HORMONES AND HORMONE ANTAGONISTS
Insulin
Pharmacological Actions of Insulin-Insulin promotes the uptake and storage of glucose, proteins and fats through effects on liver, muscles, and adipose tissues. It also influences the cell growth and metabolic function of various tissues.
Carbohydrate metabolism:
a. In liver cells, it decreases glycogenolysis by inhibiting glycogen phosphorylase and increases glycogenesis by activating glycogen synthetase. It also decreases gluconeogenesis and thus conversion of non carbohydrate substrate to glucose is inhibited.
b. In muscles: it facilitates glucose uptake by promoting translocation of intracellular GLUT-4 onto the cell surface. It promotes glycogenesis and increases glycolysis.
c. In Adipose tissue: it facilitates glucose uptake, it increases intracellular glucose oxidative metabolism.
Protein metabolism:
a. In liver cells: it decreases protein breakdown and inhibits oxidation of amino acids.
b. In muscles: it increases protein synthesis and increases amino acid uptake by muscle cells to produce a net positive nitrogen balance.
Fat metabolism:
a. In liver cells: it increases lipogenesis
b. In adipose tissues; it increases fatty acid synthesis and TG formation; decreases lipolysis and blunts lipolytic action of adrenaline growth hormone and glucagon. Thus free fatty acid and glycerol levels remain suppressed under the influence of insulin.
Effects of Insulin on Its Targets-Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells and influences cell growth and the metabolic functions of a wide variety of tissues.
Absorption, Metabolism, and Excretion
Insulin is administered subcutaneously. Intramuscular injections are used less often because absorption is more rapid. Being a polypeptide hormone, insulin is readily inactivated, if administered orally. In emergencies, such as severe diabetic ketoacidosis, insulin can be given intravenously. Plasma half life is less than 10 minutes. Hepatic insulinases destroy approximately 50% of circulating insulin, remainder degraded by circulating proteases. Insulin metabolism is accomplished both through actions of an insulin specific protease found in cytosol and by reductive cleavage of insulin disulfide bonds by glutathione–insulin transhydrogenase. In kidney, insulin that undergoes glomerular filtration is completely reabsorbed and metabolized within proximal convoluted tubules of nephron.
Therapuetic uses:
1. Patients with type-1 diabetes: NPH insulin is often combined with short-acting regular insulin and is administered S.C. before meals.
2. Many patients with type-2 diabetes ultimately require insulin therapy.
3. For gestation diabetes not controlled by diet
4. For emergency treatment of diabetic ketoacidosis (diabetic coma): this emergency is usually faced with patients suffering with type-1 diabetes. The paients are usually dehydrated, hyperventiallating with loss of consciousness.
5. Non-ketonic hyperglycaemic coma: this usually occurs in elderly type-2 diabetes cases and is characterized by dehydration and haemo-concentration and is usually fatal is untreated.
6. Short term treatment of patients with impaired glucose tolerance to overcome stress during surgery and MI.
7. For emergency treatment of hyperkalaemia, insulin given with glucose to lower extracellular potassium via redistribution into cells.
Adverse Reactions.
Hypoglycemia This may result from large dose, from a mismatch between the time of peak delivery of insulin and food intake, or from superimposition of additional factors that increase sensitivity to insulin or that increase insulin-independent glucose uptake.
Insulin Allergy and Resistance Allergic manifestations are IgE-mediated local cutaneous reactions, and patients may develop life-threatening systemic responses or insulin resistance owing to IgG antibodies. Glucocorticoids have been used in patients with resistance to insulin or more severe systemic reactions.
Lipoatrophy and Lipohypertrophy Atrophy of subcutaneous fat at site of insulin injection is probably a variant of an immune response to insulin, whereas enlargement of subcutaneous fat depots has been ascribed to the lipogenic action of high local concentrations of insulin.
Insulin Edema. Some degree of edema, abdominal bloating, and blurred vision develops in many diabetic patients with severe hyperglycemia or ketoacidosis that is brought under control with insulin. The edema usually disappears spontaneously within several days to a week unless there is underlying cardiac or renal disease. Edema is attributed primarily to retention of Na+.
Drug Interactions A large number of drugs can cause hypoglycemia or hyperglycemia or may alter the response of diabetic patients to their existing therapeutic regimens.
Different preparations of insulin are
a. Rapid-acting Insulin- Insulin Lispro, Insulin Aspart, Insulin Glulisine,
b. Short-acting Insulin- Regular Novolin R, Regular Humulin R, Velosulin BR, Regular,
c. Intermediate-acting Insulin- NPH Humulin N, NPH Novolin N
d. Premixed Insulin-Novolin 70/30, Humulin 70/30 and 50/50, 50/50 NPL, 5/25 NPL,
e. Long-acting Insulin- Insulin detemir, Insulin glargine,
Oral hypoglycaemic drugs
Classification:-
1. Insulin secretogogues
a. sulphonylureas ex: tolbutamide, gliburide, glipizide, glimepride, gliclazide
b. Meglitine analogues Ex: Ropglimide, Nateglinide
2. Insulin sensitizers
a. Biguanides Ex: Metformin, phenformin
b. Thiazolidine diones ex: roliglitazone, proglitazones
3. Alpha-glucosidase inhibitors Ex: acarbose, miglitol
Pharmacology of sulfonyl ureas:-
First-Generation Sulfonylureas: Ex-Tolbutamide, Chlorpropamide, Tolazamide
Second-Generation Sulfonylureas: Ex-Glyburide, Glipizide, Glimepiride
Mechanism of Action-The major action of sulfonylureas is to increase insulin release from the pancreas. Two additional mechanisms of action have been proposed—a reduction of serum glucagon levels and closure of potassium channels in extrapancreatic tissues. The latter is of unknown clinical significance.
i. Insulin Release from Pancreatic β Cells-Sulfonylureas bind to a 140 kDa high-affinity sulfonyl-urea receptor that is associated with a B cell inward rectifier ATP-sensitive potassium channel. Binding of a sulfonylurea inhibits the efflux of potassium ions through channel and results in depolarization. Depolarization, in turn, opens a voltage-gated calcium channel and results in calcium influx and release of preformed insulin.
ii. Reduction of Serum Glucagon Concentrations-Chronic administration of sulfonylureas to type 2 diabetics reduces serum glucagon levels, which may contribute to the hypoglycemic effect of the drugs. Mechanism for this suppressive effect is unclear but appears to involve indirect inhibition due to enhanced release of both insulin and somatostatin, which inhibit A cell secretion.
iii. Potassium Channel Closure in Extrapancreatic Tissues-Insulin secretagogues bind to sulfonylurea receptors in potassium channels in extra pancreatic tissues but the binding affinity varies among the drug classes and is much less avid than for the B cell receptors.
Schematic diagram of Mechanism of Action of sulfonyl ureas is shown below
First-Generation Sulfonylureas are not frequently used in management of diabetes mellitus because of their relatively low specificity of action, delay in time of onset, occasional long duration of action, and variety of side effects. They are occasionally used in patients who have achieved previous adequate control with these agents.
a. Acetohexamide shows uricosuric activity, an action that may be of benefit in diabetic patients who also have gout.
b. Chlorpropamide has a relatively slow onset of action, with its maximal hypoglycemic potential often not reached for 1 or 2 weeks. Several weeks may be required to eliminate the drug after discontinuation of therapy. It can cause flushing, particularly when taken with alcohol, and can also cause hyponatremia. This effect has been employed to treat some patients who have partial central diabetes insipidus, an unrelated condition due to a pituitary ADH deficiency.
c. Tolazamide is an orally effective hypoglycemic drug that causes less water retention.
d. Tolbutamide is a relatively short-acting compound that may be useful in patients who are prone to hypoglycemia.
Second-Generation Sulfonylureas display higher specificity and affinity for sulfonylurea receptor and more predictable pharmacokinetics. It may also exert mild diuretic effects on kidney and are highly protein bound, primarily through nonionic binding.
a. Glyburide, also known as glibenclamide, is approximately 150 times as potent as tolbutamide on a molar basis and twice as potent as glipizide. It is completely metabolized in liver to two weakly active metabolites before excretion in urine. Its average duration of action is 24 hours.
b. Glipizide is similar to glyburide, but it is metabolized by the liver to two inactive metabolites; these metabolites and glipizide are renally excreted.
c. Glimepiride is metabolized to at least one active metabolite. It is quickly absorbed from gastrointestinal tract within an hour of oral administration and excreted in urine and feces. Its half-life varies from 5 to 9 hours depending on frequency of multiple dosing.
Absorption, Metabolism, and Excretion
Readily absorbed from gastrointestinal tract following oral administration but undergo varying degrees and rates of metabolism in the liver and/or kidney; the biological half-lives vary greatly, Sulfonylureas and their metabolites are excreted either renally or in feces.
Clinical Uses
Sulfonylureas are effective in individuals with mild to moderate type II diabetes. The chance for successful glycemic control with sulfonylureas is poor in diabetic patients requiring more than 40 units of insulin per day.
Adverse Effects:
a. Hypoglycemia, provoked by inadequate calorie intake (e.g., skipping a meal), or increased caloric needs (e.g., increased physical activity).
b. Sulfonylureas also tend to cause weight gain; some of this weight can be due to fluid retention and edema.
c. Less common adverse reactions include muscular weakness, ataxia, dizziness, mental confusion, skin rash, photosensitivity, blood dyscrasias, and cholestatic jaundice.
Drug Interactions: A decrease in alcohol tolerance is seen. Sulfonylureas are highly bound to plasma proteins and metabolized by microsomal enzymes, coadministration of drugs capable of displacing them from their protein binding sites or inhibiting their metabolism also may potentiate hypoglycemia.
Physiological role of insulin
The biochemical actions of insulin are complex and involve many steps to integrate carbohydrate, protein, and lipid metabolism for the maintenance of fuel homeostasis. In addition to its effects on stimulating glucose uptake by tissues, insulin has five major physiological effects on fuel homeostasis. It can
(1) Diminish hepatic glycogenolysis by inhibiting glycogen phosphorylase;
(2) Promote hepatic glucose storage into glycogen by stimulating glycogen synthetase;
(3) Inhibit hepatic gluconeogenesis;
(4) Inhibit lipolysis by inhibiting hormone-sensitive lipase activity, thereby decreasing plasma free fatty acid and glycerol levels; and
(5) Promote the active transport of amino acids into cells for incorporation into protein, thereby producing a net positive nitrogen balance.
The biological actions of insulin are initiated following a reversible binding of hormone to a high affinity specific insulin receptor on cell membrane surface.
The insulin receptor is a hetero tetrameric tyrosine kinase receptor composed of two alpha-and two beta-subunits.
Insulin binds to alpha-subunit on extracellular surface of cell and activates tyrosine kinase activity in intracellular portion of β-subunit. This results in the autophosphorylation of adjacent insulin beta-receptor subunit and phosphorylation of tyrosine residues on cytoplasmic proteins, termed the insulin receptor substrate (IRS) 1 and 2. IRS phosphorylation provides a docking site for other intracellular signaling proteins. The regulatory subunit of phosphatidyl inositol-3 (PI-3) kinase becomes activated and dimerizes with its catalytic subunit, and this complex mobilizes the translocation of glucose transporters to cell membrane surface, which promotes hexose transport.
Other downstream signaling pathways include activation of p70-S6 kinase, protein kinase B, and Grb2 activation of the Ras-Raf-MAP kinase pathway, which controls glycogen synthesis and cell growth. The hormone–receptor complex may then be internalized by endocytosis, which results in degradation of insulin and recycling of
receptor to cell membrane surface.
Schematic diagram of insulin signaling pathways is shown below
Uterine relaxants
Uterine relaxants (tocolytic drugs) are administered where prolonged intrauterine life would benefit the fetus or would permit additional time to allow treatment with drugs such as corticosteroids, which promote the production of fetal lung surfactant. Tocolytics are also used when temporary uterine relaxation is desirable (e.g., intrauterine fetal resuscitation); tocolytics are more likely to inhibit labor early in gestation, especially before labor.
Classification:
1. Oxytocin receptor antagonist: atosiban
2. Beta2 adrenergic agonist: Ex: salbutamol and ritodrine.
3. calcium channel blockers
4. Magnesium sulfate, alcohol,
5. Prostaglandin inhibitors- aspirin and indomethacin.
Atosiban-It is an antagonist of the oxytocin receptor, used for treatment for preterm labor (tocolysis). Atosiban is a modified form of oxytocin that is administered by IV infusion for 2–48 hours. Atosiban appears to be as effective as beta-adrenoceptor-agonist tocolytics and to produce fewer adverse effects.
Ethanol-Intravenously employed to inhibit premature labor. Ethanol inhibits oxytocin release from the pituitary and thus indirectly decreases myometrial contractility. Beta2-adrenomimetics and magnesium sulfate have replaced ethanol for parenteral tocolysis.
Calcium channel blocking agent, nifedipine is a tocolytic agent. It acts by impairing the entry of Ca into myometrial cells via voltage dependent channels and thereby inhibits contractility.
β2-Adrenoceptor Agonists-are commonly used tocolytic agents, it acts by binding to β2-adrenoceptors on myometrial cell membranes and activating adenylyl cyclase. This in turn increases levels of cAMP in cell, activating cAMP-dependent protein kinase, hence decreasing intracellular calcium concentrations and reducing effect of calcium on muscle contraction.
Prophylactic administration to patients at high risk for preterm labor is not always effective. β2-agonists can arrest preterm labor for at least 48 to 72 hours.The efficacy of these drugs beyond this time frame is in dispute. Even a short delay in delivery can be desirable, however, in that at very early preterm gestations (24–28 weeks) a 2-day delay in delivery may mean a 10 to 15% increase in probability of survival for the newborn.
Side effects-palpitations, tremor, nausea, vomiting, nervousness, anxiety, and chest pain, shortness of breath, hyperglycemia, hypokalemia, and hypotension. Serious complications are pulmonary edema, cardiac insufficiency, arrhythmias, myocardial ischemia, and maternal death.
Terbutaline-It is specific β2-adrenoceptor agonist. It can prevent premature labor, in individuals who are more than 20 weeks into gestation and have no indication of ruptured fetal membranes or in whom labor is not far advanced. Its effectiveness in premature labor after 33 weeks of gestation is much less clear. Terbutaline can decrease the frequency, intensity, and duration of uterine contractions through its ability to directly stimulate β2-adrenoceptors.
It is used in management of premature labor, although not been marketed for such use.
Side effects, precautions, and contraindications are similar to those of all β2-adrenergic agonists. Terbutaline can cause tachycardia, hypotension, hyperglycemia, and hypokalemia. It can be given orally in addition to subcutaneous or intravenous administration.
Magnesium Sulfate-It prevents convulsions in preeclampsia and directly uncouples excitation–contraction in myometrial cells through inhibition of cellular action potentials. Magnesium sulfate decreases calcium uptake by competing for its binding sites, activating adenylyl cyclase, and stimulating calcium-dependent ATPase, which promotes calcium uptake by sarcoplasmic reticulum. Magnesium is filtered by glomerulus, so patients with low glomerular filtration will have low magnesium clearance.
Adverse Effects:
a. It has cardiac side effects; magnesium sulfate may be preferred over β-adrenergic agents in patients with heart disease, diabetes, hypertension, or hyperthyroidism.
b. Magnesium toxicity can be life threatening. Higher levels cause cardiac arrest. Toxicity can be avoided by following urine output and checking patellar reflexes in patients receiving magnesium.
c. Other side effects include sweating, warmth, flushing, dry mouth, nausea, vomiting, dizziness, nystagmus, headache, palpitations, pulmonary edema, maternal tetany, profound muscular paralysis, profound hypotension, and neonatal depression.
Prostaglandin inhibitors-Since certain prostaglandins are known to play a role in stimulating uterine contractions during normal labor, it is logical that inhibitors of prostaglandin synthesis have been used to delay preterm labor.
Ex: Indomethacin, Hydroxyprogesterone
Hydroxyprogesteroneis used prophylactically for 12th to 37th week of pregnancy, particularly in women who are in the high-risk category for premature delivery. A concern relating to teratogenic potential has limited its use. Hydroxyprogesterone as a tocolytic agent requires further evaluation.
Adverse effects: pulmonary edema, myocardial infarction, respiratory arrest, cardiac arrest, and death can occur during tocolytic therapy. Newborns of mothers given tocolytics have had respiratory depression, intraventricular hemorrhage, and necrotizing enterocolitis.
Contraindications-acute fetal distress, chorioamnionitis, eclampsia or severe preeclampsia, fetal demise, fetal maturity, and maternal hemodynamic instability.
Pharmacological actions of estrogen and progesterone
MECHANISMS OF ACTION-Estrogens and progestins exert their effects in target tissues by a combination of cellular mechanisms. There are two forms of the estrogen receptor, ER-alpha and ER-beta, and two forms of progesterone receptor, PR-alpha and PR-beta. Receptor binding by estrogens and progestins can activate a classic pathway of steroid hormone gene transcription. Gene activation is mediated by ability of steroid hormone receptor complexes to recruit nuclear coactivator proteins to transcription complex. Gene repression occurs in ligand-dependent fashion by recruitment of nuclear corepressor proteins to transcription complex. This latter effect is an important mechanism of action of estrogen antagonism.
Physiologic Effects of Estrogens:-
FEMALE MATURATION-Estrogens are required for normal sexual maturation and growth of female. They stimulate development of vagina, uterus, and uterine tubes as well as secondary sex characteristics. They stimulate stromal development and ductal growth in the breast and are responsible for accelerated growth phase and closing of epiphyses of long bones that occur at puberty. They contribute growth of axillary and pubic hair and alter distribution of body fat to produce typical female body contours.
ENDOMETRIAL EFFECTS-When estrogen production is properly coordinated with production of progesterone during normal menstrual cycle, regular periodic bleeding and shedding of endometrial lining occur. Continuous exposure to estrogens for prolonged periods leads to hyperplasia of endometrium that is associated with abnormal bleeding patterns.
METABOLIC AND CARDIOVASCULAR EFFECTS-Estrogens seem to be partially responsible for maintenance of normal structure and function of skin and blood vessels in women. Estrogens also decrease rate of resorption of bone by promoting apoptosis of osteoclasts and by antagonizing osteoclastogenic and pro-osteoclastic effects of parathyroid hormone and interleukin-6. Estrogens also stimulate adipose tissue production of leptin.
EFFECTS ON BLOOD COAGULATION-Estrogens enhance coagulability of blood. Many changes in factors influencing coagulation have been reported, including increased circulating levels of factors II, VII, IX, and X and decreased antithrombin III. Increased plasminogen levels and decreased platelet adhesiveness is found.
Pharmacokinetics
When released into circulation, estradiol binds to alpha2 globulin (sex hormone-binding globulin [SHBG]) and with lower affinity to albumin. Bound estrogen is unavailable for diffusion. Estradiol is converted by liver to estrone and estriol and their 2-hydroxylated derivatives and conjugated metabolites and excreted in bile. Conjugates may be hydrolyzed in intestine to active, reabsorbable compounds. Estrogens are also excreted in small amounts in breast milk of nursing mothers.
THERAPEUTIC APPLICATIONS
a. Oral Contraception-it is among most effective forms of birth control.
b. Osteoporosis-One in four postmenopausal women have osteoporosis. Estrogen replacement therapy can prevent bone loss. Estrogen treatment is the most effective therapy for osteoporosis and reduces incidence of bone fractures in postmenopausal women.
c. Hormone Replacement Therapy (HRT) refers to administration of estrogen– progestin combinations.
d. Cardiovascular Actions-Declining estrogen levels associated with menopause are correlated with an increased risk of cardiovascular relateddeaths in women. The protective effects of estrogenson the lipid profile are well recognized.
e. Central Nervous System Effects-Insomnia and fatigue in many postmenopausal women may be related to reduce estrogen levels. Estrogen replacement therapy may be used to treat severe cases.
f. Infertility-Anovulation, often related to altered ratios of estrogen to progestin, can be treated with a variety of agents, including estrogen–progestin replacement, clomiphene citrate, bromocriptine, FSH, LH, human chorionic gonadotropin, and GnRH.
g. Induction of Ovulation-Anovulation can be due to an insufficient release of LH and FSH during mid phase of menstrual cycle. Induction of ovulation by clomiphene citrate is result of stimulation of FSH and LH release.
Adverse Effects
UTERINE BLEEDING-Estrogen therapy is a major cause of postmenopausal uterine bleeding.
CANCER-The relation of estrogen therapy to cancer continues to be the subject of active investigation.
OTHER EFFECTS-Nausea and breast tenderness are common and minimized by using smallest effective dose of estrogen. Hyperpigmentation also occurs. Estrogen therapy is associated with an increase in frequency of migraine headaches as well as cholestasis, gallbladder disease, and hypertension.
Contraindications:Estrogens should not be used in patients with estrogen-dependent neoplasms such as carcinoma of endometrium or in those with carcinoma of breast. They should be avoided in patients with undiagnosed genital bleeding, liver disease, or a history of thromboembolic disorder. In addition, the use of estrogens should be avoided by heavy smokers.
Physiologic Effects of Progestins
a. Progesterone has little effect on protein metabolism. It stimulates lipoprotein lipase activity and favors fat deposition. The effects on carbohydrate metabolism are more marked. Progesterone increases basal insulin levels and the insulin response to glucose. In the liver, progesterone promotes glycogen storage, possibly by facilitating the effect of insulin. Progesterone also promotes ketogenesis.
b. Progesterone can compete with aldosterone for mineralocorticoid receptor of renal tubule, causing a decrease in Na+ reabsorption. This leads to an increased secretion of aldosterone by adrenal cortex (eg, in pregnancy).
c. Progesterone increases body temperature in humans.
d. Progesterone alters function of respiratory centers. The ventilatory response to CO2 is increased. This leads to a measurable reduction in arterial and alveolar PCO2 during pregnancy and in luteal phase of the menstrual cycle.
e. Progesterone and related steroids also have depressant and hypnotic effects on the brain.
f. Progesterone is responsible for alveolobular development of secretory apparatus in the breast. It also participates in preovulatory LH surge and causes maturation and secretory changes in endometrium that are seen following ovulation.
g. Progesterone decreases plasma levels of many amino acids and leads to increased urinary nitrogen excretion.
Pharmacokinetics-Rapidly absorbed following administration by any route. Its half-life in plasma is app. 5 minutes, and small amounts are stored temporarily in body fat. It is completely metabolized in one passage through liver. Metabolized to inactive products and are excreted mainly in urine.
THERAPEUTIC APPLICATIONS
a. Used in for hormone replacement therapy and hormonal contraception.
b. Useful in producing long-term ovarian suppression for other purposes.
c. In treatment of dysmenorrheal, endometriosis, and bleeding disorders, when estrogens are contraindicated, and for contraception.
d. Progesterone and medroxyprogesterone have been used in the treatment of women who have difficulty in conceiving and who demonstrate a slow rise in basal body temperature.
e. Preparations of progesterone and medroxyprogesterone have been used to treat premenstrual syndrome.
f. Abortifacients and Emergency Contraceptives-Progesterone is a hormone required for the maintenance of pregnancy. Termination of early pregnancy is effected using the steroidal antiprogestin drug, mifepristone (RU486), which acts by blocking progestin binding to the progesterone receptor.
Sex hormones
Sex hormones are the substances secreted by ovaries or testes that stimulate the development of secondary sexual characters.
Androgens are steroid hormones secreted primarily by testis, and testosterone is principal androgen secreted. Its primary function is to regulate differentiation and secretory function of male sex accessory organs. Androgens also possess protein anabolic activity that is manifested in skeletal muscle, bone, and kidneys.
PHARMACOLOGICAL ACTIONS
Androgens produce both virilizing and protein anabolic actions. The virilizing actions of testosterone include irreversible effects that occur during embryogenesis, and excitatory actions at puberty that are responsible for secondary sexual development.
In addition to effects on male reproductive function, androgens influence a number of other systems, associated with masculinity. These actions include growth of male-pattern facial, pubic, and body hair, lower vocal pitch resulting from a thickening and lengthening of vocal cords, and increase in rate of long bone growth.
The protein anabolic actions of androgens on bone and skeletal muscle are responsible for larger stature of males than females. Androgens induce some degree of anabolism in other tissues, including bone marrow, liver, kidney, and heart.
CLINICAL USES
1. Hypogonadism
2. Prepuberal Hypogonadism
3. Postpuberal Hypogonadism
4. Aging and Impotence
5. Anemia
Therapeutic Use of Androgens in Women
1. Endometriosis
2. Female Hypogonadism
3. Use of Androgens as Protein
4. Anabolic Agents
Estrogens and progestins are endogenous hormones that produce numerous physiological actions.
In women, these include developmental effects, neuroendocrine actions involved in the control of ovulation, the cyclical preparation of the reproductive tract for fertilization and implantation, and major actions on mineral, carbohydrate, protein, and lipid metabolism.
In males, including effects on bone, spermatogenesis, and behavior. The ovaries are the principal source of circulating estrogen in premenopausal women, with estradiol being the main secretory product.
ACTIONS OF ESTROGENS AND PROGESTINS IN FEMALES:-
1. The Menstrual Cycle Secretion of gonadotropin-releasing hormone (GnRH) from hypothalamus stimulates release of follicle stimulating hormone and luteinizing hormone from anterior pituitary.
2. Control of Pregnancy
3. Ovulation-During the follicular phase of menstrual cycle, one or more follicles are prepared for ovulation. FSH and estrogens are important hormones for this developmental process. Complete follicular maturation cannot occur in absence of LH. Rupture of a mature follicle follows midcycle peak of LH and FSH by about 24 hours. In humans, usually one mature ovum is released per cycle.
4. Implantation-The lining of uterus, that is, endometrium, is critical for implantation of fertilized ovum. Under the influence of estrogen and progesterone, endometrium undergoes cyclical changes that prepare it for implantation of fertilized ovum. Estrogens induce endometrial cell division and growth.
5. Growth and Development-Estrogens cause growth of uterus, fallopian tubes, and vagina. Stimulation of proliferation of vaginal epithelium is checked by cyclical exposure to progesterone during luteal phase in mature female. Estrogens are responsible for expression of female secondary sex characteristics during puberty. These include breast enlargement, distribution of body hair, body contours as determined by subcutaneous fat deposition, and skin texture. Estrogens can stimulate release of growth hormone and exert a positive effect on nitrogen balance.
Therapeutic uses
Used as oral contraceptives and hormone replacement therapy.
Progestins and SERMs are used in treatment of osteoporosis, breast cancer, endometrial cancer, and infertility.
Antithyroid drugs
Classification
1. Thioamide derivatives Ex: propyl thiouracil, carbimazole, methimazole
2. Radioactive iodine Ex: Iodine I131
3. Iodides Ex:Lugol’s solution
4. Anion inhibitors Ex: perchlorates, thiocyanates
5. Iodinated contrast media Ex: oral ipodate and ipanoid acid, diatrizoate.
The thioamides like methimazole, carbimazole and propylthiouracil are major drugs for treatment of thyrotoxicosis.
Pharmacodynamics
The thioamides act by multiple mechanisms. The major action is to prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification. In addition, they block coupling of the iodotyrosines. They do not block uptake of iodide by the gland. Propylthiouracil and methimazole inhibit peripheral deiodination of T4 and T3. Since, 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.
Schematic diagram of mechanism of action of Antithyroid drugs is shown below
Pharmacokinetics
Propylthiouracil is rapidly absorbed, reaching peak serum levels after 1 hour. The bioavailability of 50–80% may be due to incomplete absorption or a large first-pass effect in the liver. The volume of distribution approximates total body water with accumulation in the thyroid gland. Excreted by kidney as inactive glucuronide within 24 hours.
Therapeutic Uses
The antithyroid drugs are used in treatment of hyperthyroidism in following three ways: (1) as definitive treatment, to control disorder in anticipation of spontaneous remission in Graves' disease; (2) in conjunction with radioactive iodine, to hasten recovery while awaiting effects of radiation; and (3) to control the disorder in preparation for surgical treatment.
Toxicity
Nausea and gastrointestinal distress, maculopapular pruritic rash, and fever occur in 3–12% of treated patients.
Rare adverse effects include an urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, hypoprothrombinemia, exfoliative dermatitis, polyserositis, and acute arthralgia. Hepatitis and cholestatic jaundice can be fatal; although asymptomatic elevations in transaminase levels also occur.
Syndrome of diabetes mellitus
The elevated blood glucose associated with diabetes mellitus results from absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action. The disease states underlying the diagnosis of diabetes mellitus are now classified into four categories:
Type 1, insulin-dependent diabetes;
Type 2, noninsulin-dependent diabetes;
Type 3, and
Type 4, gestational diabetes mellitus
Type 1 Diabetes Mellitus
The hallmark of type 1 diabetes is selective B-cell destruction and severe or absolute insulin deficiency. Administration of insulin is essential in patients with type 1 diabetes. Type 1 diabetes is further subdivided into immune and idiopathic causes. The immune form is common form of type 1 diabetes. Although most patients are younger than 30 years of age at time of diagnosis, onset can occur at any age. Susceptibility appears to involve a multifactorial genetic linkage but only 10–15% of patients have a positive family history.
Type 2 Diabetes Mellitus
Type 2 diabetes is characterized by tissue resistance to action of insulin combined with a relative deficiency in insulin secretion. Individual have more resistance or more B-cell deficiency, and abnormalities may be mild or severe. Although insulin is produced by B cells in these patients, it is inadequate to overcome the resistance, and blood glucose rises. The impaired insulin action also affects fat metabolism, resulting in increased free fatty acid flux and triglyceride levels and reciprocally low levels of high-density lipoprotein.
Individuals with type 2 diabetes may not require insulin to survive, but benefited from insulin therapy to control the blood glucose. In individuals in whom type 2 diabetes was initially diagnosed actually has both type 1 and type 2 or a slowly progressing type 1, and ultimately will require full insulin replacement.
Although persons with type 2 diabetes ordinarily do not develop ketosis, ketoacidosis may occur. Dehydration in untreated and poorly controlled individuals with type 2 diabetes can lead to a life-threatening condition called nonketotic hyperosmolar coma. In this condition, the blood glucose may rise to 6–20 times the normal range and an altered mental state develops or the person loses consciousness. Urgent medical care and rehydration is required.
Type 3 Diabetes Mellitus-refers to multiple other specific causes of elevated blood glucose: nonpancreatic diseases, drug therapy, etc.
Type 4 Diabetes Mellitus
Gestational diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy. During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester. High-risk women should be screened immediately. Screening may be deferred in lower-risk women until 24th to 28th week of gestation.
Insulin preparations
Different types of insulin preparations are:
a. Rapid-acting Insulin- Insulin Lispro, Insulin Aspart, Insulin Glulisine,
b. Short-acting Insulin- Regular Novolin R, Regular Humulin R, Velosulin BR, Regular,
c. Intermediate-acting Insulin- NPH Humulin N, NPH Novolin N
d. Premixed Insulin-Novolin 70/30, Humulin 70/30 and 50/50, 50/50 NPL, 5/25 NPL,
e. Long-acting Insulin- Insulin detemir, Insulin glargine,
a. Rapid-Acting Insulin-Three injected rapid-acting Insulin analogs: Insulinlispro, Insulin aspart, and Insulin glulisine, and one inhaled form of rapid-acting Insulin.
i. Insulinlispro, is produced by recombinant technology. To enhance the shelf-life of Insulin in vials, when injected subcutaneously, the drug quickly dissociates into monomers and is rapidly absorbed with onset of action within 5–15 minutes and peak activity as early as 1 hour.
ii. Insulin aspart: Its absorption and activity profile is similar to that of Insulin lispro, and it is more reproducible than regular Insulin, but has similar binding properties, activity, and mitogenicity characteristics to regular Insulin and equivalent immunogenicity.
iii. Insulin glulisine: Its absorption, action, and immunologic characteristics are similar to the other injected rapid-acting Insulin. After high-dose Insulin glulisine- Insulin receptor interaction, there may be downstream differences in IRS-2 pathway activation relative to human Insulin.
iv. Inhaled human Insulin is a powder form of rDNA human Insulin administered through an inhaler device for pre-prandial and blood sugar correction use in adults with type 1 and 2 diabetes. Because of concerns about lung safety, it is not used in children, teenagers, or adults with asthma, bronchitis, emphysema, smokers. This route of administration is well tolerated; users achieve target blood glucoses after 6 months of therapy with inhaled human Insulin.
b. Short-Acting Insulin
Regular Insulin is short-acting soluble crystalline zinc Insulin made by recombinant DNA techniques. Its effect appears within 30 minutes and peaks between 2 and 3 hours after subcutaneous injection and lasts 5–8 hours.
When regular Insulin is administered at meal time, the blood glucose rises faster than the Insulin with early postprandial hyperglycemia and an increased risk of late postprandial hypoglycemia. Regular Insulin should be injected 30–45 or more minutes before the meal to minimize the mismatching. Short-acting soluble Insulin is the only type that should be administered intravenously because useful for i.v. therapy in management of diabetic ketoacidosis.
c. Intermediate-Acting and Long-Acting Insulin
i. NPH (NEUTRAL PROTAMINE HAGEDORN, OR ISOPHANE) Insulin-It is intermediate-acting Insulin wherein absorption and onset of action are delayed by combining appropriate amounts of Insulin and protamine, so that neither is present in an uncomplexed form. After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to permit absorption of Insulin. Onset of action is 2–5 hours and duration of 4–12 hours; and given two to four times daily for Insulin replacement in patients with type 1 diabetes.
ii. Insulin GLARGINE-is a soluble, ultra-long-acting Insulin analog. Has a slow onset of action (1–1.5 hours) and achieves a maximum effect after 4–6 hours. This maximum activity is maintained for 11–24 hours or longer.
iii. Insulin DETEMIR- has the most reproducible effect of intermediate- and long-acting Insulin, and its use is associated with less hypoglycemia than NPH Insulin. Onset of action of 1–2 hours and duration of action of more than 24 hours.
iv. Mixtures of Insulin-Because intermediate-acting NPH Insulin require several hours to reach adequate therapeutic levels, their use in type 1 diabetic patients requires supplements of rapid- or short-acting Insulin before meals. These are often mixed together in the same syringe before injection. Insulin lispro, aspart, and glulisine can be acutely mixed (ie, just before injection) with NPH Insulin without affecting their rapid absorption.
Oral contraceptive
Contraception means interception in the birth process at any stage ranging from ovulation to ovum implantation. An ideal contraceptive agent should not only be safe but provide reversible suppression of fertility.
Classification
1. Combination pills
a. Ethinyl estradiol (30 mcg)+ Norgestrel (300 mcg)
b. Ethinyl estradiol (30 mcg)+ Levonorgestrel (150 mcg)
c. Ethinyl estradiol (50 mcg)+ Norgestrel (0.5 mg)
d. Ethinyl estradiol (30 mcg)+ desogestrel (150 mcg)
e. Mestranol (50 mcg) + Norethindrone (1 mg)
2. Phased pill
a. Ethinyl estradiol (30-40-30 mcg)+ Levonorgestrel (50-75-125 mcg)
b. Ethinyl estradiol (35-35-35 mcg) + Norethindrone (0.5-0.75-1.0 mg)
3. Post coital (morning after) pills
a. Ethinyl estradiol (50 mcg)+ Levonorgestrel (0.25 mg)
b. Levonorgestrel (0.75 mg)
c. Mifepristone 600mg
4. Mini pills (progestin only pills)
a. Norgestrel (75 mcg)
b. Norethindrone (0.35 mg)
MECHANISM OF ACTION-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 cervical mucus, in uterine endometrium, and in motility and secretion in uterine tubes, all of which decrease the likelihood of conception and implantation.
Pharmacologic Effects
EFFECTS ON OVARY-Chronic use of combination agents depresses ovarian function. Follicular development is minimal, and corpora lutea, larger follicles, stromal edema, and other morphologic features normally seen in ovulating women are absent. The ovaries usually become smaller even when enlarged before therapy.
EFFECTS ON UTERUS-After prolonged use, the cervix may show hypertrophy and polyp formation. There are also important effects on cervical mucus, making it more like postovulation mucus, i.e., thicker and less copious.
EFFECTS ON BREAST-Stimulation of breasts occurs in most patients receiving estrogen-containing agents. Enlargement is noted. The administration of estrogens and combinations of estrogens and progestins tends to suppress lactation.
Clinical Uses:-
a. Oral contraception
b. In post coital contraception
c. Polycystic ovary syndrome
d. Dysfunctional uterine bleeding
e. Premature menopause
f. Turner’s syndrome
g. In the treatment of endometriosis
Adverse Effects
MILD ADVERSE EFFECTS
1. Nausea, mastalgia, breakthrough bleeding, and edema
2. Changes in serum proteins and other effects on endocrine function
3. Headache is mild and often transient
4. Withdrawal bleeding sometimes fails to occur
MODERATE ADVERSE EFFECTS
1. Breakthrough bleeding
2. Weight Increased
3. skin pigmentation may occur
4. Acne may be exacerbated
5. Hirsutism
6. Ureteral dilation
7. Amenorrhea occurs
Oxytocin
Oxytocin is a peptide hormone secreted by posterior pituitary that participates in labor and delivery and elicits milk ejection in lactating women. During the second half of pregnancy, uterine smooth muscle shows an increase in expression of oxytocin receptors and becomes increasingly sensitive to the stimulant action of endogenous oxytocin. Pharmacologic concentrations of oxytocin powerfully stimulate uterine contraction.
Pharmacodynamics
Oxytocin acts through G protein-coupled receptors and phosphoinositide-calcium second-messenger system to contract uterine smooth muscle. Oxytocin also stimulates release of prostaglandins and leukotrienes that augment uterine contraction. Oxytocin in small doses increases both the frequency and force of uterine contractions. At higher doses, it produces sustained contraction.
Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection. Without oxytocin-induced contraction, normal lactation cannot occur. At high concentrations, oxytocin has weak antidiuretic and pressor activity due to activation of vasopressin receptors.
Clinical Use of Oxytocin
a. Induction of Labor.
b. Augmentation of Labor.
c. Third Stage of Labor and Puerperium
d. Oxytocin Challenge Test.
Goitrogens
Goitrogens are agents that suppress secretion of T3 and T4 to subnormal levels and thereby increase TSH, which in turn produces glandular enlargement (goiter). This inturn stimulates the thyroid which shows hypertrophy, hyperplasia and increase in vasculairty. Histolgoically height of the acinal epithelium increases and quantity of colloid decreases.
Classification of goitrogens:-
1. Ion inhibitors Ex: potassium perchlorates, thiocyanates
2. Organic antithyroid drugs:
a. Thioamide derivatives Ex: propyl thiouracil, carbimazole, methimazole
b. Misc: sulfonamides, PAS, resorcinol, amine-glutethimide.
Mineralocorticoids
Mineralocorticoids (Aldosterone, Deoxycorticosterone, Fludrocortisone)
a. Mineralocorticoids act by binding to mineralocorticoid receptor in cytoplasm of target cells, the principal cells of distal convoluted and collecting tubules of kidney. The major effect of activation of aldosterone receptor is increased expression of Na+/K+ ATPase and epithelial sodium channel (ENaC).
b. Aldosterone and other steroids with mineralocorticoid properties promote reabsorption of sodium from distal convoluted tubule and from cortical collecting renal tubules, loosely coupled to excretion of potassium and hydrogen ion. Sodium reabsorption in sweat, salivary glands, gastrointestinal mucosa, and across cell membranes is also increased.
c. Deoxycorticosterone (DOC) serves as a precursor of aldosterone. Its half-life is 70 minutes. Although the response to ACTH is enhanced by dietary sodium restriction, a low-salt diet does not increase DOC secretion. The secretion of DOC may be markedly increased in abnormal conditions such as adrenocortical carcinoma and congenital adrenal hyperplasia with reduced P450c11 or P450c17 activity
d. Fludrocortisone, a potent steroid with both glucocorticoid and mineralocorticoid activity. It has potent salt-retaining activity and used in treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency.
Angiotensins
Angiotensin II inhibits renin secretion. The inhibition, which results from a direct action of peptide on juxtaglomerular cells, forms basis of short-loop negative feedback mechanism controlling renin secretion. Interruption of this feedback with inhibitors of renin-angiotensin system results in stimulation of renin secretion.
The release of renin is altered by a wide variety of pharmacologic agents. Renin release is stimulated by vasodilators (hydralazine, minoxidil, nitroprusside), beta-adrenoceptor agonists (isoproterenol), alpha-adrenoceptor antagonists, phosphodiesterase inhibitors (theophylline, milrinone, rolipram), and most diuretics and anesthetics.
Uterine stimulants
Drugs and hormones used clinically to enhance uterine contractions are primarily employed either to induce or to augment contraction during deliver or at various stages of labour. Ex: Oxytocin, Ergot alkaloids, and prostaglandins.
Oxytocin acts through G protein-coupled receptors and phosphoinositide-calcium second-messenger system to contract uterine smooth muscle. Oxytocin also stimulates release of prostaglandins and leukotrienes that augment uterine contraction. Oxytocin in small doses increases both the frequency and force of uterine contractions. At higher doses, it produces sustained contraction.
Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection. Without oxytocin-induced contraction, normal lactation cannot occur. At high concentrations, oxytocin has weak antidiuretic and pressor activity due to activation of vasopressin receptors.
Clinical Use of Oxytocin
a. Induction of Labor.
b. Augmentation of Labor.
c. Third Stage of Labor and Puerperium
d. Oxytocin Challenge Test.
Insulin
Pharmacological Actions of Insulin-Insulin promotes the uptake and storage of glucose, proteins and fats through effects on liver, muscles, and adipose tissues. It also influences the cell growth and metabolic function of various tissues.
Carbohydrate metabolism:
a. In liver cells, it decreases glycogenolysis by inhibiting glycogen phosphorylase and increases glycogenesis by activating glycogen synthetase. It also decreases gluconeogenesis and thus conversion of non carbohydrate substrate to glucose is inhibited.
b. In muscles: it facilitates glucose uptake by promoting translocation of intracellular GLUT-4 onto the cell surface. It promotes glycogenesis and increases glycolysis.
c. In Adipose tissue: it facilitates glucose uptake, it increases intracellular glucose oxidative metabolism.
Protein metabolism:
a. In liver cells: it decreases protein breakdown and inhibits oxidation of amino acids.
b. In muscles: it increases protein synthesis and increases amino acid uptake by muscle cells to produce a net positive nitrogen balance.
Fat metabolism:
a. In liver cells: it increases lipogenesis
b. In adipose tissues; it increases fatty acid synthesis and TG formation; decreases lipolysis and blunts lipolytic action of adrenaline growth hormone and glucagon. Thus free fatty acid and glycerol levels remain suppressed under the influence of insulin.
Effects of Insulin on Its Targets-Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized target cells and influences cell growth and the metabolic functions of a wide variety of tissues.
Absorption, Metabolism, and Excretion
Insulin is administered subcutaneously. Intramuscular injections are used less often because absorption is more rapid. Being a polypeptide hormone, insulin is readily inactivated, if administered orally. In emergencies, such as severe diabetic ketoacidosis, insulin can be given intravenously. Plasma half life is less than 10 minutes. Hepatic insulinases destroy approximately 50% of circulating insulin, remainder degraded by circulating proteases. Insulin metabolism is accomplished both through actions of an insulin specific protease found in cytosol and by reductive cleavage of insulin disulfide bonds by glutathione–insulin transhydrogenase. In kidney, insulin that undergoes glomerular filtration is completely reabsorbed and metabolized within proximal convoluted tubules of nephron.
Therapuetic uses:
1. Patients with type-1 diabetes: NPH insulin is often combined with short-acting regular insulin and is administered S.C. before meals.
2. Many patients with type-2 diabetes ultimately require insulin therapy.
3. For gestation diabetes not controlled by diet
4. For emergency treatment of diabetic ketoacidosis (diabetic coma): this emergency is usually faced with patients suffering with type-1 diabetes. The paients are usually dehydrated, hyperventiallating with loss of consciousness.
5. Non-ketonic hyperglycaemic coma: this usually occurs in elderly type-2 diabetes cases and is characterized by dehydration and haemo-concentration and is usually fatal is untreated.
6. Short term treatment of patients with impaired glucose tolerance to overcome stress during surgery and MI.
7. For emergency treatment of hyperkalaemia, insulin given with glucose to lower extracellular potassium via redistribution into cells.
Adverse Reactions.
Hypoglycemia This may result from large dose, from a mismatch between the time of peak delivery of insulin and food intake, or from superimposition of additional factors that increase sensitivity to insulin or that increase insulin-independent glucose uptake.
Insulin Allergy and Resistance Allergic manifestations are IgE-mediated local cutaneous reactions, and patients may develop life-threatening systemic responses or insulin resistance owing to IgG antibodies. Glucocorticoids have been used in patients with resistance to insulin or more severe systemic reactions.
Lipoatrophy and Lipohypertrophy Atrophy of subcutaneous fat at site of insulin injection is probably a variant of an immune response to insulin, whereas enlargement of subcutaneous fat depots has been ascribed to the lipogenic action of high local concentrations of insulin.
Insulin Edema. Some degree of edema, abdominal bloating, and blurred vision develops in many diabetic patients with severe hyperglycemia or ketoacidosis that is brought under control with insulin. The edema usually disappears spontaneously within several days to a week unless there is underlying cardiac or renal disease. Edema is attributed primarily to retention of Na+.
Drug Interactions A large number of drugs can cause hypoglycemia or hyperglycemia or may alter the response of diabetic patients to their existing therapeutic regimens.
Different preparations of insulin are
a. Rapid-acting Insulin- Insulin Lispro, Insulin Aspart, Insulin Glulisine,
b. Short-acting Insulin- Regular Novolin R, Regular Humulin R, Velosulin BR, Regular,
c. Intermediate-acting Insulin- NPH Humulin N, NPH Novolin N
d. Premixed Insulin-Novolin 70/30, Humulin 70/30 and 50/50, 50/50 NPL, 5/25 NPL,
e. Long-acting Insulin- Insulin detemir, Insulin glargine,
Oral hypoglycaemic drugs
Classification:-
1. Insulin secretogogues
a. sulphonylureas ex: tolbutamide, gliburide, glipizide, glimepride, gliclazide
b. Meglitine analogues Ex: Ropglimide, Nateglinide
2. Insulin sensitizers
a. Biguanides Ex: Metformin, phenformin
b. Thiazolidine diones ex: roliglitazone, proglitazones
3. Alpha-glucosidase inhibitors Ex: acarbose, miglitol
Pharmacology of sulfonyl ureas:-
First-Generation Sulfonylureas: Ex-Tolbutamide, Chlorpropamide, Tolazamide
Second-Generation Sulfonylureas: Ex-Glyburide, Glipizide, Glimepiride
Mechanism of Action-The major action of sulfonylureas is to increase insulin release from the pancreas. Two additional mechanisms of action have been proposed—a reduction of serum glucagon levels and closure of potassium channels in extrapancreatic tissues. The latter is of unknown clinical significance.
i. Insulin Release from Pancreatic β Cells-Sulfonylureas bind to a 140 kDa high-affinity sulfonyl-urea receptor that is associated with a B cell inward rectifier ATP-sensitive potassium channel. Binding of a sulfonylurea inhibits the efflux of potassium ions through channel and results in depolarization. Depolarization, in turn, opens a voltage-gated calcium channel and results in calcium influx and release of preformed insulin.
ii. Reduction of Serum Glucagon Concentrations-Chronic administration of sulfonylureas to type 2 diabetics reduces serum glucagon levels, which may contribute to the hypoglycemic effect of the drugs. Mechanism for this suppressive effect is unclear but appears to involve indirect inhibition due to enhanced release of both insulin and somatostatin, which inhibit A cell secretion.
iii. Potassium Channel Closure in Extrapancreatic Tissues-Insulin secretagogues bind to sulfonylurea receptors in potassium channels in extra pancreatic tissues but the binding affinity varies among the drug classes and is much less avid than for the B cell receptors.
Schematic diagram of Mechanism of Action of sulfonyl ureas is shown below
First-Generation Sulfonylureas are not frequently used in management of diabetes mellitus because of their relatively low specificity of action, delay in time of onset, occasional long duration of action, and variety of side effects. They are occasionally used in patients who have achieved previous adequate control with these agents.
a. Acetohexamide shows uricosuric activity, an action that may be of benefit in diabetic patients who also have gout.
b. Chlorpropamide has a relatively slow onset of action, with its maximal hypoglycemic potential often not reached for 1 or 2 weeks. Several weeks may be required to eliminate the drug after discontinuation of therapy. It can cause flushing, particularly when taken with alcohol, and can also cause hyponatremia. This effect has been employed to treat some patients who have partial central diabetes insipidus, an unrelated condition due to a pituitary ADH deficiency.
c. Tolazamide is an orally effective hypoglycemic drug that causes less water retention.
d. Tolbutamide is a relatively short-acting compound that may be useful in patients who are prone to hypoglycemia.
Second-Generation Sulfonylureas display higher specificity and affinity for sulfonylurea receptor and more predictable pharmacokinetics. It may also exert mild diuretic effects on kidney and are highly protein bound, primarily through nonionic binding.
a. Glyburide, also known as glibenclamide, is approximately 150 times as potent as tolbutamide on a molar basis and twice as potent as glipizide. It is completely metabolized in liver to two weakly active metabolites before excretion in urine. Its average duration of action is 24 hours.
b. Glipizide is similar to glyburide, but it is metabolized by the liver to two inactive metabolites; these metabolites and glipizide are renally excreted.
c. Glimepiride is metabolized to at least one active metabolite. It is quickly absorbed from gastrointestinal tract within an hour of oral administration and excreted in urine and feces. Its half-life varies from 5 to 9 hours depending on frequency of multiple dosing.
Absorption, Metabolism, and Excretion
Readily absorbed from gastrointestinal tract following oral administration but undergo varying degrees and rates of metabolism in the liver and/or kidney; the biological half-lives vary greatly, Sulfonylureas and their metabolites are excreted either renally or in feces.
Clinical Uses
Sulfonylureas are effective in individuals with mild to moderate type II diabetes. The chance for successful glycemic control with sulfonylureas is poor in diabetic patients requiring more than 40 units of insulin per day.
Adverse Effects:
a. Hypoglycemia, provoked by inadequate calorie intake (e.g., skipping a meal), or increased caloric needs (e.g., increased physical activity).
b. Sulfonylureas also tend to cause weight gain; some of this weight can be due to fluid retention and edema.
c. Less common adverse reactions include muscular weakness, ataxia, dizziness, mental confusion, skin rash, photosensitivity, blood dyscrasias, and cholestatic jaundice.
Drug Interactions: A decrease in alcohol tolerance is seen. Sulfonylureas are highly bound to plasma proteins and metabolized by microsomal enzymes, coadministration of drugs capable of displacing them from their protein binding sites or inhibiting their metabolism also may potentiate hypoglycemia.
Physiological role of insulin
The biochemical actions of insulin are complex and involve many steps to integrate carbohydrate, protein, and lipid metabolism for the maintenance of fuel homeostasis. In addition to its effects on stimulating glucose uptake by tissues, insulin has five major physiological effects on fuel homeostasis. It can
(1) Diminish hepatic glycogenolysis by inhibiting glycogen phosphorylase;
(2) Promote hepatic glucose storage into glycogen by stimulating glycogen synthetase;
(3) Inhibit hepatic gluconeogenesis;
(4) Inhibit lipolysis by inhibiting hormone-sensitive lipase activity, thereby decreasing plasma free fatty acid and glycerol levels; and
(5) Promote the active transport of amino acids into cells for incorporation into protein, thereby producing a net positive nitrogen balance.
The biological actions of insulin are initiated following a reversible binding of hormone to a high affinity specific insulin receptor on cell membrane surface.
The insulin receptor is a hetero tetrameric tyrosine kinase receptor composed of two alpha-and two beta-subunits.
Insulin binds to alpha-subunit on extracellular surface of cell and activates tyrosine kinase activity in intracellular portion of β-subunit. This results in the autophosphorylation of adjacent insulin beta-receptor subunit and phosphorylation of tyrosine residues on cytoplasmic proteins, termed the insulin receptor substrate (IRS) 1 and 2. IRS phosphorylation provides a docking site for other intracellular signaling proteins. The regulatory subunit of phosphatidyl inositol-3 (PI-3) kinase becomes activated and dimerizes with its catalytic subunit, and this complex mobilizes the translocation of glucose transporters to cell membrane surface, which promotes hexose transport.
Other downstream signaling pathways include activation of p70-S6 kinase, protein kinase B, and Grb2 activation of the Ras-Raf-MAP kinase pathway, which controls glycogen synthesis and cell growth. The hormone–receptor complex may then be internalized by endocytosis, which results in degradation of insulin and recycling of
receptor to cell membrane surface.
Schematic diagram of insulin signaling pathways is shown below
Uterine relaxants
Uterine relaxants (tocolytic drugs) are administered where prolonged intrauterine life would benefit the fetus or would permit additional time to allow treatment with drugs such as corticosteroids, which promote the production of fetal lung surfactant. Tocolytics are also used when temporary uterine relaxation is desirable (e.g., intrauterine fetal resuscitation); tocolytics are more likely to inhibit labor early in gestation, especially before labor.
Classification:
1. Oxytocin receptor antagonist: atosiban
2. Beta2 adrenergic agonist: Ex: salbutamol and ritodrine.
3. calcium channel blockers
4. Magnesium sulfate, alcohol,
5. Prostaglandin inhibitors- aspirin and indomethacin.
Atosiban-It is an antagonist of the oxytocin receptor, used for treatment for preterm labor (tocolysis). Atosiban is a modified form of oxytocin that is administered by IV infusion for 2–48 hours. Atosiban appears to be as effective as beta-adrenoceptor-agonist tocolytics and to produce fewer adverse effects.
Ethanol-Intravenously employed to inhibit premature labor. Ethanol inhibits oxytocin release from the pituitary and thus indirectly decreases myometrial contractility. Beta2-adrenomimetics and magnesium sulfate have replaced ethanol for parenteral tocolysis.
Calcium channel blocking agent, nifedipine is a tocolytic agent. It acts by impairing the entry of Ca into myometrial cells via voltage dependent channels and thereby inhibits contractility.
β2-Adrenoceptor Agonists-are commonly used tocolytic agents, it acts by binding to β2-adrenoceptors on myometrial cell membranes and activating adenylyl cyclase. This in turn increases levels of cAMP in cell, activating cAMP-dependent protein kinase, hence decreasing intracellular calcium concentrations and reducing effect of calcium on muscle contraction.
Prophylactic administration to patients at high risk for preterm labor is not always effective. β2-agonists can arrest preterm labor for at least 48 to 72 hours.The efficacy of these drugs beyond this time frame is in dispute. Even a short delay in delivery can be desirable, however, in that at very early preterm gestations (24–28 weeks) a 2-day delay in delivery may mean a 10 to 15% increase in probability of survival for the newborn.
Side effects-palpitations, tremor, nausea, vomiting, nervousness, anxiety, and chest pain, shortness of breath, hyperglycemia, hypokalemia, and hypotension. Serious complications are pulmonary edema, cardiac insufficiency, arrhythmias, myocardial ischemia, and maternal death.
Terbutaline-It is specific β2-adrenoceptor agonist. It can prevent premature labor, in individuals who are more than 20 weeks into gestation and have no indication of ruptured fetal membranes or in whom labor is not far advanced. Its effectiveness in premature labor after 33 weeks of gestation is much less clear. Terbutaline can decrease the frequency, intensity, and duration of uterine contractions through its ability to directly stimulate β2-adrenoceptors.
It is used in management of premature labor, although not been marketed for such use.
Side effects, precautions, and contraindications are similar to those of all β2-adrenergic agonists. Terbutaline can cause tachycardia, hypotension, hyperglycemia, and hypokalemia. It can be given orally in addition to subcutaneous or intravenous administration.
Magnesium Sulfate-It prevents convulsions in preeclampsia and directly uncouples excitation–contraction in myometrial cells through inhibition of cellular action potentials. Magnesium sulfate decreases calcium uptake by competing for its binding sites, activating adenylyl cyclase, and stimulating calcium-dependent ATPase, which promotes calcium uptake by sarcoplasmic reticulum. Magnesium is filtered by glomerulus, so patients with low glomerular filtration will have low magnesium clearance.
Adverse Effects:
a. It has cardiac side effects; magnesium sulfate may be preferred over β-adrenergic agents in patients with heart disease, diabetes, hypertension, or hyperthyroidism.
b. Magnesium toxicity can be life threatening. Higher levels cause cardiac arrest. Toxicity can be avoided by following urine output and checking patellar reflexes in patients receiving magnesium.
c. Other side effects include sweating, warmth, flushing, dry mouth, nausea, vomiting, dizziness, nystagmus, headache, palpitations, pulmonary edema, maternal tetany, profound muscular paralysis, profound hypotension, and neonatal depression.
Prostaglandin inhibitors-Since certain prostaglandins are known to play a role in stimulating uterine contractions during normal labor, it is logical that inhibitors of prostaglandin synthesis have been used to delay preterm labor.
Ex: Indomethacin, Hydroxyprogesterone
Hydroxyprogesteroneis used prophylactically for 12th to 37th week of pregnancy, particularly in women who are in the high-risk category for premature delivery. A concern relating to teratogenic potential has limited its use. Hydroxyprogesterone as a tocolytic agent requires further evaluation.
Adverse effects: pulmonary edema, myocardial infarction, respiratory arrest, cardiac arrest, and death can occur during tocolytic therapy. Newborns of mothers given tocolytics have had respiratory depression, intraventricular hemorrhage, and necrotizing enterocolitis.
Contraindications-acute fetal distress, chorioamnionitis, eclampsia or severe preeclampsia, fetal demise, fetal maturity, and maternal hemodynamic instability.
Pharmacological actions of estrogen and progesterone
MECHANISMS OF ACTION-Estrogens and progestins exert their effects in target tissues by a combination of cellular mechanisms. There are two forms of the estrogen receptor, ER-alpha and ER-beta, and two forms of progesterone receptor, PR-alpha and PR-beta. Receptor binding by estrogens and progestins can activate a classic pathway of steroid hormone gene transcription. Gene activation is mediated by ability of steroid hormone receptor complexes to recruit nuclear coactivator proteins to transcription complex. Gene repression occurs in ligand-dependent fashion by recruitment of nuclear corepressor proteins to transcription complex. This latter effect is an important mechanism of action of estrogen antagonism.
Physiologic Effects of Estrogens:-
FEMALE MATURATION-Estrogens are required for normal sexual maturation and growth of female. They stimulate development of vagina, uterus, and uterine tubes as well as secondary sex characteristics. They stimulate stromal development and ductal growth in the breast and are responsible for accelerated growth phase and closing of epiphyses of long bones that occur at puberty. They contribute growth of axillary and pubic hair and alter distribution of body fat to produce typical female body contours.
ENDOMETRIAL EFFECTS-When estrogen production is properly coordinated with production of progesterone during normal menstrual cycle, regular periodic bleeding and shedding of endometrial lining occur. Continuous exposure to estrogens for prolonged periods leads to hyperplasia of endometrium that is associated with abnormal bleeding patterns.
METABOLIC AND CARDIOVASCULAR EFFECTS-Estrogens seem to be partially responsible for maintenance of normal structure and function of skin and blood vessels in women. Estrogens also decrease rate of resorption of bone by promoting apoptosis of osteoclasts and by antagonizing osteoclastogenic and pro-osteoclastic effects of parathyroid hormone and interleukin-6. Estrogens also stimulate adipose tissue production of leptin.
EFFECTS ON BLOOD COAGULATION-Estrogens enhance coagulability of blood. Many changes in factors influencing coagulation have been reported, including increased circulating levels of factors II, VII, IX, and X and decreased antithrombin III. Increased plasminogen levels and decreased platelet adhesiveness is found.
Pharmacokinetics
When released into circulation, estradiol binds to alpha2 globulin (sex hormone-binding globulin [SHBG]) and with lower affinity to albumin. Bound estrogen is unavailable for diffusion. Estradiol is converted by liver to estrone and estriol and their 2-hydroxylated derivatives and conjugated metabolites and excreted in bile. Conjugates may be hydrolyzed in intestine to active, reabsorbable compounds. Estrogens are also excreted in small amounts in breast milk of nursing mothers.
THERAPEUTIC APPLICATIONS
a. Oral Contraception-it is among most effective forms of birth control.
b. Osteoporosis-One in four postmenopausal women have osteoporosis. Estrogen replacement therapy can prevent bone loss. Estrogen treatment is the most effective therapy for osteoporosis and reduces incidence of bone fractures in postmenopausal women.
c. Hormone Replacement Therapy (HRT) refers to administration of estrogen– progestin combinations.
d. Cardiovascular Actions-Declining estrogen levels associated with menopause are correlated with an increased risk of cardiovascular relateddeaths in women. The protective effects of estrogenson the lipid profile are well recognized.
e. Central Nervous System Effects-Insomnia and fatigue in many postmenopausal women may be related to reduce estrogen levels. Estrogen replacement therapy may be used to treat severe cases.
f. Infertility-Anovulation, often related to altered ratios of estrogen to progestin, can be treated with a variety of agents, including estrogen–progestin replacement, clomiphene citrate, bromocriptine, FSH, LH, human chorionic gonadotropin, and GnRH.
g. Induction of Ovulation-Anovulation can be due to an insufficient release of LH and FSH during mid phase of menstrual cycle. Induction of ovulation by clomiphene citrate is result of stimulation of FSH and LH release.
Adverse Effects
UTERINE BLEEDING-Estrogen therapy is a major cause of postmenopausal uterine bleeding.
CANCER-The relation of estrogen therapy to cancer continues to be the subject of active investigation.
OTHER EFFECTS-Nausea and breast tenderness are common and minimized by using smallest effective dose of estrogen. Hyperpigmentation also occurs. Estrogen therapy is associated with an increase in frequency of migraine headaches as well as cholestasis, gallbladder disease, and hypertension.
Contraindications:Estrogens should not be used in patients with estrogen-dependent neoplasms such as carcinoma of endometrium or in those with carcinoma of breast. They should be avoided in patients with undiagnosed genital bleeding, liver disease, or a history of thromboembolic disorder. In addition, the use of estrogens should be avoided by heavy smokers.
Physiologic Effects of Progestins
a. Progesterone has little effect on protein metabolism. It stimulates lipoprotein lipase activity and favors fat deposition. The effects on carbohydrate metabolism are more marked. Progesterone increases basal insulin levels and the insulin response to glucose. In the liver, progesterone promotes glycogen storage, possibly by facilitating the effect of insulin. Progesterone also promotes ketogenesis.
b. Progesterone can compete with aldosterone for mineralocorticoid receptor of renal tubule, causing a decrease in Na+ reabsorption. This leads to an increased secretion of aldosterone by adrenal cortex (eg, in pregnancy).
c. Progesterone increases body temperature in humans.
d. Progesterone alters function of respiratory centers. The ventilatory response to CO2 is increased. This leads to a measurable reduction in arterial and alveolar PCO2 during pregnancy and in luteal phase of the menstrual cycle.
e. Progesterone and related steroids also have depressant and hypnotic effects on the brain.
f. Progesterone is responsible for alveolobular development of secretory apparatus in the breast. It also participates in preovulatory LH surge and causes maturation and secretory changes in endometrium that are seen following ovulation.
g. Progesterone decreases plasma levels of many amino acids and leads to increased urinary nitrogen excretion.
Pharmacokinetics-Rapidly absorbed following administration by any route. Its half-life in plasma is app. 5 minutes, and small amounts are stored temporarily in body fat. It is completely metabolized in one passage through liver. Metabolized to inactive products and are excreted mainly in urine.
THERAPEUTIC APPLICATIONS
a. Used in for hormone replacement therapy and hormonal contraception.
b. Useful in producing long-term ovarian suppression for other purposes.
c. In treatment of dysmenorrheal, endometriosis, and bleeding disorders, when estrogens are contraindicated, and for contraception.
d. Progesterone and medroxyprogesterone have been used in the treatment of women who have difficulty in conceiving and who demonstrate a slow rise in basal body temperature.
e. Preparations of progesterone and medroxyprogesterone have been used to treat premenstrual syndrome.
f. Abortifacients and Emergency Contraceptives-Progesterone is a hormone required for the maintenance of pregnancy. Termination of early pregnancy is effected using the steroidal antiprogestin drug, mifepristone (RU486), which acts by blocking progestin binding to the progesterone receptor.
Sex hormones
Sex hormones are the substances secreted by ovaries or testes that stimulate the development of secondary sexual characters.
Androgens are steroid hormones secreted primarily by testis, and testosterone is principal androgen secreted. Its primary function is to regulate differentiation and secretory function of male sex accessory organs. Androgens also possess protein anabolic activity that is manifested in skeletal muscle, bone, and kidneys.
PHARMACOLOGICAL ACTIONS
Androgens produce both virilizing and protein anabolic actions. The virilizing actions of testosterone include irreversible effects that occur during embryogenesis, and excitatory actions at puberty that are responsible for secondary sexual development.
In addition to effects on male reproductive function, androgens influence a number of other systems, associated with masculinity. These actions include growth of male-pattern facial, pubic, and body hair, lower vocal pitch resulting from a thickening and lengthening of vocal cords, and increase in rate of long bone growth.
The protein anabolic actions of androgens on bone and skeletal muscle are responsible for larger stature of males than females. Androgens induce some degree of anabolism in other tissues, including bone marrow, liver, kidney, and heart.
CLINICAL USES
1. Hypogonadism
2. Prepuberal Hypogonadism
3. Postpuberal Hypogonadism
4. Aging and Impotence
5. Anemia
Therapeutic Use of Androgens in Women
1. Endometriosis
2. Female Hypogonadism
3. Use of Androgens as Protein
4. Anabolic Agents
Estrogens and progestins are endogenous hormones that produce numerous physiological actions.
In women, these include developmental effects, neuroendocrine actions involved in the control of ovulation, the cyclical preparation of the reproductive tract for fertilization and implantation, and major actions on mineral, carbohydrate, protein, and lipid metabolism.
In males, including effects on bone, spermatogenesis, and behavior. The ovaries are the principal source of circulating estrogen in premenopausal women, with estradiol being the main secretory product.
ACTIONS OF ESTROGENS AND PROGESTINS IN FEMALES:-
1. The Menstrual Cycle Secretion of gonadotropin-releasing hormone (GnRH) from hypothalamus stimulates release of follicle stimulating hormone and luteinizing hormone from anterior pituitary.
2. Control of Pregnancy
3. Ovulation-During the follicular phase of menstrual cycle, one or more follicles are prepared for ovulation. FSH and estrogens are important hormones for this developmental process. Complete follicular maturation cannot occur in absence of LH. Rupture of a mature follicle follows midcycle peak of LH and FSH by about 24 hours. In humans, usually one mature ovum is released per cycle.
4. Implantation-The lining of uterus, that is, endometrium, is critical for implantation of fertilized ovum. Under the influence of estrogen and progesterone, endometrium undergoes cyclical changes that prepare it for implantation of fertilized ovum. Estrogens induce endometrial cell division and growth.
5. Growth and Development-Estrogens cause growth of uterus, fallopian tubes, and vagina. Stimulation of proliferation of vaginal epithelium is checked by cyclical exposure to progesterone during luteal phase in mature female. Estrogens are responsible for expression of female secondary sex characteristics during puberty. These include breast enlargement, distribution of body hair, body contours as determined by subcutaneous fat deposition, and skin texture. Estrogens can stimulate release of growth hormone and exert a positive effect on nitrogen balance.
Therapeutic uses
Used as oral contraceptives and hormone replacement therapy.
Progestins and SERMs are used in treatment of osteoporosis, breast cancer, endometrial cancer, and infertility.
Antithyroid drugs
Classification
1. Thioamide derivatives Ex: propyl thiouracil, carbimazole, methimazole
2. Radioactive iodine Ex: Iodine I131
3. Iodides Ex:Lugol’s solution
4. Anion inhibitors Ex: perchlorates, thiocyanates
5. Iodinated contrast media Ex: oral ipodate and ipanoid acid, diatrizoate.
The thioamides like methimazole, carbimazole and propylthiouracil are major drugs for treatment of thyrotoxicosis.
Pharmacodynamics
The thioamides act by multiple mechanisms. The major action is to prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification. In addition, they block coupling of the iodotyrosines. They do not block uptake of iodide by the gland. Propylthiouracil and methimazole inhibit peripheral deiodination of T4 and T3. Since, 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.
Schematic diagram of mechanism of action of Antithyroid drugs is shown below
Pharmacokinetics
Propylthiouracil is rapidly absorbed, reaching peak serum levels after 1 hour. The bioavailability of 50–80% may be due to incomplete absorption or a large first-pass effect in the liver. The volume of distribution approximates total body water with accumulation in the thyroid gland. Excreted by kidney as inactive glucuronide within 24 hours.
Therapeutic Uses
The antithyroid drugs are used in treatment of hyperthyroidism in following three ways: (1) as definitive treatment, to control disorder in anticipation of spontaneous remission in Graves' disease; (2) in conjunction with radioactive iodine, to hasten recovery while awaiting effects of radiation; and (3) to control the disorder in preparation for surgical treatment.
Toxicity
Nausea and gastrointestinal distress, maculopapular pruritic rash, and fever occur in 3–12% of treated patients.
Rare adverse effects include an urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, hypoprothrombinemia, exfoliative dermatitis, polyserositis, and acute arthralgia. Hepatitis and cholestatic jaundice can be fatal; although asymptomatic elevations in transaminase levels also occur.
Syndrome of diabetes mellitus
The elevated blood glucose associated with diabetes mellitus results from absent or inadequate pancreatic insulin secretion, with or without concurrent impairment of insulin action. The disease states underlying the diagnosis of diabetes mellitus are now classified into four categories:
Type 1, insulin-dependent diabetes;
Type 2, noninsulin-dependent diabetes;
Type 3, and
Type 4, gestational diabetes mellitus
Type 1 Diabetes Mellitus
The hallmark of type 1 diabetes is selective B-cell destruction and severe or absolute insulin deficiency. Administration of insulin is essential in patients with type 1 diabetes. Type 1 diabetes is further subdivided into immune and idiopathic causes. The immune form is common form of type 1 diabetes. Although most patients are younger than 30 years of age at time of diagnosis, onset can occur at any age. Susceptibility appears to involve a multifactorial genetic linkage but only 10–15% of patients have a positive family history.
Type 2 Diabetes Mellitus
Type 2 diabetes is characterized by tissue resistance to action of insulin combined with a relative deficiency in insulin secretion. Individual have more resistance or more B-cell deficiency, and abnormalities may be mild or severe. Although insulin is produced by B cells in these patients, it is inadequate to overcome the resistance, and blood glucose rises. The impaired insulin action also affects fat metabolism, resulting in increased free fatty acid flux and triglyceride levels and reciprocally low levels of high-density lipoprotein.
Individuals with type 2 diabetes may not require insulin to survive, but benefited from insulin therapy to control the blood glucose. In individuals in whom type 2 diabetes was initially diagnosed actually has both type 1 and type 2 or a slowly progressing type 1, and ultimately will require full insulin replacement.
Although persons with type 2 diabetes ordinarily do not develop ketosis, ketoacidosis may occur. Dehydration in untreated and poorly controlled individuals with type 2 diabetes can lead to a life-threatening condition called nonketotic hyperosmolar coma. In this condition, the blood glucose may rise to 6–20 times the normal range and an altered mental state develops or the person loses consciousness. Urgent medical care and rehydration is required.
Type 3 Diabetes Mellitus-refers to multiple other specific causes of elevated blood glucose: nonpancreatic diseases, drug therapy, etc.
Type 4 Diabetes Mellitus
Gestational diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy. During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester. High-risk women should be screened immediately. Screening may be deferred in lower-risk women until 24th to 28th week of gestation.
Insulin preparations
Different types of insulin preparations are:
a. Rapid-acting Insulin- Insulin Lispro, Insulin Aspart, Insulin Glulisine,
b. Short-acting Insulin- Regular Novolin R, Regular Humulin R, Velosulin BR, Regular,
c. Intermediate-acting Insulin- NPH Humulin N, NPH Novolin N
d. Premixed Insulin-Novolin 70/30, Humulin 70/30 and 50/50, 50/50 NPL, 5/25 NPL,
e. Long-acting Insulin- Insulin detemir, Insulin glargine,
a. Rapid-Acting Insulin-Three injected rapid-acting Insulin analogs: Insulinlispro, Insulin aspart, and Insulin glulisine, and one inhaled form of rapid-acting Insulin.
i. Insulinlispro, is produced by recombinant technology. To enhance the shelf-life of Insulin in vials, when injected subcutaneously, the drug quickly dissociates into monomers and is rapidly absorbed with onset of action within 5–15 minutes and peak activity as early as 1 hour.
ii. Insulin aspart: Its absorption and activity profile is similar to that of Insulin lispro, and it is more reproducible than regular Insulin, but has similar binding properties, activity, and mitogenicity characteristics to regular Insulin and equivalent immunogenicity.
iii. Insulin glulisine: Its absorption, action, and immunologic characteristics are similar to the other injected rapid-acting Insulin. After high-dose Insulin glulisine- Insulin receptor interaction, there may be downstream differences in IRS-2 pathway activation relative to human Insulin.
iv. Inhaled human Insulin is a powder form of rDNA human Insulin administered through an inhaler device for pre-prandial and blood sugar correction use in adults with type 1 and 2 diabetes. Because of concerns about lung safety, it is not used in children, teenagers, or adults with asthma, bronchitis, emphysema, smokers. This route of administration is well tolerated; users achieve target blood glucoses after 6 months of therapy with inhaled human Insulin.
b. Short-Acting Insulin
Regular Insulin is short-acting soluble crystalline zinc Insulin made by recombinant DNA techniques. Its effect appears within 30 minutes and peaks between 2 and 3 hours after subcutaneous injection and lasts 5–8 hours.
When regular Insulin is administered at meal time, the blood glucose rises faster than the Insulin with early postprandial hyperglycemia and an increased risk of late postprandial hypoglycemia. Regular Insulin should be injected 30–45 or more minutes before the meal to minimize the mismatching. Short-acting soluble Insulin is the only type that should be administered intravenously because useful for i.v. therapy in management of diabetic ketoacidosis.
c. Intermediate-Acting and Long-Acting Insulin
i. NPH (NEUTRAL PROTAMINE HAGEDORN, OR ISOPHANE) Insulin-It is intermediate-acting Insulin wherein absorption and onset of action are delayed by combining appropriate amounts of Insulin and protamine, so that neither is present in an uncomplexed form. After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to permit absorption of Insulin. Onset of action is 2–5 hours and duration of 4–12 hours; and given two to four times daily for Insulin replacement in patients with type 1 diabetes.
ii. Insulin GLARGINE-is a soluble, ultra-long-acting Insulin analog. Has a slow onset of action (1–1.5 hours) and achieves a maximum effect after 4–6 hours. This maximum activity is maintained for 11–24 hours or longer.
iii. Insulin DETEMIR- has the most reproducible effect of intermediate- and long-acting Insulin, and its use is associated with less hypoglycemia than NPH Insulin. Onset of action of 1–2 hours and duration of action of more than 24 hours.
iv. Mixtures of Insulin-Because intermediate-acting NPH Insulin require several hours to reach adequate therapeutic levels, their use in type 1 diabetic patients requires supplements of rapid- or short-acting Insulin before meals. These are often mixed together in the same syringe before injection. Insulin lispro, aspart, and glulisine can be acutely mixed (ie, just before injection) with NPH Insulin without affecting their rapid absorption.
Oral contraceptive
Contraception means interception in the birth process at any stage ranging from ovulation to ovum implantation. An ideal contraceptive agent should not only be safe but provide reversible suppression of fertility.
Classification
1. Combination pills
a. Ethinyl estradiol (30 mcg)+ Norgestrel (300 mcg)
b. Ethinyl estradiol (30 mcg)+ Levonorgestrel (150 mcg)
c. Ethinyl estradiol (50 mcg)+ Norgestrel (0.5 mg)
d. Ethinyl estradiol (30 mcg)+ desogestrel (150 mcg)
e. Mestranol (50 mcg) + Norethindrone (1 mg)
2. Phased pill
a. Ethinyl estradiol (30-40-30 mcg)+ Levonorgestrel (50-75-125 mcg)
b. Ethinyl estradiol (35-35-35 mcg) + Norethindrone (0.5-0.75-1.0 mg)
3. Post coital (morning after) pills
a. Ethinyl estradiol (50 mcg)+ Levonorgestrel (0.25 mg)
b. Levonorgestrel (0.75 mg)
c. Mifepristone 600mg
4. Mini pills (progestin only pills)
a. Norgestrel (75 mcg)
b. Norethindrone (0.35 mg)
MECHANISM OF ACTION-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 cervical mucus, in uterine endometrium, and in motility and secretion in uterine tubes, all of which decrease the likelihood of conception and implantation.
Pharmacologic Effects
EFFECTS ON OVARY-Chronic use of combination agents depresses ovarian function. Follicular development is minimal, and corpora lutea, larger follicles, stromal edema, and other morphologic features normally seen in ovulating women are absent. The ovaries usually become smaller even when enlarged before therapy.
EFFECTS ON UTERUS-After prolonged use, the cervix may show hypertrophy and polyp formation. There are also important effects on cervical mucus, making it more like postovulation mucus, i.e., thicker and less copious.
EFFECTS ON BREAST-Stimulation of breasts occurs in most patients receiving estrogen-containing agents. Enlargement is noted. The administration of estrogens and combinations of estrogens and progestins tends to suppress lactation.
Clinical Uses:-
a. Oral contraception
b. In post coital contraception
c. Polycystic ovary syndrome
d. Dysfunctional uterine bleeding
e. Premature menopause
f. Turner’s syndrome
g. In the treatment of endometriosis
Adverse Effects
MILD ADVERSE EFFECTS
1. Nausea, mastalgia, breakthrough bleeding, and edema
2. Changes in serum proteins and other effects on endocrine function
3. Headache is mild and often transient
4. Withdrawal bleeding sometimes fails to occur
MODERATE ADVERSE EFFECTS
1. Breakthrough bleeding
2. Weight Increased
3. skin pigmentation may occur
4. Acne may be exacerbated
5. Hirsutism
6. Ureteral dilation
7. Amenorrhea occurs
Oxytocin
Oxytocin is a peptide hormone secreted by posterior pituitary that participates in labor and delivery and elicits milk ejection in lactating women. During the second half of pregnancy, uterine smooth muscle shows an increase in expression of oxytocin receptors and becomes increasingly sensitive to the stimulant action of endogenous oxytocin. Pharmacologic concentrations of oxytocin powerfully stimulate uterine contraction.
Pharmacodynamics
Oxytocin acts through G protein-coupled receptors and phosphoinositide-calcium second-messenger system to contract uterine smooth muscle. Oxytocin also stimulates release of prostaglandins and leukotrienes that augment uterine contraction. Oxytocin in small doses increases both the frequency and force of uterine contractions. At higher doses, it produces sustained contraction.
Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection. Without oxytocin-induced contraction, normal lactation cannot occur. At high concentrations, oxytocin has weak antidiuretic and pressor activity due to activation of vasopressin receptors.
Clinical Use of Oxytocin
a. Induction of Labor.
b. Augmentation of Labor.
c. Third Stage of Labor and Puerperium
d. Oxytocin Challenge Test.
Goitrogens
Goitrogens are agents that suppress secretion of T3 and T4 to subnormal levels and thereby increase TSH, which in turn produces glandular enlargement (goiter). This inturn stimulates the thyroid which shows hypertrophy, hyperplasia and increase in vasculairty. Histolgoically height of the acinal epithelium increases and quantity of colloid decreases.
Classification of goitrogens:-
1. Ion inhibitors Ex: potassium perchlorates, thiocyanates
2. Organic antithyroid drugs:
a. Thioamide derivatives Ex: propyl thiouracil, carbimazole, methimazole
b. Misc: sulfonamides, PAS, resorcinol, amine-glutethimide.
Mineralocorticoids
Mineralocorticoids (Aldosterone, Deoxycorticosterone, Fludrocortisone)
a. Mineralocorticoids act by binding to mineralocorticoid receptor in cytoplasm of target cells, the principal cells of distal convoluted and collecting tubules of kidney. The major effect of activation of aldosterone receptor is increased expression of Na+/K+ ATPase and epithelial sodium channel (ENaC).
b. Aldosterone and other steroids with mineralocorticoid properties promote reabsorption of sodium from distal convoluted tubule and from cortical collecting renal tubules, loosely coupled to excretion of potassium and hydrogen ion. Sodium reabsorption in sweat, salivary glands, gastrointestinal mucosa, and across cell membranes is also increased.
c. Deoxycorticosterone (DOC) serves as a precursor of aldosterone. Its half-life is 70 minutes. Although the response to ACTH is enhanced by dietary sodium restriction, a low-salt diet does not increase DOC secretion. The secretion of DOC may be markedly increased in abnormal conditions such as adrenocortical carcinoma and congenital adrenal hyperplasia with reduced P450c11 or P450c17 activity
d. Fludrocortisone, a potent steroid with both glucocorticoid and mineralocorticoid activity. It has potent salt-retaining activity and used in treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency.
Angiotensins
Angiotensin II inhibits renin secretion. The inhibition, which results from a direct action of peptide on juxtaglomerular cells, forms basis of short-loop negative feedback mechanism controlling renin secretion. Interruption of this feedback with inhibitors of renin-angiotensin system results in stimulation of renin secretion.
The release of renin is altered by a wide variety of pharmacologic agents. Renin release is stimulated by vasodilators (hydralazine, minoxidil, nitroprusside), beta-adrenoceptor agonists (isoproterenol), alpha-adrenoceptor antagonists, phosphodiesterase inhibitors (theophylline, milrinone, rolipram), and most diuretics and anesthetics.
Uterine stimulants
Drugs and hormones used clinically to enhance uterine contractions are primarily employed either to induce or to augment contraction during deliver or at various stages of labour. Ex: Oxytocin, Ergot alkaloids, and prostaglandins.
Oxytocin acts through G protein-coupled receptors and phosphoinositide-calcium second-messenger system to contract uterine smooth muscle. Oxytocin also stimulates release of prostaglandins and leukotrienes that augment uterine contraction. Oxytocin in small doses increases both the frequency and force of uterine contractions. At higher doses, it produces sustained contraction.
Oxytocin also causes contraction of myoepithelial cells surrounding mammary alveoli, which leads to milk ejection. Without oxytocin-induced contraction, normal lactation cannot occur. At high concentrations, oxytocin has weak antidiuretic and pressor activity due to activation of vasopressin receptors.
Clinical Use of Oxytocin
a. Induction of Labor.
b. Augmentation of Labor.
c. Third Stage of Labor and Puerperium
d. Oxytocin Challenge Test.
