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Pharmacology > Dyslipidemia Drugs > Flashcards

Dyslipidemia Drugs Flashcards

1
Q

A 56- year old retired school teacher with treated blood
pressure of 125/82 mmHg comes in for a semi annual
exam.Blood chemistry is showed LDL is 230 and HDL
is 54. You placed him on a drug and asked him to
return after one month. Usually, in managing patients
with dyslipidemia, we advise follow up after a month to
assess the response to treatment as well as the
adverse effect. On his return, his LDL is reduced to 189
but complains of cramping pain in the gastrocnemius
on both legs

The drug that will most likely have this adverse effect
is which drug?
a. Ezetimibe
b. Rosuvastatin
c. Hydrochlorothiazide
d. Niacin
e. Gemfibrozi
A

LDL is elevated. The ideal level of LDL should be <100.
So which among these drugs used in managing
dyslipidemia may cause myopathy or myositis?
It is the statins as well as Gemfibrozil.
But for this case, the most common drug that is being
used is the statins because they are the first line drugs
in managing dyslipidemia so the answer for this case
is Rosuvastatin

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2
Q

LIPOPROTEIN

A

Lipoproteins are macromolecular assemblies that contain

lipids and proteins

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3
Q

LIPID (Core)

A
  • Contains Cholesteryl ester, Triglycerides
    and Fatty Acids
  • Water insoluble
  • Surrounded by unesterified cholesterol,
    phospholipids, and apolipoproteins
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4
Q

PROTEIN (outer surface)

A 
Contains Apolipoproteins namely:
§ Apo A (seen in HDL)
§ Apo B (Apo B-48 in Chylomicrons,
Apo B-100 in VLDL, LDL, IDL)
- They have polar surface and are water
soluble
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5
Q

Density and Size are inversely related

A

As you increase the amount of lipid, it
becomes less dense than water.
- Chylomicrons: more lipid, least dense
• The higher amount of lipid, the larger the
structure. The lower amount of lipid, the smaller
the structure

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6
Q

HDL

A

most dense, smallest

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7
Q

Chylomicrons:

A

least dense, largest.

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8
Q

APO LIPOPROTEINS

A

Responsible for the structural integrity
- Functions as a ligand and bind to different
receptors
- Activates enzymes important in lipoprotein
metabolism

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9
Q

Any lipoprotein that contains Apo B-48 and Apo B-100

can cause

A

Atherosclerosis
Clinical Sequela: Atherosclerosis and Acute pancreatitis
Main goal of management: lower LDL

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10
Q

CIGARETTE SMOKING

A 
Can increase the risk of developing
Atherosclerosis
- Effects of cigarette smoking: (DICIS)
• Decrease in HDL
• Impairment of cholesterol retrieval
• Cytotoxic effects on the endothelium
• Increased oxidation of lipoproteins
• Stimulation of thrombogenesis
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11
Q

CHYLOMICRONS

A
  • Largest lipoprotein
  • Contains Apo B-48
  • Synthesized from the dietary triglyceride and
    cholesterol that comes from the diet.
    Chylomicrons are formed in the intestine and carry
    triglycerides of dietary origin, unesterified cholesterol,
    and cholesteryl esters
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12
Q

Pathway for Cholesterol Transport

A
  1. Ingestion of dietary fat
  2. The cholesterol and the triglyceride present in the diet would be esterified by Type II Acyl Coenzyme Cholesterol Transferase
    Esterification: elongation and addition of fatty acid to TAG and Cholesterol.
    The esterification is with the effect of Microsomal Triglyceride Transfer Protein (MTP)
  3. Cholesteryl Ester + long chain FA with TAG + apo B48 absorbed in the intestine via Niemann Pick C1L1 = CHYLOMICRON
  4. Once absorbed, the chylomicron enters the thoracic lymph where in it will be used by the peripheral tissue
    before it goes to the liver
  5. Chylomicron will become chylomicron remnants when it is acted upon Lipoprotein Lipase (remove the TAG within the chylomicron) LPL needs a cofactor ApoC2 to be activated
  6. Chylomicron remnants (less TAG, more cholesterol) would then be endocytosed in the liver (apoE mediated)
  7. It will then be acted upon by Hepatic lipase
  8. Degraded
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13
Q

Exogenous pathway

A

transport dietary lipids to the

periphery and the liver

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14
Q

Endogenous pathway

A

transports hepatic lipid from the

liver to the peripher

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15
Q

• Chylomicrons are converted to chylomicron

remnants by the hydrolysis of their triglycerides

A

by LPL.

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16
Q

“Remnant receptors”

A

nclude the LDL receptorrelated protein (LRP), LDL receptors, and other
receptors.
• Free Fatty acid (FFA) released by LPL is used by
muscle tissue or taken up and stored by adipose
tissue.

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17
Q

The TAG is removed from the Chylomicron by

A

LPL,

the FA will be stored in the adipose tissue

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18
Q

VLDL will then be hydrolyzed by LPL releasing free FA

producing

A

IDL

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19
Q

Intermediate Density Lipoprotein (IDL

A

will be
endocytosed to the liver which is ApoE mediated.
- Further hydrolysis of IDL by LPL and Hepatic Lipase
will release more TAG would produce LDL

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20
Q

Low Density Lipoptotein

A 
would then be endocytosed
to the liver which is ApoB mediated
- LDL binds to the LDL receptor
- Liver would have more cholesterol.
- Increased Cholesterol level à LDL receptor down
regulated
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21
Q

Decreased Cholesterol level

A

LDL receptor up

regulated

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22
Q

Chylomicron remnants

A

can indirectly increase
LDL level but do not serve as a precursor for LDL
synthesis.

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23
Q

LOW DENSITY LIPOPROTEIN

A

LDL are catabolized chiefly in hepatocytes and other cells
after receptor-mediated endocytosis.
- Clearance is mediated by LDL receptor
- Apo B100 is the ligand that binds LDL to its receptors (that is why it is called “BAD
CHOLESTEROL)
- Become atherogenic when they are modified by oxidation à FOAM CELL formation
- Increased LDL receptor à decreased LDL level

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24
Q

HIGH DENSITY LIPOPROTEIN

A

APO A1 is the major HDL apoprotein
1. The membrane transporter ABCA I facilitates the transfer of free cholesterol from cells to HDL

  1. As Cholesteryl ester of HDL increases à Cholesteryl ester begin to be exchanged for TAG
    derived from any TAG containing Lipoprotein mediated by Cholesteryl Ester Transfer Protein (CETP)
  2. HDL cholesterol selectively taken up by the liver via SR-BI (scavenger receptor class B1

Good cholesterol results from participation of HDL in Reverse Cholesterol Transport =
excess cholesterol is acquired from cells and transferred to the liver for excretion

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25
Q

Chylomicron vs VLDL

A

Chylo- apob-48

VLDL- apob-100

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26
Q

• High-density lipoproteins (HDL) exert several

A

antiatherogenic effects.
• They participate in retrieval of cholesterol from
the artery wall and inhibit the oxidation of
atherogenic lipoproteins.
• Low levels of HDL (hypoalphalipoproteinemia)
are an independent risk factor for atherosclerotic
disease and thus are a potential target for
intervention.

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27
Q

ATP binding cassette transporter A1 (ABCA1)

A

helps in the acquisition of phospholipids and

cholesterol from cells to HDL

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28
Q

Cholesterol will then be esterified by

A

Lecithin

Cholesterol Acyl Transferase (LCAT)

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29
Q 
The cholesteryl ester present in the HDL would
be exchanged with the TAG present in the TAG
rich lipoprotein (VLDL, IDL, LDL) mediated by
A

CETP (Cholesteryl Ester Transfer Protein)

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30
Q

CE will be acted upon by lipoprotein lipase and
hepatic lipase incorporating it in the LDL It will
then bind in the LDL receptor, degraded in the
liver therefore

A

reducing LDL level

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31
Q

DIRECT PATHWAY

A

HDL interacts with receptor
SR-B1 on the liver, allowing the direct delivery of
cholesterol.

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32
Q

INDIRECT PATHWAY

A

o Via Cholesterol Ester Transfer Protein
(CETP Mediated).

o CETP facilitates the exchange of cholesterol in HDL for the triglycerides.

o With the triglyceride rich particles such as VLDL and LDL.

o In this one to one exchange, HDL now
becomes enriched with triglycerides and LDL becomes enriched with cholesterol.

o LDL particles interact with LDL receptors in the liver.

o Where LDL deposit the LDL ester content at the LDL receptor

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33
Q

VERY LOW DENSITY LIPOPROTEIN

A

VLDL are secreted by liver and export
triglycerides to peripheral tissues.

VLDL triglycerides are hydrolyzed by LPL, yielding free fatty acids for storage in adipose tissue and for
oxidation in tissues such as cardiac and skeletal muscle.

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34
Q

“beta shift”

A

phenomenon, the increase of LDL
(beta-lipoprotein) in serum as hypertriglyceridemia subsides.
• Increased levels of LDL can also result from
increased secretion of VLDL and from decreased
LDL catabolism.

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35
Q

Lp(a) LIPOPROTEIN

A
  • Lp(a) lipoprotein is formed from LDL and the (a) protein, linked by a disulfide bridge.
  • The (a) protein is highly homologous with plasminogen but is not activated by tissue plasminogen activator.
  • Lp(a) is found in atherosclerotic plaques and contributes to coronary disease by inhibiting thrombolysis.
  • It is also associated with aortic stenosis.
  • A common variant (I4399M) in the coding region is associated with elevated levels.
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36
Q

Triglycerides

A

Normal : <150
High : 200-499
Goal : < 120

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37
Q

LIPOPROTEIN DISORDERS

A
  1. Primary Hypertriglyceridemias
    a. Primary chylomicronemia
    b. Familia hypertriglyceridemia
    c. Familial combined
    hyperlipoproteinemia
    d. Familial dyslipoproteinemia
  2. Primary Hypercholesterolemias
  3. Secondary Hyperipoproteinemia
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38
Q

Before giving drug therapy, identify

A

first if it is Primary or

Secondary.

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39
Q

Secondary dyslipidemia means

A

there are other disease entities that cause the increase in LDL
cholesterol levels or reduced in HDL. An example would be Metabolic Syndrome manifested as insulin
resistance, abdominal obesity, high LDL, low HDL, and hyperuricemia. Once you manage DM, dyslipidemia
would also normalize.

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40
Q

Chylomicrons can be seen in the plasma after

A

3-4 Hours

after a fatty meal.

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41
Q

DIETARY MANAGEMENT OF LIPOPROTEINEMIA

A

In managing dyslipidemia, Pharmacotherapy is
not the first line. The first line is Lifestyle
modification

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42
Q

LIFESTYLE MODIFICATION:

A
  • 20-25% lipid intake/day
  • 8% saturated fat
  • <200 mg cholesterol/ day
  • Use of complex carbohydrates and fibers
  • Cis-monounsaturated fats should predominate
  • Weight reduction
  • Caloric restriction
  • Avoidance of alcohol
  • Intake of fish oils
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43
Q

WHOM AND WHEN TO TREAT

A 
• Sex: Both gender
• Age: Men >45 yo, Women >55 yo
• Cerebrovascular disease patients: because of
elevated plasma cholesterol
• Peripheral vascular diseases: Statins
• Hypertensive patients and smokers
• TYPE 2 DM (high TAG, total chole, LDL, and low
HDL)
• Post myocardial infarction or
Revascularization patients.
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44
Q

AGE ASCVD

A

Male: >45 y/o
Female: >55 y/o

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45
Q

FAMILY HISTORY OF

PREMATURE CHD

A

a 1st degree relative (male
<55y/o, female <65y/o when
the first CHD clinical event
occurs)

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46
Q

CURRENT CIGARETTE

SMOKING

A

Defined as smoking within

the preceding 30 days

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47
Q

HYPERTENSION

A 
Systolic BP: ≥ 140
Diastolic BP: ≥ 90
Or use of antihypertensive
medication, irrespective of
blood pressure
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48
Q

LOW HDL-C

A

<40 mg/dL (consider 50

mg/dL as “low” for women

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49
Q

OBESITY

T2 DM

A

BMI: 25 kg/mg2
Waist circumference
Men : > 40 inches
Women : > 35 inches

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50
Q

“STATINS

A

Competitive Inhibitors of HMG-COA Reductase

  • Structural Analogs of HMG-CoA (3-hydroxy3methylglutaryl-coenzyme A)
  • Lovastatin
  • Atorvastatin
  • Fluvastatin
  • Pravastatin
  • Simvastatin
  • Rosuvastatin
  • Pitavastatin
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51
Q

MECHANISM OF ACTION of Statins

A

HMG-CoA reductase inhibition
- Inhibits the important step in cholesterol
synthesis which then decreases cholesterol level therefore decreasing LDL level because of the upregulation of LDL receptor (increased clearance of LDL)
- mediates the first committed step in sterol biosynthesis
- Decreased cholesterol within the cell, LDL, IDL, VLDL
- Increase in the LDL receptor synthesis- more LDL will bind to the receptor decreasing the level of
LDL; increasing the CLEARANCE of LDL
- Increased in HDL
- Given per orem wherein 40% to 75% are absorbed except for fluvastatin (98%)

All undergo first pass hepatic metabolism.
- Adverse effect: Hepatotoxicity
- Half-life ranges from 1-3 hours except for PAR
(Pitav- 12hrs, Ator- 14hrs, Rosu- 19hrs)
- All are excreted in the bile and the remaining will
be excreted in the urine.
- Contraindications:
• Pregnant women
• Nursing mothers
• Children

*Most of the drugs used for managing dyslipidemia are
contraindicated in pregnancy, lactating mothers, and
children EXCEPT for RESINS. In some literatures, they
can give statins for children above 7-8 y/o depending on
the LDL level

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52
Q

Upregulation

A

> more LDL binds to receptor > LDL levels

in plasma are reduced

53
Q

LDL level reduction

A

first drug of choice are STATINS

54
Q

TAG level reduction:

A

FIBRATES

55
Q

Increase HDL levels:

A

NIACIN

56
Q

Rosuvastatin

A
  • longest half-life

§ Absorption is enhanced by food except for PRAVASTATIN

57
Q

Most of the statins are given at night

A

t (cholesterol
synthesis is usually at night) except for PAR
(Pitavastatin, Atorvastatin, Rosuvastatin)

58
Q

Statins are classified based on their LDL lowering effect:

A

High intensity

  • Atorvastatin (40-80 mg/day)
  • Rosuvastatin (20-40 mg/day)
59
Q

Moderate intensity

A

(lowers LDL by approx. 30-

less than 50%) Lova, Pita,Prava, Atro

60
Q

Low intensity

A

y (lowers LDL by approx. <30%)
The latest recommendation is to start the patient,
especially those at risk for CHD, on HIGH intensity statins

Fluva

61
Q

A patient with LDL level of 150 mg/dl came to
your clinic. Our goal is to lower the LDL (100mg/dL). Only
fluvastatin is available. At what dose would you prescribe
fluvastatin

A

GIVE THE PATIENT FLUVASTATIN

80mg/day (to reduce the LDL level by 33%)

62
Q

Baseline LDL is 200mg/dL. Goal is 100 mg/dL.

What dosage of Atorvastatin would you give?

A

GIVE ATORVASTATIN 40 mg/day (50% reduction) interact with gemfibrozil, it would increase the incidence
of myopathy

63
Q

Hepatotoxic

A 
LFT baseline, 1-2 months then q 6-12
months
- Goodmann 13th ed
• 2012, FDA no longer recommend
routine monitoring of ALT or other
liver enzymes
64
Q

Myopathy

A
  • Elderly
  • Hepatic or Renal dysfunction
  • Small body size
  • Untreated hypothyroidism
  • Drugs that diminish statin catabolism
    (macrolide, antifungal, fibrates)
65
Q

CYP3A4 metabolizes

A

Atorvastain, Lovastatin,

Simvastatin (SAL)

66
Q

• CYP2C9 metabolizes

A

Pitavastatin, Rosuvastatin,

Fluvastatin (PiRF)

67
Q

CYP2C8

A

metabolizes Fluvastatin and Pitavastatin

68
Q

All statins would undergo glycosylation

A

interact with gemfibrozil, it would increase the incidence

of myopathy

69
Q

NIACIN (Nicotinic Acid)

A

Adipose tissue
o inhibits lipolysis of TAG by hormone
sensitive lipase

LIVER
o reduces TAG synthesis by inhibiting
synthesis and esterification of FFA →
increase Apo B degradation
o reduced TAG → decreased VLDL
secretion → decreased production of LDL
70
Q

Enhanced lipoprotein lipase activity

A

clearance

of chylomicron and VLDL triglycerides

71
Q

Decreased fractional clearance of Apo A1 in HDL

A

→ increase HDL

72
Q

Net Effects of Niacin

A

o decreased VLDL, IDL, LDL, as well as
triglycerides and Lipoprotein A
o increased HDL (by decreasing Apo A1
clearance)

Niacin [NYE-uh-sin] reduces LDL-C by 10% to 20% and is the most effective agent for increasing HDL-C. It also
lowers triglycerides by 20% to 35% at typical doses of 1.5 to 3 g/day

73
Q

Niacin can be used in combination with

A

statins, and fixed-dose combinations of long-acting niacin with lovastatin and simvastatin are available. [Note: the
addition of niacin to statin therapy has not been shown to reduce the risk of ASCVD events.]

74
Q

MECHANISM OF ACTION of Niacin

A

Niacin inhibits the lipolysis and mobilization of FFA
Decreases mobilization of FFA → decrease TAG
synthesis → decrease VLDL secretion → decreased LDL

At gram doses, niacin strongly inhibits lipolysis in adipose tissue, thereby reducing production of free fatty acids
(Figure 22.8). The liver normally uses circulating free fatty acids as a major precursor for triglyceride synthesis.
Reduced liver triglyceride levels decrease hepatic VLDL production, which in turn reduces LDL-C plasma
concentrations.

75
Q

→ decrease serum VLDL

A

→ decrease serum LDL

76
Q

→ increase HDL

A

due to reduced clearance

77
Q

increase HDL

A

15- 30%

78
Q

decrease TAG

A

35 – 45%

79
Q

decrease LDL

A

20-25%

80
Q

Absorption/Distribution/Elimination of Niacin

A

Given orally, excreted in the urine

81
Q

Clinical use of Niacin

A

As an adjunct to dyslipidemia, or when a statin is contraindicated
Because niacin lowers plasma levels of both cholesterol and triglycerides, it is useful in the treatment of familial hyperlipidemias. It is also used to treat other severe hypercholesterolemias, often in combination with other agents.

82
Q

Pharmacokinetics of Niacin

A

Niacin is administered orally. It is converted in the body to nicotinamide, which is incorporated into the cofactor
nicotinamide adenine dinucleotide (NAD+
). Niacin, its nicotinamide derivative, and other metabolites are excreted
in the urine. [Note: Administration of nicotinamide alone does not decrease plasma lipid levels.]

83
Q

Adverse effects of niacin

A

The most common adverse effects of niacin are an intense cutaneous flush accompanied by an uncomfortable
feeling of warmth and pruritus.

Administration of aspirin prior to taking niacin decreases the flush, which is
prostaglandin-mediated.

Some patients also experience nausea and abdominal pain.

Slow titration of the dosage or use of the sustained-release formulation of niacin reduces bothersome initial adverse effects.

Niacin inhibits tubular
secretion of uric acid and, thus, predisposes patients to hyperuricemia and gout.

Impaired glucose tolerance and
hepatotoxicity have also been reported.

The drug should be avoided in active hepatic disease or in patients with an
active peptic ulcer.

84
Q

Administration of aspirin prior to taking niacin

A

decreases the flush, which is

prostaglandin-mediated.

85
Q

) FIBRIC ACID DERIVATIVES (FIBRATES

A
  • Gemfibrozil
  • Fenofibrates
  • Fibrates function primarily as ligands for the nuclear transcription receptor, PPAR α
  • Fish oil activates PPAR α
  • Transcriptionally upregulate LPL, apo A-1 and apo A-2
  • A major effect is an increase in oxidation of fatty acids in liver and striated muscle
  • Increased lipolysis of lipoprotein TG, LPL
86
Q

MECHANISM OF ACTION of Fibrates

A

Peroxisome proliferator-activated receptor alpha (PPAR-α) agonist
­ Apo A-I
­ Apo A-II
­ ABCA1

87
Q

Fenofibrate is more effective than Gemfibrozil

A

increased HDL

88
Q
  • Increased HDL cholesterol
A

due to lower TG in
plasma → reduction in the exchange of TG into
HDL in place of cholesteryl ester

89
Q

Effect on lipid profile by Fibrates

A

● Upregulation of apo A-1, apo A-2 and ABCA1 →
Increase HDL
- ABCA1: facilitates uptake of cholesterol to HDL
● Decrease apo C-3 (necessary for TAG synthesis and
VLDL synthesis) → Decrease VLDL → Increase action of
LP → Decrease LDL (decrease in substrate)
● Increasing clearance → Decrease LDL and VLDL

90
Q

Clinical Application of Fibrates

A

Hypertriglyceridemia, Low HDL

91
Q

Toxicity of Fibrates

A
  1. Rashes
  2. Gastrointestinal symptoms
  3. Myopathy (Gemfibrozil + Statin)
  4. Arrhythmia
  5. Hypokalemia
  6. High blood levels of aminotransferases or alkaline phosphatase
  7. Decrease in white blood count or hematocrit
  8. Both agents potentiates the action of coumarin and indanedione anticoagulants and doses of these agents should be adjusted
92
Q

Avoided in patients with:

A
  1. Hepatic dysfunction
  2. Renal dysfunction’
  3. Biliary tract disease- Gallstones
  4. Pregnant women
  5. Children
93
Q

. Adverse effects of Fibrates

A

The most common adverse effects are mild gastrointestinal (GI) disturbances. These lessen as the therapy
progresses.

drugs increase biliary cholesterol excretion, there is a predisposition to form gallstones.

Myositis (inflammation of a voluntary muscle) can occur, and muscle weakness or tenderness should be evaluated.

Patients with renal insufficiency may be at risk. Myopathy and rhabdomyolysis have been reported in patients taking
gemfibrozil and statins together.

94
Q

The use of gemfibrozil is contraindicated with

A

simvastatin, and, in general, the use

of gemfibrozil with any statin should be avoided. Both fibrates may increase the effects of warfarin

95
Q

Fibrates should not be used in patients with

A

severe

hepatic or renal dysfunction, in patients with preexisting gallbladder disease or biliary cirrhosis

96
Q

BILE ACID – BINDING RESINS

A
  • Enhance conversion of cholesterol to bile acids in
    liver via 7-alpha- hydroxylation, which is normally
    controlled by negative feedback by bile acids.
  • Decreased bile acid pool in liver leads to:
    o increase hepatic bile acid synthesis
    o decreased hepatic cholesterol (because
    cholesterol would be used for bile acid
    synthesis)
    o Low hepatic cholesterol stimulates LDL
    receptor synthesis
    o Increase LDL clearance
  • Effect is not in the liver, but in the INTESTINE
97
Q

Therapeutic uses of BABR

A

The bile acid sequestrants are useful (often in combination with diet or niacin) for treating type IIA and type IIB
hyperlipidemias. [Note: In those rare individuals who are homozygous for type IIA and functional LDL receptors
are totally lacking, these drugs have little effect on plasma LDL levels.]

98
Q

Cholestyramine

A

can also relieve pruritus

caused by accumulation of bile acids in patients with biliary stasis

99
Q

Colesevelam

A

also indicated for type 2 diabetes
due to its glucose-lowering effects

has fewer GI side effects than other bile acid sequestrants

100
Q

Pharmacokinetics

A

Bile acid sequestrants are insoluble in water and have large molecular weights. After oral administration, they are
neither absorbed nor metabolically altered by the intestine. Instead, they are totally excreted in feces

101
Q

Adverse effects

A

The most common adverse effects are GI disturbances, such as constipation, nausea, and flatulence.

102
Q

BABR agents may impair the

A

absorption of the fat-soluble
vitamins (A, D, E, and K), and they interfere with the absorption of many drugs (for example, digoxin, warfarin, and
thyroid hormone).

103
Q

BABR agents may raise triglyceride levels and are contraindicated in patients

A

hypertriglyceridemia (greater than 400 mg/dL)

104
Q

only drug given to pregannt

A

BABR

105
Q

EZETIMIBE

A
  • A transport protein, NPCILI, is the target of
    the drug
  • Selective inhibitor of intestinal absorption of
    cholesterol and phytosterol
  • decreasing cholesterol in liver → increasing
    LDL receptor → it decreases the LDL by 15- 20%
  • it is effective even in the absence of dietary
    cholesterol because it inhibits reabsorption
    of cholesterol excreted in the bile
106
Q

Other effects of Ezetimbe

A
  • Creates a pharmacologic ileal bypass blocking
    about 55% of cholesterol absorption in the gut
    and losing the return of cholesterol from the gut
    to the liver.
  • Low incidence of reversible impaired hepatic
    function with a small increase in incidence when
    given with a reductase inhibitor
  • Myositis has been reported rarely
107
Q 
MICROSOMAL TRIGLYCERIDE TRANSFER
PROTEIN INHIBITOR (MTTP) –
A

LOMITAPIDE
• Essential role in addition of TAG to VLDL in liver
and CM in intestine
• Inhibits VLDL secretion and accumulation of TAG
in liver

108
Q

PCSK9 INHIBITORS

A

• Alirocumab
• Evolocumab
- Proprotein convertase subtilisin kexin type 9
- PCSK9 binds to the LDL receptor and degrade
the receptor → leads to increase in the level of
LDL in plasma
- PCSK9 inhibitor (antibodies) binds to the PCSK9
→ decreasing/preventing binding of PCSK to LDL
receptor → more LDL receptor present to
facilitate clearance of LDL

109
Q

Alirocumab

[al-i-ROK-ue-mab] and evolocumab [e-voe-LOK-ue-mab] are PCSK9 inhibitors, which are

A

fully-humanized
monoclonal antibodies. These agents are used in addition to maximally tolerated statin therapy in patients with
heterozygous or homozygous familial hypercholesterolemia, or in patients with clinical ASCVD who require
additional LDL-C lowering

110
Q

When combined with statin therapy, PCSK9 inhibitors

A

provide potent LDL-C lowering

(50% to 70%). They may also be considered for patients with high ASCVD risk and statin intolerance.

111
Q

PCSK9

inhibitors are only available as

A

subcutaneous injections and are administered every two to four weeks. Monoclonal
antibodies are not eliminated by the kidneys and have been used in dialysis patients or those with severe renal
impairment. PCSK9 inhibitors are generally well tolerated. The most common adverse drug reactions are injection
site reactions, immunologic or allergic reactions, nasopharyngitis, and upper respiratory tract infections.

112
Q

CHOLESTEROL ESTER TRANSFER PROTEIN

INHIBITOR (CETP INHIBITOR)

A
  • The first drug in this class, Torcetrapib, aroused great interest because they it
  • markedly increased HDL and reduced LDL
  • However, it was withdrawn from the clinical trial because it increased cardiovascular event and death in the treatment group
  • Anacetrapib and Dalcetrapib are analogs currently in clinical trials
113
Q

CETP in HDL

A

facilitate exchange of triglyceride and

cholesterol ester from HDL and VLDL

114
Q

Treatment with Drug Combination

A
  1. When VLDL are significantly increased during
    treatment of hyperchole with resin
  2. LDL and VLDL elevated initially
  3. LDL or VLDL normalized with single agent
  4. Elevated lp(a) or HDL deficiency coexist with
    other hyperlipidemia
115
Q

Omega-3 fatty acids

A

Omega-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are predominately used for triglyceride
lowering. Essential fatty acids inhibit VLDL and triglyceride synthesis in the liver

116
Q

The omega-3 PUFAs

A

eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in marine sources such as tuna, halibut,
and salmon. Approximately 4 g of marine-derived omega-3 PUFAs daily decreases serum triglyceride
concentrations by 25% to 30%, with small increases in LDL-C and HDL-C

117
Q

Icosapent [eye-KOE-sa-pent] ethyl

A

prescription product that contains only EPA and,
unlike other fish oil supplements, does not significantly raise LDL-C. Omega-3 PUFAs can be considered as an
adjunct to other lipid-lowering therapies for individuals with elevated triglycerides (≥500 mg/dL).

118
Q

The most common side effects of omega-3 PUFAs include

A

GI effects (abdominal pain,
nausea, diarrhea) and a fishy aftertaste. Bleeding risk can be increased in those who are concomitantly taking
anticoagulants or antiplatelet agents.

119
Q

Ezetimibe and PCSK9 inhibitors

A

can be
considered for add-on therapy, since there is evidence that these combinations further reduce ASCVD events in
patients already taking statin therapy

120
Q

Liver and muscle toxicity

occur more frequently with

A

lipid-lowering drug combinations

121
Q

statins

A

Lower LDL strongly
Increase HDL moderately
Lower Triglycerides- moderately

122
Q

Fibrates

A

Mild effect on LDL lowering
high effect inn HDL increase
Strong lowering effect on Trigluycerides

123
Q

Niacin

A

mild lowerinf of LDL
High increase in HDL
Moderate effects in lowering Triglycerides

124
Q

BABR

A

Mild effect in LDL decrease

Mild increase in HDL and Triglycerides

125
Q

CABI

A

mild lowering of LDL and Triglycerides

Mild increase in HDL

126
Q

PCSK9 inhib

A

High lowering of LDL
Moderate incrwase in HDL
low effect on Triglycerides

127
Q

R.L., a 42-year-old man with moderately severe coronary
artery disease, has a body mass index (BMI) of 29,
increased abdominal girth, and hypertension that is well
controlled. In addition to medicine for hypertension, he is
taking 40 mg atorvastatin.
Current lipid panel (mg/dL)
• Cholesterol: 184
• Triglycerides: 200
• Cholesterol (LDL-C): 110
• HDL-C: 34
• non-HDL-C: 150
• Lipoprotein(a) (Lp[a]) is twice normal.
• Fasting glucose is 102 mg/dL, and fasting insulin
is 38 microunits/mL.
• Liver enzymes are normal.
• Creatinine kinase level is mildly elevated.
The patient is referred for help with management of his
dyslipidemia. You advise dietary measures, exercise and
weight loss.
Which additional drugs would help him achieve his
lipoprotein treatment goals. LDL-C: 60-70 mg/dL,
Triglycerides: <120 mg/dL, HDL-C: >45 mg/ dL and
reduced level of Lp(a)?

A

NIACIN to markedly increase the HDL level. You
can give STATIN but Creatinine Kinase is mildly elevated
since an adverse effect of using STATIN is myopathy.
STATIN cannot markedly increase the HDL level.

128
Q

Would this patient also benefit from a drug to manage

insulin resistance? If so, which drug?

A 
• Best drug for patients suffering from metabolic
syndrome: STATIN because patients with
Metabolic Syndrome have increased LDL,
decreased HDL, increased TG
• Would cause pruritus? NIACIN
• Myopathy? Niacin
• Bloating? BA-BR
• Contraindicated in pregnancy- Statins
• Would increase the risk for gallstones? BA-BR

Pharmacology (19 decks)

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