Exam 2 Zhong

Drugs to reduce LDL:

Drugs to reduce LDL:

•HMG-CoA Reductase Inhibitors (Statins)

•Atorvastatin (Lipitor)

•Fluvastatin

•Lovastatin

•Pitavastatin

•Pravastatin

•Rosuvastatin (Crestor)

•Simvastatin

•Cholesterol Absorption Inhibitor: Ezetimibe (Zetia)

•PCSK9 Inhibitors

•Alirocumab (Praluent)

•Evolocumab (Repatha)

•(NEW) Inclisiran (siRNA)

•Citrate Lyase Inhibitor: Bempedoic acid

•Bile Acid Sequestrants (Resins)

•Cholestyramine /Colesevelam / Colestipol

•

Drugs to reduce triglyceride:

•Statins

•Fibric Acid Derivatives (Fibrates)

•Fenofibrate (Tricor)

•Gemfibrozil

•Fish Oil/Omega-3 Fatty Acids

•Icosapent ethyl (vascepa)

•Niacin (Nicotinic Acid, Vitamin B₃)

•ApoCIII siRNA: Olezarsen (SC)

Drugs to loss weight:

Orlistat

Primary Prevention (ages 40–75 years) (never have a CV event)

•If LDL-C ≥190 mg/dL, high-intensity statin recommended regardless of ASCVD risk

•If patient has DM, moderate-intensity statin recommended regardless of ASCVD risk

•High risk if ASCVD ≥20% (LDL-C goal reduction of ≥50%)

Intermediate risk if ASCVD ≥7.5% to <20% + LDL > 70 mg/dl or risk factors present

Secondary Prevention (patients already had CV events)

Very high-risk ASCVD if major events and/or high-risk conditions present: high-intensity statin recommended

•Lifestyle modifications

•Diet

•Emphasizes the intake of vegetables, fruits, nuts, whole grains legumes, healthy protein sources (low-fat dairy products, low-fat poultry (without the skin), fish/seafood, and nuts), and nontropical vegetable oils; and limits intake of sweets, sugar-sweetened beverages, and red meats.

•Weight loss

•For adults with overweight and obesity, counseling and caloric restriction are recommended for achieving and maintaining weight loss.

•Exercise

•150 minutes per week of accumulated moderate-intensity physical activity

•or 75 minutes per week of vigorous-intensity physical activity

•Quitting smoking

anti-hld

HMG-COA reductase inhibitors

rosuvastatin > atorvastatin >> simvastatin > lovastatin = pravastatin > fluvastatin

•Drugs: Lovastatin, Simvastatin (Zocor), Atorvastatin, Rosuvastatin, Fluvastatin, Pravastatin.

•Mechanisms:

§Reversibly and competitively inhibit HMG-CoA reductase, which results in:

             liver cholesterol synthesis

             LDL receptor expression

             plasma LDL

§Effects: decrease LDL and VLDL by 20-55%

§Intensity of statin:

Statins indications to treat

•Indications (to treat):

•Effective in lowering plasma cholesterol levels in all types of hyperlipidemias

•Used for primary and secondary prevention (relative ASCVD risk is decreased by 20% to 25% per 39-mg/dL (1 mmol/L) reduction in LDL-C)

PK Statins

•PK:

§Orally taken in evening,  because hepatic cholesterol synthesis is maximal between midnight and 2 am

§T_1/2 1-4 hours, except rosuvastatin (19h) and atorvastatin (14h).

§Metabolism in liver (uptake to live by organic anion transporter (OATP1B1))

§CYP3A4: Atorvastatin, Lovastatin, Simvastatin

§CYP2C9: Fluvastatin (50-80%), Rosuvastatin (10%) (but mainly is excreted unchanged in stool)

§Pravastatin is not metabolized by P450 and is excreted unchanged in the urine

§Glucuronosyl transferase: some statins

      Side effects of Statin

vMyopathy

•Myalgia (10-13%): Stiffness, muscle pain

•Muscle weakness (0.3-4.7/10,000) (does not due to pain)

•Lab: Creatine kinase (CK)(could be increased or not); muscle biopsy is the final diagnosis

•Rhabdomyolysis (rare, 1.6 per 100,000 patient-years): Severe, red color urine (myoglobinuria), muscle pain, renal failure, 10 times higher blood CK level

•

•Exclude Nocebo effect: symptoms triggered by anticipated side effects

vLiver damage: increased liver enzymes higher than 3x normal

Hypothetical mechanisms of statin-induced myopath

1.Anion transporter (OATP1B1) gene (SLCO1B1) variant (lower uptake statin to liver)

●

2.Decreased downstream products in cholesterol synthesis process: reduced geranylpyrophosphate and farnesyl-pyrophosphate, needed for prenylation/lipidation of signaling proteins.

statins Ci and DDI

•Pregnancy, nursing mother, children < 8 years old (myelination needs cholesterol)

•Active liver diseases

---

p450 inhibitors increase statin toxicity

Gemfibrozil increases myopathy when together with statin

Ezetimibe (Zetia)

•Mechanism:

•Inhibits cholesterol absorption in intestinal brush border (NPC1L1, Niemann-Pick C1-like 1 cholesterol absorption receptor)

•leading to upregulation of LDL receptor

•Effects: Lowers LDL by 15-20%, VLDL 7-8%

•Indication: hypercholesterolemia

•T_1/2 22 hours

•Side effect: well tolerated.

PCSK9

•PCSK9: Proprotein convertase subtilisin kexin type 9

•Normally, LDL binds to LDLR, and the complex is endocytosed; LDLR recycles back to the plasma membrane while cells metabolize LDL

•PCSK9 binds to LDLR, the complex is endocytosed, and LDLR is degraded in lysosome

•

•PCSK9 inhibitors:

•Antibody: Alirocumab, evolocumab

•siRNA: Inclisiran

PCSK9 antibody: Alirocumab, evolocumab

vMechanism: 

§PCSK9 antibody are human monoclonal antibody, binding to PCSK9, and inhibiting LDLR degradation

§Increase LDL receptor number to clear LDL

§Reduce LDL by up-70%; reduce Lp(a) 25%; reduces triglycerides 2- 20%; increase HDL 4-9%

Indications:

§Adjunct to diet and maximally tolerated statin therapy for adults with

Øheterozygous familial hypercholesterolemia (HeFH)

Øhomozygous familial hypercholesterolemia (HoFH)

Øclinical atherosclerotic cardiovascular disease

vPK: SC q2w, t ½ = 11-20 days

v  ARD: Allergy, injection site reaction (10%)

v  CI: Pregnancy

•Drugs: Cholestyramine, RESIN

Bile acid binding resin

•Mechanisms: positive charged resins bind to negative charged bile acid in gut, lead to

•↓ enterohepatic recirculation of bile salts

•↑ synthesis of new bile acid in liver by 10 fold, for which the synthesis of cholesterol must increase (cholesterol via 7a-hydroxylation converts to bile acid)

•Decreased liver cholesterol (net change)

•Up-regulate LDL receptor

•Effects: Decrease blood LDL by 20%

•Indication: Hypercholesterolemia

Resin

•PK: not absorbed

•Side effects:

•Constipation

•Increased VLDL and triglyceride

•Decreased fat-soluble vitamin absorption: vitamin K, A, D, E.

•Interfering other drugs absorption

•Other medications such as digoxin, thiazide, warfarin, tetracycline, thyroxine, iron, statin, ezetimibe, folic acid, vit C, can be given 1 hour before and at least 2 hours after resins

• CI:

•Hypertriglyceridemia

•Biliary tract disease

•(Katzung: “Increased formation of gallstones, particularly in obese persons, was an anticipated adverse effect but has rarely occurred in practice”)

Citrate Lyase Inhibitor: Bempedoic acid

vMOA:

vReduces cholesterol synthesis in the liver by inhibiting ATP citrate lyase, an enzyme that converts citrate to acetyl-CoA

vUpregulates LDL receptor

v

vEffects: Reduces LDL-C 15-20%; reduces ASCVD risk or mortality

v

vClinical Use

•In 2020 the FDA approved bempedoic acid to be added to statin to lower cholesterol;

•In 2024 FDA approved bempedoic acid (NEXLETOL and NEXLIZET) to prevent heart attacks and cardiovascular procedures in both primary and secondary prevention patients, either alone or combined with statin

Citrate Lyase Inhibitor: Bempedoic acid

vPK:

vBempedoic acid is a prodrug that is converted to an active metabolite by the very-long-chain acyl- CoA synthetase-1 (an enzyme found in hepatocytes but not in myocytes)

vUndergo glucuronidation

vEliminated in urine (OAT2).

v

vADRs: lack of myopathy is an anticipated advantage over statins

vIncrease uric acid level (compete with OAT2 in the kidney) and gout

vTendon rupture

vIncrease liver enzymes

v

vCIs: pregnancy

Fibrates: Gemfibrozil, fenofibrate

Fibrates and peroxisome proliferator activated receptor
(PPARα)

•Drugs: Gemfibrozil, fenofibrate

•MOA:

•Bind to PPAR-α receptor, as transcription factor

•Increase gene expression of LPL, Apo AI and Apo AII

•Decrease gene expression of Apo CIII (LPL activity inhibitor)

•Effects:

•50% reduction in triglyceride (TG)

•10% reduction in LDL

•10% increase in HDL  

INDICATION: TX HYPERTRIGLYCERIDEMIA

Side effects of Fibric acids

•Side effects:

•Myopathy: not as often as statins. Combination with statins is not advised.

•Fenofibrate is a safer one to combine with statin.

•Gemfibrozil should not combine with statins.

•DDI: gemfibrozil inhibits OATP1B1 and glucuronosyltransferase

•Liver injury: avoid in chronic liver diseases.

•Increase gallstone: because VLDL conversion to LDL increases, LDL uptake is increased in liver, thus cholesterol excretion is increased in bile

•In addition, fibrates decrease bile acid synthesis by reducing 7-alpha-hydraxylase mRNA, so cholesterol is increased in bile and feces

•CI: Pregnancy, liver disease, renal failure, biliary tract disease 

•DDI:

•Fibrate and warfarin: displace warfarin from protein binding and inhibit p450 2C9, enhancing warfarin-induced bleeding

•

Mechanisms of drugs reducing lipid

Omega-3 fatty acid

Prescriptions: icosapent ethyl (Vascepa) (a highly purified ethyl ester of EPA) (Vascepa); omega-3-acid ethyl esters (Lovaza)

Dietary supplements: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), fish oil (from deep sea fish)

MOA: Unclear; reduces hepatic triglyceride synthesis and increases triglyceride clearance

Reduce TG by 27-45%

Icosapent ethyl and omega-3-acid ethyl esters are FDA approved as adjunctive therapy for patients with hypertriglyceridemia

Only icosapent ethyl + statin reduced ASCVD risk by 25% (due to reduction in LDL but not TG?)

Fish oil, EPA, or DHA has not been shown significantly reducing ASCVD risk or relevant data is unavailable.

Contraindication: fish allergy

vOther drugs to reduce TG:  Statins; Olezarsen (ApoCIII siRNA)—Apo CIII is an inhibitor of LPL, then Apo CIII inhibitor will enhance activity of LPL, to reduce triglyceride; Niacin

Niacin (vitamin B3)

•Mechanisms:

•Reduce VLDL secretion from liver

•Increase VLDL breakdown via LPL

•Increase HDL by decreasing clearance of Apo A-I

•Effects:

•Decrease triglyceride by 35-50%

•Increase HDL by 30-40%

•Decreases LDL by 25%

•Decrease lipoprotein (a) (Lp(a)) by 40%

•Indication: treat hypertriglyceridemia (seldom use now because of side effects)

•Side effects:

•Flushing, pruritus, rashes (caused by increased prostaglandin, can be avoided by taking NSAIDS (aspirin 30min before niacin, or naproxen once daily)).

•Hepatotoxicity

•Increased blood uric acid (hyperuricemia)

•Worsening of insulin resistance

•CI: Pregnancy, active peptic ulcer, active liver disease, gout

•DDI: Avoid use with statin due to increasing myopathy

•

Statin monotherapy is proven to reduce

ASCVD events and mortality (primary and secondary prevention)

•Sequential addition of ezetimibe and PCSK9 inhibitors to statin further reduces risk in primary and secondary prevention

•Ezetimibe and PCSK9 inhibitors not yet shown to reduce ASCVD risk as monotherapy

•Bempedoic acid is the only non-statin monotherapy to reduce ASCVD events and mortality (primary and secondary prevention)

•Bempedoic acid can be combined with statins

Characteristics of Antihyperlipidemics

How to treat hyperlipidemia

Orlistat

•lose weight 4-8 lbs /year (4%)

•Mechanism: inhibits pancreatic lipase, decrease triglyceride breakdown in the intestine, decrease fat absorption by 30%

•Side effects: steatorrhea, diarrhea, decreases the absorption of lipid soluble vitamins

•Two weeks after a scheduled visit, a 52 y/o female returns to her family doctor.  She was recently started on antihyperlipidemic drug therapy and now complains of fatigue, muscle weakness, and generalized muscle pain.  Lab screen is remarkable for elevated serum creatine kinase. 

•A drug with which of the following mechanisms of action was likely begun two weeks ago? Inhibition of:

A.HMG-CoA reductase.

B.intestinal cholesterol absorption.

C.PCSK9.

D.triglyceride lipolysis

E.Citrate lyase

A

•Two weeks after a scheduled visit, a 52 y/o female returns to her family doctor.  She was recently started on antihyperlipidemic drug therapy.

•Which of drugs increases LDLR number?

A.Alirocumab

B.Atorvastatin

C.Ezetimibe

D.Cholystyramine

E.Bempedoic acid

F.All above

F

•A 60 y/o male who recently began an antihyperlipidemic comes to the clinic for facial flush and itching, as shown on the picture on the top.

•This drug mostly targets which site on the picture on the bottom?

•A. Site A

•B. Site B

•C. Site C

•D. Site D

•E. Site E

•

C

In 2016, the FDA withdrew approval for statin drug combinations containing fibrates or niacin due to increased risk of statin-associated myopathy and lack of evidence that the combination improves cardiovascular outcomes.

Other than avoiding combination with statins, it is also recommended that a fibrate does not use in patients with biliary tract disease. Why?

Answers: fibrates increase cholesterol gallbladder stone

Reduction of LDL level higher than 50% has significant higher benefit to reduce the cardiovascular events and mortality. Can you write down two statins that have high intensity to reduce LDL > 50%?

Answers: Atorvastatin, Rosuvastatin

review

Organic Nitrates

Nitroglycerin

Isosorbide dinitrate

Isosorbide mononitrate

Beta blockers (LOL)

Metoprolol

Atenolol

Carvedilol

Ca++ channel blockers

DHP:

Nifedipine

Amlodipine

Non-DHP

Verapamil

Diltiazem

Late sodium channel blocker

•Ranolazine

Angina pathophysiology

When an artery is severely narrowed (by more than 70%),

Angina (chest pain) usually occurs when O2 supply < O2 demand, and anaerobic metabolites are accumulated in the heart:

physical exertion or emotional distress

platelet aggregation or atheroma rupture

coronary artery spasms (without atheroma)

Classic (Stable) angina:

Occurs when the coronary artery is partly blocked.

The reduced blood flow through narrowed arteries cannot meet the increased oxygen demand.

Symptoms of angina in these cases occur with increased emotional stress or physical exertion.

EKG: ST depression

Unstable angina (Acute coronary syndrome):

Occurs when there is a significant occlusion in a coronary artery (rupture of atherosclerotic plaque).

Anginal symptoms can occur even at rest. It might signal an impending myocardial infarction, treated as a medical emergency.

EKG: ST depression

Variant angina: (also called prinzmetal angina)

Results from a spasm of one of the large coronary arteries on the surface of the heart. Happens in rest or sleep.

This can occur irrespective of the amount of physical or emotional exertion and is not because of coronary artery occlusion.

EKG: ST elevation; coronary angiography is normal, no narrowing

angina

Angina

chest pain 5-10 min

nitrate relieves pain

plasma enzymes troponin, CPK-MB normal

Myocardial infarction:

chest pain > 20 min, pressured, radiation

nitrate does not relieve pain

↑Plasma enzymes troponin, CPK-MB

EKG: Q wave, ST upwardly convex elevation, T inverse

Pericarditis (bacteria, virus):

Chest pain continues for days

Dull

Sit up and lean forward to reduce pain

Fever

A scratchy, high-pitched friction rub

Plasma enzymes troponin, CPK-MB normal

EKG: ST concave elevation

Ultrasound: pericardial effusion

WBC increases

Principles of Treatment of Angina

reduce O2 demand, increase coronary flow

Treatments

In order to set right the imbalance, pharmacotherapy focuses on:

↑myocardial O2 supply (dilate coronary artery)

↓myocardial O2 demand

Heart rate

Ventricular wall tension (volume)

Myocardial contractility

Drugs to relief acute pain:

Nitroglycerin (sublingual, spray)

Drugs to prevent angina:

Nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate)

Beta Blockers (BB) (lol)

CCB (DHP (amlodipine), non-DHP (verapamil, diltiazem))

Ranolazine

Intervention to slow atherosclerosis and clot formation

Diet

Control Bp and diabetes

Stop Smoking

Lower LDL

Anti-platelet

Exercise

Organic nitrates: Nitroglycerin

•MOA: via nitric oxide (NO)

•Nitroglycerin activation requires enzymatic action (by glutathione S-transferase or aldehyde dehydrogenase isoform 2 (ALDH2)), to release NO

•NO activates guanylyl cyclase (GC) to form cGMP, which dephosphorylates myosin light chain (MLC) leading to smooth muscle relaxation and vasodilation.

•Predicted Effects:

•Major: dilation of capacitance vessels (Vein) to reduced cardiac preload at lower dose, reduce ventricular wall pressure, reducing O₂ demand

•Minor: dilation of collateral coronary vessels, increasing O₂ supply

•Dilation of veins > dilation of artery

•At high dose, dilate artery (headache)

•Relaxation of smooth muscle of the bronchi, gastrointestinal tract (including biliary system), and genitourinary tract.

64% of blood are in veins (capacitance vessels )

veins = capacitance

Nitroglycerin dilates veins:

↓preload of heart ↓ventricular wall stress

↓O2 demand

nitroglycerin

vUses:

•Acute and chronic angina (all types, including prinzmetal angina)

vADR

•Severe headache

•Tachyphylaxis (rapid tolerance) or tolerance

•Postural hypotension

•Methemoglobinemia (nitrate NO₃→ nitrite NO₂ by nitrate reductase, nitrite converts Hb to MHb)

vContraindication:

•PDE5 inhibitors should not be prescribed to patients receiving any form of nitrates; in prescribing nitrates, the physician should warn the patient that no PDE5 inhibitor should be used in the 24 h prior to initiating nitrate therapy

•

Nitrate Tolerance/Tachyphylaxis

•Tachyphylaxis or tolerance- effect of drugs decrease over time

•24 hours IV infusion of nitroglycerine;

•within 24-48 h after oral dinitrate four times a day

•Tolerance can not overcome by increasing dose, but stopping the drug 8-12 hours helps minimize tolerance.

•Multiple mechanisms proposed (unclear)

•decrease nitrate conversion to NO

•decrease in tissue sulfhydryl group

•increased ROS (oxygen reactive species)

•Generally not a problem with sublingual nitroglycerin

•Limits the usefulness of oral and transdermal nitroglycerin and oral isosorbide mono- and dinitrate

Acebutolol (ISA) is not a good choicefor preventing angina

no bb with ISA = label ace car pin pen

beta -Blockers for Angina 

All BBs can be used, but commonly used for the treatment of angina are

β1-selective and without intrinsic sympathomimetic activity (ISA) (e.g., atenolol, metoprolol, bisoprolol) and carvedilol

MOA:

block the 1 receptors present in the heart, ↓ heart rate & contraction), only↓ the O2 demand, but usually do not have any effect on myocardial oxygen supply

No role in acute management of angina

Used for prophylaxis only, for stable angina; should not use in prinzmetal angina because of exacerbating vasospasm

Advantage: β Blockers are the only drug class (among nitrates, CCB, and BB) that is effective in reducing the severity and frequency of attacks of exertional angina and in improving survival in patients who have had an MI, therefore, BBs are the first choice to prevent angina

They are used in combination with other anti-anginal drugs.

ADRs: bradycardia, hypotension, hyperlipidemia, impotence, and muscle weakness

Contraindications: prinzmetal angina, asthma, diabetes (unselective beta blockers)

Beta Blockers Prolong Survival After MI

Propranolol significantly

reduced mortality

incidence of all coronary events.

Calcium channel blockers (CCBs)

MOA: Block voltage gated “L-type” calcium channel in vessels inducing vasodilation, and in heart decreasing heart contraction and A-V conduction

Dihydropyridine (DHP): nifedipine, amlodipine

Non-dihydropyridine (non-DHP): verapamil, diltiazem

Diltiazem increases time to angina

Heart rate (HR) and systolic blood pressure (BP) were recorded at the time of onset of anginal symptoms (rightmost points).

β blockers, nitrates, and calcium channel blockers increase time to onset of angina and ST depression during treadmill tests in patients with angina of effort 

Short-acting CCBs increase risk of MI

623 cases and 2032 controls for 4 years

The relative risk was increased in patients taking any form of calcium channel blocker (CCB), greatest with a thiazide diuretic (Tz).

There was no increase in risk with a beta blocker (β-blk) or an ACEI.

The right panel shows that the deleterious effect of calcium channel blocker therapy was seen only with moderate and high doses.

Long acting or extended-release CCBs

Long-acting or extended-release calcium channel blockers do not increase the risk of MI

Nifedipine increases reflex sympathetic activity-tachycardia

The FDA has given the long acting and heart rate lowering calcium channel blockers a "clean bill of health," while warning against short acting nifedipine, treating hypertension and unstable angina

USE: to prevent all kind of angina, with nitrates both the first line for prinzmetal angina

ADRs of CCB

Common side effects:

Constipation (more seen in verapamil, diltiazem)

Peripheral edema (precapillary dilation, more in –dipine drugs)

Nausea

Flushing

Dizziness

Serious ADR (non-DHP-CCB):

Heart failure (verapamil)

A-V blockade

Sinus node depression

Ranolazine

Was FDA approved as a second-line agent for the treatment of chronic angina in 2006

MOA:

Inhibits a late sodium current that facilitates calcium entry, therefore less calcium inside of the cell and less contraction.

Typically reserved for angina that is refractory to treatment with beta blockers, calcium channel blockers, and nitrates.

PK: Oral bioavailability is about 75%

t1/2 is about 7 h

Metabolized mainly by CYP3A4 and to a lesser extent by CYP2D6

ADRs: dizziness, headache, nausea, and constipation

Cautions: drug-drug interaction with p450 inhibitors and inducers

nitrates

Drug of choice to relieve acute angina (all types)

1st choice to prevent vasospastic angina with CCBs

2nd choice for prevention of exertional angina (longer-acting formulations)

Tolerance

CIs: phosphodiesterase-5 inhibitors within 24 hours

BBs

1st choice for exertional angina

Additional vasodilation with carvedilol and nebivolol

CIs: prinzmetal angina

Pharmacotherapies to reduce mortality after MI:

Aspirin (or clopidogrel, etc))

Statins ( or + ezetimibe, + PCSK9 inhibitor)

ACE inhibitors (the –prils) and ARBs (the –sartans)

Immediate relief of acute angina:

Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of all type angina

Prevention in chronic stable angina (Recommended on the Basis of Evidence or General Consensus)β-Blockers as initial therapy in patients with prior MI or without prior MI when no contraindicationsCCB or long-acting nitrates as initial therapy for reduction of symptoms when BB are contraindicatedCCB or long-acting nitrates in combination with β-blockers when initial BB is not success

CCB and long-acting nitrates as a substitute for β-blockers if initial BB leads to unacceptable side effects

ACEI/ARB in all patients with coronary artery disease who have also diabetes or heart failure

High-potency statins, ezetimibe, and PCSK9 inhibitors (target LDL <55 mg/dL) if LDL is higher

↓ mortality after MI:

aspirin, BB, statins, ACEI/ARB