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