Agents Used In Dyslipidaemias Flashcards
What are some risk factors of CHD?
Smoking
HTN
Obesity
DM
What are primary dyslipidemias?
Hereditary diseases affecting the lipoprotein metabolism
What are the secondary dyslipidemias?
DM Nephrotic syndrome Kidney failure Hypothyroidism Anorexia nervous a Alcoholism Liver disease Medication
What are the drug tarts of lipoprotein metabolism in the order of atherogenicity?
LDL
VLDL
Chylomicrons
HDL
What is another word for HMG-CoA reductase inhibitors?
Statins
Name the HMG-CoA reductase inhibitors
Lovastatin Simvastatin Pravastatin Atorvastatin Fluvastatin Rosuvastatin Mevastatin
What is the mechanism of action of statins?
They competitively inhibit HMG-CoA reductase
What is the result of using HMG-CoA reductase inhibitors?
Depletion of intracellular cholesterol supply from the liver Increased LDL receptor expression Decreased plasma LDL Slight decreased VLDL Slight increased HDL
What are some other benefits of using statins?
Stabilisation of atherosclerotic plaques Decreased vascular inflammation Improvement of endothelial function Increased fibrinolysis Anti thrombotic effect
What are the clinical indications of statins?
Secondary prevention of MI or stroke
Primary prevention of arterial disorders (HTN, PVD)
Familial hypercholesterolemia (Type IIa)
Severe dyslipidemias
Which statin is used to treat familial hypercholesterolemia (Type IIa)?
Atorvastatin
How are statins administered?
Orally
Which enzyme metabolises statins?
CYP3A4
Which enzyme metabolises fluvastatin?
CYP2C9
Which enzyme metabolises rosuvastatin?
CYP2C9
Which statins are metabolised by CYP2C9?
Fluvastatin
Rosuvastatin
Which statin is independent of CYP?
Pravastatin
When is Pravastatin recommended?
Why?
In the case of drug interactions
Because it is independent of CYP
What is the half life of statins?
Short half life except for atorvastatin and rosuvastatin
Which statins have a half life of 14-18h?
Atorvastatin
Rosuvastatin
What are the drug interactions of statins?
Drugs which are CYP inhibitors also inhibit the metabolism of statins
What is a side effect of Gemfibroxil?
It increases rhabdomyolysis
It will decrease the clearance of statins
What are the adverse effects of statins?
Increased plasma liver enzymes Increased creatine kinase GI symptoms Skin rashes Neurological effects (dizziness and insomnia)
When are statins contraindicated?
Pregnancy
What is the result/cause of increased CK?
Myalgia
Myosotis
Myopathy
Rhabdomyolysis
When using statins, when is there a high risk for rhabdomyolysis?
In elderly In kidney and or hepatic problems In hypothyroidism In trauma or severe physical activity In drug interactions (fibrates, macrolides)
What sort of drugs are bile acid binding resins?
Polymers
Name the bile acid binding resins
Cholestyramine
Coolest iPod
Colesevelam
What are the adverse effects of Bile acid binding resins?
GI symptoms
Steatorrhea
Decreased appetite
Decreased absorption of lipophilic vitamins (ADEK)
How are bile acid binding resins administered?
Orally
How are bile acid binding resins absorbed?
They are not absorbed or altered in the intestines
What are bile acid binding resins combined with?
Why?
Statins
To avoid the liver producing more cholesterol
What is the clinical indication of bile acid binding resins?
Type IIA and IIB dyslipidemias
What is the clinical indication for Cholestyramine?
Decreases pruritus from patients with accumulation of bile salts
what is the clinical indication of Colesevelam?
DM2 due to its glucose lowering effects
What is the mechanism of action of bile acid binding resins?
They bind bile acids and bile salts in the small intestine - this complex is then excreted in the feces, decreasing the bile acid concentration
Hepatocytes produce more bile acids from cholesterol decreasing IC cholesterol concentration and increasing the hepatic uptake of cholesterol-containing LDL
LDL decreases
VLDL and TG moderate increase
What is the mechanism of action of Colesevelam?
Inhibits the absorption of the bile acids
Name the cholesterol absorption inhibitor?
Ezetimibe
What is the mechanism of action of Ezetimibe?
Inhibits the absorption of cholesterol and phystosterols
What is the clinical indication of Ezetimibe?
Adjunct to statins (synergy)
Decreases LDL
Hypercholesterolemia and phytosterolemia
How is Ezetimibe admistered?
Orally
Is Ezetimibe absorbed or not absorbed?
Absorbed
How is Ezetimibe metabolised?
It is metabolised in the liver and small intestines via glucuronidation (not by CYP enzymes)
What are the side effects of Ezetimibe?
GI distress
Hepatotoxicity if given with Statins
Name the fibrates
Gemfibrozil
Fenofibrate
Bezafibrate
Ciprofibrate
What is the clinical indication of fibrates?
Hypertriglyceridemia
How are fibrates administered?
Orally
Are fibrates absorbed or not?
Completely absorbed
When do you take fibrates?
Why?
Only taken during a meal for its absorption
What are fibrates drug interactions?
Statins
Anticoagulants (competition with coumarin for plasma proteins)
When are fibrates counterindicated?
Pregnancy
Alcoholism
What are the adverse effects of fibrates?
GI symptoms Cutaneous symptoms Increased liver enzymes Myositis Rhabdomyolysis CNS symptoms such as insomnia and dizziness
What does PPAR-alpha stand for?
Peroxisome proliferator activated receptors alpha
What are PPAR alphas?
They control gene expression and regulate the lipid metabolism
What are the ligand for PPAR alpha ?
FA
Eicosanoids
(Fibrates)
What is the mechanism of action of fibrates?
They bind to and activate PPAR alpha receptors
What is the result of Fibrate binding to PPAR alpha?
- Increased LPL activity - VLDL secretion is inhibited - decreased VLDL
- Increased LDL receptor leading to slight decrease in LDL
- Slight increase in HDL
- Decreased lipolysis in fat tissue leading to decreased TG
What are some other effects of fibrates?
Decreased fibrinogen
Decreased insulin resistance
Decreased inflammation in the endothelium
How is Niacin administered?
Orally
What are the contraindications of Niacin?
Ulcer Diabetes Metabolic syndrome Gout Pregnancy Childhood
What are the adverse effects of Niacin?
Flushing, itching, rash GI disturbances Hepatotoxicity Increased insulin resistance Decreased Uric acid elimination
How do we prevent the Niacin induced cutaneous flushing, rash etc..?
NSAIDs
The use of NSAIDs for prophylactic treatment for the Niacin induced rash suggests what?
That the rash and flushing are PGD2 mediated
What is the clinical indication of Niacin?
Hypercholesterolemia
Hypertriglyceridemia
Low HDL
What are the effects of combining Niacin with Laropiprant?
This combination inhibits the PGD2 receptors and thus decreases unwanted side effects
What is the mechanism of action of Niacin on adipocytes?
Niacin inhibits TG synthesis through inhibition of FA formation, decreasing TG
Decreased fat release
Decreased VLDL release from the liver
Decreased LDL
What is the effect of Niacin on macrophages?
Stimulation of COX-2 leading to an increase in PGE2 and PGD2. This increase leads to unwanted effects such as cutaneous vasodilation, burning sensation of face and upper body.
What is the effect of Niacin on LPL?
- Niacin activates LPL resulting in increased liver degradation of intracellular Apo-B. Decreased VLDL and LDL
- Inhibits Apo-AI degradation leading to increased HDL half life
Name the CETP inhibitors
Darcetrapib
Torcetrapib
What is the mechanism of action of Darcetrapib and Torcetrapib?
CETP inhibitors
What is the effect of CETP inhibitors?
They inhibit the cholesterol ester transfer protein leading to decreased cholesterol transport from HDL to LDL
Name the MTP inhibitors
Lomitapide
What is the mechanism of action of Lomitapide?
Lomitapide inhibits MTP leading to decreased Apo-B level. As a result, VLDL, IDL and LDL decrease
What does MTP stand for?
Microsomal triglyceride transfer protein
What is the action of Mipomersen?
Inhibitor of Apo-B translation
Name the PCSK9 inhibitors
Alirocumab
Evolocumab
What is the mechanism of action of Alirocumab and Evolocumab?
They are PCSK9 inhibitors
What is the mechanism of action of Omega-3 fatty acids?
They work partly via the PPAR system
Increase LPL activity in the endothelium and decrease lipogenesis in the liver
Inhibition of fat synthesis
Promote beta oxidation of fatty acids