Lecture 10 Atherlsclerosis and Heart Disease

Question 1

What is the primary prevention of cardiovascular disease?

Answer 1

Statins (20mg atorvastatin) - for patients with 10% or greater 10-year risk of developing cardiovascular disease
85yo or older also 20mg atorvastatin to reduce the risk of non-fatal MI

Question 2

What are the different pathways of lipid lowering drug classes?

Answer 2

Statins - decrease synthesis of cholesterol, increase uptake of LDL
Fibrates - Increase LDL uptake, decrease VLDL secretion and enhance free fatty acid
Ezetimibe - reduction in cholesterol absorption
Resins - increase LDL uptake and bind bile acids to increase fecal elimination

Question 3

What is primary dislipidemia?

Answer 3

Combination of dietary and genetic factors
Familial hypercholesterolaemia high risk of coronary heart disease

Question 4

What is secondary dislipidaemia?

Answer 4

Consequence of other conditions
Diabetes mellitus, alcoholism and renal disease

Question 5

What are the treatment pathways of dyslipidaemia?

Answer 5

Non-pharmacological:
Cardioprotective diet
Weight loss
Physical activity
Reduced alcohol consumption
Smoking cessation
Pharmacological:
Anti-hyperlipidaemic drugs

Question 6

Name the classes of lipid lowering drugs

Answer 6

HMG-CoA reductase inhibitors (statins)
Fibrates
Cholersterol absorption inhibitors (Ezetimibe, resins)
Omega fatty acids
Nicotinic acid

Question 7

Name the different statins

Answer 7

Simvastatin(prodrug), Lovastatin(prodrug), Fluvastatin, Pravastatin (short acting)
Atorvastatin, Rosuvastatin (long acting)

Question 8

What are the pharmacokinetics of statins?

Answer 8

Well absorbed orally
Liver extraction (site of action)
Short acting - more effective in evening, reduction in C peak in morning
Prodrugs (Simvastatin and Lovastatin)
Extensive 1st pass (CYP3A4 & glucuronidation) - NOT ROSUVASTATIN
DDI with CYP3A4

Question 9

What are statins also known as?

Answer 9

HMG CoA reductase inhibitors

Question 10

What is the mechanism of statins?

Answer 10

Block HMG CoA reductase enzyme
Rate limiting step in C synthesis
Block conversion HMG CoA to mevalonic acid
Blocks cholesterol synthesis (LDL receptor synthesis)
Increased clearance of LDL

Question 11

What is the clinical use of statins?

Answer 11

Primary hyperlipidaemia (reduce LDL and inc. HDL)
Secondary hypercholersterolaemia
Diabetes mellitus
Secondary prevention of MI and stroke

Question 12

What are the adverse effects of statins?

Answer 12

Muscle pain, GI disturbance, insomnia, rash and headache
Rarely mysotitis and angio-oedema (muscle pain)

Question 13

What are the benefits of statin use in hyperdyslipidaemia?

Answer 13

Serum LDL reduced by 35%
Death reduced by 30%
Death by CHD reduced by 42%

Question 14

What are the non-pharmacological effects of statins?

Answer 14

Improved endothelial function
Improved vascularisation of ischaemic tissue
Atherosclerotic plaque stabilises
Reduction vascular inflammatory response
Reduced platelet activation
Enhanced fibrinolysis
Antithrombotic

Question 15

Name examples of fibrates

Answer 15

Gemfibrozil, fenofibrate and benafibrate

Question 16

What is the mechanism of fibrates?

Answer 16

Agonist at peroxisome proliferator-activated receptor (PPAR-α) nuclear receptor (lipid metabolism)
Increased synthesis of lipoprotein lipase (adipose)
Fatty acid oxidation in liver
Increased expression apo-A-I and apoA5
Increased hepatic LDL uptake

Question 17

What is the clinical use of fibrates?

Answer 17

Hypertriglycridemia
Mixed hyperlipidaemia
TG levels reduce 20-30%
Cholesterol reduced by 20-30%
Raised HDL

Question 18

What are the pharmacokinetics of fibrates?

Answer 18

Well-absorbed from the GI
High degree binding to albumin
Metabolised by CYP3A4 (potential DDIs)
Primarily excreted via kidneys

Question 19

What are the adverse effects of fibrates?

Answer 19

Rash, GI disturbance
Rhabdomyolysis cause renal failure (break down muscle)
Clofibrate - gall stones

Question 20

Name the cholesterol absorption inhibitor

Answer 20

Ezetimibe

Question 21

What is the mechanism of the cholesterol absorption inhibitor?

Answer 21

Inhibition of the intestinal absorption of cholesterol by interfering with Neimann-pick C1-like 1 transport protein
Decrease LDL and VLDL

Question 22

What are the pharmacokinetics of the cholesterol absorption inhibitor?

Answer 22

Administered orally
Absorbed into intestinal epithelial cells
Extensively metabolised into active metabolite
Enterohepatic recycling
t1/2 ~22 hours

Question 23

Name the cholesterol absorption inhibitor resins

Answer 23

Colestipol and cholestyramine

Question 24

What is the mechanism of the cholesterol absorption inhibitor resins?

Answer 24

Bind bile acid in gut, stop reabsorption
Hepatic cholesterol to bile acid synthesis so more LDL receptors
Increased LDL removal from blood

Question 25

What are the pharmacokinetics of the cholesterol absorption inhibitor resins?

Answer 25

Abministered by mouth and stays in GI

Question 26

What is the clinical use of the cholesterol absorption inhibitor resins?

Answer 26

Primary hypercholesterolemia when statin contraindicated Pruritus associated with biliary obstruction (itchy skin of urethra) Bile acid diarrhoea

Question 27

What are the adverse effects of the cholesterol absorption inhibitor resins?

Answer 27

Constipation, bloating Malabsorption of vitamin K, folic acid and ascorbic acid Disrupts absorption of digitalis, thiazides, warfarin and iron

Question 28

What is the mechanism of nicotinic acid?

Answer 28

Liver - ↓VLDL synthesis and reduce LDL Adipose - ↓hormone-sensitive lipase activity and reduced triglycerides Reduced catabolic rate for HDL - increase HDL Increased clearance of VLDL by activating lipoprotein lipase

Question 29

What are the pharmacokinetics of nicotinic acid?

Answer 29

Readily absorbed in GIT following oral administration Metabolised in liver Excreted via kidneys

Question 30

What is the clinical use of nicotinic acid?

Answer 30

Hypercholesterolemia Hypertriglyceridemia - low levels HDL

Question 31

What are the adverse effects of nicotinic acid?

Answer 31

Cutaneous flushing Associated with pruritus and palpitation Reduced pre-treatment aspirin/NSAIDs Dose-dependent nausea and abdominal discomfort Moderate elevation of liver enzymes - severe hepatotoxicity Hyperuricemia 20% patients

Question 32

What are the new dyslipidaemia drugs in development?

Answer 32

Bempedoic acid PCSK9 inhibitors

Question 33

What is bempedoic acid?

Answer 33

Inhibitor of adenosine triphosphate citrate lyase Clinical - heterozygous famililal hypercholesterolemia and atherosclerotic CVD lowering LDL-C Adverse - hyperuricemia, gout, myalgia and arthralgia

Question 34

What are PCSK9 inhibitors?

Answer 34

Proprotein converts subtilising/kexin type 9 is associated with LDL and worse CVD Antibodies to PCSK9 used with inadequately controlled levels of LDL-C Administered subcutaneously Clinical use: familial hypercholersterolemia

Question 35

What is apoA1?

Answer 35

HDL

Question 36

What is apoB?

Answer 36

LDL, IDL and VLDL