Exam 5

Question 1

What is the MOA for indirect thrombin inhibitors (heparin, LMW heparins)?

Answer 1

Heparin binds to antithrombin, which changes the conformation of the protein, allowing for an increase in the interaction between AT and its target factors. AT inactivates factors Xa, IXa, XIa, XIIa, IIa, and VIIa.

Low molecular weight heparins are too small to bind to AT, so their target is mostly just Xa.

Question 2

What is the MOA for direct thrombin inhibitors (hirudin, bivalirudin, argatroban, dabigatran)?

Answer 2

Hirudin - direct inhibitor of thrombin, irreversibly binds to active site and exosite I. This is a leach protein, so it can produce hypersensitivity reactions. This does not act on AT.

Bivalirudin - Synthetic peptide that binds to the catalytic site and exosite I of thrombin. This is reversible and has a short duration. No risk of hypersensitivity.

Argatroban - Reversibly binds to the active site of thrombin.

Dabigatran - A prodrug that directly binds to thrombin active site.

• with DTIs, there is a more predictable anticoagulant effect due to these not needing a cofactor. Also has antiplatelet effects due to inhibiting thrombin. These can inhibit both soluble and fibrin-bound thrombin.

Question 3

What is the MOA for Xa inhibitors (fondaparinux, rivaroxaban, apixaban)?

Answer 3

Fondaparinux - indirectly inhibits factor Xa by selectively binding AT

Rivaroxaban, apixaban - Directly bind to the active site on factor Xa to inhibit the activity of the enzyme

Question 4

What is the MOA for warfarin?

Answer 4

Warfarin inhibits the synthesis of clotting factors II, VII, IX, and X. Warfarin has 2 enantiomers, R and S. The S-enantiomer is the most active. Warfarin inhibits Vit. K epoxide reductase, which blocks oxidized vit K from getting reduced (active). This reduced vit K is needed to have g-glutamyl carboxylase modify non-functional prozymogens into functional zymogens (clotting factors).

Question 5

What is the role of plasminogen/plasmin in the process of blood clotting?

Answer 5

Plasmin plays into the fribrinolytic pathway to dissolve the blood clot after the blood vessel defect has healed. Plasmin is a proteolytic enzyme that digests fibrin and fibrinogen, thus breaking up the clot.

Question 6

What is the mechanism for the conversion of plasminogen to active plasmin?

Answer 6

t-PA (tissue plasminogen activator, a serine protease) or u-PA converts plasminogen to active plasmin by cleaving the arg-val bond.

Question 7

What are the names of the drugs that are thrombolytics (5) and what is their MOA?

Answer 7

Thrombolytics - used for acute problems (ex. acute MI, acute stroke, PE)

Alteplase (tissue-type plasminogen activator, tPA)
Reteplase (recombinant plasminogen activator, rPA
Tenecteplase (TNK-tPA)
- MOA: Binds to fibrin and activates bound plasminogen 100x more rapidly than when in circulation. This causes active plasmin to break down fibrin.

Streptokinase
Urokinase
- MOA: Forms 1:1 activator complex with plasminogen to increase amount of active plasmin.

Question 8

What is the difference between alteplase and streptokinase in terms of source, structure, and activity?

Answer 8

Alteplase: has a protease domain and a fibrin binding site that includes the finger and kringle 1/2. It’s a large protein with a short duration of action of 5-10mins.
- The most common complication is bleeding (surface and internal)

Streptokinase: comes from b-hemolytic streptococci (not used commonly in US for this reason). It’s non-enzymatic so it doesn’t have direct effects on the clot. It forms a 1:1 complex with plasminogen that produces an enzyme complex that converts plasminogen to plasmin.
- Common complications include bleeding and allergic reactions

Question 9

What are the names of the drugs that are anti-fibrinolytic agents (2) and what is their MOA?

Answer 9

Anti-fibrinolytic agents: Used to stop the bleeding that could be caused by thrombolytics. Prevents plasmin binding to fibrin by acting as a lysine analog to block plasmin blocking. Normally, there are lysine residues on fibrin that bind to plasmin and its activator. By being lysine analogs, the drug binds in that site of the plasma, preventing fibrin from binding.
- Aminocaproic acid (EACA)
- Tranexamic acid
- Biggest complication is risk of intravascular thrombosis from preventing dissolution of the clot.

Question 10

What is the pathophysiology of VTE, including the role of the coagulation cascade?

Answer 10

Stasis blood (lack of blood flow) promotes the formation of a thrombus due to decreased clotting factor clearance. These thrombi are made of RBCs, fibrin, and platelets.

Coagulation cascade:
- Epithelial injury exposes vessel wall to tissue factor, which produces a trace amount of thrombin. Thrombin promotes amplification of clotting factors, then more thrombin is made. Fibrin is produced in the propagation phase which develops the clot. As this clot grows, it could cause a DVT that could break off into a PE.

Question 11

What are the contributing factors to the development of VTE?

Answer 11

Virchow’s Triad:
1. Abnormalities of clotting components (hypercoagulable state).
- Ex. pregnancy, cancer
2. Abnormality of surfaces in contact with blood flow (endothelial injury)
- Ex. injury of blood vessels from surgery or injury
3. Abnormalities in blood flow (circulatory stasis)
- Ex. long periods of immobility

Question 12

What does the clinical presentation of a VTE look like? (DVT & PE)

Answer 12

Symptoms result when the flow is obstructed, vascular tissue wall becomes inflamed, a thrombus occurs and affects venous blood flow, or when emboli occur and enter pulmonary circulation. Some blood clots are asymptomatic.

DVT: Pain, swelling, redness in lower extremity

PE: Shortness of breath, chest pain, coughing, coughing up blood, rapid heart rate, dizziness or fainting

Question 13

What is postthrombotic syndrome and what are the consequences of this condition?

Answer 13

Postthrombotic syndrome is a long-term complication of DVT caused by damage to venous valves.

Consequences of this condition include chronic venous obstruction, chronic pain and swelling, stasis ulcers, and the development of an infection.

• Make sure to rule out recurrent thrombosis before diagnosing a pt with postthrombotic syndrome.

Question 14

What are the risk factors for development of a VTE?

Answer 14

• Age over 40 years old
• Family history of DVT
• Heart failure
• Immobilization of over 10 days
• Malignancy (extremely high risk)
• Orthopedic injury (extremely high risk)
• Obesity
• MI
• Pregnancy
• Oral contraceptive/estrogen
• Paralysis

Question 15

What are the methods of diagnosis that are appropriate for DVT and/or PE?

Answer 15

If pt has symptoms of a DVT, could do a d-dimer test (would be increased if pt has a clot) or a ultrasonography to get imaging.

For a PE, we could do a CT scan for pulmonary angiography.

Question 16

What are the goals of therapy for a VTE?

Answer 16

• Prevent the formation of a PE
• Stabilize the clot
• Reducing recurrence
• Preventing postthrombotic syndrome

Question 17

What are the non-pharmacological treatment options for a VTE?

Answer 17

• Baseline monitoring

DVT:
- Bed rest
- Elevation of feet
- Pain management
- Compression stockings

PE:
- Oxygen
- Mechanical ventilation
- Compression stockings

Question 18

Unfractionated heparin - What is the MOA? When would we use it in therapy? What are the appropriate monitoring we need to go for therapeutic and adverse effects?

Answer 18

MOA - Increases activation of AT and inactivates various clotting factors, which results in decreased clotting

Use - Acute DVT

Monitoring -
- aPTT monitoring (activated partial thromboplastic time); Goal is 1.5-2.5 x control; Check 6 hours after dose/dose change for the first 24 hours, then check daily
- Monitor platelet levels for HAT/HIT

Question 19

Unfractionated heparin - What is the dosing regimen, route of administration, and duration of therapy for this drug? What are the adverse effects? How would we manage bleeding from heparin?

Answer 19

Dosing - Weight based dosing, dependent on how many times larger the aPTT is compared to control.

Route of administration - Parenteral (IV)

Duration - Use until ready to start other therapy

Adverse effects - Bleeding, thrombocytopenia

Bleeding? - Protamine sulfate for targeted reversal

Question 20

Low molecular weight heparin - What is the MOA? When would we use it in therapy? What are the appropriate monitoring we need to go for therapeutic and adverse effects?

Answer 20

MOA - Binds to factor Xa to decrease clotting.

Use - Prophylaxis or treatment of acute DVT, maintenance therapy for treatment of DVT/PE; Better than heparin due to more predictable dose response, able to do SQ dosing and less incidence of HIT

Monitoring - None needed
- Consider monitoring anti Xa levels for children, pts with severe kidney failure, obesity, long courses of treatment, and pregnancy; Goal is 0.6-1 for BID, 0.1-0.3 for daily dosing

Question 21

LMW heparin - What is the dosing regimen, route of administration, and duration of therapy for this drug? What are the adverse effects? How would we manage bleeding from LMW heparin?

Answer 21

Dosing - Once or twice daily dosing
- Enoxaparin (Lovenox): prophylaxis -> 30mg q12h if surgical, 40mg daily if acutely ill; treatment -> 1mg/kg q12h OR 1.5mg/kg daily; renal dysfunction -> 30mg daily for prophylaxis, 1mg/kg daily for treatment

Route of administration - Parenteral (SQ)

Duration - 3 months for treatment, 5-10 days if bridging to warfarin

Adverse effects - bleeding, injection site redness

Bleeding? - Protamine sulfate for targeted reversal

Question 22

What are the differences between HAT and HIT? (pathophysiology & diagnostics)

Answer 22

HAT - Heparin associated thrombocytopenia (AKA HIT type 1)
- Not immune mediated, so this occurs earlier on (around 48-72 hours after heparin administration)
- See a mild decrease in platelets, but we don’t need to stop heparin

HIT - Heparin induced thrombocytopenia
- Immune mediated, so it takes longer (around 7-14 days) to present
- Causes thrombotic complications and it can occur up to 9 days after stopping therapy
** See a 50% drop in platelets from baseline OR < 100,000/mm^3 platelets **

Question 23

How do we manage HIT?

Answer 23

• Stop all heparin products and give an alternative anticoagulant (ex. lepirudin, argatroban, bivalirudin, or fondaparinux).
• Don’t give platelet infusions
• Don’t give any warfarin until the platelet count is back up to > 150,000
• Evaluate for thrombosis since this is a prothrombic complication

Question 24

Injectable factor Xa inhibitors (FXa) - MOA? Use in therapy? Monitoring for therapeutic and adverse effects?

Answer 24

MOA - Activates AT to inhibit factor Xa, thus reducing clotting.

Use - Prophylaxis following THA, TKA, hip replacement, abdominal surgery; Treatment of DVT or PE (can be first line), HIT

Monitoring - None needed
- Consider monitoring anti-Xa levels if renal dysfunction, pediatric, pregnant, or long course of therapy, obesity

Question 25

Injectable factor Xa inhibitors (FXa) - Dosing, route of administration, duration of therapy, adverse effects, management of bleeding?

Answer 25

Dosing - Fondaparinux 2.5mg daily for prophylaxis with the hip, knee, or abdominal surgery. Weight based dosing for treatment. Route of administration - Parenteral, SQ Duration - Unclear how long prophylaxis should go for. Adverse effects - Bleeding, injection site redness Bleeding? - Nothing for targeted reversal

Question 26

IV Direct Thrombin Inhibitors (DTI) - MOA? Use in therapy? Monitoring for therapeutic and adverse effects?

Answer 26

MOA - Binds to thrombin to inhibit clotting Use - IV DTIs used for HIT (lepirudin, bivalirudin, argatroban) Monitoring - For lepirudin, monitor aPTT; goal is 1.5-2.5 x control

Question 27

IV Direct Thrombin Inhibitors (DTI) - Dosing, route of administration, duration of therapy, adverse effects, management of bleeding?

Answer 27

Dosing - Weight based dosing, argatroban requires dose adjustment for hepatic impairment Route of administration - Parenteral (IV) Duration - Until resolution of aPTT? Adverse effects - bleeding Bleeding? - Nothing for targeted reversal

Question 28

NOAC/DOAC - MOA? Use in therapy? Monitoring for therapeutic and adverse effects?

Answer 28

MOA - Dabigatran is a prodrug that is an oral direct thrombin inhibitor; Rivaroxaban, apixaban, edoxaban, betrixaban are oral direct factor Xa inhibitors Use - Postoperative prophylaxis for knee or hip replacement surgery, non-valvular atrial fibrillation for prevention of stroke or embolism, DVT or PE treatment, secondary prevention of DVT or PE, inpatient VTE prophylaxis Monitoring -

Question 29

NOAC/DOAC - Dosing, route of administration, duration of therapy, adverse effects, management of bleeding?

Answer 29

Dosing - Dosing various for indication and drug Route of administration - Oral Duration - Depends on indication Adverse effects - Bleeding Bleeding? - - Idarucizumab for dabigatran (direct binder to dabigatran) - Hemodialysis for dabigatran only - Andexanet alfa for rovaroxaban and apixaban (binds and sequesters); dosing depends on what and when last dose was

Question 30

What indications are the NOACs approved for (Dabigatran, Rivaroxaban, Apixaban, Edoxaban, Betrixaban): postoperative prophylaxis, non-valvular atrial fibrillation, DVT/PE treatment, secondary prevention of DVT/PE, VTE prophylaxis

Answer 30

Postoperative prophylaxis: Dabigatran (hip only), rivaroxaban, apixaban Non-valvular atrial fibrillation: Dabigatran, rivaroxaban, apixaban, edoxaban DVT/PE treatment: Dabigatran, rivaroxaban, apixaban, edoxaban Secondary prevention of DVT/PE: Rivaroxaban, apixaban VTE prophylaxis: Rivaroxaban, betrixaban

Question 31

What are the appropriate INR ranges for these specific indications: Prophylaxis of VTE, treatment of VTE/PE, prevent systemic embolism, antiphospholipid antibody syndrome, mechanical aortic heart valve, mechanical heart valve (not atrial)

Answer 31

2.0-3.0 is the goal for prophylaxis of VTE, treatment of VTE/PE, prevent systemic embolism, antiphospholipid antibody syndrome, mechanical aortic heart valve 2.5-3.5 is the goal for non aortic mechanical heart valve (ex. mitral, caged ball, high risk)

Question 32

How do we make warfarin dose adjustments?

Answer 32

- Check at least one INR within the first week (ex. days 3-5). If INR is within goal, check INR in one week and proceed weekly for the first month. If INR wasn't in range, adjust the weekly dose For INR of 2.0-3.0: - INR below 2.0 -> increase dose by 5-10% - INR 3.1-3.5 -> decrease by 5-15% - INR 3.5-4.0 -> hold 0-1 dose and/or decrease by 10-15% - INR over 4.0 -> hold 0-2 doses and/or decrease by 10-15% For INR of 2.5-3.5: - INR below 2.5 -> increase dose by 5-10% - INR 3.6-4.0 -> decrease dose by 5-15% - INR 4.1-4.5 -> hold 0-1 dose and/or decrease by 10-15% - INR over 4.5 -> hold 1-2 doses, decrease by 10-15% - Don't give more than 1 strength of warfarin at a time - Don't have only 1 day that they take a different dose - Don't stack different doses Order of switching doses: 1. Mon + Fri 2. MWF 3. T, Th, Sat, Sun

Question 33

What are the common gene mutations associated with warfarin metabolism?

Answer 33

CYP2C9 - Normal is CYP2C9*1 - 2C9*2 and *3 require a decrease in dose. *3/*3 requires most decrease in dose (*2/*3 very common in white patients) - 2C9*5, *6, *11 are more common with asians and african americans. These pts need a lower dose requirement as well VKORC1 - - -1639A causes increased warfarin sensitivity, requiring a decrease in dose. (-1639AA most sensitive) - -1639G causes increased warfarin resistance, requiring an increase in dose (-1639GG most resistant) *only test if patient is warfarin naive, genetic test results are available before the 6th dose, AND the patient is at high risk of bleeding if INR is elevated (on meds that increase bleeding)

Question 34

What are the common drug interactions we are concerned with with warfarin?

Answer 34

Increase INR (more bleeding): - Metronidazole - Amiodarone - Fluconazole - Ciprofloxacin - Bactrim - actue EtOH (or w/ liver damage) Decrease INR (more clotting): - Rifampin - chronic EtOH **vit K reverses warfarin activity

Question 35

What are some important counseling points for someone starting warfarin?

Answer 35

- Need to start with at least 5 days of UFH/LMWH/Xa AND get into therapeutic INR range - Ask about the 5 Ds everytime (drugs, diseases, doses, diet, drinks) - Ask about bleeding/bruising

Question 36

What drugs are used for VTE prevention? How do we decided on which one to recommend for patients?

Answer 36

- UFH - LMW heparin - Factor Xa inhibitors - Warfarin Decided whether they are low, moderate, or high VTE risk. If high bleeding risk, mechanical prophylaxis is preferred.

Question 37

What are the general guidelines for duration of therapy for VTE prevention, including prevention for orthopedic procedures and surgeries?

Answer 37

Low risk: If VTE risk is under 10%, then no therapy is recommended (ex. minor surgery, able to walk) Mod risk: VTE risk 10-40% (most non-orthopedic surgery pts) - Surgery pts: UFH, LMWH, and fondaparinux are all recommended and want to continue up to 28 days after hospital discharge - Acutely ill: UFH, LMWH, fondaparinux, rivaroxaban, betrixaban all recommended. Rivaroxaban and betrixaban should be continued for a little over a month after discharge. High risk: VTE risk 40-80% (major orthopedic surgery, major trauma, spinal cord injury) - Orthopedic surgery (TKA or THA): LMWH, fondaparinux, rivaroxaban, apixaban, dabigatran (hip only), UFH, or warfarin all approved. Continue at least 10-14 days postop

Question 38

How can we manage bleeding due to warfarin?

Answer 38

Options: - Vitamin K 5mg PO (also parenteral) - Fresh frozen plasma (FFP) - Prothrombin complex concentrate (PCC) INR 4.5-10 + no major bleeding -> avoid vit K INR > 10 + no evidence of bleeding -> PO vit K Major bleeding on warfarin -> PCC is a better choice than FFP, and may add vit K on if needed

Question 39

What are the factors in the CHA2DS2-VASc and do they contribute 1 or 2 to the score? What do the scores mean?

Answer 39

Congestive heart failure - 1 Hypertension - 2 Age over 75yo - 2 Age 65-74 -1 Diabetes - 1 Stroke/TIA - 2 Vascular disease - 1 Female - 1 0 - do nothing 1 - individualized to the patient. Could do PO anticoagulant, antiplatelet, or nothing 2+ - oral anticoagulation

Question 40

What are the factors in the HAS-BLED score, how much do they contribute, and what does the end score mean?

Answer 40

Hypertension (systolic >160) - 1 Abnormal renal or liver function (each = 1) - 1 or 2 Stroke - 1 Bleeding tendency/predisposition - 1 Labile INRs - 1 Age > 65 years - 1 Drugs or EtOH - 1 or 2 If score 3+, there's a high risk of bleeding, so use caution with the patient

Question 41

What is the dosing schedule and important points for NOACs/DOACs for postoperative prophylaxis?

Answer 41

Dabigatran - If day of surgery, give 110mg; If not day of surgery, give 220mg daily; Maintenance 220mg daily for 28-35 days - For hip replacement ONLY Rivaroxaban - 10mg daily for 35 days (hip) or 12 days (knee) - Avoid if CrCL under 30 Apixaban - 2.5mg BID for 35 days (hip) or 12 days (knee)

Question 42

What is the dosing schedule and important points for NOACs/DOACs for non-valvular atrial fibrillation?

Answer 42

Dabigatran - 150mg BID - CrCL impacts dosing Rivaroxaban - 20mg daily - CrCL impacts dosing Apixaban - 5mg BID - SCr impacts dosing, also weight based (lower dose for underweight or elevated SCr) Edoxaban - 60mg PO daily - CrCL impacts dosing; don't use if pt have healthy CrCL (>90)

Question 43

What is the dosing schedule and important points for NOACs/DOACs for DVT/PE treatment?

Answer 43

Dabigatran - 150mg BID - requires 5-10 days of parenteral anticoagulation - only for maintenance Rivaroxaban - actue loading dose BID, then 20mg daily - acute & maintenance Apixaban - actue loading dose BID, then 5mg BID - actue & maintenance Edoxaban - 60mg daily - requires 5-10 days of parenteral anticoagulation - only for maintenance - requires dose reduction if underweight (<60kg)

Question 44

What is the dosing schedule and important points for NOACs/DOACs for secondary prevention of DVT/PE?

Answer 44

Rivaroxaban - 20mg PO daily - After 6 months of treatment Apixaban - 2.5mg PO BID - After 6 months of treatment

Question 45

What is the dosing schedule and important points for NOACs/DOACs for VTE prophylaxis (ex. inpatient)?

Answer 45

Rivaroxaban - 10mg daily Betrixaban - 160mg PO daily on day 1, then 80mg daily from days 35-42 - Duration of action is over 72 hours.

Question 46

What do we do for patients on warfarin who are going into surgery? What if they were on a NOAC?

Answer 46

(not for dental, derm, or cataract procedures) Warfarin - Stop warfarin 5 days before the surgery - Give LMWH or UFH until the procedure. Stop LMWH 24h before the procedure and stop UFH 4-6 hours before the procedure - Resume warfarin 12-24 hours after surgery NOACs - Depends on CrCL of pt and if they are at low or high risk of bleeding - At healthy CrCL, stop low risk pts 24 hours before surgery, high risk pts 48 hours before surgery - Dabigatran is more sensitive to CrCL

Question 47

What are the relative sizes, composition, and physiological function of the major classes of lipoproteins?

Answer 47

Lipoproteins - Surface made of phospholipids, free cholesterol, and protein; Core made of TGs and cholesterol ester Chylomicrons - The largest; Transports dietary lipids from the gut to the liver and adipose tissue; Has most triglycerides VLDL - Secretes by the liver into the blood as a source of TGs; Has more cholesterol than chylomicrons but less TGs IDL - VLDLs that don't have triglycerides (Depleted) LDL - Main transport form in the blood; Has most cholesterol HDL - Secreted by the liver and brings back cholesterol from peripheral tissues/atheromas to the liver (good); Has most protein

Question 48

What are the exogenous and endogenous pathways for lipid absorption and transport?

Answer 48

Exogenous - - Dietary cholesterol absorbed through the intestine, TGs go into circulation in chylomicrons. The remnants go to the liver. Bile acids and cholesterol are secreted by the liver for the intestine. Endogenous - - VLDLs go into systemic circulation to transport TGs. IDLs (depleted VLDLs) turn into LDLs. These LDLs either go back to the liver, go to extrahepatic tissues, or are oxidized and turn into foam cells (bad). In the extrahepatic tissues, HDLs bring cholesterol back to the liver

Question 49

What is the role of the LDL receptor in lipid metabolism and what factors regulate LDL receptor levels?

Answer 49

The LDL receptor binds to LDL that is in systemic circulation. It endocytoses the LDL, and that LDL is then recycled to make more LDLs or excreted in bile. The level of LDL receptors is tightly controlled by SREBP2 and SCAP by transcription and PCSK9 at the posttranslational level.

Question 50

What is the main role of the liver in cholesterol synthesis and lipid distribution?

Answer 50

The liver is where cholesterol is made (de novo synthesis is major source of cholesterol). It's made through a reaction with HMG-CoA reductase. It also forms HDLs and VLDLs that enter circulation.

Question 51

What are the plasma concentrations of total cholesterol, LDL cholesterol, and triglycerides that are desirable, borderline, and high? What levels of HDLs are desirable?

Answer 51

Total cholesterol: Desirable is <200 - Borderline is 200-329 - High is > 240 LDL cholesterol: Desirable is <130 - Borderline i 130-159 - High is > 160 Triglycerides: Desirable is <150 - Borderline is 150-199 - High is > 200 HDLs: Desirable is > 40 for me, > 50 for women. - High is > 60 - Want a TC/HDL ratio of less than 3.5, more than 4.5 is associated with risk of CVD

Question 52

What are the goals of drug therapy for hyperlipidemia (6)? How can we choose specific drugs for specific therapeutic goals?

Answer 52

- Decrease biosynthesis of cholesterol - Increase expression of LDL receptors - Decrease reabsorption of excreted bile acids - Decrease secretion of VLDL from liver (ApoB) - Increase HDL levels - Increase hydrolysis of TGs (lipoprotein lipases) There are drugs used specifically for high cholesterol, TGs, etc.

Question 53

Statins - MOA, molecular target, use, major side effects

Answer 53

MOA - Competitively inhibit HMG-CoA reductase (transition state) which is the rate limiting step of biosynthesis. By inhibiting sterol biosynthesis, the body will upregulate LDL-R so that more LDL is delivered to the liver, which decreases systemic LDLs and VLDLs Target - lowers LDLs by a lot, lowers TGs, and increases HDLs Use - Hyperchoelsterolemia Side effects - rhabdomyolysis (monitor CPK), hepatotoxicity (monitor serum transaminase activity)

Question 54

Bempedoic acid - MOA, molecular target, use, major side effects

Answer 54

MOA - prodrug that is activated by the liver (only acts in liver, not skeletal muscle like statins). Inhibits ACL, which is a precursor to HMG-CoA. Also blocks OAT2 to draw cholesterol out of circulation. Target - Decreases LDLs by a lot, no effect on TGs, maybe slight lowering of HDL Use - Adjuvant to statins Side effects - arthralgia, UTI, nasopharyngitis, gout, tendon rupture

Question 55

Ezetimibe - MOA, molecular target, use, major side effects

Answer 55

MOA - Blocks the reabsorption of cholesterol in the lumen by blocking the NPC1L1-cholesterol transporter. Does not enter systemic circulation Target - Reduces LDLs moderately, no effect on TG or HDLs Use - Statin adjuvant Side effects - Generally well tolerated

Question 56

Bile acid sequestrants - MOA, molecular target, use, major side effects

Answer 56

Cholestyramine, Colestipol MOA - Bind to bile salts to inhibit reabsorption of bile acids in the intestine, then they excreted in feces. Do not enter systemic circulation. Causes up-regulation of LDLs in liver Target - Moderately reduces LDLs, slight increase in HDLs, increases TGs (bad) Use - Primary hypercholesterolemia Side effects - Increases TGs, constipation and bloating

Question 57

Fibrates - MOA, molecular target, use, major side effects

Answer 57

Gemfibrozil, Fenofibrate MOA - Bind and activate PPAR-a to increase expression of LDL, Apo A1 and A2, which reduces serum TGs, LDLs, and elevated HDLs Target - Lowers LDLs, Reduces TGs a lot, Raises HDLs Use - Hypertriglyceridemia if VLDLs predominate, second line for mixed hyperlipidemia Side effects - GI distruvances, rash, dizziness, Increase cholesterol content of bile could result in gallstones, rhabdomyolysis if given with statins

Question 58

PCSK9 inhibitors - MOA, molecular target, use, major side effects

Answer 58

Alirocumab (praluent), Evolocumab (repatha) MOA - Inhibiting PCSK9, which prevents LDL-R recycling, resulting in lots of LDL staying in circulation Target - Increase LDLR and reduce LDL levels Use - Adjunct to statin for familial heterozygous hypercholesterolemia (genetic PCSK9 mutation) or atherosclerotic CVD. Side effects - Chest pain, difficulty breathing/swallowing, fast heart beat, joint pain, GI distrubances

Question 59

Niacin - MOA, molecular target, use, major side effects

Answer 59

MOA - In adipose tissue, it inhibits TG lipolysis by hormone-sensitive lipase. This decreases FA transport to the liver (g protein 109A). In the liver, it inhibits fatty acid synthesis and esterification, which reduces TG export via VLDLs. Also reduces clearance of apoA-I but not CEs, so this increases HDL levels. Target - Reduces LDLs and TGs moderately, increases HDLs Use - Mixed hyperlipidemias (esp. risk of pancreatitis), use in compo with resin or statins for severe cases Side effects - vasodilation (flushing), headache, tingling of upper body (treat with ASA or ibuprofen), hepatotoxicity

Question 60

Omega-3 fatty acids - MOA, molecular target, use, major side effects

Answer 60

MOA - reduce serum TGs by inhibiting synthesis of TGs in the liver (DGAT) and inhibiting esterification of other fatty acids Target - Lowers TGs, may increase LDLs Use - Use after lipid lowering diet has been initiated. Used in severe hypertriglyceridemia (>500) Side effects - burping, nausea, diarrhea

Question 61

Lomitapide - MOA, molecular target, use, major side effects

Answer 61

MOA - Inhibits ApoB lipoprotein synthesis. Inhibits MTTP, which is responsible for packaging VLDLs before its secretion Target - Lowers LDLs Use - Adjust to other treatments for patients with homozygous familial hypercholesterolemia (LDLR mutation) Side effects - risk of liver damage due to high build up of cholesterol and TGs in the liver

Question 62

Mipomersen - MOA, molecular target, use, major side effects

Answer 62

MOA - Binds mRNA and degrades the mRNA so ApoB-100 isn't made, meaning VLDLs don't get synthesized. Target - Decreases LDLs Use - Adjunct in homozygous familial hypercholesterolemia Side effects - risk for hepatotoxicity

Question 63

What are the different dosing strategies for statins?

Answer 63

- Short half-life statins (simvastatin, lovastatin, fluvastatin) are taking in the pm/hs due to inhibiting nocturnal cholesterol biosynthesis. - Slow release formulation (rosuvastatin, atorvastatin, pravastatin) can be given at any time of the day - Meal facilitates absorption for simvastatin and lovastatin

Question 64

What are the major steps in the development of atherosclerotic plaques?

Answer 64

Endothelial injury causes an inflammatory response. Macrophage infiltration and platelet adhesion occurs, smooth muscle cells proliferate, and the extracellular matrix accumulates.

Question 65

What are the names of the clinical guidelines that we follow for treatment of dyslipidemias?

Answer 65

ACC/AHA - multisociety guidelines

Question 66

What are the common signs and symptoms associated with the clinical presentation of dyslipidemias?

Answer 66

Signs - Pancreatitis, eruptive xanthomas, peripheral polyneuropathy, increased BP, large waist size, high BMI Symptoms - Largely asymptomatic, but depending on the severity and duration of the disease, may see chest pain, palpitations, sweating, anxiety, SOB, loss of consciousness due to TIAs, difficulty with speech or movement, abdominal pain, sudden death

Question 67

What are the lab parameters that are typically ordered for evaluation, monitoring, and assessment of dyslipidemia?

Answer 67

In fasting lipid panel - TC, TG, HDL-C, LDL-C (calculated) - If not fasting, TC and HDL is good LDL-C: Amount of cholesterol in LDL particles LDL-P: Number of LDL particles (not routinely ordered) Non-HDL-C: Amount of cholesterol in atherogenic particles (not routinely reported) - Non-HDL-C = TC - HDL ApoB: number of atherogenic particles (not routinely ordered) - ApoB, LDL-P, and non-HDL-C are all valid in non-fasting sample with elevated TG levels (LDL-C is not) - Ratio of TC:HDL goal is less than 5:1

Question 68

How can you identify appropriate treatment goals based on individual patient profiles?

Answer 68

1. Primary or secondary prevention? Primary: - If LDL-C is atleast 190 -> high-intensity statin - If diabetes mellitus and ages 40-75 -> moderate-intensity statin (consider high-intensity later on) - If above 75 -> risk discussion - If 40-75yo, determine ASCVD risk; if ≥20% risk, start statin to reduce LDLs by at least 50%; if 7.5-20% risk, start stating to reduce LDLs by 30-49%; If 5-7.5% risk, risk discussion maybe mod statin; if less than 5% risk, emphasize lifestyle modifications - If less than 40, focus on lifestyle modifications Secondary: Need healthy lifestyle, then high-intensity statin (if under 75) - High ASCVD risk and on high statin; If LDLs more than 70, can add ezetimibe (esp. before PCSK9-i); If LDLs above 70 and non-HDL-C is over 100, can add PSCK9-i - Not very high ASCVD and on high statin (less than 75yo); Goal is to decrease LDLs by 50%; If on max statin and LDLs are still over 70, can add ezetimibe. - Not very high ASCVD and less than 75 yo, initiate mod or high statin is okay

Question 69

What are some therapeutic lifestyle changes for a patient diagnosed with hyperlipidemia?

Answer 69

Non-pharm: - DASH diet - Only 5-6% of calories are from saturated fats - Lower sodium intake - Exercise - Soluble fiber can decrease LDLs (oat bran, psyllium, etc.) - Reduce intake of sat. fats and cholesterol (olestra) - Plant stanols and sterols and decrease LDLs

Question 70

Out of these drug classes, which ones treatment LDLs vs TGs mostly? Statins, Fibrates, Ezetimibe, BARs, Niacin, PCSK9 mAb, Inclisiran, Omega 3 fatty accids, bempedoic acid

Answer 70

LDLs - - Statins - BARs - Ezetimibe - PCSK9 mAB - Inclisiran - Bempedoic acid TGs - - Fibrates - Omega 3 fatty acids - Niacin

Question 71

When are statins contraindicated?

Answer 71

- acute liver disease - unexplained, persistent elevations of serum transaminases - pregnancy - breastfeeding

Question 72

What are the 11 risk enhancing factors for primary prevention that should be in the risk discussion for ASCVD?

Answer 72

Persistently elevated LDLs over 160 Persistently elevated TGs over 175 Pre-eclampsia Premature menopause Family history of premature ASCVD Inflammatory disease Metabolic syndrome Chronic kidney disease Ethnicity (non-white) Elevated labs (ApoB, etc.) Decreased ankle-brachial index

Question 73

What are the 9 high-risk conditions for secondary prevention?

Answer 73

Age 65 or older Chronic kidney disease Current smoker Diabetes mellitus Elevated LDL-C (despite max statin and ezetimibe) Heterozygous familial hypercholesterolemia History of prior CABG or PCI outside of major ASCVD events HTN History of congestive heart failure

Question 74

When should you follow up with patients on dyslipidemia meds?

Answer 74

Follow up 4-12 weeks after initiating statin Then, follow up every 3-12 months At each visit, get FLP and LFTs if clinically indicated (muscular side effects, hx of liver disease, etc.)

Question 75

When would these populations be considered for non-statin treatment? 1. Less than 75yo with clinical ASCVD on statin for secondary prevention 2. Over 21 yo without clinical ASCVD on statin for primary prevention 3. 40-75yo without clinical ASCVD and with DM on statin for primary prevention

Answer 75

1. Less than 75, clinical ASCVD, 2º prev: LDLs over 70 on max statin. Can consider PCSK9 is super high ASCVD risk and nothing is at goal 2. 21+, primary prevention: If LDLs over 190 not from secondary causes, can add ezetimibe if statin LDL reduction of less than 50% or LDL is above 100. 3. 40-75, DM, primary prevention: Risk assessment, if ASCVD risk > 20% and on max statin, start ezetimibe

Question 76

What defines the categories of hypertriglyceridemia?

Answer 76

Persistent hypertriglyceridemia - fasting TG over 150 even after 4-12 weeks of lifestyle intervention, max tolerated statin, and secondary cause evaluation Moderate - TGs 150-499; TGs are carried in VLDLs Severe - TGs 500+; TGs are carried in VLDLs and chylomicrons, increased risk of acute pancreatitis

Question 77

How can we use statins in treatment of TGs?

Answer 77

Moderate hypertriglyceridemia - TGs from 150-499 - ASCVD risk of over 7.5% favors initiation or intensification of a statin Severe hypertriglyceridemia - TGs over 500 - ASCVD over 7.5% requires statin treatment - If TGs over 1000, start statin AND fibrate or omega-3

Question 78

How can we treat TGs in adults with ASCVD (moderate triglyceridemia without DM)?

Answer 78

Maximize statin therapy, rule out secondary causes, optimize diet and lifestyle, optimize glycemic control If TGs persist: - LDL-C less than 70 -> after ruling out other causes & optimizing lifestyle, can consider icosapent ethyl - LDL-C 70-99 -> can do either icosapent ethyl or statin - LDL-C over 100 -> maximize statin, if needed can do icosapent ethyl

Question 79

How can we treat TGs in adults with ASCVD with diabetes (moderate triglyceridemia)?

Answer 79

Maximize statin therapy, rule out secondary causes, optimize diet and lifestyle, optimize glycemic control - If over 50 with 1 or more ASCVD high-risk features, talk with patient and can consider icosapent ethyl - If less than 50 or over 50 with no additional risk factors, continue LDL-C risk based approach (icosapent if LDL is less than 70, max satin if LDL over 100)

Question 80

How can we treat TGs in adults with no ASCVD or DM (moderate triglyceridemia)?

Answer 80

rule out secondary causes, optimize diet and lifestyle Assess ASCVD 10-year risk - Low (<5%): optimize diet and lifestyle, periodically recheck 10-year risk - Med (5-20%): shared decision-making, consider statin (or intensifying if already on statin) - High (over 20%): shared decision-making, initiate high-intensity statin

Question 81

How can we treat severe hypertriglyceridemia?

Answer 81

TGs 500-999: rule out 2º causes, optimize diet and lifestyle, glycemic control - If 20-39yo, or 40-75 with ASCVD risk is less than 5%, or if DM, or if no ASCVD: emphasize low fat diet, consider fibrate or prescription omega-3 fatty acids (icosapent ethyl or lovaza) - If 40-74 and ASCVD risk over 5%, ASCVD, or diabetes: start or increase statin -> if still persistent, emphasize low-fat diet, increase statin, consider fibrate or icosapent ethyl or lovaza Fibrates/omega-3 fatty acids are the go-to to reduce risk of acute pancreatitis

Question 82

What are the components of metabolic syndrome?

Answer 82

Over eating and decreased physical activity contribute to visceral adiposity. These cause 1. neurohormonal activation, 2. chronic inflammation, and 3. insulin resistance, resulting in metabolic syndrome.

Question 83

What is the diagnostic criteria of metabolic syndrome?

Answer 83

According to AHA/NHLBI Need 3 of the 5: 1. Waist circumference at or over 40in in men and 35in in women 2. TGs at or over 150 or drug tx for TGs 3. Low HDLs, classified by less than 40 in men and less than 50 in women 4. Elevated blood pressure over 130/85 or drug tx for BP 5. Elevated fasting plasma glucose at or above 100 or drug tx for it

Question 84

How can you calculate and classify BMI?

Answer 84

(weight in lbs x 703)/ (height in in)^2 OR weight in kg/ (height in meters)^2 Underweight <18.5 Healthy 18.5-24.9 Overweight 25-29.9 Obese 30-24.9 Severely obese 35-39.9 Morbidly obese >40

Question 85

How can you determine when a patient is a candidate for pharmacologic therapy?

Answer 85

If the patient has already altered diet and exercise and their BMI is over 30 or over 27 with atleast one weight related condition (dyslipidemia, hypertension, diabetes), then they are indicated for weight loss medications

Question 86

What are appropriate lifestyle interventions for metabolic syndrome?

Answer 86

- Lose 7-10% of body weight over 6-12 months - Ultimate weight loss goal BMI under 25 - 150min of aerobic exercise/week on 3-5 days/week - Resistance training 2-3 days/week

Question 87

How can you evaluate patient specific factors to identify appropriate medication options?

Answer 87

Semaglutide - don't use if family hx of medullary T-cell thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, or in pregnancy - d/c if pt hasn't lost 5% of body weight in 3 months of 2.4mg dose or if they can't tolerate 2.4mg dose Liraglutide - don't use if family hx of medullary T-cell thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, or in pregnancy - d/c if pt hasn't lost 4% of body weight after 16 weeks Orlistat - (lipase inhibitor) don't use in pregnancy, chronic malabsorption syndrome, or cholestastis Phentermine/Topiramate ER (Qsymia) - (sympathomimetic) don't use if it's within 14 days of using MAO-I, glaucoma, hyperthyroidism, or pregnancy Naltrexone/Buproprion (Contrave) - don't use if it's within 14 days of MAO-I, hx of abuse, bulimia or anorexia, pregnancy, seizure hx, uncontrolled HTN

Question 88

What are the goals of therapy for the aspects of metabolic syndrome in patients with HTN or T2DM?

Answer 88

HTN goals of therapy - - Reduced CVD evetns - BP under 130/80 T2DM - - A1c <7% or 8% if higher risk of hypoglycemia