5. Lipid Lowering Drugs Flashcards
Which form of lipid carries the highest risk for cardiovascular disease?
LDL - Low density lipoprotein
Why is LDL considered the most dangerous form of fat?
-It carries cholesterol from the liver to the cells
-Which can lead to the accumulation of cholesterol in the walls of arteries
-Leading to atherosclerosis
Why is HDL “good” for you?
-It helps remove cholesterol from the bloodstream
-Transporting it back to the liver for excretion
-Reducing the risk of cholesterol buildup and atherosclerosis
What are high levels of ApoA1 associated with?
High levels of ApoA1 are associated with a lower risk of cardiovascular disease.
What is ApoA1 (apolipoprotein A1)?
-ApoA1 is the primary protein component of HDL (high-density lipoprotein)
-It plays a crucial role in reverse cholesterol transport, where it helps remove cholesterol from the arteries and transport it back to the liver for excretion or recycling
What is ApoB (apolipoprotein B)?
-ApoB is the primary protein found in LDL (low-density lipoprotein) and other atherogenic lipoproteins like VLDL (very-low-density lipoprotein)
-It is essential for the transport of cholesterol and triglycerides to tissues.
What are high levels of ApoB associated with?
High levels of ApoB-containing lipoproteins are associated with an increased risk of cardiovascular diseases due to the potential for cholesterol buildup in the arteries.
What is lipoprotein A?
-Lipoprotein(a) is a lipoprotein variant that consists of an LDL particle bound to a specific protein called apolipoprotein(a)
-Elevated Lp(a) levels are genetically determined and not significantly affected by lifestyle factors, unlike other lipoproteins like LDL and HDL.
What are high levels of lipoprotein A associated with?
High levels of Lp(a) are considered an independent risk factor for cardiovascular diseases, as it can contribute to the formation of arterial plaques and promote inflammation
Describe the formation of an atherosclerotic plaque in the arteries (from LDL circulation til monocyte activation)
1: Circulating LDL gains access to subendothelial space
2: LDL particles undergo oxidation, a process that makes them more atherogenic (capable of contributing to plaque formation). Oxidized LDL is recognized as harmful by the immune system.
3: The oxidized LDL triggers the release of pro-inflammatory cytokines, including IL1 and MCP1
4: Monocytes migrate through the endothelial layer (intima) and enter the subendothelial space, where they differentiate into macrophages
Describe the formation of an atherosclerotic plaque in the arteries (from macrophage formation til plaque enlargement)
5: Macrophages engulf oxidised LDL, accumulating it, transforming them into foam cells
6: Smooth muscle cells from the middle layer of the blood vessel (media) migrate into the intima and begin to proliferate.
7: As foam cells accumulate, smooth muscle cells, lipids, and necrotic (dead) cells start to form a primitive atherosclerotic plaque.
8: Over time, the plaque enlarges, developing a fibrous cap made of collagen and smooth muscle cells. The plaque pushes into the vessel lumen (the interior space of the blood vessel), narrowing the artery and reducing blood flow.
What is a cause of primary dyslipidaemia, and its prevalence amongst the population?
-Familial hypercholesterolaemia
-1/250
What percentage of males with Familial Hypercholesterolaemia will have symptomatic heart disease by the age of 50?
50%
Give some visual symptoms of hypercholesterolaemia
-Cholesterol deposits around the eye
-Tendon Xanthomata
-Lipaemia Retinalis
-Milky serum
Give some causes of secondary dyslipidaemias
-Medications, eg beta blockers, thiazide diuretics, protease inhibitors, oral contraceptives
-Diabetes mellitus
-Obesity
-Hypothyroidism
-CKD
Give some non pharmacological treatments of dyslipidaemia
-Cardioprotective diet
-Weight loss
-Physical activity
-Reduce alcohol consumption
-Smoking cessation
Give some pharmacological treatments of dyslipidaemia
-HMG CoA reductase inhibitors (statins)
-Fibrates
-Cholesterol absorption inhibitors
-Omega fatty acids
-Nicotinic acid
What are HMG CoA reductase inhibitors also known as?
Statins
Describe the mechanism of action of statins/HMG CoA reductase inhibitors
-Block HMGCoA reductase in the mevalonate pathway, preventing formation of a cholesterol precursor, effectively reducing the endogenous production of cholesterol
-Lower cholesterol synthesis raises the number of LDL receptors on hepatocytes, incresasing LDL cholesterol uptake
-They may also modestly increase HDL
Give comparison in the use of short vs long acting statins in the treatment of dyslipidaemia
-Short-acting statins are often prescribed for patients with relatively low cholesterol levels or when cost is a significant concern, as generics for short-acting statins are more widely available.
-Long-acting statins are generally prescribed for patients who need a more consistent effect throughout the day or have more complicated lipid profiles, including very high cholesterol levels.
Why give different length of action statins?
-Cholesterol is primarily synthesized at night, so short-acting statins work best when taken before bed. In contrast, long-acting statins provide continuous inhibition of cholesterol synthesis, making them suitable for 24-hour control.
-Long-acting statins are typically easier to adhere to, as they don’t require precise timing, which is useful for patients with busy or unpredictable schedules.
-Long-acting statins are often more effective in patients with higher cholesterol levels, as they maintain steady drug concentrations, providing consistent cholesterol-lowering effects.
-Some patients may experience fewer side effects with one type over the other, depending on how their body metabolizes the drug.
Give examples of short acting and longer acting statins
Short acting: Simvastatin, lovastatin
Long acting: Atrovastatin
When are the statins used clinically?
Treatment of
-Primary hyperlipidaemia
-Secondary hypercholesterolemia (eg in Diabetes mellitus)
-Secondary prevention of MI and stroke
Give the adverse effects associated with statins
-Muscle related: Myalgia, myopathy and rhabdomyolysis
-Elevated liver enzymes
-Increased risk of diabetes
-GI disturbance
What have studies shown about the efficacy of statins
Scandinavian Simvastatin Survival Study showed that death reduced by 30%, and death by CHD reduced by 42%
Describe the mechanism of action of Fibrates
Peroxisome proliferator activated receptor alpha agonist, which has the effect of:
-Increased lipoprotein Lipase activity (breaking down tryglycerides)
-Increases HDL cholesterol by increasing ApoA1 synthesis
-Stimulates fatty acid oxidation in the liver
-Increases hepatic LDL uptake
When are fibrates used clinically?
-Hypertriglyceridaemia
-Low HDL cholesterol
-Mixed dyslipidaemia
Describe the adverse effects associated with fibrates
-Myopathy and rhabdomyolysis
-Liver enzyme abnormalities
-Gallstone formation
-GI disturbance
-Rash
Describe the pharmacokinetics of fibres
-Well-absorbed from the gastrointestinal tract
-High degree of binding to albumin
-Metabolised by the cytochrome P450 (CYP3A4)
potential drug interactions
-Primarily excreted via the kidneys
Describe the pharmacokinetics of statins
-Typically orally bioavailable
-However often at risk of first pass metabolism via CYP3A4 and glucuronidation
-Many are prodrugs that must be metabolised
-Drug interactions can occur with CYP3A4 pathway drugs
Give examples of fibrates
-Gemfibrozil
-Fenofibrate
-Bezafibrate
-Cipofibrate
Describe the mechanism of action of Ezetimibe cholesterol absorption inhibitors
-Inhibits the Niemann-Pick C1-Like 1 (NPC1L1) protein
-Preventing the absorption of dietary cholesterol and biliary cholesterol secretion, reducing the amount of cholesterol entering circulation
-This increases LDL clearance by compensation
Describe the pharmacokinetics of Etezimibe cholesterol absorption inhibitors
-Administered orally
-Absorbed into intestinal epithelial cells (site of action)
-Extensively metabolized (>80%) into active metabolite
-Enterohepatic recycling slows elimination
t1/2 ~ 22 hours
When are Ezetimibe cholesterol absorption inhibitors used clinically?
-Primary hyperlipidaemia
-Combination therapy with statins
Give the adverse effects associated with Ezetimibe cholesterol absorption inhibitors
-GI disturbance
-Headache
-Myopathy and muscle pain
-Liver enzyme abnormalities
-Rash
-May be secreted in breast milk
Describe the mechanism of action of colestipol and cholestyramine cholesterol absorption inhibitors
Binds bile acid (BA) in gut, prevents reabsorption, diverting hepatic cholesterol to BA synthesis, upregulates LDL receptors increasing LDL removal from the blood
When may colestipol and cholestyramine cholesterol absorption inhibitors be used clinically?
-Primary hypercholesterolemia when statin is contraindicated
-Pruritus associated with biliary obstruction
-Bile acid diarrhoea
Describe the adverse effects associated with colestipol and cholestyramine cholesterol absorption inhibitors
-GI disturbance
-Decreased absorption of fat soluble vitamins eg A, D, E and K
-Interference with absorption of digitalis, thiazides, warfarin, iron
Give examples of cholesterol absorption inhibitors
-Ezetimibe
-Colestipol
-Cholestyramine
Describe the mechanism of action of nicotinic acid/vitamin B3
-Reduces VLDL synthesis and LDL in the liver
-Reduces hormone sensitive lipase activity and triglycerides in adipose tissue
-Increases the levels of HDL by inhibiting CETP enzyme
When may nicotinic acid/vitamin B3 be used clinically?
-Hyperlipidaemia
-Mixed dyslipidaemia
-Nicotinic acid deficiency
Describe the adverse effects associated with nicotinic acid/vitamin B3
-Cutaneous flushing (common)
-Associated with pruritus & palpitation
-Reduced with pre-treatment of aspirin or other NSAIDs
-Dose-dependent nausea and abdominal discomfort
-Moderate elevation of liver enzymes to severe hepatotoxicity
-Hyperuricemia in 20% of the patient
Give new and investigational drugs in the treatment of dyslipidaemia
-Bempedoic acid
-PCSK9 inhibitors
Describe the mechanism of action of Bempedoic acid
-Inhibits the ATP citrate lyase enzyme in the liver (which is involved in the synthesis of cholesterol)
-LDL receptors increase, increasing LDL clearance
When may Bempedoic acid be used clinically?
-Heterozygous familial hypercholesterolaemia
-Established atherosclerotic CV disease
-In patients unable to tolerate statins
Give some side effects associated with Bempedoic acid
-Muscle pain
-Gout
-Hyperuricaemia
-Myalgia
Describe the mechanism of action of PCSK9 inhibitors
-Monoclonal antibodies that target PCSK9, a protein that regulates LDL receptor function
-By inactivating this, they prevent the destruction of LDL receptors, allowing more of these receptors to remain active on the liver cell surface
-MUST BE ADMINISTERED SUBCUTANEOUSLY
