6. Pharmacology of Lipid Lowering Agents Flashcards
Statins
- Specific reversible inhibitors of HMG-CoA reductase which prevents hepatic cholesterol synthesis
- Anti-inflammatory
- Increase plaque stability
- Improve endothelial cell function
- Reduce platelet aggregability
Upregulation of LDL receptor synthesis -> increased uptake of LDL -> reduced plasma LDL-C cholesterol levels
Statins - PK/PD features
- Well-absorbed orally, reaches Cmax within 1-2h
- Terminal half-life 14-77h
- Therapeutic effects on biomarkers (e.g. LDL-C) observed within 1-2 weeks with maximal effects observed by 4-6 weeks
- Reduction in LDL-C maintained over years at close to maximal level
- Effect on clinical outcomes apparent after several months
Statins - drug interactions
- CYP3A4 & 2A9 enzymes are involved in statin metabolism – there are >30 drugs that are 3A4 inhibitors
- CYP inhibitors (e.g. cyclosporin, ketoconazole, erythromycin, verapamil, protease inhibitors) can cause elevated statin & toxicity
- Grapefruit juice is also a CYP3A4 inhibitor – increases simvastatin plasma concentration
- Co-administration with other lipid-lowering drugs (fibrates, nicotinic acid) can cause myopathy (fibrates inhibit statin-acid glucuronidation)
Statins - ADRs
Mild side effects:
- Muscle pain
- GI disturbance
- Raised liver enzyme levels in plasma
Serious ADRs:
- Myositis (rhabdomyolysis) – skeletal muscle damage
- Hepatotoxicity
- Angio-oedema
Incidence increases with risk factors & statin dose
Fibrates
Bind to nuclear receptors that increase transcription of specific target genes involved in lipoprotein catabolism
Also increase transcription of other genes that provide beneficial non-lipid-medicated effects
- Reduces blood viscosity, inhibits platelet aggregation
- Controls the production of anti-inflammatory & pro-inflammatory stimuli in the artery wall
Fibrates - PK features
- Rapidly absorbed, Cmax 1-2h
- Metabolised in liver
- Exclusively eliminated by renal excretion
- Caution needed for specific patient groups (e.g. elderly)
Fibrates - drug interactions
Often used with other lipid-lowering drugs so dose adjustment needed
- With simvastatin – increased risk of myopathy/rhabdomyolysis
- With cholestyramine – reduces fibrate absorption
Fibrates - ADRs
- GI disturbances
- Rare – rhabdomyolysis
Ezetimibe
- Inhibits the intestinal absorption of cholesterol & related plant sterols by blocking a transport protein (NPC1L1) in the brush border of enterocytes
- Cholesterol availability to hepatocytes reduces, leading to increased absorption of cholesterol from the circulation
Used in combination with statin when statin response is inadequate or statin use is contraindicated
Ezetimibe - PK features
- Cmax 1-2h
- Long half life
- Extensively metabolised in the liver & small intestine via glucuronide conjugation, with subsequent renal & biliary excretion
Ezetimibe - Interactions & ADRs
Interactions:
- Bile acid sequestrates or fibrates - adjust dose
ADRs:
- GI disturbances, rash, angio-oedema
PCSK9 inhibitors
- Liver enzyme which regulates internalisation of LDL receptors
- Inhibits PCSK9 resulting in decreased LDL-C
Used in combination with statin when statin response is inadequate or statin use is contraindicated
PCSK9 - PK features
- Subcutaneous injection every 2 weeks
- Cmax reached in ~3-7 days
- Long half-life e.g. 17-20 days
PCSK9 - interactions & ADRs
Interactions:
- Statins & other lipid modifying agents can increase PCSK9 -> increased target mediated clearance & reduced systemic exposure to Alirocumab
ADRs:
- Upper respiratory tract symptoms
- Local injection site reactions
Cholestyramine (bile acid sequestrant)
- Loss of bile acids causes an increase in bile acid synthesis in the liver
- More plasma cholesterol is converted to bile acids -> decreased cholesterol levels
