Transcript Integrative Management of Patients with Dyslipidemia

GETTING TO THE HEART OF INTEGRATIVE MEDICINE
Integrative Management of Patients with
Dyslipidemia
Presenter:
Amie Steel ND
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
1
Incidence of high cholesterol
 In 2004-5, 7% of the population reported having
been told by a doctor or nurse that they have high
blood cholesterol.
 For those aged over 65 years, the rate was 22%
 Of Australians reporting a cardiovascular condition,
40% also have reported having high blood
cholesterol
 True levels may be as high as 51%
 High Cholesterol is not considered a cardiovascular
disease, it is a risk factor
ABS (2006) Cardiovascular Disease in Australia: A Snapshot, 2004-05
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
2
Allopathic Management of Dyslipidemia
 Common interventions
 Statins
 Fibrates
 Ezetimibe
 Targets




Total Cholesterol <4.0mmol/L
LDL Cholesterol <2.5mmol/L
HDL Cholesterol >1.0mmol/L
Triglycerides <2.0mmol/L
(NHF and CSANZ (2006) Position Statement on Lipids)
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
3
Cholesterol synthesis and associated pathways
Acetyl CoA
Phenylalanine
Myocyte Regeneration
(selN)
Acetoacetyl CoA
Tyrosine
HMG CoA Synthase
HMG CoA
4OH-Phenylpyruvate
HMG CoA Reductase
4OH-Phenyllactate
Mevalonate
Mevalonate-P
4OH-Cinnamate
4OH-Benzoate
Thyroxine Homeostasis
(deiodinase)
Decaprenyl-PP
Decaprenyl-4OH
Benzoate Transferase
Decaprenyl-4OH-Benzoate
Ubiquinone (CoQ10)
Lymphocyte Activation
(SPS2, Sep15)
Antiviral Defense
(GPx1)
Selenoproteins
Antioxidant Defense
(GPx, TrxR)
Isopentyl Sec-tRNA
Mevalonate-PP
tRNA isopentenyl
transferase
Isopentyl-PP
Geranyl-PP
Farnesyl-PP
Sec-tRNA precursor
B3and Mg/Mn
B2
Squalene
Squalene synthase
Cholesterol
Squalene monooxygenase
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
4
LDL Receptor activity
LDL Receptor
(Coated pit)
LDL
Cholesteryl
linoleate
Cholesteryl Oleate
Protein
Cholesterol
Lysosome
LDL Binding
Internalization
Amino Acids
Lysomal hydrolysis
Regulatory actions
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
5
Cholesterol Degradation
Cholesterol
2-α-hydroxylase
HEPATOCYTE
7- α -hydroxy cholesterol
Reductase
7- α,4-cholesten-3-one
12 – hydroxylase
3α, 7α – Dihydroxy cholestane
3 α,7α,12 α -Trihydroxycholestane
27 – hydroxylation
Conjugation with CoASH
taurine
Chendeoxycholyl CoA
taurine
glycine
Oxidation of side chain
Cholyl - CoA
glycine
CoASH
CoASH
CoASH
Taurocholic Acid
Glycocholic acid
Cholic acid
GALL BLADDER
CoASH
Taurocheno
deoxycholic acid
SMALL INTESTINE
Bacterial removal of 7-hydroxyl
group
Glycocheno
deoxycholic acid
Chenodeoxycholic acid
Deoxycholic acid
Lithocholic acid
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
E
N
T
E
R
O
H
E
P
A
T
I
C
C
I
R
C
U
L
A
T
I
O
N
6
Carbohydrates and cholesterol synthesis
Glucose
Hexokinase
Mg+
Glucose – 6 - P
G
L
Y
C
O
L
O
S
I
S
Acyl CoA:cholesterol acyl
transferase (ACAT)
Cholesterol
VLDL
Cholesteryl Esters
Mevalonate
HMG CoA
Citrate
CoA
Citrate Synthase
Pyruvate
KREBS CYCLE
Oxaloacelate
Acetyl CoA
ATP
CELL MEMBRANE
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
7
Lipitor (Atorvastatin)
HMG CoA Reductase Inhibitor Drug Class
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
8
Lipitor (Atorvastatin)
HMG CoA Reductase Inhibitor Drug Class
 Product Name: Lipitor (10mg;20mg;40mg;80mg)
 Use: HMG CoA reductase inhibitor. Adjunct to diet in
treatment of hypercholesterolaemia
 Precautions: Hepatic dysfunction (monitor liver
function); excessive alcohol intake; myopathy
(monitor CK); risk factors for rhabdomyolysis eg
severe acute infection, hypotension, major surgery,
trauma, severe metabolic, endocrine, electrolyte
disorders, uncontrolled seizures
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
9
Lipitor (Atorvastatin)
HMG CoA Reductase Inhibitor Drug Class
Pharmacology: Atorvastatin is a synthetic lipid lowering agent.
 Atorvastatin is an inhibitor of HMG-CoA reductase, the rate limiting
enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to
mevalonate, a precursor of sterols, including cholesterol.
 Triglycerides and cholesterol in the liver are incorporated into very low density
lipoprotein (VLDL) and released into the plasma for delivery to peripheral
tissues. Low density lipoprotein (LDL) is formed from VLDL and is catabolised
primarily through the high affinity LDL receptor.
 Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting
HMG-CoA reductase and cholesterol synthesis in the liver and by
increasing the number of hepatic LDL receptors on the cell surface to
enhance uptake and catabolism of LDL.
 Atorvastatin reduces LDL production and the number of LDL particles.
 Atorvastatin produces a marked and sustained increase in LDL receptor
activity coupled with a beneficial change in the quality of circulating LDL
particles.
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
10
Adverse Reactions
 Rhabdomyolysis; myopathy; myalgia; GI upset; headache; rash;
neuropathy; raised LFTs
 Reduced cholesterol in cell membranes causes instability of the
plasma membrane and damage to cells
 High doses of statins reduces the levels of CoQ10 in skeletal
muscle
 The ratio of lactate to pyruvate increases, lipid storage increases
and red muscle fibres become ragged, suggesting mitochondrial
dysfunction
 Statins also affect isopenyl adenosine contained in transfer RNA
and dolichols for the synthesis of glycoproteins and CoQ10
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
11
Adverse Reactions
 Immunosuppression, mostly associated with T-cell activation,
particularly by reducing CD4+ Th1 lymphocytes, and decrease
the responsiveness to protein kinase C activators, and may be
due to a loss in selenoprotein N.
 Some reports have described a drop in thyroxine and an
increase in TSH in response to lovastatin in hypothyroid
patients (related to inhibition of iodothyronine-5’-deiodinases
 Statins also reduce prenylated proteins which are required for
cell signal transduction, differentiation, proliferation, myelination
and cytoskeleton dynamics
 May result in increased plasma arachidonic acid, related to
increased conversion of linoleic acid to arachidonic acid via the
fatty acid desaturases.
(Shitara and Sugiyama, 2006; e-mims; Mooseman and Behl, 2004;
Hrboticky, Zimmer and Weber, 1996)
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
12
Lipitor (Atorvastatin)
HMG CoA Reductase Inhibitor Drug Class
 Pharmacokinetics:
 Transportation: Rapidly absorbed
 Peak blood levels achieved: 1-2 hours post
dosage;
 Bioavailability: 14% post dosage;
 Half-life: 14 hours for plasma atorvastatin but 20-30
hours for HMG CoA reductase inhibitory activity
 Clearance: Extensively metabolised by the liver to
metabolites which still maintain therapeutic activity
(70% of atorvastatin activity is due to its
metabolites). Further metabolism is via
glucuronidation. Primarily excreted through the bile.
 CYP450 Clearance Iso-enzymes: 3A4
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
13
Lipitor (Atorvastatin) Interactions & Potentiations
HMG CoA Reductase Inhibitor Drug Class
Herb
Constituent
Rationale
Action
Withania
somnifera
Unspecified
Lowered total lipids, cholesterol and triglycerides, whilst raising HDL,
HMG CoA reductase and bile acid content in hypercholesterolemic
rats (Visavadiya and Narasimhacharya, 2006)
Potentiation
Cinnamomi
cassiae
Unspecified
Increased HDL cholesterol and lowered total cholesterol through
what appears to be an insulin sensitivity effect (Kim, Hyun and
Choung, 2006)
Potentiation
Golden seal,
Barberry,
Greater
celandine
Berberine
Lowers cholesterol by upregulating LDL receptor expression via a
post-transcriptional mechanism that stabilised mRNA (Kong et al,
2004)
Potentiation
Silybum
marianum
Taxifolin
Inhibits HMG CoA reductase, cellular cholesterol esterification,
triacylglycerol and phospholipid synthesis. ApoA-1 secretion was
increased and apoB was reduced, but not at a transcriptional level.
apoB was affected via degredation (Theriault et al, 2000)
Potentiation
Embilica
officinalis
Unspecified
flavonoids
Inhibited HMG CoA reductase (Anila and Vilayalakshmi, 2002)
Potentiation
Magnifera
indica
Unspecified
flavonoids
Increased HMG CoA reductase activity. Also increased cholesterol
degredation and turnover (as seen with a higher rate of bile acid
synthesis). This may be due to increased activity of LCAT (Anila and
Vijayalakshmi, 2002)
Possible potentiation
Garcinia
cambogia
Unspecified
flavonoids
Inhibited HMG CoA reductase, but not on a high fat diet. HDL was
elevated whilst LDL and VLDL was reduced, the activity of
lipoprotein lipase was stimulated, and lipogenesis (G-6-P
dehydrogenase and isocitrate dehydrogenase) was reduced (Koshy,
Anila and Vilayalakshmi, 2001)
Potentiation
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
14
Lipitor (Atorvastatin) Interactions & Potentiations
HMG CoA Reductase Inhibitor Drug Class
Herb
Constituent
Rationale
Action
Trigonella foenumgraecum
4-hydroxyisoleucine
Significantly decreased the plasma triglyceride levels, total
cholesterol and free fatty acids, as well as an increase in
HDL-C/TC ratio in dyslipidaemic hamsters fed a high fat
diet (Narender et al, 2006)
Potentiation
Cynara scolymus
Cynaroside and luteolin
In vitro rat studies found inhibition of HMG CoA reductase,
which lasted 20 hours after removal of the extracts and
was fully reversed within 20 hours (Gebhardt, 1998) and
this has been identified in type 2 diabetic indviduals
through reduced total cholesterol, serum triglyceride and
LDL, as well as an increase in HDL (Nazni et al, 2006)
Potentiation
Gymnema
sylvestre
Unspecified
Decreases total cholesterol and serum triglyceride levels
and increases lecithin-cholesterol acyltransferase (LCAT),
increased colonic fermentation and resulted in increased
levels of propionic acid and acetic acid (Shigematsu et al,
2001)
Potentiation
Curcuma longa
Curcumin
Increased LDL-receptor mRNA, but mRNA for HMG CoA
reductase and farnesyl diphosphate synthase were only
slightly increased, and the levels of curcumin which
induced these small changes were outside safety levels
(Peschel, Koerting and Nass, 2006). An animal study also
found curcumin increased levels of cholesterol-7αhydroxylase activity (Babu and Srinivasan, 1997)
Potentiation
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
15
Lipitor (Atorvastatin) Interactions & Potentiations
HMG CoA Reductase Inhibitor Drug Class
Food
Constituent
Rationale
Action
Citrus fruit
Hesperitin
(derived from
hesperidin)
Decreased HMG CoA reductase and ACAT activities, thereby lowering
plasma cholesterol and triglyceride levels, while increasing HDL-C/totalC ratio (Kim et al, 2003; Jung et al, 2006)
Potentiation
?
Tannic acid
Decrease hepatic HMG CoA reductase and ACAT activities (Park et al,
2002)
Potentiation
Did not affect HMG CoA reductase, but increased biliary excretion of
cholesterol, bile acids, uronic acids and phospholipids, as well as
lowering cholesterol levels (Kumar, Sambaiah and Lokesh, 2000)
Potentiation
Ghee
Citrus fruit
Naringin
In conjunction with lovastatin, naringin lowered total and LDL cholesterol
and hepatic lipid levels, whilst significantly increasing HDL-C/total-C
ratio. Hepatic HMG CoA reductase was higher, and acylCoA:cholesterol acyltransferase was significantly lower (Jeon, Park and
Choi, 2004; Jung et al, 2006). Has also been shown to lower plasma
cholesterol without significantly affecting HMG CoA reductase and
ACAT activities (Lee et al, 2003)
Potentiation
Olive oil
Squalene
Comparisons between an olive oil based diet and a high carbohydrate,
low fat diet, showed higher HDL and lower total cholesterol:HDL-C
ratios and lower triglycerides (Kiran et al, 2006). May be due to the
squalene content which has a strong HMG CoA reductase inhibitory
activity (Newmark, 1999)
Potentiation
Ganoderma
lucidum
Lanosterol
Inhibited HMG CoA reductase and overall reduced LDL cholesterol in
vivo (animal study) and in vitro (Berger et al, 2004)
Potentiation
Onion
Quercetin
Inhibited Hsp27 (heat shock protein) which enhances neuroprotection
after optic nerve axotomy, and may therefore affect this beneficial role of
statins
(Kretz et al, 2006)
Cardiovascular Medication
Interactions,
Potentiations and Elimination Seminar
Interaction
16
Lipitor (Atorvastatin) Interactions & Potentiations
HMG CoA Reductase Inhibitor Drug Class
Food
Constituent
Rationale
Action
Reduced LDL cholesterol and increased HMG CoA reductase
(Fernandez, Roy and Vergara-Jimenez, 2000)
Possible
potentiation
γ-oryzanol and γtocotrienol
Increased LDL-receptor activity and an increase in HMG CoA
reductase mRNA (Chen and Cheng, 2006)
Possible
potentiation
Stanols
Increased LDL receptor mRNA and the resulting LDL receptor
proteins (Plat and Mensink, 2002)
Potentiation
Quercetin and
resveratrol
Dealcoholised wine increased LDL receptor gene expression and
reduced ApoB. Both regular and dealcoholised wines increased
HMG CoA reductase mRNA and LDL receptor binding activity (Pal et
al, 2003)
Possible
potentiation
Increased serum concentrations of simvastatin (Lilja, Kivisto and
Neuvonen, 1998)
Interaction
Genistein, diadzein
and glycitein
Inhibited HMG CoA reductase (Sung et al, 2004)
Potentiation
Myristic acid
The principal saturated fatty acid that raises plasma cholesterol,
increasing LDL more than HDL (Castillo et al, 1999)
Interaction
Inhibited HMG CoA reductase (Jung et al, 2005)
Potentiation
Resistant starch
Rice bran oil
Red wine
Grapefruit juice
Miso
Kiwifruit
Refined
carbohydrates
Sucrose
Increases HMG CoA reductase activity when compared with intake
of saturated fatty acids and starch-based diets (He and Fernandez,
1998)
Interaction
Soy foods
Proteins
Hypocholesterolemic effect was enhanced by simvastatin compared
with animal proteins (casein and cod) (Giroux et al, 1997)
Potentiation
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
17
Lipitor (Atorvastatin) Interactions & Potentiations
HMG CoA Reductase Inhibitor Drug Class
Nutrient
Rationale
Action
Docosohexanoic
acid
Inhibits HMG CoA reductase activity and increases hepatic microsomal
fluidity, thus leading to a reduction in plasma lipids (Park, Choi and Kim,
2000)
Potentiation
Selenium
Downregulates apoB and HMG CoA reductase expression during
hypercholesterolemia (Dhingra and Bansal, 2006)
Potentiation
Tocotrienols
A mixture of tocotrienols and lovastatin showed greater effects than did the
individual treatments alone (Qureshi and Peterson, 2001)
Potentiation
α-linolenic acid
Repression of the activity and mRNA expression of HMG CoA reductase,
with a larger hypocholesterolemic effect than γ-linolenic acid (Watanabe et
al, 1999). Supplementing with ALA can compete with linoleic acid for the
upregulated desaturases, resulting in higher levels of EPA and DHA
(Hrboticky, Zimmer and Weber, 1996)
Potentiation
Chromium (as
picolinate)
Decreased elevated cholesterol through increasing insulin sensitivity in
peripheral (skeletal and adipose tissue) (Shinde et al, 2004)
Potentiation
Policosanol
Down-regulates the cellular expression of HMG CoA reductase (McCarty,
2002)
Potentiation
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
18
Lipitor (Atorvastatin) Interactions & Potentiations
HMG CoA Reductase Inhibitor Drug Class
 A study compared a very-low saturated fat
diet, the same diet with 20mg of lovastatin
and a diet high in – plant sterols, soy-protein
foods, almonds and viscous fibers from oat,
barley, psyllium and the vegetables okra and
eggplant.
 The statin and portfolio diets achieved similar
levels and some participants achieved their
lowest LDL cholesterol concentrations on the
portfolio diet
(Jenkins et al, 2005)
Cardiovascular Medication Interactions, Potentiations and Elimination Seminar
19