgery
Niacin (Vitamin B3)
Drug
Nicotinic Acid
Pharmacokinetic
Absorption
 Readily absorb through gut
mucosa
 Hydrophilic in nature therefore
absorbed together with water
Distribution
 Tends to accumulate in blood
 Also tends to accumulate in
water-filled compartment of
the body
Metabolism
 Extensively metabolized into
amide
 Incorporated into Niacinamide
Adenine Dinucleotide (NAD)
Excretion
 Excreted readily through urine
as
o Unmodified form
o Several metabolites
1.
2.
3.
4.
Mechanism of Action
Magnifies the activity of Lipoprotein Lipase
of adipose tissues
a. ↑clearance of triglycerides from
i. Chylomicron
ii. VLDL
b. ↑excretion of sterol acutely as
cholesterol is mobilized from tissue
i. New steady state reached
Inhibits the activity of Hormone Sensitive
Lipase of adipose tissue via receptor
mediated signalling
a. ↓hydrolization of peripheral tissues
(adipose) of TG
b. ↓influx of fatty acids into the liver
i. Consequently ↓VLDL synthesis and
plasma level
No effect on bile acid formation
Therefore, Nicotinic Acid
a. ↓VLDL
b. ↓chylomicron
c. ↓TG
d. ↓LDL
e. ↓TC
f. ↑HDL
1.
2.
3.
4.
5.
6.
Adverse Effects
Hyperglyceamia
a. ↑activity of LPL,
which needs
insulin as an
activator
b. ↑prolong usage
of insulin
↑insulin
tolerence
c. Therefore
partially
contraindicate
d in insulin
dependent
diabetis mellitus
pts
Gastritis
Pruritus
Rashes
Abdominal
discomfort
Hepatotoxicity
Fibrates
Drug
Pharmacokinetic
Absorption
Gemfibrozil
1. Should be avoided  Quantitatively absorbed
through intestinal mucosa
in patient with
 ↑absorption when taken with
a. Hepatic failure
food
b. Renal failure
Distribution
Drug Drug Interaction  Undergoes Enterohepatic
Recycling
1. Potentiate
o
↑half life (1.5 hours)
Warfarin effect
a. Displace warfarin  Readily passes placental
barrier
from plasma

Tightly bound to plasma
protein
protein
Metabolism
 Hepatic modification into
o Hydroxylmethyl
o Carboxyl
o Quinol derivatives
Excretion
 Renal clearance in
unmodified form
Mechanism of Action
1. Fibrate is a ligand of nuclear
transcription factor; PPAR-a
a. Activation of this transcription factor
will lead
i. ↑ up-regulate
1. LPL
2. Apo-A1
3. Apo-AII
ii. ↓trancription of apo-CIII
1. ↓inhibition of lipolysis
2. Major effect
a. ↑oxidation of fatty acids in
i. Liver
ii. Striated muscles
b. ↑lypoprotein lipase activity
i. ↓VLDL
ii. ↓TG
c. ↓activity of Hormone Sensitive Lipase
i. ↓liberation of TG from adipose
tissues into the circulation
d. Moderately ↑HDL level
Adverse Effects
1. Rhabdomyolisis
a. ↑when it is given with
statins
b. EXCEPT rosuvastatin
2. Cholestasis (gallstones)
a. ↑in liver uptake of
plasma cholesterol
b. ↑clearance of
cholesterol via bile
acids
c. Should be used in
caution for patient
with
i. Billiary tract disease
ii. High risk; women
3. Hepatotoxicity
a. ↑aminotransferase
b. ↑alkaline
phosphatase
Bile Acid Sequestrants (Resins)
Drug
Cholestyramine
1. Should be given
with Niacin in
patient having
combined
hyperlipidaemia
1.
2.
3.
4.
Pharmacokinetic
Large polymeric cationic
exchange resins
Insoluble in water
Bind with bile acid in the
intestinal lumen
Not being absorbed
Mechanism of Action
1. Binds to bile acid in the gut, reduces
bile acid reabsorption as high as ten
folds.
2. ↑excretion of bile acid
a. ↑cholesterol secretion
b. ↓hepatic cholesterol level
c. ↑uptake of LDL from circulation
i. ↓plasma LDL
ii. ↓plasma cholesterol level
d. Compensatory mechanism of the
loss of LDL will ↑VLDL and therefore
↑plasma TG level
3. It most be clear that Resins is not
effective in patient having
homozygous Familial
Hypercholeterolaemia due to the
absence of LDL receptor in the liver,
but useful in heterozygous
1.
2.
3.
4.
5.
6.
7.
8.
9.
Adverse Effects
Hypertriglyceridaemia
Constipation
Bloating
Flatulence
Heartburn
Diarrhea
Steatorrhea
Malabsorption of Vitamin K
a. Hypoprothrombinaemia
Gallstones formation
Intestinal Sterol Absorption Inhibitor
Drug
Ezetimibe
1. No
interaction
with
warfarin
Pharmacokinetic
Absorption
 Readily absorp in the intestinal mucosa
Distribution
 Undergoes Enterohepatic Recycling
 Half life is 22 hours
 Peak level within 12-24 hours
Metabolism
 Conjugated with glucuronide into active form
Excretion
 Bile acids (therefore reduce reabsorption
when given with resins)
Mechanism of Action
1. Selective inhibitor of transport protein
NPCL1L1, important in the absorption
of
a. Cholesterol
b. Phytosterols
2. Effective even when there is an
absence of dietary cholesterol, as it
also inhibits reabsorption of
cholesterol in the bile acids
Adverse Effects
1. Myositis (rare)
2. Hepatotoxicity
(rare)
a. When given
with statin