Pharmacokinetics and

pharmacodynamics of drugs in lipid

z
metabolism disorders

Putu Nita Cahyawati

Department of Pharmacology and Pharmacy, Faculty of
Medicine, Warmadewa University
Classes
z of agent for modification of lipid metabolism

Inhibitors of cholesterol synthesis

Inhibitors of bile acid absorption

Inhibitors of cholesterol absorption

Fibrates

Niacin

Omega-3 fatty acids

 z INHIBITORS OF CHOLESTEROL SYNTHESIS
(STATINS)

HMG-CoA
HMG-CoA reductase catalyses
reductase the conversion of
inhibitor HMG-CoA to
mevalonate

Most highly prescribed

medications worldwide STATINS
High tolerability

Based on preclinical
Pleiotropic reseach
effect

HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A)
Pharmacokinetics
z
▪ Lovastatin and simvastatin are inactive lactone prodrugs that are hydrolyzed in the gastrointestinal tract to the
active β-hydroxyl derivatives
▪ Absorption varies from 40% to 75% with the exception of fluvastatin, which is almost completely absorbed.
▪ All have high first-pass extraction by the liver.
▪ Most of the absorbed dose is excreted in the bile; 5–20% is excreted in the urine.
▪ Plasma half lives range from 1 to 3 hours except for atorvastatin (14 hours), pitavastatin (12 hours), and
rosuvastatin (19 hours).
Mechanism of Action
z

▪ Inhibition of HMG-CoA reductase→prevent the

endogenous production of cholesterol.

▪ ↓ cholesterol concentration→ activates a cellular

signaling cascade→ activation of sterol regulatory
element binding protein 2 (SREBP2)→ a transcription
factor that up-regulates expression of the gen
encoding the LDL receptor

▪ ↓ cholesterol concentration within hepatocytes→

triggers up-regulation of LDL-receptor expression→
promotes the uptake of LDL and LDL-precursors from
systemic circulation.
 z
▪ Terapeutic use
▪ Hyperlipidemia
▪ Pleiotropic effect (independent of their lipid-
lowering actions)
▪ →heart disease, chronic kidney disease,
rheumatoid ds

▪ Toxicity
▪ Statin-Associated Muscle Symptoms (SAMS)→ can
present as myalgia, myopathy, myositis with elevated
CK (creatinine kinase), or at its most severe,
rhabdomyolysis
▪ SAMS usually presents as a symmetrical
(bilateral) condition that affects the large proximal
muscles, particularly of the lower extremities.
▪ Other side effects : new-onset type 2 diabetes mellitus,
neurological and neurocognitive effects, hepatotoxicity,
renal toxicity, and other conditions
 z INHIBITORS OF BILE ACID ABSORPTION
(RESINS)

▪ Normally, over 90% of bile acids, metabolites of cholesterol, are reabsorbed in the GI tract and
returned to the liver for reuse

▪ Bile acid-binding resins (cholestyramine, colestipol, and colesevelam) are large nonabsorbable
polymers that bind bile acids and similar steroids in the intestine and prevent their absorption

▪ By preventing the recycling of bile acids, bile acid-binding resins divert hepatic cholesterol to
synthesis of new bile acids, thereby reducing the amount of cholesterol

▪ A compensatory increase in the synthesis of LDL receptors increases→↑ the removal of LDL
lipoproteins from the blood

▪ The resins cause a modest reduction in LDL cholesterol but have little effect on HDL or TG
z

▪ Clinical Use
▪ patients with hypercholesterolemia

▪ ↓pruritus in patients with cholestasis and bile salt

accumulation.

▪ Toxicity
▪ bloating, constipation, and an unpleasant gritty
taste.

▪ Absorption of vitamins (eg, vitamin K,

dietary folates) and drugs (eg, thiazide diuretics,
warfarin, pravastatin, fluvastatin) is impaired by the
resins
 z
INHIBITORS OF CHOLESTEROL ABSORPTION
(EZETIMIBE)

▪ Ezetimibe is a prodrug that is converted in the liver to the active glucuronide form.

▪ This active metabolite inhibits a transporter that mediates gastrointestinal uptake of cholesterol and
phytosterols

▪ By preventing absorption of dietary cholesterol and cholesterol that is excreted in bile, ezetimibe
reduces the cholesterol

▪ A compensatory increase in the synthesis of LDL receptors increases the removal of LDL lipoproteins
from the blood.

▪ As monotherapy, ezetimibe reduces LDL cholesterol by about 20% →more effective when combined
with an HMG-CoA reductase inhibitor
z

▪ Clinical Use
▪ treatment of hypercholesterolemia and
phytosterolemia, a rare genetic disorder that results
from impaired export of phytosterols

▪ Toxicity
▪ Ezetimibe is well tolerated.

▪ When combined with HMG-CoA reductase inhibitors,

it may increase the risk of hepatic toxicity.
 NIACIN (NICOTINIC ACID/VITAMIN B3)
z

▪ Niacin is converted in the body to the amide, which is incorporated into niacinamide adenine
dinucleotide (NAD).
▪ It is excreted in the urine unmodified
▪ Activation of the nicotinic acid receptor GPR109A
on adipocytes → a Gi-mediated inhibition of
adenylyl cyclase (AC) activity → decrease of
cAMP levels→ decrease in lipolysis →decrease in
free fatty acid (FFA) levels →hepatic triglyceride
(TG) synthesis →less triglycerides and
less VLDL are produced by the liver
→ VLDL as well as LDL plasma levels drop

▪ The mechanism of the nicotinic acid–induced

increase in HDL cholesterol levels is less clear
→ mediated by CETP ?
 z

• Clinical Use
Heterozygous familial hypercholesterolemia hypercholesterolemia (premature atherosclerosis
and xanthomatosis), hypertriglyceridemia, and low levels of HDL cholesterol

▪ Toxicity
▪ Cutaneous flushing ( e.c prostaglandin release )→ pretreatment
with aspirin or NSAIDs reduces the intensity of this flushing,
▪ Moderate elevations of liver enzymes and even severe
hepatotoxicity may occur
▪ Pruritus, rashes, dry skin or mucous membranes, and acanthosis
nigricans have been reported.
▪ Niacin should be avoided in most patients with severe peptic
disease.
▪ Niacin may increase insulin resistance in some patients.
 z FIBRIC ACID DERIVATIVES
(FIBRATES)

▪ Fibric acid derivatives (eg, gemfibrozil, fenofibrate) are ligands for the peroxisome proliferator-
activated receptor-alpha (PPAR-α) protein, a receptor that regulates transcription of genes
involved in lipid metabolism
▪ This interaction with PPAR- α results in increased synthesis by adipose tissue of lipoprotein lipase,
which associates with capillary endothelial cells and enhances clearance of triglyceride-rich
lipoproteins
▪ In the liver, fibrates stimulate fatty acid oxidation, which limits the supply of triglycerides and
decreases VLDL synthesis. They also decrease expression of apoC-III, and increases the expression
of apoA-I and apoA-II, which in turn increases HDL level
z

▪ They transcriptionally up-regulate LPL,

apo A-I and apo A-II, and down-regulate
apo C-III, an inhibitor of lipolysis.

▪ A major effect is an increase in oxidation

of fatty acids in liver and striated muscle
 z
OMEGA-3 FATTY ACIDS

▪ The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), also
referred to as fish oils, are effective at reducing plasma triglycerides by up to 50% in patients
with hypertriglyceridemia.

▪ The likely mechanism of triglyceride lowering involves regulation of nuclear transcription

factors, including SREBP-1c and PPAR, to cause reduced triglyceride biosynthesis and
increased fatty acid oxidation in the liver

▪ Omega-3 fatty acids are generally added to therapy when plasma triglyceride concentrations
exceed 500 mg/dL.

▪ The influence of omega-3 fatty acid use on clinical outcomes is uncertain.

z
 COMBINATION THERAPY
z
▪ All patients with hyperlipidemia are treated first with dietary modification→insufficient →drugs must be added
▪ Drug combinations → To achieve the minimum toxicity and to achieve the desired effect
▪ Resins interfere with the absorption of certain HMG-CoA reductase inhibitors → must be given at least 1 h before or 4
h after the resins.
▪ The combination of reductase inhibitors with either fibrates or niacin increases the risk of myopathy
18

THANK YOU
Refference
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The Pathophysiologic Basis of Drug Therapy 3rd ed. Lippincott Williams & Wilkins
• Katzung, BG., Masters, SB., Trevor, AJ. 2012. Basic & Clinical Pharmacology 12nd ed. The
McGraw-Hill
• Trevor, AJ., Katzung, BG., Kruidering-Hall, M. 2015. Pharmacology Examination & Board
Revie 12nd ed. The McGraw-Hill.
• Cahyawati PN et al. 2017. Simvastatin attenuates renal failure in mice with a 5/6 subtotal
nephrectomy. Int J Pharm Pharm Sci; 9: 12-7.
• Cahyawati PN et al. 2020. Simvastatin Improves Renal Function and Glomerulosclerosis in
Ischemic-reperfusion Injury. Indones Biomed J.12(2): 143-8
• Cahyawati, PN et al. 2018. Statin and anemia in chronic kidney disease (CKD): an
experimental study. MATEC Web Conf., 197:07003
• Cahyawati, PN et al. 2018. Effect of statin on vascular wall thickness in kidney disease model.
IOP Conf. Ser.: Mater. Sci. Eng. 434 012324