In this essay we will discuss about the drugs used for treating the diseases of endocrine system.
Essay # 1. Insulin and Oral Antidiabetic Drugs:
Insulin is a protein hormone produced by the beta cells of the islets of Langerhans of the pancreas gland. It plays a key role in the regulation of carbohydrate, fat and protein metabolism. Lack of insulin or resistance to its action causes diabetes mellitus.
There are two types of diabetes:
Type 1 Diabetes:
This is known as insulin-dependent diabetes mellitus (IDDM) in which there is no circulating insulin in the plasma due to autoimmune destruction of pancreatic beta cells. Insulin deficiency leads to a rapid rise in the blood glucose concentration with subsequent loss of glucose with water and salt in the urine.
Fats in the body are broken down releasing ketone bodies in blood, which cause acidosis. Protein breakdown releases amino acids in the blood, which are converted to pyruvate, glucose, and urea in the liver. The excess urea produced is excreted in urine resulting in negative nitrogen balance and weight loss may be marked. If not treated with insulin, patient will lapse into coma (hyperglycemic ketoacidosis).
Type 2 Diabetes:
This is known as non-insulin dependent diabetes mellitus (NIDDM), which is due to reduced secretion of insulin or due to peripheral resistance to the action of insulin. The blood glucose concentration is raised with glycosuria, but ketoacidosis is not common and the symptoms are often those of late complications of diabetes.
These complications occur with both type of diabetes and are due to micro-vascular diseases including myocardial infarction, retinopathy, renal failure, and serious interference with the circulation to the legs sometimes requiring amputation and neuropathy. Type 2 diabetes may be controlled on diet alone, but many require administration of oral anti-diabetic drugs or insulin to maintain optimal glycaemic control.
Insulin:
Insulin lowers the concentration of glucose in the blood mainly by:
a. Facilitating glucose transport across cell membrane resulting in increased uptake of glucose by the tissues.
b. Facilitating glycogen synthesis from glucose in liver, muscles and fat.
c. Inhibiting gluconeogenesis (from protein) in liver and lipolysis in adipose tissue with increased production of fat and protein.
Sources of Insulin:
There are three sources of insulin, bovine, porcine and human. Bovine insulin extracted from beef pancreas is immunogenic and is rarely used. Porcine insulin extracted from pork pancreas is very similar to human insulin.
Nonhuman insulin can stimulate the production of anti-insulin antibodies (AIA), which occasionally give rise to local and systemic allergic reactions, but immunological resistance to insulin action is uncommon. Human insulin is prepared semisynthetically by enzymatic modification of porcine insulin or biosynthetically by recombinant DNA technology using Escherichia coli. Virtually all insulin now used is human insulin.
Mechanism of Action:
Insulin interacts with a highly specific receptor located on the cell membrane of practically all cells, particularly liver and fat cells. Glucose is transported from the blood into the cells across the cell membranes by so called glucose transporters, and insulin increases the activity of the glucose transporters.
Pharmacokinetics:
Insulin is inactivated by GIT enzymes and must therefore be given by injection. The subcutaneous route is ideal for self- administration. A different site should be used each time to minimize fat hypertrophy. Liver and kidney are of primary importance in the degradation of insulin by a proteolytic enzyme.
Insulin Administration:
Insulin Syringes:
Most diabetic patients use disposable plastic insulin syringe available in 0.5 ml (up to 50 units) and 1 ml (up to 100 units) sizes for subcutaneous injection.
Pen Devices:
Insulin pen devices contain a cartridge of insulin that is automatically injected. A wide range of insulin is available in cartridges and is more convenient for the patient.
Jet Injection:
Jet injection is high-pressure devices that eject insulin through a fine nozzle without a needle being used. Jet injections have not become popular because of delayed pain, greater bleeding and possibility of increased immunogenicity.
Syringe Pumps:
For intensive insulin requirements, soluble insulin can be given by subcutaneous infusion using a syringe pump. The rate of infusion can be modified to the patient’s needs and produce an accurate control of the diabetes. However, this technique has a limited place since it requires regular monitoring of blood glucose by patients themselves with an access to expert advice at all times.
Insulin Preparations:
Short-Acting Insulins:
These include soluble insulin, insulin lispro and insulin aspart. Soluble insulin is used by intravenous route for the treatment of diabetic coma (ketoacidosis), and for diabetic patients undergoing surgical operations. Soluble insulin is also used subcutaneously in combination with longer acting insulin in the long-term control of diabetes.
Insulin lispro and insulin aspart are modified forms of human insulin, which are very rapidly mobilized from the injection site, and their onset of action is even more rapid than subcutaneous soluble insulin. They are generally given before a meal for controlling the rise in blood sugar and their action mimics more closely to the response of the normal pancreas.
Intermediate-Acting Insulins:
These include NPH (isophane), lente (zinc) and glargine (Lantus). The insulin is released slowly from injection sites and act for varying periods. They are usually given once or twice daily and may be combined with soluble insulin. NPH (isophane) insulin consists of insulin complexes with protamine. This is mixed with soluble insulin to produce an intermediate effect. The most commonly used preparation is Human mixtard 30/70 (30% soluble and 70% isophane insulin).
Lente insulin is a mixture of amorphous and crystalline forms of insulin zinc suspension. Amorphous form contains small particles and has a rapid and short lived action, while crystalline form of insulin zinc suspension contain larger particles with a prolonged duration of action. The commonly used preparation is Human monotard (30% amorphous, 70% crystalline).
Insulin glargine (Lantus) is bioengineered human insulin analog that is given subcutaneously once daily at bedtime. It forms micro- crystals of insulin under the skin, which dissolve slowly and release insulin into the bloodstream. Insulin glargine produces no significant insulin peaks (peakless) in the bloodstream.
Insulin glargine has been claimed to produce less nocturnal hypoglycaemia, but may cause allergic reactions.
Long-Acting Insulins:
These include protamine zinc insulin and ultralente insulin. They are absorbed more slowly than the intermediate- acting preparations. Long-acting insulin’s provide a steady “basal” supply of circulating insulin. Protamine zinc insulin (PZI) is produced by adding protamine and zinc to bovine insulin. It may give rise to skin rashes and painful lumps at the site of injection. Ulralente is the crystalline form of human insulin zinc suspension (Human Ultratard).
After subcutaneous injection, there is an individual variation in the duration and peak activity of insulin preparations.
Choice of Insulin:
Human insulin is the least immunogenic and is preferred insulin for treatment. It does not give rise to allergic reaction, does not cause local reaction and does not lead to antibody production. Human insulin does not contain impurities and is preferred in pregnancy, because impurities in insulin from animal sources can cross the placenta and damage the islet tissue of the fetus.
Factors Altering Insulin Requirements:
Insulin requirement may be increased by infection, stress, accidental or surgical trauma, puberty, during second and third trimester of pregnancy, obesity and certain hormones (glucagon, adrenaline and growth hormones). Insulin requirements may be decreased in patients with renal or hepatic impairment and in those with some endocrine disorders (e.g. Addison’s disease, hypopituitarism) or coeliac disease.
Insulin Regimens:
In normal subjects insulin is secreted at two rates:
a. A basal rate during fasting to exert an inhibitory control on the catabolic processes of glycogenolysis, gluconeogenesis, lipolysis and the breakdown of proteins.
b. A rapid rate and response to meals to promote the storage of absorbed fuels. Insulin requirement regimens should mimic this pattern to achieve good control.
Insulin-Dependent Diabetes Mellitus (IDDM or Type I Diabetes):
In type I diabetes there is no circulating insulin due to autoimmune destruction of pancreatic beta cells. The insulin regimen used is a combination of short and intermediate acting insulin injected twice a day before breakfast and before the evening meal to mimic the normal insulin blood concentration. Alternatively soluble insulin three times a day may provide a good glycemic control.
Non-Insulin Dependent Diabetes Mellitus (NIDDM or Type II Diabetes):
Insulin requirement for patients with dominant insulin deficiency do not differ from those used for type I subjects and twice daily biphasic isophane insulin remains the choice.
Adverse Effects:
a. Hypoglycemia is a potential problem and is more likely to occur with human insulin. Alcohol and beta blockers may aggravate it. Warning signs of hypoglycemia such as faintness, dizziness, tremors, sweating and abnormal behavior are thought to be brought about by the compensatory secretion of adrenaline. It can be relieved by giving sugar or parenteral glucagon, if required. Failure of treatment may lead to convulsions, come and death. β blockers mask the symptoms of hypoglycemia in patients of diabetes receiving insulin.
b. Local reaction- Irritation at the site of injection can lead to fat hypertrophy, which can be minimized by rotating the injection sites. Local allergic reaction and infection may occur due to impurities.
c. Immunogenic response- Non-human insulin can stimulate the production of anti-insulin antibodies (AIA), which may lead to hypersensitivity reaction and to insulin resistance.
d. Growth promoting properties of insulin may be a factor in the micro-vascular complications of diabetes including micro-angiopathy, nephropathy, neuropathy, retinopathy and atherosclerosis.
e. Weight gain is an undesirable effect of intensive insulin therapy.
Diabetic Ketoacidosis (Diabetic Coma):
Patients with type I diabetes who are not treated or who develop infection during treatment, may rapidly pass into a diabetic coma, which is a potentially fatal complication. It is less likely to occur in type 2 diabetes.
Diabetic coma gives rise to prominent GI symptoms, dehydration, respiratory distress, shock, and coma and is due to very high blood and urinary glucose levels, production of large quantities of ketone bodies leading to acidosis (ketoacidosis), and severe diuresis resulting in depletion of sodium, potassium and water.
The aim of the treatment is fluid replacement, adequate insulin administration, and maintenance of normal plasma potassium levels, which constitutes a first-line management of diabetic ketoacidosis. Bicarbonate, phosphate, magnesium, antimicrobials or anticoagulants therapies may be required as part of specific therapy, once the patient has been stabilized.
Fluid replacement would restore the circulating blood volume, replenish total body water deficits and ensure its maintenance. This is achieved by giving infusion of normal saline at a speed depending on degree of dehydration and cardiac and renal status.
Insulin therapy- Sufficient insulin requires to be administered to turn off ketoacidosis and correct hyperglycemia. Soluble human insulin is given intravenously by an infusion pump and the dose is adjusted to produce a decrease in blood glucose of 50-75 mg/dl/ hour. Once oral intake resumes, insulin can be administered by subcutaneous injection.
Potassium supplements- Potassium should be added routinely to IV fluids, regardless of plasma levels on admission, because insulin therapy causes a rapid shift of potassium into the intracellular compartment. The goal is to maintain plasma potassium in the normal range and thereby prevent the potentially fatal cardiac effects of hypokalemia.
Potassium supplements are contraindicated in patients with hyperkalemia (ECG evidence), renal failure or oliguria confirmed by bladder catheterisation.
Bicarbonate therapy is not necessary routinely, but is indicated in patients who develop shock or coma, severe acidosis; acidosis- induced cardiac or respiratory dysfunction and severe hyperkalemia.
Restoration of electrolyte and water balance is usually sufficient and the kidneys will correct the acidosis by excreting acid urine.
Frequent examination of the urine for sugar and ketones, of the blood sugar hourly and of the electrolytes is important in controlling the treatment.
IV antimicrobial therapy for any possible bacterial or fungal infections and prophylactic subcutaneous heparin to prevent common deep vein thrombosis is indicated.
Essay # 2. Oral Anti-Diabetic Drugs:
Oral anti-diabetic drugs are used to supplement dietary control and exercise in the treatment of non-insulin dependent (type 2) diabetes.
Type 2 diabetes is characterized by three major pathophysiologic abnormalities, namely impaired insulin secretion leading to relative insulin deficiency, insulin resistance and increased hepatic glucose output (due to hepatic insulin resistance).
Oral anti-diabetic drugs include:
i. Insulin secretagogues
ii. Metformin
iii. Alpha-glucosidase inhibitors
iv. Thiazolidinedione
Essay # 3. Insulin Secretagogues (Sulphonylureas):
Mechanism of Action:
This group of drugs lowers blood glucose by augmenting insulin secretion. They may also increase the sensitivity of the tissues to insulin.
Pharmacokinetics:
There are several drugs in this group, which differ in duration of action, route of elimination and side effects (Table 8.2). Except for gliclazide, the hypoglycemic effect of all the second-generation drugs, though metabolized by liver, is potentiated in patients with renal failure.
Sulphonylureas are well absorbed orally. They are highly bound to plasma protein. The binding sites on albumin are different for second generation drugs and displacement interaction with drugs (e.g. warfarin, NSAIDs), which increase the hypoglycemic response to tolbutamide and chlorpropamide may perhaps be less with second generation drugs.
Therapeutic Uses:
Sulphonylureas are used in patients with NIDDM, who are usually middle-aged or elderly and obese. They should be taken 30-60 minutes before food and should not be administered to fasting patients. Gliclazide is the most commonly used; its action lasts up to 24 hours and it rarely causes hypoglycemic episodes. The first generation sulphonylureas are generally not used. Tolbutamide is safe and may be used the treatment of elderly patients because the risk of hypoglycemia is reduced due to its short duration of action (about 6 hours).
Adverse Effects:
Hypoglycemia and weight gain are notable adverse effects of sulphonylurea. Fluid retention, blood dyscrasias and skin rashes are other occasional side effects.
Drug Interactions:
ACE inhibitors, NSAIDs, antibacterial drugs, warfarin, MAOIs, antidepressants, β blockers, and cimetidine enhance hypoglycemic effects. Phenthiozine antidepressants, corticosteroids, diuretics (thiazide and loop) and oral contraceptives reduce the hypoglycemic effects of sulphonylureas.
Essay # 4. Prandial Glucose Regulators:
These are unique in that they act postprandially, i.e. they deal with the rise in circulating glucose that occurs immediately after a meal. Repaglinide augments food-stimulated insulin secretion with a similar glucose-lowering effect as suphonylureas, but in contrast to the latter it does not promote insulin release in the absence of glucose. Adverse effects include hypoglycemia and weight gain.
Nateglinide acts directly on the pancreatic β cells to stimulate early insulin secretion. The drug is well tolerated and the risk of hypoglycemia appears minimal. Both drugs are taken before a meal and are omitted if the meal is missed. METFORMIN, the only available biguanide, is an effective drug that requires the presence of insulin for its action. It does not stimulate insulin secretion.
Mechanism of Action:
There are multiple factors involved in its hypoglycemic action, which include:
i. Reduction of glucose absorption from GIT
ii. Inhibition of hepatic glucose output
iii. Stimulation of glucose uptake by peripheral tissues
iv. Inhibition of gluconeogenesis (biosynthesis of glucose from non-carbohydrate sources i.e. amino acids).
Pharmacokinetics:
Metformin is absorbed orally, though absorption is slow and variable. It has duration of action of 6-12 hours. Metformin is not appreciably metabolized and is rapidly eliminated via the kidneys by glomerular filtration and active tubular secretion.
Therapeutic Uses:
Metformin (in doses 500 mg daily, increased slowly every 1-2 weeks up to 2000 mg/day) is the drug of first choice in the treatment of non-insulin dependent diabetes in obese patients in whom dietary control has failed to control diabetes.
Metformin has the advantage of having some anorexic properties, which tend to lead to weight reduction. Metformin does not stimulate insulin secretion and hence does not cause hypoglycemia. It inhibits plasma LDL cholesterol and therefore reduces the danger of atheroma. It may be combined with insulin or sulphonylurea, if necessary.
Adverse Effects:
Metformin in doses of up to 2 g/day in 2-3 divided doses with meals causes mild GIT discomfort, nausea and anorexia. Lactic acidosis is the most serious adverse effect of metformin which though rare, may be fatal. Metformin is contraindicated in situations which predispose to lactic acidosis, e.g. severe dehydration, infection, shock, liver, renal, cardiac and pulmonary dysfunction, conditions associated with hypoxia or tissue ischemia, alcohol dependency, use of X- ray contrast media, major surgery, pregnancy and breast feeding.
Essay # 5. Alpha-Glucosidase Inhibitors:
Acarbose and miglitol inhibit the enzyme intestinal α-glucosidasr. This enzyme is part of the gastrointestinal metabolism for converting carbohydrate to glucose. Thus, they block carbohydrate digestion and decrease postprandial hyperglycemia when administered with food.
Monotherapy with these drugs seldom gives satisfactory results, but their addition to other drugs improves glycemic control. Dose related side effects are due to symptoms of carbohydrate malabsorption and include diarrhea, bloating, and abdominal cramps. The role of these drugs in diabetes is not yet determined, but they may be a useful adjunct to treatment of NIDDM.
Essay # 6. Thiazolidinediones(TZDs):
Pioglitazone and rosiglitazone are the available TDZs for clinical use. They act by increasing insulin sensitivity in muscle, adipose tissue and liver, thus lower tissue resistance to insulin. They are used alone as an adjunct to diet and exercise or in combination with either metformin or sulphonylureas. Pioglitazone can also be used with insulin.
Anorexia and nausea are troublesome and may require discontinuation of the treatment with these drugs. Hepatotoxicity, increased plasma volume leading to edema and cytopenia, precipitation of congestive heart failure especially in alcoholics, liver, renal and cardiac failure are more serious and rare complications. These drugs are contraindicated in pregnancy, breast-feeding, liver and cardiovascular diseases.
Essay # 7. Glucagon:
Glucagon is a polypeptide hormone produced by the alpha cells of the islets of Langerhans. It increases blood glucose by several mechanisms which include- breakdown of glycogen to glucose in the liver, stimulation of gluconeogenesis, inhibition of glycogen synthesis, inhibition of glucose oxidation, lipolysis in fat, and increase release of insulin.
It has the advantage of administration by intravenous, intramuscular or subcutaneous routes and is an effective initial therapy for severe hypoglycemia in patients who are unable to take glucose orally or in whom IV route is not easily accessible. The dose is 0.5-1.0 unit. Side effects are GIT disorders, hyperkalemia and rarely hypersensitivity reactions.
Essay # 8. Anti-Obesity Drugs:
Obesity is a serious health hazard, associated with many health problems including CVS diseases, diabetes mellitus, gall stones and osteoarthritis. Anti-obesity drugs should be avoided and the treatment should consist of a balanced diet, exercise and changes in life style. Appetite suppressants such as amphetamines, tobacco and thyroid hormones should not be used in the treatment of obesity.
Essay # 9. Orlistat:
Orlistat is a pancreatic lipase inhibitor and has been used in obesity. It inhibits the action of lipase in the intestine and reduces fat absorption. It may impair the absorption of fat soluble vitamins. The main drawback of orlistat is steatorrhea. Orlistat is contraindicated in chronic malabsorption syndrome, cholestasis, and pregnancy and breast-feeding.
Essay # 10. Thyroid Drugs:
Thyroxine (T4) and tri-iodothyronine (T3) are the two hormones stored in the thyroid gland as thyroglobulin. Thyroid hormones are important for normal growth and development and for energy metabolism. T4 in the tissues is converted to T3, which is the active hormone and T4 is generally regarded as a prohormone.
Thyroid hormone increases the metabolism of lipids, carbohydrates and proteins and this calorigenic effect is manifested as an increase in basal metabolic rate. It has a very important action on normal growth, partly by a direct action on cells and partly indirectly by stimulating the normal secretion of growth hormone. It is essential for the maturation of the CNS.
Therapeutic Uses:
Thyroid hormone is used in hypothyroidism and the treatment is usually continued for the rest of patient’s life. In infants, congenital absence or incomplete development of the thyroid results in cretinism, which is characterized by stunted development of the baby, causing dwarfism, mental retardation, and coarsened facial features and skin. It is also called congenital hypothyroidism.
In adults thyroid deficiency may be due to different causes which include:
i. Primary hypothyroidism (due to disease of the thyroid itself) accounts for more than 90% of cases.
ii. Insufficient iodine in the diet; this is called simple or nontoxic goiter.
iii. Chronic lymphocytic thyroiditis (Hashimoto’s disease), which is the most common and is an immunological disorder, when the body reacts against the protein thyroglobulin, which is the mechanism for storing T3 and T4 in the thyroid gland.
iv. Iatrogenic hypothyroidism due to thyroidectomy or radioactive iodine (131I) therapy.
v. Secondary hypothyroidism due to TSH is uncommon but may occur in disorders of the pituitary or hypothalamus.
vi. Drugs that may cause hypothyroidism include lithium, interferon-alpha, interleukin-2, thalidomide, NSAIDs, glucocorticoids, X-ray contrast agents, sympatholytics, sulphonylureas and tranquillizers.
When thyroid deficiency is severe it causes a condition called myxedema, which is mainly characterized by symptoms like, mental impairment, slow or slurred speech and hoarseness, bradycardia, fatigue, myalgias, constipation, cold intolerance, facial and periorbital edema, dry skin and non-pitting edema.
Thyroxine sodium (T4, levothyroxine sodium) is the drug of choice for maintenance therapy. The treatment is started with small doses, which are increased until the desired effects are produced. It is desirable to monitor the therapy with occasional T4 and TSH estimations to ensure the correct dose. Liothyronine (T3, Triiodothyronine) has actions similar to thyroxine but are much more rapid in onset. It is not so useful in the treatment of myxedema but is the treatment of choice in myxedema coma, when given intravenously.
Adverse Effects:
Excessive doses of thyroid hormones lead to cardiovascular disorders (anginal pain, arrhythmia, and tachycardia), muscle cramps, GIT disorders (especially constipation), muscle weakness and loss of weight. Hypnotics should be avoided for insomnia.
Essay # 11. Anti-Thyroid Drugs:
Anti-thyroid drugs are used for hyperthyroidism, either to prepare patients for surgical excision of the thyroid gland, or for its regular treatment. The common types of hyperthyroidism are diffuse toxic goiter (also called thyrotoxicosis or Grave’s disease) and toxic nodular goiter. The treatment of choice for diffuse toxic goiter is by drugs whereas for toxic nodular goiter is surgery. Anti-thyroid drugs used for the treatment of thyrotoxicosis are aqueous iodine solution (Lugol’s solution), radioiodine (radioactive iodine; 131I) and thionamides.
i. Aqueous Iodine Solution:
It is also called Lugol’s solution and is only indicated (1-2 drops orally given 12 hourly) to inhibit thyroid hormone secretion release as part of the treatment of thyroid crisis and also as premedication before thyroid surgery to make the thyroid gland less vascular. Its actions are temporary and after 10 days or so, the beneficial actions start wearing off. It is likely to give rise to allergic reactions.
ii. Radioiodine:
Radio-iodine (radioactive iodine; 131I) is the treatment of choice for almost all patients of Grave’s disease except during pregnancy. It is a radioactive isotope of iodine that is taken selectively by thyroid gland, where it emits powerful rays that kill cells.
It is a rare example of a “magic bullet”- i.e. a drug that targets the thyroid gland, because of its selective property of trapping the circulating iodine in the blood. A single dose permanently controls hyperthyroidism in 90% of patients. Radioiodine emits both β-particles and y-rays and has a short half-life of about 8 days.
Radioiodine does not increase the risk of malignancy, since its cytotoxic effects are mainly confined to thyroid gland because of relative short path of β-particles, which destroys quickly the thyroid tissue and the radio activity decays away completely because of its short half-life.
The common side effect is hypothyroidism, which occurs in more than half of patients within the first year and continues to develop at a rate of approximately 3% /year. Hypothyroidism is easily treated by administration of thyroxine.
iii. Thionamides:
Carbimazole, methimazole and propylthiouracil are thiourea derivatives that act primarily by interfering with the synthesis of thyroid hormone.
Mechanism of Action:
These drugs inhibit thyroid hormone synthesis, possibly by preventing the oxidation of iodide to iodine. Propylthouracil also blocks the conversion of T4 to T3 in target tissues. They do not have any permanent action on thyroid function and the symptoms recur, if the therapy is stopped.
Pharmacokinetics:
Thionamides are well absorbed orally. Carbimazole is a prodrug and is rapidly metabolized in the blood to methimazole. They are distributed throughout the extracellular water and have a short half-life. Though, not concentrated in thyroid, they have a prolonged effect on the thyroid and need only to be given once daily. These drugs are metabolized in the liver. Carbimazole should be used with care during pregnancy, as excessive doses may suppress the fetal thyroid. It is also excreted in maternal milk and may cause goiter and hypothyroidism in the newborn.
Therapeutic Uses:
Methimazole and propylthiouracil are commonly used. They act quickly to block the oxidation of iodide, but the beneficial effects are delayed because the circulating T3 and T4 have a long half-life and the thyroid has large stores of the hormones in the colloid. Propylthiouracil has a more rapid onset of action because of its extra-thyroidal (conversion of T4 to T3) inhibiting action. In the majority of patients with Graves’ disease, hypothyroidism recurs within 6 months after therapy is stopped. Spontaneous remission is likely to occur in mild, recent-onset hyperthyroidism and if the goiter is small.
Adverse Effects:
Minor side effects include rashes, joint pains, enlarged lymph nodes and transient depression of the white cell counts. Life- threatening side effects include agranulocytosis, hepatitis, vasculitis and drug-induced lupus erythematosus. Drug should be discontinued if jaundice or symptoms of agranulocytosis (e.g. fever, chills, and sore throat) develop.
Symptomatic Therapy:
β blockers reduce those symptoms of thyrotoxicosis that are due to over activity of the sympathetic system, such as palpitation, tremor, sweating and anxiety until hyperthyroidism is controlled by specific therapy. Verapamil can be used to control tachycardia in lieu of β blockers, if the latter is contraindicated.
Essay # 12. Corticosteroids:
The adrenal cortex produces a number of hormones which belong to three main groups:
i. Mineralocorticoid Hormone:
Aldosterone is the principal mineralocorticoid that causes retention of Na+, phosphate, Ca+ and bicarbonate and reduction of serum K+. It acts on Na+ and K+ transport in the distal tubule of the kidney to enhance Na+ reabsorption. Its secretion is governed by the renin mechanism and its main function is to ensure maintenance of constant body fluid volume. It is not used as a drug.
ii. Sex Corticoid Hormones:
These are secreted in small amounts and are of no pharmacological importance.
iii. Glucocorticoid Hormones:
Cortisol or hydrocortisone is the main glucocorticoid hormone released from the adrenal cortex. Its main physiological role is concerned with metabolism of carbohydrate, fat and protein, maintenance of cardiovascular and skeletal muscle functions, a feeling of wellbeing and modification of the responses of body in conditions of stress. In addition to Cortisol, there are a number of synthetic hormones with similar actions and the whole group is called the corticosteroid or steroid hormones.
The pharmacological actions of glucocorticoids generally fall under three main groups:
(a) General metabolic and systemic effects,
(b) Negative feedback effects on the anterior pituitary and hypothalamus and
(c) Suppression of disease process.
General Metabolic and Systemic Effects:
Carbohydrate and Protein Metabolism:
Glucocorticoids tend to cause hyperglycemia due to a decrease utilization of glucose by peripheral tissues, an increase in gluconeogenesis, an increase production of glucose from protein and decrease sensitivity to insulin. Prolonged treatment may rarely give rise to diabetes mellitus. Glucocorticoids decrease protein synthesis and increase protein breakdown, particularly in muscles. This catabolic action may result in muscle wasting (proximal myopathy) and thinning of the skin, which becomes susceptible to bruising. They increase uric acid secretion.
Fat Metabolism:
Glucocorticoids promote lipolysis. The peripheral tissues loose fat which is deposited over face, neck and shoulders giving rise to round “moon-like” face with a picture similar to that of Cushing’s disease.
Bone:
Glucocorticoids inhibit osteoblast formation as well as intestinal absorption of calcium. They stimulate the secretion of parathyroid hormone that mobilizes calcium from bone. The bone production is thus reduced resulting in osteoporosis, which may cause osteoporotic fractures of the hip or vertebrae in the elderly. High doses are associated with avascular necrosis of the femoral head.
Stomach:
Glucocorticoids increase secretion of gastric acid and pepsin and may exacerbate peptic ulcer. Their anti-inflammatory action may mask the symptoms of perforation of peptic ulcer.
Central Nervous System:
Glucocorticoids usually produce a feeling of wellbeing (euphoria). In patients with mental disorders, they may cause serious mental disease, a serious paranoid state or depression with risk of suicidal tendency.
Miscellaneous Effects:
In children, administration of glucocorticoids results in suppression of growth.
Negative Feedback Effects:
Glucocorticoid administration depresses the secretion of corticotrophin releasing hormone from the hypothalamus and adrenocorticotropic hormone from the anterior pituitary with a resultant decrease in secretion of endogenous glucocorticoids and atrophy of adrenal cortex. Adrenal atrophy can persist for years after stopping prolonged corticosteroid therapy and any illness or surgical emergency may require corticosteroid therapy to compensate for lack of sufficient adrenocortical response.
Suppression of Disease Processes:
Glucocorticoids have potent anti-inflammatory and immunosuppressive effects. The anti-inflammatory action may be due to the synthesis of a new protein, lipocortin, which inhibits the production of prostaglandins, leukotriene’s and platelet activating factor by inflammatory cells.
In certain disease antibody producing system may become deranged and produce antibodies against various body tissues. Diseases, which arise in this way, are called “autoimmune” and steroids, by suppressing the antibody system, can be useful in the management of such autoimmune disorders. Anti-inflammatory and immunosuppressive effect constitutes the main uses of glucocorticoids and their other pharmacological actions are responsible for the adverse effects seen in therapy.
Glucocorticoids have marked antitumor effects in acute leukemia and lymphomas. They have anti-lymphocyte action. They enhance appetite and produce a sense of wellbeing in the management of symptomatic end-stage malignant disease. In cerebral tumors, they help in reducing edema.
Pharmacokinetics:
Glucocorticoids are readily absorbed from GIT. Almost 90% of the drug is bound to plasma proteins. They are metabolized in the liver. Inhaled corticosteroids using spacer devices have high topical potency due to increased airway deposition and a low systemic bioavailability due to reduced oropharyngeal deposition.
Preparations:
Hydrocortisone and cortisone, the natural hormones exhibit some mineralocorticoid activity. Large number of semisynthetic analogues of the natural hormones does not possess mineralocorticoid activity and can be given in anti-inflammatory (pharmacological) doses without the adverse effect of sodium retention.
Hydrocortisone:
The relative high mineralocorticoid activity makes it unsuitable for disease suppression on a long- term basis. It is used on a short-term basis by intravenous injection for emergency conditions.
Prednisolone:
It has predominant glucocorticoid activity and is the steroid most commonly used for long-term disease suppression.
Deflazacort:
It is derived from prednisolone and has a high glucocorticoid activity.
Triamcinolone:
It causes marked muscle wasting which may result in proximal myopathy. It is not indicated for chronic therapy. Methylprednisolone, betamethasone and dexamethasone.Lack significant mineralocorticoid activity, which make them particularly suitable for high dose therapy in cerebral edema, where water retention would be a disadvantage.
Corticosteroid Inhalations:
Inhaled corticosteroids are useful adjunct to β2 stimulants in the management of asthma. Beclometasone, budesonide and fluticasone are highly lipophilic and employed.
Therapeutic Uses:
a. Suppression of Disease Processes:
Corticosteroids can save or prolong life by suppressing the effects of the disease process, but do not cure the under lying condition, although remission may occur.
b. Inflammatory Conditions:
The anti-inflammatory effect of steroids is used for treatment of systemic lupus, polyarteritis nodosa, nephrotic syndrome and related diseases. In rheumatoid arthritis, steroids although very effective, are rarely used over long periods because of high incidence of adverse effects.
c. Autoimmune Diseases:
Steroids are useful in idiopathic thrombocytopenic purpura, certain hemolytic anemia’s, acute chronic hepatitis and prevention and rejection of organ transplant rejection.
d. Allergic Conditions:
Hydrocortisone (100-300 mg IV) is life-saving in acute hypersensitivity reaction when used as an adjunct to adrenaline and septic shock.
e. Bronchial Asthma:
Inhaled steroids are the drugs of choice for prophylaxis of bronchial asthma. Oral or IV steroids are required with beta blockers in life threatening attacks.
f. Malignant Diseases:
Steroids are used for acute lymphoblastic leukemia, Hodgkin’s disease, lymphomas and cerebral tumors.
g. Intestinal Diseases:
Topical (by enema) and systemic (oral or IV) steroids are used for ulcerative colitis and Crohn’s disease.
h. Skin Diseases:
Inflammatory conditions of skin, such as eczematous disorders and psoriasis respond to topical steroids. Prolonged application to the skin can produce atrophy of the skin and a tendency to bacterial or fungal infections.
i. Eye:
Steroids may be used for short-term local treatment (eye drops or ointment or sub-conjunctival injection) of anterior segment inflammation. Steroid cataract, glaucoma and infection are dangerous hazard to indiscriminate use.
j. Replacement Therapy:
Small (physiological) doses of steroids are needed in adrenal insufficiency, which may arise in Addison’s disease, hypopituitarism, or adrenalectomy. A combination of hydrocortisone and fludrocortisone is indicated since hydrocortisone alone does not provide sufficient mineralocorticoid activity for complete requirements.
Adverse Effects:
Mineralocorticoid side effects include hypertension, edema and potassium loss.
Glucocorticoid side effects may be dangerous, when given in high suppressive (pharmacological) doses and include:
Diabetes especially in the elderly patients.
Osteoporosis with resultant fracture of the hip or vertebrae and high doses may cause avascular necrosis of femoral head.
Mental disturbances- Serious paranoid state or depression with risk of suicide may be induced, particularly in patients with history of mental disorder.
Muscle wasting,
Peptic ulcer may rarely occur.
Modification of tissue reactions may result in spread and masking of clinical signs of infection. Serious infection, e.g. septicemia and tuberculosis may reach an advance stage before being recognized. Chicken pox, herpes zoster and measles may become life threatening in patients taking steroids, if they have no immunity from a previous attack.
Cushing’s syndrome, growth suppression, glaucoma or cataract and adrenal cortical atrophy are other possible side effects. Side effects are minimized by using lowest effective dose for minimum possible period. Steroids are contraindicated in systemic infections unless specific antibacterial therapy is given and with live virus vaccines.
Essay # 13. Drugs Used to Cure Female Infertility:
i. Gonadotropins:
Follicular stimulating hormone and luteinizing hormone are the gonadotropins secreted by anterior pituitary, which act in concert to release female sex hormones responsible for the fertility and maintenance of pregnancy or menstruation. Follicular stimulating hormone (FSH) causes ripening of the ovarian follicle, which releases estrogen.
In males, it is necessary for the production of spermatozoa. Luteinizing hormone (LH) helps in the development of corpus luteum, which produces the hormone progesterone. In males, it stimulates the interstitial cells of the testis to produce androgens.
Follicular stimulating hormone (urofollitropin or follitropin alpha and beta) and luteinizing hormone (chorionic gonadotropin) or a combination of FSH and LH (human menopausal gonadotrophins) are used in female infertility due to lack of normally secreted gonadotrophins.
ii. Clomifene:
Clomifene releases gonadotrophins from the anterior pituitary and is used in the treatment of female infertility due to failure of ovulation. It has the advantage of oral administration and a high success rate. It should not be used for longer than 6 cycles (5 days early in the menstrual cycle) because of the risk of ovarian cancer. Adverse effects include hot flushes, abdominal discomfort, menorrhagia, endometriosis, weight gain and visual disturbances.
iii. Gonadorelin Analogues:
Buserelin and goserelin produce an initial phase of stimulation, followed by a reduction in the secretion of gonadotrophins, which in turn leads to inhibition of androgen and estrogen production. They are used in the treatment of endometriosis and carcinoma of prostate.
iv. Gonadotrophin Inhibitors:
Danazol and gestrinone inhibit both gonadotrophin-releasing hormone and gonadotrophin release and are used to treat endometriosis and various benign breast disorders. They combine androgenic activity with antiestrogenic and antiprogestrogenic activity. Adverse effects are due to androgenic activity, which include abnormal hair growth, greasy skin, acne, fluid retention, weight gain and nausea.
v. Estrogens:
Estrogens are necessary for the development of female secondary characteristics. The important actions of estrogens are myometrial hypertrophy and endometrial hyperplasia, sensitisation of uterine muscle to certain stimulating agents, increase in the duct tissue in the breast and inhibition of production of prolactin by pituitary.
Estrogen used therapeutically belongs to three groups:
a. Natural Estrogens:
Estradiol, estrone and estriol
b. Synthetic Estrogens:
Ethinylestradiol, mestranol and dienestrol+
c. Conjugated Estrogen:
Premarin- +Used topically in the vagina
Therapeutic Uses:
Estrogens are used for hormone replacement therapy (HRT), rarely in neoplastic diseases, oral contraception and atrophic vaginitis (as a cream).
Hormone Replacement Therapy:
Natural and conjugated estrogens have a more appropriate profile for hormone replacement therapy (HRT) than synthetic estrogens. They are used during and after menopause to relieve vasomotor symptoms, and hot flushes. They are very effective in preventing osteoporosis, which is a serious problem in postmenopausal women. Progestogen is combined with estrogen to prevent the risk of carcinoma of the uterus.
Estrogen can be given by different routes. Topical estrogen can be used in atrophic vaginitis. Oral preparations of estrogens are subject to first pass metabolism, therefore, subcutaneous or transdermal administration is more akin to endogenous hormone activity.
Tibolone is a synthetic hormone that combines estrogenic and progestogenic activity with weak androgenic activity. It is used to control postmenopausal symptoms. Raloxifene blocks the action of estrogen on the breast and uterus. It prevents vertebral fractures in postmenopausal women at increased risk of osteoporosis. It does not reduce menopausal vasomotor symptoms and does not cause menstrual bleeding.
Side effects of HRT are nausea, weight gain, headache, fluid retention and risk of breast cancer and venous thrombosis. HRT is contraindicated in thromboembolic disorders, breast or endometrial cancer, undiagnosed uterine bleeding and liver diseases.
Neoplastic Diseases:
i. Prostate Cancer:
Diethylstilbesterol suppresses the production of androgens that stimulate the neoplasm. Toxicity is common and the standard treatment of metastatic cancer of the prostate includes cyproterone, which directly blocks the action of androgens on the prostate or orchidectomy or gonadorelin analogue, which reduce androgen secretion.
ii. Breast Cancer:
Estrogens are more usually associated with a worsening of breast cancer, but have been used with some success for the treatment of advanced breast cancer. Estrogens are occasionally used in advanced metastatic breast cancer in postmenopausal women, who obtain temporary but sometimes striking remissions of their disease.
iii. Atrophic Vaginitis:
Dienestrol cream is applied daily in the vagina for 1 week and then reduced in atrophic vaginitis, which occurs in postmenopausal women due to estrogen deficiency.
vi. Progestogens:
Progesterone is the natural progestogen and is mainly produced by the ovary. It is concerned in the maintenance of the pregnancy by thickening and development of the secretary phase in the endometrium and by damping down the excitability of the uterine muscle.
Progestogens used therapeutically belong to two groups:
a. Progesterone and Its Analogue:
Progesterone, dyhydro- gesterone, hydroxyprogesterone and medroxyprogesterone.
b. Testosterone Analogues:
Norethisterone, norgestrel, levonorgestrel, norgestimate, desogestrel and gestodene. Progesterone and its analogues are less androgenic and do not cause virilisation, However, they have adverse effects on plasma lipids and increase the possibility of vascular diseases. Testosterone analogues have no adverse effects on lipids and are commonly used.
Therapeutic Uses:
Progestogens have a very limited place in therapeutics, except for oral contraception where used either alone or in combination with estrogens. Progestogens prevent the development of intrauterine cancer by causing cyclical shedding of the endometrium. The other uses of progestogens are endometriosis, menstrual disorders and neoplastic diseases such as breast, endometrial and renal cell carcinoma.
Adverse Effects:
GIT disorders, fluid retention, weight gain, breast discomfort, acne, urticaria and menstrual disturbances are common side effects. They may cause CNS symptoms, alopecia and rarely jaundice. Progestogens are contraindicated in undiagnosed vaginal bleeding, severe arterial disease, breast or genital tract carcinoma and active liver disease.
vii. Oral Contraception:
There are two main types of oral contraceptive pill (the Pill):
a. The combined oral contraceptive pill
b. The progestogen only pill
a. Combined Oral Contraception pill:
The combined oral contraceptive pill containing estrogen and progestogen is the most effective method of fertility control.
It prevents conception by following mechanisms:
i. The estrogen inhibits the release of FSH by a negative feedback effect, thus inhibiting follicular development.
ii. The progestogen inhibits the release of LH, so that ovulation cannot occur. Together, estrogen and progestogen render the endrometrium hostile to implantation.
iii. Both estrogen and progestogen may upset the coordinated contractions of the fallopian tubes, uterus and cervix.
The oral combined contraceptive pill usually contains ethinylestradiol (30-50 microgram) and progestogens (norethisterone or levonorestrel or desogestrel or gestodene). The combined pill preparations are available in low strength (ethinylestradiol 20 microgram), standard strength (ethinylestradiol 30 microgram) and high strength (ethinylestradiol 50 microgram). The choice depends on the age and presence of risk factors for venous and arterial thrombosis such as obesity, diabetes, hypertension, migraine, varicose veins, etc.
Adverse Effects of the Combined Pill:
Thromboembolic Complications:
Though combined contraceptive pills may reduce the risk or incidence of menstrual disorders and benign breast disease and cancer of the ovary and uterus, there is now clear evidence that women, who are heavy smokers and are in the 40-44 age group run the risk of developing thromboembolic complications and therefore should not use combined contraceptive pills.
Thrombosis is believed to be due to the estrogen in the Pill and for this reason the estrogen content of these preparations is kept as low as possible. Progestogen fraction of the Pill has been associated with the arterial disease, which is due to alteration in blood lipids.
The new progestogens desogestrel and gestodene are less likely to cause changes in plasma lipids with consequent lesser risk of vascular disease (e.g. coronary thrombosis and strokes), but may actually increase the incidence of venous thrombosis in the legs and, thus, the risk of pulmonary embolism and therefore it is advisable to avoid contraceptives containing new progestogens in women, who are overweight, immobile or have a history of thrombosis.
Cancer:
There has been conflicting reports about the causation of cancer of breast and cervix with the use of combined Pill. However, a recent study suggests that current or former use of oral contraceptives is not associated with an increased risk of breast cancer. The incidence of cancer of the cervix has been found to be more common in those taking oral contraceptives, and it is advisable that women who have taken oral contraceptives for than 5 years should have an annual cervical smear checkup.
Other Effects:
Other side-effects like weight gain, GI upsets, acne, flushing, dizziness, irritability, depression, and gallstones have been reported, but they are of no significance and as a matter of fact many women feel better while taking these preparations.
b. Progestogen-Only Pill:
Use of preparations which only contain progestogens only prevent ovulation in about half the menstrual cycles and thus are less efficient as contraceptives. Progestogen Pill, which inhibits the ovulation and changes the character of the cervical mucus, is less safe contraceptive than the combined pill, but has virtually no risk of thrombotic disease and may be preferred in older women or those at special risk from thrombosis.
Progestogen preparations are available as oral pills, depot injections and intrauterine progestogen coil. The intrauterine coil releases a progestogen, levonorgestrel, directly into the uterine cavity, and is used as a contraceptive and to treat primary menorrhagia. It acts by causing thickening of cervical mucus and preventing endometrial proliferation. The main adverse effects of the progestogen-only Pill are amenorrhea, spotting, vomiting, breast discomfort, depression, and weight changes.
Contraindications of Oral Contraceptives:
The oral contraceptives should not be used in thromboembolic disease, carcinoma of breast and cervix, undiagnosed vaginal bleeding, severe liver disease, hypertension, migraine, depression and epilepsy. Drugs, which induce hepatic enzyme activity, decrease the efficacy of the contraceptive pill. The most important drug in this respect is rifampicin but anti-epileptics, isoniazid, griseofulvin, and broad spectrum antibiotics also reduce the efficacy of the Pill.
Postcoital Contraception (Yuzpe Method):
Oral contraceptive pills, progestogen alone or combined pill, if taken within 72 hours of unprotected intercourse are effective in reducing the risk of pregnancy. Centchroman (Saheli) is a non-steroidal estrogen antagonist developed by CDRI, India and is used as oral contraceptive. Its exact mode of action is not known. It is claimed to prevent implantation of the ovum and to be free of the side effects of contraceptive pill.
Essay # 8. Drugs Used to Cure Male Fertility:
Testosterone, the natural androgen, is produced by the interstitial cells of testis. It is responsible for the secondary male sex characteristics including distribution of hair, deepening of the voice and the growth of genitals. The luteinizing hormone (LH) of the pituitary controls its release from the testis. Testosterone also has an anabolic action.
Therapeutic Uses:
Testicular Hormone Deficiency:
Testosterone is used in testicular hormone deficiency due to hypopituitarism. It is given orally, as an implant or skin patches. Esters of testosterone (Sustanon) can be given intramuscularly every 3 weeks and is released slowly from the injection site. Mesterolone is similar to testosterone and is given orally. Unlike testosterone it does not cause jaundice or depress spermatogenesis.
Carcinoma of the Breast:
Testosterone is effective in about 30% of postmenopausal patients with advanced carcinoma of the breast for relieving symptoms and causing temporary regression of secondary deposits. It does, however, has virilising effects and causes the growth of facial hair, deepening of the voice and acne.
Adverse Effects:
Testosterone may lead to prostate abnormalities, prostate cancer and cholestasis jaundice. It may also cause electrolyte disturbances including sodium retention with edema and hypercalcemia, increased bone growth and virilism in women. Testosterone is contraindicated in breast cancer in men, prostate cancer, liver tumors, hypercalcemia and pregnancy.
Anti-Androgens:
Cyproterone acetate and flutamide block the action of testosterone at the cell receptors. They inhibit spermatogenesis and produce reversible infertility. Anti-androgens are used in various endocrine disorders, where there is overproduction of male hormone causing hirsutism in the female (when it is combined with estrogen) and severe hyper-sexuality and sexual deviations in the male. They are also used in patients with metastatic prostate cancer refractory to gonadorelin analogue therapy. Anti-androgens are hepatotoxic and are mainly indicated to palliate symptoms of advanced prostate cancer.
Finasteride is a specific inhibitor of testosterone metabolism and interferes with its action on the prostate gland. The size of the prostate gland is reduced and the obstructive symptoms of enlarged prostate are relieved. Its use is limited to benign prostatic hyperplasia, where it improves the urinary flow rate. The other drugs used for benign prostatic hyperplasia are selective alpha-blockers such as prazosin.
Anabolic Steroids:
These are the derivatives of male sex hormones that have less virilisation effects in women, but have significant anabolic action (protein building property). Their protein building property is thought to be useful to hasten convalescence and in senile osteoporosis (a condition due to lack of protein in bone), but clinically their effectiveness is not proven. Their use as body builders or tonics is quite unjustified. They are abused by athletes. The use of anabolic steroids is only limited in the treatment of some aplastic anemias.
Drugs for Impotence:
Male erectile dysfunction is commonly due to psychological factors, but endocrine abnormalities and certain drugs (e.g. alcohol, tricyclic antidepressants, neuroleptics, anti-hypertensives, and cimetidine) may also result in a failure to produce a satisfactory erection. Erection depends on the relaxation of the penile smooth muscle, with subsequent engorgement with blood following necessary stimulus.
Prostaglandin E1 (alprostadil) or papaverine given by intra-cavernosal injection relaxes smooth muscle and produces a satisfactory erection. The procedure is not only cumbersome, but leads to multiple penile problems. Erection lasting for longer than 4 hours (priapism) is an emergency requiring penile aspiration, intra-carvernosal injection of sympathomimetic vasoconstrictors or even surgical intervention.
Sildenafil (viagra) inhibits the phosphodiesterase 5 in the blood vessels of penis leading to vasodilatation and enhanced erection, when taken an hour or two before intercourse. It has the advantage of oral administration and being highly effective.
Common side effects of sildenafil are dyspepsia, headache, flushing, dizziness, visual disturbances and increased intraocular pressure. Sildenafil is contraindicated in recent stroke or myocardial infarction, hypotension (it should not be used in patients receiving nitrates) and hereditary degenerative retinal disorders. Antibiotics (erythromycin), antifungal, antiviral and ulcer healing (cimetidine) drugs increase the plasma sildenafil concentration and may cause priapism.