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Hyperlipidemic Drugs Flashcards

1
Q

Lipid Membrane

A

Phospholipids

Cholesterol

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2
Q

Hydrophobic core

A

Triglycerides

Cholesterol Esters

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3
Q

Apolipoproteins

A

Structural proteins and ligands for particle uptake

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4
Q

LDL

A

Bad

60% Cholesterol

25% Triglyceride

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5
Q

IDL

A

35% Cholesterol

55% Triglyceride

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6
Q

VLDL

A

20% Cholesterol

55% Triglyceride

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7
Q

Chylomicrons

A

85% Triglyceride

3% Dietary Cholesterol

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8
Q

HDL

A

Good

35% Phospholipid

20% Cholesterol

5% Triglyceride

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9
Q

LDLs and atherosclerosis

A

Endothelial injury allows LDL to enter

Monocytes migrate to activated endothelium

Foam cells (full of cholesterol) secrete proteases and GF to activate SMC proliferation

Increased ECM, increased migration of SMC = growing atherosclerotic plaque

Necrotic foam cells release cholesterol/debris = fatty streak

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10
Q

Protective Role of HDL

A

Inhibit oxidation of LDLs

Inhibit expression of adhesion molecules on endothelium

Inhibit formation of foam cells

Promote REVERSE CHOLESTEROL TRANSPORT (periphery -> liver -> bile)

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11
Q

Very High Lipid Levels

A

LDL-C: >190 mg/dL

Triglyceride: >500 mg/dL

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12
Q

Moderate Hypercholesterolemia with low CV risk

A

Therapeutic lifestyle change

Dietary reduction of cholestrol intake

Exercise/ weight reduction

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13
Q

Severe Hypercholesterolemia and/or a high CV risk

A

LDL > 190 or 70w/diabetes

Clinical evidence of CVD 10 yr

CVD risk

Drug therapy: reduce LDL via STATIN

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14
Q

STATINs

A

Most prescibed drug in US

Significant reduction in LDL

Modest reduction in TG

Modest increase in HDL

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15
Q

STATINs MoA

A

HMG-CoA analog (rate-limiting enzyme in cholesterol biosynthesis) and act as substrate for HMG-CoA reductase

Competetively inhibit HMG-CoA reductase

Decrease endogenous cholesterol synthesis

Triggers signal to activate SREBP transcription factor

SREBP upregulates expression of LDL receptor gene

More LDL receptors

More LDL is taken up from bloodstream

Decreased serum LDL

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16
Q

Other activities of STATINs

A

Inhibits endothelial adhesion molecule expression

Inhibits adhesion of monocytes to endothelium

Inhibits monocyte proliferation and migration

Inhibits oxidation of LDLs (decreases Foam cell formation)

Inhibits SMC proliferation

Inhibits inflammatory responses

Stabilizes endothelium (decreases risk of plaque rupture)

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17
Q

Therapeutic Use of STATINs

A

Drug of choice for increased LDL

Drug of choice for primary and secondary prevention of CVD

STATINS EFFECTIVE IN REDUCING CHD RISK IRRESPECTIVE OF INITIAL BASELINE LDL

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18
Q

Dosing of STATINs

A

Doubling dose minimally improves efficacy while increasing potential for adverse effects

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19
Q

STATIN

Adverse Effects

A

Generally well tolerated

Rare: increase in liver enzymes

Type2 diabetes has small increase in risk

RHABDOMYOLYSIS: Myalgia and myopathy

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20
Q

Rhabdomyolysis

A

Muscle inflammation and disintegration

Rare side effect from statin use

Fever, malaise, myalgia, elevated serum CK, myoglobin, dark urine

High STATIN doses or drug interactions (CYP34A inhibitors)

Polymorphism of STATIN HAT

PRAVASTATIN has fewer adverse muscle effects

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21
Q

STATINs

A

Most potent -> least potent

Rosuvastatin (Crestor)

Atorvastatin (Lipitor)

Simvastatin (Zocor)

Pravastatin (Pravachol)

Lovastatin (Mevacor)

Fluvastatin (Lescol)

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22
Q

STATIN

Pharmacokinetics

A

Absorbed in intestine

Interaction with grapefruit juice DEC bioavailability

Taken up in liver by OATP2

5-30% bioavailability

Metabolized in liver and excreted in bile/feces

Glucoronidated

Variably metabolized by CYP450 system

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23
Q

STATIN Drug Interactions

CYP34A inhibitors

A

INCREASE L,S,A

Cyclosporin, erythromycin, ketaconazole, HIV protease inhibitors, grapefruit juce, Ca-channel blockers, anti-arrhythmia drugs (amiodarone), warfarin

24
Q

STATIN Drug Interactions

CYP2C9 Inhibitors

A

INCREASE F, R

Ketoconazole, itraconazole, metronidazole, sulfinpyrazone

25
STATIN Drug Interactions Inducers of CYP2A4
Reduce L,S,A Reduce clinical efficacy Phenytoin Barbiturates Rifampin Thizolidnediones
26
STATIN Drug Interactions General
Pravastain is NOT metabolized by P450, drug of choice when interactions are a concern (transplant patients) Gemfibrozil: inhibits OATP2 and increases ALL statins, rhabdomyolysis
27
STATIN Contraindications
Pregnancy, nursing mothers (inhibition of cholesterol synthesis may adversely affect the newborn) Liver disease
28
Bile Acid-Binding Resin Clinical Effect
Modest reduction in LDL Can cause small increase in TG
29
Bile Acid-Binding Resins
Cholestyramine (Questran) Colestipol (Colestid) Colesevelam (Welchol)
30
Bile Acid-Binding Resin MoA
Cationic polymers Bind to (-)bile acids, prevent reaborption in small intenstine Causes increase bile acid production, decreases hepatic holesterol concentration Upregulation of LDL-R Increases LDL clearance
31
Therapeutic Use of Bile Acid-Binding Resin
Second line agent to reduce CHD events Used in combination with STATIN (aggressively reuduce) Used in patient who can't have STATINs (children, PREGGOS)
32
Bile Acid-Binding Resin Side Effects
Not absorbed or metabolized Very safe/few side effects GI disturbances Cholestyramine and Colestipil impair absorption of fat soluble vitamins (ADEK)
33
Bile Acid-Binding Resins Drug Interactions
Cholestyramine and Colestipol, but NOT Colesevelam, interfere with absorption of many drugs. Should be taken 1-2 hours before or 4-6 hours after Resins
34
Bile Acid-Binding Resins Contraindications
TYPE IIY Dysbetalipoproteinemia Raised triglycerides Increased VLDL levels can lead to pancreatitis
35
Inhibitors of Cholesterol Absorption
Ezetimibe (Zeita)
36
Inhibitors of Cholesterol Absorption MoA
Inhibits NPC1L1 protein in intestine, cholesterol not absorbed Reduced cholesterol decreases VLDL and LDL production LDL-R increased, more cholesterol taken up from serum
37
Inhibitors of Cholesterol Absorption Therapeutic Uses
Reduces LDL in patients Not dependent on intact LDL-R Combined with STATIN significantly reduces LDL levels (more efficacy, less STATIN side effects)
38
Inhibitors of Cholesterol Absorption Adverse Effects
Generally well tolerated GI disturbance: flatulence and diarrhea
39
Inhibitors of PCSK9
Alirocumab Evolocumab
40
Inhibitors of PCSK9 MoA
PCSK9 is secreted by liver, binds to LDL-R and prevents LDL-R recycling (instead sends it to lysosome) Thought to be responsible for tonically controlling the levels in LDL-R expressed on liver cells Some people with FH have gain of function mutations and have overactive protein Drugs are human antibodies to the protein, prevents it from binding to the LDL-R
41
Lomitapide
New drug for homo FH Mutation in LDL- R, cannot treat with STATIN Inhibits microsomal TG transfer protein (MTP) MTP required for assembly of chlyo/VLDLs Less chylo/VLDL, less LDL
42
Mipomersen
New drug for homo FH Mutation in LDL-R, cannot treat with STATINs Antisense oligonucleotide for apoB100 Reduces apoB100, less production of VLDL, less LDL
43
Tx Options for Hyperglyceridemia
TG 150-199: Lifestyle modifications TG \> 500: lower TG with drugs, prevent pancreatitis
44
Niacin Clinical Effect
Nicotonic acid with vit B3 30-80% reduction in TG 10-20% reduction in LDL 10-30% increase in HDLs\*\*\*\*(most effective drug) FH, dysbetalipoproteinemia, (cholesterol and TG are elevated) Often combined with STATINs or Resins
45
Niacin MoA
1. Agonist for Gi receptor in adipose (inhibits lypolysis, reduces FFA, less TG synthesis/less VLDL 2. Inhibits DGAT2, RLE in hepatic TG synthesis, reduces hepatic VLDL synthesis 3. Reduces liver ApoC3, increased LPL activity, VLDL breakdown, increased VLDL clearance 4. Increase 1/2 life ApoAI, increases [serum HDLs}, reverse cholesterol transport 5. Inhibits macrophage recruitment to atherosclerotic lesions
46
Niacin Adverse Effects
GI distress, nausea, abdominal pain Skin flushing/itching (tx with NSAIDs) Inhibits uric acid secretion -\> GOUT Exacerbate peptic ulcers Modest hyperglycemia in Type2 diabetes Rare: Hepatic toxicity
47
Niacin Contraindications
Peptic Ulcer disease Pts with hx of Gout Caution in diabetics Caution in pts with impaired liver function
48
Fibrates
Fenofibrate (Tricor/Lofibra) Gemfibrozil (Lopid)
49
Fibrates Clinical Effect
40-60% reduction in Tg Mild (10-20%) reduction in LDL 10-30% increase in HDL Tx of dysbetaliporoteniema and Type III hyperlipoproteinemia Reduce coronary events, stroke and TIA
50
Fibrates MoA
Ligands for nuclear hormone TF PPARalpha Activate PPARalpha and express genes involved in FFA oxidation/transport Increased HDL, decreased TG
51
Fibrates Adverse Effects
Generally well tolerated Mild GI disturbance Increased predisposition to galltones (inhibit cholesterol 1alpha-hydroxylase) Myopathy and Rhabdomyolysis (more common in Gem), increased risk with HIGH DOSE STATIN Hepatitis
52
Fibrates Drug INteractions
Strong protein binder, displace other drugs (warfaring, sulfonylureas) Gem can increases serum [STATINs] and cause myopathy and rhabdomyolysis Fenofibrate is durg of choice for combination therapy
53
Fibrates Contraindications
PREGGOS Severe hepatic dysfunction/renal disease Pre-existing gallbladder disease (the increased risk of gallstones)
54
Fish Oils
Omega 3 long chain polyunsaturated fatty acids Eicosapentaenoic acid Docosahexaenoic acid
55
Fish Oils Clinical Effect
Lowers serum TG Minor increase in HDL Increase of LDL in some pts
56
Fish Oils Therapeutic Uses
Only as an adjunct to diet in treatment of hypertriglyceridema in individuals with TG \> 500
57
Fish Oils MoA
Unclear, maybe inhibits expression of genes involved in TG synthesis Anti-inflammatory activity (acts via GPC-R expressed on macrophages)

Pharmacology (44 decks)

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