DRUGS FOR

DYSLIPIDAEMIA
Lesson 5
PPB 531 – Haematopoietic & Nutritional Disorders
KU – BPHARM 5, TRIMESTER III

Dr. H. Nderitu
15th October 2019
 Topic overview
| Outline the various drug classes & drugs
used for dyslipidaemia
| Discuss the following pharmacological
properties of drugs used for dyslipidaemia
{ Mechanism of action
{ Pharmacodynamic effects
{ Pharmacokinetic properties
{ Adverse effects
{ Caution & contraindications
{ Clinical indications
 Drug classes & drugs used for
dyslipidaemia
HMG-CoA Reductase inhibitors (Statins)

Niacin

Fibrates

Bile acid– binding resins

Cholesterol absorption inhibitors

Omega-3 fatty acids

• Drugs may be used alone or in combination

• Drug therapy should always be accompanied by lifestyle
modifications! –exercise, diet low in saturated fats
STATINS
 HMG-CoA Reductase
Inhibitors
Simvastatin

Atorvastatin

Lovastatin

Pravastatin

Fluvastatin

Pitavastatin

Rosuvastatin
 HMG-CoA Reductase
Inhibitors
| 3-Hydroxy-3-methylglutaryl coenzyme A
(HMG - CoA) reductase inhibitors
| ‘ Statins’

| Pitavastatin
Most potent
| Rosuvastatin
| Atorvastatin
| Simvastatin
| Pravastatin Decreasing
| Lovastatin potency
| Fluvastatin
 Mode of action
| Competitive inhibitors of HMG CoA reductase (rate-
limiting step in cholesterol synthesis)
| Result in inhibition of de novo cholesterol synthesis,
depleting the intracellular supply of cholesterol
| Depletion of intracellular cholesterol causes the cell
to é the number of cell surface LDL receptors that
can bind & internalize circulating low density
liporoteins (LDLs)
| Thus, plasma cholesterol is ê, by both êcholesterol
synthesis & é LDL catabolism
| Also ê triglyceride levels
| May é HDL cholesterol levels in some patients
HMG-CoA reductase
inhibition
 Effects
| ê elevated LDL-C
{ Results in a substantial ê in coronary events &
death from coronary heart disease (CHD)
| Plaque stabilization (é stability of
atherosclerotic lesions)
| Improvement of coronary endothelial
function
| Inhibition of platelet thrombus formation
| Inhibition of anti-inflammatory activity (ê
vascular inflammation)
| ê oxidative stress
 PK Properties
Simvastatin
• Pro drug
• Hydrolyzed in the GIT to
the active β-hydroxyl
derivative
• Variable absorption: 40% -
75%
• High 1st-pass metabolism by
the liver, hence dominant
effect is on the liver
(cytochrome P450 3A4)
• Most of the absorbed dose is
excreted in bile & faeces
• 5 - 20% is excreted in urine
• Plasma t ½:1 - 3 hours
Lovastatin
• Pro drug
• Hydrolyzed in the GIT to
the active β-hydroxyl
derivative
• Variable absorption: 40% -
75%
• High 1st-pass metabolism by
the liver, hence dominant
effect is on the liver
• Most of the absorbed dose is
excreted in bile
• 5 - 20% is excreted in urine
• Plasma t ½:1 - 3 hours
 PK Properties - ii
Atorvastatin Fluvastatin
• Variable absorption: 40% • Almost completely
- 75% absorbed
• High 1st-pass extraction • High 1st-pass extraction
by the liver, hence by the liver, hence
dominant effect is on the dominant effect is on the
liver liver
• Most of the absorbed • Most of the absorbed
dose is excreted in bile dose is excreted in bile
• 5 - 20% is excreted in • 5 - 20% is excreted in
urine urine
• t ½:14 hours • Plasma t ½:1 - 3 hours
 PK Properties -iii
Rosuvastatin Pravastatin
• Variable absorption: 40% • Variable absorption: 40%
- 75% - 75%
• High 1st-pass extraction • High 1st-pass extraction
by the liver, hence by the liver, hence
dominant effect is on the dominant effect is on the
liver liver
• Most of the absorbed • Most of the absorbed
dose is excreted in bile dose is excreted in bile
• 5 - 20% is excreted in • 5 - 20% is excreted in
urine urine
• t ½: 19 hours • t ½: 12 hours
Summary of PK properties &
effects of statins
 Clinical indications
| 1st line treatment for patients with é risk
of atherosclerotic cardiovascular
disease (ASCVD)
| ê plasma cholesterol levels in all types
of hyperlipidaemias
 Adverse effects
| Elevated liver enzymes –
may lead to liver failure
| Myopathy
| Rhabdomyolysis
(disintegration of skeletal
muscle; rare)
{ Simvastatin is metabolized by
cytochrome P450 3A4 &
inhibitors of this enzyme may
é risk of rhabdomyolysis
{ Monitor plasma creatine
kinase levels in patients with
muscle complaints
 Drug interactions &
contraindications
|Drug interactions |Contraindications
{é effect of warfarin {Pregnancy
|Monitor INR {Breast feeding
frequently mothers
Niacin (Nicotinic acid)
 Mechanism of action
|At gram doses, it strongly inhibits
lipolysis in adipose tissue

|Thereby ê production of free fatty

acids

|The liver normally uses circulating free

fatty acids as a major precursor for
triglyceride (TG) synthesis

|ê liver TG levels, ê hepatic VLDL

production, which in turn ê LDL-C
plasma concentrations
 Effects
| ê LDL-C by 10% - 20%

| Most effective agent for é HDL-C

| ê TG by 20% - 35% at typical doses of

1.5 - 3 grams/day
 PK properties
| Administered PO

| Converted in the body to nicotinamide,

which is incorporated into the cofactor
nicotinamide adenine dinucleotide (NAD+)
| Niacin, its nicotinamide derivative & other
metabolites are excreted in urine
| Note: Nicotinamide alone does not ê
plasma lipid levels
 Clinical indications
| Familial (primary) dyslipidaemias
{ Since it lowers plasma levels of both
cholesterol & triglycerides
| Severe hypercholesterolemias
{ Often in combination with other agents

| Used in combination with statins

{ FDC of lovastatin & long-acting niacin
available
 Adverse effects
| Most common
{ Intense cutaneous flush (accompanied by an
uncomfortable feeling of warmth)
{ Pruritus

{ Prevention
| Administration of aspirin prior to taking
niacin ê the flush, which is prostaglandin
mediated
| Slow titration of the dosage or usage of the
sustained-release formulation of niacin ê
flushing & pruritus
 Adverse effects - ii
| Other adverse effects
{ Nausea
{ Abdominal pain
{ Predisposition to hyperuricamia & gout
| Due to niacin inhibiting tubular secretion
of uric acid
{ Impaired glucose tolerance
{ Hepatotoxicity
 Contraindications
| Avoid in liver disease
Fibrates
 Fibrates
| Derivatives of fibric acid

• Fenofibrate
• Gemfibrozil
 Mechanism of action
| Bind to peroxisome proliferator–activated receptors
(PPARs) & activate them
| PPARs then bind to peroxisome proliferator response
elements
| This results in é expression & activation of lipoprotein
lipase enzyme
| This ultimately leads to:
{ ê TG concentrations through é expression of
lipoprotein lipase
{ ê apolipoprotein (apo) CII concentrations
| PPARs
{ Members of the nuclear receptor family that
regulates lipid metabolism
{ Function as ligand-activated transcription factors
{ Upon binding to their natural ligands (fatty acids or
eicosanoids) or antidyslipidaemic drugs, PPARs are
activated
Activation of
lipoprotein
lipase
 Effects
| ê serum TG

| Fenofibrate is more effective than

gemfibrozil in ê TG levels
| é HDL-C levels by é expression of apo AI &
apo AII
 PK properties
| Completely absorbed after PO administration

| Widely distributed

| Bound to albumin

| Undergo extensive
biotransformation/metabolism
| Excreted in urine as glucuronide conjugates

| Fenofibrate
{ Prodrug, converted to the active moiety fenofibric
acid
 Clinical indications
| Treatment of hypertriglyceridemias
{ Esp. type III hyperlipidemia
(dysbetalipoproteinemia) in which IDL-C
particles accumulate
 Adverse effects
| Most common adverse effects:
{ Mild GIT disturbances
| ê as therapy progresses

| Other adverse effects

{ Gallstones formation
| Drugs é biliary cholesterol excretion, hence
predisposition to form gallstones
{ Myositis (inflammation of a voluntary muscle)
| Monitor for muscle weakness or tenderness
| Patients with renal insufficiency may be at risk
{ Myopathy & rhabdomyolysis
| In patients taking gemfibrozil & statins together
Interactions & contraindications

|Caution |Contraindications
{Both fibrates may é {Use of simvastatin
effects of warfarin together with
gemfibrozil
|Frequent
monitoring of INR {Severe hepatic
in patients taking dysfunction
both drugs
{Renal dysfunction

{Patients with
preexisting
gallbladder disease
Bile acid–binding resins
(Bile acid sequestrants)
Bile acid–binding resins

• Cholestyramine
• Colestipol
• Colesevelam
 Mode of action
| Anion-exchange resins that bind –vely charged bile
acids & bile salts in the small intestine
| The resin - bile acid complex is then excreted in
faeces
| Results in ê of bile acid concentration
| This then causes hepatocytes to é conversion of
cholesterol to bile acids, which are essential
components of bile
| Consequently, intracellular cholesterol
concentrations ê, which activates an é hepatic
uptake of cholesterol- containing LDL particles,
leading to a fall in plasma LDL-C
| Note: This é uptake is mediated by an up-
regulation of cell surface LDL receptors
Mode of action of
bile acid – binding
resins

| Have significant LDL

cholesterol– lowering
effects, although the
benefits are less than those
observed with statins
 PK properties
| Insoluble in water
| Have large molecular weights

| After PO administration, they are

neither absorbed nor metabolically
altered by the intestine
| Totally excreted in faeces
 Clinical indications
| Type IIA & type IIB hyperlipidemias
{ Useful (often in combination with diet or
niacin)
| Relief of pruritus caused by
accumulation of bile acids in patients
with biliary stasis

| Colesevelam
{ Type 2 diabetes due to its glucose-lowering
effects
 Adverse effects
| Most common:
{ GI disturbances, such as
| Constipation
| Nausea
| Flatulence

| Colesevelam
{ Has fewer GI side effects than other bile
acid sequestrants
 Interactions
| Impair absorption of fat-soluble vitamins (A, D, E
& K)
| Interfere with absorption of many drugs e.g.
{ Digoxin
{ Warfarin
{ Thyroid hormone
{ Therefore, drugs to be taken at least 1 - 2 hours
before, or 4 - 6 hours after, the bile acid–binding
resins
| Raise TG levels
{ Contraindicated in patients with significant
hypertriglyceridemia (≥400 mg/dL)
Cholesterol absorption
inhibitors
 Cholesterol Absorption
inhibitors
| Ezetimibe
{ Mechanism of action
| Selectively inhibits absorption of dietary &
biliary cholesterol in the small intestine
| Leading to ê in delivery of intestinal
cholesterol to the liver
{ Effects
| ê of hepatic cholesterol stores
| é in clearance of cholesterol from blood
| ê LDL cholesterol by approx.17%
 Ezetimibe
| PK properties
{ Primarily metabolized in the small intestine & liver via
glucuronide conjugation
{ Biliary & renal excretion

| Clinical indications
{ Adjunct to statin therapy - due its modest LDL-lowering
effects
{ In patients intolerant to statins

| Contraindications
{ Patients with moderate to severe hepatic insufficiency

| Adverse effects
{ Uncommon
Omega-3-fatty acids
 Omega-3 fatty acids
| ‘Omega-3 polyunsaturated fatty acids
(PUFAs)’ – essential FA

| Mechanism of action
{ Inhibit VLDL & TG synthesis in the liver

| Clinical indication
{ Adjunct to other lipid-lowering therapies for
individuals with significantly elevated
triglycerides (≥500 mg/dL) - used to ê TG levels
 Omega-3 fatty acids - ii
| Sources
① Sea fish: tuna, halibut & salmon contain: (dietary sources)
{ Omega-3 PUFAs: eicosapentaenoic acid (EPA) &
docosahexaenoic acid (DHA)
{ Approx. 4g of marine-derived omega-3 PUFAs daily result in:
| ê serum TG concentrations by 25% - 30%
| Small é in LDL-C & HDL-C

② Over-the-counter or prescription fish oil capsules

(EPA/DHA) supplements
{ For supplementation, difficult to consume enough omega-3
PUFAs from dietary sources alone

③ Icosapent ethyl - contains only EPA (Prescription drug)

{ Does not significantly raise LDL-C
 Omega-3 fatty acids - iii
| Most common side effects
{ GI effects
| Abdominal pain
| Nausea
| Diarrhoea
| Fishy aftertaste

| Drug interactions
{ é bleeding risk in those who are taking
anticoagulants or antiplatelets at the same
time
 SUMMARY - USES
Condition Diet & Single drug
Primary chylomicronemia (Type I) Dietary management
• Familial lipoprotein lipase or (omega-3 fatty acids,
cofactor deficiency; Others niacin, or fibrate)
Severe & moderate familial Omega-3 fatty acids,
hypertriglyceridemia niacin, or fibrate
Familial combined Omega-3 fatty acids,
hyperlipoproteinemia (Type IIB) niacin, fibrate, or statin
Niacin, reductase
inhibitor, or ezetimibe
Omega-3 fatty acids,
niacin, or statin
Familial dysbetalipoproteinemia Omega-3 fatty acids,
(Type III) fibrate, or niacin
Familial hypercholesterolaemia (Type • Statin, resin, niacin, or
IIA) ezetimibe
• Heterozygous • Niacin, atorvastatin,
• Homozygous rosuvastatin, or
ezetimibe
Familial ligand-defective apo B Niacin, statin or
ezetimibe
Lp(a) hyperlipoproteinemia Niacin
Drug combination
Niacin plus fibrate
Niacin plus fibrate
2 or 3 of the
individual drugs
2 or 3 of the
individual drugs
Niacin or fibrate plus
statin
Fibrate plus niacin, or
either plus statin
• 2 or 3 of the
individual drugs
• Niacin plus statin
plus ezetimibe
Niacin plus statin or
ezetimibe