Transcript Statin Drugs Mechanism of Action

STATIN DRUG
SIDE EFFECTS
The misguided war
on cholesterol
By Duane Graveline
MD MPH
4/2/2017
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The five faces of statins
(drug Co’s anticipated but one)
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Cholesterol reduction
CoQ10 inhibition
Dolichol inhibition
Anti-inflammation via NFkB
Impair Immunodefense
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My Personal Encounters
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First TGA – 10 mg Lipitor
Second encounter – 5 mg
Lipitor
(the repeated admonition from
scores of doctors and
pharmacists alike that
“STATIN DRUGS DON’T DO
THAT!”
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What is TGA?
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Anterograde Memory Loss
Retrograde Memory loss
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Statin Amnesia – How
large a problem?
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FDA Medwatch Program
UCSD Statin Study
PFIZER Clinical
investigational Phase
We can expect 150, 000
cases this year alone)
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Other Forms of Memory
Loss
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Confusion
Disorientation
Forgetfulness
Short-term TGA
Increase of pre-existing
senility
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Statin Drugs Mechanism
of Action
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Decrease cholesterol
biosynthesis
Ubiquinone (CoQ10)
inhibition
Dolichol inhibition
Nuclear factor kB
suppression
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Glial cell cholesterol
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Sole source of brain
cholesterol
Vital for all synaptic
transmissions
Mechanism of action for all
cognitive dysfunction
Unknown until 2003 (Pfrieger)
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Ubiquinone inhibition
(coenzyme Q10)
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Sole source for
mitochondrial energy (CHF
and chronic fatigue)
Vital for cell wall integrity
(hepatitis, myopathy,
rhabdomyolysis and
neuropathy
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Dolichol inhibition
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Vital for neuropeptide
formation and cell messaging
Every thought , sensation and
emotion dependant upon
these neuropeptide linkages
Without cholesterol, this
process cannot take place
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Statin’s AntiInflammatory Role
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Nuclear factor kappa B
inhibition
Anti-inflammation and
decreased CV risk: (platelets,
smooth muscle, macrophages ,
lymphocytes)
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immuno-modulation and
increased CA and infection
risk
(you can’t have one without the other)
4/2/2017
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Other statin pathways
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Activation of post polio syndrome
Activation of genetically
preordained myopathies
Activation of tau protein leading to
neuro-degenerative diseases.
ALS (Lou Gehrig)
Parkinsonism
Frontal lobe dementias
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Still other statin
pathways
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Moose and Behl selenoprotein deficiency
Draeger – cholesterol per
se
Campbell – terpenoids and
cholesterol rafts
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McCully’s homocysteine
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Inflammation is the true cause
of CV disease
40% of atherosclerosis caused
by homocysteine elevation
Remainder due to defects in
platelet, coagulation and antioxidant factors, omega 6 and
trans fats.
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The great cholesterol
scam
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For 35 years I recommended
the low fat/low cholesterol diet
Wrote thousands of Rxs for
anti-cholesterol drugs
Raised my family on skim milk,
margarine and no eggs.
I deeply regret my failure to
challenge
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Dr. Paul Dudley White
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“Waited 7 years back in the 20’s
for my first MI”
Convinced that corn oil was
triggering CV disease increase, not
cholesterol
Ancel Keys’ cholesterol
bandwagon rolled over him
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35 years of a Failed
National Diet
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Present epidemic of gross obesity
and type 2 diabetes
Prevalence of atherosclerosis
unchanged
CV mortality down by “high-tech”
surgery, NOT nutrition
(so much for a skim milk and no
egg diet)
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Statin drugs DO work
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By nuclear factor kappa B
inhibition, not cholesterol
Statins now promoted for organ
transplant and auto-immune
diseases
Promotion of cholesterol drugs an
all time high
Cholesterol no longer considered
causative in CV disease.
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TREATMENT FOR CV
DISEASE
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Must be directed at inflammation –
omega 3, Q10, B6, 12 and folic
acid, buffered aspirin and antioxidants
If high risk, consider low dose
statins with dosage based on
inflammation, not cholesterol
Statin dosing must not be based
on cholesterol response
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Inflammatory markers
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CRP - too nonspecific
Homocysteine – a better
indicator of susceptibility to
inflammation
Lipoprotein (a) – same
What is needed is a NF-kB
derived marker
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Statin of the future
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Must NOT compromise our
mevalonate pathway!
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MUST be based solely on nuclear
factor kappa B suppression
Dosage must be based on reversal
of suitable marker.
Hopefully will not compromise our
cancer and infectious disease
defense
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LIPOPROTEIN (a)
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45 million years ago, we primates
substituted Lipoprotein (a) for the
ability to synthesize Vitamin C
Coated with receptors for proline,
and lysine – major components of
collagen - promoting
thrombogenesis
Vitamin C, proline and lysine vital
for control of this process
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RED YEAST RICE
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Mother Nature’s statin
Identical to lovastatin
Same side effects with high doses
Each 600 mg capsule equals 2.5
mg lovastatin
An ideal anti-inflammatory when
combined with other supplement
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Statin Action on
Mevalonate Pathway
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CHOLESTEROL
COQ10
DOLICHOLS
TAU PROTEIN
SELENO-PROTEIN
OTHERS
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DOLICHOL EFFECTS
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NEUROPEPTIDE SYNTHESIS
D-LINKED GLYCOPROTEIN
SYNTHESIS (DOLICHOL)
SUBSTANTIA NIGRA/DOPAMINE
OTHER
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NEUROPEPTIDE
SYNTHESIS
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EVERY THOUGHT, SENSATION
OR EMOTION, CAUSED BY
PEPTIDE LINKAGES
IN THE E.R. THROUGH GOLGI
TO NEURONE
ALL ORCHESTRATED BY
DOLICHOLS
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GLYCOPROTEIN
SYNTHESIS
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OCCURS IN BOTH E.R. AND
GOLGI APPARATUS
PEPTIDE LINKED TO SUGARS
WITH MANNOSE PRIMARY
IN MAMMALS - D-LINKAGE OF
GLYCOPROTEINS (DOLICHOL)
GUIDES PROTEIN FOLDING AND
ULTIMATE PROTEIN EFFECT.
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EIGHT PRIMARY
GLYCONUTRIENTS;
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GLUCOSE, GALACTOSE
FUCOSE, MANNOSE
XYLOSE
N-ACETYLGLUCOSAMINE
N-ACETYLGALACTOSAMINE
N-ACETYLNEURAMINIC ACID
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