CAM201 Pharmacological Management of Dyslipidaemia Flashcards
Describe the main effect (not cellular mechanism) of Statin drugs, and their primary indications.
Statins are LDL-lowering drugs. They do this by inhibiting endogenous (hepatic) LDL production.
They are indicated for primary prevention of arterial (atherosclerotic) disease in patients with hypercholesterolemia
They are indicated for secondary prevention of stroke and AMI in patients with atherosclerotic disease
Describe the cellular mechanism of Statin drugs and how this affects plasma LDL levels
Statin drugs decrease circulating LDL-C by inhibiting endogenous (hepatic) production of LDL.
They do this by inhibiting the rate-controlling enzyme, HMG-CoA Reductase.
By inhibiting HMG-CoA Reductase, statin drugs prevent the conversion of HGM-CoA into Mevalonate.
In doing this, they obviously prevent the conversion of Mevalonate into cholesterol (which is the normal pathway for cholesterol synthesis in the liver).
By decreasing endogenous LDL synthesis, statins cause an increase in uptake of LDL from the blood: there is increased LDL receptor synthesis and, subsequently, increased clearance of LDL. This means more LDL is taken up from the blood, decreasing plasma LDL concentrations.
Statins also cause small decreases in TG levels and increase HDL
Statins are the first-line pharmacological treatment option in hypercholesterolaemia (even in high TG cases). Can be used in combination with Fibrates, and Fibrates + Nicotinic Acid, in stubborn hypercholesterolaemia.
Most concerning adverse effect of statins
Rhabdomyolysis
Describe the Cellular Mechanisms of Gemfibrozil
Gemfibrozil is a Fibrate - TG-lowering drug.
Gemfibrozil lowers circulating TG levels by antagonising the transcription factor PPAR, which is present in the nuclei of macrophages and brown adipose tissue. Generally, PPAR increases lipid metabolism.
By inhibiting the actions of PPAR, lipid metabolism decreases, leading to increased uptake of VLDL and Chylomicrons from the blood into the liver. This, by extension, reduces endogenous TG production (because there is not a need for more due to suppressed lipid metabolism).
Additionally, Gemfibrozil also causes increased excretion of cholesterol from the liver in the faeces.
In stubborn Hypercholesterolaemia, Gemfibrozil is often used in combination with a statin. In very stubborn hypercholesterolaemia, a Nicotinic acid may also be added to the mix.
Gemfibrozil is the next option for treatment of hypercholesterolaemia in patients that do not tolerate statins.
Gemfibrozil can also be used in combination with Nicotinic acid, in this case, if Gemfibrozil alone is not enough.
Treatment of Hypercholesterolaemia
First line approach is through lifestyle adjustments: dietary adjustments are pivotal, as well as increasing physical activity, and decreasing other co-morbidity risk factors such as smoking, alcohol consumption, Na+ intake, etc.
The role of lifestyle adjustments and the time given to make these adjustments depends on the risk profile of the patient at hand, although even throughout treatment, lifestyle modification is important.
First-line pharmacological treatment: Statins
If persistent, statins + fibrates (Gemfibrozil) can be used - smaller doses of the two combined is preferential to using very high doses of one.
Additionally, in very stubborn hypercholesterolaemia, Nicotinic Acid can be used in combination with Fibrates + Statins.
If fibrates and statins are not tolerated, the next choice is Nicotinic Acid (a TG-lowering drug)
Describe the cellular mechanisms of Nicotinic Acid
Nicotinic Acid is a TG-lowing drug
It is a vitamin that decreases production of TG
It also inhibits VLDL secretion, increases HDL and decreases levels of Lipoprotein(a) (which is highly atherosclerotic - an independent CVD risk factor)
Nicotinic Acid is used in patients who do not tolerate Statins or Fibrates (which are generally preferred treatments)
Nicotinic acid may also be used in combination with Statins and Fibrates in stubborn hypercholesterolaemia.
