HISTAMINE and ANTIHISTAMINIC AGENTS *HISTAMINE – or B- imidazolylethylamine; enzyme that expressed in many mammalian tissues including gastric mucosa

parietal cells, most cells, and basophils and the CNS. *NOMENCLATURE – structurally composed of an imidazole heterocycle and ethylamine side chain. HISTAMINE AS A CHEMICAL MESSENGER BIOSYNTHESIS and DISTRIBUTION synthesized in golgi apparatus of its principle storage cells, mass cells, and basophils; found in almost all mammalian tissues in conc. Raging from 1-100+ ug/g. mass cells and histamines are particularly high conc. In skin and the mucosal cells of the bronchi, intestines, urinary tract and tissues adjacent to the circulation.

STORAGE and RELEASE mostly biosynthesized and stored as protein complexes in most cells (complexed with heparin) and basophilic granulocytes (complexed with chondroitin) the release of histamines as one of the mediators hypersensitivity reactions is initiated by the interaction of an antigen- IgE complex with the membrane of a histamine storage cells. Released from mast cells in the gastric mucosa by gastric and acetylncholine.

HISTAMINE RECEPTORS and HISTAMINE MEDIATED PHYSIOLOGIC FUNNCTIONS extensive pharmacological and molecular biology studies have revealed the presence of at least 4 different histamine receptor subtypes in mammalian systems designated as H1, H2, H3, H4.

HISTAMINE RRECEPTOR SUBTYPES H1 RECEPTOR receptor proteins in human: 487 amino acids chromosomal location: 3p25, 3p14-21 G-protein coupling: G9g11 Activated intracellular signals: Ca2+, cGMP, phospholipase A2, C, and D, NFkB, cAMP, NOS. Inverse agonist for clinical use: first and second- generation antihistamines receptor proteins in human: 359 amino acids, 40 kd chromosomal location: 5q35.3 G-protein coupling: Gas Activated intracellular signals: cAMP, Ca2+, phospholipase C, proteinkinase C, c-FOS. Inverse agonist for clinical use: H2-blockers receptor proteins in human: 445 amiino acids, 70 kd; splice variants chromosomal location: 20q13.33 G-protein coupling: Gi/o Activated intracellular signals: Ca2+, MAPkinase; inhibition of cAMP Inverse agonist for clinical use: None to date receptor proteins in human: 390 amino acids

H2 RECEPTOR -

H3 RECEPTOR -

H4 RECEPTOR -

piperazines. FIRST GENERATION ANTIHISTAMINE CLASSES  AMINOALKYL ETHERS (ethanolamines). etc. rhinorrhea and itching of eyes.) An emerging role as a neurotransmitter in the CNS. c. Also reduce the number. Cellular uptake: Animal studies have documented the uptake of histamine by many cells. Second generation or non-sedating antihistamines derivatives of several first generation agent but have been modified to be more specific. but limited. pollinosis) chronic idiopathic urticia. H1. Widely used to relieve symptoms of asthma and upper respiratory infections including common cold. MAPkinase. inhibition of cAMP Inverse agonist for clinical use: None to date TERMINATION OF HISTAMINE ACTION Three principle ways exist to terminate the physiological effects of histamine: 1. 2. -recommended in various allergic conditions and to a lesser as an antitussive and Parkinson’s drug.dependent process in rabbit gastric glands and the histamine is metabolized once in the cell. and sinusitis. FUNCTIONS OF HISTAMINE AS RELATED TO PHARMACOLOGICAL INTERVENTION a.) It’s important. size. shifting the equilibrium toward the inactive state. -CAUTION: concurrent use of alcohol and other CNS depressant should be avoided. b. dibenzocycloheptanes. In particular.antihistamines acts as inverse agonists that combine with and stabilize the inactive from of the H1-receptor. perhaps as result of receptor modification. -ADR drowsiness. and duration of wheals and itching in chronic urticia when used promptly. seasonal rhinitis. these drugs best relieve the symptoms of allergic disease at the beginning of the reason when pollen counts are low. alcohol (1:2) and chloroform (1:2).2 G-protein coupling: Gi/o Activated intracellular signals: Ca2+.- chromosomal location: 18q11. nose and throat) of allergy rhinitis(have fever. uptake is a temperature and partially Na+. ANTIHISTAMINES drugs that blocked the action of histamines at H1-receptors rather than other histamine subtypes first generation or classical antihistamines: aminoalkyl ethers. MECHANISM OF ACTION - GENERAL PHARMACOLOGICAL AND THERAPEUTIC CONSIDERATIONS classical antihistamines has been used extensively for symptomatic treatment (sneezing. Desensitization of cells: Some H1. otitis media. -orally or parentally in treatment of urticaria. Metabolism: The most common pathway for terminating histamine action involves enzymatic inactivation. . propylamines. ethylenediamines.receptor containing tissues exhibit homogenous loss of sensitivity to the actions of histamine.) A major role in the regulation of gastric acid secretion. role as a chemical mediator of hypersensitivity and allergic inflammatory reaction. 3.diphenhydramine HCL. and some dermatitis. tannate and citrate are soluble in water (1:1).

77) and in alcohol (1:6).adults and children 12 year old of age and older: 1 tablet (8mg) twice daily.5 and 25mg). usual adult dose: oral (25mg/4 to 6 hours) DOXYLAMINE SUCCINATE.  DIPHENYLPYLAMINE HCL. solution (4mg/5ml).soluble in water (1:0. liquids (12. motion sickness (25 to 50mg every 4 to 6 hours maximum of 300mg/day).67mg twice daily maximum of 4. capsules (10mg). dose should be taken at least 0. inj.67mg/ml). children 2 to younger than 6 years of age: ¼ to ½ chewable tablet (12. antitussive liquid (25 to 50mg every 4 hours not exceeding 300mg/day). children 6 to 12 year old of age: ½ tablet twice daily every 12 hours.525mg) every 6 to 8 hours. extended-release tablets (100mg/ 8 to 12 hours)  PYRILAMINE MALEATE.dosage form: capsules and elixir. - 1% of the solution has the pH of 4. Dosage form: tablets (5mg). capsules (25 and 50mg). Caution: concurrent use of alcohol and other CNS depressants should be avoided.1% solution has the pH of 5.5 hr before beginning a trip.5ml) Usual adult dose: oral (12.highly soluble in water and freely soluble in alcohol and chloroform.  DIMENHYDRATE.5 to 25mg/4 to 6 hours)  CARBINOXAMINE MALEATE. it has a pKa of about 9 and 0. for children 6 to 12 years of age (syrup only).4). - dosage forms: tablets (1.2mg/5ml) Usual dose (tablets). The tablets are not recommended for children younger than 6 years of age. oral solution (1mg/ml) and oral liquid (2.68mg in 24 hours for tablets).has long duration of action.02mg.62mg/ml). with an activity that reaches a maximum in 5 to 7 hours and persist in 10 to 12 hours. liquid (1.1 Dosage forms: tablets (4 and 8mg). not to exceed 8 chewable tablets or 400mg in 24 hours.34mg every 12 hours or twice daily (maximum 8. suspensions (25mg/5ml). extended-release tablets Usual dose: oral tablets (25 to 50mg/4 to 6 hours). not exceeding 1 ½ tablets in 24 hours.68mg) and syrup (0. oral disintegrating strips (12. a 1% of the solution has the pH of 5 - indicated for the relief of seasonal rhinitis symptoms. (150mg/ml). alcohol (1:2) and chloroform (1:2). usual adult dose: oral (25 to 50mg/ 4 to 6 hours) TRIPELENNMINE HCL. Dosage forms: tablets .34 and 2. for nausea of motion sickness and for hyperemesis gravidanem (nausea of pregnancy).04mg/day for syrups/2.5. 25 and 50mg).-DOSAGE FORMS: tablets (12.6 and 5. -USUAL ADULT DOSES: antihistamines (25 to 50mg every 4 hours maximum of 300mg/day).1.  CLEMASTINE FUMMATE. to prevent motion sickness. but is also used as a nightmare sedative.first useful antihistamines. dosage forms: elixir.soluble in water (1:1). Dosage forms: tablets. freely soluble in alcohol. should not be swallowed. ADULT DOSE: tablets (50mg). taken with food.soluble on water or alcohol.very soluble in water and freely soluble in alcohol and in chloroform.5mg/ml) and (15.5 - ADR: drowsiness and may impair the ability to perform task requiring alertness. and suspension (3. TRIPELENNMINE CITRATE. less potent antihistamine - local anesthetic.   BROMODIPHENHYDRAMINE HCL. adult/children >12 years of age: 1 to 2 chewable tablet (50-100mg) evry4 to 6 hours.for oral administration in liquid forms. injection (50mg/ml) USUAL DOSAGE: for motion sickness.5mg/2. for adults: 0.67mg/5ml) usual adult dose: allergic rhinitis.soluble in water (1:0. potent antihistaminic and the usual dose is 2mg 3 or 4 times daily - dosage forms: extended release capsules (5mg) usual adult dose: oral 5mg/2hours)    ETHYLENEDIAMINES.

usual adult dose: 1 or 2 tabs (6-12mg) every 12 hrs.soluble in water. dosage forms: tabs (6. ALCOHOL (1:5). dosage forms: tabs (25mg). use primarily in prophylaxis and treatment of motion sickness.soluble in water (1:0. room temperature several months - dosage forms: tablets HCL (25 and 50 HCL) and injections (lactate) usual adult dose : 1 tablet every 4 to 6 hours for adults.insoluble on water.0 and a 2% solution ahs the pH of 4. in alcohol (1:6). oral suspension (4. pka of 10.moderately potent antihistamines. capsules (12mg). IM.12mg). less active.25mg/5ml) and oral suspension (2. treatment of motion sickness CYCLIZINE HCL.  MECLEZINE HCL. extended-release capsules (8.soluble in water (1:115). primarily as antinauseant in the prevention and treatment of motion sickness and of nausea and vomiting associated with vertigo - dosage forms: tablets (5. oral (25 to 50mg/6 to 8 hours)      METAPYRILENE HCL.12mg).12.soluble in water (1:1). peak effect occurs about 3. insomnia when taken just before bedtime. slow onset. children 12 yrs of age: ½ tablet/ 6 to 8 hours.5). has a half life of 12 to 15 hours - dosage forms: tablets (2. PIPERAZINES (CYCLINES).- Usual adult dose.sparingly soluble to water (1:40).soluble in water (1:5) and very soluble in alcohol.5. or 5 to 10 ml of solution or suspension DEXBROMPHENIRAMINE MALEATE PYRROBUTAMINE PHOSPHATE.half life: 25 hrs. vertigo: 25 to 100mg daily in divided doses    BUCLIZINE HCL.5.soluble in water (1: 34).10. less soluble HCL is given orally.soluble in water and alcohol.soluble to the extent of 10% in warm water TRIPROLIDINE HCL.25.12mg/5ml). usual adult dose: 1 tab every 4 to 6hrs not exceeding 6 tabs in 24 hrs DIMETHINDINE MALEATE.dosage forms: extended-release tabs (4 to 6hrs). stored in cold place. principal effect: sedation or ddrowsiness . usual dose: 50mg/ 4x daily ANTALOLINE PHOSPHATE. more than twice the local anesthetic potency. antiemetic and antihistaminic properties PROPYLAMINES (MONOAMINOPROPYL OR ALKYLAMINE DERIVATIVES) PHENISAMINE MALEATE.5 hrs after oral administration and the duration effect is about 12 hrs    - dosage forms: oral liquid (1. in chloroform (1:4).8. alcohol (1:10) and in chloroform (1:10). and suspension (4 and 8mg/5ml) usual adult dose: oral (4mg/4to 6 hrs).000). liquid (2mg/5ml). and in chloroform (1:3).sparingly soluble in water.5mg/5ml) usual adult doses: 10 ml every 4 to 6 hrs. IM. usual dose is 2 to 4mg 3 or 4 times daily. a 2% solution has the pH of 5. has CNS depressant. solutions are alkaline to litmus.50mg) and capsules (25mg) usual adult dose: motion sickness: 25 to 50mg meclizine HCL should be taken 1 hour prior. IV or subcutaneous (5 to 40mg)   DEXCHLORPHENNIRAMINE MALEATE. syrup (2mg/5ml).5% solution. usual adult dose: 4 or 6mg at bedtime or every 8 to 10 hrs BROMPHENIRAMINE MALEATE AND TANNATE. pH of 5.12mg). long duration of action.5. Do not exceed 40ml in 24 hrs   PHENINDAMINE TARTRATE. produce drowsiness and sleepiness. usual adult dose is 20 to 40mg 3 times daily CHLORPHENIRAMINE MALEATE. use as antiemetics and antivertigo agents. oral drops (1mg). applied topically to the eye 0.4.practically insoluble on water (1:1. extended-release capsules (8 to 12 hrs). potencial carcinogen THONZYLAMINE HCL. alcohol (1:115) and chloroform (1:75). syrup (2mg/5ml).8. cause drowsiness and psychomotor and cognitive disfunction.

5 hrs. 25. In about 2.5 hrs elimination half-life raging 8 to 15 hrs dosage forms: tablets (5.5 to 5. 50mg). allergic conjunctivitis. has a pronounced antipruritic action. dosage forms: tabs (40mg) and syrups (2mg/5ml). used as antipruritic agent.5mg may be taken before meals or on retiring if necessary. however.10mg). sadation is the common ADR. chewable tablets and syrup (5mg) once daily for children 2 to 5 yrs of age  DESLORATIADINE.dosage forms: tablets (1mg). 25. usual adult dose: oral 25mg 4 times daily METHDILAZINE.slightly soluble in water and sparingly soluble in alcohol. oral disintegrating tablets (30mg) and an oral suspension (6mg/ml) usual dosage: chronic idiopathic urticaria: 60mg twice daily or 180mg once daily for adults and >12. usual adult dose: 1 to 2mg twice daily  SECOND GENERATION ANTIHISTAMINES  FEXOFENADINE HCL.5 to 25mg every 6 to 6 hrs if necessary. injection (25. 60-70% protein bounded the mean elimination half-life is about 14hrs dosage forms: tablets (30.insoluble in water but very soluble in acetone. rapidly disintegrating tablets (2. transfusion reaction: 25mg of doses to control transfusion reaction.5. 12. slightly soluble in chloroform and water and insoluble in hexane treatment of seasonal allergic rhinitis and chronic adiopathic urticaria rapidly absorbed after oral administration. syrup (2. presurgical. alcohols and chloroforms - For the relief of nasal and non-nasal symptoms of seasonal allergic rhinitis rapidly absorbed after oral administration. syrups (5mg/5ml) usual adult dose (allergic rhinitis) : 10mg once daily for adults and children 6 yrs and older.freely soluble in water and soluble in alcohol.10mg). prophylactic dosage: 25mg every 4 to 6 hrs given during surgery and the postoperative period and 25 to 50mg with analgesics postoperatively or preoperatively.PHENOTHIAZINES  PROMETHAZINE HCL. perennial. or obstetrical sedation    TRIMEPRAZINE TARTRATE. 50mg). oral syrup (6.practically insoluble on water.5mg/5ml) - .5.freely soluble in methanol and ethanol. producing peak serum conc. dosage forms: syrup and tablets. vasodilator rhinitis.very soluble in water and not absolutely soluble in alcohol and chloroform dosage form: tabs (12. antihistamine and antiserotonin sesquihydrate. usual adult dosage: oral (4mg/ 3 or 4 times daily) AZATADINE MALEATE.salt is freely soluble in water and alcohol DIBENZOCYCLOHEPTENES & DIBENZOCYCLOHEPTANES  CYPROHEPTADINE HCL.25mg/5ml). uncomplicated allergic skin manifestation of urticaria and angioedema. producing peak plasma levels in about 1.0mg). 60. rectal suppositories (12. lower doses are recommended for children  LORATADINE. amelioration of allergic reactions to blood or plasma and urticaria. sedation: 25 to 50mg for nightmare. oral disintegrating tablets (5. 50mg/ml) usual adult dose: allergy: 25mg taken before retiring.slightly soluble in water but very soluble in ethanol and propylene glycol - indicated for the symptomatic relief of pruritis and reduction of the number and size of lives in chronic idiopathic urticaria patients 6 months of age and older and for the relief of nasal and non-nasal symptoms of perennial allergic rhinitis in patients 6 months and older and seasonal rhinitis in patients 2 yrs and older the mean elimination half0life is 6hrs and the drug and its metabolites are eliminated in the urine and feces dosage forms: tablets (5mg). and seasonal allergic rhinitis. 180mg). nausea and vomiting: 12. motion sickness: 25mg taken before 30 to 60 mins travel and repeated 8 to 10 hrs if necessary. chewable tabs because it’s slow solubility in water contributes to its tastelessness METHDILAZINE HCL. treatment of hypersensitivity reactions.

. Testosterone. dosage forms: tablets : various combination products. the steroid backbone.4ml/min/kg.are representative of the distinct steroid-receptor ligands. 2.Most widely used classes of therapeutic agents.5mg/5ml) usual dose: 5mg one tablet or 10 ml oral solution once daily in the evening for adults and children 12 yrs and older. Chemical and Physical Properties of Steroids Steroids .Defect in the STAR gene lead to congenital lipoid Adrenal Hyperplasia – rare condition marked by a deficiency of adrenal and gonadal steroid hormones.A key protein involved in the translocation is the (STAR) Steroidogenic Acute Regulatory Protein. 2. inflammatory condition and cancer treatment.soluble in water. . terminal half-life about 8. indicated for the relief of symptoms associated with allergic rhinitis (seasonal/ perennial) in adults and children 6 yrs and older and for the treatment of the uncomplicated skin manifestation of chronic idiopathic urticaria - dosage forms: tablet (5mg) and solution (2. Progesterone. orally administered drug and has a half-life of about 1. Estradiol. usual adult dose: oral ( 8 or 60mg 3 or 4 times daily) STEROID HORMONES AND THERAPEUTICALLY RELATED COMPOUNDS Steroid Hormones And Related Products .5mg once daily  CETIRIZINE. up to max of 10mg daily for adults and children 6 yrs and older. . Cytochromes P450 and Dehydrogenase – enzymes involved in the transformation of cholesterol to the hormones. and oral syrup (1mg/ml) usual adult dose (allergies/ hay fever and urticaria): 5 to 10mg once daily depending on the severity of symptoms.3 hrs. a greater amount (about 1g) is biosynthesized per day. Steroid Nomenclature Stereochemistry and Numbering Steroid Biosynthesis .Most of these agent are chemically based on a common structural backbone. Aldosteron and Hydrocortisone .Steroid hormones in mammals are biosynthesized from cholesterol which interm is made in vivo from acetyl-coenzyme A (acetyl-coA) via the mevalonate pathway.Human do obtain approximately 300mg of cholesterol per day in their diets.7 hrs and a total clearance of 4 . and watery eyes caused by fever or other respiratory allergies food slows the rate of absorption but does not effect the overall extent high protein bounded (93%). dosage form: tablets (5. rapid onset on activity.Used primarily in birth control. . sneezing. children 6 to 11 yrs of age: 2. pharyngitis and dizziness concurrent use of this drug with alcohol and other CNS depressants should be avoided indicated for the temporary relief of runny nose. .5mg once daily of the oral solution for children younger than the age of 6  LEVOCETIRIZINE DIHYDROCHLORIDE.soluble on chloroform and alcohol and slightly soluble in water. itching of the nose or throat.- usual doses: adult and children 12 yrs and older: 5mg once daily. has the advantage to appear to be its long action (once daily dosing). hormone-replacement therapy (HRT).10mg).5mg half of the tablet or 5ml oral solution once daily in the evening for 6 yrs to 11 yrs * ACRIVASTINE. minimal CNS effects and a lack of clinically significance in cardiac rhythm - may interfere in the performance of the job or activity side effects: fatigue. dry mouth.water soluble.

2. – Bec. – Salt are the most water soluble Changes to Modify Pharmacokinetic Properties of Steroids . C-terminal ligand-binding (E) domain (LBD) – Includes about 250 amino acids. Steroid Hormone Receptor The Steroid receptors themselves are key players in gene expression but many other proteins are involved in the process. Progesterone receptor beta – mainly mediates the stimulatory actions of progesterone. glucocorticoid receptor (GR). and vasculator. and testosterone) are particularly susceptible to rapid metabolism after absorption or rapid inactivation in the GI tract before absorption.– Are white crystalline solids. depending on the particular compound.Some steroids (estradiol. Hinge (D) domain – this variable linker region appears to be involved with nuclear localization and transport of the steroid-receptor complex into the nucleus. organized into two zinc finger motifs that are important for recognition and binding to the DNA response elements. . Acts as transcriptional inhibitor of ER. leaflets. platelets or amorpous particles. 4. receptor dimerization. but these are divided from a single gene. . binding to chaperone proteins. Estrogen receptor beta – found in greatest abundance in the ovaries and the prostate with reduced occurrence in the lungs. Progesterone Receptor – can be found in two forms. DNA-binding (C) domain.The Steroid can be made more lipid soluble or more water soluble by making suitable ester derivatives of hydroxyl (OH) groups .These inactivation processes limit the effectiveness of the hormones as orally available drugs. brain. although micronized form of estradiol and progesterone are available for oral administration. only one gene and one protein are known for each receptor. Progesterone receptor alpha – has had 164 amino acids translocated from the N-terminus of PRbeta.More lipid-soluble derivatives also have improved skin absorption properties and thus. Structure of Steroid Hormone Receptors 1. . Gonadotropi-Releasing Hormone and Gonadotropins Gonadotropins – are pedtides that have a close functional relationship to estrogen.Derivatives with increased water solubility are needed for intravenous preparations. 3. N-terminal (A/B) domain – once the steroid-receptor complex has bound to the target genes this domain ( also called A/B modulator domain) activates the hormone response elements adjacent to the genes. progesterone and testosterone.the hypothalamus release GnRH. endothelial cells and vascular smooth muscle. are preferred for dermatological preparation. Gonadotropin-Releasing Hormone (GnRH) – regulates release of the gonadotropins. . – They may be in the form of needles.They control ovulation. as well as in the breast.the two distict estrogen receptors. Contain about 12-18 base-pair DNA sequences and consist of two half sites that are separated by a variable receptor. it is not surprising that they tend to be water insoluble. Estrogen Receptor Estrogen receptor alpha(ERalpha) and Estrogen receptor beta . vagina and ovaries. Androgen. a peptide that stimulates the anterior pituitary to secrete LH and FSH in males and .Derivatives with increased lipid solubility are often made to decrease the release rate of the drugs from IM injection sites. the hypothalamus. providing a receptor that has different interaction with target genes and associated proteins.short section is made up of about 65 amino acids. . mineralocorticoid receptor (MR) and PRb. Glucocorticoid and Mineralocoticoid Receptor – are present only as single form. Estrogen receptor alpha – found in high abundance in the uterus. This section has the steroid hormonebinding site and is also involved with ligand-dependent transcriptional activation. androgen receptor (AR). . progesterone.they are called Gonadotropins because of their actions on the gonads. The steroids have 17 or more carbon atoms. . spermatogenesis and development of sex organs and they maintain pregnancy.

coronary atherosclerosis and gout become potential health problems for the first time. They are normally produced in relatively large quantities in the ovaries and the placenta. Also stimulate the dev. Estrogen and Progesterone – are produced much larger amount in females. Physical differences. 17beta-estradiol – is produced in the greatest amount. Included in this group are the following: GnRH Luteinizing Hormone (LH) Follicle-Stimulating Hormone (FSH) Sex Hormones Estrogen and Progesterone are usually called sex hormones and testosterone is called male sex hormone.females.in the plasma. All of these steroid are biosynthesized in both male and female. however testosterone in males. Estrone – is converted to estriol. These hormones play profound roles in reproduction in menstrual cycle and in giving women and men their charac. reducing post-menopausal symptoms and preventing osteoporosis. 2. The peptide controls and regulates both male and female reproduction. Steroidal Estrogen – conjugated Estrogen. Esterified Estrogens – are also mainly a combination of estrone sodium sulfate and equilin sodium sulfate. Metabolism of Estrogen 3 primary Estrogen in women are the ff: 1. uterus.related metabolites originally obtained from the urine of horses especially pregnant mares. 2. Strutural Classes Estrogens 1.of lipid and other tissues that contribute to breast shape and function. Estrdiol – provides the greatest estrogenic activity with estriol. Esterified Estrogen – steroidal. Estrogen Endogenous estrogens – are estradiol. 3. Directly stimulate the growth and dev. Therapeutic Uses of Estrogen . Of the vagina. the estrogen found in highest conc. Estrogen – cause a profeliration of the breast ductile system. including preventing and treating cardiovascular disease. and fallopian tubes and in combination with other hormones play a primary role in sexual arousal and in producing the body contours of the mature woman. and progesterone stimulates development of the alveolar system. 3. Biological Activities of Estrogens In addition to having important roles in the menstrual cycle. by hydroxylation at C16 and reduction of the C17 ketone. the estrogens and to a lesser extent progesterone are largely responsible for the development of secondary sex characteristics in women at poberty. estrone and estriol. it is quickly oxidized. In human placenta. Diethystilbestrol – have the same activity as estradiolor other estrogen. Testosterone – is one of the precursors of estrogen. Phytoestrogen – found in certain legumes. the most abundant estrogen synthesized is estriol. in lower amount in the adrenal glands and in trace quantities in the testes. Estriol Estradiol – can also be directly converted to estriol. Biosynthesis Estrogen – are synthesized by the action of the enzyme aromatase on an drostenidione or testosterone. and the bones begin to use density because of decreased mineral content. Have antifertility activity in animals. Many claims have been about the beneficial effects of consuming product containing these phytoestrogen. the major estrogen found in human urine. Pigmentation of the nipples and genital tissues and growth stimulation of pubic and underarm hair (possibly with the help of small amout of testosterone) are other resuppleness. to estrone.

Used to prevent and treatment of osteoporosis in postmenopausal women. Equilenin sulfate. estriol.offer a useful approach to decreasing estrogen levels in the treatment of estrogen-dependent breast cancer. 5. USP – (Fareston) chloroethyl group. USP (IM injection) 2. Tamoxifen conc. sod. in combination with progestins. Treatment of moderate to severe vasomotor symptoms and valvar and vaginal atrophy associated with menopause. Toremifene 3. Used as adjuvant treatment for breast cancer in women ff. USP – ester group. Used in the treatment of metastatic breast cncer in postmenopausal women. failure or after ophorectomy. but is post menopausal women aromatase is largely in muscle and adipose tissue. 4. The major metabolite of tamoxifen is N-desmethyltamoxifen. 6. Aromatase inhibitors . Used as second-line therapy in postmenopausal women who failed on tamoxifen therapy. Esterified Estrogen. Hormone Replacement Therapy – for postmenopausal women. except birth control. which is used as an ovulation stimulant and Raloxifene which is used for the prevention and treatment of osteoporosis. the conjugated estrogens are used for the entire range of indications described previously. Birth control . USP – has the greatestadv. Toremifene Citrate. Raloxifene. Estriol. Most commonly used in HRT to treat postmenopausal symptoms. Fulvestrant Two additional agents that can antagonize ERs are clomiphine. USP (oral.reduced if coadministration with rifampin a cytochrome P450 inducer.over other estradiol product of being orally active. Ethinyl Estrdiol. USP (IM injection) Estradiol 3-acetate.1. Treatment of advanced inoperable breast cancer in women and postmenopausal women and advanced inoperable prostate cancer in men. Most commonly used estrogen in oral contraceptives. It can be used alone or in combination with estradiol (Bi – est) or with estradiol and estrone (Tri – est) 8. Bazedoxifene. Tamoxifen Citrate. NADPH – cytochrome P450 reductose. Estrogen and cancer – use an increased risk of breast cancer Estrogen Products 1. sodium equilin sulfate. . Pharmacological action quite similar to tamoxifen. 3. SERM – is drug that has tissue-specific strogenic activity. Piperazine Estrone sulfate. Aromatase Inhibitors Aromatase – is a cytochrome P450 enzyme complex that catalyzes the conversion of androstenedione to estrone and testosterone to estradiol. aromatase is primarily found in ovaries. Tamoxifen 2. 2. USP – (Clomid) used as an ovulation stimulant in women desiring pregnancy. mastectomy and breast irradiation. USP – one less active than estradiol but more active than its metabolite. Conjugated Estrogen. SERM and Antiestrogen Products 1. Treatment of obesity. sod. Clomiphene Citrate. 2. Estradiol 17-Valerate. USP – (viviant) prevention of postmenopausal osteoporosis 5. USP – (Nolvadex) is a triphenylethylene SERM used to treat early and advanced breast carcinoma in postmenopausal women. 4. 6. In premenopausal women. Fulvestrant.formulations for use HRT. USP – (Faslodex) pure antagonist at both ERalpha and ERbeta and ER down regular completely lacking the agonist activity that is seen with tamoxifen or raloxifene. Estrone. Selective Estrtogen Receptor Modulator and Antiestrogens 3 compounds that are used clinically for estrogen antagonist action in the treatment of breast cancer are 1. Synthetic Conjugated Estrogen – is a mixture of 9 estrogenic substances sodium estrone sulfate. USP – (Premarin) refers to the mix of sulfate conjugates of estragenic components isolated from pregnant mare urine. and cytochrome P450 hemoprotein. vaginal ring) Estradiol 17-cypionate. 4. Used in oral contraceptives. USP 7. USP – all the estrone 3 sulfate salts have the obvious pharmaceutical advantage of increased water solubility and better oral availability. Obtain from the urine of pregnant mares. Treatment of Estrogen Defficiency from ovarian. 3.major use of estrogen is for inhibition of ovulation. Estradiol. 3.17alpha-estradiol sulfate. USP – (Evista) carbonyl group. USP – available for compounding into several diff.

Much of the progesterone that is synthesized from prenenoloneis immediates and is not secreted. USP – (4-Aminophenyl) is mainly used to treat cushing syndrome. such as apotting or amenorrhea Birth control . Of better available options. Structural Classes – Progestins 3 Structural Classes: a.Aminoglutethimide – also inhibits other P450s involved in steroid hormone biosynthesis.is exploited rather than its aromatase inhibition. 20-30mg/d during the last or Luteal stage of the menstrual cycle. The action of progesterone in the uterus include development of the secretory endometrium. Is a weak inhibitor of aromatase and has been used successfully in the treatment of estrogen-dependent breast cancer. USP – (Femara) dibenzonitrile. and the brain. with the main target tissue being the uterus. The principal excretory product of progesterone metabolism. Metabolism of this drug includes by hydroxylation and glucoronadation. Is critical for the maintenance of pregnancy by suppressing menstruation and decreasing uterine contractility. Letrozole. Its action is believed to be caused by irreversible inhibition of aromatase. Biosynthesis Progesterone is produced in the ovaries. USP – (Aromasin) is the first steroid. which limits its use in breast cancer treatment. It is a mechanism based inactivator that irreversibly inhibits the enzyme. Reduce serum estradiol approx. Also acts to thicken cervical secretory. USP – indicated for first-line treatment of postmenopausal women with advanced or metastatic breast cancer of women with early breast cancer. All other endogenous steroids lack significant progestational action. CYPs 3A4 and 2A6 are involved in the metabolism of letrozole to the major carbinol metabolite which is inactive. bec. Exemestane. 20alpha-dioland its conjugates. testes and adrenal glands. dec. Testolactone. Aminoglutethimide.of rapid metabolism. Only limited used in breast cancer treatment bec. Based aromatase inhibitor approved for the treatment of breast cancer in US. Progestins Endogenous Progestins – the key endogenous steroid hormone that acts at the PRs is progesterone. It is orally available and highly selective for aromatase Aromatase Inhibitor Products Anastozole. a use in which the P450scc inhibition of this comp.) Testosterone and 19-Nortestosterone Derivatives c. the breast.) Miscellaneous Synthetic Progestins Progesterone itself has low oral bioavailability because of poor absorption and almost complete metabolism in one passage through the liver. Normal men secrete about 1-5mg of progesterone daily. Decrease the frequency of the hypothalamic pulse generator and increase the amplitude of LH pulses released from the pituitary. A condition of adrenal steroid excess. Metabolism of Progesterone Progesterone has a half-life of only about 5 minutes when taken orally. however is 5B-prognane – 3alpha. USP – (Teslac) lacks androgenic effects in vivo. Therapeutic Uses of Progestins Progestins therapy may cause menstrual irregularities. Has importance actions in the breast during pregnancy.cervical penetration by sperm.of estrogen by 75% to 95%. 80% after 14 days of daily dosing. with maximal suppression achieved within 2-3 days. acting in conjugation with estrogen to prepare for lactation. The Corpus luteum secretes the most progesterone.) Progesterone and Derivatives b. It reduces conc. Biological Activities of the Progestins Progesterone has a various pharmacological actions. Used for mostof the same indication as anastozole. Exemestane – is a newersteroidal aromatase inhibitor.

USP – orally active and used in combination with an estrogen in oral contraceptives. (17beta-lactyl group) in place of the typical acetyl group. 6. ANTINEOPLASTIC AGENTS Antineoplastic agents. USP – is a prodrug of norethindrone. USP – (Ethyl group) Norgestel – used only in oral contraceptives.refers to drugs that are used to kill cells and includes both antibiotics and agents used in the treatment of cancer DRUG CLASSSES: Alkylating agents. 7. Drospirenone. Primary and secondary Amenorrhea and functional uterine bleeding caused by insufficient Progesterone. widely used for all theusual indication of the progestins. Trimegesterone – highly modified norprogesterone derivative. 8. antimetabolites. antibiotics. Progesterone. Ethyrodiol Diacetate.containing thiohposphoramide functionally was found to be more stable than the oxa-analog (TEPA) but is metabolically converted to TEPA by desulfuration in vivo -also metabolized by oxidative desulfuration mediated by CPY2B1 CPY211 Busulfan-utilizes two sulfonate functionalities as leaving the groups separated by afour carbon chain that reacts with DNA primarily from intrastrand cross-link 5’GA-3’ sequences -once inside the tumor cells. as well as being components of oral contraceptive. USP – is so rapidly metabolized that is not particularly effective orally. metabolism. Desogestrel. Birth control products. USP. Norethinedrone. Megetrol Acetate. 3. Etonogestrel. 13. USP and Levonorgestrel. 11. For appetite enhancement in patient with AIDS. or metastic endometrial or breast carcinoma. Angeliq. 10. Levonorgestrel – used in both oral and combination birth control products and polymetric implants that provide contraceptive for up to 5years.class of drugs that are capable of forming covalent bonds with important biomomlecules Nitrogen mustards. being only one twelfth as active as intramuscularly. Lacks androgenic action and has little to no affinity for the ER and GR. It is the progestin component in a newer implantable contraceptive ( implanon) and in the vaginal contraceptive ring (Nuvaring) 12. it can be very irritating.in the newer oral contraceptives. Light sensitive and should be protected from light.group of the diseases characterized by uncontrolled growth and spread of abnormal cells that left untreated may lead to death. Yasmin and Yaz and in the HRT product. Nomegestrol Acetate.use. A combination of hydrolysis of both estes and oxidation of the C3 alcohol to the ketone is necessary to provide the fully active progestins. If given intramuscularly . however and norgestrel. an active metabolite and other hydroxylated and conjugated metabolite are formed. The IM formulation is useful in the palliative treatment of advanced endometrial breast and renal carcinomas. USP – orally active. Was originally obtained from animal ovaries but is now prepared synthetically from plant sterol precursors. Norelgestromin. USP – ( Provera) very active orally and has such a long duration of action intramuscularly that it cannot be routinely used intramuscularly for treating many menstrual disorder.compounds that are chemically similar to sulfur mustard or mustard gas developed and used in world war Thiotepa. USP – is the progestin component in the contraceptive patch (ortho evra) first-pass metabolism in the liver is avoided by thr transdermal application. Use as prevention of preterm labor 2. 4. USP – ketodesogestrel is the active metabolism of desogestrel. Vaginal gel containing 4% or 8% progesterone offers an alternative dosage form. 1. 9. the drug encounters a lower chloride concentration and once chloro group is substituted by a water molecule in a process known as “aquation” . USP – progestin component of new oral contraceptives 5. USP – prodrug that is orally active and used with an estrogen in oral contraceptive products. natural products.with estradiol component of oral contraceptive. Norgestimate. Hepatic metabolism does occur.Reduction of the risk of Endometrial cancer from postmenopausal Estrogens. Chemotherapy. Cancer. incorporate. Approved for treating HRT in comb. Medroxyprogesterone Acetate. and adverse effects profiles for the alkylating agents. Breast or Endometrial canciroma Progestin Products Progestin – primarily used in oral contraceptive products and in hormone replacement regimens for women. USP – (Megace ) used primarily for the palliative management of recurrent. USP – is the progestin comp. Norgestrel. and Norethynodrel. Metabolized to 17-deacetyl norgestimate (norelgestromin) and norgestrel with provide the progestational action. and tyrosine kinase inhibitors used in the treatment of cancer.

brain cell tumors. breast and ovarian cancer and in high dose therapy when bone marrow transplant is being utilized -halflife of 38-108 minutes Cyclophosphamide (CTX.activation of the agent occurs through the action of CYP to give the demethylated product monomethyl triazeno imidazole carboxamide (MTIC) -tautomerization allows for decomposition to give the amino-carboxamide imidazole and diazomethane which is capacble of alkylating DNA INDIVIDUAL AGENTS: Mechlorethamine hydrochloride (NH2 mustargen) -available in 10 mg vials for intravenous administration in the treatment of hodgkin’s lymphoma -used topically in the treatment of mycosis fungoides. alkeran. well distributed into tissues and crosses the blood-brain barrier Cisplatin (cis. chronic lymphocytic leukemia.diamine dichloroplatinum. ovarian cancer. DDP. L-phenylamine mustard) -available in 2mg tablets and 50 mg vials for oral and IV administration -treatment of multiple myeloma.were discovered as a result of drug screening by the cxancer chemotherapy national service center which identified Nmethyl-N nitroguanidine as having activity against L1210 leukemia -stable at ph 4.life of 2 to 6 hours . 200. and 2000 mg vials for IV -used in treatment of a wide variety of cancers. myleran) -available as 2mg tablets for oral administration and 10 ml vials for IV administration in the treatment of chronic myelogenous leukemia -the agent is well absorbed when given orally. lenkeran) -available as 2mg tablets for oral administration in the treatment of hodgkin’s lymphoma. chronic lymphocytic leukemia in combination with prednisone and as a single agents -absorbed 75% upon oral administration and highly protein bound -eliminated via kidney. cfalen. ovarian cancer. 500.Nitrosoureas. bone and soft tissue sarcoma.antineoplastic agents that was originally developed as a result of efforts to find new inhibitors of monoamine oxidase. thiapex) -available in 15 mg for Iv administration in the treatment of bladder cancer.life of 2 to 3 hours -adverse effects include dose limiting myelosuppression and mucositis Busulfan (busulfex. stepa. neozar) -available in 25 and 50 mg tablets for oral aministration and 100. small cell lung cancer and NSCLC -half. half.life of 1-2 hours Melphalan (L-pam. stepa. CPA.1000. bladder cancer. CPM. abmochlorin. and breast cancer -half.5 but undergo both acid and base catalyzed decomposition at lower and higher ph respectively Procarbazine. including breast cancer . a rare type of of cancer but the most common type of cutaneous Tcell lymphoma Chlorambucil-(ambochlorin. head and neck cancer. cytoxin. platinol) -available in 10 and 50 mg vials for IV administration in the treatment of ovarian cancer. neuroblastoma wilnis tumor Thiotepa (girostan. subsequent screening revealed sntineoplastic activity Dacarbazine.

PCB. bicnu. fludara) -available as the phosphate salt in a 50 mg vial for IV use -used for chronic lyphocytic leukemia.chlorodeoxyyadenosine.deoxyroformycin. abitrexate.platinum. eloxatin) -available in 50 and 100 mg vials for IV administration in the treatment of ovarian cancer nad metastatic colorectal cancer -activation of the agent occurs in low chloride environments to give the aqauted species with subsequently reacts with DNA in a manner similar to cisplatin Carmustine (carmubris. carnicoid cancer. purinthol) -available as a 50 mg tablet for oral use -used to treat lymphoblastic leukemia.Oxaliplatin (platinum. folex) -available in 50. matulane) -available in 50 mg tablets for oral administration in the treatment of hodgkins disease and mycosis which removes the methyl group from the 0-6 of guanine -half. mercapropurinum.life of 1 hour Dacarbazine (DTIC.hodgkin’s disease and multiple myeloma -half. zonozar) -available in 1g vials for IV administration in the treatment of metstatic islet cell carcinoma of the pancreas. 200. alimta) -available in 100mg sterile vial for IV use . hairy cell leukemia and non. acute lymphocytic leukemia and chronic disease Pentostatin (2. malignant melanoma. DTIC-DOME) -available in 100 and 200 mg vials for IV administration in the treatment of hodgkins disease.life of the agent in plasma is short 15-20 minutes because of rapid decomposition Streptozocin (streptozocin. DCF) -available in 10 mg vials for IV use . 100 mg vials for IV use -used to treat several types including breast cancer.bladder. 2-CDA. colon cancer and godgkin’s disease -the hydrophilic agnt is rapidly cleared from the plasma with an elimination half. colorectal cancer and head and neck cancer Pemetrexed (Mta. chronic lymphocytic leukemia and lyphoblastic leukemia Methotrexate (MTX. mexate.f-ara-amp.hodgkin’s lymphoma Mercartopurine (6-MP.life of 35 minutes Procarbazine hydrochloride (PCZ. and soft tissue sarcoma -the agent is not highly protein bound and is metabolized in the liver by CPY ti give MTIc and 3 amino imidazole carcoxamide Cytarabine (2.used to treat leukemias such as hairy cell leukemia. and non.100. becenum) -available in a 100mg vial for IV administration in the treatment of several types of brain tumors. leustatin) -treatment of acute myelogenous leukemia and CML Fludarabine (2.nipent. dach.

actinomycin. VUMON) -available in 50mg ampules with cremophor El for IV administration in the treatment of of acute lymphocytic leukemia. DNR. CERUBINIDE) -available in 20 and 100mg vials for reconstitution -the agent is given intravenously for the treatment of acute nonlymphocytic and lymphocytic leukemia EPIPODOHYLOTOXINS: TENIPOSIDE (vm. neutrexin) -available as a lyophilized powder in 5 or 30 mg vials for IV use -used to treat colorectal cancer. DNM. colorectal cancer. head and neck cancers -elimination occurs primarily in the bile with aterminal elimination half life of 23 to 85 hours Vinorelbine ditartrate (VNB. ADR. ixempra) -approved for the treatment of metastatic breast cancer that is resistant to the taxanes -elimination occurs primarily in the feces with terminal half-life with 9-15 hours . taxol) -available in single dose vial of 30mg per 5 ml for IV administration in the treatment of breast .cancer. histiocytic lymphoma. head and neck cancer as well as NSCLC Dactinomycin (Act. navelbine) -available in 1 and 5 ml vials of concentration of 100mg per ml for IV use -It is FDA approved for the treatment of NSCLC -this is 3 to 13 times higher than the lung concentration seen with vincristine -the elimination half.ovarian. testicular. bladder cancer and lung cancer Trimetrexate (TMTX.ADRIA.velban. NSCLC.liver cancer. VCR. .oncovin) -used to treat rhabdomyosarcoma.d.5 mg of drug for reconstitution in sterile water IV administration -effective in treatment of rhabdomyosarcoma and wilnis tumor in children as as well as in the treatment of choriocarcinoma. camptosar) -available in 100 mg or 5ml vials for IV administration and is used in combination with S-FU and leucoyorin as a first line treatment of metastatic colon cancer ALKALOIDS: Vinbastine sulfate (VCB.LCR. adriamycin) -available as both the conventional dosage form and liposomal preparation. Kaposi sarcoma and testicular carcinoma Doxorubicin hydrochloride( ADM. The agent is more potent as an inhibitor of topoisomerase II Irinotecan hydrochloride (CPT 11. Kaposi sarcoma -the elimination half life is 25 hour Vincristine sulfate. cosmegen) -available in vials containing 0.26.o. leurocristine.-effective against range tumors including mesothelomia.neuroblastoma. advanced testicular carcinoma.ife of 11 hours Docetaxel (azaepothilone. both of which are administed by infusion -used to treat various cancer including leukemias Daunorubicin hydrochloride (daunomycin. lymphocytic lymphoma. VRL.velsar) -a powder in 10 mg vials and as a solution in 10 and 25mg vials for IV administration in the treatment of various cancers including hodgkin’s disease. AIDS-related Kaposi sarcoma -elimination occurs primarily eliminate in the feces with a terminal hal-l.life is 27 to 43 hours TAXANES: Paclitaxel (tax. advanced mycosis fungoides.

anorexia. and 8.Mitomycin c (MITC. anthracycline.the metabolites are primarily eliminated in the feces and the terminal half.10 hours respectively .life of 48 hours Sunitinib (Su11248. and 150 mg tablets for oral and is used after failure of the first line therapy in metastatic NSCLC and in first line therapy in combination with gemcitabine in the treatment of metastatic pancreatic cancer and in malignant gliomas . mutamycin) -available in 5. neutropenia and thrombocfytopenia Lapatinib ditosylate (GSK 572016. pulmonary edema. 20 vials for IV administration in the treatment of cancers of the stomach and pancreas when other treatments have failed -adverse effects include dose limiting myelosuppression. bioavailability is more lower values with ranging between between 14 to 34% -is 95% protein bound with a terminal halflife of 3-5 hours Erlotinib hydrochloride (CP_358-774. PROTEIN KINASE INHIBITORS: Imatinib mesylate (STI-571. and fatigue.life of the agent increases upon repeated dosing.gleecvec) -available in 100 and 400 mg capsules for oral administration and is indicated for the treatment of CMI. MTC. 100. taking 6 days to reach steady state that gives an effective half. iressa0 -available as 25mg tablets for oral administration in the treatment of NSCLC for those patients who have failed to respond to platinum based therapies and docetaxel and has also been used against squamous cells cancer of the head and neck -the agent is absorbed slowly after administered orally with 60% bioavalability -the parent metabolites are primarily in the feces with a terminal half. and trastuzumab therapy -the half.life of 36 hours Gefitinib (2D1389. gastrointestinal stromal tumors that express KIT and acute lymphoplastic leukemia that is positive for the Philadelphia chromosome -elimination occurs in the feces and the terminal half. 50 and 70 mg tablets for oral administration in the treatment of CMI and all that are ph positive -although dasatinib is more potent than imatinib.60 hours. sutent) -available in 25 and 50 mg capsules for oral administration in treatment of advance RCC -the terminal elimination half. TYKERB) -available as 250 mg tablets for oral administration and is used in treatment of breast cancer for the patient that over express the type 2 EGF-R and who have previously received taxane.life of 24 hours Dasatinib (BMs. mucositis. mild nausea and vomiting.life for the parent N-desemethyl derivative are 40. larcena) -available as 25.life is 18 hours for the parent and 40 hours of the N-desmethyl metabolite -severe side effects include heart burn. sprycel) -available in 20.354825.

Master your semester with Scribd & The New York Times

Special offer for students: Only $4.99/month.

Master your semester with Scribd & The New York Times

Cancel anytime.