Dyslipidemia.docx

Cholesterol is lipid serves as precursor to steroid hormones , bile acid, and the main component of cell membrane.

Cholesterol in blood reflect 40-60% of endogenous cholesterol.

Cholesterol , triglyceride and lipid transport through lipoprotein.

Saturated ,unsaturated fats and cholesterol digested, reformulated and packaged into chylomicrons by cell of intestinal endothelium.

Source:clinical pharmacy &therapeutic 5th edition

Category Composition

Chylomicrons Triglycerides

exogenous\dietary

Very low density lipoproteins (VLDLs) Triglycerides

Intermediate density lipoproteins

(IDL)

Triglycerides &Cholesterol

Low density lipoproteins (LDL) Cholesterol

High density lipoproteins (HDL) Cholesterol


Chylomicrons enter the lymphatic system and travel through body until broken down by lipoprotein lipase in the capillary beds to chylomicron remnant (smaller , less dense and contain apolipoprotein B48,E and then cleared from circulation by LDL receptor in the liver

This is replenishing cholesterol pool in the liver which synthesize cholesterol also by endogenous pathway and transported by LDL,VLDL and HDL.

Triglyceride (TG) synthesis by the liver in the excess of carbohydrate and secreted as VLDL


VLDL contain five times more TG than

cholesterol and contain apolipoprotein

C-II,B-100 ,E. Apolipoprotein B-100 and E

link with LDL cell receptor.

Apo lipoprotein C-II function as cofactor

for lipoprotein lipase.


VLDL

VLDL remnant

Clearance by hepatic receptor

IDL

LDL TG

TG

TG

Free fatty acid


LDL is primary atherogenic lipoprotein and

the smaller size of LDL particle of more able

to penetrate into sub endothelial tissue

where it contribute to the development of

atherosclerosis .

Two type of LDL been associated with CHD:

1\ Lipoprotein(a) LP(a) particle is LDL particle

surrounded by plasminogen –like protein

2\Atherogenic lipoprotein phenotype B found

in30%population associated with CHD risk.


The atherosclerotic plaque formation initiated by entrance of LDL and LP(a)into sub endothelial space with their oxidative modified free radicals produced by cells which activated macrophage yielding lipid rich foam which continue to progress with same times of the cell proliferation and collagen synthesis.

HDL rich in cholesterol and very small ,However appears in reverse cholesterol transport resulting in anti atherogenic effect.


source:www.pharmacy times .com

HDL may prevent or remove cholesterol in the intimae by :

1\competitively inhibit uptake of LDL by endothelial cells

2\ prevent LDL oxidation.

3\ inhibit platelet activation by LDL and aggregation by increase prostacyclin production.

4\promote fibrolysis by stabilizing prostacyclin.

LDL serve as marker of metabolism of chylomicron and VLDL (increase TG, decrease HDL).


1- Type I (high level of chylomicrons).

2-Type II a (high level of LDL)

3-Type II b (high level of LDL+VLDL)

4-Type III (high level of IDL )

5-Type IV (high level of VLDL)

6-Type V ( high level of VLDL

+chylomicrons)

Source:hand book of pharmacotherapy 8th edition

Dyslipidaemia defined as elevated of

total cholesterol ,LDL, TG, low HDL or

combination of these abnormalities.

According to etiology dyslipidaemia

classified to:

1- primary or genetic lipoprotein disorder.

2-secondary dyslipidaemia (drugs

&diseases).


Secondary dyslipidaemia due to:

1. Diseases( liver disease ,chronic renal

failure ,nephrotic syndrome, obesity

,hypothyroidism ,diabetes ,alcohol )

2. Drugs (corticosteroids,thiazide diuretic

,cyclosporine ,oral contraceptive , HIV

protease inhibitors ,B-blockers)

Source:clinicl pharmacology 5th edition

In type I there are:

1-repeated attack of pancreatitis.

2-abdominal pain.

3-euraptive cutanous xanthomatosis.

4-hepatosplenomegaly beginning in childhood.

Note: symptoms severity increased with increased dietary fat intake. accelerated atherosclerosis not associated with this disease


Type III the clinical feature appears after 20 years :

1- xanthoma

2- severe atherosclerosis

Type IV occur in adult and similar to secondary dyslipidaemia.

Type V :

-abdominal pain , pancreatitis ,xanthoma ,peripheral polyneuropathy and renal insufficient.

Note: atherosclerosis is increased with this disorder


Angina.

Myocardial infraction (MI).

Arrhythmias.

Stroke.

Peripheral arterial disease.

Abdominal aortic aneurysm.

Sudden death.


CVD is the leader amongst the causes of death worldwide.

Prevalence of CVD including CHD is increasing rapidly in Sudan.

Increasing burden of risk factors like:› Hypertension

› Smoking

› Obesity

› Diabetes

› Dyslipidemia


CVD 30%

17.4 million

OTHERS

Total 58 million death worldwide

3.3 times than the total

no. of death due to HIV,

Malaria, and

Tuberculosis combined

Cardiovascular disease is the leading cause of death

among adults worldwide

CVD 7.2 million

Cancer 6.3 million

Cerebrovascular Disease 4.6 million

Acute Lower Respiratory Tract Infections 3.9 million

Tuberculosis 3.0 million

COPD (Chronic Obstructive Pulmonary Disease) 2.9 million

Diarrhoea (Including Dysentery) 2.5 million

Malaria 2.1 million

AIDS 1.5 million

Hepatitis B 1.2 million

Source: WHO 2005

Source:A&D journal pubmed 2013 online .article about cholesterol and cardiovascular disease

Sex and country Total cholesterol

Women ≥200 mg/dl* ≥240 mg/dl**

China, 65–74 yrs 47.8% 18.2%

Spain, ≥65 yrs 77.6% 45.8%

England, ≥65 yrs 91.7% 54.6%

Mexico, ≥60 yrs 44.2% --

South Africa, ≥60 yrs 58.0% --

Thailand, ≥60 yrs -- 10.8%

Turkey, ≥70 yrs 58.5% 23.8%

Men ≥200 mg/dl* ≥240 mg/dl**

China, 65–74 yrs 30.6% 7.5%

Spain, ≥65 yrs 52.5% 23.1%

England, ≥65 yrs 81.9% 40.4%

Mexico, ≥60 yrs 56.9% --

South Africa, ≥60 yrs 78.7% --

Thailand, ≥60 yrs -- 18.4%

Turkey, ≥70 yrs 42.5% 17.0%

DM in Africa: Up to 13% or more adults in

urban communities.

Diabetes is present in 10% of all hospital

admission in Sudan.

Diabetes is responsible for 10% of

hospital mortality.

Source:Diabetes Int 2000; 10: 18-9.

Variables Mean (SD) Values P-value

Diabetic patients

N=250

Controls

N=60

Total cholesterol

(mmol/L)

5.69 (0.29) 5.20 (0.15) NS

Triglycerides

(mmol/L)

1.71 (0.27) 1.16 (0.21) <0.05

HDL-C

(mmol/L)

0.93 (0.15) 1.11 (0.18) <0.05

LDL-C

(mmol/L)

3.68 (0.21) 3.45 (0.14) NS

VLDL-C

(mmol/L)

1.01 (0.26) 0.81 (0.11) NS

TC/HDL-C 6.11 (1.86) 4.69 (0.13) NS

Source:Eastern Mediterranean Health Journal, Vol. 14, No. 2, 2008

Half of the diabetic

population in Sudan suffers

from dyslipidemia

Diabetic Dyslipidemia in Sudan

What is being tested?

Cholesterol &Triglyceride in the blood sample.

Total cholesterol is determined from the

amount of cholesterol found in HDL, LDL and

VLDL.

LDL - if triglycerides < 400 then LDL is

calculated using Friewald formula:

((Calculated LDL=chol−HDL−TG/5)).

If triglycerides > 400 then LDL is measured

directly.

Non HDL= Total cholesterol – HDLc.Source: labtest online.org

How to ensure quality of the sample?

Fasting for 9-12 hrs before making the test

,only water is permitted.

When it is ordered ?

Adult:

Healthy adult with no risk factor for heart

disease once every 5 years.

Source: labtest online.org

Children &Adolescent :

AAP(American academy of pediatrics) recommended one test between 9 -11 yrs &again between 17- 21 yrs .

What does test results means?

LDL CholesterolOptimal: Less than 100 mg/dL (2.59 mmol/L) Near/above optimal: 100-129 mg/dL (2.59-3.34 mmol/L) Borderline high: 130-159 mg/dL (3.37-4.12 mmol/L) High: 160-189 mg/dL (4.15-4.90 mmol/L) Very high: Greater than 190 mg/dL (4.90 mmol/L)


http://labtestsonline.org/understanding/analytes/ldl/

Total CholesterolDesirable: Less than 200 mg/dL (5.18 mmol/L) Borderline high: 200-239 mg/dL (5.18 to 6.18 mmol/L) High: 240 mg/dL (6.22 mmol/L) or higher

HDL CholesterolLow level, increased risk: Less than 40 mg/dL (1.0 mmol/L) for men and less than 50 mg/dL (1.3 mmol/L) for women Average level, average risk: 40-50 mg/dL (1.0-1.3 mmol/L) for men and between 50-59 mg/dl (1.3-1.5 mmol/L) for women High level, less than average risk: 60 mg/dL (1.55 mmol/L) or higher for both men and women


http://labtestsonline.org/understanding/analytes/cholesterol/

http://labtestsonline.org/understanding/analytes/hdl/

Fasting TriglyceridesDesirable: Less than 150 mg/dL (1.70 mmol/L)Borderline high: 150-199 mg/dL(1.7-2.2 mmol/L) High: 200-499 mg/dL (2.3-5.6 mmol/L) Very high: Greater than 500 mg/dL (5.6 mmol/L)

Non-HDL CholesterolOptimal: Less than 130 mg/dL (3.37 mmol/L) Near/above optimal: 130-159 mg/dL (3.37-4.12mmol/L) Borderline high: 160-189 mg/dL (4.15-4.90 mmol/L) High: 190-219 mg/dL (4.9-5.7 mmol/L) Very high: Greater than 220 mg/dL (5.7 mmol/L)


http://labtestsonline.org/understanding/analytes/triglycerides/

Result in children and adolescents

Test Acceptable

mg/dl

Borderline

mg/dl

High mg/dl

Total

cholesterol

Less than 170 170 -199 Greater than

or equal 200

Non HDL

cholesterol

Less than 120 120-140 Greater than

or equal 145


Therapeutic lifestyle change(TLC)should

be the first approach tried in all patient

this includes:

Dietary restriction of cholesterol and

saturated fatty acid.

Regular exercise.

Weight reduction.

Source:pharnacotherapy text book 7th edition

Inhibit cholesterol synthesis by inhibit

(HMG-Co A), increase LDL receptor and

enhance receptor mediated metabolism

and clearance of LDL from serum.

Beneficial effect on lipid parameters:

LDL c ↓ 18%-55%

HDL c ↑5-15%

TG ↓7%-30%

24%-40% reduction in coronary events.

source: medescape.org/ view article/561751

Potential adverse effects:

Myalgia ,Myopathy and increased liver enzymes

Contraindications:

Liver disease.

Precautions:

CYP3A4 enzyme inducer(phenytoin & barbiturate)

CYP3A4 enzyme inhibitors(ciclosporin & ketoconazole)


Potential pleiotropic effects:

Improve endothelial function(up regulate eNOs, scavenge superoxide)

Antithrombotic effects(improve fibrinolytic balance ,inhibit platelet aggregation)

Anti-inflammatory effects(decrease activation of NF ,decrease macrophage infiltration)

Enhance plaque stability

Attenuate vascular smooth muscle cell proliferation


Response to statin

Is there a role of ‘GENE’?

Genetic variation in HMGCR may

contribute to variation in the response

The CAP study, a 6-week simvastatin (40

mg/d) trial.

Designed to examine role of gene in

ethnic variability in statin response in

African/African Americans and

Caucasians.

Source :Circulation 2008;117;1537-1544

People carrying either H-2 or H-7 haplotypes:

African/African American: 64%

Caucasians: 11.6%

12 people carrying both, H-2 and H-7 haplotypes

11 were African/African American

1 was Caucasian

LDL-C reduction in carriers of both, H-2 and H-7 haplotypes vs. non-carriers -28% vs. -41.5%

Source:Circulation 2008;117;1537-1544

We need high dose of statins: Increasing prevalence of risk factors

Presence of multiple risk factors is also very high.

Studies have established that African respond lesser to statins compared to Caucasians.

Two (H-2 and H-7) SNP haplotypes are commonly associated with poor response to statins and these haplotypes are highly prevalent in African compared to Caucasians.

Statins: benefits are beyond LDL-C and are dose dependent.

Source :Circulation 2008;117;1537-1544

Early, intensive lipid-lowering treatment with statin, initiated during the acute phase of unstable angina or non–Q-wave MI, reduces early recurrent ischemic events

A benefit was observed in a population with low to normal baseline LDL-C levels.

Source:Schwartz et al JAMA 2001;285:1711-8

Increase peripheral lipolysis and decrease hepatic TG production(by binding to peroxysome proliferators activated receptors alpha in hepatocytes PPAR alpha)

Beneficial effects on lipid parameter:

TG ↓ 25%-50%

LDLc ↓ or remain the same or↑

LDL &HDL ↑ 10%-25% in hypertriglyceridemia

Adverse effects:

GIT up set, cholelithiasis , myositis .

Contraindication: hepatic or renal dysfunction ,gallbladder diseases.

Indication: hypertrigylceridemia(type IV&V)combined hyperlipidemia(type IIb) with low HDLc.


Beneficial effect on lipid parameter:

LDLc ↓ 5%-25%

TG ↓20%-60%

HDL ↑15%-39%

Reduce coronary events

Adverse effect :

Flushing ,itching ,headache

Hepatotoxicity

Activation of peptic ulcer

Hyperglycemia/reduced insulin senetivity

Contraindications:

Active liver disease, peptic ulcer disease

NOTE: Tredaptive(nicotinic acid +laropriprant)2008

Laropriprant(selective antagonist of prostaglandin D2 receptor).


Binding to bile acid and increase excretion of cholesterol


LDL c↓ 15%-30%

HDL c ↑3%-5%

TG may increase in patient with elevated TG

Reduced coronary events

Adverse effect:

GIT intolerance ,constipation, bloating ,abdominal pain, flatulence

Drug interaction:

Bind negatively to charged drugs, interfere with absorption of drugs/fat soluble vitamins(other drugs 1hr before or 4-6 hrs after)


Reduce cholesterol absorption by

binding to intestinal cholesterol

transporter (inhibit delivery of cholesterol

to liver &increase hepatic LDL receptor)


LDL c ↓18%-20%(in monotherapy or

“add-on” to statin no change in TG&HDL.


Fish oil:It is rich in omega3 fatty acid ,decrease VLDL

synthesis and little change in LDL and HDL level.

Omega 3 fatty acids protect against CHD mortality particularly sudden death.

Can be used as alternative to fibrate or in combination with statins.

Soluble fibers:Bind to bile acids in the gut and increase

conversion of cholesterol to bile acids in the liver.



CETP:

It transfers cholesterol from HDL to LDL&VLDL ,so it inhibition will result in increase of HDL level and reduce cardiovascular events.

Combination drug therapy:

First monotherapy is used ,then if there is alack of response combination is used.

In general Statins + bile acid sequestrants .

niacin+ bile acid sequesterant.

Both provide great reduction in total &LDL cholesterol.

To increase HDL level gemifebrozil or niacin is used.

drug Dosage forms Usual daily dose Maximum

daily dose

cholestyramine Bulk powder 4g

packet

8g TID 32g

Colestipol

hydrochlorid

Bulk powder 5g

packet

10g BID 30g

colesevelam 625 mg tablet 1,875mg BID 4,375mg

niacin 50,100,250,500mg

tab

125,250,500mg

cap

1,000-2,000 mg

once daily

6g

Extended release

niacin

500,750,1000mg

tab

1000-2000mg

once daily

2000mg

Fenofibrate 67.134,200mg cap

54,160,40,120mg

tab

54mg or 67mg 201mg

gemfibrizol 300mg cap 600mg BID 1.5g

ezetimibe 10mg tab 10mg 10mg

source:pharmacotherapy text book.7th edition

drug Dosage form Usual daily dose Maximum daily

dose

lovastatin 20,40mg tab 20-4-mg 80mg

pravastatin 10,20,40,80mg

tab

10-20mg 40mg

simvastatin 5,10,20,40,80mg

tab

10-20mg 80mg

atorvastatin 10,20,40,80mg

tab

10mg 80mg

rosuvastatin 5,10,20,40 mg

tab

5mg 40mg

pitavastatin 1,2,4mg 2mg 4mg

source:pharmacotherapy textbook. 7th edition

According to the NCEP(national cholesterol education programme &the national institute of health (USA):

The most important step in management of high cholesterol level in the blood is assessing person’s risk status. By 3 steps:

First: detecting fast lipoprotein profile (total cholesterol , LDL c, HDL c ,TG).

Second: identifying any risk determinants.

Third: estimation of 10 years CHD risk according to Framingham scoring.

Major risk determinants:

Cigarette smoking

Hypertension

Low HDL ≤ 40mg\dl

Family history of CHD

Age { men ≥45 yrs women≥55ys}

Note :there are other factors ,but only the major factors modify LDL c goals

Source: Ntional cholesterol education programme.National heart,lung&blood

institute NIH publication No .01-3670 May 2011

For individual

with

Trial of

dietary

therapy

&counseling

Initiate drug

therapy if LDL

remain

LDL

cholesterol

goal

Risk of CHD

for

10yrs(framing

ham score)

No CHD&>0-

1 risk factor

6 – 12 month ≥ 190 mg/dl

≥4.9 mmol/L>160 mg /dl

>4.1 mmol/L

> 10 %

No CHD &<2

CHD risk

factor

3 – 6 month ≥ 160 mg/dl

≥4.1 mmol/L

>130 mg/dl

> 3.4 mmol/L

10 -20%

Established

CHD

6 – 12 weeks ≥ 130 mg/dl

≥3.4 mmol/L

≤ 100 mg/dl

≤ 2.6 mmol/L

< 20%

source:www.nhlbi.nih.gov/guidelines/cholesterol/atp3/index.htm

source:www.cvtoolbox.com

source:www.cvtoolbox.com

source:www.clinrisk.uk

It constitute due to , life habit risk factors

and emerging factors .

It characteristic by atherogenic

dyslipideamia, abdominal obesity, insulin

resistance and high blood pressure

(DROP syndrome)



Risk factors Defining level

Men >102 cm (>40 in)

Women >88 cm (>35 in)

≥150 mg/dL

Men <40 mg/dL

Women <50 mg/dL

≥130/85 mmHg

Fasting glucose ≥110 mg/dL

Abdominal Obesity Waist

Circumference

Triglycerides

HDL cholesterol

Blood pressure


Target of therapy :

1\ primary target (LDL cholesterols)

2\ secondary target (metabolic syndrome)

Modalities of therapy:

1\Therapeutic lifestyle change(TLC)

2\Drug therapy



Nutrient Recommended intake

Saturated fat Less than 7% of total

calories

Polyunsaturated fat Up to 10% of total calories

Monounsaturated fat Up to 20% of total calories

Total fat 25-35% of total calories

Carbohydrate 50-60% of total calories

Fiber 20-30 g/day

Protein Approximately 15% of total calories

Cholesterol Less than 200 mg/day


Visit 1

Begin Lifestyle

Therapies

Visit 2

Evaluate LDL

response

If LDL goal not

achieved, intensify

LDL-lowering therapy

Visit 3

Evaluate LDL

response

If LDL goal not

achieved, consider

adding drug Tx

Visit N

Monitor

Adherence to

TLC



Initiate

LDL-lowering

drug therapy

If LDL goal not

achieved, intensify

LDL-lowering

therapy

If LDL goal not

achieved, intensify

drug therapy or

refer to a lipid

specialist

Monitor

response and

adherence to

therapy



the clinical approach calls for TLC for

primary prevention of CHD .

For higher risk persons , clinical

approach intensifies prevention

strategies . aiming to reduce long tern

risk > 10 years.



The recent clinical trials demonstrate that

LDL lowering therapy reduce (coronary

mortality, major coronary events,

procedures and strokes)

For persons with established CHD or CHD

equivalent ,ATPIII specifies an LDL c <

100 mg/dl as the goal of therapy for

secondary prevention.



pharmacists should always counsel patients on the disease process, and reinforce lifestyle modifications, with added emphasis on the benefits of intervention and compliance.

The most important message pharmacists can relay to patients is that the management of dyslipidemia is not a short- term assignment with immediate, visible outcomes. Rather, it is a long-term process that should be integrated into one’s daily life.

Source: pharmacytimes.com

Implementing clinical pharmacy services in Jordan has improved the lipid profile of dyslipidemic patients, majority of pharmacist recommendation (90.4%) were followed by physician and the overall lipid lowering agent use was increased to (91.8%) in intervention group patient & (86.5%) in control group compared to (69.9%-78.8%) respectively at baseline.

Article: (The role of clinical pharmacist on lipid control in dyslipidemic patients in Jordan)

Source: Int J clin pharm 2011 Ap;33(2):229-236

Interdisciplinary medication team that include clinical pharmacists in lipid lowering management resulted in improved treatment success as measured by reduction in LDL level (5 %-22% per visit)

Article: (Assessment of clinical pharmacist management of lipid lowering therapy in primary care)

Source: J manage care pharm 2003May;9(3):269-273

66

Dyslipidemia.docx

Education

lipoprotein lipase

endogenous cholesterol

clinical pharmacy therapeutic

cholesterol pool

apo lipoprotein c

reverse cholesterol

vldl source

ldl receptor