Etimib Denk 10 mg

Indications

• Adjunct to dietary measures in primary hypercholesterolaemia
• Adjunct to dietary measures and statin treatment in homozygous familial hypercholesterolaemia
• Adjunct to dietary measures in homozygous sitosterolaemia

Dosage

Children: Refer to the BNF for Children for appropriate dosing information, as the

Adults: The typical adult dosage of ezetimibe is 10 mg once daily.

Mechanism of action

Ezetimibe mediates its cholesterol-lowering effects by selectively inhibiting the absorption of cholesterol and phytosterols in the small intestine. It primarily targets the Niemann-Pick C1-Like 1 (NPC1L1) protein, which is vital for the internalization of free cholesterol into enterocytes. By blocking this protein at the jejunal brush border, ezetimibe reduces intestinal cholesterol uptake, consequently lowering hepatic cholesterol levels and enhancing cholesterol clearance from the blood.

Pharmacodynamics

Ezetimibe effectively reduces levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), apoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides while increasing high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia. Its lipid-lowering effects are significantly enhanced when used in combination with statins or fenofibrate, resulting in substantial reductions in LDL levels and modest increases in HDL-C.

Pharmacokinetics

Ezetimibe is absorbed in the gastrointestinal tract and undergoes extensive first-pass metabolism to its active form. The elimination half-life is approximately 22 hours, and it is primarily excreted in the bile. The pharmacokinetics may be affected by hepatic impairment, and its use is not recommended in patients with significant liver disease. Ezetimibe does not require exocrine pancreatic function for its activity.

Contra-indications

• Gall bladder disease
• Hypoalbuminaemia
• Nephrotic syndrome
• Severe hepatic impairment

Adverse effects

• Common or very common: Asthenia, gastrointestinal discomfort, decreased appetite, diarrhea, dizziness, headache, muscle complaints
• Uncommon: Acute kidney injury, alopecia, cholestasis, erectile dysfunction, nausea, photosensitivity reaction
• Rare or very rare: Cholelithiasis, depression, insomnia, interstitial lung disease, pancreatitis, pancytopenia, peripheral neuropathy, rhabdomyolysis

Interactions

• Ciclosporin: Increases exposure to ciclosporin when co-administered
• Bulevirtide: Unknown interaction affecting efficacy

Precautions

• Use with caution in patients with moderate to severe hepatic impairment
• Monitor for signs of muscle pain or weakness, especially if used concurrently with statins

Pregnancy

Manufacturer advises use only if potential benefit outweighs risk; no information available.

Breast-feeding

Manufacturer advises avoiding use; no information available.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Ezetimibe 10 mg tablets

Mechanism of action

Ezetimibe mediates its blood cholesterol-lowering effect via selectively inhibiting the absorption of cholesterol and phytosterol by the small intestine without altering the absorption of fat-soluble vitamins and nutrients. The primary target of ezetimibe is the cholesterol transport protein Niemann-Pick C1-Like 1 (NPC1L1) protein. NPC1L1 is expressed on enterocytes/gut lumen (apical) as well as the hepatobiliary (canalicular) interface and plays a role in facilitating internalization of free cholesterol into the enterocyte in conjunction with the adaptor protein 2 (AP2) complex and clathrin. Once cholesterol in the gut lumen or bile is incorporated into the cell membrane of enterocytes, it binds to the sterol-sensing domain of NPC1L1 and forms a NPC1L1/cholesterol complex. The complex is then internalized or endocytosed by joining to AP2 clathrin, forming a vesicle complex that is translocated for storage in the endocytic recycling compartment. Ezetimibe does not require exocrine pancreatic function for its pharmacological activity; rather, it localizes and appears to act at the brush border of the small intestine. Ezetimibe selectively blocks the NPC1L1 protein in the jejunal brush border, reducing the uptake of intestinal lumen micelles into the enterocyte. Overall, ezetimibe causes a decrease in the delivery of intestinal cholesterol to the liver and reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. While the full mechanism of action of ezetimibe in reducing the entry of cholesterol into both enterocytes and hepatocytes is not fully understood, one study proposed that ezetimibe prevents the NPC1L1/sterol complex from interacting with AP2 in clathrin coated vesicles and induces a conformational change in NPC1L1, rendering it incapable of binding to sterols. Another study suggested that ezetimibe disrupts the function of other protein complexes involved in regulating cholesterol uptake, including the CAV1–annexin 2 heterocomplex. Niemann-Pick C1-like 1 (NPC1L1) is a polytopic transmembrane protein that plays a critical role in cholesterol absorption. Ezetimibe, a hypocholesterolemic drug, has been reported to bind NPC1L1 and block cholesterol absorption. However, the molecular mechanism of NPC1L1-mediated cholesterol uptake and how ezetimibe inhibits this process are poorly defined. Here we find that cholesterol specifically promotes the internalization of NPC1L1 and that this process requires microfilaments and the clathrin/AP2 complex. Blocking NPC1L1 endocytosis dramatically decreases cholesterol internalization, indicating that NPC1L1 mediates cholesterol uptake via its vesicular endocytosis. Ezetimibe prevents NPC1L1 from incorporating into clathrin-coated vesicles and thus inhibits cholesterol uptake. ... Niemann-Pick C1-like protein (NPC1L1) mediates the absorption of dietary cholesterol in the proximal region of the intestine, a process that is blocked by cholesterol absorption inhibitors (CAIs), including ezetimibe. Using a proteomic approach, /it is/ demonstrated that NPC1L1 is the protein to which ezetimibe and its analogs bind. Next, ... the site of interaction of ezetimibe analogs /was determined/ with NPC1L1 by exploiting the different binding affinities of mouse and dog NPC1L1 for the radioligand analog of ezetimibe, [(3)H]AS. Chimeric and mutational studies indicate that high-affinity binding of [(3)H]AS to dog NPC1L1 depends on molecular determinants present in a 61-aa region of a large extracellular domain (loop C), where Phe-532 and Met-543 appear to be key contributors. These data suggest that the [(3)H]AS-binding site resides in the intestinal lumen and are consistent with preclinical data demonstrating in vivo efficacy of a minimally bioavailable CAI. Furthermore, these determinants of [(3)H]AS binding lie immediately adjacent to a hotspot of human NPC1L1 polymorphisms correlated with hypoabsorption of cholesterol. These observations, taken together wit

Pharmacodynamics

Ezetimibe was shown to reduce the levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG), and increase high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia. This therapeutic effect was more profound when ezetimibe was co-administered with a statin or fenofibrate compared to either treatment alone. In clinical trials involving patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia, a recommended therapeutic dose of ezetimibe was effective in reducing the LDL levels by 15-20% while increasing HDL-C by 2.5-5%. The effects of increased exposure to ezetimibe secondary to moderate-severe hepatic impairment have not been assessed - patients meeting these criteria should avoid the use of ezetimibe. Post-marketing reports indicate the potential for myopathy and rhabdomyolysis in patients taking ezetimibe, and this risk appears to be exacerbated in patients concurrently receiving, or having recently received, statin therapy.