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Hyperlipidemia
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Hyperlipidemia
Types of hyperlipidemia
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Hyperlipidemia
Types of hyperlipidemia
hyperlipidemia
hyperlipoproteinemia
low HDL
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high LDL
hypercholesterolemia
hypertriglyceridemia
Hyperlipidemia
Types of hyperlipidemia
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Hyperlipidemia
Types of hyperlipidemia
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Hyperlipidemia
Types of hyperlipidemia
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Hyperlipidemia
Types of hyperlipidemia
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Hyperlipidemia
Types of hyperlipidemia
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Hyperlipidemia
Types of hyperlipidemia
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Hyperlipidemia
Types of hyperlipidemia
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Hyperlipidemia
2003
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Hyperlipidemia
Background
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Hyperlipidemia
Background
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Hyperlipidemia
Background
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Hyperlipidemia
Background
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Hyperlipidemia
Risk factors
• genetic (family history)
• lifestyle (obesity, physical inactivity, smoking, atherogenic diet)
• emerging markers (homocysteine, proinflammatory factors…)
• age (men>45yr, women>55yr)
• concomitant diseases:
- HTN (>140/90 and/or on anti-HTN Tx)
- diabetes
- renal-liver disease
- hypothyroidism
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Hyperlipidemia
Background
NCEP ATP-III classification of LDL, total, and HDL cholesterol
LDL cholesterol, mg/dL
<100
Optimal
100 to 129
Near or above optimal
130 to 159
Borderline high
160 to 189
High
190
Very high
Total cholesterol, mg/dL
<200
Desirable
200 to 239
Borderline High
240
High
HDL cholesterol, mg/dL
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<40
Low
60
High
Hyperlipidemia
Background
NCEP ATP-III LDL-cholesterol goals and cutpoints for therapeutic
lifestyle changes and drug therapy in different risk categories
Risk category
LDL level at which to initiate
therapeutic lifestyle changes
LDL level at which to
consider drug therapy
coronary heart disease
(CHD) or CHD risk
equivalent
(10-year risk >20%)
100 mg/dL
130 mg/dL;
drug optional at 100-129
mg/dL
2 or more risk factors
(10-year risk < 20%)
130 mg/dL
160 mg/dL
160 mg/dL
190 mg/dL;
LDL-lowering drug optional
at 160-189 mg/dL
0 to 1 risk factor
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Hyperlipidemia
2004 NCEP updates
population
updated recommendation
LDL target of <70mg/dl in very high risk
high risk
initiate drug therapy at LDL>100mg/dl
moderate risk
initiate drug therapy at LDL>100mg/dl
high/moderate risk
intensify drug therapy to reduce LDL by ≥30%
NCEP ATP IV expected release – fall 2011
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Hyperlipidemia
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Hyperlipidemia
Pharmacotherapy
• HMG-CoA-reductase inhibitors (statins)
• fibrates
• resins
• niacin (vitamin B3)
• ezetimibe
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Hyperlipidemia
Pharmacotherapy
• HMG-CoA-reductase inhibitors (statins)
• fibrates
• resins
• niacin (vitamin B3)
• ezetimibe
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Hyperlipidemia
Pharmacotherapy
HMG-CoA-reductase inhibitors (statins)
• simvastatin (Simovil®, Simvacor®, …)
• pravastatin (Pravalip®)
• fluvastatin (Lescol®)
• atorvastatin (Lipitor®)
• rosuvastatin (Crestor®)
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Hyperlipidemia
Pharmacotherapy - statins
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Hyperlipidemia
Pharmacotherapy - statins
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Hyperlipidemia
Pharmacotherapy - statins
additional mechanism:
HMG-CoA reductase inhibition
↓ de-novo cholesterol synthesis
depletion of intracellular cholesterol
up-regulation of LDL-receptors
↑ internalization of circulating LDL
↓ plasma cholesterol
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Hyperlipidemia
Pharmacotherapy - statins
T1/2 (hr)
atorva
fluva
prava
rosuva
simva
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0.5-2.5
1.5-3
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2-3
long pharmacological T1/2 allows once daily dosing
administer
anytime
evening
evening
anytime
evening
food effect
-
-
↓ absorption
-
-
metabolites
active
inactive
inactive
inactive
active
solubility
lipophilic
lipophilic
hydrophilic
hydrophilic
lipophilic
% bound
85
99
50
90
95
CYP metabol.
+
+
-
+/-
+
excretion
hepatic
hepatic
20% renal
10% renal
13% renal
LDL reduction
40-55%
15-35%
20-40%
50-65%
30-50%
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Hyperlipidemia
Pharmacotherapy - statins
PD – LDL reduction
Statins also:
- ↓ TG
- ↑ HDL
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Hyperlipidemia
Pharmacotherapy - statins
ADEs
rhabdomyolysis, myopathy, lactic-acidosis (CK elevations)
• rare but potentially life-threatening
• risk factors:
- statin properties: lipophilicity, dose, DDIs
- pre-existing renal function
- advanced age
- surgery
- uncontrolled seizures
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monitor CK:
- baseline
- periodically
- dose changed
<3×ULN: acceptable
Hyperlipidemia
Pharmacotherapy - statins
ADEs
rhabdomyolysis, myopathy, lactic-acidosis (CK elevations)
N
W
A
R
D
H
WIT
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Hyperlipidemia
Pharmacotherapy - statins
ADEs
• impaired LFTs (monitor, avoid in liver disease)
• headaches
• sleep disturbances
• GI (constipation/nausea/vomiting)
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Hyperlipidemia
Pharmacotherapy - statins
DDIs
• mainly affect simvastatin
• ↑ levels by itraconazole, amiodarone, diltiazem,
verapamil, cyclosporin, fluvoxamine, grapefruit juice
• ↑ rhabdomyolysis with other antilipemics
• ↑ warfarin levels (all but prava)
• ↑ digoxin levels (all but prava, rosuva)
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Hyperlipidemia
Pharmacotherapy
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Hyperlipidemia
Pharmacotherapy
fibrates
• bezafibrate (Bezalip®, Norlip®)
• ciprofibrate (Lipanor®)
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Hyperlipidemia
Pharmacotherapy - fibrates
PPARα-agonists (peroxisome proliferator-activated receptors)
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Hyperlipidemia
Pharmacotherapy - fibrates
bezafibrate / ciprofibrate PK
• good oral absorption
• non-CYP hepatic metabolism
• renal excretion
• T1/2 - 2hr / 80hr
• IR - TID, SR - double-dose OD / OD
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Hyperlipidemia
Pharmacotherapy - fibrates
ADEs
• GI … (mild)
• gallstones
• ↓ LFTs (?)
• headache. dizziness, insomnia
• rhabdomyolysis (rare)
DDIs - PD, with other anti-lipemics
↓ TG, LDL, ↑ HDL (<statins)
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Hyperlipidemia
Pharmacotherapy
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Hyperlipidemia
Pharmacotherapy
resins (bile-acid sequestrants)
• cholestyramine (Chol-Less®, Questran®)
• colestipol (Colestid®)
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Hyperlipidemia
Pharmacotherapy
resins
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Hyperlipidemia
Pharmacotherapy
resins - PK
• oral administration
• unabsorbed
• not metabolized
• “local activity” within GI
• fecal excretion
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Hyperlipidemia
Pharmacotherapy
resins - ADEs
• GI – constipation, nausea, flatulence
resins - DDIs
• impaired intestinal absorption of drugs and nutrients
(digoxin, warfarin, aspirin, statins, thiazides, ADEK vitamins, …..)
• stagger (1-2hr before, 4-6hr after)
mainly ↓ LDL (<statins)
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Hyperlipidemia
Pharmacotherapy
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Hyperlipidemia
Pharmacotherapy
niacin - vitamin B3 (various OTC “nutraceuticals”)
high-dose
niacin
lipolysis in fat tissue
↑ circulating free fatty-acids (FFAs)
precursor for triacylglycerol
hepatocyte: conversion to VLDL
plasma: conversion to LDL
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HDL increase
unexplained
Hyperlipidemia
Pharmacotherapy
niacin - vitamin B3 (various OTC “nutraceuticals”)
HDL-raising properties discovered 1955,
proposed mechanism published 2008
impaired (-35%) hepatic removal of HDL from blood
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Hyperlipidemia
Pharmacotherapy
niacin - PK
• oral administration
• conversion to nicotinamide
• incorporated into nicotinamide-adenine nucleotide (NAD+)
• renal excretion
• fecal excretion
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Hyperlipidemia
Pharmacotherapy
niacin - ADEs
• flushing + warmth (PGD2-mediated cutaneous vasodilation)
• SR formulations, “no-flush” derivatives
(inositol-hexaniacinate)
• USA: a single prescription product (SR, Niaspan®)
• prevention: low-dose aspirin 30min prior to niacin?
• abdominal pain, nausea, pruritis, liver impairment
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Hyperlipidemia
Pharmacotherapy
niacin/laropiprant (Tredaptive®)
• niacin + peripheral PGD2-receptor selective antagonist
• reduced flushing
• Approved for use within EU
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Hyperlipidemia
Pharmacotherapy
niacin - effects
• most potent HDL elevation
• LDL reduction
• TG reduction
• may be combined with other antilipemics
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Hyperlipidemia
Pharmacotherapy
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Hyperlipidemia
Pharmacotherapy
• HMG-CoA-reductase inhibitors (statins)
• fibrates
• resins
• niacin (vitamin B3)
• ezetimibe
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Hyperlipidemia
Pharmacotherapy
ezetimibe (Ezetrol®)
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Hyperlipidemia
Pharmacotherapy
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Hyperlipidemia
Pharmacotherapy
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Hyperlipidemia
Pharmacotherapy
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Hyperlipidemia
Pharmacotherapy
adherence…
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Hyperlipidemia
Pharmacotherapy - hyperlipidemia
DRUGS FOR EXAM
• simvastatin
• bezafibrate
• cholestyramine
• niacin
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