lecture 33 dyslipidemia pharmacology b-rod · lecture 33 dyslipidemia pharmacology b-rod ldl...
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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)
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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
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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
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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:
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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:
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