Lecture 33 Dyslipidemia Pharmacology B-Rod LDL RECEPTORS: present in liver and is responsible for uptake of IDL and LDL from plasma

PCSK9 IN REGULATION OF LDL RECEPTOR EXPRESSION:

PCSK9 is a protease which is synthesized in the hepatocyte

It binds to the LDL + receptor LDL + PCSK9 + LDL receptor complex o Entire complex is engulfed through endocytosis o PCSK9 prevents LDL receptor from pinching off = prevents recycling of LDL receptor o Entire complex comes into contact with lysosome and is ALL degraded = lose LDL receptors

WAYS OF REDUCING LDL CHOLESTEROL:

DRUG THERAPY TO LOWER LIPIDS:

Decrease cholesterol o HMG CoA Reductase

Inhibitors (Statins) o Bile acid-binding Resins o Ezetimibe (Ezetrol) o PCSK9 Inhibitors (Alirocumab)

Decrease triglycerides o Nicotinic Acid (Niacin) o Fibric Acid Derivatives

(Fibrates)

Lecture 33 Dyslipidemia Pharmacology B-Rod

HMG CoA REDUCTASE INHIBITORS: (“Statins”)

EFFECTIVENESS:

First line agents to reduce cholesterol – major effect on liver o Reduces plasma LDL by 18-55% o Minor reduction in VLDL

triglyceride (7-30%) o Marginal elevation of HDL (5-15%)

Effective with once daily administration

NON-CHOLESTEROL RELATED ACTIONS: 1. Improving endothelial function – decreased oxidative stress

(prevents atherosclerosis) 2. Modulate inflammatory response – reduction of inflammation

at site of plaque (prevent infiltration of monocytes) 3. Maintain plaque stability – reduced degradation of

extracellular matrix (blocks action of MMPs which degrade the plaque)

4. Prevent thrombus formation – reduced platelet aggregation

ADVERSE EFFECTS:

Myopathy (minor muscle weakness & tenderness) rhabdomyolysis o Monitor serum CPK in symptomatic patients

Hepatic toxicity o Monitor with liver function tests (serum

transaminases) in symptomatic patients)

Metabolzed: o CYP3A4: Atorva, Lova, Simova

GRAPEFRUIT INHIBITS o CYP2C9: Fluva, Rosuva

WARFARIN o No CYP: Prava

Pregnancy: skeletal malformation in fetus

Lecture 33 Dyslipidemia Pharmacology B-Rod

BILE ACID SEQUESTRANTS:

Two available o Colestipol HCl

(Colestid) Granules: mix with

fluid/pulpy fruits, soups, cereals

Tablets: swallow whole with fluids

o Colesevelam HCl (Lodalis) Tablets: swallow

whole with fluids

Decreases LDLs o Weakly stimulates

hepatic triglyceride synthesis

With time, efficacy of resins can become blunted o Up-regulation of HMG-

CoA reductase o ↑ in hepatic

cholesterol synthesis o ↓ in hepatic LDL

receptors

Biologically inert

Rarely used in therapeutics

ADVERSE EFFECTS:

Interactions: o Binds negatively charged drugs reduced absorption (digoxin,

beta blockers, warfarin, thiazide) o Prevents re-absorption of fat soluble vitamins o Take other PO meds either an hr before or 4h after resin

GI (bloating, constipation)

EZETIMIBE: novel inhibitor of intestinal cholesterol absorption at the brush border

Rapidly metabolized to glucuronide (active metabolite) o 400x potency of EZE =

prolongs action

No important adverse effects OR significant drug interactions

Monotherapy/combination with statin o 25% reduction in LDL

PLANT STENOLS: veggies, fruits

Normally bile acids make cholesterol into micelles which allow it to be absorbed

Plant stenols look like cholesterol but are more hydrophobic, so they displace cholesterol from the micelles cholesterol excreted

Lecture 33 Dyslipidemia Pharmacology B-Rod

PCSK9 INHIBITORS:

Alirromumab o Injected sc once every 2 wks

Evolocumab o Injected sc once every 4 wks

Can reduce LDL-C by up to 65% o Very good for familial

hypercholesteremia

Modest side effects (URTI, rash, injection site reactions)

ROLE OF TRIGLYCERIDES:

TRIGLYCERIDE MOVEMENT FROM STORAGE LIVER:

Lecture 33 Dyslipidemia Pharmacology B-Rod

NICOTINIC ACID (Niacin):

EFFECTS:

Reduced HSL

Reduced FA release

Reduced VLDL synthesis o Results in reduced LDL

Increase LPL

Decrease TGs by 20-50%

Reduction in cholesterol: