Endocrine and reproductive systems

6 Endocrine and reproductive systems

After reading this chapter, you will:

• Understand the main functions of the endocrine and reproductive systems

• Know which drugs affect the functioning of these systems and how

• Be aware of indications, contraindications and adverse drug reactions.

The thyroid gland

Basic concepts

Production of thyroid hormones

The thyroid gland secretes three hormones, triiodothyronine (T₃), thyroxine (T₄) and calcitonin.

The principal effects of the thyroid hormones are: determination of basal metabolic rate and influence of growth through stimulation of growth hormone synthesis and action. Other effects are summarized in Figure 6.1.

Fig. 6.1 Physiological effects of thyroid hormones

From Page et al. 2006.

The follicular cells of the thyroid gland synthesize and glycosylate thyroglobulin before secreting it into their lumen. Iodination of the tyrosine residues on this molecule is catalysed by thyroid peroxidase and results in the formation of monoiodotyrosine (MIT) or diiodotyrosine (DIT), according to the position on the ring at which this occurs. The coupling of MIT with DIT produces T₃, and the coupling of two DIT molecules produces T₄. Coupling is also catalysed by thyroid peroxidase.

Thyroglobulin, now known as colloid, is endocytosed into the follicular cells, where it is broken down to release T₃, T₄, MIT and DIT T₃ and T₄ are secreted into the plasma; MIT and DIT are metabolized within the cells and their iodide is recycled (Fig. 6.2).

Fig. 6.2 Synthesis of thyroid hormones and the site of action of some antithyroid drugs. (DIT, diiodotyrosine; MIT, monoiodotyrosine; PTU, propylthiouracil; T₃, triiodothyronine; T₄, thyroxine; TSH, thyroid-stimulating hormone.)

(From Page et al. 2006.)

The iodine required for the synthesis of T₃ and T₄ comes mainly from the diet in the form of iodide. Through the action of a thyrotrophin-dependent pump, iodide is concentrated in the follicular cells, where it is converted into iodine by thyroid peroxidase.

Control of thyroid hormone secretion

The hypothalamus contains thyroid-hormone receptors that are able to detect and respond to decreased levels of T₃ and T₄ by causing the release of thyrotrophin-releasing hormone (TRH). TRH reaches the anterior pituitary via the portal circulation and stimulates TRH receptors on thyrotroph cells which in turn secrete thyroid-stimulating hormone (TSH).

TSH reaches the thyroid gland through the systemic circulation where it stimulates thyroid hormone secretion (Fig. 6.3). Both T₃ and T₄ bind to proteins in the plasma (mostly thyroxine-binding globulin), and less than 1% of total thyroid hormones are free. It is the free thyroid hormones which exert the physiological effects. T₃ is about five times more biologically active than T₄, and T₄ is converted to T₃ in some peripheral tissues.

Fig. 6.3 Hypothalamic–pituitary–thyroid axis: control of thyroid hormone synthesis. (T₃, triiodothyronine; T₄, thyroxine; TSH, thyroid-stimulating hormone; TRH, thyrotrophin-releasing hormone.)

(Redrawn from Page et al. 2006.)

T₃ and T₄ exert negative feedback on the hypothalamus and pituitary.

Most modern laboratory thyroid function tests measure just TSH, although levels of free and total T₃ and T₄ can be measured as well as thyroxine-binding globulin.

Thyroid dysfunction

Hypothyroidism

Hypothyroidism, thyroid insufficiency, is relatively common in adults and associated with tiredness and lethargy, weight gain, intolerance to cold, dry skin, bradycardia and mental impairment. Children with hypothyroidism manifest delayed bone growth, whereas a deficiency in utero also results in mental retardation – this condition is known as cretinism.

Hashimoto’s thyroiditis is an autoimmune disease resulting in fibrosis of the thyroid gland. It is the most common cause of hypothyroidism and, like most autoimmune diseases, is more prevalent in women. Myxoedema is also immunological in origin, and represents the most severe form of hypothyroidism, sometimes causing coma.

Thyroid-hormone resistance and reduced TSH secretion will also produce the symptoms of hypothyroidism.

The causes of hypothyroidism are summarized in Figure 6.4.

Fig. 6.4 Causes of hypothyroidism

From Page et al. 2006.

Management of hypothyroidism

Liothyronine sodium (L-triiodothyronine sodium)

As liothyronine is bound only slightly by thyroid binding globulin, it has a more rapid onset of effects and a shorter duration of action than levothyroxine.

Hyperthyroidism

Hyperthyroidism, thyroid excess, results either from the overproduction of endogenous hormone or exposure to excess exogenous hormone. Symptoms include increased basal metabolic rate (BMR) with consequent weight loss, increased appetite, increased body temperature, and sweating, as well as nervousness, tremor, tachycardia and classic ophthalmic signs.

Graves’ disease (diffuse toxic goitre) is the most common cause of hyperthyroidism. It is an autoimmune disease caused by the activation of TSH receptors by antibodies. This results in an enlargement of the gland and therefore excess hormone production.

Toxic nodular goitre is the second most common cause of hyperthyroidism. It is due to either a single adenoma (hyperfunctioning adenoma) or multiple adenomas (multinodular goitre).

The causes of hyperthyroidism are summarized in Figure 6.5.

Fig. 6.5 Causes of hyperthyroidism

From Page et al. 2006.

Mrs Akasuki, 41 years old, presents to her GP with tremor and weight loss of 6.5 kg (1 stone) over 4 weeks, despite increased appetite. She admits to feeling hot and sweaty both day and night, which has affected her sleep. On examination a diffuse goitre is seen. Her pulse is rapid and she has noticeable exophthalmos. A pregnancy test is negative. A blood sample is taken and reveals an elevated serum T₃ and T₄ with suppressed TSH levels. Mrs Akasuki is diagnosed as having hyperthyroidism. She is given propanolol for her symptoms and is started on carbimazole to suppress her thyroid. After 4 weeks she is reviewed and checked for neutropenia, a possible dangerous side-effect of carbimazole treatment.

Management of hyperthyroidism

Thioureylenes

The thioureylenes are the first-line drugs for treatment of hyperthyroidism. Carbimazole, thiamazole, and propylthiouracil (PTU) are examples of thioureylenes.

In the body, carbimazole is rapidly converted to active compound thiamazole.

Mechanism of action

The thioureylenes cause inhibition of thyroid peroxidase with a consequent reduction in thyroid hormone synthesis and storage (see Fig. 6.2). The effects of PTU may take several weeks to manifest as the body has stores of T₃ and T₄. PTU also inhibits the peripheral deiodination of T₄ to T₃.

Route of administration

Indications

Thioureylenes are used for hyperthyroidism. Patients sensitive to carbimazole are given PTU.

Contraindications

Thioureylenes should not be given to people with a large goitre. PTU should be given at a reduced dose in patients with renal impairment.

Adverse effects

Nausea and headache; allergic reactions, including rashes; hypothyroidism; and, rarely hepatotoxicity, bone marrow suppression, alopecia.

Therapeutic regimen

Carbimazole is given at 20–60 mg daily until the patient is euthyroid (4–11 weeks later), then the dose is progressively reduced to a maintenance level of 5–15 mg daily. Treatment is usually given for 18 months. PTU is given at 300–600 mg daily until the patient is euthyroid, then the dose is progressively reduced to a maintenance level of 50–150 mg daily.

Anion inhibitors

Iodine, iodide and potassium perchlorate are examples of anion inhibitors.

Potassium perchlorate inhibits the uptake of iodine by the thyroid (see Fig. 6.2), but is no longer used owing to the risk of aplastic anaemia.

Iodide is the most rapidly acting treatment against thyrotoxicosis and is given in thyrotoxic crisis (thyroid storm).

Radioiodine

The use of radioactive iodine to treat hyperthyroidism is not classically considered pharmacology, although it is used in the management of thyroid disorders.

The endocrine pancreas and diabetes mellitus

Control of plasma glucose

Blood glucose levels are maintained at a concentration of about 5 mmol/L, and usually do not exceed 8 mmol/L. A plasma glucose concentration of 2.2 mmol/L or less may result in hypoglycaemic coma and death due to a lack of energy reaching the brain. A plasma glucose concentration of more than 10 mmol/L exceeds the renal threshold for glucose and means that glucose will be present in the urine. Osmotic diuresis then occurs.

The islets of Langerhans, located in the pancreas, contain glucose receptors and secrete the hormones glucagon and insulin. These hormones are short-term regulators of plasma glucose levels with opposite effects. In addition, their release can be influenced by gastrointestinal hormones and autonomic nerves.

Glucose receptors are also found in the ventro-medial nucleus and lateral areas of the hypothalamus. These are able to regulate appetite and feeding, and also indirectly stimulate the release of a variety of hormones, including adrenaline, growth hormone and cortisol, all of which affect glucose metabolism.

The hormones involved in blood glucose regulation target the liver, skeletal muscle and adipose tissue.

Insulin

Insulin is a 51 amino acid peptide made up of an α- and a β-chain linked by disulphide bonds. It has a half-life of 3–5 minutes and is metabolized to a large extent by the liver (40–50%), but also by the kidneys and muscles.

In response to high blood glucose levels (as occurs after a meal), as well as to glucosamine, amino acids, fatty acids, ketone bodies and sulphonylureas, the β-cells of the endocrine pancreas secrete insulin along with a C-peptide.

Insulin release is mediated by ATP-dependent potassium channels, located in the membrane of the β-cells. These close in response to elevated cytoplasmic ATP and decreased cytoplasmic ADP levels, resulting in depolarization of the membrane. This triggers calcium entry into the cell through voltage-dependent calcium channels, and subsequent insulin release (Fig. 6.6).

Fig. 6.6 Mechanism of insulin secretion from pancreatic β-cells.

Insulin release is inhibited by low blood glucose levels, growth hormone, glucagon, cortisol and sympathetic nervous system activation.

The insulin receptor consists of two α and two β subunits linked by disulphide bonds. Insulin binds to the extracellular α subunits, resulting in the internalization of the receptor and its subsequent breakdown. The β subunits display tyrosine kinase activity on the binding of insulin to the receptor. Autophosphorylation of the β subunits ensues, resulting in the phosphorylation of phospholipase C with subsequent liberation of diacylglycerol (DAG) and inositol triphosphate (IP₃).

The effects of insulin are summarized in Figure 6.7.

Fig. 6.7 Metabolic effects of insulin on fuel homeostasis

From Page et al. 2006.

Mrs Raye, 26 years, is 25 weeks into her first pregnancy. Her body mass index (BMI) is 30 and there is a family history of both diabetes and stroke. She is found to have glucose in her urine on routine testing. She has an oral glucose tolerance test. Her fasting plasma glucose is 4.7 mmol/L and her 2 hours post glucose load level is 12.1 mmol/L, indicative of diabetes. The test should be repeated to confirm the result, however, prompt action is also required to prevent harm to the fetus. There is a higher chance of congenital abnormalities with elevated plasma glucose concentrations. Fetal ultrasound is used to exclude this. Mrs Raye is told to try a diabetic diet with small and frequent meals. Since she is overweight, her diet should also be calorie-restricted. After 4 days it is noted this has not worked and insulin injections are started. Her insulin regimen is insulin aspart (rapid and short action), before meals and isophane insulin (delayed onset and intermediate length of action), at breakfast and bedtime. She is warned about symptoms of hypoglycaemia and told to eat if she recognizes them.

Diabetes mellitus

Diabetes mellitus is characterized by an inability to regulate plasma glucose within the normal range. There is an absolute or relative insulin deficiency leading to hyperglycaemia, glycosuria (glucose in the urine), polyuria (production of large volumes of dilute urine) associated with cellular potassium depletion and polydipsia (intense thirst).

There are two types of diabetes mellitus:

• Insulin-dependent (Type 1; IDDM)

• Non-insulin-dependent (Type 2; NIDDM).

The differences between the two types are summarized in Figure 6.8.

Fig. 6.8 Features of type 1 and type 2 diabetes mellitus

The long-term consequences of both types of diabetes are similar, and include increased risk of cardiovascular and cerebrovascular events, peripheral and autonomic neuropathy, nephropathy and retinopathy.

Type 1 diabetes

In type 1 diabetes, pancreatic β-cells are destroyed by an autoimmune T-cell attack. This leads to a complete inability to secrete insulin and ketoacidosis is a problem. Some untreated patients have a plasma glucose concentration of up to 100 mmol/L due to insulin deficiency. In this situation, lipolysis is increased, as is the production of ketone bodies from fatty acids. This leads to ketonuria and metabolic acidosis; body fluids become hypertonic, resulting in cellular dehydration, and eventually in hyperosmolar coma.

Type 1 diabetes is apparent at a young age.

Type 2 diabetes

In type 2 diabetes, insulin is often secreted as on average 50% of the β-cells remain active, although there is also peripheral resistance to insulin. Unlike type 1 diabetes, this is relatively common in all populations enjoying an affluent life-style. The prevalence of type 2 diabetes increases with age and the degree of obesity.

Ketosis is not a feature of type 2 diabetes as ketone production is suppressed by the small amounts of insulin produced by the pancreas. Hyperosmolar non-ketotic coma is the type 2 diabetes equivalent to ketoacidosis, and can be fatal if untreated, although responds rapidly to fluids and insulin.

Secondary diabetes mellitus

Not to be confused with type 2 diabetes, secondary diabetes mellitus accounts for less than 2% of all new cases of diabetes, and is most commonly due to pancreatic disease (pancreatitis, carcinoma, cystic fibrosis), endocrine disease (Cushing’s syndrome, acromegaly) or drug-induced (thiazide diuretics or corticosteroid therapy).

Management of diabetes mellitus

Insulin

The aim of exogenous insulin preparations is to mimic basal levels of endogenous insulin and meal-induced increases in insulin.

Nowadays the insulin preparation used is mostly the human (recombinant) insulin (however, insulin preparations of bovine origin are also available). Insulin is available as short-, intermediate-, and long-acting preparations (Figure 6.9).

Fig. 6.9 Insulin preparations

Short-acting insulins are soluble. These preparations most resemble endogenous insulin, and can be given intravenously in hospital. The rapid-acting insulins aspart and lispro have a faster onset and shorter duration of action than the traditional short-acting insulin. Exubera^® is a short-acting insulin in the form of an inhaled powder, which could potentially eliminate the need for multiple injections. However, as yet it has not replaced the standard route of administration. Furthermore, patients must have stopped smoking for 6 months prior to commencement of Exubera^® and must not also have severe lung disease.

Intermediate- and long-acting insulins are not as soluble as the short-acting preparations. Their solubility is decreased by precipitating the insulin with zinc or protamine (a basic protein), which prolongs their release into the blood stream.

Mechanism of action

Insulin preparations mimic endogenous insulin.

Route of administration

Insulin must always be given parenterally (intravenously, intramuscularly or subcutaneously), as it is a peptide and thus destroyed in the gastrointestinal tract. Short-acting insulin is given intravenously in emergencies, but administration of the insulin preparations in maintenance treatment is usually subcutaneous.

Indications

Type 1 diabetes; type 2 diabetes uncontrolled by other means.

Adverse effects

Local reactions and, in overdose, hypoglycaemia. Protamine can cause allergic reactions. Rarely, there may be immune resistance.

Therapeutic notes

Preparations are now available which contain mixtures of short and intermediate-and long-acting insulins, allowing patients to inject themselves only once each time they administer their insulin.

Oral hypoglycaemics

Oral hypoglycaemics act to lower plasma glucose. The sulphonylureas and the biguanides are the main drugs used from this class, but newer drugs are also now available.

Sulphonylureas

Gliclazide, tolbutamide, chlorpropamide and glibenclamide are examples of sulphonylureas.

Mechanism of action

Sulphonylureas block ATP-dependent potassium channels in the membrane of the pancreatic β-cells, causing depolarization, calcium influx and insulin release.

Route of administration

Indications

Sulphonylureas are given for diabetes mellitus, in patients with residual β-cell activity.

Contraindications

Breastfeeding women, or people with ketoacidosis. Long-acting sulphonylureas (chlorpropamide, glibenclamide) should be avoided in elderly people and in those with renal and hepatic insufficiency, as these drugs can induce hypoglycaemia.

Adverse effects

Weight gain; sensitivity reactions, including rashes; gastrointestinal disturbances; headache; hypoglycaemia.

Therapeutic regimen

Tolbutamide is given at 500 mg two or three times daily and lasts for 6 hours; chlorpropamide is given at 100–250 mg daily and lasts for 12 hours; and glibenclamide is given at 2.5–15 mg daily and lasts for 12 hours.

Biguanides

Metformin is the only drug in this class.

Mechanism of action

Metformin increases the peripheral utilization of glucose, by increasing uptake, and decreasing gluconeogenesis. To work, metformin requires the presence of endogenous insulin; thus, patients must have some functioning β-cells.

Route of administration

Indications

Type 2 diabetes where dieting and sulphonylureas have proved ineffective.

Contraindications

Metformin should not be given to patients with hepatic or renal impairment (owing to the risk of lactic acidosis) or heart failure.

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Tags: Crash Course Pharmacology

Apr 8, 2017 | Posted by admin in PHARMACY | Comments Off

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