Pharm E3: cardio lipid lowering agents

What is ApoB-100?

the only apoprotein of LDL; is the legal that binds LDL to it’s receptor

what is the half life of LDL particles arising from catabolism of IDL?

1.5-2 days

What is plasma clearance of LDL particles primarily mediated by?

LDL receptors (responsible for ~75 % clearance)

Where are most LDL receptors found?

liver

What does decreased LDL receptor activity lead to?

LDL particle accumulation → atherosclerosis

if the liver is full of cholesterol…

won’t express LDL receptors → inc LDL concentration bc stuck in blood

If liver is deprived of cholesterol…

more receptors expressed on surface → dec LDL in blood

What classes of drugs are antihyperlipidemics?

HMV-CoA reductase inhibitors

Cholesterol absorption inhibitor

Fibrates

Bile acid sequestrants

Nicotinic acid

PCSK9 inhibitors

What is another name for HMG-CoA reductase inhibitors?

statins (all drug names end in statin)

What drug is a cholesterol absorption inhibitor?

Ezetimibe

What drugs are Fibrates/Fibric acid derivatives?

Gemfibrozil (Lopid)

Fenofibrate (Tricor)

Bezafibrate (Bezalip SR)

What drugs are bile acid sequestrants?

Cholestyramine (Questran)

Colesevelam (Colestid)

Colestipol (Welchol)

What is the MOA of statins?

inhibit HMG-CoA reductase → reduce hepatic cholesterol synthesis → lower intracellular cholesterol stimulates up regulation of LDL receptors → inc uptake of non-HDL particles from systemic circulation

dec LDL and VDL; inc HDL uptake

What are pleiotropic effects of statins?

additional side benefits not explained through its MOA;

have extra benefits besides lowering LDL when the drug is used to tx ASCVD

(improve endothelial function, atherosclerotic plaque stabilization, etc)

Which statins are metabolized through the CYP3A4 pathway and are more prone to interactions w/ 3A4 inhibitors?

atorvastatin, lovastatin, simvastatin

which statin is metabolized through the CYP2C9 pathway?

Fluvastatin

What are common SE w/ statins?

HA, sleep disturbances, fatigue, GI intolerance, flu like sx, inc liver enzymes, myalgia, myopathy & rhabdomyolysis (rare)hatW

What labs do you need to monitor w/ statins?

LFTs and CPK

How do you reduce the risk of rhabdomyolysis/myopathies when prescribing statins?

• use w/ caution in pts w/ impaired renal function

• use lowest effective dose

• use caution when combining w/ fibrates

• avoid drug interactions (CYP)

• carefully monitor labs (CPK, LFTs)

**presence of muscle toxicity required discontinuation of drug

What are contraindications of statins?

hepatic disease

pregnancy- absolutely contraindicated

relative Cl- concomitant use of cyclosporin/immunosuppressants, gemfibrozil, niacin, erythromycin

What are drug interactions assoc. w/ statins?

• CYP-450 mediated interactions (esp. CYP3A4 inhibitors and substrates)

• Verapamil

• Amiodarone

• Niacin

• Fibric acid derivatives

  • Grapefruit juice

What are the most efficacious and best tolerated agents when treating hyperlipidemia?

statins

WHa tis the first line therapy when LDL-C lowering drugs are indicated?

Statins

What is MOA of Ezetimibe?

• selectively inhibits intestinal cholesterol absorption

  • dec intestinal delivery of cholesterol to liver

  • inc expression of hepatic LDL receptors

  • dec cholesterol content of atherogenic particles

• circulates enterohepatically

Why does Ezetimibe have less systemic SE?

circulates enterohepatically and delivered back to the site of action;

once absorbed into liver → eliminated through biliary tract → limited systemic exposure

Ezetimibe dosing

• 10 mg PO daily w/ or w/o meals

• additional 15-20% LDL lowering when added to statin

What are adverse effects w/ Ezetimibe?

GI related effects, elevations in hepatic transaminases w/ statins (** monitor LFTS)

What are drug interactions assoc. w/ Ezetimibe?

• fabric acid derivatives- inc hepatobiliary SE leading to cholelithiasis and myopathies

• bile acid sequestrants may dec concentrations

• antacids dec concentrations

• cyclosporine (immunosuppressants) inc concentrations

What is the MOA of fibrates?

activate PPAR-alpha (nuclear transcription factor) → inc fatty acid oxidation → dec VLDL secretion → dec triglycerides

inc expression of ApoA-1 → inc HDL

mostly used to lower TGs and inc HDL (more specific for VLDL/HDL than statins)

what are adverse effects of fibrates?

GI- N, D, abdominal pain

cholelithiasis

myopathy- be careful when combining w/ statins or ezetimibe

(**if complaining of muscle pain, monitor CPK)

what are contraindications for fibrates?

pregnancy, severe hepatic or renal dysfunction, existing gallbladder dz

what are drug interactions w/ fibrates?

• inc anticoagulant effects of warfarin (potential bleeding concern)

• HMG-CoA reductase inhibitors

• Ezetimibe

• Bile acid sequestrants

What is the primary indication for fibrates?

TG > 1000 mg/dL or low HDL

What is another name for bile acid sequestrants?

resins

what is the MOA of bile acid sequestrants?

works in lumen of GI tract to bind to bile acids → prevent enterohepatic recirculation of cholesterol → excreted in feces

liver produces more bile acids and LDL receptors → reduction in LDL

not absorbed in GI tract: limited systemic SE and approved for children, adolescence, pregnancy

What may result w/ an inc in dose of bile acid sequestrants?

inc in SE w/o gaining more beneficial effects

Bile acid sequestrants administration

• powders must be mixed w/ water or fruit juice

• mix in pulpy drink to mask taste

• take w/in one hour of meal

• separate other medications

What are adverse effects of bile acid sequestrants?

• not absorbed from GI tract (no systemic SE)

• GI- bloating, flatulence, fullness, constipation, N (not ideal for pregnancy pts)

• malabsorption of vit ADEK and folic acid

• may inc VLDL production → inc TGs

• inc Ca excretion by direct binding and dec absorption

What are drug interactions assoc. w/ bile acid sequestrants?

anionic exchange resins; interfere w/ absorption of some drugs: digoxin, warfarin, thyroxine, B-blockers, thiazide diuretics

avoid interactions by administering drug 1 hour before or 4 hours after

what are contraindications of bile acid sequestrants?

absolute: familial dysbetalipoproteinemia (inc TG), TG > 400 mg/dL

relative: TG > 200 mg/dL

Describe bile acid sequestrants place in therapy

• safest drug bc no systemic SE

• poorly tolerated

• primary use in conjunction w/ statin or for those needing only modest reductions in LDL

What is niacin / nicotinic acid?

B-complex vitamin; used as an antilipemic

What form of nicotinic acid is not effective as an antilipemic?

amid form- niacinamide (nicotinamide)

List examples of niacin products

immediate release: Niacin (supplement) and Niacor (Rx)

long acting: Niacin (supplement)

extended release: Niaspan (Rx)

Inositol hexaniacinate

What is the MOA of niacin?

not able to liberate fatty acids from adipose tissue as effectively → dec TGs formed as VLDL in liver (less TG synthesis = less VLDL)

dec hepatic production of VLDL and apo B; inc HDL (later effect)

Which dosage form of niacin is preferred?

extended release (Niaspan) - helps prevent SE

what happens with immediate release niacin?

produces prostaglandins → cutaneous flush; blood vessels dilate and pt becomes warm, hot, red; GI sx

What minimizes prostaglandin flush seen w/ Niacin?

premedication w/ ASA (decreases prostaglandin formation)

What are adverse effects of Niacin?

cutaneous flushing, GI- N, abd discomfort

larger doses: inc LFTs, glucose, and uric acid; dec glucose tolerance

(**monitor LFTs and glucose)

what are contraindications for niacin?

absolute: chronic liver dz

relative: peptic ulcer dz, h/o symptomatic gout, significant hyperuricemia, diabetes (glucose intolerance)

What drug interactions are assoc. w/ Niacin?

statins- worsens LFTs

bile acid sequestrants

EtOH- synergistic flushing

describe Niacin’s place in therapy?

useful for pts w/ atherogenic dyslipidemia

useful as combo therapy for pts w/ atherogenic dyslipidemia and elevated LDL

What drug is a combo of statin and niacin?

Lovastatin/Niaspan (Advicor)

What effect does Lovastatin/Niaspan (Advicor) have on lipids?

LDL: 50% reduction

HDL: 30% increase

TG: 40% reduction

What are adverse effects of Lovastatin/Niaspan (Advicor)?

hepatotoxicity, myopathy, flushing

**have to monitor LFTs

What drugs are PCSK9 inhibitors?

Alirocumab (Praluent)

Evolocumab (Repatha)

(injectable monoclonal abs)

What is the MOA of PCSK9 inhibitors?

PCSK9 is responsible for processing/metabolizing hepatic LDL receptors

monoclonal abs bind/block PCSK9 proteins → dec PCSK( activity → keeps LDL receptors active longer → dec LDL concentrations

What are disadvantages of PCSK9 inhibitors?

injectable only, expensive

hypersensitivity rxns are most serious adverse rxn (bc monoclonal ab)

What causes an increase in HDL?

exercise

What is the formula for VLDL (if TG < 400)?

TG/5

What is the goal of tx according to the AHA/ACC guidelines?

tx of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults, currently the leading cause of death and disability in America

(treating the risk, not the numbers)

Why are you measuring lipids according to AHA/ACC guidelines?

to assess adherence to tx, not to achieve specific LDL target

What are the 4 major statin benefit groups?

individuals-

• with clinical ASCVD (previous coronary event)

• with LDL > 190 mg/dL

• with DM, 40-75 y/o w/ LDL 70-189 mg/dL and w/o clinical ASCVD

• without clinical ASCVD or DM with LDL 70-189 mg/dL and estimated 10 year ASCVD risk

What are the highest intensity statins?

Atorvastatin

Rosuvastatin

If high or moderate intensity statin not tolerated…

use maximum tolerated dose instead