Statin Mechanism and Effects

• Antihyperlipidemic drugs are used to treat hyperlipidemia.
• Fat is tasteful within limits, but dangerous in excess.

What is Hyperlipidemia?

• Hyperlipidemia, also called hyperlipoproteinemia, is a common disorder in developed countries.
• Hyperlipidemia is a major contributor to coronary heart disease
• Hyperlipidemia arises from abnormalities in lipid metabolism or plasma lipid transport.
• Conditions in the synthesis and degradation of plasma lipoproteins can also cause hyperlipidemia.

Causes of Hyperlipidemia

• Lifestyle habits or treatable medical conditions often cause hyperlipidemia.
• Hyperlipidemia can be inherited from conditions like obesity, inactivity, smoking, diabetes, obstructive jaundice, and an underactive thyroid gland.

Biochemistry of Plasma Lipids

• Lipids are heterogeneous mixtures of fatty acids and alcohol in the body.
• The main lipids in the bloodstream include cholesterol and its esters, triglycerides, and phospholipids.

Cholesterol

• Cholesterol is a C27 steroid that serves as an important component of all cell membranes.
• Cholesterol is a precursor molecule for the biosynthesis of bile acids, steroid hormones, and fat-soluble vitamins.
• Cholesterol is necessary for new cells to form and for older cells to repair themselves after injury.
• The adrenal glands use cholesterol to form hormones like cortisol, the testicles to form testosterone, and the ovaries to form estrogen and progesterone.
• The liver produces cholesterol, and can also be consumed through meat and dairy products.

Triglycerides and Phospholipids

• Triglycerides supply energy for immediate needs in muscles or store fat for future energy needs.
• Phospholipids create cell membranes, generate second messengers, and store fatty acids for prostaglandin generation.

Lipoproteins

• Lipoproteins contain proteins and lipids bound to apolipoproteins.
• Apolipoproteins allow fats to move through the water inside and outside cells.
• Lipoproteins provide structural support and stability and bind to receptors.

Classification of Lipoproteins

• Chylomicrons transport dietary triglycerides to adipose tissue and muscle, consisting of 99% triglycerides and 1% protein.
• VLDL transports endogenous triglycerides(TGs) to adipose tissue and muscle, consisting of 90% lipids and 10% protein.
• IDL is intermediate between VLDL and LDL, and is not usually detectable in the blood.
• LDL transports endogenous cholesterol from the liver to tissues, consisting of 80% lipids and 20% protein.
• HDL collects cholesterol from the body's tissues, consisting of 60% lipids and 40% protein, and returns it to the liver.

Classification of Hyperlipidemia

• Hyperlipidemias are classified according to the Fredrickson classification, based on the pattern of lipoproteins on electrophoresis or ultracentrifugation.
• The World Health Organization (WHO) later adopted the Fredrickson classification.
• The Fredrickson classificaion does not account for HDL, or distinguish among the different genes that may be partially responsible for some of these conditions.
• Groups of Hyperlipidemia can be primary or familial hyperlipoproteinaemia and secondary hyperlipoproteinaemia
• Current classification of hyperlipidemias depends on the pattern of lipid abnormality in the blood.

Primary Familial Hyperlipoproteinaemia

• Primary familial hyperlipoproteinaemia is subclassified into six phenotypes: I, IIa, IIb, III, IV, and V, based on elevated lipoproteins and lipids.
• Current literature favors the more descriptive classifications and subclassification.
• Type I hyperlipoproteinemia is rare, known also as "Buerger-Gruetz syndrome". Increased Lipoprotein = Chylomicrons by reduced LPL. Treatment = Diet control
• Type IIa "Polygenic hypercholesterolaemia" Increased Lipoprotein = LDL+TG. Treatment = Bile acid sequestrants, statins, niacin
• Type IIb hyperlipoproteinemia is "Combined hyperlipidemia" with LDL and VLDL. Treatment = Statins, niacin, fibrate
• Type III Hyperlipoproteinemia is rare - Familial dysbetalipoproteinemia. Increased Lipoprotein = IDL, Fibrates, statins
• Type IV is Familial hyperlipidemia, Increased Lipoprotein = VLDL. Treatment = Fibrate, niacin, statins
• Type V hyperlipoproteinemia is also rare. Called "Endogenous hypertriglyceridemia" Increased Lipoprotein = VLDL and Chylomicrons. Treatment = Niacin, fibrate.

Secondary Hyperlipidemias

• Secondary hyperlipidemias can be due to hypothyroidism, nephrotic syndrome, diabetes mellitus (NIDDM), or chronic renal failure

Classification of Antihyperlipidemic Drugs

• Different classes of drugs are used to treat hyperlipidemia.
• These drug classes vary in their mechanism of action, type of lipid reduction, and reduction magnitude.
• These classes include HMG CoA Reductase inhibitors, Fibric acid derivatives, Bile acid sequestrants, LDL oxidation inhibitor, Pyridine derivative, Cholesterol absorption inhibitors and Miscellaneous agents

HMG-CoA Reductase Inhibitors (Statins)

• HMG-CoA Reductase Inhibitors (statins) are the most effective and best-tolerated.
• Agents include Lovastatin, Pravastatin, Simvastatin, Atorvastatin, Fluvastatin and Rosuvastatin

Mechanism of Action

• Statins competitively inhibit HMG-CoA reductase, inhibiting cholesterol biosynthesis.
• Statins deplete cholesterol in hepatocytes, activating Scap (SREBP cleavage activating protein).
• This stimulates proteolytic cleavage of SREBP and translocates to nucleus.
• Ultimately, this increases LDL-R expression on hepatocytes.
• HMG-CoA reductase decreases hepatic uptake of LDL and IDL, decreasing plasma LDL by 20-55%.
• Major effect are dose and agent dependent
• There is a 6% reduction with doubling of dose

HMG-CoA Reductase

• HMG-CoA Reductase is the enzyme that catalyzes the conversion of HMG-CoA to mevalonate.
• This reaction is the rate-determining step in the synthetic pathway of cholesterol.
• Lovastatin was isolated from Aspergillus terreus.
• Natural statins include Lovastatin (mevacor), Pravastatin (pravachol), and Simvastatin (Zocor).
• Synthetic Statins include Atorvastatin (Lipitor) and Fluvastatin (Lescol).
• Statins competively inhibit HMG-CoA reductase. Because statins are bulky, they get stuck in the active site.
• This blocks to prevent the enzyme from binding with its substrate, HMG-CoA.
• Statins decrease VLDL by decreasing hepatic VLDL synthesis, reducing cholesterol, and reducing LDL-C by ~25%.
• Homozygous familial hypercholesterolemia results in absent LDLR.
• If TGs are >250 mg/dL, the % decrease ~ % decrease in LDL-C.
• If TGs are <250 mg/dL, there is a decrease of < 25% decrease in TG levels.
• Rosuvastatin shows an increase in HDL ~15-20%.

Statin ADR and Uses

• Lovastatin can cause increased creatinine phosphokinase, flatulence, and nausea. Lovastatin is used as an Antihyperlipoproteinemic agent
• Simvastatin can cause headache, nausea, flatulence, heartburn, and abdominal pain, and is used an antihyperlipdemic agent.
• Pravastatin can cause GI disturbances, headache, insomnia, chest pain, and rash, and is used an antihyperlipoproteinemic agent.
• Atorvastatin can cause headache, flatulence, and diarrhea. It is used for primary hyperlipidemia and secondary hypercholesterolemia.
• Rosuvastatin can cause headache, dizziness, constipation, nausea, and vomiting. It is used for high LDL, total cholesterol, and TGs.

Statin Pharmacokinetics

• Absorption of ingested doses for reductase inhibitors varies from 40% to 75%, except for fluvastatin, which is almost completely absorbed.
• All statins have high first-pass extraction by the liver.
• Most of the absorbed dose is excreted in the bile, with 5-20% excreted in the urine.
• Plasma half-lives of these drugs range from 1 to 3 hours except for atorvastatin (14 hours), pitavastatin (12 hours), and rosuvastatin (19 hours).
• Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing congeners.
• Short-acting statins are given at night to reduce peak cholesterol synthesis in the early morning.
• Statins are absorbed and extracted by the liver, their site of action, and are subject to extensive presystemic metabolism via cytochrome P450 and glucuronidation pathways.
• Lovastatin and simvastatin are inactive lactone prodrugs that are hydrolyzed in the gastrointestinal tract.
• These hydrolyze to active β-hydroxyl derivatives; pravastatin has an open, active lactone ring.

Clinical Uses of Statins

• Secondary prevention of myocardial infarction and stroke in patients who have symptomatic atherosclerotic disease (angina, transient ischaemic attacks).
• Primary prevention of aterial desease in patients at high risk because of elevated serum cholesterol concentration.
• Ezetimibe is combined with statin treatment in severe drug-resistant dyslipidaemia (e.g., heterozygous familial hypercholesterolaemia).
• Statins are contraindicated in pregnancy.

Other Actions of Statins

• Statins improve endothelial function and reduce vascular inflammation and platelet aggregability.
• Statins increase neovascularisation of ischaemic tissue and circulating endothelial progenitor cells.
• Statins stabilize atherosclerotic plaque, have antithrombotic actions, and enhance fibrinolysis.
• Statin use inhibits germ cell migration during development, causes immune suppression, and protects against sepsis.

Adverse Effects of Statins

• Statins are well tolerated, and patients typically have mild unwanted effects.
• Mild unwanted effects include myalgia, gastrointestinal disturbance, raised liver enzyme concentrations in plasma, insomnia and rash are also possible side effects.
• Serious adverse effects are rare, including severe myositis (rhabdomyolysis) and angio-oedema.
• It is commoner in patients with low lean body mass or uncorrected hypothyroidism.

Statin Doses

• Doses required to obtain various LDL-C reductions from the Baseline are found in the slide

Fibrates Overview

• Fibrates are antihyperlipidemic agents used widely in the treatment of hyperlipidemia and hypercholesterolemia.
• Fibrates are 2-phenoxy-2-methyl propanoic acid derivatives stimulate β-oxidation of fatty acids in mitochondria.
• These drugs decrease plasma levels of fatty acid and triacylglycerol

Fibric Acid Derivatives

• Fibrates activate PPARα, which is a gene transcription regulator expressed primarily in the liver and brown adipose tissue
• • First generation Fibrates comprise Gemfibrozil (600-mg BD, 30 minutes before morning and evening meals).
• Second generation Fibrates comprise Clofibrate (~500 mg QID), Fenofibrate (~145 mg OD), and Bezafibrate(~200 mg TDS)

Mechanism of Action

• Fibrates decrease plasma triglyceride levels more than cholesterol levels.
• Fibrates reduce blood triglyceride levels by reducing the liver's production of VLDL.
• VLDL is the triglyceride-carrying particle that circulates in the blood. Triglyceride reduction occurs by activating lipoprotein lipase and speeding up removal from the blood, supported by PPAR-α.
• Fibrates modestly increase blood HDL cholesterol, but are not very effective in lowering LDL cholesterol.

Fibrate ADR and Uses

• Clofibrate can cause Cholecystitis, gall stone, eosinophilia and pneumonia. Clofibrate can be used for Type III Hyperlipoproteinemias
• Gemfibrozil can cause Myositis syndrome, Cholelithiasis, GI disturbances, rash and headache. This drig is used for Hyperlipidemia
• Fenofibrate can cause Headache, dizziness, asthaenia, fatigue, arrhythmia and are more potent hypercholesterolemic and triglycerides lowering agent.

Fibrate Pharmacokinetics

• Several fibric acid derivatives (fibrates) include bezafibrate, ciprofibrate, gemfibrozil, fenofibrate and clofibrate.
• Fibrates reduce circulating VLDL, and hence triglycerides, with a 10% reduction in LDL and a 10% increase in HDL.
• Gemfibrozil is absorbed quantitatively from the intestine and is tightly bound to plasma proteins, undergoes enterohepatic circulation and readily passes the placenta.
• Gemfibrozil has a plasma half-life of 1.5 hours.
• Gemfibrozil is Seventy is eliminated through the kidneys, mostly unmodified.
• The liver modifies some of the drug to hydroxymethyl, carboxyl, or quinol derivatives.
• Fenofibrate is an isopropyl ester that is hydrolyzed completely in the intestine, with a 20 hour half life.
• For Fenofibrate ,60% is excreted in the urine as the glucuronide, and about 25% in feces.

Adverse Effects and Therapeutic Uses

• Fibrates can cause abdominal discomfort, Diarrhea, and Nausea.
• Fibric acid Derivatives increase the risk of gallstones (clofibrate) and prolong prothrombin time.
• Myopathy is a risc when combined with statins (followed at 3 months).
• Gemfibrozil causes the highest incidence, whereas Fenofibrate if safer (glucuronidated by enzymes not involved in statin glucuronidation)
• C/I: Children & pregnant women and renal Failure should avoid Fibrates
• Fibrates are used to treat Mixed dyslipidaemia (i.e. raised serum triglyceride as well as cholesterol) and Fenofibrate may be useful where hyperuricaemia coexists with mixed dyslipidaemia.
• In patients with low high-density lipoprotein and high risk of atheromatous disease (often type 2 diabetic patients, Fibrates can be combines with other lipid-lowering drugs in patients with severe treatment-resistant dyslipidaemia, but can increase the risk of rhabdomyolysis.

Bile Acid Sequestrants

• Bile Acid Sequestrants include cholestyramine (Questran), colestipol hydrochloride (Colestid.) and colesevelam (tablet form)
• Bile Acid Sequestrants are called bile acid-binding resins and ion-exchange resins.
• Cholestyramine (Questran) is a non-absorbed bile acid sequestrant.
• Cholestyramine is used for hyperlipidemia and for the pruritis of chronic liver disease and biliary obstruction.
• Cholestyramine is a large, highly positively charged anion exchange resin that binds to negatively charged anions such as bile acids, creating an insoluble compound that cannot be reabsorbed and is excreted in the feces.
• Bile Acid Sequestrants are moderately effective with an excellent safety record , and are Large MW polymers containing Cl. Resin binds to bile acids and the acid-resin complex is excreted.
• Bile Acid Sequestrants prevent enterohepatic cycling of bile acids and obligate the liver to synthesize replacement bile acids from cholesterol.
• Bile acid sequestrants reduce levels of LDL-C in the serum as more cholesterol is delivered to the liver.
• Bile Acid Sequestrants have little effect on levels of HDL-C and TG, and are an excellent choice for people that cannot tolerate other types of drugs

Colesevalam

• Colesevalam is a third generation drug that are similar to the previous ones without Chloride Ions
• It is not an anion exchange resin, with selectivity for hydroxylated form of bile acids which reduces the side effect of constipation.

Pharmacokinetics and therapeutic uses

• Colestipol, cholestyramine, and colesevelam are useful only for isolated increases in LDL.
• In patients who also have hypertriglyceridemia, VLDL levels may be further increased during treatment with resins.
• The bile acid-binding agents are insoluble, large polymeric cationic exchange resins.
• They bind bile acids in the intestinal lumen and prevent their reabsorption.
• The resin itself is not absorbed
• Bile Acid Sequestrants such as Cholestyramine are 4g packets while and Colestipol is available in 5g packets / 1g tab.
• Colesevelam comes in 1.875 g packet/ 625 mg tab.
• Dosing depends on the drug chosen. Ideal, pt should take resins BBF and before supper, starting with one packet twice daily.
• Therapeutic Uses include heterozygous familial hypercholesterolemia and it is a drug of choice for children and females in reproductive age group.
• They are Contraindicated in people with Hypertriglyceridemia.

Adverse effects and interaction

• Bile Acid Sequestrants can cause heart burn, dyspepsia, bloating, gritty sensation and suspending powder in liquid several hours before ingestion.
• Bile Acid Sequestrants can also cause malabsorption of Vitamin K, and folic acid and can also cause constipation (adequate water intake and psyllium)
• Bile Acid Sequestrants rarely cause hyperchloremic acidosis.
• Bile Acid Sequestrants bind to digoxin, warfarin, thyroxine, some statins, furosemide, and thiazides and prevents absorption. So it is important to dose 1 hr before or 3-4 hrs after administration

Ezetimibe

• Ezetimibe (Zetia) is a cholesterol absorption Inhibitor.
• Ezetimibe lowers plasma cholesterol levels by decreasing cholesterol absorption in the intestine, and is the drug responsible for that
• The decrease in cholesterol delivery to the liver results in more cholesterol being cleared from the blood.
• The levels of LDL-C in the serum are reduced as in bile acid sequestrants.
• Therapeutic uses include use as monotherapy or in combination with HMGRI for reduction of elevated total cholesterol.
• Ezetimibe does not appear to be a substrate for cytochrome P450 enzymes.
• Low incidence of reversible impaired hepatic function with a small increase in incidence when given with a reductase inhibitor can occur.
• Also myositis has uncommonly reported.

Other Uses

• Type IIa hyperlipoproteinemia may be treated with Bile Acid Sequestrants
• Relief of pruritus associated with partial biliary obstruction can be treated with Cholestyramine

Niacin

• Niacin (Nicotinic Acid) is a water soluble vitamin of the B family.
• Once converted to the amide, it is incorporated into NAD.
• It has to be dosed at the rate of 1.5 to 3.5 gm daily, with a sustained release dosage form is available
• Niacin Lipid-lowering properties require much higher doses than when used as a vitamin.
• Itis effective, inexpensive, often used in combination with other lipid-lowering drugs
• Niacin Increases activity of lipase, which breaks down lipids, reducing the metabolism of cholesterol and triglycerides
• Effective in lowering triglyceride, effective in treatment of types IIa, IIb, III, IV, and V hyperlipidemias.

Niacin MOA and Theraputic Uses

• Niacin Increases activity of lipase, which breaks down lipids ad reduces the metabolism of cholesterol and triglycerides
• Niacin increases HDL levels and is effective in the treatment of types IIa, IIb, III, IV, and V hyperlipidemias
• Niacin inhibits the synthesis of TGs by HS Lipases while stimulating Stimulates expression of SR-CD36 & ABCA1
• Niacin Increases LPL activity,. It inhibits a rate-limiting enzyme of TG synthesis,
• Use in the treatment of Hypertriglyceridemia and high LDL-C associated with low HDL
• is the DOC for Familial combined hypertriglyceridemia
• Useful in Familial dysbetalipoproteinemia (type 3), Severe mixed hypertriglyceridemia(type 4) and Heterozygous familial hypercholesterolemia (+ resins/statins)
• Dosing starting from 100mg TDS to 1gTDS in immediaterelease, 250mg BD to 1.5g BD in sustained and 500mg HS to 2g HS in extended

Niacin ADRs

• Flushing (due to histamine release)
• Pruritus
• GI distress
• Liver dysfunction and jaundice serious risk of liver damage
• Flushing, warmth (PGD₂ & E₂)
• Pruritus, rashes
• Dyspepsia
• Skin dryness
• Acanthosis nigricans
• Liver dysfunction (flu like fatigue)
• Hyperglycemia, Hyperuricemia
• Risk of myopathy if combined with statins. (dose not >25% of maximum)
• C/I of Niacin may be include: Peptic ulcer disease , Gout, DM and Pregnancy

LDL Oxidation Inhibitor

• The most studied LDL Oxidation Inhibitor is probucol

Probucol

• Probucol has two tertiary butylphenol groups linked by a dithiopropylidene bridge, giving it a high lipophilic with strong antioxidant.
• Probucol causes reduction of both liver and serum cholesterol levels, but it does not alter plasma triglycerides.
• Probucol reduces to a lesser extent HDL levels by a unique mechanism, and the reduction of HDL may be caused by the ability of probucol to inhibit the synthesis of apoprotein A-1.
• Administering it is effective at reducing levels of LDL and is used in hyperlipoproteinemias. GI disorders and prolongation of GI intervals are the ADR
• It is used as antihyperlipoproteinemic agent.

PCSK9 Inhibitors for elevated LDL-C

• PCSK9 physiological enzyme ligand of LDL-R decreases the LDL-R to lower the recycling of of LDL out of the liver
• Drugs Alirocumab and Evolocumab were Approved in 2015 to lower LDL. Specifically for Heterozygous FH, Lower LDL-C by 50-72% (effect persists for 2-4 weeks after single S.C. injection and Lower PCSK9 activity upto 80%; Reduce Lp(a))
• Alirocumab and Evolocumab both require an SC q2weeks dose with evolocumab being higher at 140 mg SC than Alirocumab and 75 mg SC if the LDL-C lowering response is inadequate, may increase to 150 mg SC q2weeks
• PCSK9 has also been involved in degradation of many receptors that are also receptors for viruses which means that viral infections need to be monitored in patients on PCSK9 inhibitors
• Bococizumab is a drug in Phase III

ApoB Synthesis Inhibitors

• Mipomersen inhibits ApoB-100 synthesis in the liver, decreasing VLDL and LDL-C
• It is Useful in heterozygous and homozygous FH who lack LDL-R which requires 200 mg SC weekly and reduces apoB(33-54%), LDL-C(34-52%), and Lp(a)(24%)
• The drug is known for severe injection site reaction, flu-like reactions, headache, and hepatotoxicity
• It Has been Approved for t/t of homozygous FH with restriction due to hepatotoxicity, which leads to availability through restricted Risk Evaluation & Mitigation Strategy(REMS) program

MTP Inhibitors

• Lomitapide reduces decrease in VLDL & LOL-C for people who have a MTP that transfers TG to apoB in the liver
• This medication is most useful in homozygous FH who lack LDL-R and reduces LDL-C (42-50%)
• Initial dose is 5mg/day orally→ 10, 20 40→ upto 60 mg
• It Has been Approved for t/t of homozygous FH with restriction and leads to hepatotoxicity.
• Can use in a restricted Risk Evaluation & Mitigation Strategy(REMS) program

ApoC-III Synthesis Inhibitors

• Volanesorsen are specific for people with ApoC-III who tend to inhibits LPL, and reduces lipolysis of TG rich lipoproteins leading to increasing their TG
• The dug aids in inhibting hepatic lipase and thus the reduced catabolism and uptake of TG rich lipoprotein remnants
• It will soon be intorducted in an Early Phase 3 for people hypertriglyceridemia, familial chylomicronemia syndrome

Omega-3 Fatty Acids

• Fish oil derivatives contain PUFAs: eicosa penta-enoic acid EPA and docosa hexa-enoic acid DHA.
• Fish oils help increases TG catabolism while being membrane stabilizing and anti-oxidant
• Typical dose is 4g/day

Explore statin administration, mechanism variations (like lovastatin vs. pravastatin), and pleiotropic effects on cardiovascular health. The content covers bioavailability, treatment strategies for hypercholesterolemia, impact on vascular function, and structural similarities among statins.