Octreotide

Mechanism of Action

Octreotide is an analog of the polypeptide hormone somatostatin.[1] Octreotide acts on the somatostatin receptors, which couple to phospholipase C via inhibitory G proteins, and causes vascular smooth muscle contraction. The alpha and beta-gamma subunits of the G proteins inhibit adenyl cyclase and stimulate phospholipase C, respectively. At a cellular level, like somatostatin, octreotide induces an increase in calcium entry via L-type calcium channels, which leads to increased calcium-induced calcium release via ryanodine receptor calcium release channels from the sarcoplasmic reticulum in the smooth muscle cells, thus, activating myosin light-chain kinase via its interaction with calcium-calmodulin, and therefore, initiating the contraction cycle. The release of calcium from the sarcoplasmic reticulum is also due to the formation of 1, 4,5-inositol triphosphate, potentiated by phospholipase C.[6] Hence, octreotide, similar to the action of endogenous somatostatin, inhibits the release of hormones from the anterior pituitary gland, including thyroid-stimulating hormone and growth hormone, and hormones of the gastroenteropancreatic endocrine system such as insulin and glucagon.[1]

Administration

There are no oral formulations available for octreotide. Octreotide administration may be through a subcutaneous or intravenous route. Drug administration is usually as octreotide acetate injection, either as a subcutaneous or a long-acting release form. Compared to subcutaneous octreotide, the bioavailability of the long-acting release form is relatively low at about 60%. The subcutaneous form is available either as sterile 1-mL ampules in three strengths; 50 mg, 100 mg a, d  500 mg, or a  sterile 5-mL multidose vials in two strengths; 200 mg/mL and 1000 mg/mL. They are usually dosed three-times-daily, whereas the long-acting release form is a depot formulation containing a 10 to 30 mg dose of octreotide and is available in three strengths; 10 mg per 6 mL, 20 mg per 6 mL, and 30 mg per 6 mL, usually administered intramuscularly every 28 days.[2][7]

Adverse Effects

1. Gastrointestinal abnormalities (34% to 61%) are transient and usually mild to moderate. They include diarrhea, nausea, abdominal discomfort, gallbladder abnormalities, such as cholelithiasis and microlithiasis, biliary sediment and sludge due to alteration of fat absorption, and possibly by decreasing motility of the gallbladder.[7]
2. Bradycardia occurs in 25% of patients with acromegaly, conduction abnormalities (10%), and arrhythmias (9%).
3. Hypoglycemia (3%) and hyperglycemia (16%) occur due to alteration in glucose metabolism, usually mild in severity.
4. Hypothyroidism: In patients with acromegaly, subclinical hypothyroidism occurred in 12%, and goiter occurred in 6% during treatment with octreotide acetate. In patients without acromegaly, isolated cases of hypothyroidism have been reported. However, there was no incidence of goiter in this subset of patients.
5. Dermatologic: Itching (18%).[2]
6. Pain at the injection site (7.7%).[1]
7. Headache and dizziness (6%).
8. Other side effects, documented in less than 4% of patients on octreotide, include cold and flu symptoms, weakness, fatigue, depression, blurred vision, pruritus, hair loss, vision disturbance, flushing of the skin, arthralgia, lower back pain, increased urinary frequency especially during waking hours, and urinary tract infection, edema, bruising and hematoma formation at the injection site, and malabsorption of fat and other nutrients.[2]

Contraindications

Hypersensitivity reaction on administration, due to octreotide or any of its components, is the main contraindication to its future use. Octreotide should also be used very cautiously in patients with insulinoma and type 2 diabetes mellitus who require intensive blood glucose monitoring and control because it can lower glucose levels dramatically and reduce the insulin requirements in these patients by up to 50%. Therefore, serum glucose concentrations should be monitored carefully during octreotide therapy. Octreotide also increases the bioavailability of bromocriptine by up to 40%, which is a matter of concern because octreotide and bromocriptine are both used to treat acromegaly. Octreotide may also lead to bradycardia, arrhythmias, or conduction defects and, therefore, should be used with caution in the at-risk groups of patients.[2]

Monitoring

Octreotide, being a somatostatin analog, requires close monitoring because of the numerous physiological actions of somatostatin in the body. Additionally, various markers are specific indicators of the therapeutic effect of octreotide and the body's response to drug therapy.

In the treatment of acromegaly, serum growth hormone (GH) and insulin-like growth factor (IGF) require monitoring. However, the frequency of monitoring differs by the formulation of octreotide administered. Use of the short-acting formulation requires measurement of serum IGF-1 only once, around 14 days after initiating octreotide therapy or after any change in dose, or a GH assay after every 1 to 4 hours for 8 to 12 hours after administration of every dose. The use of octreotide’s newer long-acting formulation needs less intensive monitoring in the form of a serum GH assay and a serum IGF-1assay around three months before administering the subsequent dose. The maintenance phase in the treatment of acromegaly also requires monitoring to detect delayed adverse effects. Hence, serum GH and serum IGF-1 levels should be obtained every 3 to 6 months.

During the management of carcinoid syndrome, the measurement of 5-hydroxyindole-acetic acid, serotonin, and substance P levels are necessary.

Octreotide treatment for VIPomas requires periodic measurement of the vasoactive intestinal peptide to monitor tumor burden and risk of relapse.

In addition to the above, patients on long-term octreotide therapy require monitoring of various clinical parameters, both at baseline and periodically, for prevention and early detection of adverse effects. These effects include blood glucose levels, including monitoring of glycemic control in patients with type 2 diabetes mellitus, cardiac function with periodic electrocardiograms, thyroid function tests, plasma vitamin B and zinc, especially in patients receiving total parenteral nutrition who are at risk of excessive fluid loss, and an abdominal ultrasound to look for abnormalities of the gall bladder in the presence of clinical findings.[8]

Toxicity

Limited studies have assessed octreotide toxicity. However, isolated studies have shown a mild degree of bone marrow suppression and impairment in spermatogenesis due to inhibition of serum inhibin B and concomitant increase in FSH in supratherapeutic doses. There is a need to conduct significantly larger studies and trials to define and establish the therapeutic index of octreotide and identify its toxic effects and its management.[9]

Enhancing Healthcare Team Outcomes

Although it has been a few decades since the synthesis of octreotide, its use has limitations to a few indications.[10] However, in recent times, octreotide has found utility in various other previously unexplored therapeutic modalities. Although the understanding of octreotide is increasing due to the numerous studies and clinical trials, further reviews and trials are required to better understand the pharmacokinetics and pharmacodynamics of the drug to recognize better and control the adverse effects of octreotide. Also, there is a need for coordination amongst the healthcare team members to enhance evidence-based outcomes for patients on octreotide therapy.

Octreotide therapy requires an interprofessional team approach, including clinicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results while minimizing adverse events. [Level 5]