Transcript ภาพนิ่ง 1

Presented by
Yaowapruek W.
22 Dec 2006
Question
When should you start anti obesity
agents?
What is the agent of choice for your
patient?
And, how long for the pts use drug?
Contents
Introduction
Nonpharmacological approach
History of pharmacotherapy
Appetite suppressants
Nutrient absoption reducer
Strategies for use of drugs
Endocannabinoid system and
Rimonabant
Introduction
Obesity is a heterogeneous disease
involoving genetic, environmental,
psychological, and other factors.
Occurs when energy intake exceeds the
amount of energy expended over time.
Reports warn of a catastrophic impact of
the global obesity epidemic on rates of DM
and CVS in the upcoming years.
Introduction
Currently in the U.S., 28% of men and 34% of
women are obese, and the largest increases in
obesity rates have affected children and
minorities.
Introduction
จากการสารวจสุ ขภาพประชากรโดยกระทรวงสาธารณสุ ขในปี 2540
พบว่าอุบตั ิการณ์ของภาวะน้ าหนักเกิน (BMI > 25) ในประชากร
ไทยที่อายุ ≥ 20 ปี อยูท่ ี่ 28.3% โดยพบในผูห้ ญิงมากกว่าผูช้ าย
(33.9% vs 19.2%) และพบในผูส้ ู งอายุมากกว่าวัยหนุ่มสาว
และในประชากรเมืองมากกว่าประชากรที่อยูใ่ นชนบท (34.8% vs
26.4%) และพบว่าประชากรในภาคกลางมีอุบตั ิการณ์มากกว่าใน
ภาคอื่น ๆ (37% ในภาคกลาง vs 22-25 % ในภาคอื่น)
Introduction
Well-established relations between
excess BW and such medical conditions
as type 2 diabetes, HT, and osteoarthritis.
Medications for the treatment of obesity
are currently approved for use in adults
who have a BMI of ≥ 27 plus obesityrelated medical conditions or a BMI ≥ 30
in the absence of such conditions.
Nonpharmacological Approaches
Only about 20% report restricting caloric
intake and increasing physical activity
simultaneously, despite recommendations
indicating that this combination is effective.
Obese adults can lose about 0.5 kg/wk
by decreasing their daily intake to 5001,000 kcal below the caloric intake
required for the maintainace of their
current weight.
Nonpharmacological Approaches
More severe caloric restriction, with the
use of diets that are very low in calories,
increases the rapidity of wt.loss but not the
rate of long-term success in maintaining a
reduced wt.
Combined caloric restriction and exercise
with behavioral Rx may be expected to
lose about 5 – 10 % of BW over 4-6 mo.
Nonpharmacological Approaches
For the vast majority, wt. loss is followed
by a slow, inexorable climb to the
preintervention BW or even higher.
Bariatric surgical Rx, can induce wt.loss
, but are appropriate only for selected pts
with a BMI ≥ 40 or ≥ 35 with obesityrelated medical conditions.
“Losing wt. is difficult for
most obese persons, yet longterm maintenance of a reduced
wt. is even more challenging!”
History of Pharmacotherapy
For many years, obesity was approached
as if it were either a moral failing or
evidence of underlying psychopathology.
Medications were proposed as short term
adjuncts -> but unsuccessful.
In 1992 by Weintraub et al. concerning
the efficacy of the combination of
behavioral Rx and 2 med (fenfluramine
and phentermine).
History of Pharmacotherapy
Those studies found that wt.loss could be
sustained for as long as 3.5 yrs with
continuing pharmacotherapy.
-> Obesity should be treated in the
same manner as any other chronic dz
that might be ameliorated through the
long-term use of medication.
Mechanisms of Action
2 categories
– Appetite suppressants
– Medications that reduce nutrient
absorption
Third category, med that increase energy
expenditure, includes ephedrine, not
currently approved.
Appetite-Suppressant
Noradrenergic Agents
Serotonergic Agents
Mixed Noradrenergic-Serotonergic Agents
Noradrenergic Agents
Phentermine, diethylpropion,
phendimetrazine, and benzphetamine
Amphetamine -> potential for abuse
FDA approved for use of ≤ 12 wks for the
Rx of obesity.
SE -> insomnia, drymouth, constipation,
euphoria, palpitations, and HT.
Serotonergic Agents
Increasing the release of serotonin,
inhibiting its reuptake, or both.
Fenfluramine and dexfenfluramine were
withdrawn in 1997 because of
associations with valvular heart disease.
Efficacy appeared similar to that of the
noradrenergic agents.
Serotonergic Agents
Some SSRIs (fluoxetine, sertraline) have
induced wt.loss in short term studies, but
steady regain occurred.
Mixed NE-5-HT Agents
Sibutramine (Reductil), an inhibitor of
both NE reuptake and 5-HT reuptake that
also weakly inhibits DA reuptake.
Approved by the FDA for wt.loss and
wt.maitaince in conjunction with a
reduced-calorie diet.
Mixed NE-5-HT Agents
Dosage : 10 -15 mg once daily (may be 5
mg if do not tolerate)
Over 6 mo with reduced-calorie diet ->
loss 5-8 % vs 1-4 % placebo
Wt.reduction mostly maintained for
periods of up to one year.
Mixed NE-5-HT Agents
SE -> increases in BP and pulse (5%
discontinuation) , dry mouth, headache,
insomnia, and constipation.
Other metabolic risk fators improve;
hyperlipidemia, hyperuricemia, as well as
glycemic control, plasma insulin levels in
type 2 diabetes.
Nutrient Absorption Reducer
Only FDA-approved is orlistat (Xenical)
Acts by binding to GI lipases in the lumen
of the gut, preventing hydrolysis of dietary
fat (TG) into absorbable free fatty acids
and monoacylglycerols.
Nutrient Absorption Reducer
120 mg of orlistat with or up to one hr
after meals excrete in the stool
approximately one third of the dietary fat.
Moderate efficacy for wt. loss in aduls.
(9% vs 5.8% placebo)
Metabolic risk factors also improved.
Nutrient Absorption Reducer
SE -> flatulence with discharge, fecal
urgency, fecal incontinence, steatorrhea,
oily spotting, and increased frequency of
defecation.(mild to moderate)
Decreases absorption of fat-soluble
vitamins, so daily MTV at least 2 hr before
or after a dose of orlistat needed.
Dietary Supplements and Herbal
Cannot claim that it treats a disease
but may claim that it reduces the risk of
a disease in a population.
Chitosan, chromium picolinate,
conjugated linoleic acid, ephedra alkaloids
(ma huang), and garcinia cambogia
There were insufficient data to provide
evidence of any as agents promoting
wt.loss.
Dietary Supplements and Herbal
Ephedra alkaloids and caffeine are the
only types for which there are data from
RCTs indicating efficacy.(in short term)
Case reports concerning ephedra
alkaloids -> serious CVS and CNS side
events( HT, arrhythmia, stroke, seizure, MI
and sudden death)
Dietary Supplements and Herbal
Because of the unpredictable amounts of
active ingredients ant the potential for
harmful effects.
NIH -> herbal preparations are not
recommended as part of a wt.loss
program.
Other medications
Bupropion
Topiramate (Topamax)
Metformin (Glucophage)
Investigational Medications
Levels of leptin, a hormone secreted by
adipocytes, reflect the lipid content of the
total body of a nonfasting person.
Severe, early-onset obesity has been
associated with an inability to produce
functional leptin protein.
Rx of a leptin-deficient girl with rh-leptin ->
dramatic reduction in BW.
Strategies for Use of Drugs
Pharmacotherapy should be initiated with
the expectation that long-term use will
most likely be needed.
Risk of long term medications VS
potential improvements in the pt’s risk of
obesity-related disease.
Strategies for Use of Drugs
Identification of pts. with a response to
treatment
Pharmacotherapy for the prevention of wt.
regain
Off-label use of FDA-approved drugs
– Intermittent use
– Drug combinations
– Treatment of children and adolescents
Journal of the American
College of Cardiology
Vol.47, No. 10, 2006
Introduction
New combined approach to treating the
obesity and glucose intolerance
features of metabolic syndrome, as well
as aiding smoking cessation, involves
manipulation of the endogenous
cannabinoid system, specifically with the
cannabinoid receptor type 1 (CB1)
antagonist rimonabant.
Endocannabinoid System
Cannabis
– main psychoactive alkaloid is Δ-9tetrahydrocannabinol (THC)
– synthetic THC (dronabinol) is used to rx postchemotherapy nausea and emesis, as well as
anorexia ass with HIV
Endocannabinoid System
Cannabinoid receptors and ligands
– CB1 receptors -> brain and adipose tissue
, but also found in myocardium, vascular
endothelium, and sympathetic nerve terminals
– CB2 receptors -> lymphoid tissue and
peripheral macrophages
– Both receptors function as transmembrane
G-proteins.
Endocannabinoid System
Cannabinoid receptors and ligands
– At least 2 endogenous ligands :
arachidonylethanolamide (anandamide), 2arachidonoylglycerol (2-AG)
Under normal conditions, the system in
not tonically active, rather
endocannabinoids are produced on
demand, act locally, and are rapidly
inactivated via cellular uptake and
enzymatic hydrolysis.
Physiology of the Cannabinoid
System
Cardiovascular effects
– Acute -> vasodilatation and tachycardia with
variable net effect on systemic BP
– Long term -> CB1 –mediated hypotension
and bradycardia
– Seem to be involved in regulation of vascular
tone in hepatic disease, HT, and other
disorders.
– Recently, system also plays a role in
hemodynamics of shock states.
Physiology of the Cannabinoid
System
Metabolic effects
– Central role in regulating metabolism and
body composition by
Enhancing the central orexigenic drive
Increasing peripheral lipogenesis.
Physiology of the Cannabinoid
System
Endocannabinoids and addiction
– Regions of the brain thought to be involved in
drug relapse behavior contain high levels of
CB1 receptors, and compelling evidence
suggests a role for the endocannabinoid
system in formulation and propagation of
addiction to psychoactive substances.
Rimonabant
First described in
1994
Selective CB1
receptor antagonist
RIO = Rimonabant
in Obesity
Rimonabant
In pts with obesity, including those with
cardiovascular comorbidities
Significant reduction in BW and waist
circumference
Improvement in
–
–
–
–
Cardiometabolic risk
Glycemic control in type 2 DM
Lipid profile (except LDLc)
Overall decrease in the prevalence of metaboloic
syndrome
Other study
STRADIVARIUS
– Obese with smoking or metabolic syndrome
and in whom clinically indicated coronary
angiography reveals a 20%-50% stenosis
– End point = change in the volume of target
atheroma at 18 mo.
Other study
STRATUS
– Potential role of rimonabant as an adjunct in
smoking cessation
– Smoked ≥ 10 cigarettes/day for at least 2 mo
and who were motivated to quit
– Receive rimonabant or placebo for 10 wks
– Rate of abstinence was significantly higher in
the high-dose(20 mg/d) group compared with
placebo (36.2% vs 20.6%, p < 0.001)
Rimonabant
Adverse effects
– Generally well tolerated
– One-yr dropout rates were high (36%-49%) ,
but were typical of obesity trials and did not
differ from placebo
– Most common was mild nausea
– The percentage of pts experiencing
neuropsychiatric(anxiety,depression) side
effects is small.
Rimonabant
Cochrane review 2006, Issue 4
To assess the effects of rimonabant and
obese people
Compared with placebo
– Rimonabant 20 mg -> 4.9 kg greater
reduction in BW in trials with one yr result.
– Improvements in waist circumference, HDL,
TG, and systolic and diastolic BP were also
seen
Rimonabant
However, the results with rimonabant 5
mg -> wt.reduction only 1.3 kg, no relevant
effects on lipids and BP.
Rimonabant 20 mg -> more adverse
effects both of general and serious nature,
esp of nervous system, psychiatric or GI.
Attrition rates were approximately 40% at
the end of one yr.
Rimonabant
The observed results should be
interpreted with some caution, though,
since the evaluated studies presented
some deficiencies in methodological
quality.
Studies with longer F/U after the end of
Rx and of more rigorous quality should be
done before definitive recommendations
can be made.
Contents
Introduction
Nonpharmacological approach
History of pharmacotherapy
Appetite suppressants
Nutrient absoption reducer
Strategies for use of drugs
Endocannabinoid system and
Rimonabant