Mechanism of Action of Octreotide

Introduction

Octreotide is a synthetic somatostatin analog used to treat acromegaly, carcinoid syndrome, VIPoma, and control of panhormonal secretion. It mimics somatostatin, binding to somatostatin receptors (SSTRs), especially SSTR2, to inhibit hormone release and reduce symptoms caused by hormone-secreting tumors.

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Step-by-Step Mechanism of Action

1. Agonism of somatostatin receptors
   Octreotide binds predominantly to SSTR2 and SSTR5, which are G_i/o protein-coupled receptors.
2. Inhibition of adenylate cyclase
   Binding triggers G_i-mediated inhibition of adenylate cyclase, decreasing intracellular cAMP and suppressing hormone secretions (e.g., growth hormone, insulin, glucagon).
3. Activation of potassium channels and inhibition of calcium influx
   G-protein subunits open potassium channels—hyperpolarizing cells—and block voltage-gated calcium channels, reducing hormone exocytosis.
4. Antisecretory and anti-proliferative effects
   These actions lower secretion of hormones and peptides, and reduce cell proliferation via SSTR-mediated intracellular pathways.
5. Vascular smooth muscle effects
   Octreotide induces vasoconstriction by activating GPCR/PLC and calcium-mediated pathways in blood vessels, useful in controlling bleeding varices.

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Pharmacokinetic Parameters

Parameter	Value
Administration	Subcutaneous/Intramuscular/Long-acting IM
Bioavailability	~75–100% for SC injection
Peak Plasma Time	~30 minutes (SC); variable (LAR formulation)
Protein Binding	~65%
Metabolism	Hepatic (minimal CYP involvement)
Elimination Half-life	~1.5 hours (SC); ~70 hours (long-acting IM)
Elimination	Renal and fecal

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Clinical Uses

• Acromegaly (control of GH/IGF-1)
• Carcinoid syndrome (reduces flushing and diarrhea)
• VIPoma-induced secretory diarrhea
• Prevention of bleeding in esophageal varices
• Off-label use in endocrine tumors and GI fistula output reduction

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Adverse Effects

• Injection-site pain
• Gastrointestinal disturbances (e.g., abdominal pain, nausea, steatorrhea)
• Gallstone formation and biliary sludge
• Bradycardia, arrhythmias
• Hyperglycemia or hypoglycemia
• Hypothyroidism and vitamin B12 deficiency with long-term use

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Comparative Analysis

Agent	SSTR2 Selectivity	Half-life	Use in Acromegaly
Octreotide	High	Short (1.5 h)	SC or LAR depot injection
Lanreotide	Similar	~28 days (LAR)	Deep SC depot
Pasireotide	Broad SSTR action	Short/IM	Cushing’s disease

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MCQs (15)

1. Octreotide is an analog of which peptide?
a) Insulin b) Somatostatin c) Vasopressin d) Glucagon
Answer: b) Somatostatin

2. Octreotide primarily binds to which receptor subtype?
a) SSTR1 b) SSTR2 c) SSTR3 d) SSTR4
Answer: b) SSTR2

3. Main intracellular effect after binding is:
a) Increased cAMP b) Decreased cAMP c) Increased IP₃ d) Increased DAG
Answer: b) Decreased cAMP

4. It reduces hormone release by:
a) Blocking sodium channels
b) Opening K⁺ channels and blocking Ca²⁺
c) Activating adenylate cyclase
d) Inhibiting G-proteins
Answer: b) Opening K⁺ channels and blocking Ca²⁺

5. Used in acromegaly to reduce:
a) TSH b) GH/IGF-1 c) ACTH d) PTH
Answer: b) GH/IGF-1

6. Octreotide treats carcinoid syndrome by:
a) Reducing serotonin release
b) Inhibiting prostaglandin synthesis
c) Blocking dopamine receptors
d) Stimulating gastrin release
Answer: a) Reducing serotonin release

7. A long-acting formulation has a half-life of approximately:
a) 1.5 hours b) 12 hours c) 70 hours d) 24 hours
Answer: c) 70 hours

8. Adverse effect associated with bile is:
a) Pancreatitis b) Gallstones c) Nephrolithiasis d) Hepatitis
Answer: b) Gallstones

9. Cardiovascular side effect may include:
a) Vasodilation b) Bradycardia c) Tachycardia d) Hypertension
Answer: b) Bradycardia

10. Octreotide’s vasoconstriction mechanism involves:
a) NO release b) GPCR/PLC activation c) Histamine antagonism d) Beta-blockade
Answer: b) GPCR/PLC activation

11. It is administered via:
a) Oral tablets b) IV bolus c) SC or IM injection d) Transdermal patch
Answer: c) SC or IM injection

12. Octreotide is contraindicated in patients with:
a) Hypertension b) Biliary disease c) Asthma d) Renal failure
Answer: b) Biliary disease

13. Long-term use may lead to:
a) Pancreatic hypersecretion b) Vitamin B12 deficiency c) Hypotension d) Hyperthyroidism
Answer: b) Vitamin B12 deficiency

14. Octreotide differs from pasireotide by:
a) Receptor selectivity b) Half-life c) Route d) Adverse profile
Answer: a) Receptor selectivity

15. Which is an off-label use?
a) Acromegaly b) VIPoma diarrhea c) Carcinoid crisis d) Type 2 diabetes
Answer: c) Carcinoid crisis

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FAQs

1. Can octreotide shrink tumor size?
Primarily reduces hormone secretion; may slightly reduce tumor size, especially in acromegaly.

2. How is treatment monitored?
By measuring GH, IGF-1, or relevant hormone levels every 3–6 months.

3. Does octreotide affect glucose metabolism?
Yes—can cause hyper- or hypoglycemia due to effects on insulin and glucagon.

4. Is it safe in pregnancy?
Category B; use only if benefits outweigh risks and monitoring is implemented.

5. How to manage gallstone risk?
Monitor gallbladder via ultrasound; consider prophylaxis if long-term use is planned.

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References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition
• KD Tripathi. Essentials of Medical Pharmacology, 8th Edition
• StatPearls: Octreotide clinical pharmacology
• DrugBank: Octreotide pharmacology go.drugbank.com
• Nature Commun.: Molecular mechanism at SSTR2 nature.com+1en.wikipedia.org+1

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