Pharmacogenomics In Endocrine Pharmacology Notes

Endocrine Pharmacology Introduction

The hormone is a substance produced by specialized cells in specific glands and transported to a distance where it acts on target tissues.

1. Types of hormones
   • Peptides: Hypothalamic regulatory hormones, pituitary hormones, insulin, glucagon, parathyroid hormones.
   • Steroids: Adrenocortical hormones, sex steroids.
   • Catecholamines: Adrenaline, noradrenaline.
   • Others: Thyroxine (T₄), and triiodothyronine (T₃).
2. Site and mode of action of hormones Hormones act on their specific receptors situated:
   • On the cell membrane:

Read And Learn More: Pharmacology for Dentistry Notes

• • • Some hormones bind with the cell membrane receptors and increase cAMP concentration, for example, catecholamines, most of the peptide hormones.
    • Some hormones cause inhibition of cAMP production by binding to cell membrane receptors, for example, somatostatin.
  • In the cytoplasm:
• 
  • In the nucleus:

Hypothalamic And Pituitary Hormones

Hypothalamic Regulatory Hormones

The hypothalamus produces releasing and inhibitory hormones that control pituitary secretion. The hypothalamus controls the secretion of the anterior pituitary through portal circulation that carries the releasing and inhibitory hormones. The posterior pituitary is the direct extension of the hypothalamus.

Anterior Pituitary Hormones

1. Growth hormone (GH).
2. Prolactin (PRL).
3. Gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]).
4. Adrenocorticotropic hormone (ACTH).
5. Thyrotropin- or thyroid-stimulating hormone (TSH).
6. Melanocyte-stimulating hormone (MSH)

Thyroid Hormones And Antithyroid Drugs

The hormones secreted by the thyroid gland are thyroxine (T₄), triiodothyronine (T₃) and calcitonin. The thyroid follicular cells have specialized mechanisms for the synthesis of thyroid hormones. This is regulated by TSH secreted by the anterior pituitary, which, in turn, is inhibited by free thyroid hormone levels. The ‘C’ cells of the thyroid secrete calcitonin which is a functionally distinct hormone regulating calcium metabolism.

A deficiency of thyroid hormones in children results in cretinism characterized by mental retardation and other features of hypothyroidism; in adults, it results in myxoedema. Hypersecretion of these hormones also has effects on various organ systems resulting in ‘thyrotoxicosis’.

• Features of Hyperthyroidism and Hypothyroidism

Thyroid Hormones

1. Synthesis of thyroid hormones
   • Iodide trapping: Active transport of iodide ions (I^–) into follicular cells of the thyroid gland is known as iodide trapping and takes place by a basement membrane protein called the sodium/iodide symporter.
   • Oxidation and iodination: The iodide ion is oxidized to iodine by the peroxidase enzyme. Iodine combines with tyrosine residues of thyroglobulin molecule and forms monoiodotyrosine (MIT) and diiodotyrosine (DIT).
   • Coupling: This is the final step in the synthesis of thyroid hormones; this is catalysed by thyroid peroxidase. Two molecules of DIT couple to form thyroxine (T₄), and one molecule of MIT with one molecule of DIT forms triiodothyronine (T₃).
   • MIT + DIT → T₃ ; DIT + DIT → T₄
   • Hormone release: The release of thyroid hormones takes place under the control of TSH. The process involves endocytosis and proteolysis of iodinated thyroglobulin and results in the release of T₄, T₃, MIT and DIT.
   • Peripheral conversion of T₄ to T₃: Most of the hormone released from the thyroid is T₄, which is less potent than T₃. Conversion of T₄ to T₃ in the periphery is inhibited by propylthiouracil, iopanoic acid, propranolol and glucocorticoids.
     • Differences between T₃ and T₄
       
       
2. Mechanism of action The mechanism of action of thyroid hormones is similar to that of steroid hormones. Thyroxine needs to be converted into T₃ inside the cell for binding to the nuclear receptor.

1. Preparations
   • Levothyroxine sodium (T₄): Tablets and parenteral preparation (i.v.).
   • Liothyronine (T₃, triiodothyronine): Oral tablets, parenteral preparation (not commonly available).
2. Therapeutic uses: Replacement therapy in hypothyroid states
   • Cretinism and myxoedema: For cretinism, treatment of newborns should be started as early as possible after birth to ensure normal growth and cognitive development. In young adults with hypothyroidism, full replacement doses of levothyroxine sodium can be administered (50–100 mcg daily as a single dose orally in the morning on an empty stomach). The goal of the therapy is to relieve symptoms and restore serum TSH to normal levels; treatment is for a lifetime.
   • Myxoedema coma: This is a medical emergency and is usually common in long-standing untreated myxoedema cases. It is treated with levothyroxine, intravenously (i.v.) if available, otherwise via nasogastric tube.
   • Thyroid carcinoma: In papillary carcinoma, thyroid hormone administration suppresses TSH levels and prevents its stimulation of the growth of the tumour.

Antithyroid Drugs

These drugs reduce the level of thyroid hormones by reducing thyroid hormone synthesis or release or both. These drugs play an important role in the management of hyperthyroidism caused by both benign and malignant conditions of the thyroid gland.

• Classification
  • Thyroid hormone synthesis inhibitors (thioamide derivatives): Propylthiouracil, methimazole, carbimazole.
  • Inhibitors of iodide trapping: Thiocyanates, perchlorates
  • Hormone-release inhibitors: Iodine, iodides of Na⁺ and K⁺, organic iodide.
  • Thyroid tissue-destroying agent: Radioactive iodine (¹³¹I).
  • Others: Propranolol, diltiazem, dexamethasone.

1. Thioamides (thiourea derivatives) Propylthiouracil, methimazole and carbimazole are thioamides used to treat hyperthyroidism. Their mechanism of action is depicted in Fig.
   • Mechanism of action of thioamides
     • Thioamides act by inhibiting
       1. Thyroid peroxidase enzyme, which converts iodide to iodine.
       2. Iodination of tyrosine residues in thyroglobulin.
       3. Coupling of iodothyronine (MIT and DIT).
          • Propylthiouracil also inhibits the peripheral deiodination of T₄ to T₃. Other thioamides do not have this action.
   • Pharmacokinetics Thioamides are well absorbed orally. Propylthiouracil is most rapidly absorbed. Carbimazole is converted to methimazole after absorption.
     • They are widely distributed but accumulate in the thyroid gland. They are excreted in the urine. Both propylthiouracil and methimazole are safe for use in pregnancy.
   • Adverse effects Skin rashes are the most common. The other side effects are joint pain, fever, hepatitis, nephritis, etc. A dangerous but rare adverse effect is agranulocytosis, which usually occurs during the first few weeks or months of therapy; but it may occur later also.
   • Uses
     • For long-term treatment of hyperthyroidism due to Grave’s disease/toxic nodular goitre, in which surgery is not indicated or not feasible and radioactive iodine is contraindicated.
     • Along with radioactive iodine to hasten recovery in thyrotoxicosis.
     • Preoperatively in thyrotoxic patients before partial thyroidectomy.
     • For treatment of thyrotoxic crisis.
2. Iodine and iodides Iodides are the oldest agents used to treat hyperthyroidism. They inhibit almost all steps in the synthesis of thyroid hormones, but the major effect is the inhibition of the release of thyroid hormones.
   • Preparations and uses
     • Lugol’s iodine (5% iodine in 10% solution of KI): It is used orally preoperatively before thyroidectomy and in thyroid storm. It renders the gland firm, and less vascular and decreases its size, which makes surgery convenient with less bleeding and complications.
     • As an expectorant: Potassium iodide (KI) acts as a mucolytic agent that enhances expectoration.
     • As an antiseptic: Tincture of iodine (iodine in alcohol).
     • Prophylaxis of endemic goitre: Iodized salt is used.
   • Adverse effects
     • Allergic reactions: Angioedema, laryngeal oedema, arthralgia, fever, eosinophilia and lymphadenopathy may occur acutely (type-3 hypersensitivity). Chronic overdose with iodide results in iodism. The symptoms are headache, sneezing and irritation of the eyes with swelling of the eyelids. These resolve after a few days of stopping iodine.
3. Radioactive iodine
   • Therapeutically used radioactive iodine is ¹³¹I. Sodium iodide ¹²³I is used for diagnostic scans.
   • Radioactive iodine gets concentrated in the same way as stable iodine in the thyroid and emits γ-rays and β-particles. The β-particles cause the destruction of the follicular cells leading to fibrosis and correction of the hyperthyroid state.
     • Preparation ¹³¹I is used orally as a solution or capsule. The dose is expressed in microcurie.
     • Uses and contraindications Radioactive iodine is used for the treatment of hyperthyroidism. It is contraindicated in pregnant women, children and nursing mothers.
     • Advantages
       1. Treatment is simple; does not require hospitalization – and can be done in the outpatient department.
       2. Low cost.
       3. No risk of surgery and scarring.
       4. Permanently cures hyperthyroidism.
     • Disadvantages
       1. It is slow-acting. The incidence of hypothyroidism is high.
4. β-Adrenoceptor blockers (β-blockers) Propranolol, metoprolol and atenolol can be used. They produce dramatic improvement in symptoms of thyrotoxicosis like tachycardia, palpitation and tremors. Propranolol also has an inhibitory effect on the peripheral conversion of T₄ to T₃.
   • Uses
     • To control symptoms of thyrotoxicosis initially till antithyroid drugs act.
     • In thyrotoxic crisis.
     • Preoperatively before thyroid surgery.

Anabolic Steroids

Anabolic steroids promote protein synthesis and increase muscle mass, resulting in weight gain. They are synthetic androgens with greater anabolic and lesser androgenic activity.

Testosterone has a potent anabolic effect, but it cannot be used because of its strong androgenic effect. The ratio of anabolic to androgenic activity with testosterone is

Some of the commonly used anabolic steroids are Nandrolone (i.m.), Oxandrolone (oral), Stanozolol (oral), Ethylestrenol (oral) and Methandienone (oral, i.m.) [Mnemonic: NOSE].

1. Uses
   • In chronic illness, to improve appetite and feeling of well-being.
   • During recovery from prolonged illness, surgery, burns, trauma or chronic debilitating diseases.
   • In postmenopausal and senile osteoporosis.
     • Anabolic steroids are often misused by athletes to increase muscle strength and athletic performance, hence they are included in the ‘dope test’.
2. Adverse effects
   • In females, androgens cause hirsutism, menstrual irregularities, breast atrophy, acne and deepening of voice.
   • In children, impairment of growth is due to premature closure of epiphyses.
   • Sodium and water retention lead to oedema.

Corticosteroids

The adrenal gland has a cortex and medulla. Adrenal cortex secretes steroidal hormones; adrenal medulla secretes adrenaline and noradrenaline. Hormones of the adrenal cortex are given in Table.

• Anatomical and Functional Divisions of Adrenal Cortex

Synthesis and release of glucocorticoids is controlled by pituitary adrenocorticotropic hormone (ACTH), which in turn is stimulated by a corticotrophin-releasing factor (CRF) produced by the hypothalamus. Glucocorticoids have negative feedback control on ACTH and CRF secretion.

Mineralocorticoid (for example aldosterone) release is controlled by the renin-angiotensin system. There is a diurnal variation in the rate of release of ACTH and cortisol (circadian rhythm). The plasma cortisol levels are highest in the early hours of the morning and the lowest in the late evening. During stress, glucocorticoid secretion is increased.

1. Mechanism of action of steroid hormones The mechanism of action of steroid hormones is depicted in Fig.
   
   • Classification and important features of corticosteroids:
   • Comparison of Corticosteroids Using Hydrocortisone as a Standard
     
     
     
2. Pharmacological actions
   • Corticosteroids with predominant sodium- and water-retaining properties, for example, aldosterone and desoxycorticosterone are mineralocorticoids.
   • Corticosteroids with predominant liver glycogen deposition and gluconeogenic effects, for example, hydrocortisone (cortisol) and cortisone, are glucocorticoids.
   • The two actions (mineralocorticoid and glucocorticoid) are not completely separated in naturally occurring steroids, whereas synthetic preparations are available with selective action.
     • Carbohydrate metabolism The net result is:
       1. hyperglycaemia,
       2. decreased tissue sensitivity to insulin and
       3. diabetes may be exacerbated. Therefore, glucocorticoids are (relatively) contraindicated in diabetics.
     • Lipid metabolism Prolonged use of glucocorticoids causes a redistribution of body fat that is deposited over the neck, face, shoulder, etc. resulting in ‘moon face’, ‘buffalo hump’ and ‘fish mouth’ with thin limbs.
     • Protein metabolism
     • Electrolyte and water metabolism Glucocorticoids have weak mineralocorticoid action, cause sodium and water retention; promote potassium excretion.
       • Thus, prolonged use of these drugs may cause oedema and hypertension.
       • Some of the synthetic glucocorticoids (dexamethasone, betamethasone, and triamcinolone) have no sodium- and water-retaining properties.
     • Calcium metabolism (anti-vitamin D action) Prolonged use of these drugs may lead to osteoporosis and pathological fracture of vertebral bodies.
     • Cardiovascular system Glucocorticoids have sodium- and water-retaining properties; and exert a permissive effect on the pressure action of adrenaline and angiotensin. On chronic administration, these drugs may cause hypertension and worsening of congestive cardiac failure (CCF).
     • Skeletal muscle Corticosteroids are required for the normal function of skeletal muscles. Weakness occurs in both hypocorticism and hypercorticism. Prolonged use of glucocorticoids may cause muscle wasting and weakness (steroid myopathy).
     • Central nervous system Corticosteroids have a number of indirect effects on CNS through the maintenance of blood pressure, blood glucose concentration and electrolyte levels.
       • They also have direct effects on the CNS and influence mood and behaviour. Patients with Addison’s disease show depression, irritability and even psychosis. On the other hand, glucocorticoid therapy can cause euphoria, insomnia, restlessness and psychosis.
     • Gastrointestinal tract
     • Blood and lymphoid tissue Glucocorticoid therapy leads to a decrease in the number of circulating lymphocytes, eosinophils, basophils and monocytes. This is due to the redistribution of cells. They have a marked lymphocytic action; therefore, they are used in lymphomas and leukaemias.
     • Anti-inflammatory effect They have powerful anti-inflammatory and immunosuppressant effects. They prevent or suppress the clinical features of inflammation such as redness, heat, pain and swelling. At the tissue level, they suppress the early phenomena (capillary permeability, oedema, cellular infiltration and phagocytosis) and late responses like capillary proliferation, collagen deposition, fibroblast activity and scar formation.
       1. Glucocorticoids induce a protein called lipocortin, which inhibits phospholipase A₂, hence prostaglandins (PGs), leukotrienes (LTs) and PAF are not formed.
       2. Production of cytokines like IL-1, IL-6 and TNF-α necessary for initiating inflammation is inhibited.
       3. Chemotaxis is suppressed.
       4. Glucocorticoids stabilize the lysosomal membrane and prevent the release of inflammatory mediators.
       5. Glucocorticoids inhibit the expression of various adhesion molecules on endothelial cells, thus inhibiting leukocyte migration to the site of injury.
     • Immunosuppressant effect Glucocorticoids have an immunosuppressant effect. They inhibit both B-cell and T-cell lymphocyte functions, and this results in impairment of humoral and cell-mediated immunity.
       • Cell-mediated responses are suppressed indirectly by inhibiting the production of cytokines, including TNF-α and interleukins. They also suppress all types of hypersensitivity or allergic reactions.
3. Adverse reactions A single dose of glucocorticoids is practically harmless; rather they are life-saving drugs in conditions like anaphylactic shock and acute adrenal insufficiency. The use of glucocorticoids in supraphysiological doses for more than 2–3 weeks causes a number of undesirable effects. Most of the adverse effects are extensions of pharmacological actions.
   • Metabolic effects: Hyperglycaemia, or aggravation of pre-existing diabetes.
   • Cushing’s habitus: Abnormal fat distribution causes peculiar features with moon face, buffalo hump and thin limbs.
   • Gastrointestinal tract: Peptic ulceration, sometimes with haemorrhage or perforation.
   • Salt and water retention: Mineralocorticoid effect may cause oedema, hypertension and even precipitation of CCF, particularly in patients with primary hyperaldosteronism. This can be minimized by using synthetic steroids like dexamethasone and betamethasone.
   • Muscle: Steroid treatment can cause hypokalaemia leading to muscle weakness and fatiguability. Long-term steroid therapy leads to steroid myopathy.
   • Bone: Osteoporosis with pathological fractures of vertebral bodies is common. Ischaemic necrosis of the femoral head can also occur.
   • Growth retardation in children is more common with dexamethasone and betamethasone.
   • Eye: Glaucoma and cataracts may occur on prolonged therapy.
   • Central nervous system: Behavioural disturbances like nervousness, insomnia, mood changes and even psychosis may be precipitated.
   • Long-term therapy with steroids leads to immunosuppression, which makes the patient vulnerable to opportunistic infections like fungal (candidiasis, cryptococcosis), viral (herpes, viral hepatitis) and bacterial (reactivation of latent tuberculosis). Inhalational steroids can cause local irritation and fungal infection of the upper respiratory tract, which can be prevented by the use of a spacer and by rinsing the mouth after inhalation.
   • Hypothalamo-pituitary-adrenal (HPA) axis suppression: The most dangerous side effect of long-term steroid therapy is HPA axis suppression. Long-term use of corticosteroids in large doses will decrease ACTH secretion through negative feedback effects on the hypothalamus and pituitary, which results in adrenal cortical atrophy. Hence, abrupt stoppage of glucocorticoid therapy following prolonged use leads to:
     • Flaring up of the underlying disease being treated.
     • Withdrawal symptoms like fever, myalgia, arthralgia and malaise.
     • Acute adrenal insufficiency on exposure to stress manifests as anorexia, nausea, vomiting, abdominal pain, hypotension, dehydration, hyponatraemia, hyperkalaemia, etc.
       • Therefore, important precautions to be taken during long-term steroid therapy to minimise HPA axis suppression are as follows:
         1. Whenever possible, topical use is preferred.
         2. Short- or intermediate-acting steroids (for example hydrocortisone, prednisolone)should be preferred.
         3. Give steroids as a single morning dose at 8 a.m.; if the daily dose is high, administer two-thirds of the dose in the morning and one-third in the evening, which will mimic endogenous hormone levels and minimize the chances of HPA axis suppression.
         4. Try alternate-day steroid therapy in chronic conditions like bronchial asthma, nephrotic syndrome and systemic lupus erythematosus (SLE).
         5. Withdrawal of steroids after long-term (>2 weeks) treatment should be very slow to allow recovery of normal adrenocortical function. The doses of steroids should be tapered gradually and then stopped. It will take days/weeks or even longer for the HPA axis to recover after the stoppage of therapy. During this period, a patient will require treatment with steroids on exposure to stress.
4. Therapeutic uses of glucocorticoids
   • Replacement therapy
     • Acute adrenal insufficiency: It is a medical emergency. It is treated with i.v. hydrocortisone and i.v. normal saline with 5% glucose to correct fluid and electrolyte imbalance. Precipitating causes such as trauma, infection or haemorrhage should be treated.
     • Chronic adrenal insufficiency: Treated with oral hydrocortisone (two-thirds of the daily dose is given in the morning and one-third in the evening) along with adequate salt and water.
   • Nonendocrine diseases Corticosteroids are an important group of drugs used clinically in a variety of diseases.
     • Because of their dramatic symptomatic relief, they are often misused. Nonendocrine diseases require supraphysiological doses of steroids.
     • The beneficial effects of glucocorticoids are mainly due to their anti-inflammatory and immunosuppressant effects. They also have anti-allergic and lymphocytic properties.
     • In dentistry: Topical or systemic glucocorticoids are used in:
       1. Recurrent aphthous stomatitis
       2. Chronic ulcerative stomatitis
       3. Oral pemphigoid
       4. Erythema multiforme
       5. Temporomandibular joint pain: Intra-articular triamcinolone is used.
     • Rheumatoid arthritis: They produce immediate and dramatic symptomatic relief in rheumatoid arthritis, but they do not halt the progression of the disease. The intra-articular injection is preferred only if one or two joints are involved. Steroids could be given as an adjunct to nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs).
     • Osteoarthritis: They are rarely used in osteoarthritis. The intra-articular injection is recommended for acute episodes involving one or two joints.
     • Rheumatic fever: Glucocorticoids produce more rapid symptomatic relief than aspirin and are indicated in cases with carditis and CCF. Prednisolone is given along with aspirin and should be continued until the erythrocyte sedimentation rate (ESR) comes to normal, then the steroid is tapered off gradually.
     • Allergic diseases: The manifestations of allergic diseases, such as hay fever, reactions to drugs, urticaria, contact dermatitis, angioneurotic oedema and anaphylaxis, can be suppressed by glucocorticoids; but they have a slow onset of action. Hence, severe reactions such as anaphylaxis and angioneurotic oedema require immediate therapy with adrenaline. In hay fever and mild allergic reactions, antihistamines are the preferred drugs.
     • Bronchial asthma: Glucocorticoids have anti-inflammatory and antiallergic effects, hence they reduce mucosal oedema and bronchial hyperirritability. In acute severe asthma, i.v. hydrocortisone is given along with nebulized β₂– agonist and ipratropium bromide. If a chronic asthmatic needs steroids, it is better to give inhalational preparations like beclomethasone, budesonide or fluticasone because they cause minimal systemic adverse effects.
     • Collagen diseases: Collagen diseases such as polymyositis and polyarteritis nodosa can be controlled with large doses of glucocorticoids. Steroids with negligible salt- and water-retaining properties are preferred.
     • Renal disease: Glucocorticoids are the first-line drugs in nephrotic syndrome.
     • Ocular diseases: They are frequently used to suppress inflammation in the eye, thus preventing damage to vision. Agents may be administered topically, subconjunctivally, systemically or by retrobulbar injection, depending upon the condition. Steroids are contraindicated in herpes simplex keratitis and ocular injuries.
     • Skin diseases: Glucocorticoids dramatically relieve itching, pain, and inflammation in allergic and other dermatoses. To minimize systemic effects, topical steroids are preferred. Systemic steroid therapy is needed in severe conditions like exfoliative dermatitis, dermatomyositis and pemphigus. Psoriasis, keloids and hypertrophic scar are sometimes treated by intralesional injection of steroids.
     • Haematological disorders: Autoimmune haemolytic anaemias usually respond to glucocorticoids. Because of their lymphocytic action, glucocorticoids are used to treat certain malignancies, leukaemia, lymphomas, Hodgkin’s disease, multiple myeloma, etc., usually in combination with antineoplastic drugs.
     • Cerebral oedema: The effectiveness of glucocorticoids in cerebral oedema depends upon the underlying cause. They are very effective when the oedema is caused by brain tumours, metastatic lesions and tubercular meningitis. A steroid without salt and water-retaining activity (for example dexamethasone) is preferred.
     • Intestinal diseases: They are used in ulcerative colitis when the patient is not responding to other forms of treatment. Methylprednisolone can be administered as a retention enema during acute episodes.
     • Shock: Prompt intensive treatment with i.v. glucocorticoids may be life-saving in septic shock.
     • Organ transplantation: Glucocorticoids are used to prevent as well as treat graft rejections.
     • Hypercalcaemia of malignant diseases and vitamin D intoxication respond to prednisolone.
     • Other uses include Bell’s palsy and acute polyneuritis.
     • Dexamethasone can be used to test the HPA axis function.
5. Relative contraindications for the use of corticosteroids
   • Hypertension
   • Diabetes mellitus
   • Peptic ulcer
   • Tuberculosis
   • Herpes simplex keratitis
   • Osteoporosis
   • Epilepsy
   • Psychosis
   • Congestive cardiac failure
   • Renal failure
   • Glaucoma

Insulin And Oral Antidiabetic Agents

Diabetes mellitus (DM) is a clinical syndrome characterized by hyperglycaemia due to absolute or relative deficiency of insulin. Lack of insulin affects the metabolism of carbohydrates, protein and fat.

1. Type 1 DM: The aetiology is immunological or idiopathic. It appears when more than 90% of β-cells of the pancreas are destroyed by an autoimmune process. The peak incidence is around 15 years. In type 1 DM, there is insulin deficiency. Insulin is essential for all patients with type 1 DM.
2. Type 2 DM: Genetic influence is much more powerful in type 2 DM. It is the most common form of diabetes. Overeating, obesity, activity and ageing are the main risk factors. Type 2 DM is associated with increased hepatic production of glucose and resistance of target tissues to the action of insulin.
3. Hormones of the pancreas: There are four types of cells in islets of Langerhans: β (B) cells secrete insulin, α (A) cells secrete glucagon, δ (D) cells secrete somatostatin and F (PP) cells secrete pancreatic polypeptide.

Insulin

Insulin was discovered by Banting and Best. Insulin is synthesized by the β cells of pancreatic islets from a single-chain polypeptide precursor called preproinsulin, which is converted to proinsulin.

Insulin is formed by the removal of C-peptide from proinsulin by proteolysis. Insulin consists of two peptide chains, chain A and chain B.

These two chains are connected by two disulfide bridges. C-peptide (connecting peptide) can produce immunogenic reactions.

1. Regulation of insulin secretion is regulated by chemical, neural and hormonal mechanisms.
   • Chemical: Glucose, amino acids and fatty acids in the blood stimulate β cells to release insulin.
   • Neural: Both parasympathetic and sympathetic fibres supply the islet cells. Parasympathetic stimulation causes an increase in insulin secretion and lowers raised blood sugar levels. The islet cells have both α-adrenergic and β-adrenergic receptors. Adrenergic β2 stimulation increases insulin release and the blood sugar falls. Adrenergic α2 activation causes hyperglycaemia by inhibiting the release of insulin.
   • Hormonal. Counter-regulatory hormones like adrenaline, cortisol and glucagon promote glucose release from the liver. Glucagon stimulates insulin release, whereas somatostatin inhibits it.
2. Actions of insulin Insulin has profound effects on the metabolism of carbohydrates, fat and protein. Insulin facilitates the entry of glucose into all cells of the body.
   • However, the entry of glucose into red blood cells (RBCs), white blood cells (WBCs), and liver and brain cells can occur independently of insulin.
   • Exercise also facilitates the entry of glucose into muscle cells without the need for insulin.
     • Insulin inhibits hepatic glycogenolysis and gluconeogenesis and also inhibits lipolysis in adipose tissue.
     • Insulin enhances the entry of amino acids into muscles and cells – and promotes protein synthesis in muscle, lipogenesis, hepatic and muscle glycogenesis.
     • Insulin also promotes peripheral utilization of glucose and K⁺ uptake into the cells.
3. Mechanism of action of insulin Insulin binds to specific receptors (tyrosine kinase receptor) present on the cell membrane. The receptor consists of 2α and 2β subunits.
   • The binding of insulin to the receptor activates tyrosine kinase; a complex series of events occurs resulting in various actions of insulin. This results in a complex series of phosphorylation–dephosphorylation reactions, which promotes the entry of glucose into the cell.
4. Pharmacokinetics Insulin is destroyed by proteolytic enzymes in the gut, hence not effective orally. Insulin is administered usually by subcutaneous (s.c.) route; but in emergencies, regular (soluble) insulin is given by i.v. route. After i.v. injection, soluble insulin is rapidly metabolized by the liver and kidney with a half-life of about 6 min.
5. Insulin preparations
   • Conventional insulin preparations Bovine (beef) insulin and Porcine (pig) insulin are antigenic as they contain pancreatic proteins, proinsulin, etc. Hence, they are not used.
   • Monocomponent insulins Monocomponent insulins are purified insulins. They are less antigenic than conventional preparations, and cause less insulin resistance and lipodystrophy at the injection site, for example, monocomponent porcine regular insulin, and monocomponent porcine isophane insulin.
     • Human insulins: They are produced by recombinant DNA technology using Escherichia coli or yeast. They are the least immunogenic; insulin resistance and lipodystrophy at the site of injection are rare, for example, human regular insulin and human neutral protamine Hagedorn (NPH) insulin. Human insulins are the most commonly used insulin preparations.
       • Insulin analogues are produced by DNA recombinant technology. The amino acid sequence is slightly different from endogenous insulin. Though actions are similar, the pharmacokinetic profile is altered. They are either fast and short-acting or slow and long-acting. Hypersensitivity reactions and lipodystrophy are less than conventional preparations.
       • Insulin preparations based on onset and duration of action
       • Rapidly acting insulin analogues Modification in B chain: for example, insulin lispro, insulin aspart and insulin glulisine.
         1. On s.c. administration: rapidly absorbed → rapid onset of action within 5–15 min; peak effect in 1 h. They are administered just before meals.
         2. Duration of action is less than regular insulin.
         3. Can be mixed with NPH insulin.
       • Short-acting insulin Regular (soluble insulin):
         1. Short-acting, soluble, crystalline zinc insulin.
         2. After s.c. injection, it is slowly absorbed → onset of action is within 30 min; administered 30–45 min before meals.
         3. Can be mixed with NPH insulin.
         4. Can be administered by s.c., i.m. and i.v. routes.
       • Intermediate-acting insulin NPH (neutral protamine Hagedorn) insulin or isophane insulin
         1. Intermediate-acting insulin.
         2. Insulin complexed with protamine and zinc; dissociates slowly on s.c. administration → onset of action is delayed and duration of action is 10–20 h.
         3. Intermediate-acting insulin takes several hours to achieve effective plasma concentration. Hence, they are combined with regular insulin/rapidly acting insulin analogues.
       • Long-acting insulins Long-acting insulin analogues, for example, insulin glargine and insulin detemir.
         1. On s.c. administration: slowly absorbed → delayed onset of action with ‘peakless’ plasma concentration.
         2. Cannot be mixed with other insulins.
            • Insulin Preparations Based on Onset and Duration of Action
6. Insulin therapy Insulin is the main drug for all patients with type-1 DM and for patients with type-2 DM who are not controlled by diet and oral antidiabetic drugs. The main goal of insulin therapy is to maintain the fasting blood glucose concentration between 90 and 120 mg/dL and postprandial glucose level below 150 mg/dL.
7. Insulin administration
   • Insulin syringes and needles.
   • Pen devices: They are convenient to carry; a preset amount is delivered subcutaneously.
   • Insulin pumps are available for continuous subcutaneous insulin infusion.
   • Short-acting insulin, for example, regular insulin is used. An advantage is that it is programmed to deliver insulin to maintain basal levels and also a bolus dose prior to meals. It is expensive and there could be mechanical problems with the pump.
8. Indications for insulin
   • Type-1 DM.
   • Diabetic ketoacidosis: It is a complication of type-1 DM. It is very rare in type-2 DM.
   • Diabetes during pregnancy
   • The stress of surgery, infections and trauma (temporarily to tide over trauma, infection, surgery, etc.)
   • Patients with type-2 DM unresponsive to oral antidiabetic drugs
9. Site of administration Insulin is usually administered subcutaneously in the abdomen, buttock, anterior thigh or dorsal arm.
10. Complications of insulin therapy
    • Hypoglycaemia is the most common and dangerous complication. Prolonged hypoglycaemia may cause permanent brain damage. Hypoglycaemia can occur
      in any diabetic and may be due to delay in taking food, too much physical activity or excess dose of insulin.
      • Symptoms of hypoglycemia:
        • Autonomic symptoms: They occur initially and are due to counterregulatory sympathetic stimulation – sweating, tremor, palpitation, anxiety and tachycardia.
        • Neuroglycopenic symptoms like headache, blurred vision, confusion, loss of fine motor skill and abnormal behaviour. They usually occur at lower plasma glucose levels. With further lowering of blood glucose levels, convulsions and loss of consciousness can occur.
        • Treatment: All these manifestations are relieved by the administration of glucose. If the patient is conscious, oral glucose or if the hypoglycaemia is severe (unconscious patient) 50 mL of 50% dextrose is injected intravenously.
        • Glucagon 1 mg i.v. may be injected to treat severe hypoglycaemia.
    • Allergic reactions are rare; local skin reactions (swelling, redness) at the site of injection can occur, which may be due to minor contaminants.
    • Lipodystrophy (either atrophy or hypertrophy) may occur at the site of injection. It may be avoided by using purified insulin preparations and changing the injection site by rotation.
11. Insulin resistance It is a state in which there is a decreased response of peripheral tissues to insulin. Acute insulin resistance develops during stressful conditions like trauma, infection, surgery and psychological stress. The dose of regular insulin should be increased.
12. Diabetic ketoacidosis is a complication of type-1 DM. It is very rare in type-2 DM. The common precipitating factors are infection, trauma, severe stress, etc. The clinical features are anorexia, nausea, vomiting, polyuria, abdominal pain, hypotension, tachycardia, hyperventilation, altered consciousness or coma in untreated cases. Diabetic ketoacidosis is a medical emergency.
13. Management of diabetic ketoacidosis
    • Insulin replacement: Regular insulin is administered as an intravenous bolus in a dose of 0.2–0.3 U/kg followed by 0.1 U/kg/h i.v. infusion. Blood glucose levels should decrease by 10% in the first hour. Monitoring of blood glucose levels should be done for optimal insulin replacement. Once a patient becomes conscious, insulin can be administered subcutaneously.
    • Fluid replacement: Initially, normal saline is infused intravenously at 1 L/h, then the rate of infusion is gradually decreased depending on the requirement of the patient. Once blood glucose levels fall to about 250 mg/dL, 5% glucose in ½N saline is administered to prevent the development of hypoglycaemia and cerebral oedema.
    • Potassium: Following insulin therapy and correction of acidosis, potassium shifts into the cells resulting in hypokalaemia. Potassium chloride 10–20 mEq/h is infused after 4 h of initiation of insulin therapy. Serum potassium and ECG should be monitored to determine potassium replacement.
    • Sodium bicarbonate is administered intravenously if required.
    • Phosphate: Patients with severe hypophosphatemia require phosphate replacement.
    • Antibiotics to treat associated infection, if any.
14. Drug interactions
    • β-Blockers × insulin
    • Salicylates × insulin: Salicylates exert a hypoglycaemic effect by increasing the sensitivity of pancreatic β-cells to glucose and potentiating insulin secretion.

Oral Antidiabetic Drugs

1. Sulfonylureas
   • First generation: Tolbutamide
   • Second generation: Glyburide (glibenclamide), glipizide, gliclazide, glimepiride.
2. Biguanide: Metformin.
3. Meglitinide analogue: Repaglinide.
4. d-Phenylalanine derivative: Nateglinide.
5. Thiazolidinediones: Pioglitazone.
6. α-Glucosidase inhibitors: Acarbose, miglitol, voglibose.
7. Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, saxagliptin.
8. SGLT-2 (sodium-glucose co-transporter-2) inhibitor: Dapagliflozin.
   • Oral and Newer Antidiabetic Drugs: Dosage and Duration of Action

1. Other antidiabetic agents (parenteral)
   • Glucagon-like peptide-1 (GLP-1) analogues: Exenatide, lixisenatide.
   • Others: Pramlintide.
2. Note:
   • Biguanides and thiazolidinediones are insulin sensitizers.
   • Sulfonylureas, meglitinides, DPP-4 inhibitors and GLP-1 analogues are insulin secretagogues (enhance insulin secretion).
3. Sulfonylureas are divided into two generations. All these drugs have the same mechanism of action but differ in potency and duration of action. Second-generation drugs are more potent than first-generation drugs.
   • Mechanism of action
     • Sulfonylureas stimulate insulin secretion from β cells of the pancreas. It is an insulin secretagogue. For successful therapy with sulfonylureas, at least 30% functioning beta cells are necessary. Sulfonylureas are ineffective in type-1 DM because of the absence of functioning β cells in the islets of the pancreas.
     • Sulfonylureas increase the sensitivity of peripheral tissues to insulin by increasing the number of insulin receptors.
     • They reduce the release of glucagon.
   • Pharmacokinetics Sulfonylureas are well absorbed after oral administration, highly bound to plasma proteins and have low volume of distribution. They are metabolized in the liver and excreted mainly in urine.
   • Adverse effects
     • Hypoglycaemia is common, particularly with glibenclamide due to its long duration of action. Glibenclamide is best avoided in elderly patients because of the high risk of hypoglycaemia.
     • GI disturbances like nausea, vomiting, diarrhoea and flatulence.
     • Weight gain is due to the stimulation of appetite.
     • Allergic reactions: Skin rashes, itching and photosensitivity.
     • Teratogenicity: Sulfonylureas are not safe during pregnancy.
     • Chlorpropamide has disulfiram-like action and, hence, produces intolerance to alcohol.
   • Sulfonylureas are useful in patients with type-2 DM.
   • Drug interactions
     • Sulfonylureas × salicylates/sulfonamide/warfarin: They potentiate the effects of sulfonylureas (severe hypoglycaemia). Warfarin and sulfonamide inhibit the metabolism of sulfonylureas, thereby increasing the plasma levels of sulfonylureas leading to severe hypoglycaemia.
     • Propranolol × sulfonylureas: Propranolol by blocking hepatic β₂-receptors inhibits glycogenolysis and delays recovery from hypoglycaemia. Propranolol also masks the symptoms of sulfonylureas-induced hypoglycaemia, such as tachycardia and palpitation (by blocking β1-receptors of the heart) and tremors (by blocking β2-receptors in the skeletal muscle).
     • Rifampicin, phenobarbitone × sulfonylureas: Rifampicin and phenobarbitone are enzyme inducers, hence they accelerate the metabolism of sulfonylureas and reduce their effects.
4. Biguanide Metformin is the only biguanide used clinically.
   • Mechanism of action The mechanism of action of biguanides is shown It is as follows.
     • Metformin:
       1. Decreases hepatic gluconeogenesis (major action).
       2. Increases peripheral utilization of glucose in skeletal muscle and fat. They improve tissue sensitivity to insulin.
       3. Biguanides do not affect insulin release.
   • Pharmacokinetics Metformin is taken orally, well absorbed through the GI tract and is excreted mostly unchanged in the urine.
   • Adverse effects are metallic taste, anorexia, nausea, vomiting, diarrhoea, loss of weight and skin rashes. Lactic acidosis is the most serious complication, but it is rare with metformin. Prolonged use can cause vitamin B₁₂ deficiency due to malabsorption. The risk of hypoglycaemia is very low with metformin.
   • Metformin is used in patients with type 2 DM either alone or in combination with other antidiabetic agents. Hypoglycaemia is rare. It protects against vascular complications of diabetes.
5. Meglitinide analogue (repaglinide) and d-phenylalanine derivative (nateglinide) Repaglinide and nateglinide are structurally unrelated to sulfonylureas, but their mechanism of action is similar to sulfonylureas.
   • They stimulate insulin release by the closure of ATP-sensitive potassium channels in β cells of islets of the pancreas → depolarization → insulin release.
   • Repaglinide and nateglinide are well absorbed from the GI tract, metabolized mainly in the liver and should be avoided in patients with hepatic failure.
   • They have rapid onset but short duration of action. They are less potent than sulfonylureas. They are used only in type-2 DM to control postprandial hyperglycaemia.
   • The main side effects of repaglinide are weight gain and hypoglycaemia, but the episodes are less frequent; meglitinide causes nausea and flu-like symptoms.
6. GLP-1 analogues (for example, exenatide) GLP-1, an incretin, is released from the gut after meals. It stimulates insulin secretion, suppresses glucagon release and slows gastric emptying.
   • It is degraded by DPP-4; its plasma half-life is 1–2 min; hence, it cannot be used therapeutically. GLP-1 analogues are resistant to DPP-4.
   • Their actions are similar to GLP-1. They are used in patients with type-2 DM.
7. DPP-4 inhibitors (for example, sitagliptin) They inhibit the enzyme DPP-4 → prevent inactivation of GLP-1 → increase plasma concentration of GLP-1 → increase insulin secretion, suppress glucagon release and improve control of fasting and postprandial hyperglycaemia.
   • They are administered orally in patients with type-2 DM. Allergic reactions can occur with sitagliptin. The risk of hypoglycaemia is low.
8. Thiazolidinediones increase the sensitivity of peripheral tissues to insulin.
   • Other actions: Pioglitazone reduces serum triglyceride and increases HDL levels.
   • Pharmacokinetics Pioglitazone is almost completely absorbed from the GI tract, highly bound to plasma proteins (95%) and metabolized in the liver.
   • Adverse effects Nausea, vomiting, anaemia, weight gain, oedema and precipitation of heart failure in patients with low cardiac reserve; rarely hepatotoxicity and bladder cancer may occur.
     • There is an increased risk of cardiovascular events with rosiglitazone, so its use has been suspended in some countries.
   • Pioglitazone is used alone or in combination with sulfonylureas/metformin in patients with type-2 DM.
9. α-Glucosidase inhibitors These drugs should be given just before food.
   • Acarbose, miglitol and voglibose
     • They reduce intestinal absorption of carbohydrates by inhibiting the enzyme α-glucosidase in the brush border of the small intestine and reduce postprandial hyperglycaemia.
     • They are mainly used in obese patients with type-2 DM. Side effects are mainly on GI tract: flatulence, fullness and diarrhoea.

Agents Affecting Calcium Balance

Calcium

1. About 99% of the calcium in our body is in bones and teeth. Calcium metabolism is chiefly regulated by three hormones: parathormone (PTH), vitamin D (dihydroxycholecalciferol) and calcitonin.
2. Parathormone plays a central role in regulating calcium homeostasis.
3. Calcium metabolism is also intimately connected with phosphorus and magnesium metabolism. The normal serum calcium level is 9–11 mg/dL.
4. Functions of calcium
5. 
6. Preparations of calcium
   • Oral: Calcium gluconate, calcium citrate, calcium lactate and calcium carbonate. Calcium carbonate is cheap, tasteless and is preferred because of its high percentage of calcium.
   • Parenteral:
     • Intravenous calcium gluconate: Nonirritant, hence it is preferred.
     • Intravenous calcium chloride: Highly irritant and causes tissue necrosis.
7. Therapeutic uses of calcium salts
   • To correct calcium deficiency:
     • In growing children, pregnant and lactating women.
     • In dietary deficiency.
     • In osteoporosis.
     • In rickets and osteomalacia along with vitamin D.
     • In long-term corticosteroid therapy along with vitamin D.
     • After the removal of the parathyroid tumour.
   • Intravenous calcium gluconate (10%) in tetany.
   • Calcium carbonate is used as an antacid.

Parathyroid Hormone (PTH)

Parathormone is a polypeptide hormone, which is synthesized by chief cells of the parathyroid gland. PTH secretion is chiefly controlled by the concentration of free Ca²⁺ in plasma – low plasma Ca²⁺ stimulates secretion and vice versa.

• Actions of PTH

1. 1. Hypoparathyroidism (deficiency of parathyroid hormone) Serum calcium levels are decreased.
      Treatment Emergency treatment of acute attack (hypoparathyroidism tetany)
      • • 10% calcium gluconate given i.v. slowly until tetany ceases.
          • Treatment of chronic hypoparathyroidism
        • The treatment of choice is vitamin D₂(ergocalciferol).

Hyperparathyroidism

Hyperparathyroidism is characterized by increased levels of parathormone, often due to parathyroid tumours. There is hypercalcaemia and hypercalciuria. Treatment involves surgical removal of the tumour.

1. Teriparatide
   • Recombinant preparation of PTH.
   • Route: Administered subcutaneously, once daily.
   • Stimulates bone formation.
   • Use: Treatment of severe osteoporosis – improves bone mineral density.
   • Adverse effect: Hypercalcaemia.
   • Expensive.

Calcitonin

Calcitonin is synthesized by the ‘C’ cells of the thyroid. It is a peptide hormone. The main actions of calcitonin are to lower serum calcium and phosphate by direct action on bone and kidney. Calcitonin secretion is stimulated when the serum calcium level becomes high and vice versa.

1. Actions of calcitonin (generally opposite to that of PTH)
2. 
3. Preparations of calcitonin Calcitonin is given by s.c. or i.m. route. Salmon calcitonin is also available as a nasal spray.
4. Therapeutic uses
   • In hypercalcaemic states (for example, associated with neoplasia).
   • In Paget’s disease of bone: Chronic use of calcitonin relieves pain and reduces some of the neurological complications, but bisphosphonates are the treatment of choice.
   • In postmenopausal osteoporosis: Salmon calcitonin is used as a nasal spray along with calcium and vitamin D supplements.
5. Adverse effects They are nausea, vomiting, flushing and pain at the site of injection.

Vitamin D

• Vitamin D is a fat-soluble vitamin. It is a prohormone, which is converted in the body into a number of biologically active metabolites that function as true hormones.
• Vitamin D, together with PTH, plays a central role in the maintenance of plasma calcium and bone formation. Vitamin D is found in fish liver oils and dairy products; it is also synthesized in the skin upon exposure to sunlight.

1. Pathways of vitamin D production
2. 
3. Actions of Vitamin D
   • Vitamin D deficiency causes rickets in children and osteomalacia in adults.
   • Hypervitaminosis D may occur due to acute large doses or long-term use of vitamin D.
   • The signs and symptoms of hypercalcaemia are nausea, weakness, fatigue and polyuria.
   • If hypercalcaemia persists, calcium salts are deposited in the kidney, resulting in renal failure and renal stones. Treatment includes immediate stoppage of vitamin D, low calcium diet, intravenous hydration and administration of glucocorticoids.
4. Preparations of vitamin D
   • Ergocalciferol (vitamin D₂): Oral capsules 400 IU/day for prevention of rickets in children and osteomalacia in adults.
   • Cholecalciferol (vitamin D₃): Oral and i.m. injection.
   • Calcitriol: Active form of vitamin D. Oral capsules and solution.
   • Alfacalcidol: Prodrug, orally effective, does not require activation in the kidney; is rapidly biotransformed into calcitriol in the liver.
5. Therapeutic uses of vitamin D
   • Prevention (400 IU/day) and treatment (4000 IU/day) of nutritional rickets and osteomalacia.
   • In hypoparathyroidism, there is hypocalcaemia and hyperphosphataemia. Calcitriol and alfacalcidol are effective for the temporary treatment of hypocalcaemia.
   • Administration of vitamin D with calcium in senile or postmenopausal osteoporosis improves calcium balance and may reduce the risk of fractures.
   • Metabolic rickets: Calcitriol (active form) or alfacalcidol (does not require hydroxylation in the kidney) is used.

Bisphosphonates

Bisphosphonates are analogues of pyrophosphate. They are Pamidronate (i.v. infusion), Alendronate (oral), Zoledronate (i.v. infusion), Etidronate (oral, i.v.), Tiludronate (oral), etc. (Mnemonic: PAZET)

1. Mechanism of action Bisphosphonates exert an antiresorptive effect.
   • They have a high affinity for calcium in the bone → accumulate in areas of bone resorption → taken up by osteoclasts → promote their apoptosis.
   • They interfere with the mevalonate pathway of cholesterol synthesis, which is required for the normal function of osteoclasts.
2. Pharmacokinetics Bisphosphonates are highly polar, hence poorly absorbed through the GI tract; a part of the absorbed drug is incorporated into bone and remains for long from months to years. The free drug is excreted unchanged in urine. Zoledronate is less irritating to the veins; it is administered once a year.
3. Uses
   • Paget disease of bone: Bisphosphonates are the treatment of choice for Paget disease. They reduce bone pain and decrease alkaline phosphatase levels.
   • For the prevention and treatment of postmenopausal osteoporosis: These drugs improve bone mineral density and reduce the incidence of vertebral fracture.
   • To prevent corticosteroid-induced osteoporosis along with oral calcium carbonate.
   • Hypercalcaemia of malignancy: Bisphosphonates control hypercalcaemia by inhibiting bone resorption. Zoledronate is the most potent and is the drug of choice for malignant hypercalcaemia.
   • Bisphosphonates are also useful to control hypercalcaemia of hyperparathyroidism.
4. Adverse effects
   • They include nausea, vomiting, diarrhoea, heartburn, oesophagitis, peptic ulcer, fever, myalgia hypocalcaemia, headache and skin rashes.
   • Oral bisphosphonates should be taken with plenty of water and the patient should remain upright for at least 30 min to prevent oesophagitis.
   • Flu-like symptoms can occur on parenteral administration. Rarely, osteonecrosis of the jaw may occur.