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270 Cards in this Set

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syndrome =
presence of various symptoms
is IBS a disease
no, there is no structural abnormalities so it is a syndrom
IBS is considered a "______" disorder
functional
what does funtional disorder mean
therr is an absence of any overt, organic strucutal disorders
prevalence of IBS
World wide: 7-10%
North America = 10-15%
most prevalent GI disorder
epidemiology of IBS
Incidence higher in:
Women
Lower socioeconomic status
Gulf war veterans


Patients < 50 years of age more likely to be diagnosed
why are IBS drugs just FDA approved for women
because the studies have only been done in women
classifications of IBS
Constipation predominant (IBS-C)

Diarrhea predominant (IBS-D)

Mixed (IBS-M)
what is the key feature of IBS
pain located in the abdominal area
IBS pathophys
psychococial factors (altered pain perception)

gas retention

altered motility and secretions

prior gastroenteritis or bacterial overgrowth

altered sensation
Role of Serotonin in IBS
95% of serotonin (5-HT) is found in the _GIT______

Also an important CNS neurotransmitter

7 subtypes of receptors: 5-HT1-7
1-4 most involved in GI processes
Effects differ on subtype
95% of serotonin (5-HT) is found in the _______
GIT
Stimulation of serotonin leads to _______ motility and secretion & possibly pain modulation
increased
clinical features of IBS
Gastrointestinal
Diarrhea and/or constipation
Abdominal pain (can be absent, intermitent, or constant)
Bloating, distention, spasm
Urgency

Psychiatric (up to 60%)
Stress induced alterations in bowel function
Depression
Anxiety
consequences of IBS
Significant reductions in patient quality of life

Increase absence from work

Decreased productivity

Significant healthcare/societal costs
Rome III Criteria (don't need to memorize just know concept)
Abdominal pain or discomfort > 3 days per month in the last 3 months plus:

Presence of at least 2 of 3 features:
Relief with defecation
Onset associated with a change in frequency of stools
Onset associated with change in stool form (appearance)
Onset of symptoms > 6 months prior

Absence of:
rectal bleeding
anemia
weight loss
fever
family history of colon cancer
onset after age 50

No Identifiable physical, radiologic, or laboratory evidence of organic disease

long standing diagnosis
diagnosis of IBS (know!!!!)
2009 ACG Guideline Definition
Abdominal pain or discomfort that occurs in association with altered bowel habits over a period of at least 3 months.

Patients will often have an extensive work-up
Lab tests
Radiology
Scopes

Often a “diagnosis of exclusion”

Check for celiac disease in IBS-D and IBS-M

Food allergy testing or use of exclusion diets is not endorsed
Lactose intolerance may be more prevalent (treat it)


Role of small intestinal bacterial overgrowth (SIBO)
(no good way to test for)

ruling out other causes
Patients will often have an extensive work-up of IBS
Lab tests: stool samples to check for infections
Radiology: MRI, motility, cat scan
Scopes: determine that there are no structural abnormalities
Appropriate Referrals for IBS (know!!!)
Age > 50
Unintentional weight loss
Family history of GI malignancy, IBD, or Celiac Sprue (underlying strructural disorder)
Severe unrelenting large volume diarrhea
Fevers, chills (>102)
Recent travel to an endemic area (over the last 1-2 months)
Nocturnal symptoms (GIT should not be functioning at night)
Hematochezia (blood in stool)
bright red blood indicates what knid of bleed
lower GI
what does dark red blood indicate in the stools
upper GI bleed
melena=
upper GI bleed, black stools
treatment of IBS and drug therapy targets
Drug therapies may target:
Central pain perception
Altered GI motility and secretion
Altered GI sensation
Gas/bloating
non-pharm for IBS
Dietary: avoid aggravating foods
Psychosocial modification
Drug Treatment types for IBS
Select based on predominant symptoms


Multiple types of agents utilized:
Laxatives
Motility ( or ) or change perception
Antispasmodic agents
Psychotropic agents
Combinations
anticholinergis target symptoms of ______ in IBS
diarrhea and pain
anticholinergis and IBS
Targets symptoms of: Pain and diarrhea
Avoid in: IBS-C
Major adverse effects:

could be long term but mainly PRN
Hyoscyamine (Levsin®)
0.125-0.25 mg PO/SL q 4h prn (fast acting so good for prn)
Dicyclomine (Bentyl®)
10-40 mg PO QID schedule or PRN
are anticholinergis scheduled or prn for IBS
prn mainly because of SE
TCA and IBS most common agents
Amitriptyline
Doxepin
Desipramine
Nortriptyline
TCA effects in IBS
reduce visceral sensitivity (altered sensation in the GI tract)
target symptoms of pain
avoid in IBS-C
are TCAs scheduled or prn for IBS
scheduled
efficacy of TCAs for IBS
Doses lower than depression (25-75mg/day)
May need to increase dose
Pain reduction may only be minimal in some cases
adverse effects of TCAs
anticholinergic effects
sedation
ortho-static hypertension (may be less with TCAs such as nortriptyline because it is a secondary amine not tertiary
drug drug interactions with TCA
are numerouse because of P450s
do TCAs treat the aniety and depression asspect of IBS
no
what is the difference between SSRIs/SNRIs
SSRI only increase the levels of 5HT whereas SNRIs increase the levels on 5HT and NE
GI afffects of SSRIs/SNRIs
decrease visceral sensitivity so targets pain
increawswe motility/secretions so targets motility
what is the additional benefit of using a SSRIs/SNRIs
also may treat depression and anxiety
names of SSRIs
Sertraline, fluoxetine, citalopram, escitalopram
Paroxetine:
names of SNRIs
venlafaxine, duloxetine
what is the first line agent for IBS-C
SSRI
roles for SSRI/SNRI
increase motility in IBS-C
treat depression
is a SSRI/SNRI contraindicated in a patient with IBS-D
no
are SSRI/SNRI scheduled or prn
scheduled
Diarrhea Predominant IBS options
Antimotility agents
Loperamide:
Does not treat Pain

Diphenoxylate/atropine ( can cause a little bit if cramping)


PPIs and H2RAs
Role?
only in people with reflux or heartburn
what is the max dose of loperamide RX strength
16 mg/day
what is the max dose of loperamide OTC strength
8 mg/day
Alosetron (Lotronex®)
Serotonin (5 HT3) antagonist

Diarrhea predominant IBS
Modifies pain response
Slows transit and secretion

Indication: severe IBS-D in women failing other therapies
>18 years of age
Symptoms > 6 months

Pregnancy category B
what is the only approved 5HT antagonit for IBS-D
alosetron/lotronex
what is the major SE of Alosetron (Lotronex®)
constipation (10-29%)
why was Alosetron (Lotronex®) from the market
ischemic colitis: like a infarct of the GIT
incidence of the ischemic colitis
Incidence: 1.1/1000 patient-years
syptoms of ischemic colitis
Symptoms: worsening abdominal pain, bloody stool
contraindications for Alosetron (Lotronex®)
Constipation

Obstruction, stricture, perforation

Impaired intestinal circulation

Hypercoaguable states

IBD

Diverticulitis

Strong CYP 1A2 or 3A4 inhibitors
Fluvoxamine (SSRI)
prescribing Alosetron (Lotronex®)
Physician must register in prescribing program
Appropriate indication for drug
Sign attestation form (signed consent that is kept on record)

Receive prescribing kit

Read educational materials

Discuss risk/benefits with patient
Give patient copy of medication guide
Signed inform consent (MR)
prescritptions for alosetron
Place sticker on prescription
May write refills
Report any adverse events

The sticker indicates that this prescription is in compliance with the prescribing program for lotronex
dispensing alosetron
Cannot accept prescriptions via:
Phone, Fax, or computer

Dispense retail pack
Medication guide, medication, survey, package insert
Counsel on appropriate use

Encourage patient to fill out follow-up survey (so the manufacture can determine if it is working and SE)
Alosetron Efficacy for IBS-D
What can patients expect?
10-50% greater ↓ in pain/discomfort

Increase in number of formed stools

13-60% greater reduction in urgency
May reduce to ~ 1 day per week

Greater reduction in stool frequency to 1 or 2 BM per day (clinically significant)
what asspects of IBS-D do antisasmodics, TCAs and SSRI treat
Pain
when does a patient turn to alosetron
as a last resort when every thing else has failed
Constipation Predominant IBS and bulk forming agents
Bulk forming agents
Generally considered first line
Targeted symptom(s) constipaiton


Most evidence with psyllium
May worsen symptoms of gas and bloating


Alternative fibercon and methylcellulose (the synthetic products)
May increase number of stools

Role of dietary fiber?
contraversial
what is the first line therapy for IBS-C
bulf forming agents
osmatic laxatives and IBS-C
May increase number of stools
No effects on other symptoms only treats constipation
Preferred agents miralax, PEG
what is the major SE of MOM
cramping
what is the major draw back of saline laxitives
short term use
stimulants and IBS-C
second line may worsen syptoms of cramping
Lubiprostone (AMITIZA®)
Chloride channel activator (CIC-2) (whihc is the epithelium of the gut)
Increases fluid secretion in intestinal tract
Targeted symptom(s) constipation and bloating

FDA approved for IBS-C in women > 18 years old

Dose: 1 capsule (8 mcg) twice daily with meals

Prescription only
Lubiprostone (AMITIZA®) SE
Nausea
Diarrhea
Abdominal pain
Lubiprostone (AMITIZA®) pregnancy category
c
what is the efficacy of Lubiprostone (AMITIZA®)
a 17% decrease in syptoms
Tegaserod (Zelnorm®) class
5HT partial agonist
what is the role of Tegaserod (Zelnorm®)
Constipation predominant IBS
Stimulates peristalsis and secretion
Reduces visceral sensitivity
efficaciy of Tegaserod (Zelnorm®)
39%-67% response rate
Increase to average of 6 stools/week
~10% better than placebo for:
abdominal pain, discomfort, bloating, straining
why was Tegaserod (Zelnorm®) pulled from the market
Cardiovascular ischemic events (18,600 patients)
(0.11%) Tegaserod (1 per 7,031) (causes platelet aggregation)
(0.01%) placebo (p = 0.024)
Withdrawn from market: 3/07

2007: Reintroduced with restricted Access

2008: Available only for emergent situations
“immediately life-threatening or serious enough to qualify for hospitalization.”
Probiotics in IBS MOA (don't really need to know, just thought I would include it)
Possible Mechanisms
Immunomodulatory effects
Enhanced barrier function
Inhibit bacterial adhesion
Alteration in nutrient fermentation
Alterations in mucosal response to stress
Inhibition of visceral hypersensitivity
probiotic products
Products
Lactobacillus
Bifidobacteria infantis
Streptococcus
Combinations
what probiotic plays the biggest role in IBS
Bifidobacteria infantis
Probiotics compared to placebo1
RR of IBS not improving = 0.71; 95% CI = 0.57 to 0.88 with an NNT = 4 (95% CI = 3 to 12.5).

Improvement in global IBS symptoms compared to placebo2
RR 0.77 (95% CI 0.62-0.94)

Abdominal pain compared to placebo2
RR 0.78 (95% CI 0.69-0.88)
22% decreaase in abdominal pain

overall it is shown that probiotics imporve syptoms

these results were all significant
Rifaximin (Xifaxan®) in IBS
Nonabsorbable antibiotic

Use based on potential contribution of small intestinal bacterial overgrowth (SIBO)

Most studies in patients with IBS-D

can reduce certain symptoms

FDA approved for travelers diarrhea
effacay of Rifaximin (Xifaxan®)
8-23 % more likely to experience global improvement in IBS symptoms compared with placebo
effacacy of Rifaximin (Xifaxan®)
8-23 % more likely to experience global improvement in IBS symptoms compared with placebo
most improvement of syptoms with Rifaximin (Xifaxan®) is seen in
bloating and gas
cons of Rifaximin (Xifaxan®)
Cost
No FDA approved indication for IBS
Effects may not last
IBS-M
Get a good idea of patient’s baseline

Evaluate adherence to treatment (bulk forming agents do not have good adherance rates)

Avoid medications that may exacerbate diarrhea or constipation

May try PRN options for each episode first

Avoid over treating diarrhea

treat the symptom at that time
Alternative Therapies for IBS
Peppermint oil

Artichoke extract

Teas
Agrimony, blackberry or raspberry leaf
Tannins: antisecretory properties

Acupuncture

Psychological therapies
Cognitive behavioral therapy (CBT)
Dynamic psychotherapy
Hypnotherapy
natural stimulants
Cascara
Aloe
Senna
European buckthorn
natural sources of fiber
Apple pectin, flaxseed, fenugreek
BMI classifications
BMI 25-29.9 kg/m2 = overweight
BMI ≥ 30 kg/m2 = obese
BMI ≥ 40 kg/m2 = “extremely”
waist cicumference (wc)
Estimates central adiposity
Strong marker for health risks (visercial adipose tissue is mor metabolically acitve therefore poses more of a health risk)
_____ and _____ are better assessments than weight
BMI
WC
Obesity and Comorbidities
Cardiovascular
* Hypertension
* Left ventricular hypertrophy
* Congestive heart failure
* Coronary artery disease
* Stroke
Pulmonary
* Obstructive airway disease
* Sleep apnea
* Pulmonary hypertension
Metabolic
* Hypercholesterolemia
* Hypertriglyceridemia
* Low serum HDL
* Diabetes mellitus
* Hyperinsulinemia
* Polycyctic ovarian syndrome
Musculoskeletal
* Degenerative joint disease
Dermatologic
* Acanthosis nigricans
* Stretch marks
* Hirsutism
* Skin tags
Gastrointestinal
* Cholelithiasis
* Esophageal reflux
* Hiatus hernia
Psychological
* Eating disorders
* Depression
* Affective disorders
* Social stigma
Neoplasm
* Breast cancer
* Colon cancer
Obesity and Comorbidities associated with metabolic x syndrome
HTN
Hypercholesterolemia
Hypertriglyceridemia
Low serum HDL
Diabetes mellitus
Hyperinsulinemia
central fat distribution
apple
Mostly visceral fat
Intra-abdominal best estimated by CT or MRI
Increased cardiovascular risk (lipids, DM)
deadly fat because it is more metabolically active and it is the deep fat that surrounds the organs
gynecoid/gluteofemoral fat distribution
pear shaped
Mainly subcutaneous fat
Lower risk of mortality
Adipose Endocrine Functions
Release of free fatty acids (FFAs)

Production of adipokines (fat produces and secretes)
Leptin, adiponectin, resistin

Pro-coagulation
Plasminogen activator inhibitor (PAI-1) (stops the breakddown of fibrin clots)

Promotion of insulin resistance
TNFα
IL-6
(these cause insulin resistance and inflammation)
what is leptins role
a saitiety hormone it has been shown that obese can be leptin resistant

determines energy balance
Adipose Types
White Fat
Dominant form of adipose in adults
Storage of fat for energy
the main type of fat found in adults

Brown Fat
Abundant in newborns and hibernating animals
(newborns cannot shiver therefore the brown fat generates heat)
Generates body heat
Present in adults in upper chest and neck\burns white fat
etiology of obesity
Multi-factorial
Environmental, genetic, physiologic
Increased calorie intake (portion distortion)
From 1970 to 1990 ↑kcal by 200/day
This translates to 1 extra lb every 17-18 days

Sedentary behavior
Less physical work required with jobs
Less emphasis in schools, play at home

“Thrifty gene” theory
* use to be a survival strategy to be able to store body fat (now it is a survival disadvantage)
can resting metabolic rate be changed
yes, when a person exercise they burn more calories throughout the day
Other Weight Gain Causes
Medical causes
Hypothyroidism
Cushing’s syndrome (increase cortisol)
Binge eating disorders
Genetic syndromes

Medication causes
Diabetes medications (insulin is a growth factor)
Atypical antipsychotic agents (decreased CNS effects but weight gain is substantial)
Anticonvulsants
other wieght gain causes
Medical causes
Hypothyroidism
Cushing’s syndrome (increased cortisol)
Binge eating disorders
Genetic syndromes

Medication causes
Diabetes medications
Atypical antipsychotic agents
Anticonvulsants
what are the main organs/tissues controlling appetite
sotmach
pancreas
brain
adipose tisse
GIT
appetite
Complex behavioral process influenced by multiple factors
Involves hypothalamus, limbic system, brainstem, hippocampus, cortex
Influenced by hormones released by adipose and by GI tract (encretins are hormones secreted whe food is tasted and released by the small intestine)
Influenced by large number of neurotransmitters and neuropeptides
appetite Controlled beyond basic hunger/satiety
Humans eat in response to much broader stimuli
Reward, pleasure, learning, memory all involved
weight loss
Losing only 5% of total body weight beneficial
Evidence of improved blood pressure
Improved lipid profile
Improved insulin sensitivity, glucose tolerance

~$30-$50 billion spent annually in the United States on weight loss attempt

At any given time, 50% of women and 25% of men in the US are trying to lose weight
the best wieght loss programs incorpoarte multiple approaches being
Dietary adjustments
Physical activity
+/- Pharmacologic therapy
what are the 5 As of weight loss
ask
advise
assess
assist
arramge
what is the first question you should ask an obese patient in regards to weight loss
are you comfortable with you weight?

If yes: the conversation ends there
what sould you advise a patient about in regards to obesity
the risks and how it can negatively impact there health
what is to be assessed in regards to obesity
readiness to change
BMI
diet
physical ativity
health risks
cultural asspects
enviromental/psschological eating
barriers
assist a patinet with weight loss by
setting realistic goals for wieght loss and how to maintain the weight loss
when arranging asspects of weight loss
referral and or follow up to acheive weight loss and maintain it
at what category should an obese patient consider medications
BMI>/= 30
or
BMI >/= 27 with comorbidities
at what category should an obese patient consider surgery
BMI>/= 40
or
BMI >/= 35 with comorbidities
at what category should an obese patient consider liestyle modifications onle
BMI>/= 25
at which BMI should a patient avoid weight gain
all except <18
Nutritional Considerations
Calorie restriction vs macronutrients
Overall restriction most important
Debate as to “optimal” macronutrient balance
“Portion distortion”
Calorie restriction is much easier than focusing on particular nutrients in order to loose weight (because the more focused diets are harder to maintain)
Ingestion of fat
Both animals and humans prefer high-fat foods
Fat has a desirable texture and sensory characteristics in mouth
Fat enhances the flavor of other foods
Barriers to weight loss
Financial
Surgery extremely expensive, limited coverage
Weight loss medications rarely covered
Successful programs (ie Weight Watchers) have monthly membership fees
(loss with less money have a harder time lossing weight)

Losing weight vs maintaining weight loss
Dieters describe relative ease in losing weight
Relapse to original weight occurs at very high rates
(the body has a particular set point it wants to be at)
Motivational Interviewing
Are you currently comfortable with the weight you are at?”
Patient needs to be committed to weight loss
Provider should identify person’s motivations, outline health risks
Discussions of benefits of losing weight
Recognize difficulty of sustained weight loss
Multifactorial approach

acknowledge the amount of work the patient is undertaking
figure out what is important to the patient and use ti to help them

they need encouragement
lifestyle modifications
Calorie Restriction
Total calories > any “type” of calorie
Fat is the most calorie-dense food type
skip the second portion

Physical Activity
Energy balance between energy in and energy out
Data shows exercise key component in maintaining weight loss

Behavioral Therapy (use different apporaches to change habits)
What are some ideas for consuming less food???
cut the portion in half a t a resturant before eating
drink a glass of water before you eat
don't go to the grocery store hungry
don't getr too hungry
weight loss goals
Small, gradual weight loss
Avoid the “30 lbs in 30 days”
Target 5% of total body weight for goal
1-2 lbs/week (1 lb = ~3500 calories)
decreasin daily calories by 500/day

it is not healthy to loose weight quickly, looking for lifestyle changes that can be maintained
Weight loss followed by maintenance
Lifestyle changes
Program must be something that can be followed long-term
bariatric surgery
Indicated for patients with BMI ≥ 40 kg/m2

Indicated for BMI ≥ 35 kg/m2 with co-morbidity

Numbers of U.S. procedures climbing rapidly
47,000 in 2001
68,000 in 2003
220,000 in 2008

Gastric Banding and Roux-en-Y most common
gastric banding
Restrictive procedure
No “bypassing” of stomach or intestines
Sustained weight loss not as pronounced as with malabsorptive procedures
~66 lbs at 1 year, 77 lbs at 3 years

creates an artificial stomach so it restricts how much food can be eaten so the patient feels full more quickly
chronic disease remission and gastric banding
~70% T2DM remission, ~80% HTN, ~80% dyslipidemia
Chronic disease remission increases as more weight is loss
gastric banding risks
0.4% mortality with procedure
Risk of band slipping, eroding, failing
Price of gastric banding
Expensive procedure
Not always covered by insurance
$12,000-$36,000 for surgery
main SE of gastric banding
N/V (the patient has to re-learn how to eat)
Roux-en-Y Gastric Bypass
Bypasses most of stomach and some of duodenum

Small “pouch” created as stomach

Unidirectional intestine prevents bile from spilling back into pouch

produces big metabolic changes
it works by limiting intake

by passing the stomach
price of Roux-en-Y Gastric Bypass
~$25,000 for Roux-en-Y procedure
Does not include complications/extended hospital stay
Cosmetic surgery sometimes done to remove “unsightly” skin
this doesn't include any complications
T2DM remission occurs before weight loss in the Roux-en-Y Gastric Bypass
30-35% of patients are in remission before hospital discharge, ~83% remission overall
Greatest success in younger, shorter disease duration ( so do sooner rather than later)
Mechanisms for Remission and gastric bypass surgery?
Duodenum bypass theory
Suggests changes in gut hormone behavior
Animal models demonstrate diabetes remission
“Sleeve” procedures reinforce this theory

Lower intestinal theory
Nutrient-sensing L cells are hyperstimulated
Increased secretion of GLP-1 (a good regulator of blood glucose) and PYY
Unresolved Issues- Bar. Surgery
Gallstone formation and cholecystitis
Related to surgery and weight loss
Present in ~30% of patients at 6 months
Prevented with ursodiol, but poorly tolerated

Food intolerance
Both banding and bypass causes
Significant meat and protein intolerance
Vomiting can occur on weekly or even daily basis
malabsorption is common because maybe only taking in 1000 calories a day
problems with urosdiol and gastric bypass surgery
SE are GI and these patients are already having GI problems
why is ursodiol givern to patients that have undergone gastric bypass surgery
to prevent gallstone formation and cholecystitis
Hyperinsulinemic Hypoglycemia in regards to gastric bypass surgery
Severe hypoglycemia, usually post-prandial
Overfunction of β-cells
New β-cells or overstimulated β-cells?
Late onset: 1-9 years after procedure (typically 2-4)
Cause debated- could be increased GLP-1 levels

145 cases as of 2008
1/3 required partial pancreatectomy (in order to get rid of some of the beta cells and reduce insulin production)

Mayo clinic reports 2 new patients/month
Unresolved Issues- Nutrients in regards to gastric bypass surgery
Nutrient deficiency
Iron, B12, folate, riboflavin, niacin, thiamin
Calcium, vitamin D, zinc
Vitamin A, vitamin C
Nutrients’ absorption enhanced by gastric acid

Duodenum essential for nutrient absorption
Proteins, fats, carbohydrates
Calcium, magnesium, trace vitamins & elements
what nutrients can patients be deficient in after gastric bypass surgery
Iron, B12, folate, riboflavin, niacin, thiamin
Calcium, vitamin D, zinc
Vitamin A, vitamin C
Nutrients’ absorption enhanced by gastric acid

can become anemic
deficiencies in B1 can cause neurological problems
Bariatric Surgery Considerations
Surgical professional societies want to extend coverage to all T2DM with BMI > 30 kg/m2
~18 million T2DM patients in the U.S.
~50% have a BMI > 30 kg/m2

Nutrient replacement suboptimal
36% non-compliance rate
Those who comply may still be deficient
13% deficient in folate
30% deficient in B12 and iron
nutrient replacement maybe suboptimal after gastric bypass
36% non-compliance rate
Those who comply may still be deficient
13% deficient in folate
30% deficient in B12 and iron

these patients have to be closely monitored
Gastric Sleeve (Endo-Barrier)
Gastric sleeve that lines upper duodenum

13.3 kg weight loss at 12 weeks (n=24) vs 5.5 kg weight loss in diet control (n=11)

A1C reduction of >2.4% at 24 weeks (better reduction than meds provide)

creates an impermeable barrier
Indications for Treatment of obesity with meds
American College of Physicians (ACP) recommendations

Pharmacologic tx for BMI ≥ 30 kg/m2

BMI ≥ 27 kg/m2 with co-morbidities
Diabetes, CV disease, obstructive sleep apnea
Ephedra / ephedrine
CNS stimulant, appetite suppressant, thermogenic agent
FDA removed from market due to safety concerns in 2004
Caffeine sources
Listed as guarana (SR formulation), cola nut, tea extract, or mate
Decreased food intake- appetite suppressant
what effects does caffenine as a CAm product for obesity
stimulant
thermogenic
Appetite suppressants
5-HTP, Hoodia, St Johns Wort (like an SSRI in a sense)
Thermogenic agents
Bitter orange (works just like ephedran and still has CV risks), ephedra
Digestion inhibitors
Barley, bean pod, blond psyllium, chitosan, glucomannan, guar gum, guggul, inulin

binds fat so does not absorb
Miscellaneous Cam agents for weight loss
7-keto-DHEA, aristolochia, calcium, cha de bugre, chromium, conjugated linoleic acid, garcinia, pyruvate, irvingia gabonensis, usnea
Possibly Effective Agents for weight loss
Calcium
Adults/children with lower calcium intake more likely to gain weight
Increasing dairy consumption seems to increase weight reduction/fat loss (~1000mg/day)
Benefits not observed with supplements

Conjugated linoleic acid (CLA)
Fatty acid found primarily in dairy, beef
Theorized efficacy by shrinking adipose tissue by inducing apoptosis of fat cells
Some evidence shows decrease of body fat mass but not overall BMI reduction
May cause insulin resistance- more data needed
Cautions with OTC Diet Aids
No FDA regulation
Content/purity not guaranteed
No labeling regulation

Increased risk of overuse
“If 1 is good, 2 is better!”
Dexatrim example
High chance for CV risks, arrhythmias
Pharmacologic Agents for weight loss
Noradrenergic Agents (NE)
Phentermine (Fastin, Ionamin, Adipex)
Diethylpropion (Tenuate)

Noradrenergic/Serotonergic Agents
Sibutramine (Meridia)

Gastrointestinal Lipase Inhibitors
Orlistat (Xenical, Alli)
what are the 2 products that are FDA approved for long term weight loss
sibutraime
orlistat
Phentermine
Stimulates release of NE in CNS
Differ from amphetamine due to no DA release from synapse
Reduction of appetite with NE binding

~3.6kg weight loss in 6 months
Phentermine shown to produce greater weight loss vs. diethylpropion
FDA Approval limited to short-term use (<12 weeks)

Dosed 18.75-37.5 mg/day
$34.99/30 30mg capsules
SE phentermine
Headache, insomnia, irritability, palpatations, nervousness
SE diethylpropion
Headache, insomnia, irritability, palpatations, nervousness
SE fluoxetine
Agitation, nervousness
SE sibutramine
Headache, insomnia, dry mouth, constipation
SE Orlistat
Diarrhea, flatulence, bloating, abdominal pain, dyspepsia
what agent is more effective for weight loss phentermine or diethylpropion
phentermine
when the patient stops taking phentermine what happens to their appetite
it increses
phentermine contraindications
hyperthyroidism, glaucoma, advanced arteriosclerosis, moderate HTN, pulmonary HTN
what needs to be monitored when taking phentermine
Monitor blood pressure, weight
Phentermine previously combined with fenfluramine (Phen-Fen)
Resulted in primary pulmonary HTN and heart valve damage
Both fenfluramine and dexfenfluramine are withdrawn

it was the fenfluamine that was BAD
Sibutramine
Activity primarily through 2 active metabolites on both NE and 5-HT reuptake
N-desmethyl, N-bisdesmethyl sibutramine
Supresses appetite, increases satiety, increases thermogenesis

~4.45 kg weight loss at 12 months
FDA approved for long-term (>12 months) management of obesity
Data show weight regained once treatment is stopped
what biochemical risk factors are reduced while taking sibutramine
Reduction in TGs, TC, LDL-C, ↑HDL-C
Slight improvement in glucose control
BP increases were observed (~2 mm Hg)


provides the patient with better glucose control
contraindications of sibutramine
MAO-I tx or centrally-active appetite suppressants
Anorexia or bulimia nervosa
History of CHF, arrhythmia, stroke
dose of sibutramine
Dosed 10-15mg qd up to 2 years
30 10mg capsules: $109.99
scout trial
Sibutramine Cardiovascular OUTcomes

Phase 3 trial started in 2002
Almost 10,000 patients enrolled
Investigating long-term use of sibutramine

Increased cardiovascular risk in patients
Rate of CV events 11.4% vs 10% placebo
Removed from European market (1/21/10)
FDA- Now contraindicated in patients with cardiovascular disease


increases BPand dyslipidemia
orlistat
Reversible gastrointestinal lipase inhibitor
Inactivates hydrolyzation of dietary fat
Prevents absorption of dietary fat by ~30%

2.59 kg loss at 6 mo, 2.89 kg at 12 mo
Approved for long-term (>12 mo) obesity management
Some evidence of LDL-C, BP and glucose improvements

for long-term use
blocks the breakdown of fat so it cannot be absorbed
SE of orlistat
Pronounced GI side effects
Diarrhea, flatulence, bloating, abdominal pain, dyspepsia, oily “leaky” stools
Decreased fat soluble vitamin absorption (A,D,E,K)
Changes in eating patterns due to orlistat
Fat intake results in bad GI side effects
Ideally people make lower fat food choices
the patients learn to make better, healthier decisions because the med makes them feel like poo

the colon does adjust but is does take time

take it with high fat containing meals

could use fiber to decrease the SE
Orlistat availiability
Available by prescription and OTC
Rx: 120mg TID with fat-containing meals
OTC: 60mg TID with fat-containing meals
90 120mg: $325.30, 90 60mg: $54.95
FDA safety review of orlistat
Possibly implicated in liver injury
32 case reports including 6 liver failure cases, mostly (30) outside of U.S.
investigational drugs for weight loss
CB1 (cannobiod receptor)selective antagonists
Rimonabant approved 4/06 in Europe
trying to block the urdge to eat, but blocking may cause nerve damage
4.8 kg weight loss at 12 months
Improvements in HDL-C and TG
Removed 10/08 due to psychiatric SE

Currently over 30 drugs in development
GLP-1 agonists
Leptin agonists
LOSS study
390 volunteers, 2-year randomized controlled “pragmatic clinical trial”
200 in IMI vs 190 in UCC
187 of 390 patients completed 2 years (~50%)

Protocols followed at 8 study sites
14 hours of training given to providers
Monthly monitoring of sites throughout study
2 sites withdrawn

Intensive group given diet, medications, and behavior treatments
LOss study intensive group
Intensive intervention group- 3 phases
Phase 1= low calorie liquid diet + 10g fat (12 weeks preferred)

Phase 2= Highly structured diet + behavior therapy + medication (4 months)
Sibutramine preferred, orlistat & diethylpropion also dispensed

Phase 3= Medications + 1 meal replacement + monthly group sessions (7-24 months)
LOSS study results
in a primary care setting patients had sustainable weight loss

there was a mulifactorial intervention
* diet
* drugs
* behavioral changes
it was found that the above can induce wieght loss in those he do nto want surgery
obesity summary
Obesity epidemic continues to increase in numbers

Modest weight loss can greatly reduce serious health risks

Multifactorial causes require multifactorial treatment approach

Person needs to be committed to losing weight

Bariatric surgery shows strong, sustained weight loss & risk reduction but has its own risks and limitations

Some OTC/herbal therapies may have efficacy but many have too high of risks for use
What are the major clinical issues with using or recommending CAAM?
drug interactions
efficacy (placebo effect)
no FDA regulated
no safety data
Where can you look to find accurate information about CAM products
natural medicine database
german monographs
traditional CAM
accupuncture
traditional chinese medicine
homeopathy
herbal medicine
ayrvedic medicine
osteopathy and chiropratice
hypnotherapy
faith healing
complementary CAM
aromatherapy
biofeedback
detoxification
reflexology
arts therapies
nutritioal medicine
probiotics
GI conditions treated with CAAM
Constipation/Diarrhea
IBS
IBD
N/V
PUD
Hepatic conditions treated with CAAM
Cirrhosis
Alcoholic liver disease (ALD)
Viral hepatitis (hepatitis C)
Ingestion of hepatotoxic substances
plantago
AKA: Psyllium seed or plantain
Up to 80% insoluble fiber

Main uses = __constipation______

Dose = 7-40 g per day
Take with adequate_____water___
Don’t chew or crush seeds
Avoid co-administration with other drugs

Some chance of allergic reaction
Avoid “black” psyllium in non-commercial products
(this is a pigment released if chewed or crushed and it is nephrotoxic)

like a bulk forming laxitive
main use of plantago
constipation
what is the difference between soluble and insoluble fiber
solube absorbs water and breaksdown and swells

insoluble doesn't breakdown in water
buckthorn
like senna

AKA: cascara, buckthorn root or bark

MOA: __stimulant_________ Main Use:___constipation_____
Bacterial conversion of anthroglycosides
Works on large intestine
Dose = 20-30mg (Caps, Teas)

Chronic use can lead to __potassium__ depletion
Can increase toxicity of digoxin

Avoid in pregnancy and lactation (don't want abdominal cramping)
chamomile
MOA: anti-inflammatory
0.3-2% essential oils
? Inhibition of COX and lipoxygenase
May have “calming” properties

Uses = diarrhea, IBD, PUD, dyspepsia, “colic”

Roman, German, or common
Teas, capsules, tablets, flowers

Dose = 1 ml 3 times per day of extract
ADRs: Allergic reactions 1-2%
Contraindicated in pregnancy and lactation
aloe vera
Main components: gel + latex
Main Pharmacologic effects
Laxative: 30% anathraquinones
Antioxidant and inhibition of PGs

Products
Juice, capsules, softgels
100-200 mg aloe or 50 mg aloe extract taken in the evening

Adverse effects
Abdominal pain, cramping, potassium depletion
Hypoglycemia
Avoid on pregnancy and lactation
what componenet of aloe vera provides the GI effect
the latex it is a stimulant
is it ok to use aloe vera in patients with a latex allergy
yes
Ginger main uses
anti-emetic
MOA of ginger
antiemetic
evidence suggests that ginger has similar efficacy to
metoclopramide

it does not block D2
can ginger be used in pregnancy
yes
similar to pyridoxine (B6)
what drug does ginger interact with
warfarin has anti-platelet effects
licorice
Active constituents
Triterpene glycoside
Glycyrrhizin (DL)→ metabolized to glycyrrhetinic (GA)
DGL = De-Glycyrrhizinated Licorice

May inhibit PG breakdown and decrease gastric acid secretion
Similar results to cimetidine

Main uses =stomach upset

Dose = 200-600mg daily x 4-6 weeks
May use grated roots to make tea
DGL licorice
does not have Glycyrrhizin (DL)→ metabolized to glycyrrhetinic (GA) which can be harmful to some patients
adverse effects of licorice
Sodium, water retention
hypokalemia
 BP: Avoid in CV and renal disease
drug interactions with licorice
May reduce antihypertensive effects: __promote Na and water retention to increase BP
DGL__may avoid this effect
May inhibit CYP450 3A4
Potential for increased digoxin toxicity due to ↓ K
May decrease effectiveness of warfarin
should licorice be used in pregnancy
avoid
what form of licorice can be used inHTN patients
DGL because it prevents the increase in BP
peppermint MOA
relax smooth muscle
main use of peppermint
anit-spasmotic, colic and IBS
adverse effects of peppermint
heartburn
constiuents of peppermint
essential oils (potent)
menthol
what enzymes may peppermint inhibit
May inhibit CYP 3A4 and 2C9
MOA artichoke
several different components
Antiemetic
Antispasmodic
Cholerectic (stimulates bile to flow through the bilary system)
uses of artichoke
IBS
N/V
adverse effects of artichoke
Well tolerated
Avoid in pregnancy and lactation
probiotic definition
live microorganisms which when administered in adequate amounts confer a health benefit to the host”
400 species of bacteria in the human intestine
how are probiotics administered
May be adminsitered via extracts or through food
common strains of probiotics
Lactobacillus
Bifidobacterium
Streptococci
Saccharomyces
what is a prebiotic
the food that probiotics eat (insulin, lactolose)
take the prebiotics to stimulate the growth of our own flora
how do probitics work
the normal microflora and probiotics interact with the host metabolic activites and immune function and prevent colonization of opportunistic and pathogenic microorganisms

stimulate good immune health and get rid of the bad guys
Uses for Probiotics (KNOW!!!!)
Helicobacter pylori eradication
Appears to possibly augment antibiotic therapy
Lactobacillus
Saccharomyces

Antibiotic Associated Diarrhea (biggest use)
Lactobacillus GG
Saccharomyces boulardii
(giving back what is killed off)

Recurrent Clostridium difficile infection
Saccharomyces boulardii
Adjunctive to antibiotic therapy (metronidazole)

Prevention of radiation induced diarrhea
Post-op adjunctive therapy
VSL #3

IBD
Questionable benefit
May lead to higher remission rates when used adjunctively
Ulcerative colitis for patients with “pouchitis”
Saccharomyces, Bifidobacterium
VSL #3

IBS
Possible improvement
Large placebo effect
Bifidobacterium, VSL #3, or Lactobacillus GG
safety of probiotics
Generally considered safe

Rare reports of systemic infections
Mostly with Lactobacillus GG

Some studies in immunocompromised that show products are safe
HIV

Risk may outweigh benefit if use prevents infection with more serious organisms
milk thistle
Uses = viral hepatitis, “hepatoprotection”, hepatotoxin ingestion

AKA: Silybum marianum

Active constituent
Silymarin
Undergoes enterohepatic recirculation

MOA:
Alters the hepatocyte membrane to prevent entry of hepatotoxic substances
Stimulates ribosomal synthesis via polymerase “A”
Inhibits leukotriene production
Inhibits TNF-α
Antioxidant properties
efficacy of milk thistle
Lowers LFTS, but questionable for ALD and chronic hepatitis
High study dropout rates because of diarrhea
SE of milk thistle
Diarrhea, allergic reactions
what may milk thislt inhibit
May inhibit CPY 2C9
does milk thistle decrease LFTs
yes it does, but is does not necessarily mean in is providing clinical benefits
Potentially Hepatotoxic Agents
Kava
Used for anxiety, ADHD, insomnia, chronic fatigue

Skullcap
Used for anxiety, insomnia

Mistletoe
Abortifacient properties

Valerian
Used for anxiety, insomnia
Colonic Cleansing
AKA: “Colonic” or colonic irrigation

Based on “autointoxication” by undigested by products
Imbalance of “bodily humors”
Cleanses the bowel

Benefits?

Risks
Water intoxication
Electrolyte disturbances
Perforation
everything from the liver and pancreas drain into which duct
common bile duct
what kind of digestive organ is the pancreas primary or secondary
secondary
(excessory)
are enzymes stored in active or inactive forms
inactive so they do not digest the organ they are stored in (if enzymes were sotred in the active form in the pancreas they would cause pancreatitis)
zymogen granules
inactive enzymes
aciner cells
secrete enzymes from the pancreas
pancreatic functions exocirne
Exocrine (Digestive)
Major Enzyme Groups
release of enzymes
major enzymes released form the pancreas
Proteolytic: Proteases
trypsinogen
chymotrypsinogen
Procarboxypeptidase

Amylolytic: Amylase
Also found in:_saliva__________

Lipolytic: Lipase/prophospholipase A2
what do the ductal cells of the pancreas release
bicarb and Na
what is the purpose of bicarb released from the pancreas
to neutralize the acidic chyme coming form the stomach in order to protect the enzymes so they are not degraded
what pH do enzymes function at
physiological pH
what is the most important enzyme released from the pancreas
lipases
when the gallstone goes into the duct what happens
it obstructs the flow causing an increase in pressure which leads to enzyme activation and inflammation
why is ursodiol prescribeb for
not effective for acute gallstone dissolution (6-12 mo)

it is used as a preventative after gastric by-pass surgery
etiologies of chronic pancreatitis
Alcohol (70-90 % of Cases)
Usually > 10 years of heavy use
Idiopathic (~20%)
Various Others: genetic, autoimmune, infections, chronic duct obstruction
funtional and srtuctural damgae in chronic pancreatitis
Progression to irreversible state
Pancreatic insufficiency
alcohol and pancreatitis
there is a genetic component that possibly can cause alterarions in the metabolism causing oxidative stress which leads to activation of the stellate cells which then produce fibrotic molecules
Chronic Pancreatitis Features
Chronic Abdominal Pain (because of continual stimulation)
May be related to CCK

Maldigestion

Malabsorption
Fat malabsorption leads to steatorrhea
>90% loss of exocrine function

Diabetes: because beta cells are dysfunctioning so give insulin

weight loss: cachexia

Jaundice (10%)
maldigestion
cannot digest food because the enzymes are not present
what comes first maldigestion of malabsorption
maldigestion
fat malabsorption leads to
steatorrhea
chronic pancreatitis
Acute exacerbations
Complications
Pseudocysts
Pleural Effusions
Ascites or peripheral edema
Bile duct stricture
Calcification
Mortality
50% within 20-25 years of diagnosis
general management of chronic pancretitis
Abstinence from alcohol
Nutritional support
Low fat diet
Small frequent meals
Possibly TPN/Enteral for severe cases
Pain Management
Treat Malabsorption
Surgery: refractory cases
Management of endocrine dysfunction
chroninc pain managment for pancreatitis
Analgesics
Multidisciplinary stepped approach
Use same drug for as needed and scheduled narcotic analgesics if possible
Recommend non-narcotic drugs to reduce narcotic utilization

Pancreatic Enzymes
Negative feedback inhibition of pancreas related to CCK release (want to shut off pancreas secreations)
should a patient that has alcohol induced pancreatitis be put on APAP
no
chronic pain mangement products for chronic pancreatitis
Long-acting oral narcotics
Every 8-12 hour dosing
Morphine (Oramorph®, MS Contin®)
Oxycodone (Oxycontin®)

Transdermal fentanyl patches every 3 days (Duragesic®)

Short acting
Acetaminophen
Tramadol (Ultram®) or Ultracet®
NSAIDs (ibuprofen, celecoxib, etc)
Oxycodone, morphine

try to keep the same drug on board so as morphine IR + morphine ER
what is the problem with non-narcotic analgesics and chronic pancreatitis pain management
there are a lot of limitations

with nsaids you don't want Na and H2O retention

tramadol use with caution with ETOH

APAP is bad if alcoholic
treating malabsorption and pancreatitis
Goals of therapy
Reduce Steatorrhea
Weight gain
Pain reduction
Prevention/treatment of nausea
Improve QOL
Alcohol abstinence

Non-adherence or failure of medical therapy may result in long term parenteral nutrition
enzyme supplementation and chronic pancreatitis
Theory: simulate pancreatic enzyme release in relation to meals
lipase is most important determinant, so dosing is based on this component

Requires mixture with food and delivery to duodenum
Enzymes inactivated at pH < 4

5% of maximal pancreatic enzyme output required
should pancreatic supplemental enzymes be given with or without food
with to stimulate the endogenous process

especially with high fat meals so the fat can be digested and therefore prevent steatorrhea
pancreatic enzyme preperations
All are porcine based products
Also referred to as pancrelipase (includes 3 enzyems)

Enteric coated (preferred), because it protects it from gastric acid)
(Mini) Microspheres or microtablets
Each sphere or tablet is enteric coated
Designed to release at pH of 5.5-6
Do NOT crush, some products may be opened

Superior weight gain seen clinically
Need for less enzymes overall
can a person with pork allergies take pancreas enzyme supplements
no
what pH are the pancreas enzyme supplement active
5.5-6
past regualtion of pancreatic enzymes
1968 FDA-DRUG EFFICACY STUDY IMPLEMENTATION (DESI)
implemented recommendations of the National Academy of Sciences
Of 3443 products tested only 68% were found to be effective

Pre-DESI Drugs
Generally recognized as safe due to many years of public use
Have not undergone efficacy studies
are all pancreatic enzymes equal
prior to 2010 no

Differences existed in:
Enzyme content
Formulation
Dissolution

Enzyme products were not traditionally FDA approved

Products were not considered interchangeable
decoding the pancreatic enzyme label
MS or MT = microsphere or microtablet

Number (6-20): refers to the lipase content of each tablet/capsule in increments of 1000 units

Need to look at label for:
Amylase and Protease
prior to 2010 were pancreatic enzymes AB rated
no, so there were problems with switching between products
what are the regulations on pancreatic enzymes now
Bethesda, Md; April 27, 2004

Today the FDA initiated a requirement that all manufacturers of pancreatic enzyme replacements obtain FDA approval for their products within the next 4 years.

Manufacturers need to file an NDA

now have to be FDA approved
common pancreatic enzyme preperation
FDA Approved Products as of today

Creon® 6,000, 12,000, 24,000
Enteric coated minimicrospheres

ZENPEP® 5,000/10,000/15,000/20,000
Enteric coated beads

Uncoated Products (Viokase®)
Enteric coated microspheres (Ultrase ®)
Enteric coated microtablet (Ultrase MT® , Pancrease MT®)
Enteric coated microspheres with sodium bicarbonate buffer (Pancrecarb MS ®)
decoding the label of pancreatic enzymes 2010
MS or MT = may or may not specify

Number (6,000-20,000): refers to the lipase content of each tablet/capsule

Need to look at label for:
Amylase and Protease
Both are ~ 3-5 times lipase content

No more generic products
pancreatic enzyme supplementation dosing
Empiric: ~30,000 units lipase per meal
Weight based: 500-1000 U lipase/kg/meal
Max = 2500 u/kg/meal or 10,000 u/kg/day
~ ½ dose for snacks

Give enzymes immediately before or during meals

Consider  lipase content to reduce number of tabs/caps per meal
pancreatic enzyme SE
GI: nausea/cramping
Hyperuricosuria, hyperuricemia
Kidney stones
Impaired folate absorption
Possible drug interactions with bicarbonate

Fibrosing colonopathy
Due to enzyme overdosing
Results in scarring and strictures
Reason for 10,000 u/kg/day max and no products with > 20,000 units lipase
guidelines for titrating the dose of pancreatic enzymes
No set guidelines for titration of doses
Titrate by capsule/tablet strength
Use steatorrhea and weight gain as clinical markers of efficacy
if pancreatic enzymes seem to be ineffective what can be done
Consider adding antisecretory drug if enzymes ineffective
Check adherence and proper dosing first
Start with H2RA
Advance to PPI if necessary

pH may not be high enough in duodenum