Cholesterol lowering meds - pharmacology, PKPD, genomics

Brand name of atorvastatin

Lipitor

Brand name of fluvastatin

Lescol XL

brand name of lovastatin

Mevacor

brand name of pitavastatin

Livalo

brand name of pravastatin

Pravachol

brand name of rosuvastatin

Crestor

brand name of simvastatin

Zocor

Indication for atorvastatin

hyperlipidemia, primary/secondary prevention of atherosclerotic cardiovascular disease, familial hypercholesterolemia

MOA of -statins

HMG-CoA reductase inhibitors competitively inhibit conversion of HMG-CoA to
mevalonate, an early rate-limiting step in cholesterol synthesis. A compensatory increase in LDL receptors, which bind and remove circulating LDL-cholesterol, results. (Blocks the rate limiting step of cholesterol synthesis)

CI for atorvastatin

Breastfeeding, active liver disease

ADRs for atorvastatin

myopathy, diarrhea, rhabdomyolysis, hepatotoxicity

Key PKPD parameters for atorvastatin

Most statins have a short half-life and should be taken at night (when cholesterol is being produced) - not true for Atorvastatin and Rosuvastatin!! Most statins are lipophilic and have a higher risk of muscle pain

Statin DDI’s

Many statins are metabolized by CYP3A4!!

HMG-CoA Reductase inhibitor impact on cholesterol?

decreases cholesterol synthesis

increases expression of LDL receptors

decreases total cholesterol

decreases LDL 18-55%

decreases TG 7-30%

decreases CRP

increases HDL 5-15%

HMG-CoA Reductase inhibitor pleiotrophic effects

improved endothelial function, atherosclerotic plaque stabilization, decreased oxidative stress and inflammation, inhibition of thrombogenic response

High intensity statins?

Atorvastatin 40-80mg, Rosuvastatin 20-40mg

High intensity statin impact on LDL?

> 50% LDL reduction

Moderate intensity statins?

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

Moderate intensity statin impact on LDL?

30-49% LDL reduction

Low intensity statins?

Simvastatin 10mg, Pravastatin 10-20mg, Lovastatin 20mg, Fluvastatin 20-40mg, Pitavastatin 1mg

Low intensity statin impact on LDL?

<30% LDL reduction

Atorvastatin metabolism?

CYP3A4 (less than simva and lova)

Atorvastatin lipophilic?

yes

atorvastatin half-life?

20-30 hours

fluvastatin metabolism?

CYP2C9, CYP3A4

fluvastatin lipophilic?

yes

fluvastatin half-life

~3 hours

Lovastatin metabolism?

CYP3A4

Lovastatin lipophilic?

yes

Lovastatin half-life

1.1-1.7 hours

Pitavastatin metabolism?

glucuronidation

Pitavastatin lipophilic?

yes

Pitavastatin half-life?

8-12 hours

pravastatin metabolism

sulfation

pravastatin lipophilic?

no

pravastatin half-life

2-3 hours

rosuvastatin metabolism

CYP2C9, CYP2C19

rosuvastatin lipophilic?

no

rosuvastatin half-life

19 hours

simvastatin metabolism

CYP3A4

simvastatin lipophilic?

yes

simvastatin half-life

2-3 hours

Examples of CYP3A4 inhibitors:

-azoles, amiodarone

Examples of CYP3A4 inducers:

Phenytoin, rifampin

Side effects of statins:

HMGCA: Hepatotoxicity, myopathy, GI side effects (diarrhea), CPK increase (this enzyme increases in rhabdomyolysis), avoid in breastfeeding

Statin monitoring:

1. Fasting lipid panel (4-12 weeks after initiation or therapy change, thereafter, 3-12 months as clinically indicated)

2. transaminases (ALT, AST): baseline, may measure in patients with symptoms suggesting hepatotoxicity

3. Monitor for new-onset diabetes (especially in patients with pre-diabetes)

What mediates the uptake of statins for hepatic metabolism and biliary elimination?

Organic anion-transporting polypeptide |B| (OATP|B|)

What gene encodes for OATP|B|?

SLCO|B|

The allele of c.388G*5 and *15 with a haplotype of low-activity has what impact on statins?

decreased hepatic uptake = increased plasma exposure of statin = potential for increased myalgias (but no impact on effectiveness)

The allele of c.388G*IB with a haplotype of high-activity has what impact on statins?

increased hepatic uptake = decreased plasma exposure of statin = ??

If SLCO|B| variant is known and low functioning, what should be avoided?

avoid simvastatin or use lower doses

Brand name of ezetimibe

Zetia

Indication for ezetimibe

Hyperlipidemia, familial hypercholesterolemia

MOA for ezetimibe

Inhibits absorption of cholesterol at the brush border of the small intestine via
Niemann-Pick C1-Like1 (NPC1L1). This leads to a decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores and an increased clearance of cholesterol from the blood

CI for ezetimibe

Gallbladder disease, severe hepatic dysfunction

ADRs for ezetimibe

URTI, diarrhea, arthralgia, sinusitis, pain in extremities, +statin = myalgia, rhabdomyolysis, hepatotoxicity

key PKPD for ezetimibe

Enterohepatic circulation, half-life ~22 hours

DDI’s for ezetimibe

Plasma concentrations are significantly increased when administered with fibrates or cholestyramine

Ezetimibe impact on cholesterol:

decrease total cholesterol

with statin decreases LDL by ~25%

monotherapy: decrease LDL ~18%, decrease ApoB ~15%, decrease TG ~8-14%, increase HDL-cholesterol ~5%

Brand name of alirocumab

Praluent

Brand name of evolocumab

Repatha

Indication for alirocumab and evolocumab

hyperlipidemia, familial hypercholesterolemia,

MOA for alirocumab and evolocumab

human monoclonal antibody that binds to PCSK9 and increases the number of LDL receptors available to clear circulating LDL

CI for alirocumab and evolocumab

None

ADRs for alirocumab and evolocumab

nasopharyngitis, influenza, URTI, injection site reactions, back pain.

Key PKPD for alirocumab and evolocumab

subcutaneous injection every 2 or 4 weeks

DDIs for alirocumab and evolocumab

None identified

PCKS9-Inhibitors impact on cholesterol?

decrease total cholesterol, LDL ~50-70%, ApoB ~50%, TG~7-30%, Lp(a) ~25%, and increases HDL ~5-10%

Brand name of inclisiran

Leqvio

Indication for inclisiran

primary/secondary prevention of atherosclerotic cardiovascular disease, familial hypercholesterolemia

MOA of inclisiran

Small-interfering RNA (siRNA) LDL-C lowering therapy. Inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9 (PCSK9) by blocking its synthesis, which is dependent on messenger RNA

CI for inclisiran

Pregnancy

ADRs for inclisiran

Injection site reactions, arthralgia

Pearls of inclisiran

subcutaneous injection into the abdomen, upper arm, or thigh once, then in 3 months, then every 6 months thereafter. Currently cannot be administered at home/pharmacy

Inclisiran impact on cholesterol

monotherapy: decrease LDL ~50%

Brand name of bempedoic acid

Nexletol

indication for bempedoic acid

primary/secondary prevention of atherosclerotic cardiovascular disease, familial hypercholesterolemia

MOA for bempedoic acid

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

CI for bempedoic acid

Pregnancy

ADRs for bempedoic acid

hyperuricemia (can cause gout flares with prior gout history), tendon rupture

Key PKPD for bempedoic acid

N/A

DDI for bempedoic acid

increases concentrations of pravastatin (max dose 40mg) and simvastatin (max dose 20mg)

Bempedoic acid impact on cholesterol

monotherapy: decreases LDL ~20-30%

with statin: additional 17% from statin lowering

Brand name of colesevelam

Welchol

Brand name of colestipol

Colestid

Brand name of cholestyramine

Prevalite, Questran

Indication for colesevelam

hyperlipidemia

MOA for colesevelam

Colesevelam binds with bile acids in the intestine to form an insoluble complex
that is eliminated in feces. This increased excretion of bile acids results in an increased oxidation of cholesterol to bile acid and a lowering of the serum cholesterol

CI for colesevelam

history of bowel obstruction, triglycerides > 500 mg/dL, hypertriglyceridemia induced pancreatitis

ADRs for colesevelam

constipation, dyspepsia, nausea, pancreatitis, bowel obstruction

Key PKPD for colesevelam

Drugs DO NOT ABSORB!! Excreted in feces

DDIs with colesevelam

Impacts drug absorption! Most medications need to be taken 1 hour before or
2 hours after the BAS to ensure adequate absorption:

• Increases seizure activity or decreases phenytoin levels in patients taking phenytoin.

• Decreases INR in patients taking warfarin

• Increase TSH in patients taking thyroid hormone replacement therapy

Pearls of colesevelam

take with food:

packet/granules mix with 120-240ml of water, stir well and drink

tablets swallow with liquid

most need to be started at low dose and gradually increased

Bile acid sequestrants impact on cholesterol

Decrease LDL: colesevelam monotherapy 15%, colesevelam + statin 10-16%, colestipol monotherapy 16-27%, cholestyramine monotherapy 10.4%

Increase VLDL: may increase TGs

Brand name of omega-3-ethyl-esters?

Lovaza

Brand name of icosapent ethyl?

Vascepa

Indication for omega-3s

hyperlipidemia, hypertriglyceridemia

MOA of omega-3s

Reduction in the hepatic production of triglyceride-rich very low-density
lipoproteins. Possible cellular mechanisms include inhibition of acyl CoA:1,2 diacylglycerol acyltransferase, increased hepatic mitochondrial and peroxisomal beta-oxidation, and a reduction in the hepatic synthesis of triglycerides

CI for omega-3s

Hypersensitivity to drug, fish, or shellfish (use with caution)

ADRs for omega-3s

diarrhea, fishy breath, burping, change in taste, elevated LFTs