Atherosclerosis Pharmacology

Question 1

How do cells obtain/regulate cholesterol?

Answer 1

1. receptor-mediated uptake of LDL cholesterol
2. de novo synthesis
3. excess cholesterol stored as cholesterol esters (ACAT enzyme)
4. diet

Question 2

What is the relationship between HDL-C and CHD, for any level of LDL-C?

Answer 2

For any level of LDL-C, HDL-C is inversely related to CHD risk

Question 3

Therapeutic overview: Why do we administer cholesterol treatment?

Answer 3

1. Reduce formation and rate of progression in coronary and peripheral atherosclerosis from childhood to old age
2. Prevention of coronary events and strokes in apparently healthy persons at risk, particularly middle-aged and elderly
3. Prevention of heart attacks, strokes, need for revascularization in persons with established atherosclerosis
4. Prevention and treatment of pancreatitis in hypertriglyceridemia

Question 4

What is the dominant mechanism for controlling hepatic LDL plasma concentrations?

Answer 4

REGULATION OF HEPATIC LDL RECEPTOR PATHWAY

Question 5

What is ASCVD?

Answer 5

Atherosclerotic cardiovascular disease

• Heart attacks + strokes + peripheral arterial disease

Question 6

What is the basis of treating lipid disorders that cause ASCVD?

Answer 6

• Lowering LDL with statins lowers risk
• Base treatment on risk
• Secondary prevention (already has ASCVD event) is treated aggressively with high intensity statin
• Primary prevention (no clinical disease) is assessed.
  
  • If 10-year risk
    
    • > 7.5% ⇒ treat with statins
    • 5% to 7.5% ⇒ review other risk factors
    • < 5%, ⇒ lifestyle
• Everyone else (kids) ⇒ primordial risk ⇒ lifestyle

Question 7

List the HMG CoA Reductase Inhibitors/Statins:

Answer 7

1. Atorvastatin (Lipitor) (synthetic compound)
2. Lovastatin (Mevacor) (fungal metabolite)
3. Simvastatin (Zocor) (synthetic compound)
4. Pravastatin (Pravachol) (fungal metabolite)
5. Rosuvastatin (Crestor) (synthetic compound)
6. Fluvastatin (Lescol) (synthetic compound)

Question 8

**Statins: **

Mechanism of Action

Answer 8

• Competitive inhibitor for active site on HMG CoA reductase
  
  • Rate limiting step in cholesterol biosynthesis
  • statins inhibit HMGR by binding to the active site of the enzyme, thus sterically preventing substrate from binding
• Structural analog of the HMG CoA intermediate
  
  • All statins share a structural component that is very similar to the HMG portion of HMG-CoA
  • more bulky and more hydrophobic than HMG-CoA

Question 9

How do statins affect the LDL receptor?

Answer 9

• increase in LDL receptor gene
  
  • mechanism:
    
    • In response to the reduced free cholesterol content within hepatocytes, membrane-bound Sterol Regulatory Element-Binding Proteins (SREBPs) are cleaved by a protease and translocated to the nucleus
    • transcription factors then bind the sterol-responsive element of the LDL receptor gene
    • enhance transcription
    • increase the synthesis of LDL receptors
• up-regulation of LDL receptor results in increased catabolism of LDL
  
  • Plasma concentration of LDL falls
  • less LDL is available to react with cellular elements in blood and blood vessel walls

Question 10

Pharmacokinetics of Statins:

Answer 10

Extensive first-pass metabolism by the liver

• Limits systemic bioavailability
• Targets liver/site of action
  
  • mediated primarily by the organic anion transporter OATP1B1

Question 11

1. All the statins, except simvastatin and lovastatin, are administered in the what form?
2. What form are simvastatin and lovastatin adminstered?

Answer 11

1. **-hydroxy acid **
   
   • which is the form that inhibits HMG-CoA reductase
2. lactones
   
   • converted to the -hydroxy acid form via the liver

Question 12

What is the major CYP reponsible for metabolizing atorvastatin, lovastatin and simvastatin?

Answer 12

CYP3A4

Question 13

What are the half-lives of the different statins?

Answer 13

1. lovastatin (1 - 4 hours)
2. simvastatin (1 - 2 hours)
3. atorvastatin ( 20 hours )

Question 14

What do statins have a high affinity for?

Answer 14

highly bound to plasma proteins

Question 15

**Statins: **

Major Adverse Effect

Answer 15

all statins have been associated with myopathy and rhabdomyolysis

Question 16

Definitions:

1. Myopathy
2. Rhabdomyolysis

Answer 16

1. Myopathy
   
   • muscle pain without creatinine kinase (CK) elevation or less frequently with mild CK elevation
   • Muscle disease/weakness
2. Rhabdomyolysis
   
   • muscle symptoms with marked CK elevation and with creatinine elevation
   • breakdown of muscle fibers that leads to the release of myoglobin into the bloodstream
   • Myoglobin is harmful to the kidney and often causes kidney damage

Question 17

What are minor adverse effects caused by statins?

Answer 17

• GI side effects
• Increase in liver enzymes

Question 18

Myopathy risk increases in ______ relationship to statin dose and plasma concentration

Answer 18

Myopathy risk increases in direct relationship to statin dose and plasma concentration

Question 19

How do genetics play a role in statin intolerance?

Answer 19

• A single nucleotide polymorphism in SLCO1B1
  
  • ​which encodes an organic anion transporter that regulates the hepatic uptake of statins
• Genetic variants of SLCO1B1 lead to reduced hepatic uptake and increased levels of statins in the blood,
  
  • provide the mechanism for increased risk of myopathy

Question 20

What other drugs can increase the risk of myopathy when taken in combination with statins?

Answer 20

• Drugs are those metabolized primarily by CYP3A4
  
  1. certain macrolide antibiotics (e.g., erythromycin )
  2. azole antifungals (e.g., itraconazole )
  3. cyclosporine
  4. HIV protease inhibitors
  5. gemfibrozil
     
     • inhibits OAT1B1
     • interferes with transformation of most statins by glucuronidases
• Associated with increased plasma concentrations of statins and their active metabolites

Question 21

What is contraindicated in statin therapy?

Answer 21

• Hypersensitivity
• Active liver disease
• Women who are pregnant, lactating, or likely to become pregnant should not be given statins
  
  • May down-regulate biosynthesis of cholesterol as well as many important metabolic intermediates
  • May have secondary effects on sterol-dependent signaling molecules (Sonic Hedgehog)

Question 22

Statin Lipoprotein Profile:

1. TG
2. LDL
3. HDL

Answer 22

1. TG
   
   • > 250 mg/dl: decrease by 20-55%
   • < 250 mg/dl: decrease by 25%
   • the higher the baseline TG level, the greater the TG-lowering effect​
2. LDL
   
   • ​decrease by 20-55%
3. HDL
   
   • ​increase by 5-10%​

Question 23

Statins:

Clinical Use

Answer 23

First line therapy in hypercholesterolemia when at risk for myocardial infarction

Question 24

Statins are effective in almost all patients with high LDL-C levels. What is the exception?

Answer 24

patients with homozygous familial hypercholesterolemia

• have very attenuated responses to the usual doses of statins because both alleles of the LDL receptor gene code for dysfunctional LDL receptors
• the partial response in these patients is due to a reduction in hepatic VLDL synthesis associated with the inhibition of HMG-CoA reductase–mediated cholesterol synthesis

Question 25

Statins: Potential Cardioprotective Effects Other Than LDL Lowering

Answer 25

1. Increased endothelium-dependent relaxation 2. Stabilize plaques/prevent plaque rupture 3. Decrease LDL oxidation 4. Decrease platelet aggregation 5. Decrease C-reactive protein

Question 26

Bile Synthesis and Function

Answer 26

* _Cholesterol converted to bile acid by enzyme 7alpha-hydroxylase_ * Conjugated bile acids secreted from the liver and stored in the gall bladder * passed through the bile duct into the intestine * Function is to **emulsify lipids in food to enable fat digestion and absorption** through the intestinal wall. * _Most bile acids are reabsorbed_, returned to the liver via the portal vein, and _re-secreted_ * **Conversion to bile salts is the only mechanism by which cholesterol is excreted (~0.8 g/day)**

Question 27

Name a bile acid-binding agent:

Answer 27

**cholestyramine**

Question 28

**Cholestyramine: ** **Mechanism of Action**

Answer 28

* **anion-exchange resins** * _highly positively charged and binds negatively charged bile acids_ * _Large size_ ⇒ resins are not absorbed, and the bound bile acids are excreted in the stool * more than 95% of bile acids are normally reabsorbed. * interruption of this process depletes the pool of bile acids ⇒ _hepatic bile-acid synthesis increases_ * As a result, _hepatic cholesterol content declines_, _stimulating the production of LDL receptors_ * an effect similar to that of statins

Question 29

How is cholestyramine similar to statins?

Answer 29

Like statins, **bile acid binding resins lower intracellular cholesterol** ⇒ **activates the SREBP transcription factor** ⇒ **increases LDL receptor gene transcription**

Question 30

**Cholestyramine****:** ## Footnote **Pharmacokinetics**

Answer 30

* Quaternary amine, hygroscopic powder administered as chloride salt/insoluble in water * **Pharmacokinetics** * **not absorbed** * reduction in plasma cholesterol concentrations usually seen within first month of therapy * stop drug, levels return to normal in 1 month

Question 31

**Cholestyramine:** **Adverse Effects**

Answer 31

* **most common-constipation/bloating sensation** * gritty consistency * nausea and vomiting * constipation * interferes with absorption of other drugs * Digitalis, thiazides, warfarin, statins, aspirin * modest INCREASE in TG/with time returns to baseline values

Question 32

**Cholestyramine Lipoprotein Profile** 1. **TG** 2. **LDL** 3. **HDL**

Answer 32

1. **TG** * ​​**Normal levels:** only transient increase * **Levels \> 250 mg/dl:** further significant increase 2. **LDL** * **​**decrease by 12-25%​ 3. **HDL** * increase by 4-5%

Question 33

**Cholestyramine: ** **Clincal Uses**

Answer 33

* _hypercholesterolemia_ * Not recommended for individuals with hypercholesterolemia and increased TG * most often used as _second agents if statin therapy does not lower LDL-C levels sufficiently_ * recommended for patients _11-20 years of age_

Question 34

What is the main effect of **nicotinic acid (niacin)?**

Answer 34

**MAIN EFFECT IS TO DECREASE TG** * _But it does decrease cholesterol_ * Water-soluble B-complex vitamin * Lipid lowering effect is unrelated to its effect as a vitamin * Much larger doses required

Question 35

Describe how **niacin** acts in **adipose tissue:**

Answer 35

**inhibits FFA mobilization** * role for **niacin receptor 1** (GPR109A) in adipose tissue 1. Activation of receptor causes a decrease in cAMP 2. No activation of PKA 3. No phosphorylation of perilipin and Hormone Sensitive Lipase (HSL) 4. No conformational change in perilipin 5. So no access of HSL to TG in the fat droplet 6. TG IS NOT broken down into glycerol and FFA 7. A DECREASE in FFA that is delivered to the liver 8. Decrease in VLDL synthesis means overall decrease in TG

Question 36

Describe how **niacin** acts in the **liver:**

Answer 36

**decreases synthesis of VLDL-TG** * **Inhibits DGAT2** (diacylglycerol acyltransferase 2), * enzyme that catalyzes the final reaction in TG synthesis 1. _Inhibits synthesis and reesterification of fatty acids_ 2. _Increases ApoB degradation_ * apoB is major protein of VLDL/LDL

Question 37

Describe how **niacin** affects **HDL:**

Answer 37

* **increases HDL-apoAI particles** * inhibits hepatocyte surface expression of ß-chain ATP synthase * **increases HDL biogenesis** * increasing hepatic expression of ABCA1 This is a _GOOD THING_

Question 38

**Nicotinic Acid (Niacin): ** **Pharmacokinetics**

Answer 38

* **Oral** administration * 3 different formulations * immediate release * Long acting release * extended release preparation * Remember that _doses_ used for lowering cholesterol/TG _much greater than those used as vitamin_ * Prescription only

Question 39

**Nicotinic acid (niacin):** **Major Adverse effect**

Answer 39

**MAJOR ADVERSE EFFECT** * **Intense cutaneous flush/pruritus** * Occurs soon after taking the drug * poor compliance * Mediated by vasodilatory PGs * PGD2 from dermal macrophages * use of NSAIDs to block the effect

Question 40

**Nicotinic acid (niacin): ** **Other Adverse Effects**

Answer 40

* GI effects * nausea/vomiting, abdominal pain, diarrhea * Avoid in patients with peptic ulcer * _elevated liver enzymes/usually no hepatic toxicity_ * **BUT MAJOR concern if combined with statins** * Hyperurecemia * Contraindicated in patients with gout * Increases fasting glucose levels/niacin-induced insulin resistance * Questionable use in patients with diabetes

Question 41

What are the contraindications for niacin?

Answer 41

1. Peptic Ulcer 2. Gout 3. Hepatic Disease 4. Diabetes

Question 42

What can happen if niacin is combined with statins?

Answer 42

Combined use with statin _increases risk of myopathy_

Question 43

**Niacin Lipoprotein Profile** 1. **TG** 2. **LDL** 3. **HDL** 4. **Lp(a)**

Answer 43

1. **TG** decreased by 35-50% * Within 4-7 days 2. **LDL** decreased by 25% * 3-6 weeks for maximal effect 3. **HDL** increased by 15-30% * added benefit is increased HDL 4. **Lp(a)** reduced by 40% * May be risk factor

Question 44

**Nicotinic acid (niacin): ** **Clincal Uses**

Answer 44

* **Hypercholesterolemia & hypertriglyceridemia** * High LDL and low HDL * Typically not first line therapy for hypercholesterolemia * Severe cases that do not respond to resins * _Not first choice because of side effects_ * _Only lipid-lowering drug that reduces Lp(a)_

Question 45

**What inhibits cholesterol absorption?**

Answer 45

**Ezetimibe**

Question 46

**Ezetimibe: ** **Mechanism of Action** * What is the net result?

Answer 46

**inhibits cholesterol transfer from intestinal lumen into intestinal cell** * binds to a protein transporter called **Niemann Pick Cl-like 1 protein** (NPCL1) * on or within brush border membranes of intestinal cells. * **net result:** * decreased rate of cholesteryl ester incorporation into chylomicrons * reduced flux of cholesterol from intestine to liver * reduced flux of cholesterol to VLDL * _lowers plasma LDL-C because increased expression of LDL receptors_

Question 47

**Ezetimibe:** **Pharmacokinetics**

Answer 47

* **Oral** administration * _Metabolized (glucuronidation) to active metabolite_ * Half-life: 22 hours

Question 48

**Ezetimibe: ** **Adverse Effects**

Answer 48

* Well tolerated * Side effects increase if combined with other drugs, like statins

Question 49

**Ezetimibe Lipoprotein Profile** 1. **TG** 2. **LDL** 3. **HDL**

Answer 49

1. **TG** * decrease by 5% 2. **LDL** * decrease by 15-20% 3. **HDL** * increase by 1-2%

Question 50

**Ezetimibe:** **Clinical Uses**

Answer 50

* **Primary hypercholesterolemia** * Combined with statins * Simvastatin + ezetimibe * Further decrease in LDL-cholesterol * Two differing pharmacological approaches

Question 51

What is a potential downside to combination therapy of ezetimibe + statins?

Answer 51

**may increase risk of myopathy**

Question 52

What are the **Fibric Acids/Fibrates/PPAR activators?** What is the general function of these drugs?

Answer 52

1. **Gemfibrozil** 2. **Fenofibrate** (2nd generation drug) * Primarily lower the levels of TG-rich lipoproteins

Question 53

**Fibric Acids/Fibrates/PPAR activators:** **Mechanism of Action**

Answer 53

* effects mediated by _interaction with peroxisome proliferator activated receptors_ (PPARs) that regulate gene transcription * _bind to PPAR-alpha_ (expressed 1˚ in liver and brown adipose tissue) * _PPAR bind as heterodimers with retinoid X receptor_ to specific response elements and _alter the transcription rate_ of target genes

Question 54

What are the net effects of fibric Acids/fibrates/PPAR activators?

Answer 54

1. increased lipolysis and plasma clearance of TG-rich lipoproteins * activation of lipoprotein lipase * reduce production of lipoprotein lipase inhibitor, apoCIII 2. reduced availability of FFA for TG synthesis * increase B-oxidation pathway 3. c. inhibition of de novo fatty acid synthesis * decrease acetyl-CoA carboxylase * decrease fatty acid synthase 4. increases in HDL – cholesterol * increases synthesis of 2 proteins in HDL: apoA1 and apoAII

Question 55

**Fibric Acids/Fibrates/PPAR activators: ** **Pharmacokinetics** * What is the difference of metabolism between **fenofibrate** and **gemfibrozil**?

Answer 55

* **Oral** administration * _Plasma protein binding_ * _Half-life varies_ (1 hr for gemfibrozil/20 hrs for fenofibrate (increased with renal impairment) 1. **Fenofibrate** is _metabolized to active metabolite_ * excreted predominantly as glucuronide conjugates * 60-90% of an oral dose is excreted in the urine 2. **Gemfibrozil** _metabolized into inactive metabolites_

Question 56

**Fibric acids/Fibrates/PPAR actvators:** **Adverse effects**

Answer 56

**Generally well-tolerated** * GI symptoms-most common * Increased risk of gall stones * Less common are hematological/hepatic function abnormalities * increased creatine kinase if also being treated with a statin….lead to renal failure * Use is contraindicated in patients with renal impairment * Gemfibrozil can increase systemic statin concentrations by blocking transporter in liver

Question 57

What drugs does **gemfibrozil** interact with?

Answer 57

**Statins** * Gemfibrozil _inhibits uptake of active hydroxy acid forms of statins_ by transporter * first-pass hepatic uptake of these statins by transporter _OATP1B1_ after their oral administration * If not taken up into liver, _increased plasma concentration_

Question 58

**Fibric acid Lipoprotein Profile** 1. **TG** 2. **LDL** 3. **HDL**

Answer 58

1. **TG** * decrease 30-50% 2. **LDL** * decrease 15-20% * HIGHLY VARIABLE * 2nd generation drugs (fenofibrate) more likely to decrease LDL 15-20% in patients with TG \< 400 mg/dL 3. **HDL** * increase 5-15%

Question 59

**Fibric acids/Fibrates/PPAR activators****:** ## Footnote **Clinical Uses**

Answer 59

patients with _high TGs and low HDL_ associated with metabolic syndrome or type 2 diabetes * treatment of hypertriglyceridemia * reduces the risk of CHD development in Fredrickson type IIb

Question 60

**Drugs of choice for hypercholesterolemia:** What are some things to consider when choosing such drugs?

Answer 60

1. **HMG CoA reductase inhibitors**-first choice agents * Which one? * Safety? * Lifetime treatment 2. **Bile acid resins** * Long-term safety * Younger patient age range * Add on to statins 3. **Ezetimibe** * Safety as monotherapy vs MAYBE…add-on to statins 4. **Niacin** 1. Patient compliance side effects 2. Both elevated TG and cholesterol 3. Low HDL 4. Care when combined with statins

Question 61

**Drugs of choice for hypertriglyceridemia:**

Answer 61

1. **gemfibrozil/fenofibrate** * drug of choice in patients with _type III hyperlipoproteinemia and severe hypertriglyceridemia_ (TG \> 1000 mg/dl) 2. **niacin** * second line choice 3. **omega-3 fatty acid**

Question 62

What are the **omega-3-fatty acids** that have therapeutic effects?

Answer 62

* **Eicosapentaenoic acid** * (EPA 20:5 n−3) * **Docosahexaenoic acid** * (DHA 22:6 n−3)

Question 63

What is the therapeutic mechanism of omega-3-fatty acids?

Answer 63

* **inhibit (−) lipogenesis** * inhibit diacylglycerol acyl transferase (DGAT), phosphatidic acid phosphohydrolase (PA), and hormone-sensitive lipase * **stimulate (+):** * β-oxidation * phospholipid synthesis * apolipoprotein (apo) B degradation * end result is a _reduced rate of secretion of very-low-density lipoprotein_ (VLDL) _TG_

Question 64

Omega-3-fatty acids: Pharmacokinetics

Answer 64

* **Oral:** * 4 g/day as a single daily dose or in 2 divided doses * _Onset of action is slow_

Question 65

Omega-3-fatty acids: Adverse Effects

Answer 65

* _Fish allergy_ * May increase LDL levels * May increase liver enzymes * Prolongation of bleeding time has been observed in some clinical studies

Question 66

What are omega-3-fatty acids clinically used for?

Answer 66

_Adjunct_ to diet therapy in the _treatment of hypertriglyceridemia_ (≥500 mg/dL)

Question 67

What are targets of future drug therapies?

Answer 67

1. **Proprotein convertase subtilisin/kexin 9 (PCSK9) Inhibitors** 2. **Microsomal triglyceride transfer protein (MTP) Inhibitors** 3. **Apolipoprotein B-100 (apoB-100) Inhibition**

Question 68

Describe the **physiological role of** **PCSK9** (Proprotein convertase subtilisin/kexin type 9): Why is it a potential target for therapy?

Answer 68

* **Decreases the steady-state level of expression of the LDL receptor on the hepatocyte cell membrane** * Autocatalytic cleavage in the ER followed by secretion into plasma where it _binds the EGF-A domain of the LDLr_ * LDLr/PCSK9 complex gets internalized and _targeted to the lysosomal compartment for degradation_ ⇒ * _Inhibition of the recycling of the LDLr back to the cell surface_ ⇒ **increased plasma LDL levels** (antibodies, siRNA) * _No change in plasma cholesterol levels_ in PCSK9/LDLr KO’s ⇒ _effect of PCSK9 is mediated solely via LDLr_

Question 69

What does a _PCSK9 antibody_ prevent? * What is the result?

Answer 69

PCSK9 antibody prevents **binding of PCSK9 to the LDLR-LDL complex** * _Result:_ * increases the availability of cell-surface LDLRs

Question 70

What is **microsomal triglyceride transfer protein** (MTP)? What is its role?

Answer 70

* **major cellular protein that transfers neutral lipids between membrane vesicles** * _essential chaperone for the biosynthesis of apolipoprotein B_ (apoB)-containing triglyceride-rich lipoproteins * abetalipoproteinemia patients carry mutations in the MTTP gene resulting in the loss of its lipid transfer activity. * **Role in the regulation of cholesterol ester biosynthesis**

Question 71

What is the FDA approved **MTP inhibitor**? What is the mechanism of action?

Answer 71

* _Lomitapide_ * **directly binds to and inhibits MTP** * MTP inhibition _prevents the assembly of apo-B containing lipoproteins_ in enterocytes and hepatocytes _resulting in reduced production of chylomicrons and VLDL_ and _subsequently reduces plasma LDL-C concentrations_

Question 72

**MTP Inhibitors: ** **Clinical Use**

Answer 72

Adjunct to dietary therapy and other lipid-lowering treatments to reduce: * LDL-C * total cholesterol * apolipoprotein B * non-HDL-C in patients with **homozygous familial hypercholesterolemia**

Question 73

What is **apolipoprotein B-100?** What is its function?

Answer 73

* structural apolipoprotein that is an **essential component of LDL-C and VLDL** * ApoB-100 is the ligand that _binds LDL to its receptor_ and is important for the _transport and removal of atherogenic lipids_ * _Elevated levels of apoB_, LDL-C and VLDL are _associated with increased risk of atherosclerosis and cardiovascular diseases_

Question 74

What is the FDA approved **Apo B-100 inhibitor**? What is the mechanism of action?

Answer 74

Mipomersen * 20-base sequence second-generation _antisense oligonucleotide_ developed to _inhibit synthesis of apoB-100_ in the liver * hybridizes within the coding region of apoB-100 mRNA and _activates RNase H_ * _​_RNase H degrades the mRNA strand but _leaves the antisense oligonucleotide intact_

Question 75

What is apo B-100 inhibition first-line therapy for?

Answer 75

first-in-class drug for treatment of _homozygous familial hypercholesterolemia_

Question 76

How is apo B-100 inhibtion administered? What are adverse effects?

Answer 76

* Pharmacokinetics: * subQ * Side Effects: * injection site reactions * flu-like symptoms * headache * elevation of liver enzymes