Drugs Used in Endocrinology and Hormones

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Corticosteroids

Overview

Corticosteroids are a group of steroid hormones produced in the adrenal cortex. The two main corticosteroids produced are cortisol (a glucocorticoid) and aldosterone (a mineralocorticoid). Cortisol (also known as hydrocortisone) is the most important human glucocorticoid and is essential for life.

Synthetic glucocorticoids are widely used as either replacement therapy in glucocorticoid deficiency (e.g. adrenal insufficiency), or to suppress the immune system (e.g. induction of remission in rheumatoid arthritis).

To help make sense of this chapter, it may be helpful to refer to Endocrine and Metabolic Physiology.

Glucocorticoids

In general, glucocorticoids have immunosuppressive effects and raise blood glucose concentration through stimulation of hepatic gluconeogenesis and fat breakdown. This makes them useful in scenarios such as inducing remission in inflammatory disease.

Mineralocorticoids

Mineralocorticoids affect electrolyte and fluid balance, and aldosterone is the main endogenous mineralocorticoid. In summary, it retains sodium ions and increases the excretion of potassium ions. Since the sodium ions are retained, water follows, increasing the water content in the body.

Types

Commonly used corticosteroids are:

  • Fludrocortisone and aldosterone:
    • Minimal glucocorticoid activity, high mineralocorticoid activity
  • Hydrocortisone (cortisol):
    • Moderate glucocorticoid activity, high mineralocorticoid activity
    • Suppresses adrenocorticotropic hormone (ACTH) release for 8-12 hours
  • Prednisolone and methylprednisolone:
    • Mainly glucocorticoid activity, low mineralocorticoid activity
    • Suppresses ACTH release for 18-36 hours
  • Dexamethasone and betamethasone:
    • Very high glucocorticoid activity, minimal mineralocorticoid activity
    • Suppresses ACTH release for 36-54 hours

Choice of steroid

The properties of each synthetic corticosteroid can help in choosing which one to use. In general:

  • Hydrocortisone is often used intravenously in emergencies:
    • This is because it has glucocorticoid activity, but relatively high mineralocorticoid activity, making it less suitable for long-term use (except topically)
  • Prednisolone is often used as a longer-term treatment:
    • This is because it has less mineralocorticoid activity
  • Dexamethasone is used where high doses of glucocorticoid are needed (e.g. suppressing severe inflammation), or where a long duration of glucocorticoid activity is desired:
    • Because it has very minimal mineralocorticoid activity, the effects of fluid retention are minimised.

Glucocorticoid adverse effects

  • Endocrine and metabolic:
  • Cushing’s syndrome:
    • ‘Moon face’
    • Truncal obesity
    • Dorsolumbar fat deposits
    • Acne
    • Violaceous skin striae
    • Impotence
    • Irregular periods
  • Cardiovascular:
  • Gastrointestinal:
  • Neuropsychiatric:
    • Psychosis
    • Insomnia
    • Mania
    • Depression
  • Immune:
    • Immunosuppression and increased susceptibility to severe infection
    • Reactivation of tuberculosis
  • Musculoskeletal:
  • Ophthalmic:
    • Cataracts
    • Increased intraocular pressure and glaucoma

Mineralocorticoid adverse effects

  • Hypertension
  • Fluid retention
  • Hypokalaemia

Cautions in surgery

Adrenal suppression due to glucocorticoid use can lead to adrenal insufficiency due to the adrenal glands not being able to respond effectively to the stresses associated with surgery.

Anaesthetists must be informed of corticosteroid use within the last 3 months. Sometimes the corticosteroid is given orally before the surgery or throughout and after surgery, depending on the situation at hand.

Cautions in infection

Due to the immunosuppressive effects of glucocorticoids, patients are more susceptible to severe infection. Patients should avoid exposure to conditions such as chickenpox and should seek help immediately if there is any exposure.

Glucocorticoids may activate or exacerbate tuberculosis.

Cautions in live vaccines

Live vaccines should not be given to patients with high doses of glucocorticoid use due to immunosuppression.

Withdrawal of steroids

Long-term use of systemic corticosteroids leads to suppression of the production of endogenous corticosteroids from the adrenal glands. They must not be stopped suddenly, as this can precipitate an adrenal crisis.

Corticosteroids should be withdrawn gradually to allow the adrenal glands to ‘wake up’ and release endogenous corticosteroids again. Withdrawal should be done if patients have:

  • Received >40 mg prednisolone daily for >1 week
  • Received >3 weeks of treatment
  • Recently received repeated courses
  • Taken a short course within 1 year of stopping long-term therapy

Aldosterone Antagonists

Overview

Example aldosterone antagonists in the UK are spironolactone and eplerenone. Their action leads to increased sodium ion and water excretion, and potassium retention, leading to a diuretic and antihypertensive effect.

Cautions

  • Patients with acute porphyria
  • Elderly patients

Contraindications

Adverse effects

  • Hyperkalaemia
  • Gynaecomastia – less common in eplerenone
  • Acute kidney injury

Interactions

  • ACE inhibitors:
    • Both can lead to hyperkalaemia, which can be potentially dangerous
  • Digoxin

Drugs Used in Type 2 Diabetes

Metformin

Metformin belongs to a class of drugs known as biguanides. Its mechanism of action involves decreasing hepatic gluconeogenesis, reducing intestinal glucose absorption, and increasing insulin sensitivity by increasing peripheral glucose uptake and metabolism.

Its adverse effects may be:

  • Gastrointestinal disturbance: (diarrhoea, nausea, anorexia)
    • This often resolves by using modified-release formulations instead of standard-release
  • B12 deficiency:
    • Seen more often in long-term use at higher doses
  • Lactic acidosis – rare but potentially fatal:
    • Presents insidiously with non-specific signs such as abdominal pain, lethargy, nausea and vomiting, and respiratory distress.

The contraindications of metformin are:

  • People at risk of lactic acidosis:

Metformin should be used with caution in the following scenarios:

  • Potential renal impairment (e.g. due to the use of nephrotoxic drugs/material such as IV contrast media) due to the risk of lactic acidosis

Sulfonylureas

Example sulfonylureas used in the UK are gliclazide, glibenclamide, glimepiride, glipizide, and tolbutamide. They work by binding to receptors in the pancreatic beta cells leading to increased insulin secretion. 

Adverse effects of sulfonylureas may be:

The contraindications of sulfonylureas are:

  • Acute porphyria
  • Ketoacidosis
  • Severe hepatic impairment (due to increased risk of hypoglycaemia)
  • Pregnancy and breastfeeding

Sulfonylureas should be used with caution in the following scenarios:

  • Mild-moderate renal/hepatic impairment – can cause hypoglycaemia
  • Obesity – can cause weight gain
  • G6PD deficiency

Pioglitazone

Pioglitazone belongs to a class of drugs called thiazolidinediones and is the only one licensed for use in the UK. It is an agonist at the peroxisome proliferator-activated receptor-gamma (PPARγ) in adipose, skeletal muscle, and liver tissue to reduce peripheral insulin resistance.

The adverse effects of pioglitazone may be:

  • Weight gain
  • Fluid retention – contraindicated in heart failure
  • Increased risk of bladder cancer
  • Increased fracture risk
  • Increased infection risk
  • Hepatic impairment – monitor LFTs

The contraindications of pioglitazone are:

  • Heart failure or history of heart failure
  • Previous or active bladder cancer
  • Uninvestigated macroscopic haematuria
  • Hepatic impairment

Pioglitazone should be used with caution in the following scenarios:

  • Elderly patients – increased risk of bladder cancer/heart failure/fractures
  • Patients that use insulin – increased risk of heart failure
  • Presence of bladder cancer risk factors
  • Presence of heart failure risk factors
  • Presence of bone fracture risk factors

SGLT-2 inhibitors

Example SGLT-2 inhibitors in the UK are canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin (-gliflozins). They work by inhibiting the sodium-glucose cotransporter 2 (SGLT2) in the proximal tubules of nephrons, leading to glucose being excreted in the urine.

Their adverse effects may be:

  • Weight loss – which may be beneficial for people who are overweight with diabetes
  • Urinary tract infections – due to glucose in the urine
  • Normoglycaemic diabetic ketoacidosis
  • Fournier’s gangrene – life-threatening necrotising fasciitis of the genitalia and perineum (more common in men)
  • Increased risk of lower limb amputation 

The contraindications of SGLT-2 inhibitors are:

  • Diabetic ketoacidosis
  • Renal impairment – eGFR <60 ml/min/1.72m2
  • Severe hepatic impairment
  • Active foot disease (e.g. ulceration, osteomyelitis, or gangrene)

SGLT-2 inhibitors should be used with caution in the following scenarios:

  • History of foot disease
  • Complicated urinary tract infections

DPP-4 inhibitors

Example DPP-4 inhibitors used in the UK are alogliptin, linagliptin, sitagliptin, saxagliptin, and vildagliptin (-gliptins). They work by inhibiting dipeptidyl peptidase-4, which slows down the breakdown of glucagon-like peptide-1 (GLP-1). GLP-1 stimulates the release of insulin from pancreatic beta cells and inhibits the release of glucagon.

Their side effects may be:

  • No weight gain:
  • Not necessarily an adverse effect, but important to note as other antidiabetic drugs affect weight
  • Gastrointestinal disturbance: abdominal pain, nausea, vomiting, diarrhoea, or constipation
  • Acute pancreatitis – stop treatment if this occurs
  • Skin rashes

The contraindications of DPP-4 inhibitors are:

  • Ketoacidosis
  • Severe hepatic impairment
  • Severe heart failure

DPP-4 inhibitors should be used with caution in the following scenarios:

  • Renal impairment
  • Hepatic impairment
  • History of pancreatitis
  • Mild-moderate heart failure

GLP-1 receptor agonists

Example GLP-1 receptor agonists used in the UK are exenatide, liraglutide, lixisenatide, dulaglutide, and semaglutide (-tides). They are given via subcutaneous injection and work by activating the GLP-1 receptor, leading to increased insulin and decreased glucagon secretion. There is also slowing of gastric emptying leading to a slower and prolonged release of glucose into the systemic circulation.

Their adverse effects may be:

  • Weight loss – which may be beneficial for people who are overweight with diabetes
  • Gastrointestinal disturbance: abdominal pain, nausea, vomiting, diarrhoea, or constipation
  • Acute pancreatitis
  • Skin rashes

The contraindications of GLP-1 receptor agonists are:

  • Ketoacidosis
  • Pancreatitis
  • Severe renal disease (eGFR <30 ml/min/1.73m2)
  • Severe hepatic impairment
  • Severe gastrointestinal disease

GLP-1 receptor agonists should be used with caution in the following scenarios:

  • History of pancreatitis – discontinue if acute pancreatitis develops
  • Renal impairment
  • Heart failure
  • Elderly people – due to weight loss

Insulin

Overview

Insulin is a peptide hormone secreted from beta cells in the Islets of Langerhans in the pancreas and is essential in the regulation of carbohydrates and fats in the body. It is secreted in response to hyperglycaemia.

Insulin has the following overall effects:

  • Decreases blood glucose concentration:
    • Stimulates glycogenolysis
    • Stimulates glucose metabolism
    • Inhibits lipolysis
  • Decreases serum potassium concentration:
    • Insulin promotes the uptake of potassium ions into cells

Secretion

Pro-insulin is made in the rough endoplasmic reticulum of the beta cells. It is then cleaved to form insulin and C-peptide before being released. This is why C-peptide is low in type 1 diabetes mellitus and can be used to differentiate it from type 2 diabetes mellitus.

Overview and classification of therapeutic insulin

Subcutaneous injections of insulin are used in the treatment of type 1 diabetes mellitus and type 2 diabetes mellitus if oral hypoglycaemic agents are insufficient.

Insulin can be classified according to its source:

  • Animal insulin – extracted and purified from animals (cows and pigs)
  • Human insulins – made with recombinant DNA technology and are the same as endogenous human insulin
  • Human insulin analogues – made with recombinant DNA technology but modified to have different kinetics (e.g. extended duration of action, faster absorption and onset of action)

Insulin can be classified according to the duration of action:

  • Short-acting insulins:
    • Rapid-acting insulin (e.g. insulin aspart, insulin glulisine, insulin lispro:
      • Generally injected immediately before meals
      • Onset: 15 minutes
      • Duration: 2-5 hours
    • Soluble insulin:
      • Generally injected 15-30 minutes before meals
      • Onset: 30-60 minutes
      • Peak: 1-4 hours
      • Duration: up to 9 hours
  • Intermediate-acting insulin (e.g. isophane insulin):
    • Designed to mimic the effect of endogenous basal insulin. Taken as one or more daily injections with separate mealtime short-acting insulin or mixed with short-acting insulin in the same syringe.
    • Onset: 1-2 hours
    • Peak: 3-12 hours
    • Duration: 11-24 hours
  • Long-acting insulin analogues (e.g. insulin detemir, insulin glargine, insulin degludec):
    • Designed to mimic endogenous basal insulin and given once daily or twice daily depending on the analogue used and patient requirements.
    • Duration: up to 36 hours

Premixed insulins (e.g. biphasic insulins) with combinations of short-acting and intermediate-acting insulins are also available.

Patients taking insulin use a mixture of short- and long-acting insulin preparations to maintain normoglycaemia.

Adverse effects

  • Hypoglycaemia
  • Lipodystrophy – lumps/scarring at the injection site
    • Occurs due to repeated injection in the same site and can reduce absorption
    • Prevented by changing the location of the injection site

Glucagon

Glucagon is a peptide hormone that has opposing effects on blood glucose concentration to insulin. It is secreted from alpha cells in the Islets of Langerhans in the pancreas and acts to increase blood glucose concentration. It does this through:

  • Glycogenolysis
  • Gluconeogenesis
  • Lipolysis

Antithyroid Drugs

Carbimazole

Carbimazole is an antithyroid drug that decreases the uptake of iodine by the thyroid gland, leading to reduced thyroid hormone production. It can have the following adverse effects:

Propylthiouracil

Propylthiouracil is another type of antithyroid drug that binds to thyroid peroxidase and inhibits the conversion of iodide to iodine, leading to reduced thyroid hormone production. Carbimazole is preferred where possible. It can have the following adverse effects:

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