Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Somatostatin and analogues, ATC code: H01CB02 
Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a considerably prolonged duration of action. It inhibits pathologically increased secretion of growth hormone (GH) and of peptides and serotonin produced within the GEP endocrine system.

In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than somatostatin is, with greater selectivity for GH and glucagon suppression.

In healthy subjects Octreostat has been shown to inhibit
• release of GH stimulated by arginine, exercise- and insulin-induced hypoglycaemia, • postprandial release of insulin, glucagon, gastrin, other peptides of the GEP endocrine system, and arginine-stimulated release of insulin and glucagon,
• thyrotropin-releasing hormone (TRH)-stimulated release of thyroid-stimulating hormone (TSH).

Unlike somatostatin, octreotide inhibits GH secretion preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. GH in patients with acromegaly).

In acromegalic patients Octreostat lowers plasma levels of GH and IGF-1. A GH reduction by 50% or more occurs in up to 90% patients, and a reduction of serum GH to <5 ng/mL can be achieved in about half of the cases. In most patients Octreostat markedly reduces the clinical symptoms of the disease, such as headache, skin and soft tissue swelling, hyperhidrosis, arthralgia, paraesthesia. In patients with a large pituitary adenoma, Octreostat treatment may result in some shrinkage of the tumour mass.

In patients with functional tumours of the GEP endocrine system, Octreostat, because of its diverse endocrine effects, modifies a number of clinical features. Clinical improvement and symptomatic benefit occur in patients who still have symptoms related to their tumours despite previous therapies, which may include surgery, hepatic artery embolization, and various chemotherapies, e.g. streptozocin and 5-fluorouracil.

Octreostat's effects in the different tumour types are as follows

Carcinoid tumours
Administration of Octreostat may result in improvement of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid.

VIPomas

The biochemical characteristic of these tumours is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of Octreostat results in alleviation of the severe secretory diarrhoea typical of the condition, with consequent improvement in quality of life.
This is accompanied by an improvement in associated electrolyte abnormalities, e.g.
hypokalaemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. In some patients, computed tomography scanning suggests a slowing or arrest of progression of the tumour, or even tumour shrinkage, particularly of hepatic metastases.
Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.

Glucagonomas

Administration of Octreostat results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of the condition. The effect of Octreostat on the state of mild diabetes mellitus which frequently occurs is not marked and, in general, does not result in a reduction of requirements for insulin or oral hypoglycaemic agents.
Octreostat produces improvement of diarrhoea, and hence weight gain, in those patients affected. Although administration of Octreostat often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.

Gastrinomas/Zollinger-Ellison syndrome

Therapy with proton pump inhibitors or H2 receptor blocking agents generally controls gastric acid hypersecretion. However, diarrhoea, which is also a prominent symptom, may not be adequately alleviated by proton pump inhibitors or H2 receptor blocking agents.
Octreostat can help to further reduce gastric acid hypersecretion and improve symptoms, including diarrhoea, as it provides suppression of elevated gastrin levels, in some patients.

Insulinomas

Administration of Octreostat produces a fall in circulating immunoreactive insulin, which may, however, be of short duration (about 2 hours). In patients with operable tumours Octreostat may help to restore and maintain normoglycaemia pre-operatively. In patients with inoperable benign or malignant tumours, glycaemic control may be improved without concomitant sustained reduction in circulating insulin levels.


GRFomas
These rare tumors are characterized by production of GH releasing factor (GRF) alone or in conjunction with other active peptides. Octreostat produces improvement in the features and symptoms of the resultant acromegaly. This is probably due to inhibition of GRF and GH secretion, and a reduction in pituitary enlargement may follow

Complications following pancreatic surgery

For patients undergoing pancreatic surgery, the peri- and post-operative administration of Octreostat reduces the incidence of typical postoperative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, postoperative acute pancreatitis).

Bleeding gastro-oesophageal varices

In patients presenting with bleeding gastro-oesophageal varices due to underlying cirrhosis, Octreostat administration in combination with specific treatment (e.g. sclerotherapy) is associated with better control of bleeding and early re-bleeding, reduced transfusion requirements, and improved 5-day survival. While the precise mode of action of Octreostat is not fully elucidated, it is postulated that Octreostat reduces splanchnic blood flow through inhibition of vaso-active hormones (e.g. VIP, glucagon).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

After s.c. injection, Octreostat is rapidly and completely absorbed. Peak plasma concentrations are reached within 30 minutes.

Distribution

The volume of distribution is 0.27 L/kg and the total body clearance 160 mL/min. Plasma protein binding amounts to 65%. The amount of Octreostat bound to blood cells is negligible.

Elimination

The elimination half-life after s.c. administration is 100 minutes. After i.v. injection, the elimination is biphasic, with half-lives of 10 and 90 minutes. Most of the peptide is eliminated via the faeces, while approximately 32% is excreted unchanged into the urine.

Special patient population

Impaired renal function did not affect the total exposure (AUC) to octreotide administered as s.c. injection.

The elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease.