Metabolic Drugs

ENDOCRINE DRUGS

Hormones are the biological active substances that are produced by endocrine glands. They possess high activity being present in small doses. Hormones regulate processes of reproduction, growth, development of organism and model it’s protective reactions. By chemical structure hormone drugs are divided on next groups:

1. Substances of protein or peptide structure (drugs of hypothalamus, pituitary, parathyroid and pancreatic hormones, and calcitonin);

2. Derivatives of aminoacids (agents of thyroid hormones);

3. Steroid substances (drugs of adrenal cortex and gonadal hormones).

Hormones interact with specific receptors, located on cellular membranes or intracellularly. Hormones of protein structure predominantly bind with receptors on cellular membranes. Mostly these receptors are co-operated with adenylate cyclase system, which stimulating leads to increasing of cAMP forming, and it’s through protein kinases influence on intracellular processes. Adenylat cyclase, cAMP and calcium-ions are mediators among receptors and intercellular processes. Steroid hormones enter cells of target tissues and binds to an intracellular specific receptor. The hormone receptor complex translocates into the nucleus and binds to nucleotides on various genes and regulate their transcription and proteins synthesis.

Hormonal drugs are received from different sources. Some agents are extracted from correspondent animal gland (thyreoidine, bovine insulin), another are synthesized (L-thyroxine, triiodothyronine). Also, hormones can be produced by recombinant DNA techniques (human insulin) by inserting the human proinsulin gene into E coli or yeast.

Hormonal drugs are used for the treatment of endocrine diseases (substitutive, stimulating, and inhibiting therapy) and nonendocrine diseases (allergic disorders, cancer). It is necessary to remember, that during prolonged using of high doses of hormonal substances, the atrophy of endocrine glands is possible, in result of which during sudden cessation of the treatment “syndrome of breaking” (withdraw) may develop. It is characterized by symptoms of acute endocrine insufficiency.

SUBSTANCES OF PROTEIN AND AMINOACID STRUCTURE

HYPOTHALAMIC AND PITUITARY HORMONES

Neuroendocrine control of metabolism, growth, and certain aspects of reproduction is mediated by a combination of neural and endocrine systems located in the hypothalamus and pituitary gland (hypophysis). The pituitary gland consists of anterior and intermediate lobes (adenohypophysis), and a posterior lobe (neurohypophysis), which release a number of hormones that either control the secretion of other endocrine glands or affect the metabolic actions of target tissues directly. The secretion of anterior lobe hormones is regulated by hormones formed in the hypothalamus. These hormones are small peptides that function as releasing or inhibiting hormones. The posterior lobe hormones are synthesized in the hypothalamus and transported to the pituitary posterior lobe, from which they are released into the circulation.

Six anterior pituitary hormones are recognized: somatotropin (growth hormone), thyrotropin (TSH), adrenocorticotropin (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL).

Somatotropin (growth hormone) is a peptide hormone. It deficiency leads to short stature. Somatotropin for pharmacologic use is produced with recombinant DNA technology. Somatotropin can be administered intramuscularly. Pharmacologic doses of growth hormone cause longitudinal growth indirectly via another class of peptide hormones, the somatomedins, or insulin-like growth factors that are synthesized predominantly in the liver. Also somatotropin stimulates growing of skeletal muscle and organs. It increases protein synthesis, which results in nitrogen retention. Somatotropin cause the retention of phosphorus, sodium, and potassium through promotion of cellular growth. The metabolic action of growth hormone is an initial insulin-like effect with increased tissue uptake of both glucose and amino acids and decreased lipolysis. Within a few hours, there is a peripheral insulinantagonistic effect with impaired glucose uptake and increased lipolysis. Somatotropin is indicated for long-term treatment of growth failure in children caused by pituitary growth hormone deficiency (pituitary dwarfism). Adverse effects often include arthralgia and fluid retention.

Somatostatin is found in the hypothalamus. It has been synthesized. Somatostatin has been shown to inhibit the release of growth hormone, glucagon, insulin, and gastrin. Somatostatin has limited therapeutic usefulness because of its short duration of action (half-life 2-3 minutes) and its multiple effects on many secretory systems. Octreotide is synthetic analogous of somatostatin. It is more potent than somatostatin in inhibiting growth hormone release. Because of this relatively reduced effect on pancreatic β-cells, octreotide has been particularly useful in treating acromegaly and carcinoid tumors (gastrinoma, glucagonoma) without provoking hyperglycemia. The serum half-life of octreotide is about 80 minutes. Adverse effects of therapy include biliary sludge and steatorrhea.

Thyrotropin is normally secreted as part of a feedback system of thyroid hormone level regulation. It stimulates each step of thyroid hormone synthesis, including iodine uptake. In hyperthyroidism, the serum thyrotropin level is suppressed. Therapeutic thyrotropin is prepared from bovine anterior pituitaries. Thyrotropin is used diagnostically to differentiate between primary and secondary hypothyroidism. Thyroid tenderness and symptoms of hyperthyroidism may occur. Thyrotropin-releasing hormone that is found in the hypothalamus stimulates the pituitary to produce thyrotropin. Thyrotropin-releasing hormone stimulation of thyrotropin is blocked by thyroxine and potentiated by lack of thyroxine. Protirelin (rifathyroin) is a synthetic analogous of thyrotropin-releasing hormone. Protirelin is indicated as an adjunct for distinguishes between secondary (pituitary) and tertiary (hypothalamic) hypothyroidism.

Adrenocorticotropins (ACTH) primary endocrine function is to stimulate synthesis and release of cortisol by the adrenal cortex. Corticotropin is an ACTH that is obtained from porcine or bovine pituitary glands. Synthetic human ACTH is known as cosyntropin. Both animal and synthetic corticotropin are well absorbed by the intramuscular route. Cosyntropin is preferred because it is less antigenic. The biologic half-live of agents is under 20 minutes. The effects of long-acting repository forms of corticotropin persist for up to several days with a zinc hydroxide complex. Corticotropin shares many actions of the corticosteroids due to its ability to increase endogenous corticosteroid synthesis. Corticotropin is indicated as an aid in diagnosing adrenocortical insufficiency and after prolonged using of glucocorticoids for restoring of adrenal’s cortex functioning. But it may also cause depression of ACTH production. The toxicity of therapeutic doses of ACTH resembles that of the glucocorticoids with the added mild virilism (hyperandrogenism) in women.

Follicle-stimulating hormone (FSH) stimulates gametogenesis and follicular development in women and spermatogenesis in men. It is needed for proper ovarian estrogenesis. Human menopausal gonadotropins (hMG) are a mixture of partially catabolized human FSH and LH extracted from the urine of postmenopausal women. They are used in states of infertility to stimulate ovarian follicle development in women and spermatogenesis in men and for pituitary or hypothalamic hypogonadism with infertility. In both sexes, they must be used in conjunction with a luteinizing hormone. Overstimulation of the ovary with hMG can lead to ovarian enlargement.

Luteinizing hormone (LH) acts on testicular Leydig cells to stimulate testosterone production. In the ovary, LH acts on the mature follicle to induce ovulation, and it stimulates the corpus luteum in the luteal phase of the menstrual cycle to produce progesterone. Human chorionic gonadotropin is a hormone produced by the human placenta and excreted into the urine, whence it can be extracted and purified. It is very similar to LH in structure. hCG can be used in combination with human menotropin to induce ovulation in women and for stimulation of testosterone secretion by the testes of men with hypogonadotropic hypogonadism. hMG and hCG are administered intramuscularly. Androgen-dependent neoplasia and precocious puberty are contraindications to hCG use.

Gonadotropin-releasing hormone (GnRH) is produced by hypothalamus and controls the release of gonadotropins (FSH, LH). Pharmaceutical GnRH is synthetic. Analogs (e.g., leuprolide, nafarelin) are more potent and longer-lasting than native GnRH. GnRH and its analogs are administered parenterally. Pulsatile intravenous administration stimulates FSH and LH secretion. Thus, GnRH is used to treat infertility caused by hypothalamic hypogonadism in both sexes. In contrast, GnRH administered continuously or GnRH analogs administered in depot formulations inhibit gonadotropin release and induce hypogonadism. Leuprolide, nafarelin are used to treat prostate cancer, uterine fibroids, and endometriosis. Danazol is gonadotropin inhibitor. It suppresses the output of pituitary gonadotropins (FSH, LH). As a result, anovulation and associated amenorrhea occur. Danazol is being used to treat gynecomastia, endometriosis, and menorrhagia.

Prolactin is the principal hormone that stimulates the development of mammary glands and lactation. Its preparation - lactin is obtained from bovine pituitary glands. Lactin is available for use in lactation-deficient women in period following birth. For patients with symptomatic hyperprolactinemia, inhibition of prolactin secretion can be achieved with bromocriptine and other dopamine agonists. Also bromocriptine may be used to treat acromegaly and Parkinson’s disease.

The hormones of the intermediate lobe have melanocyte-stimulating properties. Its preparation – intermedin that is obtained from bovine pituitary gland is used for the treatment of degenerative processes in retina and hemeralopia (impairment of vision in reduced illumination) in eye-drops form.

Two posterior pituitary hormones are known: vasopressin and oxytocin. Their structures are very similar. Pharmaceutical vasopressin and oxytocin are synthetics. Pituitrine and adiurecrine are used in clinics also. They are the extracts of bovine pituitary gland. In pharmacologic doses, oxytocin can be used to induce uterine contractions and maintain labor. It can also be used for control of postpartum uterine hemorrhage. Oxytocin elicit milk ejection in lactating women. Oxytocin is administered intravenously or intramuscularly. It circulating half-life is 5 minutes. Contraindications include fetal distress, prematurity, abnormal fetal presentation, cephalopelvic disproportion, and other predispositions for uterine rupture. Desaminooxytocin is a synthetic analog of oxytocin. It is act longer than parental agent and is used subglossal.

Vasopressin (antidiuretic hormone, ADH) possesses antidiuretic and vasopressor properties. A deficiency of this hormone results in diabetes insipidus. Vasopressin interacts with two types of receptors. V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction. V2 receptors are found on renal tubule cells and mediate antidiuresis through increased water permeability and water resorption in the collecting tubules. Vasopressin is administered by intravenous, intramuscular, or intranasal routes. The half-life of circulating ADH is approximately 20 minutes. Desmopressin is a long-acting synthetic analog of vasopressin with an antidiuretic-to-pressor ratio 4000 times that of vasopressin. Vasopressin and desmopressin are the alternative treatments of choice for pituitary diabetes insipidus. Vasopressin (but not desmopressin) can cause vasoconstriction and should be used cautiously in-patients with coronary artery disease.

THYROID AND ANTITHYROID DRUGS

The normal thyroid gland secretes the thyroid hormones - triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine). These hormones contain iodine as an essential part of the molecule. Nearly all of the iodide intake is via the gastrointestinal tract from food, water, or medication. Once taken up by the thyroid gland, iodide undergoes a series of enzymatic reactions that convert it into active thyroid hormone. First of all iodide is oxidized to iodine, in which form it rapidly iodinates tyrosine residues within the thyroglobulin molecule to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). This process is called iodide organification. Two molecules of DIT combine within the thyroglobulin molecule to form l-thyroxine (T4). One molecule of MIT and one molecule of DIT combine to form T3. Thyroid hormones are released from thyroglobulin by proteolysis of thyroglobulin. T4 and T3 in plasma are reversibly bound to globulin. Thyrotropin (pituitary) stimulates the synthesis and release of T4 and T3. These thyroid hormones, in a negative feedback fashion, act in the pituitary to block the action of thyrotropin-releasing hormone and in the hypothalamus to inhibit it synthesis and secretion.

The free forms of thyroid hormones, T4 and T3 enter the cell. Within the cell, T4 is converted to T3, which is more potent than T4, and the T3 enters the nucleus, where it binds to a specific receptor. Most of the effects of thyroid on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increased formation of RNA and subsequent protein synthesis.

Thyroid hormones have both catabolic (calorigenic) and anabolic effects. Thyroid hormones increase basal metabolism and consequent increase oxygen consumption of tissues and body temperature. They speed up the catabolism of carbohydrates, fats, and proteins. However, it potentiates the secretion and action of growth hormone. Many of the manifestations of thyroid hyperactivity resemble sympathetic nervous system overactivity (tachycardia, cardiac arrhythmia, tremor, excessive sweating, and nervousness). The secretion and degradation rates of hormones, including catecholamines, cortisol, estrogens, testosterone, and insulin, are affected by thyroid status. Diminished production of thyroid hormone (hypothyroidism, myxedema) leads to clinical manifestations of thyroid insufficiency, including low metabolic rate, tendency to weight gain, somnolence and edema of subcutaneous tissue. Thyroid deprivation in early life results in cretinism (mental retardation, dwarfism).

Thyroid preparations may be synthetic (L-thyroxine, triiodothyronine) or of animal origin (thyreoidine).

Synthetic L-thyroxine is the preparation of choice for thyroid replacement because of its stability, lack of allergenic foreign protein, and long half-life (7 days), which permits once-daily administration. Oral absorption of current preparations of L-thyroxine is averaging 80%. Although triiodothyronine (liothyronine) is 3-4 times more active than L-thyroxine, it is not recommended for routine replacement therapy because of its shorter half-life (24 hours), which requires multiple daily doses. Furthermore, because of its greater hormone activity and consequent greater risk of cardiotoxicity, T3 should be avoided in-patients with cardiac disease. T3 is almost completely absorbed (95%) and minimally interfered with by intraluminal binding proteins. Thyreoidine (thyroid) is the preparation of bovine desiccated thyroid gland. It contains the combination of thyroid hormones. Thyreoidin has variable hormone concentrations and high protein antigenicity.

Thyroid hormones are indicated as replacement therapy in the treatment of hypothyroidism. In general, L-thyroxine is the preferred thyroid hormone because of the absence of variability. Triiodthyronine is recommended because of its short half-life and readily reversible effects for initial therapy in myxedema and myxedema coma. It may also be preferred when gastrointestinal absorption processes are impaired.
Antithyroid drugs are used in case of hyperthyroidism.

The thioamides mercazolil (methimazole) and propylthiouracil are major drugs for treatment of thyrotoxicosis. Mercazolil is about ten times more active than propylthiouracil. Mercazolil and propylthiouracil are rapidly absorbed. They are readily accumulated by the thyroid gland. The major action is to prevent thyroid hormones synthesis by inhibiting iodine organification. A single dose of mercazolil exerts an antithyroid effect for longer than 24 hours; thus it can be used one time a day. Since the synthesis rather than the release of hormones is affected, the onset of these agents is slow, often requiring 3-4 weeks before stores of T4 are depleted. The adverse effects are rash, leukopenia, and goiter. It can be explained by decreasing of thyroid hormones level in blood that leads to increasing of thyrotropin synthesis. The last one stimulates thyroid gland hypertrophy and hyperplasia. For preventing of goitergenic effect iodine drugs are used. Potassium perchlorate (KClO4) can block uptake of iodide by the gland. Since these effects can be overcome by large doses of iodides, their effectiveness is somewhat unpredictable. Potassium perchlorate is rarely used clinically because it’s mild antithyroid activity and adverse effects (leukopenia, anemia).

Iodides – potassium iodide, sodium iodide - have multiple effects on the thyroid gland. They decrease the thyrotropin synthesis. Also iodides inhibit hormone's release and decrease the size and vascularity of the hyperplastic gland that make these drugs valuable as preoperative preparation for surgery. Disadvantages of iodide therapy include an increase in intraglandular stores of iodine, which may delay onset of thioamide therapy or prevent use of radioactive iodine therapy for several weeks. Iodide should not be used alone, because the gland will "escape" from the iodide block in 2-8 weeks. Adverse reactions include acneiform rash (similar to that of bromism), swollen salivary glands, conjunctivitis, and rhinorrhea.

Radioactive iodine (131I) is used for treatment of thyrotoxicosis. It is concentrated by the thyroid gland. Its therapeutic effect depends on emission of β-rays with an effective half-life of 5-8 days. Within a few weeks after administration, destruction of the thyroid parenchyma is evidenced by epithelial necrosis and follicular disruption.

The calcitonin secreted by the thyroid gland. The principal effects of calcitonin are to lower serum calcium and phosphate by actions on bone and kidney. Calcitonin inhibits osteoclastic bone resorption. In the kidney, calcitonin reduces both calcium and phosphate reabsorption. Also it decreases gastrin secretion and reduces gastric acid output. Human calcitonin monomer has a half-life of about 10 minutes. Salmon calcitonin (miacalcic) has a longer half-life. Both human calcitonin and miacalcic are synthesized. In addition, calcitonin is present in calcitrin that is obtained from porcine thyroid gland. The ability of calcitonin to block bone resorption and lower serum calcium makes it a useful drug for the treatment of hypercalcemia and osteoporosis.

Parathormone (parathyroid hormone, PTH) is produced by the parathyroid gland. PTH enhances calcium and phosphate absorption in intestine. In bone, PTH increases the activity and number of osteoclasts, the cells responsible for bone resorption. It increases bone remodeling, a specific sequence of cellular events initiated by osteoclastic bone resorption and followed by osteoblastic bone formation. In the kidney, PTH increases the ability of the nephron to reabsorb calcium but reduces its ability to reabsorb phosphate. Another important action of PTH on the kidney is its stimulation of 1,25-dihydroxyvitamin D production. All these effects are result in increasing serum calcium.

Parathyreoidine is produced from bovine parathyroid gland. It is injected intramuscularly or subcutaneous. Its action starts in 4 hours and last 24 hours. Parathyreoidine is used for hypothyroid tetany treatment.

PANCREATIC HORMONES AND ANTIDIABETIC DRUGS

Insulin is synthesized in β-cells islets of Langerhans, which interspersed throughout the pancreatic gland. Insulin is a small protein that contains 51 amino acids arranged in two chains linked by disulfide bridges. Within the β-cell, insulin precursor is produced and than proinsulin is hydrolyzed into insulin. Insulin releasing from pancreatic β-cells is stimulated in response to a glucose, mannose, certain amino acids (e.g., leucine, arginine), and vagal activity. Hyperglycemia results in increased intracellular ATP levels, which close the ATP-dependent potassium channels, and results in depolarization of the β-cell and opening of voltage-gated calcium channels. The resulting increased intracellular calcium triggers secretion of the hormone. The liver and kidney remove insulin from the circulation, presumably by hydrolysis of the disulfide connections through the action of insulinase. The half-life of circulating insulin is 3-5 minutes. Once insulin has entered the circulation, it is bound by specialized receptors that are found on the membranes of most tissues. The full insulin receptor consists of α-subunit, which is entirely extracellular and constitutes the recognition site, and a β-subunit that spans the membrane. The β-subunit contains a tyrosine kinase. When insulin binds to the α-subunit at the outside surface of the cell, tyrosine kinase activity is stimulated in the β-portion that leads to the series of phosphorylation within the cell. Finally, the insulin-receptor complex is internalized where insulin is act.

Insulin promotes uptake of carbohydrates, proteins, and fats in most tissues. Also, insulin stimulates protein and free fatty acid synthesis, and inhibits release of free fatty acid from adipose cells. Insulin increases active glucose transport through liver, muscle and adipose cellular membranes, and promotes conversion of intracellular glucose and free fatty acid to the appropriate storage forms (glycogen and triglyceride, respectively). In liver and muscles it inhibit glycogenolysis and gluconeogenesis. In addition, insulin decreases protein catabolism and ketogenesis.

Administered insulin substitutes for the lack of endogenous insulin secretion and partially corrects the disordered metabolism and inappropriate hyperglycemia of diabetes mellitus. They’re two types of diabetes mellitus. Type I diabetes (IDDM, insulin-dependent diabetes mellitus) is a catabolic disorder in which circulating insulin is virtually absent. Exogenous insulin is therefore required. Type II diabetes (NIDDM, non-insulin-dependent diabetes mellitus) represents a group comprising milder forms of diabetes that occur predominantly in obese. Circulating endogenous insulin is relatively inadequate because of tissue insensitivity. When dietary treatment fail to correct hyperglycemia, sulfonylurea drugs are usually prescribed. Insulin therapy may be required to achieve satisfactory glycemic control. Three principal types of insulins are available (1) short-acting – insulin, (2) intermediate-acting – insulin-semilente, insulin-lente, (3) long-acting – insulin-ultralente.

Short-acting insulin is dispensed as solutions and contains small amounts of zinc to improve their stability and shelf-life. Another insulins have been modified to provide prolonged action and are dispensed as suspensions with varying concentrations of zinc in acetate buffer (ultralente and lente insulins). Conventional subcutaneous insulin therapy presently consists of split-dose injections of mixtures of short-acting and intermediate-acting insulins or multiple doses of short-acting insulin preprandially in association with any of insulin suspensions (lente, or ultralente) whose prolonged duration of action provides overnight basal insulin levels. Clinical trials have demonstrated that optimal time of preprandial subcutaneous injection of regular human insulin is 30 minutes before the meal. Short-acting soluble insulin is the only type that should be administered intravenously and it is particularly useful when the insulin requirement is changing rapidly, such as diabetic ketoacidosis or after surgery.

According to the sources insulins are divided into beef, pork, and human. The beef hormone is slightly more antigenic than pork insulin. Human insulin, which is less expensive and immunogenic than pork insulin, has generally supplanted it. Currently, all insulins in Ukraine are available in a concentration of 40 units/ml.

Hypoglycemic reactions are the most common complication of insulin therapy. They may result from a delay in taking a meal or an overdosing of insulin. The symptoms of hypoglycemia are tachycardia, palpitations, sweating, tremulousness, nausea, and hunger. They may progress to convulsions and coma if untreated. In a case of mild hypoglycemia orange juice, glucose, or any sugar-containing beverage or food may be given. In case of unconsciousness the treatment of choice is to give 20 ml of 40% glucose solution by intravenous infusion or solutions of adrenaline or glucagon injected either subcutaneously or intramuscularly.

Because sensitivity is often to noninsulin protein contaminants, the new highly purified insulins have markedly reduced the incidence of insulin allergy, especially local reactions. Some diabetic patients have a high titer of circulating anti-insulin antibodies. This results in extremely high insulin requirementsoften more than 200 units daily. Atrophy or hypertrophy of subcutaneous fatty tissue may occur at the site of injection.

Oral hypoglycemic drugs
The major oral medications currently available for treating hyperglycemia in non-insulin-dependent diabetics are the class of compounds known as sulfonylureas.

Sulfonylureas release insulin from β-cells and potentiate the action of insulin on its target tissues. Sulfonylureas inhibit the efflux of potassium ion through the channel and results in depolarization. Depolarization, in turn, opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin. Sulfonylurea drugs might restore peripheral tissue sensitivity to insulin. Sulfonylureas are absorbed from gastrointestinal tract readily and completely. Mostly they bind with blood proteins (70-99%). Sulfonylureas are metabolized in liver and excreted mainly via kidneys. The most serious adverse effect is hypoglycemia. Also disulfiram-like reaction (flushing of the face, neck, and arms) may occur with any of the sulfonylureas when alcohol is ingested concurrently.

There are two generations of sulfonylureas: first generation are butamide, chlorpropamide; second generation are glibenclamide, glipizide. Butamide (tolbutamide) is well absorbed but rapidly oxidized in the liver. Its duration of effect is relatively short (6-10 hours). It is administered before each meal and at bedtime. Chlorpropamide has a long duration of effect (24-48 hours) and is slowly metabolized in the liver. The maintenance dose is given in the morning. Potential for serious adverse effects is high because of chlorpropamide prolonged action. Also chlorpropamide can cause antidiuretic effect. Diabetes patients who have not responded to butamide or chlorpropamide may respond to the more potent second-generation sulfonylureas.

Duration of action of glipizide and glibenclamide (gliburide) is approximately 24 hours. These agents should be ingested 30 minutes before breakfast, since rapid absorption is delayed when the drug is taken with food. The dose is given once a day. Serious adverse effect occurs more often with glibenclamide than with chlorpropamide and glipizide, because of prolonged action of glibenclamide. Gliclazide has the same serum half-life and duration of action as glibenclamide. In addition, it reduces platelet adhesiveness and aggregation and has fibrinolytic activity – hence gliclazide has prevent possible disorders of microcirculation during mellitus diabetes.

Second group of oral hypoglycemic compounds consists of the biguanides. These agents reduce blood glucose even in the absence of pancreatic β-cell function. Currently proposed mechanisms of action include direct stimulation of glycolysis in tissues, with increased glucose removal from blood, and slowing of glucose absorption from the gastrointestinal tract. Biguanides cause the accumulation of lactic acid in muscles (probably due to stimulation of anaerobic glycolysis). Biguanides have been most often prescribed for patients with refractory obesity. To this group belongs buformin (glibutide) and meformin. They are well absorbed from gastrointestinal tract. The onset of maximal hypoglycemic effect is 5 hours and duration of effect is 14 hours. A common schedule would be to begin with a single daily tablet given for several days. If this is well tolerated, to add a second tablet if hyperglycemia persists. The toxic effects of biguanides are gastrointestinal upset (nausea, vomiting, and diarrhea) and lactic acidosis. Biguanides does not provoke hypoglycemia.

Glucagon is synthesized in α-cells of Langerhans islets. The pharmacologic result of glucagon infusion is to raise blood glucose at the expense of stored hepatic glycogen. Glucagon has a potent inotropic and chronotropic effect on the heart. Thus, it produces an effect very similar to that of β-adrenoreceptor agonists without requiring functioning β-receptors. The major use of glucagon is for emergency treatment of severe hypoglycemic reactions in insulin-dependent patients when unconsciousness precludes oral feedings and use of intravenous glucose is not possible.

HORMONES OF STEROID STRUCTURE

ADRENOCORTICOSTEROIDS

The adrenal cortex releases a large number of steroids that may be classified as those having important effects on intermediary metabolism (glucocorticoids), those having principally salt-retaining activity (mineralocorticoids), and those having androgenic or estrogenic activity. The glucocorticoids (corticosteroids) in humans are cortisol (major) and cortisone. They are synthesized from cholesterol. The rate of their secretion changes in a circadian rhythm governed by irregular pulses of adrenocorticotropin (ACTH) that peak in the early morning hours and after meals. In plasma, they are bound to plasma proteins. Free hormone diffuses across cell membranes and complex with specific cytoplasmic receptors. These complexes then enter the cell nucleus, bind to DNA, and stimulate transcription of messenger RNA (mRNA) and subsequent protein synthesis. Glucocorticoids in rapid feedback way suppress the synthesis of pituitary ACTH. Most of the glucocorticoids are inactivated in the liver by reduction and conjugation with glucuronic acid or sulfate, and are excreted into the urine.

Effects of glucocorticoids. The glucocorticoids have important dose-related effects on carbohydrate, protein, and fat metabolism. In the liver, glucocorticoids increase glycogen deposition by stimulating glycogen synthase activity and increasing glucose production from protein (gluconeogenesis). Glucocorticoids inhibit the peripheral glucose uptake and lead to hyperglycemia. Glucocorticoids have catabolic effects in lymphoid and connective tissue, muscle, fat, and skin. In children, the catabolic effects of excessive amounts of glucocorticoid reduce growth. Glucocorticoids increase lipolysis and mobilize fatty acids from adipose tissues, leading to increased plasma fatty acid concentrations. Glucocorticoids increase bone resorption and calcium excretion, and decrease gastrointestinal absorption of calcium. These actions may lead to inhibition of bone growth in children and adolescents and the development of osteoporosis at any age.

Glucocorticoids have immunodepressive and anti-inflammation activities. Glucocorticoids decrease or prevent tissue responses to inflammatory processes, thereby reducing development of symptoms of inflammation without affecting the underlying cause. Glucocorticoids inhibit accumulation of inflammatory cells, including macrophages and leukocytes, at sites of inflammation. They also inhibit phagocytosis, lysosomal enzyme release, and release of several chemical mediators of inflammation. They reduce the permeability of inflamed capillaries and reduce of leukocyte adherence to the capillary endothelium, leading to inhibition of both leukocyte migration and edema formation; and diminish the activity of the phospholipase A2 with subsequent inhibition of the inflammation mediators synthesis (prostaglandins, thromboxanes, and leukotrienes) from arachidonic acid. Mechanisms of immunosuppressant action may involve prevention or suppression of cell-mediated (delayed hypersensitivity) immune reactions as well as more specific actions affecting the immune response. Glucocorticoids reduce the concentration of thymus-dependent lymphocytes (T-lymphocytes), monocytes, and eosinophils. They also decrease binding of immunoglobulin to cell surface receptors and inhibit the synthesis, and release of interleukins, thereby decreasing T-lymphocyte blastogenesis and reducing expansion of the primary immune response. Glucocorticoids may also decrease concentrations of complement components and immunoglobulins.

The structural and functional changes in the lungs near term, including the production of pulmonary surfactant required for air breathing, are stimulated by glucocorticoids. Treatment of the mother with large doses of glucocorticoid reduces the incidence of respiratory distress syndrome in infants delivered prematurely.

Steroids having glucocorticoid activity have become important agents for use in the treatment of many inflammatory and allergic disorders. Indications. Glucocorticoids are indicated for their anti-inflammatory and immunosuppressant effects in the treatment of allergic disorders (allergic rhinitis, angioedema, anaphylactic reactions, bronchial asthma, transfusion reactions), collagen disorders (dermatomyositis, vasculitis, lupus erythematosus, rheumatic fever), dermatitis, autoimmune anemia, chronic hepatitis, leukemia, ophthalmic disorders (iridocyclitis, keratitis). For most indications, glucocorticoid administration provides symptomatic relief but has no effect on the underlying disease processes. Use of these medications does not eliminate the need for other therapies that may be required.

Glucocorticoids are indicated (in physiologic doses) as replacement therapy in the treatment of adrenal insufficiency states. For this purpose are indicated cortisone, hydrocortisone (cortisol), and fludrocortisone because of their significant mineralocorticoid activity (see table 8.2). Cortisone is transformed in organism to hydrocortisone. It is used orally (tablets) or intramuscularly (suspension). Hydrocortisone can be injected intra-articulate (suspension) for the treatment of arthritis or can be applied topically (ointment) for dermatitis treatment. Fludrocortisone, a synthetic corticosteroid, is the most commonly prescribed salt-retaining hormone.

Natural glucocorticoids are used mostly in those cases, when their mineralocorticoid activity is desirable (adrenal insufficiency). However, agents having minimal mineralocorticoid activity are preferred in all another cases. This group includes prednisolone, methylprednisolone, fluorinated glucocorticoids (triamcinolone, dexamethasone, betamethasone), and bisfluorinated glucocorticoids (flumethasone, synaflane). It is consider, that presence of the fluor atom in glucocorticoids molecule has decrease its mineralocorticoid activity and its absorption from skin. Prednisolone is used orally, topically. It must be injected intramuscularly or intravenously for emerge states (anaphylactic reaction, bronchial asthma attack, shock states of different etiology). In generally, triamcinolone and dexamethasone are produced as tablets. Thanks to their bed absorption from skin (that diminish their systemic effects) flumethasone, synaflane (fluocinolone) are prescribed in ointment form for the treatment of dermatitis of different etiology.

Adverse effects. When the glucocorticoids are used less than 1 week, it is unusual to see serious adverse effects. The major undesirable effects of the glucocorticoids are the result of their hormonal actions and lead to the clinical picture of iatrogenic Cushing's syndrome. The appearance of the face is altered by rounding. Fat tends to be redistributed from the extremities to the trunk and face. Over a period of time can appear such adverse effects as weight gain, thinning of the skin (with striae), hyperglycemia, osteoporosis, and hypertension. Wound healing is also impaired. Other serious complications include the development of peptic ulcers, bacterial and mycotic infections. Glucocorticoids (especially, cortisone and hydrocortisone) cause some sodium and fluid retention and loss of potassium. Nowadays antagonists of the synthesis or action of the glucocorticoids are well-known. They can be used in the treatment of Cushing's syndrome. Mifepristone is a glucocorticoid antagonist that binds to glucocorticoid as well as to progesterone receptors. Metyrapone is an inhibitor of glucocorticoids and mineralocorticoids synthesis.

The most important mineralocorticoid in humans is aldosterone. However, small amounts of desoxycorticosterone (DOC) are also formed and released. Its actions, effects, and metabolism are similar to aldosterone. ACTH and angiotensin produce a stimulation of aldosterone release. Also its secretion is enhanced by dietary sodium restriction. Mineralocorticoids act by binding to the receptor in the cytoplasm of cells of the kidneys collecting tubules. Aldosterone promotes the reabsorption of sodium from urine by the distal renal tubules, loosely coupled to the secretion of potassium ion. Excessive levels of aldosterone lead to hypernatremia, hypokalemia, increased plasma volume, and hypertension. Desoxycorticosterone acetate (DOCSA) is used in practice. It is prescribed in case of chronic adrenal glands insufficiency, myasthenia and adynamia. Adverse effects of DOCSA are edema, hypertension.

Spironolactone is steroid that competes with aldosterone for binding sites and decrease its effect peripherally. It is used as diuretic drug (chapter “Diuretic drugs”) and for the treatment of hyperaldosteronism.

THE GONADAL HORMONES. ESTROGENS AND PROGESTINS

The ovary has important gametogenic and hormonal functions. First of all hypothalamic produce gonadotropin-releasing hormone (GnRH) which stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (see “Hypothalamic and pituitary hormones”). At the beginning of each cycle, a variable number of follicles, each containing an ovum, begin to enlarge in response to FSH. After 5 or 6 days, one of the follicles begins to develop more rapidly. The granulosa cells of this follicle synthesize estrogens. When ovum is matured, follicle is ruptures and ovulation is appearing. Following the above events, the cavity of the ruptured follicle fills is transformed to the corpus luteum. The cells of this structure produce estrogens and progesterone for the remainder of the cycle, or longer if pregnancy occurs. If pregnancy does not occur, the corpus luteum begins to degenerate and ceases hormone production. The endometrium, which proliferated during the follicular phase and developed its glandular structure during the luteal phase, is shed in the process of menstruation.

The major estrogens produced by women are estradiol, estrone, and estriol. Estradiol appears to be the major secretory product of the ovary. Most estrone and estriol are formed in the liver from estradiol. As noted above, estrogens are produced in the ovarian follicle and in corpus luteum. During pregnancy, the fetoplacental unit synthesizes a large amount of estrogen. When released into the circulation, estradiol binds strongly to a sex hormone-binding globulin. Estrogens are metabolized in the liver and their conjugated metabolites excreted in the bile. However, the conjugates may be hydrolyzed in the intestine to active, reabsorbable compounds.

Physiologic effects. Free plasma estrogens enter the cell and bind to their receptor. The receptor-hormone complex binds to nucleotides on various genes and regulates their transcription and proteins synthesis.

Estrogens stimulate the development of the vagina, uterus, and uterine tubes as well as the growth of the axillary and pubic hair. They stimulate stromal development and ductal growth in the breast and are responsible for the accelerated growth phase and the closing of the epiphyses of the long bones that occur at puberty. Estrogen also plays an important role in the development of the endometrial lining (proliferation). Estrogens decrease the rate of resorption of bone. Estrogens increase high-density lipoproteins level, slightly reduce low-density lipoproteins and cholesterol levels. Estrogens enhance the coagulability of blood. They are responsible for estrous behavior in animals and influence libido in humans. They facilitate the loss of intravascular fluid into the extracellular space, producing edema.

Many agents of steroid estrogens are used in medicine. They are estrone, estradiol dipropionas, and ethinyl estradiol. Estrone and estradiol are produced as oil solutions and are injected intramuscularly. Estrone is acts during 24 hours, however estradiol – 2-4 days. Ethinyl estradiol is a semisynthetic estrogen. It’s in 50 times more potent than estrone. Furthermore, ethinyl estradiol is available for ingestion. In addition to the steroid estrogens, a variety of nonsteroid compounds with estrogenic activity have been synthesized and used clinically. These include synestrol, diethylstilbestrol. Synestrol is the synthetic analogue of estradiol. It is taken orally and injected intramuscularly.

Indications. Estrogens are indicated for replacement therapy in estrogen-deficient patients (upset of menstrual cycle - dysmenorrhea, amenorrhea, castration, or menopause). They are indicated for complex treatment of breast carcinoma in postmenopausal women and prostatic carcinoma in men. Estrogens alone or combined with progestins can be used for contraception. They have been used extensively to replace estrogen in the treatment of vasomotor symptoms, and osteoporosis associated with menopause. For this purpose patients can use estrogens or their combination with gestagens: proginova (contains estradiol valeriat; 21 dragee for month), clinorm (two-phase agent; 9 dragee that contain estradiol valeriat; 12 dragee - estradiol valeriat + levonorgestrel [gestagen]).

Adverse effects. Estrogen therapy may cause a menorrhagia, endometrial hyperplasia. They can be prevented by administration of a progestin agent with estrogen in each cycle. Nausea and breast tenderness are common and can be minimized by using the smallest effective dose of estrogen. Estrogen can lead to cholestasis, thrombophlebitis, peripheral edema, and hypertension. Diethylstilbestrol should be avoided during pregnancy.

Nowadays antiestrogen agents are well-known. Tamoxifen is a competitive inhibitor of estrogen receptors and is extensively used in the palliative treatment of breast cancer. It is a nonsteroidal agent that is given orally.

Progesterone is the most important progestin in humans. It is synthesized in the ovary (corpus luteum), testis, adrenal, and in placenta during pregnancy. The level of progesterone in the female is higher the luteal phase than during the follicular phase of the cycle. Progestins enter the cell and bind to progesterone receptors. The ligand-receptor complex binds to a response element to activate gene transcription, resulting in an increase in protein synthesis. Progesterone causes the maturation and secretory changes in the endometrium that are seen following ovulation. Also it leads to relaxation of uterine smooth muscle and stimulation of mammary alveolar tissue growth. Progesterone is responsible for pregnancy preservation. It also has depressant and hypnotic effects on the brain.

Progesterone is rapidly absorbed following administration by any route. It is almost completely metabolized in one passage through the liver, and for that reason it is quite ineffective when administered orally. In the liver, progesterone is metabolized and conjugated with glucuronic acid. It is excreted into the urine. A variety of progestin compounds have been synthesized. In general, such compounds as oxyprogesterone (hydroxyprogesterone) and medroxyprogesterone are the most closely related, pharmacologically as well as chemically, to progesterone. Oxyprogesterone and medroxyprogesterone have a long duration of action. They are used in oil solution intramuscularly once in 7-14 days. Pregnine is in 5 times weaker than progesterone. However, pregnine is available for oral and subglossal (sublingual) route of using. A group of testosterone-derivatives with progestin activity - levonorgestrel, norethisterone (norethindrone) - has been introduced, principally as components of oral contraceptives. They do not support pregnancy in test animals, are more effective gonadotropin inhibitors, and may have minimal androgenic or anabolic activity.

Progestins have been used in the first trimester of pregnancy to prevent habitual abortion or to treat threatened abortion, however their usefulness is doubtful. Progestins are used for the treatment of amenorrhea in the presence of estrogen. They are useful in producing long-term ovarian suppression for the treatment of dysmenorrhea, endometriosis, and for contraception. Progestins may cause changes in menstrual flow, edema, and hypertension.

It is already synthesized antiprogestin agent – mifepristone. It binds strongly to the progesterone receptor and inhibits the activity of progesterone. Mifepristone is used for termination of early pregnancies.

CONTRACEPTIVES.

A large number of oral contraceptives containing estrogens or progestins (or both) are now available for clinical use. Two types of preparations are used for oral contraception: (1) combinations of estrogens and progestins and (2) continuous progestin therapy. The estrogenic component of commercially oral contraceptive combinations is ethinyl estradiol. The progestinic component is levonorgestrel, norethisterone (norethindrone), or norgestrel. The combinations of estrogens and progestins exert their contraceptive effect largely through selective inhibition of pituitary function that results in inhibition of ovulation. The combination agents also produce a change in the cervical mucus, endometrium, and uterine tubes, which decrease the likelihood of conception and implantation.

Estrogen-progestin oral contraceptives are usually classified according to their formulation. Monophasic preparations contain fixed-combination of estrogen and progestin (non-ovlon, rigevidon, and microgynon). Biphasic (anteovin) and triphasic (trisiston, tri-regol) preparations are consist of 2 or 3 sequentially administered fixed combinations of estrogen and progestin. Bi- and triphasic contraceptives are more physiological, because differences of estrogen-progestin correlation are imitate normal fluctuation of female sex hormones.

Most combinations are available as 21-day dosage preparations. In establishing an oral contraceptive dosage cycle, the menstrual cycle is usually considered to be 28 days. The first day of bleeding is counted as the first day of the cycle. Administration of oral contraceptives usually begins on the fifth day of the menstrual cycle and is usually administered once daily for 21 consecutive days. The pregnancy rate with combination agents is estimated to be about 0.5-1 per 100 woman years at risk. About 97% of patients will ovulate by the third posttreatment cycle. Progestins and estrogens are also useful in the treatment of endometriosis. It is now clear that these compounds reduce the risk of endometrial and ovarian cancer.

Adverse effects. Minor adverse effects are frequent, but most are mild and many are transient. Mild adverse effects are headache, nausea, mastalgia, breakthrough bleeding, weight gain, and edema. Severe adverse effects are rare and include increasing coagulability of blood (risk of thromboembolic disease), hypertension, reduction of glucose tolerance, cholestatic jaundice, depression. These drugs should be avoided in patients with estrogen-dependent neoplasm. These agents are contraindicated in adolescents in whom epiphysial closure has not yet been completed.

Small doses of progestins can be used for contraception also. Progestin-only contraceptives alter cervical mucus and endometrium so that sperm migration into the uterus and probable implantation is inhibited. In addition, continuous administration of the drugs decreases the ovum transport by altering motility in fallopian tubes. Although progestin-only oral contraceptives are less effective than estrogen-progestin combinations, they are particularly suited for use in patients for whom estrogen administration is undesirable. Orally can be taken continuin, microlut. Unlike estrogen-progestin combinations, progestin-only oral contraceptives must be taken daily, without interruption, to be effective. The main adverse effect is incidences of abnormal bleeding.

Pregnancy can be prevented following coitus by the administration of large doses of estrogens or progestins (postcoital contraceptives). For example postinor (contain l-norgestrel). When treatment is begun within 72 hours, it is effective 99% of the time. Postcoital contraceptives can be used not more than 4 times a month.

ANDROGENS, ANABOLIC STEROIDS AND ANTIANDROGENS

The testis, like the ovary, has both gametogenic and endocrine functions. In humans, the most important androgen secreted by the testis (in the interstitial or Leydig cells) is testosterone. Endogenous plasma testosterone is maintained and regulated by gonadotropins within a normal range by a negative feedback system involving the hypothalamus and pituitary. In blood circulating testosterone is bound to sex hormone-binding globulin. In many target tissues (for example in prostate), testosterone is converted to dihydrotestosterone. Androgens are highly lipid-soluble and enter cells of target tissues by passive diffusion. Testosterone or dihydrotestosterone binds to an intracellular androgen receptor. The hormone-receptor complex translocates into the nucleus and initiates or suppresses transcription, and protein synthesis. In the liver testosterone is transformed into nonactive substances such as androsterone that is then conjugated and excreted into the urine.

Physiologic effects. Androgens stimulate spermatogenesis, development of male sexual organs (seminal vesicles, penis, and scrotum) and secondary sexual characteristics (male hair, enlargement of the larynx, and thickening of vocal cords). Androgens increase linear bone growth and bone density, and help fuse the epiphysial growth centres. They cause nitrogen retention that indicates an increasing of protein synthesis within the body (anabolic effect). That leads to growing of skeletal muscles and parenchymal organs. They also stimulate erythrocyte production.

The ethers of testosterone have been used extensively in clinics (testosterone propionate and testosterone enanthate). They are injected intramuscularly one time in 2 days or in 3-4 weeks correspondently. These derivatives are hydrolyzed to release free testosterone at the site of injection. Methyltestosterone is testosterone derivative that is active when given by mouth (subglossal).

Indications. Androgens are used to replace or augment endogenous androgen secretion in hypogonadal men. Androgens have also been used in the treatment of breast cancer as a supplement to chemotherapy in women until 60 years. Androgens are sometimes given for the therapy of dysmenorrhea, postmenopausal syndrome. In women, the administration of testosterone is associated with masculinizing actions (virilism): hirsutism, acne, depression of menses, and deepening of the voice. Sodium retention and edema may appear also.

Anabolic steroids are synthetic derivatives of testosterone. Chemical changes results in reduction of their androgenic properties comparatively with testosterone and retention of their anabolic features. Many anabolic steroids are used in clinics: methandrostenolone, phenoboline (nandrolone phenylpropionate), retabolil (nandrolone decanoate). Phenoboline and retabolil are used intramuscularly. Duration of action is 2-3 weeks. Methandrostenolone is used orally daily. Anabolic steroids have been used for reversing of protein loss after trauma, surgery, or prolonged immobilization and in patients with debilitating diseases. Anabolic agents are indicated for the treatment of osteoporosis. These agents have been used to stimulate growth in boys with delayed puberty.

Since complete dissociation of anabolic and androgenic effects is not possible, anabolic steroids produce slight masculinizing actions. In addition, anabolic steroids can cause nausea, edema, hypercalcemia, and upset of liver function.

The potential usefulness of antiandrogens for the treatment of patients producing excessive amounts of testosterone has led to the search for effective drugs that can be used for this purpose. Since dihydrotestosterone appears to be the essential androgen in the prostate, androgen effects in this tissues can be reduced by an inhibitor of 5-reductase. Finasteride, an inhibitor of this enzyme, produces a reduction in dihydrotestosterone levels. It has been reported to be moderately effective in reducing prostate size in men with benign prostatic hyperplasia. Cyproterone acetate is effective antiandrogen that inhibits the action of androgens at the target organ. These compounds have been used in women for the treatment of hirsutism and in men to decrease excessive sexual drive. Flutamide, is a competitive antagonist at the androgen receptor that has been used in the treatment of prostatic carcinoma. Spironolactone, a competitive inhibitor of aldosterone (see “Diuretic drugs”) also competes for the androgen receptors in target tissues. It also reduces the synthesis of testosterone. It is used for the treatment of hirsutism in women.

VITAMINS

Vitamins (lat. vita, life, + amine) are the organic substances, present in minute amounts in natural foodstuffs, that are essential to normal metabolism, usually as coenzymes; insufficient amounts in the diet may cause deficiency diseases.

Vitamins are usually divided on water-soluble and fat-soluble vitamins. To water-soluble are concerned vitamins B1 (thiamine), B2 (riboflavin), PP (nicotinic acid), B5 (panthotenic acid), B6 (pyridoxine), B12 (cyanocobalamin), B15 (pangame acid), Bc (folic acid), C (ascorbic acid), P (group of bioflavonoids). To fat-soluble are concerned - vitamins A (retinol), D2 (egrocalciferol), D3 (cholecalciferol), E (tocopherol), K (phyloquinone).

Needs of organism in vitamins are changed in dependence to age, work, climate, character of feeding, etc. The hard work, neuro-psychical stress, pregnancy, and breast-feeding, hard climate conditions lead to the higher vitamin demands. Also it is higher in children than in adults. Hypovitaminosis and avitaminosis appear during vitamin’s deficiency. Nowadays avitaminosis is observed comparatively seldom. Hypovitaminosis is more often observed. It is characterized by not determined symptoms (fatigue, headache, weakness, lowering of capacity for work, lowering of resistance for infections and other diseases, etc.). Avitaminosis is the brightest appearance of vitamin's insufficiency. It is characterized by clearly expressed specific symptomatology and is stipulated by full absence or prolonged vitamin deficiency. Reasons of vitamin's deficiency in organism include low content of vitamins in meals (“alimentary” hypovitaminosis), disorders of vitamin's absorption from intestine that evoked by diseases of GI and liver (“secondary” or “endogenic” hypovitaminosis), and considerable increasing of dietary requirements. However, prolonged overdosing of vitamins, usually fat-soluble (vitamins A, D), can cause development of hypervitaminosis.

Vitamin drugs are used in substitutive, adaptive and pharmacodynamic therapy. Substitutive vitaminotherapy is used during treatment of avitaminosis and hypovitaminosis. Adaptive vitaminotherapy is used for bettering of organism's adaptation for quickly changing conditions of environment (spring-autumn) and in hard conditions (polar or tropical climate, climbing, work under surface of water, during flying by plains, etc.). Doses for substitutive and adaptive therapy are in 2-3 times higher than physiologic dietary requirements and are used for course therapy.

Pharmacodynamic vitaminotherapy is used during treatment of diseases that are not caused by vitamin's deficiency. It's basic difference from substitutive therapy is in using of higher vitamin's doses, which in dozens and hundreds times exceed daily requirements. Example is using of vitamin D2 (ergocalciferol) by 100000 IU per day for treating of tubercular lupus of skin.

WATER-SOLUBLE VITAMINS

Ascorbic acid (vitamin C, antiscorbutic vitamin) is a water-soluble vitamin, which is present in fresh fruits, vegetables, berries (wild rose). Citrus fruits are a particularly good source of vitamin C. Ascorbic acid is synthesized for use as a drug. Ascorbic acid is reversibly oxidized to dehydroascorbic acid in the body. These two forms of the vitamin are believed to be important in oxidation-reduction reactions.

Ascorbic acid is required for collagen formation, tissue repair and preservation of blood vessel integrity. The vitamin is involved in tyrosine metabolism, conversion of folic acid to folinic acid, carbohydrate metabolism, synthesis of lipids and proteins, resistance to infections, and cellular respiration. In addition, ascorbic acid enhances the absorption of nonheme iron.

Ascorbic acid deficiency results in scurvy. Collagenous structures are primarily affected, and lesions develop in bones and blood vessels: ulceration of the gums hemorrhages into the skin and from the mucous membranes, debility, and immunity impairment.

Vitamin C is readily absorbed after oral administration. Ascorbic acid is widely distributed in body tissues. Large concentrations of the vitamin are found in the liver, leukocytes, and adrenal glands. Mostly ascorbic acid is metabolized to oxalates, which are excreted in the urine. Large doses of ascorbic acid may cause acidification of the urine, occasionally leading to precipitation of urate, oxalate stones, or drugs in the urinary tract. Ascorbic acid is used to prevent and to treat scurvy. It has been prescribed for hemorrhagic states, fever, infection, and trauma, poisoning by different substances, anemia, atherosclerosis, peptic ulcer, and the common cold. Ascorbic acid may be useful to treat idiopathic methemoglobinemia. Ascorbic acid injection has been reported to be incompatible with many drugs.

Thiamine (vitamin B1, antineuritic vitamin) is a water-soluble vitamin, which is present in many foods including yeast, cereal grains, nuts, and meat. Thiamine combines with adenosine triphosphate (ATP) in the liver, kidneys, and leukocytes to form thiamine diphosphate (thiamine pyrophosphate) which is a coenzyme in carbohydrate metabolism (in the decarboxylation of pyruvic and alpha-ketoglutaric acids). Thiamine diphosphate is also a coenzyme of transketolase in the utilization of glucose in the pentose phosphate pathway.

Thiamine deficiency leads to increased pyruvic and lactic acids concentration in the blood (acidosis). The organ systems principally affected by thiamine deficiency are the peripheral nervous system (polyneuritis), cardiovascular system (heart failure), and GI tract. In severe cases thiamine deficiency results in beriberi (paresis, paralysis) and encephalopathy syndrome. Administration of thiamine completely reverses the cardiovascular and GI symptoms of thiamin deficiency; however, the degree of improvement in neurologic symptoms depends on the duration and severity of the lesions.

Following oral administration thiamine is readily absorbed; however, the total amount absorbed following oral administration of a large dose is limited. GI absorption of thiamine is decreased in alcoholics and in patients with cirrhosis or malabsorption. Thiamine is rapidly and completely absorbed following intramuscular administration.

Thiamine is used to prevent and to treat thiamin deficiency syndromes including beriberi, encephalopathy syndrome, and peripheral neuritis. It is also used for the treatment of paresis, neuritis, heart failure, arrhythmia, and ketoacidosis. Thiamine commercially is available in form of thiamin bromide or thiamin chloride for oral and intramuscular administration. The probable adverse effect is hypersensitivity.

Riboflavin (vitamin B2) is a water-soluble vitamin, which is present in many foods including milk, meat, eggs, nuts, cereal grains, and yeast. In humans, an exogenous source of riboflavin is required for tissue respiration. Riboflavin is converted to the coenzyme, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These coenzymes act as hydrogen-carrier molecules for several enzymes (flavoproteins) involved in oxidation-reduction reactions of organic substrates and in intermediary metabolism. Riboflavin is also indirectly involved in maintaining erythrocyte integrity.

Riboflavin deficiency (ariboflavinosis) results in cheilosis (angular stomatitis), glossitis, keratitis, ocular changes (photophobia, hemeralopia), and anemia.

Riboflavin is readily absorbed from the upper GI tract. FAD and FMN are widely distributed into body tissues, including GI mucosal cells, erythrocytes, and the liver. Free riboflavin is present in the retina. Vitamin B2 is used to prevent riboflavin deficiency and to treat ariboflavinosis. Riboflavin may be useful in treating keratitis, iritis, skin and infectional diseases. Commercially available is riboflavin (oral, topical), riboflavin mononucleotide (injection). Riboflavin is nontoxic.

Vitamin PP (B3) has two forms: nicotinic acid (niacin) and nicotinamide (niacinamide). Nicotinic acid and tryptophan (that is converted to nicotinamide) present in many foods including yeast, meat, fish, milk, eggs, green vegetables, and cereal grains. Commercially available nicotinic acid and nicotinamide are prepared synthetically. Nicotinic acid is incorporated into 2 coenzymes: nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). They act as hydrogen-carrier molecules in glycogenolysis, tissue respiration, and lipid metabolism (more than 150 reactions). In large doses, nicotinic acid (not nicotinamide) produces peripheral vasodilatation, predominantly of cutaneous vessels in the face, neck, and chest; decreases serum low-density lipoprotein concentrations; activates the fibrinolytic system. Nicotinic acid reportedly increases gastric acid secretion. Vitamin PP deficiency results in pellagra that accompanied by dermatitis, diarrhea, and dementia (loss of cognitive functions).

Vitamin PP is readily absorbed from the GI tract following oral administration, as well as from subcutaneous and i.m. injection site. It is widely distributed into body tissues. Metabolites of vitamin PP are excreted in urine. Vitamin PP is used to prevent and to treat nicotinic acid deficiency. Large doses of nicotinic acid are used for the treatment of atherosclerosis (antilipemic agent); conditions associated with deficient circulation (e.g., peripheral vascular disease and vascular spasm), gastritis, and liver diseases.

Large doses of nicotinic acid can cause flushing (face, neck), pruritus, heartburn, hypotension, and headache. Long-term using of nicotinic acid may impair glucose tolerance and lead to lipid dystrophy of liver (methionine can prevent liver damage).

Nowadays some drugs include nicotinic acid. For example, nicoverine (nicotinic acid + papaverine), nicoshpan (nicotinic acid + no-spa). Papaverine and no-spa relieve smooth muscle spasm (spasmolytics) and nicotinic acid enhances their action, especially vasodilatation. Thus, nicoverine and nicospan are used for the treatment of hypertonia. Litonit (lithium salt of nicotinic acid) is known as tranquilizer. The head of department pharmacology of Odessa medical university prof. V.I.Kresyun investigated it. Nowadays litonit is used for alcoholism treatment. Current work of department pharmacology OMU is based on the study of neurotropic and hepatotropic activities of newly synthesized compounds of germanium and nicotinic acid as well as nicotinamide. These substances possess tranquilizer and hepatoprotective effects, that open’s perspective of their purpose investigation.

Vitamin B6 (as pyridoxine, pyridoxal, and pyridoxamine) is a water-soluble vitamin, which is present in many foods including cereal grains, vegetables, liver, meat, and eggs. Pyridoxine, pyridoxal, and pyridoxamine are converted to the active forms of the vitamin, pyridoxal phosphate and pyridoxamine phosphate, which act as coenzymes in a wide variety of reactions in nitrogenous metabolism. They are involved in transamination, deamidation, and decarboxylation of amino acids, in the conversion of tryptophan to nicotinamide. Pyridoxine appears to be essential in the synthesis of gamma-aminobutyric acid (GABA) within the CNS and in the synthesis of heme. The vitamin is also involved in lipid metabolism.

Deficiency of the vitamin has rarely been identified in humans. Artificial pyridoxine deficiency affects the peripheral nerves (neuritis), CNS (seizure), skin (dermatitis), and the hematopoietic system (leukopenia). Pyridoxine deficient state can occur during treatment of tuberculosis with isoniazid that inhibits the conversion of vitamin B6 to the pyridoxal phosphate.

Vitamin B6 is readily absorbed from the GI tract following oral administration. It is stored mainly in the liver. Pyridoxine is used to prevent and to treat vitamin B6 deficiency. Also it is indicated for the treatment of hematopoietic upset (leukopenia, anemia), disorders of nervous system (neuritis, parkinsonism, and vertigo), and hepatitis.

Commercially available form is pyridoxine hydrochloride (oral, injection). Long-term administration of megadose of pyridoxine can cause sensory neuropathy.

Pantothenic acid (vitamin B5) is a water-soluble vitamin, which is widely distributed in plant and animal tissues. Rich sources of pantothenic acid include meat, vegetables, cereal grains, eggs, and milk. Also it is synthesized in bowel by E.coli. In humans, an exogenous source of pantothenic acid is required for intermediary metabolism of carbohydrates, proteins, and lipids. Pantothenic acid is a precursor of coenzyme A which is required for acetylation reactions in gluconeogenesis, in the release of energy from carbohydrates, in the synthesis and degradation of fatty acids, and in the synthesis of steroid hormones, acetylcholine, and other compounds.

Dietary deficiency of pantothenic acid has not been clinically identified in humans. Experimentally produced pantothenic acid deficiency resulted in drowsiness, fatigue, headache, paresthesia of legs, and GI complaints.

Pantothenic acid is readily absorbed from the GI tract following oral administration. It is widely distributed into body tissues, mainly as coenzyme A. Highest concentrations are found in the liver and adrenal glands. Pantothenic acid is excreted unchanged. The vitamin is commercially available as the calcium salt (calcium pantothenate). It has been used orally and parenterally. Calcium pantothenate is indicated for the treatment of peripheral neuritis, toxicosis during pregnancy, hepatitis, atony of intestine, streptomycin neurotoxicity, and catarrhal respiratory disorders. Pantothenic acid is usually nontoxic even in large doses. Allergic reactions to it have been reported occasionally.

Pangame acid (vitamin B15) is considered to vitamin-like substances. It is donator of methyl groups and possesses antihypoxant action. It is used in form of calcium pangamate during dystrophy of myocardium, angina pectoris, atherosclerosis, diseases of liver, and during treatment of alcoholism.

Rutine (vitamin P) unites group of bioflavonoids, which are present in green tea, citrus's, wild rose, etc. Together with ascorbic acid it takes part in oxidizing-restoring processes and prevents forming of lipid's peroxides. It increases firmness and lowers penetrability of capillaries. So, it is used in combination with ascorbic acid (ascorutine) for the treatment of increased penetrability of vessels (capillary toxicosis, hemorrhagical diathesis), allergy, and polyarthritis.

Vitamin U is contained in cabbage, asparagus, and fresh tomato. It is donator of methyl groups and takes part in oxidizing-restoring processes. It is used enterally during ulcerative disease of stomach and duodenum, gastritis, and colitis.

Vitamin B12 (cyanocobalamin) and folic acid (vitamin Bc, pteroylglutamic acid) are discussed in chapter “Agents used in anemias”. Multivitamins. When a single vitamin deficiency is evident, other vitamin deficiencies (clinical or subclinical) often accompany it. Therapeutic multivitamin preparations may, therefore, be useful in these patients. Therapeutic multivitamins may also be indicated in pathologic conditions in which nutritional requirements are greatly increased (e.g., alcoholism, hyperthyroidism, severe illness or injury, cachexia) or in conditions in which absorption, utilization, or excretion of vitamins is abnormal (including malabsorption syndromes).

The vitamin combination chosen should fit the needs of the individual patient. It should be remembered that some vitamins (especially vitamins A and D) and many minerals may be toxic in large doses, and dosage of multivitamin preparations containing these agents should take the patient's dietary intake into account. Vitamins are usually administered orally; however, the drugs may be given parenterally in patients in whom oral administration is not feasible, including those receiving total parenteral nutrition. Multivitamin injections are reportedly incompatible with i.v. solutions containing various drugs. Multivitamin preparations are tablets or dragee “Hexavit”, “Pangexavit”, “Decamevit”, “Aerovit”, “Glytamevit”, “Unicap”, etc. For instance, dragee “Hexavit” includes vitamin A, B1, B2, PP, B6, C.

FAT-SOLUBLE VITAMINS

Vitamin A is a fat-soluble vitamin that is present in foods in a variety of forms: retinol (vitamin A1), dehydroretinol (vitamin A2), and retinoic acid. Vitamin A is present in esterified form in eggs, milk, butter, and oily salt-water fish. Provitamin A carotenoid pigments (including α-, β-, and γ-carotene), the most active of which is β-carotene, are present in green and yellow vegetables and fruits and are converted to retinol in humans.

In humans, an exogenous source of vitamin A is required for growth, vision, reproduction, and the integrity of mucosal and epithelial surfaces. Vitamin A has been reported to act as a cofactor in mucopolysaccharide synthesis. In the retina, retinol is converted to the aldehyde (retinal), which combines with opsin to form rhodopsin, the visual pigment. Under the influence of light rhodopsin is splited into retinal and opsin that accompanied with perceiving of light. In darkness the resynthesis of rhodopsin is occur. Thus, rhodopsin is necessary for visual adaptation for darkness.

Vitamin A deficiency leads to night blindness (nyctalopia or hemeralopia - impairment of vision in reduced illumination), xerophthalmia (dryness of the cornea) and keratomalacia (ulceration of the cornea), hyperkeratosis of the skin, immunodeficiency, and epithelial metaplasia of mucous membranes that decrease resistance to infections. That’s why, vitamin A is known also as “antiinfection agent”.

Vitamin A is readily and completely absorbed if fat absorption is normal. Retinol esters are hydrolyzed in the GI lumen by pancreatic enzymes and in presence of bile. Retinol is absorbed and then reesterified, mainly to retinyl palmitate. It is stored in the liver. Normal body stores of vitamin A are sufficient to meet the body's requirements for several months. Retinol is released from the liver bound to the plasma proteins. Vitamin A metabolites are excreted in urine and feces.

Vitamin A is used to prevent and to treat symptoms of vitamin A deficiency such as xerophthalmia and night blindness. Oral administration of water-miscible vitamin A preparations may be useful in preventing deficiency in patients with malabsorption. Vitamin A may be useful in infections, skin disorders (burns, ichthyosis, and psoriasis), however, other retinoids (e.g., etretinate, isotretinoin) are currently being investigated for use in the treatment of these dermatological disorders. Vitamin A has been studied in animals as an anticarcinogen; further study in humans is needed to determine efficacy. For clinical use, vitamin A is available as retinol (vitamin A alcohol) or esters of retinol formed from acetic and palmitic acids. Vitamin A activity is preferably expressed in International units (IU).

Doses of vitamin A that do not exceed the physiologic requirement are usually nontoxic. Effects of acute overdosing are vomiting, diarrhea, confusion or unusual excitement. Chronic overdosing includes bone or joint pain, painful hyperostosis of the bones (thickening of bones), drying or cracking of skin, loss of hair, unusual tiredness. Large doses of vitamin A are teratogenic in animals. Treatment of hypervitaminosis A consists of discontinuance of vitamin A and symptomatic therapy as indicated.

Group of vitamin D (antirachitic vitamins) includes fat-soluble vitamins that possess antirachitic and hypercalcemic activity. Because they are activated in the body and have regulatory effects, they are sometimes considered hormones. Vitamin D analogs include cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). Vitamin D is present in fish oil, liver of aquatic mammals (e.g., seals, polar bears), eggs, butter, and milk. Ergocalciferol is formed from ergosterol. Cholecalciferol is formed from 7-dehydrocholesterol in the skin after exposure to ultraviolet light. In the human body, cholecalciferol is hydroxylated to calcifediol (25-hydroxyvitamin D3) in liver and then to calcitriol (1,25-dihydroxyvitamin D3) and secacalcifediol (24,25-dihydroxyvitamin D3) in kidneys. Ergocalciferol has the same conversion as cholecalciferol.

Calcitriol and calcifediol enhance the efficiency of intestinal calcium and phosphorous absorption in the small intestine and stimulate renal reabsorption of calcium and phosphate. They exhibit potent antiproliferative and prodifferentiation effects. Recent evidence suggests that 24,25-dihydroxyvitamin D3 stimulates bone formation. Vitamin D deficiency results in skeletal demineralization. In children, vitamin D deficiency leads to rickets that is characterized by skeletal deformations (e.g., frontal bossing), and outward and inward deformities of the lower limbs resulting in bowed legs and knocked knees, respectively. In adults, vitamin D deficiency leads to an osteoporosis (reduced bone mass) and osteomalacia (softening of the bones). Any alteration in cutaneous production of cholecalciferol, GI vitamin D absorption, or metabolism of the vitamin to its active form (i.e., calcitriol) can result in it deficiency.

Vitamin D is readily absorbed from the GI tract following oral administration. The presence of bile is required for it absorption. Vitamin D is incorporated into chylomicrons and absorbed via the lymphatic system and then associates mainly with a specific α-globulin as well as vitamin D hydroxylated metabolites. 25-hydroxylatedvitamin D2, D3 are stored in fat and muscles. The metabolites of vitamin D analogs are excreted principally in bile and feces. Activity of ergocalciferol and cholecalciferol is expressed in International Units (IU).

For clinical use, vitamin D is available as cholecalciferol, ergocalciferol, calcitriol, and calfediol. Vitamin D is used to prevent or treat rickets, osteoporosis, hypocalcemic tetany, and to manage psoriasis and hypoparathyroidism. Administration of excessive doses of vitamin D may lead to hypervitaminosis D manifested by hypercalcemia. Early symptoms of hypercalcemia may include weakness, drowsiness, metallic taste, vomiting, vertigo, and bone pain. Later consequences of hypercalcemia may include impairment of renal function, osteoporosis, and metastatic calcification of organs and vessels. Treatment of vitamin D intoxication consists of withdrawal of the drug, administration of fluids, corticosteroids, and calciuric diuretics (e.g., furosemide and ethacrynic acid).

Vitamin E (antisterility vitamin) is a fat-soluble vitamin, which is present in many foods including vegetable oils, cereal grains, animal fats, meat, eggs, fruits, and vegetables. The vitamin exists in a variety of forms: α-, β-, and γ-tocopherols. The most biologically active natural form of the vitamin is α-tocopherol.

The exact biologic function of vitamin E in humans is unknown, although the vitamin is believed to act as an antioxidant. It has been postulated that vitamin E protects polyunsaturated fatty acids (which are components of cellular membranes) and other oxygen-sensitive substances (vitamins A, C) from oxidation. Vitamin E delays the accumulation of free radicals resulting in excessive lipid peroxidation. Thus, it limits atherosclerosis and CNS neuronal generation (Alzheimer's disease). Vitamin E also may inhibit platelet aggregation and adhesion. Vitamin E deficiency does not cause specific disease in adults; however, in premature neonates thrombosis and hemolytic anemia may occur. In animals, avitaminosis E is associated with infertility in male and spontaneous abortion in female, dystrophy of skeletal muscles and myocardium.

Absorption of vitamin E from the GI tract depends on the presence of bile and only half of the vitamin obtained from dietary sources is absorbed. After absorption, vitamin E reaches the lymph circulation and then is transported with plasma proteins. Vitamin E is distributed to all tissues and is stored in adipose tissue. Vitamin E is metabolized in the liver is excreted primarily in the bile.

Vitamin E has been used for the treatment of habitual abortion, infertility, myodystrophy, dementia, angina pectoris, and thrombophlebitis. For drug use, vitamin E is available as tocopherol acetate. Vitamin E is usually nontoxic, however it may cause allergic reactions and pain in site of injection.

ENZYME PREPARATIONS AND ENZYME INHIBITORS

Enzyme agents are the preparations of enzymes. They are widely used in medicine for the different purposes. The first enzyme agents group (trypsin) is indicated for purulent-necrotic processes; the second group (pancreatin) increases digestive activity; the third group (streptokinase) has fibrinolytic properties; the fourth group includes different enzyme drugs (lydaza, penicillinase).

Trypsin is a proteolytic enzyme that formed in the small intestine. It hydrolyzes peptides, amides, etc. Crystallized trypsin, a purified preparation of the pancreatic enzyme. It is used in medicine for debridement (excision) of wounds and ulcers for dead tissues, fibrin, and viscous secretes. In addition it has antiinflamation activity and permit antibodies, leukocytes, and antibiotics better access to the infected area. Trypsin is nonactive (safe) relatively for undamaged tissues. It is used in inhalation for the cleaning of bronchi for viscous mucus or exudate during bronchitis, pneumonia. Trypsin is injected intramuscularly or used topically for the treatment of thrombophlebitis, parodontitis, osteomyelitis, and purulent infections of soft tissues. The agent can irritate tissues at the site of its application and can cause allergic reactions or intoxication that predominantly are evoked by absorption of necrotic tissues. Chymotrypsin is a proteinase of the gastrointestinal tract. It hydrolyzes proteins. Chymotrypsin is similar in indications to trypsin.

Deoxyribonuclease and ribonuclease are the enzymes. They hydrolyze phosphodiester bonds in DNA and proteins. These agents have the same to trypsin using. Deoxyribonuclease and ribonuclease are obtained from the cattle pancreas as well as chymotrypsin and trypsin.

Collagenase is a proteolytic enzyme capable of specifically hydrolyzing peptide bonds of collagen. The enzyme debrides necrotic tissue without damaging granulation tissue. It is derived from cattle pancreas. Collagenase is used to promote debridement of necrotic tissue in the treatment of severe burns and dermal ulcers. Pain and burning may occur at the site of collagenase application.

Pepsin is the principal digestive enzyme (protease) of gastric juice, formed from pepsinogen; it hydrolyzes peptide bonds at low pH values, reducing proteins to smaller molecules. For medical purpose it is obtained from stomach mucous membrane of hog. Pepsin is indicated for replacement therapy of stomach upset such as achlorhydria (absence of hydrochloric acid in the gastric juice) or hypoacidity (lower than normal level of hydrochloric acid). Natural gastric juice is digestive fluid secreted by the stomach glands of the dogs or horses. It normalizes secretion and motility of gastrointestinal tract. Abomin is received from the stomach mucous membrane of calf or lamb. It contains the summary of proteolytic enzymes. Gastric juice and abomin have the same indications as pepsin.

Pancreatin is a substance containing enzymes, principally amylase, lipase, and protease, obtained from the pancreas of the cattle and hog. Pancreatin is used as replacement therapy in the symptomatic treatment of chronic pancreatitis, pancreatectomy, or other conditions in which pancreatic insufficiency impairs fat digestion. Pancreatic exocrine replacement therapy should not delay or supplant treatment of the primary disorder. The medication is taken before meals. Because pancreatin has a high purine content, hyperuricemia, uric acid renal stones may be seen as a side effect. Hypersensitivity reactions have been reported. Panzynorm forte (contain pancreatin, bile extract, and extract of stomach mucous membrane), festal (pancreas enzymes and bile extract), mezym forte (pancreas enzymes) are the digestive enzyme replacement products also. Their are used for the treatment of digestive insufficiency of gastro-intestinal tract.

Fibrinolytic drugs (fibrinolysine, streptokinase, and urokinase) are discussed in chapter “Anticoagulant drugs”. Lydaza (hyaluronidase) is a protein enzyme that found widely distributed in nature. Lydaza for injection is a sterile, dry, soluble enzyme product prepared from cattle’s testes. The potency of the drug is expressed in conventional units. Lydaza modifies the permeability of connective tissue through the hydrolysis of hyaluronic acid. Occurring as one of the principal viscous polysaccharides of connective tissue and skin, hyaluronic acid is one of the chief ingredients of the tissue cement, which offers resistance to the diffusion of liquids through tissue. Lydaza is indicated in the treatment of ankylosis (stiffening) of the joints and postburn scars. The enzyme also hastens the disappearance of swelling after hemorrhage. Adverse effects from lydaza are rare. Occasional sensitivity reactions (e.g., urticaria) have been reported.

Penicillinase is a β-lactamase enzyme, which destroy all biosynthetic and majority of semisynthetic penicillins. It is produced by certain strains of microbes (e.g. staphylococci). Penicillinase is used in case of acute or delays hypersensitivity for penicillins.

Asparaginasa is an enzyme that is isolated for clinical use from various bacteria. The drug is used to treat leukemia. It acts indirectly by catabolic depletion of serum asparagine. These results in inhibition of protein synthesis in neoplastic cells, requiring an external source of asparagine (see chapter “Immunodepressants”).

Enzyme inhibitors are discussed in other topics: (1) proteinase inhibitors (contrycal) one can see in chapter “Drugs used in gastrointestinal diseases”; (2) fibrinolytic inhibitors (aminocapronic acid) see in “Drugs used in bleeding disorders”; (3) cholinesterase-inhibiting drugs (proserine) see in “Cholinomimetics”; (4) monoamine oxidase (MAO) inhibitors (nialamide) see in “Antidepressant agents”; (5) carbonic anhydrase inhibitors (diacarb) see in “Diuretic agents”; (6) xanthine oxidase inhibitors (allopurinol) see in “Drugs used in gout”; (7) acetaldehyde dehydrogenase inhibitors (teturam) see in “The alcohols”.