Module Six: Lipid Lowering Drugs Flashcards
What are the two types of stroke?
Ischemic Stroke: blockage of blood vessel
Haemorrhagic Stroke: rupturing of blood vessels leading to bleeding and leakage into brain
Causes of heart failure?
- Myocardial Infarction
- High Blood Pressure
- Damaged Heart Valve
- Cardiomyopathy
Modifiable Risk Factors for CVD
- Smoking
- Obesity
- Poor dietary intake
- High Alcohol consumption
- Lack of excercise
- T2D
- Inflammation
- Hypertension
- Dislipidemia
Non-Modifiable Risk Factors for CVD
Personal history of CVD, family history, race, ethnicity, age, gender
BMI measurements
Healthy: 20-24.99
Overweight: 25-29.9
Obese: >30
Waist circumference
Caucasian
Men: >104cm
Women: >88cm
Newer indirect measurements of obesity
Body fat % Skin fold Hydrostatic/underwater weight measuring Bio electrical impedance analysis Dual energy X Ray absopbtiometry
Newer direct methods of measuring obesity
Ultrasound
Computed tomography
MRI/ MRS
Diagnosis for Diabetes
Oral Glucose Tolerance Test Impaired fasting glucose if: Fasting glucose: 6.1-7 mM Blood glucose after 2 hrs is less than 7.8mM Impaired glucose tolerance if: Blood glucose after 2hrs is 7.8-11mM Diabetic if: glucose >11.1 mM
HbA1C: marker for average glucose conc over previous months
A1c >6.5%; >48mM
Recommended lipid levels
Total: <5.5mM
HDL: men: >1.04; women:1.30mM
LDL: <2mM
Triglyceride: <1.7mM
Lipoprotein lipid components
Cholesterol
Triglycerides
Phospholipids
Lipoprotein protein component
Structural: ApoB-100: major structural protein for LDL; ApoA-I: major structural protein for HDL
Enzyme modulator: ApoC-II: co activator of lipoprotein lipase activity
Receptor Ligands: ApoE and ApoB binds to LDL receptor
Patterns of Dislipidemia
Increased total and LDL cholesterol
Increased triglycerides (increased triglycerides and LDL)
Increased triglycerides, decreased HDL cholesterol
What enzyme converts cholesterol into cholate?
Cholesterol 7alpha-hydroxylase
What are the three pathways of lipid metabolism?
Exogenous
Endogenous
Reverse cholesterol transport pathway
Cholesterol uptake into the enter ochre across the luminal membrane occurs via what transporter?
Niemann Pick C1 like protein
What are mixed micelles?
Structures that carry cholesterol and triglycerides to the intestinal brush border for absorption
What enzyme converts 2 fatty acids and monoglyceride back into triglyceride within the enterocyte?
Acyl Co-enzyme A-diglycerol acyltransferase
What packages TG and cholesterol esters to form nascent chylomicrons with ApoB-48
Microsomal transfer protein
VDVL formation
Packaged in the endoplasmic reticulum of the hepatocytes
DG converted to TG via DGAT
Acetyl co A to free cholesterol via HMG-CoA reductase
Free cholesterol to cholesteryl ester via ACAT
Where are cholesteryl ester and TG packaged?
ApoB100 via microsomal transfer protein
Sequence of LDL formation
VLDL to FFA by lipoprotein lipase forms IDL
IDL to FFA by hepatic lipase to LDL
LDL taken up by liver receptors facilitated by apoB100 and ApoE
What secretes lipid-free ApoA-I and what does ApoA-I do?
Liver and intestine; recruits cholesterol from macrophages via ABCA1
What enzyme converts nascent HDL into mature HDL
Lecithin cholesterol acetyltransferase
What is a tracee?
Endogenous molecule
Protein - AA e.g. Leucine
Lipid moiety - glycerol
Tracer?
Same as tracee but labelled
Stable isotope
What kinetic parameters do tracer methods identify
Production rate
Fractional catabolic rate
What n3 polyunsaturated fatty acids are in fish and fish oil?
Eicoapentaenoic acid
Docosahexaenoic acid
Factors to consider with dietary interventions
Individual nutrition needs Maintenance of pleasure eating Personal preferences Practicality Cultural preferences Lifestyle match Willingness to change Affordability Adherence
Examples of Fungus derived statins
Lovastatin
Pravastatin
Simvastatin
Examples of synthetic statins
Fluvastatin
Atorvastatin
Rosuvastatin
Effects of statins
LDL cholesterol lowering
HDL raising
Plasma TG lowering
Other effects of statins
Antioxidant, anti thrombotic, anticoagulation, improve endothelial function, cytoprotection, anti inflammatory
Adverse effects of statins
Muscle damage and pain Rhabdomyolosis Renal failure Liver damage GI problems Rash and flushing Increased risk of T2D Neurological side effects
What is the structure of NPC1L1
13 Tm domain
Penta-domain
Sterol sensing domain
Mechanism of action of Ezetimbe
Inhibition of the NPC1L1 transporter - prevents cholesterol absorption at brush border membrane
Undergoes glucuronidation in the intestinal wall
What are the three subtypes of PPAR agonists?
Greek: a, y sigma/b
Mechanism and affects of PPAR agonists
Once activates: forms heterodimer with retinoid X receptor; the complex binds to specific nucleotide sequence response element in promoter region of target gene => activation or repression of gene transcription
Lipid metabolism, immune/ inflammation response, proliferation, differentiation
PPAR alpha agonist examples and targets
Liver, kidney, heart, muscle and macrophages
E.g. Fibrates: fenofibrate, gemfibrozil, bezafibrate
Effect of PPAR alpha agonists
Lowering plasma TG concentrations lipoprotein lipase up regulation Down regulation of apoC-III Increases ApoA-III Up regulation of APOA-I
