Week 6: Drugs to Lower Cholesterol

coronary heart disease occurs when _, and is primarily caused by_

cornary blood fails to supply heart with blood

atherosclerosis

coronary heart disease is directly correlated with

level of cholesterol in the blood

CVD accounts for_ of all deaths in Canada

1/3

3 physiological roles of cholesterol

component of cell membranes

precursor to steroid hormones

precursor to bile salts

ratio of endogenous to exogenous cholesterol

80% endogenous synthesized by liver

20% dietary

explain the structure of lipoproteins

outer hydrophilic shell: phospholipid, lipoproteins

core: hydrophobic, cholesterol and trigylcerides

role of opolioproteins

recognition by cells to bind and take up lipoproteins

activate enzynes for metabolism

increase structural stability

function of lipoprotein A-1

transport cholesterol from non hepatic tissues back to the liver

function of apolipoprotein b-100

transports cholesterol to non hepatic tissues

How are lipoproteins classified

based on density, protein has higher density than fat

3 classes of lipoproteins

very low density (VLDL)

low density (LDL)

high density (HDL)

structure and function of very low density lipoproteins

delivers triglyceride from liver to adipose tissue and muscle

has a triglyceride rich core that accounts for almost all triglyceride in blood

structure and function of low density lipoprotein

delivers cholsterol to non hepatic tissues

cholesterol rich core, 60-70% of cholesterol in core

there is a clear link between _ density lipoprotein and atherosclerosis

low

high density lipoprotein structure and function

deliver cholsterol from non hepatic tissue back to liver, removal from blood

cholesterol as main core lipid, 20-30% of all blood cholesterol

which density of lipoprotein is considered good

high density

explain the pathophysiology progression of atherosclerosis

damage to endothelial

fatty streak

fibrous plaque

complications

explain the role of cholesterol in the progression of atherosclerosis

the molecules oxidize, which initiates the immune response

damage to endothelial cells

this is the initiation of atherosclerosis

initiated by smoking, hypertension, immune reactions, elevated blood lipids

explain how a fatty streak forms

LDL accumulates in sub endothelial cells, are oxidized and recruit macrophages

macrophages ingest oxidized LDL, cholesterol forms foam cells, which make a fatty streak as they accumulate

explain how a fibrous cap forms

accumulation of foam cells causes endothelium to rupture: collagen, smooth muscle cells and platelets form a fibrous cap

possible complications of fibrous cap

if the fibrous cap is not strong it can rupture, a thrombus will form and block blood flow

Cholesterol screening guidelines (age and sex)

all males over the age of 40 and all females over 50 or post menopause

6 times when you are cholesterol screened regardless of age

diabetes

heart disease or family

history

hypertension

waist circumferebce us over 82 or 102

smoker or recently quit

inflammatory or renal disease

components on the framingham risk score (6)

gender

age

total blood cholesterol

smoking status

HDL cholesterol

systolic BP

a framingham risk score represents a _ year risk of developing coronary heart disease

10

High framingham score

>20%, diabetes or heart disease

with a high risk score _ patients are treated

all

target treatment in high risk scores

LDL < 2mmol or > 50% decrease in LDL

moderate risk framingham score

10-19%

when do you initiate treatment in someone with a moderate risk framingham score (3)

LDL cholesterol is over 3.5 mmol

ratio of HDL is > 5.0

significant inflammation

LDL target

LDL < 2mmol or > 50% decrease in LDL

Low framingham risk score

< 10%

when is treatment initiated in someone with a low framingham risk score

if LDL is > 5 mmol, should initaiate even if low risk

target goal for low framingham risk treatment

equal to or greater 50% decrease in LDL

metabolic syndrome diagnostic criteria

at least 3 of...

1. Waist circumference > 102 or 88cm

2. Blood triglyceride > 1.7 mmol/L

3. Low HDL cholesterol: <1.03 mmol in men, 1.29 women

4. hyperglycemia: > 5.6 mmol/L

5. Hypertension >135/85

approximately _% of canadians have metaboltic syndrome

25%

general dietary recommendations

no eggs or fried foods

lots of fibre

daily intake of cholesterol should be less than

200mg/day

intake of saturated fats should be less than

7% of total calories

soluable fibre intake should be

10-25g/day

plant sterol and stenols daily intake

2mg/day

exercise targets

reduces LDL, increases HDL and decreases BP and insulin resistance

30-60 minutes a day

smoking will _ HDL and _ LDL

decrease

increase

leading preventable cause of death and disease

first line of treatment

dietary

exercise

smoking

difficult to adhere and often targets are not met

2nd line of treatment

when targets are not met through lifestyle changes

classes of drugs in 2nd line of treatment

statins

nicotinic acid

bile acid sequestrants

cholesterol absorption inhibitors

fibrates

cholesterol synthesis pathway

acetyl-Co A

MMG Co-A

Mevalonic acid

Cholesterol

what step in the cholesterol pathway is commonly targeted

the converstion of MMG Co-A into Mevalonic acid is the rate limiting step that is targeted

when is cholesterol synthesized and what does this imply for timing of dosing

at night

taking dosage in the evening

Statins MoA

inhibit HMG-CoA reductase, which blocks conversion into melavonic acid and causes uptake of hepatic LDL receptors

Liver removes more LDL from blood, and there is a decrease in hepatocyte synthesis

cholesterol is metabolized to be used for __ by hepatocytes

bile salts

statins work to _LDL, _ HDL and _ triglycerides

decrease

increase

decrease

primary prevention via statins

prevent development of CVD, decrease incidence of coronary events such as MI or stroke

secondary prevention via statins

prevent reoccurance of CV events (if they have already happened)

what is the #1 prescribed drug in canada

Atorvastatin

atrovastatin oral bioavailability

14%

atrovastatin distribution

primarily in liver but also in spleen, adrenal glands and skeletal cels

atrovastatin metabolism

CYP3A4

atrovastatin excretion

excreted in feces, minimal renal excretion

Rosuvastatin bioavailabilty

20%

Rosuvastatin distribution

primarily in liver but also skeletal

Rosuvastatin metabolism

CYP2C9 but not extensively metabolized

Rosuvastatin excretion

primarily in feces, minimal in renal

which populations do you need to have caution with using Rosuvastatin and why

Asian populations

plasma conc is 2X, so initial dose should be 5mg and caution before increasing

Adverse effects of statins

most common myopathy

hepatotoxicity

rhabdomyolysis

rhabdomyolysis

muscle cells undergo lysis and rupture, SEVERE MUSCLE PAIN

what lab tests must you preform while taking statins

liver function: AST and ALT before initiating and periodically after/during

Pregnancy and statins

should avoid taking if pregnant or trying to become

cholesterol is used for the synthesis of cell membranes and hormones, can be potentially teratogenic

Nicotinic acid MoA

inhibits hepatic secretion secretion and synthesis of VLDL, which increases HDL

Nicotinic acid side effects

intense facial flushing

hepatotoxicity

hypergylcemia

skin rash

increased uric acid levels

used way less commonly due to side effects

Bile acids are __ charged, and produced in the liver from___ metabolism

negatively

CYP7A1 mediated cholesterol

bile salts are secreted___ and function to ____

into the intestine

aid in absorption of dietary fats and fat soluble vitamins

over _% of bile salts are naturally reabsorbed via enterohepatic recycling

95

MoA of Bile Sequestrants

bile sequestarnts are positively charged molecules, that attract and bind bile acids, causing an increased demand for bile synthesis in the liver

this increased demand causes an increase in LDL uptake receptors on hepatocytes, which decreases blood LDL levels

adverse effects of bile sequesterants

not absorbed, do not have systemic effects.. limited to gi: constipation and bloating

drug-drug interactions with bile sequesterants

designed to bind to negatively charged molecules.. so will bind with: thiazide, diuretics, warfarin and certain drugs

protein NPC1L1

the protein for intestinal uptake of dietary cholesterol

cholesterol absorption inhibitor

works to inhibit protein NPC1L1

Eztetimibe

cholesterol protein inhibitor

Ezetimibe will decrease intestinal absorption by _% and decreases LDL cholesterol by _

54%

15-20%

Cholesterol absorption inhibitors can often produce a compensatory _

increase in hepatic synthesis of cholesterol

cholesterol absorption inhibitor is often prescribed as..

an adjuvant therapy to statins

vytorin

combination pill of ezetimibe and a statin which will decrease LDL in blood by 60%

fibrates are the most effective class for

lowering plasma triglyceride levels

fibrate effect on HDL vs LDL

increase HDL

no effect on LDL

PPAR alpha protein

fibrates bind to this protein

when fibrates bind to PPAR alpha protein this causes (3)

1. an increase in lipoprotein lipase

2. a decrease in apolioprotein C-III

3. an increase in apololioprotein A-I and A-II

lipoprotein lipase

enhances the clearance of triglyceride rich lipoproteins

apolipoprotein c-III

an inhibitor of lipoprotein lipase

apolioprotein a-i and a-ii

causes an increase in HDL levels

side effects of fibrates (3)

gall stones **

hepatotoxicity

myopathy