Pharmacology, PK/PD and Genomics of Cholesterol Lowering Medications

Question 1

HMG-COA Reductase Inhibitors (Statins)

Indications

Answer 1

1. Hyperlipidemia
2. Primary/Secondary prevention of atherosclerotic cardiovascular disease
   3.Familial hypersholesterolemia

Question 2

Satins Contraindications

Answer 2

• Breastfeeding
• Acute liver disease

Question 3

ADRs of Statin

Answer 3

• Myopathy
• Diarrhea
• Rhabdomyolysis
• Hepatoxicity

Question 4

Statins PK/PD Parameters

Answer 4

• Most statins have a short half-life and should be taken at night (whencholesterol is being produced)- not true for atorvastatin and rosuvastatin
• Most statins are lipophilic- higher risk of mucle pain

Question 5

Statins DDI

Answer 5

Many statins are metabolized by CYP3A4

Question 6

Impacts of Statins on Cholesterol

Answer 6

• Cholesterol impacts
  1. Decrease cholesterol synthesis
  2. Increase expression of LDL receptors
  3. Decrease total cholesterol
  4. Decrease LDL 18-55%
  5. Decrease TG 7-30%
  6. Decrease CRP
  7. Increase HDL 5-15%
• Pleitropic effects
  1. Improved endothelial function
  2. Atherosclerotic plaque stabilization
  3. Decreased oxidative stress and inflammation
  4. Inhibition of thrombogenic response

Question 7

Statin Intensities

Answer 7

• High Intensity(reduce LDL more than 50%)
• Moderate intensity(reduce LDL 30-49%)
• Low intensity(reduce LDL </ _ 30)

Question 8

High intensity

Answer 8

Atorvastatin 40mg-80mg

Question 9

Moderate Intensity

Answer 9

• Atorvastatin 10mg-20mg
• Rosuvastatin 5mg -10mg
• Simvastatin 20mg-40mg
• Pravastatin 40mg-80mg
• Lovastatin 40mg
• Fluvastatin 80mg
• Pitavastatin 2-4mg

Question 10

Low intensity

Answer 10

• Simvastatin 10mg
• Pravastatin 10-20mg
• Lovaststatin 20mg
• Fluvastatin 20-40mg
• Pitavastatin 1mg

Question 11

Statin side effects/Contraindications

Answer 11

H–>Hepatotocicity
M–>Myopathy
G–>GI Side effects(Diarrhea)
C–>CPK increase
A–>Avoid in Breastfeeding

Question 12

Statin Monitoring

Answer 12

1. Fasting Lipid Panel
   * 4-12 weeks after initiation or therapy change, 3 to 12 months as clinically indicated
   2.Transaminase(ALT,AST)
   * Baeline
   * May measure in patients w/symptoms suggesting hepatoxicity
   3.Monitor for new-onset diabetes
   * Especially in pateints w/ pre-diabetes

Question 13

Statins Genomics

Answer 13

OAT1B1
* Mediate uptake of statins for hepati metabolism and biliary elimination
* SLCO1B1–> The gene that encodes OAT1B1

If SLCO1B1 variant is known and low functioning, avoid simvastatin or use lower doses

Question 14

Cholesterol Absorption Inhibitor

Answer 14

Ezetimibe

Question 15

Ezetimibe

Indication

Answer 15

1. Hyperlipidemia
2. Familial hypercholesterolemia

Question 16

Ezetimibe

MOA

Answer 16

Inhibits absorption of cholesterol at the brush border of the small intestine via Nieman-Pick CI(NPCILI).This leads to a decreased delivery og cholesterol to the liver, reduction of hepati cholesterol stores and an increased clearance of cholesterol from the blood

Question 17

Ezetimibe

Contraindications

Answer 17

• Gallbladder disease
• Severe hepatic dysfunction

Question 18

ADRs of Ezetimibe

Answer 18

• UTRI, diarrhea,arthralgia,sinusitis, pain in extremities
• Rhabdomyolysis
• Hepatotoxicity

Question 19

Ezetimibe impact on cholesterol

Answer 19

• Decreases total cholesterol
• used w/ statin: decreases LDL ~25%
• Monotherapy:
  1.decrease LDL ~ 18%
  2.decreases ApoB: ~15%
  3.decreases TG:~8-14%
  4.increases HDL-cholesterol:~5%

Question 20

PCSK-9 inhibitors

Answer 20

• Alirocumuab(Praluent)
• Evolumuab(Repatha)

Question 21

PCSK-9 inhibtor MOA

Answer 21

Human Mab that binds to PCSK- and increases the number of LDL receptors available to clear circulating LDL

Question 22

PCSK-9 inhibitor ADRs and Key PK/PD

Answer 22

• Naspharyngitis,influenza,UTRI
• Injection site reactions
• Back pain
• PK/PD–>Back pain

Question 23

PCSK-9 impact on cholesterol

Answer 23

• Decrease total cholesterol
• decrease LDL:~50-70%
• decrease ApoB:~50%
• decreases TG~7-30%
• decreases Lp(a)~25%
• increase HDL-cholesterol~5-10%

Question 24

RNAI inhibitor of PCSK-9

Answer 24

Inclisiran(Leqvio)

Question 25

RNAI inhibitor PCSK-9 MOA

Answer 25

Small- interfering RNA LDL-C lowering therapy–>inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9(PCSK9) by blocking its synthesis, which is dependent on mRNA

Question 26

RNAI inhibitor PCSK-9 contraindications

Answer 26

Pregnancy

Question 27

Inclisiran impact on cholesterol

Answer 27

decreases LDL~50%

Question 28

ATP Citrate Lysase inhibition

Answer 28

Bempedoic Acid(Nexletol)

Question 30

Bempedoic Acid MOA

Answer 30

Adenosine triphosphate-citrate lyase (ACL) inhibitor
* ACL is an enzyme upstream in the cholesterol biosynthesis pathway
* Bempedoic acid and its active metabolite require coenzyme A (CoA) activation by very
long-chain acyl-CoA synthetase 1 (ACSVL1)
* ACSVL1 is expressed primarily in the liver
* Inhibition decreases cholesterol synthesis and lowers LDL-C in blood via upregulation of
LDL receptors

Question 31

Bempedoic Acid contraindications

Answer 31

Pregnancy

Question 32

Bempedoic Acid DDI

Answer 32

Increases conc. pravastatin (max dose=40mg)and simvastatin(max dose= 20mg)

Question 33

Bempedoic acid impact on cholesterol

Answer 33

• Monotehrapy: decreases LDL ~20-30%
• W/ statin: additional 17% from statin lowering

Question 34

Bile Acid Sequestrant

Answer 34

• Colesevelam(Welchol)
• Colestipol(Colestid)
• Cholestyramine(Prevalite,Questran)

Question 35

Colessevelam