LECTURE 1 : LIPID-LOWERING DRUGS

Purpose Class Examples PK MOA , Clinical use ADR

Inhibit 1.Statins -20 98 % absorbed MOA : -GIT disturbances
cholestero -Extensive 1st pass -Increase liver enzyme
l synthesis extraction 1.Inhibits HMG-COA reductase in plasma
-Excreted in bile decrease cholesterol concentraion -Rhabdomyolysis
-5 20 % excreted in inside cell (muscle toxicity )
urine 2. Stimulates synthesis of LDL receptors Starts with
-T : Varies from 1-19 3.Promote uptake of LDL rom blood myalgia, then
hours 4.Low intracellular cholesterol will lower inflammation with
-Oral the secretion of VLDL increase plasma
-Most = metabolised 5.Also lower the plasma TG creatinine kinase
by P= P450 system Insomnia
-Drugs that compete OTHER ACTIONS : Rash
for enzyme increase -Improve endothelial function
plasma level of statins -Reduce vascular inflammation CAUTION :
Antibiotics -Reduce platelet aggregability Monitor liver
Cyclosporine -Increase new vascularisation of enzyme and
Ketoconazole ischaemic tissue CK
HIV Protease -Stabilisation of artheriosclerotic plaque Do not co-
inhibitors -Anti-thrombotic actions adminisrer
Fibrates -Enhanced fibrinolysis with Fibric acid
-Drugs that increase -Immune suppression derivatives;
expression of P450 Cyp
cause
3A CLINICAL USE : myopathies
Phenytoin
Griseofulvin -Secondary prevention of MI,Stroke
Barbiturates -Primary prevention of arterial disease
Rifampicin
in homozygous familial
hypercholestrolaemia
-In severe drug-resistant dyslipidemia,
bile acid binding resin / Ezetimide
 added
-Reduce CVS risk
-Reduce LDL cholestrol
1. Pitavastatin Not metabolised by
T : 12 CYP 450
h
2. Pravastatin
3. Rosuvastati
n
T : 19
h
4. Atovastatin
T : 14
h
5. Lovastatin -Inactive prodrug ;
metabolised in GIT into
active form
6. Simvastatin
Decrease 2. Coles- 7. Colestyrami -Oral -Mostly second in line therapy after -Constipation,bloating
absorption ne statins -Dyspepsia
of 8. Colestipol Up to 28 % reduction in LDL CAUTION
exogenous 9. Colesevela cholesterol Avoid in pt w
cholestero m -Taken by mouth sequester bile acid diverticulitis
l+ ( anion in intestine prevent reabsorption of Heartburn,diarrh
Increase exchange cholestrol oea
endogeno resins ) May increase TG
us Can reduce
cholestrol absorp of fat-
metabolis soluble vitamins
m

Inhibit 3.Cholestr 10.Plant sterol / -Similar to cholesterol; -Dispplace cholesterol from micelles
cholestrol ol Stanols more hydrophobic prevent reabsorption
absorption absorption -Gram quantities
inhibitors required
11.Ezetimide -Absorbed from -Can be used alone / with statin ( extra
intestine converted 15 % red than statins alone )
into active glucuronide -Inhibits Newman-Pick like transporter
conjugate that carries cholesterol from gut to cells
-Localised in brush -Decrease cholesterol absorption bby
boader of intestine 50 b%
-Inhibit absorption of -Doesnt affect TG, fat-soluble vitamins
biliary and dietary
cholesterol
-T : 22 H
-Eliminated in
urine,faeces
4.Fibrates 12.Gemfribrazil -Tightly bound to Against PPAR -Rare
/ Fibric plasma protein Nuclear receptor activates gene -Rashes
acid -T : 1.5 H transcription stimulates -GIT
derivative -70 % eliminated by degradation of FA by Beta oxidation -Myopathy
s kidney; mainly (Increase lipoprotein lipase exp ) -Potentiate action of
unmodified Increase ApoA-I.APOA-II synthesis in Warfarin For primary /
hepatocytes secondary prevention
Increase plasma HDL ( 10-20 only when statin is not
13.Fenofibrate -T : 20 h ; sustained %) tolerated
release Decrease Apoc-III synthesis in -Not used routinely, little
-60 % excreted in hepatocytes and increase lipoprotein evidence in
urine, lipase in vascular beds increase effectiveness in
25 % as glucuronide in FA uptake and oxidation in muscle reducing mortality
faeces cells
14.Bezafibrate Decrease plasma TG ( up to
15.Ciprofibrate 50 % )
Increase FA oxidation in hepatocytes
decrease TG synthesis
 Decrease plasma TG
Stimulate transcription of lipoprotein
lipase increase hydrolysis of TG
Decrease hepatic VLDL production
Increase hepatic LDL uptake
Decrease plasma fibrinogen
Improve glucose tolerance
Inhibit vascular smooth muscle
inflammation
Decrease 5.Niacin/ 16.Niacin -Oral -Inhibits lipolyis in adipose tissue -Cutaneous flushing and
VLDL,LDL Vitamin -Converted in body into -Liver normally use FA for TG synthesis pruritis
and Lp(a) , B3/ nicotinamide -Reduce liver TG synthesis ( 45 % ) -Hepatotoxicity
often Nicotinic -Incorporated into -TG required in VLDL production; reduce -Impaired glucose
increase acid NAD+ VLDL tolerance
HDL -Excreted in urine -Reduced VLDL reduce LDL ( 20 % ) CAUTION
-Increase HDL ( 30 % ) Use with caution
-Increase secretion of tissue in Diabetics
plasminogen activator ( tPA )increase Combination w
plasminogen Lorapiprant to
prevent flushing
failed
Not
recommended;
lack evidence of
reducing
mortality
Not available in
Europe
New 17.PCSK9 -Monoclonal antibodies -PCSK 9 regulates the recycling of LDLR
treatment inhibitors -Subcutaneous by targeting the LDLR for degradation
s -1/week -Monoclonal antibodies against PCSK 9
-Effects = 2-4 weeks block PCSK9-LDLR interaction
 -Increase LDLR decrease LDL
cholestrol
18.Cholestrol
ester
transfer
protein
inhibitors
19.Microsomal
TG transfer
protein
inhibitor
20.Apoliprotein
CIII inhibitor
21.Farenesoid
XZ receptor
modulation
22.Lipoprotein-
asspciated
Phospholipa
se A2
inhibitor