intestinal failure: drug management · aims of treatment . prevention of thirst & dehydration ....
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Intestinal Failure: Drug Management
Jackie Eastwood Pharmacy Manager St Mark’s Hospital
Aims of Treatment
Prevention of thirst &
dehydration
Stomal output <2L/day
or manageable
diarrhoea
Prevention of electrolyte deficiencies
Drugs used in IF
• Loperamide • Codeine
phosphate
• Magnesium
• Omeprazole • Octreotide • Racecadotril
• Electrolyte mix
• Dioralyte® (double strength) Oral
hypertonic solutions
Antisecretory
Antimotility Supplements
3
Patient types Respond differently to medications
Absorbers Secretors
Residual small Bowel length
>100 cm <100 cm
Net Na &H2O balance
Intestinal output < oral intake
Intestinal output > oral intake
Jejunostomy output ~2 L/day ~4-8 L/day
Antisecretory Drugs
• Competes with histamine for receptor site • Less effective in food-stimulated secretion Ranitidine
• Irreversible inhibition of proton pump preventing secretion of H+ ions Omeprazole
• Somatostatin analogue Octreotide
5
Mechanism of action Parietal Cell
H2 receptor antagonists Ranitidine
X
Proton pump inhibitors Omeprazole
X
Ranitidine vs Omeprazole
Jeppesen et al, 1998 13 patients, double blind, crossover trial Median SB length = 100cm 2 treatments with 2 day washout period (IV ranitidine 150mg vs omeprazole 40mg BD) Assessing effect on wet weight absorption
Jeppesen et al (1998) Gut:43;763-769
ranitidine
Omeprazole more effective than ranitidine at increasing wet weight absorption
Oral Omeprazole
Nightingale et al, 1991 11patients (7 secretors & 4 absorbers) SB length < 150cm Oral omeprazole for 3 days
9 Nightingale.J et al (1991). 5: 405-412
Reduction in intestinal output not sufficient to stop parenteral fluid & electrolyte replacement
Antisecretory Drugs
Only effective in net secretors
Omeprazole High dose often necessary (40mg BD) Titrate against stomal pH Oral omeprazole may be ineffective in patients
<50cm jejunum
Antimotility drugs
Act on μ-receptors
• ↓ peristalsis • ↑ water absorption
Codeine phosphate
• 120-240mg daily
Loperamide
• 16-64mg daily • Not addictive or sedating • More favourable than codeine
Greater effect
• if used in combination1
12 1Nightingale et al, 1992 Clin Nutr 11:101-105
Effect of codeine & loperamide
0
100
200
300
400
500
600
700
800
900
1000
Placebo Codeine Loperamide
Stom
al w
et w
eigh
t (g)
King at al, 1982 Aust NZ Surg:52:121-124
Loperamide preparations
Preparation Absorption (hrs)
Onset of action (hr)
Half life (hrs) Cost for 2mg dose (£)
Loperamide syrup 1mg/5ml 2.4 +/- 0.7 1 11 0.12
Loperamide capsules 5.2 +/- 0.3 1 11 0.11
Loperamide tablets No data 1 11 0.09
Loperamide melts No data 1 11 0.33
14
Locally acting on the gut, only 1% systemically absorbed. All formulations bioequivalent MI, Jonson & Jonson,
Nov14
Octreotide
Delays gastric & small bowel emptying
↓ salivary, gastric & pancreatic-biliary secretions
Absorbers / secretors • Greatest effect in net secretors
Effective for • ileostomy diarrhoea • large volume jejunostomy & Na losses
No effect on energy/nitrogen absorption1
1 O’Keefe et al, (1994) JPEN;18:26-34
Side Effects Very common Common
Hyperglycaemia Thyroid dysfunction Diarrhoea Hypoglycaemia
Abdominal pain Bradycardia Nausea Dyspnoea
Constipation Dyspepsia Headache Vomiting
Cholelithiasis Bloating Injection site pain Steatorrhoea
Dizziness Cholecystitis
Rash Alopecia
16
Octreotide
• Expensive • Unlicensed • Inhibits adaptation
Problems
• Trial use for 2-3 days • Stop if no effect • Long acting
preparations if sustained effect
Suggested use
17
Racecadotril
Enkephalinase inhibitor
Enkephalins act on δ-opiate receptors – reducing hypersecretion of water and electroytes
Enkephalins are broken down by enkephalinases
Licensed for acute diarrhoea, especially secretory
Possible role in secretors?
Magnesium
• Common in SBS Mg deficiency
• Reduced area of absorption • Fat malabsorption • Na depletion • Hyperaldosteronism • PPI treatment
Causes of deficiency
• Mg oxide, Mg glycerophosphate, Mg aspartate • Form used dependent on response1 • Doses used:12-24mmol/day2
• Intestinal transit slowest at night
Oral replacement
• S/c: maximum of 8mmol in 1L 0.9% saline • IV: higher doses can be given
Parenteral replacement
19 1. Ross. J.R.et al (2001) Gut 48;6:857-858. 2. Nightingale JMD et al (2006) Gut 55(Suppl IV):1-12
Drug administration: Tips
• Give drugs 30mins to 1hour before food
Timing
• High osmolality • May contain
sorbitol • Will increase
stomal output Caution with liquids/syrups
• If comes out of stoma bag then crush tablet or open capsules
Use capsules/tablets
20
Glucagon-like Peptide 2
Naturally occurring 33 AA peptide
⇑ Bone density
⇑ Intestinal perfusion
⇑ Nutrient absorption
⇑ Mucosal proliferation ⇑ Cytoprotection
Production Intestinal L cells (ileum & colon) Release stimulated by luminal nutrition Receptors Mainly in jejunum & proximal ileum Action Strong intestinotrophic properties
Teduglutide: [gly2]-hGLP-2 Novel recombinant analogue of GLP-2 (orphan drug) 33 AA peptide that differs from GLP-2
Substitution of ALA by GLY at 2nd position (from N-terminus) Resistance to in vivo degradation by dipeptidyl peptidase-IV
Half life GLP-2 7 minutes Teduglutide 2 hours
Revestive
Gly
H2N
HOOC
His Gly Asp Ser Phe Ser Asp Glu Met Asn Asn
Asn
Asp Thr
Thr Thr
Ile
Ile Ile Ile
Leu Leu
Leu
Asp Ala Ala Arg
Phe
Trp Gln Lys Asp
Teduglutide in SBS with IF
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1/16 16/35 8/32
Placebo Low dose (0.05mg/kg/day) High dose (0.1mg/kg/day)
>=20
% re
duct
ion
in H
PN re
quire
men
ts **
Jeppesen PB et al Gut 2011;60:902-14
Teduglutide: 24 week RCT
Jeppesen PB et al, Gastroenterology 2012;143(6):1473-1481
0
10
20
30
40
50
60
70
Placebo Teduglutide
% re
spon
ders
(>20
% P
N re
duct
ion)
27/43
13/43
12.4 11.5
10.5 9.6
8.9 8.0 7.8
7.1 6.7 6.8 7.2
6.9 5.9 5.8 5.2
4.8 4.9
0
2
4
6
8
10
12
14
BL 4 8 12 16 20 24 1 2 3 6 9 12 15 18 21 24
PS V
olum
e, L
/wee
k
STEPS2: sustained response (TED/TED completers)
Sustained reductions in PS volume requirements were observed over 30 months (TED/TED group)
STEPS STEPS-2
Weeks Months
TED/TED (n=30)
7
1
3
1
2 2
0
1
2
3
4
5
6
7
8
>25 to ≤50 >50 to ≤75 >75 to ≤100 >100 to ≤125 >125 Unknown
Remaining SB length in patients, cm
No.
pat
ient
s sto
ppin
g PN
Remnant SB length & discontinuing PN with teduglutide
No colon in continuity Colon in continuity
Jeppesen et al. Poster ESPEN 2014 (PP131-SUN)
Identifying suitable patients
• Patients should be stable following adaptation
Probably all adult patients with SBS could benefit
• Patients with smaller PS requirements (A–D1) • Patients with high PS volume requirements (A–D4)
Reasonable to start with
•Contra-indications •Active or suspected malignancy •Patients with a history of a GI malignancy within the last 5 years
Remember it is a growth factor
Conclusion
Drug management
in IF
Electrolyte mix
Loperamide
Codeine phosphate
Mg supplements Omeprazole
Octreotide
New therapies?
28