O1i / 23A06 / 15A06: Outline the physiology of pancreatic secretion (80 marks) and outline the pharmacology of octreotide (20 marks)

23A06: Exam Report

Describe pancreatic secretions and their regulation.

21% of candidates passed this question.

It was vital to recognise and describe both the exocrine and endocrine secretions of the pancreas and their regulation. Insulin, glucagon, and somatostatin are all secreted from the pancreas and their omission was the most common reason for not passing this question.

Many candidates unfortunately wrote solely on exocrine secretions. Satisfactory answers provided a moderate amount of detail on both the endocrine (insulin, glucagon and somatostatin) and exocrine (bicarbonate and digestive enzymes; trypsin/chymotrypsin, pancreatic amylase and lipase) secretions of the pancreas including what determines their secretion.

15A06: Exam Report

Outline the physiology of pancreatic secretion (80% of marks) and outline the pharmacology of octreotide (20% of marks).

38% of candidates passed this question.

An outline of exocrine function should have included the sources of secretions,  secretions involved in the digestion of proteins, carbohydrates and fats, the roles of trypsin inhibitors and bicarbonate secretion and the regulation of enzyme and  bicarbonate secretion.” Knowledge of endocrine physiology was good whereas the depth of knowledge regarding exocrine function was generally shallow with many errors.

Only some general facts around the pharmacology of octreotide were required to pass this section of the question. Responses revealed limited knowledge and contained many errors.

O1i / 23A06 / 15A06: Outline the physiology of pancreatic secretion (80 marks) and outline the pharmacology of octreotide (20 marks)

Definition

Pancreas = intra-abdominal organ involved in digestion with both exocrine and endocrine functions → consists of head, body and tail

  • \( \text{Mass of pancreas} \begin{cases} \text{95% EXOCRINE = Acinar + Ductal cells} \\ \text{5% ENDOCRINE = Islets of Langerhans} \end{cases} \)

Exocrine

  • Gland which secrets hormones via ducts, opening into epithelium rather than into blood
  • 5L pancreatic juice produced/day
  • Pancreatic juice secreted by 2 cells
    • ACINAR → digestive enzymes
    • DUCTAL → HCO3–, H2O

Acinar

  • Pancreatic enzymes = PROENZYMES
  • Synthesised by ribosomes → secreted by exocytosis
  • Stimulated by ACh, Gastrin, CCK
  • Proteolytic enzyme → trypsinogen + chymotrypsinogen, which are converted to Trypsin by enterokinase or by autocatalysis (self)
  • Pancreatic α-amylase → hydrolyses carbs into dissachs
  • Pancreatic lipases → hydrolyses TAGs → glycerol + FFA (but bile is required to make TAGs H2O soluble for lipase access)

Ductal Cells

  • Secretion stimulated by CHOLECYSTOKININ, SECRETIN, ACh
  • Electrolytes + H2O
  • pH of pancreatic juice = 8
  • Buffers gastric acid
  • Optimal pH for pancreatic enzyme activity
  • HCO3– secreted by ductal cells:

a. Diffuses down [ ] gradient

  1.  OR

b. CO2 + H2O ⮂ H2CO3 ⮂ HCO3– + H+

      • HCO3– diffuses into pancreatic ducts in exchange Cl –
      • H+ is transported by Na/K/ATPase system
  • H2O diffuses freely via paracellular route
  • Na, K, Cl, secreted in similar [ ] to plasma

Endocrine

  • A gland which secretes hormones directly into the bloodstream
  • Islets of Langerhans → 4 cell types

Cell Type

%

Secrete

α cells

25%

Glucagon

β cells

75%

Insulin

δ cells

5%

Somatostatin

F cells

5%

Pancreatic polypeptide

β Cells

  • \( \text{PREPROINSULIN} \xrightarrow{\text{Cleared in ER}} \text{PROINSULIN} \xrightarrow{\text{Cleared by Golgi}} \textbf{INSULIN}\) 
  • Insulin stored in granules with Zinc
  • Secretion: CHO, α-acids, ACh (when ↑BGL), catecholamines
  • T½ 5 mins, degraded by liver + kidneys

α Cells

  • Proglucagon → glucagon
  • T ½ 5 mins: degraded by liver
  • Secretion: ↑BGL inhibits, ↓BGL stimulates

δ Cells

  • Synthesised + stored by δ cells & hypothalamus
  • T ½ 3 mins
  • Secretion:↑BGL, α-acids, FAs

Somatostatin

  • Aka Growth Hormone Inhibiting Hormone
  • Peptide hormone
  • Affects neurotransmission + cell proliferation via GPCR somatostatin receptors
  •  

Production

  • δ cells of Pyloric Antrum, duodenum, pancreatic islet
    • Portal venous system → systemic circulation
    • Locally in stomach → PARIETAL CELLS → ↓HCl secretion
    • Also indirectly ↓HCl secretion by preventing release of gastrin, secretin, histamine
    • Brain → neurons of Hypothalamus → APG → inhibits secretion of GH from somatotrope cells

Actions

  • Inhibit GH release
  • Inhibit TSH release
  • Inhibit Prolactin release

GI

  • Suppresses release of GI hormones
  • Gastrin, CCK, secretin, motilin, vasoactive intestinal peptide, gastric inhibitory peptide, glucagon
  • ↓rate of gastric emptying
  • ↓smooth m. contraction of GI
  • ↓BF to GI
  • Suppresses release of Pancreatic Hormones

Octreotide

  • An octapeptide Somatostatin Analogue

Chemical

Octapeptide Somatostatin Analogue

Use

  1. Carcinoid tumours
  2. Variceal bleed
  3. Acromegaly
  4. Hypoglycaemic OD

Presentation

50mcg/mL in 1mL ampoule

Route / Dose

Poor PO absorption

(S/C) 50mcg BD (endocrine tumours)

(IV) 25mcg/hr (variceal bleed)

MoA

  • Binds somatostatin receptor
  • GPCR → ∴inhibits AC
  • Many effects depending on location of receptor

GI

  • More potent inhibitor of GH, glucagon & insulin than somatostatin
  • Inhibits hormone secretion: gastrin, CCK, glucagon, insulin, secretin
  • ↓fluid production by pancreas
  • ↓GI motility
  • Inhibits GB contraction
  • Mesenteric VC ∴↓portal venous P
  • Mesenteric VC ∴↓splanchnic BF

APG

  • Inhibits GH release
  • Inhibits BH release
  • Inhibits Prolactin release

PD

Metabolic – ↓pancreatic hormone secretion

GI – ↓splanchnic BF & ↓portal venous P

MSK – normalises GH (in Acromegaly)

 NB: vasoactive intestinal peptide tumours → VIP secreting tumours assoc with massive diarrhoea → ∴↓diarrhoea

Carcinoid tumours → ↓severe diarrhoea + flushing

OHG O/D → ↓insulin release

PK

A

Poor oral absorption

Given IV

S/C → absorbed quickly & completely

Peaks in 30 mins

D

VD 13L

PPB 65%

M

Hepatic metabolism

Prolonged action in renal + liver failure

E

30% unchanged in urine

Adverse Effects

Diarrhoea

Vomiting

Hyperglycaemia