ph.chem2 - coverage for finals (3 topics)

7/28/2019 Ph.chem2 - Coverage for FINALS (3 Topics)

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HISTAMINE and ANTIHISTAMINIC AGENTS

*HISTAMINEor B- imidazolylethylamine; enzyme that expressed in many mammalian tissues including gastric mucosa parietalcells, most cells, and basophils and the CNS.

*NOMENCLATUREstructurally 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 inconc. 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 andtissues 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- IgEcomplex 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 receptorsubtypes 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

H2 RECEPTOR

- 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

H3 RECEPTOR

- 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

H4 RECEPTOR

- receptor proteins in human: 390 amino acids


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- chromosomal location: 18q11.2- G-protein coupling: Gi/o- Activated intracellular signals: Ca2+, 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. Cellular uptake: Animal studies have documented the uptake of histamine by many cells. In particular, uptake is a

temperature and partially Na+- dependent process in rabbit gastric glands and the histamine is metabolized once in thecell.

2. Desensitization of cells: Some H1- receptor containing tissues exhibit homogenous loss of sensitivity to the actions ofhistamine, perhaps as result of receptor modification.

3. Metabolism: The most common pathway for terminating histamine action involves enzymatic inactivation.FUNCTIONS OF HISTAMINE AS RELATED TO PHARMACOLOGICAL INTERVENTION

a.) Its important, but limited, role as a chemical mediator of hypersensitivity and allergic inflammatory reaction. b.) A major role in the regulation of gastric acid secretion.c.)

An emerging role as a neurotransmitter in the CNS.

ANTIHISTAMINES

- drugs that blocked the action of histamines at H1-receptors rather than other histamine subtypes- first generation or classical antihistamines: aminoalkyl ethers, ethylenediamines, piperazines, propylamines,

dibenzocycloheptanes.

- Second generation or non-sedating antihistamines derivatives of several first generation agent but have been modified to bemore specific.

MECHANISM OF ACTION

- H1- antihistamines acts as inverse agonists that combine with and stabilize the inactive from of the H1-receptor, shifting theequilibrium toward the inactive state.

GENERAL PHARMACOLOGICAL AND THERAPEUTIC CONSIDERATIONS

- classical antihistamines has been used extensively for symptomatic treatment (sneezing, rhinorrhea and itching of eyes, noseand throat) of allergy rhinitis(have fever, pollinosis) chronic idiopathic urticia, etc.

- these drugs best relieve the symptoms of allergic disease at the beginning of the reason when pollen counts are low.- Also reduce the number, size, and duration of wheals and itching in chronic urticia when used promptly.- Widely used to relieve symptoms of asthma and upper respiratory infections including common cold, otitis media, and sinusitis.

FIRST GENERATION ANTIHISTAMINE CLASSES

AMINOALKYL ETHERS (ethanolamines)- diphenhydramine HCL, tannate and citrate are soluble in water (1:1), alcohol(1:2) and chloroform (1:2);

-recommended in various allergic conditions and to a lesser as an antitussive and Parkinsons drug;

-orally or parentally in treatment of urticaria, seasonal rhinitis, and some dermatitis;

-ADR drowsiness;

-CAUTION: concurrent use of alcohol and other CNS depressant should be avoided;


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-DOSAGE FORMS: tablets (12.5, 25 and 50mg), capsules (25 and 50mg), oral disintegrating strips (12.5 and 25mg),suspensions (25mg/5ml), inj. (150mg/ml);

-USUAL ADULT DOSES: antihistamines (25 to 50mg every 4 hours maximum of 300mg/day), antitussive liquid (25 to 50mgevery 4 hours not exceeding 300mg/day), motion sickness (25 to 50mg every 4 to 6 hours maximum of 300mg/day).

DIMENHYDRATE- highly soluble in water and freely soluble in alcohol and chloroform;- for nausea of motion sickness and for hyperemesis gravidanem (nausea of pregnancy);- to prevent motion sickness, dose should be taken at least 0.5 hr before beginning a trip;- ADULT DOSE: tablets (50mg), liquids (12.5mg/ml) and (15.62mg/ml), injection (50mg/ml)- USUAL DOSAGE: for motion sickness; adult/children >12 years of age: 1 to 2 chewable tablet (50-100mg) evry4 to 6 hours,

not to exceed 8 chewable tablets or 400mg in 24 hours; children 2 to younger than 6 years of age: to chewable tablet (12.5-25mg) every 6 to 8 hours, not exceeding 1 tablets in 24 hours.

BROMODIPHENHYDRAMINE HCL- dosage form: capsules and elixir; usual adult dose: oral (25mg/4 to 6 hours) DOXYLAMINE SUCCINATE- soluble in water (1:1), alcohol (1:2) and chloroform (1:2); a 1% of the solution has the pH of

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- indicated for the relief of seasonal rhinitis symptoms, but is also used as a nightmare sedative.- Caution: concurrent use of alcohol and other CNS depressants should be avoided.- Dosage form: tablets (5mg), oral solution (1mg/ml) and oral liquid (2.5mg/2.5ml)- Usual adult dose: oral (12.5 to 25mg/4 to 6 hours)

CARBINOXAMINE MALEATE- very soluble in water and freely soluble in alcohol and in chloroform.- 1% of the solution has the pH of 4.6 and 5.1- Dosage forms: tablets (4 and 8mg), capsules (10mg), liquid (1.67mg/ml), solution (4mg/5ml), and suspension (3.2mg/5ml)- Usual dose (tablets)- adults and children 12 year old of age and older: 1 tablet (8mg) twice daily; children 6 to 12 year old of

age: tablet twice daily every 12 hours. The tablets are not recommended for children younger than 6 years of age.

CLEMASTINE FUMMATE- has long duration of action, with an activity that reaches a maximum in 5 to 7 hours andpersist in 10 to 12 hours.

- dosage forms: tablets (1.34 and 2.68mg) and syrup (0.67mg/5ml)- usual adult dose: allergic rhinitis- 1.34mg every 12 hours or twice daily (maximum 8.04mg/day for syrups/2.68mg in 24 hours

for tablets), for adults: 0.67mg twice daily maximum of 4.02mg, for children 6 to 12 years of age (syrup only).

DIPHENYLPYLAMINE HCL- soluble on water or alcohol; potent antihistaminic and the usual dose is 2mg 3 or 4 timesdaily

- dosage forms: extended release capsules (5mg)- usual adult dose: oral 5mg/2hours)

ETHYLENEDIAMINES- first useful antihistamines. TRIPELENNMINE CITRATE- for oral administration in liquid forms; dosage forms: elixir; usual adult dose: oral (25 to

50mg/ 4 to 6 hours)

TRIPELENNMINE HCL- soluble in water (1:0.77) and in alcohol (1:6); it has a pKa of about 9 and 0.1% solution has thepH of 5.5- ADR: drowsiness and may impair the ability to perform task requiring alertness.- Dosage forms: tablets, extended-release tablets- Usual dose: oral tablets (25 to 50mg/4 to 6 hours), extended-release tablets (100mg/ 8 to 12 hours)

PYRILAMINE MALEATE- soluble in water (1:0.4), freely soluble in alcohol; less potent antihistamine- local anesthetic; should not be swallowed; taken with food.- Dosage forms: tablets


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- Usual adult dose; oral (25 to 50mg/6 to 8 hours) METAPYRILENE HCL- soluble in water (1:0.5), ALCOHOL (1:5), and in chloroform (1:3); pH of 5.5; potencial

carcinogen

THONZYLAMINE HCL- soluble in water (1:1), in alcohol (1:6), in chloroform (1:4); a 2% solution has the pH of 5.5; usualdose: 50mg/ 4x daily

ANTALOLINE PHOSPHATE- soluble in water; pka of 10.0 and a 2% solution ahs the pH of 4.5; less active; appliedtopically to the eye 0.5% solution; less soluble HCL is given orally; more than twice the local anesthetic potency.

PIPERAZINES (CYCLINES)- moderately potent antihistamines; cause drowsiness and psychomotor and cognitivedisfunction; slow onset; long duration of action; use as antiemetics and antivertigo agents; treatment of motion sickness CYCLIZINE HCL- soluble in water (1:115), alcohol (1:115) and chloroform (1:75); use primarily in prophylaxis and

treatment of motion sickness; IM; stored in cold place; 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; children 12 yrs of age: tablet/ 6 to 8 hours.

MECLEZINE HCL- practically insoluble on water (1:1,000); primarily as antinauseant in the prevention and treatment ofmotion sickness and of nausea and vomiting associated with vertigo

- dosage forms: tablets (5,12,25,50mg) and capsules (25mg)- usual adult dose: motion sickness: 25 to 50mg meclizine HCL should be taken 1 hour prior, vertigo: 25 to 100mg daily in

divided doses

BUCLIZINE HCL- insoluble on water; has CNS depressant, antiemetic and antihistaminic propertiesPROPYLAMINES (MONOAMINOPROPYL OR ALKYLAMINE DERIVATIVES)

PHENISAMINE MALEATE- soluble in water (1:5) and very soluble in alcohol; usual adult dose is 20 to 40mg 3 timesdaily

CHLORPHENIRAMINE MALEATE- soluble in water (1: 34), alcohol (1:10) and in chloroform (1:10); usual dose is 2 to4mg 3 or 4 times daily; has a half life of 12 to 15 hours

- dosage forms: tablets (2,4,8,12mg), extended-release capsules (8,12mg), syrup (2mg/5ml), and suspension (4 and 8mg/5ml)-

usual adult dose: oral (4mg/4to 6 hrs), extended-release capsules (8 to 12 hrs); IM, IV or subcutaneous (5 to 40mg)

DEXCHLORPHENNIRAMINE MALEATE- dosage forms: extended-release tabs (4 to 6hrs), syrup (2mg/5ml); usualadult dose: 4 or 6mg at bedtime or every 8 to 10 hrs

BROMPHENIRAMINE MALEATE AND TANNATE- half life: 25 hrs; dosage forms: tabs (6,12mg), oral drops (1mg),capsules (12mg), liquid (2mg/5ml), oral suspension (4,8,10,12mg/5ml); usual adult dose: 1 or 2 tabs (6-12mg) every 12 hrs,or 5 to 10 ml of solution or suspension

DEXBROMPHENIRAMINE MALEATE PYRROBUTAMINE PHOSPHATE- soluble to the extent of 10% in warm water TRIPROLIDINE HCL- soluble in water and alcohol; solutions are alkaline to litmus; peak effect occurs about 3.5 hrs after

oral administration and the duration effect is about 12 hrs- dosage forms: oral liquid (1.25mg/5ml) and oral suspension (2.5mg/5ml)- usual adult doses: 10 ml every 4 to 6 hrs. Do not exceed 40ml in 24 hrs

PHENINDAMINE TARTRATE- sparingly soluble to water (1:40); produce drowsiness and sleepiness; insomnia whentaken just before bedtime; dosage forms: tabs (25mg); usual adult dose: 1 tab every 4 to 6hrs not exceeding 6 tabs in 24 hrs

DIMETHINDINE MALEATE- sparingly soluble in water; principal effect: sedation or ddrowsiness


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PHENOTHIAZINES

PROMETHAZINE HCL- very soluble in water and not absolutely soluble in alcohol and chloroform- dosage form: tabs (12.5, 25, 50mg), oral syrup (6.25mg/5ml), rectal suppositories (12.5, 25, 50mg), injection (25, 50mg/ml)- usual adult dose: allergy: 25mg taken before retiring, however, 12.5mg may be taken before meals or on retiring if necessary;

transfusion reaction: 25mg of doses to control transfusion reaction; motion sickness: 25mg taken before 30 to 60 mins traveland repeated 8 to 10 hrs if necessary; nausea and vomiting: 12.5 to 25mg every 6 to 6 hrs if necessary; prophylactic dosage:25mg every 4 to 6 hrs given during surgery and the postoperative period and 25 to 50mg with analgesics postoperatively orpreoperatively; sedation: 25 to 50mg for nightmare, presurgical, or obstetrical sedation

TRIMEPRAZINE TARTRATE- freely soluble in water and soluble in alcohol; has a pronounced antipruritic action;dosage forms: syrup and tablets; usual adult dose: oral 25mg 4 times daily

METHDILAZINE- practically insoluble on water; chewable tabs because its slow solubility in water contributes to itstastelessness

METHDILAZINE HCL- salt is freely soluble in water and alcohol

DIBENZOCYCLOHEPTENES & DIBENZOCYCLOHEPTANES

CYPROHEPTADINE HCL- slightly soluble in water and sparingly soluble in alcohol; antihistamine and antiserotoninsesquihydrate; used as antipruritic agent; treatment of hypersensitivity reactions, perennial, and seasonal allergic rhinitis,vasodilator rhinitis, allergic conjunctivitis, uncomplicated allergic skin manifestation of urticaria and angioedema,amelioration of allergic reactions to blood or plasma and urticaria; sadation is the common ADR; dosage forms: tabs (40mg)and syrups (2mg/5ml); usual adult dosage: oral (4mg/ 3 or 4 times daily)

AZATADINE MALEATE- dosage forms: tablets (1mg); usual adult dose: 1 to 2mg twice daily

SECOND GENERATION ANTIHISTAMINES

FEXOFENADINE HCL- freely soluble in methanol and ethanol, slightly soluble in chloroform and water and insoluble inhexane

- treatment of seasonal allergic rhinitis and chronic adiopathic urticaria-

rapidly absorbed after oral administration, producing peak serum conc. In about 2.5 hrs; 60-70% protein bounded- the mean elimination half-life is about 14hrs- dosage forms: tablets (30, 60, 180mg), 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; lower doses are

recommended for children

LORATADINE- insoluble in water but very soluble in acetone, alcohols and chloroforms- For the relief of nasal and non-nasal symptoms of seasonal allergic rhinitis- rapidly absorbed after oral administration, producing peak plasma levels in about 1.5 hrs- elimination half-life raging 8 to 15 hrs- dosage forms: tablets (5,10mg), oral disintegrating tablets (5.10mg), syrups (5mg/5ml)- usual adult dose (allergic rhinitis) : 10mg once daily for adults and children 6 yrs and older, chewable tablets and syrup (5mg)

once daily for children 2 to 5 yrs of age

DESLORATIADINE- 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 6months 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), rapidly disintegrating tablets (2.5 to 5.0mg), syrup (2.5mg/5ml)


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- usual doses: adult and children 12 yrs and older: 5mg once daily; children 6 to 11 yrs of age: 2.5mg once daily CETIRIZINE- soluble in water; has the advantage to appear to be its long action (once daily dosing), rapid onset on

activity, 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, 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, sneezing, itching of the nose or throat, 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%); terminal half-life about 8.3 hrs;- dosage form: tablets (5,10mg), and oral syrup (1mg/ml)- usual adult dose (allergies/ hay fever and urticaria): 5 to 10mg once daily depending on the severity of symptoms, up to max of

10mg daily for adults and children 6 yrs and older; 2.5mg once daily of the oral solution for children younger than the age of 6

LEVOCETIRIZINE DIHYDROCHLORIDE- water soluble; indicated for the relief of symptoms associated with allergicrhinitis (seasonal/ perennial) in adults and children 6 yrs and older and for the treatment of the uncomplicated skinmanifestation of chronic idiopathic urticaria

- dosage forms: tablet (5mg) and solution (2.5mg/5ml)- usual dose: 5mg one tablet or 10 ml oral solution once daily in the evening for adults and children 12 yrs and older; 2.5mg half

of the tablet or 5ml oral solution once daily in the evening for 6 yrs to 11 yrs

* ACRIVASTINE- soluble on chloroform and alcohol and slightly soluble in water; orally administered drug and has a half-life ofabout 1.7 hrs and a total clearance of 4 .4ml/min/kg; dosage forms: tablets : various combination products; usual adult dose: oral ( 8or 60mg 3 or 4 times daily)

STEROID HORMONES AND THERAPEUTICALLY RELATED COMPOUNDS

Steroid Hormones And Related Products

- Most widely used classes of therapeutic agents.- Used primarily in birth control, hormone-replacement therapy (HRT), inflammatory condition and cancer treatment.- Most of these agent are chemically based on a common structural backbone, the steroid backbone.

Steroid Nomenclature Stereochemistry and Numbering

Steroid Biosynthesis

- 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, a greater amount (about 1g) is biosynthesizedper day.- A key protein involved in the translocation is the (STAR) Steroidogenic Acute Regulatory Protein.- Defect in the STAR gene lead to congenital lipoid Adrenal Hyperplasia rare condition marked by a deficiency of adrenaland gonadal steroid hormones.

Cytochromes P450 and Dehydrogenaseenzymes involved in the transformation of cholesterol to the hormones.Estradiol, Testosterone, Progesterone, Aldosteron and Hydrocortisone- are representative of the distinct steroid-receptor ligands.

Chemical and Physical Properties of Steroids

Steroids


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Are white crystalline solids.They may be in the form of needles, leaflets, platelets or amorpous particles, depending on the particular compound.Bec. The steroids have 17 or more carbon atoms, it is not surprising that they tend to be water insoluble.Salt are the most water soluble

Changes to Modify Pharmacokinetic Properties of Steroids- The Steroid can be made more lipid soluble or more water soluble by making suitable ester derivatives of hydroxyl (OH)groups- Derivatives with increased lipid solubility are often made to decrease the release rate of the drugs from IM injection sites.- More lipid-soluble derivatives also have improved skin absorption properties and thus, are preferred for dermatological

preparation.- Derivatives with increased water solubility are needed for intravenous preparations.- Some steroids (estradiol, progesterone, and testosterone) are particularly susceptible to rapid metabolism after absorptionor rapid inactivation in the GI tract before absorption.- These inactivation processes limit the effectiveness of the hormones as orally available drugs, although micronized formof estradiol and progesterone are available for oral administration.

Steroid Hormone Receptor

The Steroid receptors themselves are key players in gene expression but many other proteins are involved in the process.

Structure of Steroid Hormone Receptors

1. N-terminal (A/B) domainonce the steroid-receptor complex has bound to the target genes this domain ( also calledA/B modulator domain) activates the hormone response elements adjacent to the genes. Contain about 12-18 base-pairDNA sequences and consist of two half sites that are separated by a variable receptor.2. DNA-binding (C) domain- short section is made up of about 65 amino acids, organized into two zinc finger motifs thatare important for recognition and binding to the DNA response elements.3. Hinge (D) domainthis variable linker region appears to be involved with nuclear localization and transport of thesteroid-receptor complex into the nucleus.4. C-terminal ligand-binding (E) domain (LBD)Includes about 250 amino acids. This section has the steroid hormone-binding site and is also involved with ligand-dependent transcriptional activation, receptor dimerization, binding tochaperone proteins.

Estrogen Receptor

Estrogen receptor alpha(ERalpha) and Estrogen receptor beta- the two distict estrogen receptors.

Estrogen receptor alphafound in high abundance in the uterus, vagina and ovaries, as well as in the breast, thehypothalamus, endothelial cells and vascular smooth muscle.Estrogen receptor betafound in greatest abundance in the ovaries and the prostate with reduced occurrence in the lungs,brain, and vasculator.

Progesterone Receptorcan be found in two forms, but these are divided from a single gene.Progesterone receptor alphahas had 164 amino acids translocated from the N-terminus of PRbeta, providing a receptorthat has different interaction with target genes and associated proteins. Acts as transcriptional inhibitor of ER, androgenreceptor (AR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and PRb.

Progesterone receptor betamainly mediates the stimulatory actions of progesterone.Androgen, Glucocorticoid and Mineralocoticoid Receptorare present only as single form, only one gene and one proteinare known for each receptor.

Gonadotropi-Releasing Hormone and Gonadotropins

Gonadotropinsare pedtides that have a close functional relationship to estrogen, progesterone and testosterone.- they are called Gonadotropins because of their actions on the gonads.- They control ovulation, spermatogenesis and development of sex organs and they maintain pregnancy.

Gonadotropin-Releasing Hormone (GnRH)regulates release of the gonadotropins.- the hypothalamus release GnRH, a peptide that stimulates the anterior pituitary to secrete LH and FSH in males and


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females. The peptide controls and regulates both male and female reproduction.Included in this group are the following:GnRHLuteinizing Hormone (LH)Follicle-Stimulating Hormone (FSH)

Sex Hormones

Estrogen and Progesterone are usually called sex hormones and testosterone is called male sex hormone. All of thesesteroid are biosynthesized in both male and female.Testosteroneis one of the precursors of estrogen.Estrogen and Progesteroneare produced much larger amount in females, however testosterone in males.These hormones play profound roles in reproduction in menstrual cycle and in giving women and men their charac.Physical differences.

Estrogen

Endogenous estrogensare estradiol, estrone and estriol.Estrdiolprovides the greatest estrogenic activity with estriol.

BiosynthesisEstrogenare synthesized by the action of the enzyme aromatase on an drostenidione or testosterone.They are normally produced in relatively large quantities in the ovaries and the placenta, in lower amount in the adrenalglands and in trace quantities in the testes.

Metabolism of Estrogen3 primary Estrogen in women are the ff:1. 17beta-estradiolis produced in the greatest amount, it is quickly oxidized, to estrone, the estrogen found in highestconc.in the plasma.2. Estroneis converted to estriol, the major estrogen found in human urine, by hydroxylation at C16 and reduction of theC17 ketone.3. Estriol

Estradiolcan also be directly converted to estriol. In human placenta, the most abundant estrogen synthesized is estriol.

Biological Activities of Estrogens

In addition to having important roles in the menstrual cycle, the estrogens and to a lesser extent progesterone are largelyresponsible for the development of secondary sex characteristics in women at poberty.Estrogencause a profeliration of the breast ductile system, and progesterone stimulates development of the alveolarsystem.Also stimulate the dev.of lipid and other tissues that contribute to breast shape and function.Directly stimulate the growth and dev. Of the vagina, uterus, and fallopian tubes and in combination with other hormonesplay a primary role in sexual arousal and in producing the body contours of the mature woman.Pigmentation of the nipples and genital tissues and growth stimulation of pubic and underarm hair (possibly with the helpof small amout of testosterone) are other resuppleness, coronary atherosclerosis and gout become potential health problemsfor the first time, and the bones begin to use density because of decreased mineral content.

Strutural Classes Estrogens

1. Steroidal Estrogenconjugated Estrogen, Esterified Estrogensteroidal- related metabolites originally obtained fromthe urine of horses especially pregnant mares.Esterified Estrogensare also mainly a combination of estrone sodium sulfate and equilin sodium sulfate.2. Diethystilbestrolhave the same activity as estradiolor other estrogen.3. Phytoestrogenfound in certain legumes. Have antifertility activity in animals. Many claims have been about thebeneficial effects of consuming product containing these phytoestrogen, including preventing and treating cardiovasculardisease, reducing post-menopausal symptoms and preventing osteoporosis.

Therapeutic Uses of Estrogen


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1. Birth control - major use of estrogen is for inhibition of ovulation, in combination with progestins.2. Hormone Replacement Therapyfor postmenopausal women.3. Treatment of Estrogen Defficiency from ovarian, failure or after ophorectomy. Treatment of advanced inoperable breastcancer in women and postmenopausal women and advanced inoperable prostate cancer in men.4. Estrogen and canceruse an increased risk of breast cancer

Estrogen Products

1. Estradiol, USPester group. Most commonly used estrogen in oral contraceptives.Estradiol 17-Valerate, USP (IM injection)

Estradiol 3-acetate, USP (oral, vaginal ring)Estradiol 17-cypionate, USP (IM injection)2. Estrone, USPone less active than estradiol but more active than its metabolite, estriol. Obtain from the urine ofpregnant mares. Treatment of obesity.3. Piperazine Estrone sulfate, USPall the estrone 3 sulfate salts have the obvious pharmaceutical advantage of increasedwater solubility and better oral availability.4. Conjugated Estrogen, USP(Premarin) refers to the mix of sulfate conjugates of estragenic components isolated frompregnant mare urine. Most commonly used in HRT to treat postmenopausal symptoms, the conjugated estrogens are usedfor the entire range of indications described previously, except birth control.5. Synthetic Conjugated Estrogenis a mixture of 9 estrogenic substances sodium estrone sulfate, sodium equilin sulfate,sod. Equilenin sulfate, sod.17alpha-estradiol sulfate. Treatment of moderate to severe vasomotor symptoms and valvar andvaginal atrophy associated with menopause.6. Esterified Estrogen, USP7. Estriol, USPavailable for compounding into several diff.formulations for use HRT. It can be used alone or in

combination with estradiol (Biest) or with estradiol and estrone (Tri est)8. Ethinyl Estrdiol, USPhas the greatestadv.over other estradiol product of being orally active. Used in oralcontraceptives.

Selective Estrtogen Receptor Modulator and Antiestrogens3 compounds that are used clinically for estrogen antagonist action in the treatment of breast cancer are1. Tamoxifen2. Toremifene3. Fulvestrant

Two additional agents that can antagonize ERs are clomiphine, which is used as an ovulation stimulant and Raloxifenewhich is used for the prevention and treatment of osteoporosis.SERMis drug that has tissue-specific strogenic activity.

SERM and Antiestrogen Products

1. Tamoxifen Citrate, USP(Nolvadex) is a triphenylethylene SERM used to treat early and advanced breast carcinoma inpostmenopausal women. Used as adjuvant treatment for breast cancer in women ff. mastectomy and breast irradiation. Themajor metabolite of tamoxifen is N-desmethyltamoxifen. Tamoxifen conc.reduced if coadministration with rifampin acytochrome P450 inducer.2. Toremifene Citrate, USP(Fareston) chloroethyl group. Pharmacological action quite similar to tamoxifen. Used in thetreatment of metastatic breast cncer in postmenopausal women.3. Raloxifene, USP(Evista) carbonyl group. Used to prevent and treatment of osteoporosis in postmenopausal women.4. Bazedoxifene, USP(viviant) prevention of postmenopausal osteoporosis5. Fulvestrant, USP(Faslodex) pure antagonist at both ERalpha and ERbeta and ER down regular completely lackingthe agonist activity that is seen with tamoxifen or raloxifene.6. Clomiphene Citrate, USP(Clomid) used as an ovulation stimulant in women desiring pregnancy.

Aromatase Inhibitors

Aromataseis a cytochrome P450 enzyme complex that catalyzes the conversion of androstenedione to estrone andtestosterone to estradiol.NADPHcytochrome P450 reductose, and cytochrome P450 hemoprotein.In premenopausal women, aromatase is primarily found in ovaries, but is post menopausal women aromatase is largely inmuscle and adipose tissue.Aromatase inhibitors - offer a useful approach to decreasing estrogen levels in the treatment of estrogen-dependent breastcancer. Used as second-line therapy in postmenopausal women who failed on tamoxifen therapy.


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Aminoglutethimidealso inhibits other P450s involved in steroid hormone biosynthesis, which limits its use in breastcancer treatment.Exemestaneis a newersteroidal aromatase inhibitor. It is orally available and highly selective for aromatase

Aromatase Inhibitor Products

Anastozole, USPindicated for first-line treatment of postmenopausal women with advanced or metastatic breast cancer ofwomen with early breast cancer. Reduce serum estradiol approx. 80% after 14 days of daily dosing. Metabolism of this drugincludes by hydroxylation and glucoronadation.Letrozole, USP(Femara) dibenzonitrile. Used for mostof the same indication as anastozole. It reduces conc.of estrogen by

75% to 95%, with maximal suppression achieved within 2-3 days. CYPs 3A4 and 2A6 are involved in the metabolism ofletrozole to the major carbinol metabolite which is inactive.Exemestane, USP(Aromasin) is the first steroid. Based aromatase inhibitor approved for the treatment of breast cancer inUS. It is a mechanism based inactivator that irreversibly inhibits the enzyme.Aminoglutethimide, USP(4-Aminophenyl) is mainly used to treat cushing syndrome. A condition of adrenal steroidexcess, a use in which the P450scc inhibition of this comp.is exploited rather than its aromatase inhibition. Is a weakinhibitor of aromatase and has been used successfully in the treatment of estrogen-dependent breast cancer.Testolactone, USP(Teslac) lacks androgenic effects in vivo. Its action is believed to be caused by irreversible inhibition ofaromatase. Only limited used in breast cancer treatment bec. Of better available options.

Progestins

Endogenous Progestinsthe key endogenous steroid hormone that acts at the PRs is progesterone. All other endogenoussteroids lack significant progestational action.

Biosynthesis

Progesterone is produced in the ovaries, testes and adrenal glands. Much of the progesterone that is synthesized fromprenenoloneis immediates and is not secreted. The Corpus luteum secretes the most progesterone, 20-30mg/d during thelast or Luteal stage of the menstrual cycle. Normal men secrete about 1-5mg of progesterone daily.

Metabolism of Progesterone

Progesterone has a half-life of only about 5 minutes when taken orally, bec.of rapid metabolism. The principal excretoryproduct of progesterone metabolism, however is 5B-prognane3alpha, 20alpha-dioland its conjugates.

Biological Activities of the Progestins

Progesterone has a various pharmacological actions, with the main target tissue being the uterus, the breast, and the brain.Decrease the frequency of the hypothalamic pulse generator and increase the amplitude of LH pulses released from thepituitary. The action of progesterone in the uterus include development of the secretory endometrium. Also acts to thickencervical secretory, dec.cervical penetration by sperm. Is critical for the maintenance of pregnancy by suppressingmenstruation and decreasing uterine contractility. Has importance actions in the breast during pregnancy, acting inconjugation with estrogen to prepare for lactation.

Structural Classes Progestins

3 Structural Classes:

a.) Progesterone and Derivativesb.) Testosterone and 19-Nortestosterone Derivativesc.) Miscellaneous Synthetic Progestins

Progesterone itself has low oral bioavailability because of poor absorption and almost complete metabolism in one passagethrough the liver.

Therapeutic Uses of Progestins

Progestins therapy may cause menstrual irregularities, such as apotting or amenorrhea

Birth control


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Reduction of the risk of Endometrial cancer from postmenopausal Estrogens.Primary and secondary Amenorrhea and functional uterine bleeding caused by insufficient Progesterone.Breast or Endometrial canciroma

Progestin Products

Progestinprimarily used in oral contraceptive products and in hormone replacement regimens for women.

1. Progesterone, USPis so rapidly metabolized that is not particularly effective orally, being only one twelfth as active asintramuscularly. If given intramuscularly , it can be very irritating. Vaginal gel containing 4% or 8% progesterone offers an

alternative dosage form. Was originally obtained from animal ovaries but is now prepared synthetically from plant sterolprecursors. Light sensitive and should be protected from light. Use as prevention of preterm labor2. Medroxyprogesterone Acetate, USP( Provera) very active orally and has such a long duration of actionintramuscularly that it cannot be routinely used intramuscularly for treating many menstrual disorder. The IM formulationis useful in the palliative treatment of advanced endometrial breast and renal carcinomas. Birth control products.3. Megetrol Acetate, USP(Megace ) used primarily for the palliative management of recurrent, incorporate, or metasticendometrial or breast carcinoma. For appetite enhancement in patient with AIDS.4. Nomegestrol Acetate, USPprogestin component of new oral contraceptives5. Norethinedrone, USP, and Norethynodrel, USPorally active, widely used for all theusual indication of the progestins,as well as being components of oral contraceptive.6. Ethyrodiol Diacetate, USPis a prodrug of norethindrone. A combination of hydrolysis of both estes and oxidation ofthe C3 alcohol to the ketone is necessary to provide the fully active progestins.7. Norgestrel, USP and Levonorgestrel, USP(Ethyl group) Norgestelused only in oral contraceptives. Levonorgestrelused in both oral and combination birth control products and polymetric implants that provide contraceptive for up to

5years.8. Desogestrel, USPorally active and used in combination with an estrogen in oral contraceptives.9. Norgestimate, USPprodrug that is orally active and used with an estrogen in oral contraceptive products. Metabolizedto 17-deacetyl norgestimate (norelgestromin) and norgestrel with provide the progestational action.10. Norelgestromin, USPis the progestin component in the contraceptive patch (ortho evra) first-pass metabolism in theliver is avoided by thr transdermal application. Hepatic metabolism does occur, however and norgestrel, an activemetabolite and other hydroxylated and conjugated metabolite are formed.11. Etonogestrel, USPketodesogestrel is the active metabolism of desogestrel. It is the progestin component in a newerimplantable contraceptive ( implanon) and in the vaginal contraceptive ring (Nuvaring)12. Drospirenone, USPis the progestin comp.in the newer oral contraceptives, Yasmin and Yaz and in the HRT product,Angeliq.13. Trimegesteronehighly modified norprogesterone derivative. (17beta-lactyl group) in place of the typical acetyl group.Lacks androgenic action and has little to no affinity for the ER and GR. Approved for treating HRT in comb.with estradiol

component of oral contraceptive.

ANTINEOPLASTIC AGENTS

Antineoplastic agents- use, metabolism, and adverse effects profiles for the alkylating agents, antibiotics, natural products,antimetabolites, and tyrosine kinase inhibitors used in the treatment of cancer.

Cancer- group of the diseases characterized by uncontrolled growth and spread of abnormal cells that left untreated may lead todeath.

Chemotherapy- 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- class of drugs that are capable of forming covalent bonds with important biomomlecules

Nitrogen mustards- compounds that are chemically similar to sulfur mustard or mustard gas developed and used in world war

Thiotepa- containing thiohposphoramide functionally was found to be more stable than the oxa-analog (TEPA) but is metabolicallyconverted 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 DNAprimarily from intrastrand cross-link 5GA-3 sequences

-once inside the tumor cells, the drug encounters a lower chloride concentration and once chloro group is substituted by awater molecule in a process known as aquation


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Nitrosoureas- were discovered as a result of drug screening by the cxancer chemotherapy national service center which identifiedNmethyl-N nitroguanidine as having activity against L1210 leukemia

-stable at ph 4.5 but undergo both acid and base catalyzed decomposition at lower and higher ph respectively

Procarbazine- antineoplastic agents that was originally developed as a result of efforts to find new inhibitors of monoamine oxidase,subsequent screening revealed sntineoplastic activity

Dacarbazine- activation of the agent occurs through the action of CYP to give the demethylated product monomethyl triazenoimidazole carboxamide (MTIC)

-tautomerization allows for decomposition to give the amino-carboxamide imidazole and diazomethane which is capacbleof alkylating DNA

INDIVIDUAL AGENTS:

Mechlorethamine hydrochloride (NH2 mustargen)

-available in 10 mg vials for intravenous administration in the treatment of hodgkins lymphoma

-used topically in the treatment of mycosis fungoides, a rare type of of cancer but the most common type of cutaneous T-cell lymphoma

Chlorambucil-(ambochlorin, abmochlorin, lenkeran)

-available as 2mg tablets for oral administration in the treatment of hodgkins lymphoma, chronic lymphocytic leukemia incombination with prednisone and as a single agents

-absorbed 75% upon oral administration and highly protein bound

-eliminated via kidney; half- life of 1-2 hours

Melphalan (L-pam, alkeran, L-phenylamine mustard)

-available in 2mg tablets and 50 mg vials for oral and IV administration

-treatment of multiple myeloma, breast and ovarian cancer and in high dose therapy when bone marrow transplant isbeing utilized

-halflife of 38-108 minutes

Cyclophosphamide (CTX, CPM, CPA, cfalen, cytoxin, neozar)

-available in 25 and 50 mg tablets for oral aministration and 100, 200, 500,1000, and 2000 mg vials for IV

-used in treatment of a wide variety of cancers, including breast cancer , chronic lymphocytic leukemia, ovarian cancer,bone and soft tissue sarcoma, neuroblastoma wilnis tumor

Thiotepa (girostan, stepa, stepa, thiapex)

-available in 15 mg for Iv administration in the treatment of bladder cancer, ovarian cancer, and breast cancer

-half- life of 2 to 3 hours

-adverse effects include dose limiting myelosuppression and mucositis

Busulfan (busulfex, 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, well distributed into tissues and crosses the blood-brain barrier

Cisplatin (cis- diamine dichloroplatinum, DDP, platinol)

-available in 10 and 50 mg vials for IV administration in the treatment of ovarian cancer, bladder cancer, brain cell tumors,head and neck cancer, small cell lung cancer and NSCLC

-half- life of 2 to 6 hours


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Oxaliplatin (platinum, dach- 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 withDNA in a manner similar to cisplatin

Carmustine (carmubris, bicnu, becenum)

-available in a 100mg vial for IV administration in the treatment of several types of brain tumors, and non- hodgkinsdisease and multiple myeloma

-half- life of the agent in plasma is short 15-20 minutes because of rapid decomposition

Streptozocin (streptozocin, zonozar)

-available in 1g vials for IV administration in the treatment of metstatic islet cell carcinoma of the pancreas, colon cancerand godgkins disease

-the hydrophilic agnt is rapidly cleared from the plasma with an elimination half- life of 35 minutes

Procarbazine hydrochloride (PCZ, PCB, 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- life of 1 hour

Dacarbazine (DTIC, DTIC-DOME)

-available in 100 and 200 mg vials for IV administration in the treatment of hodgkins disease, malignant melanoma,carnicoid cancer, 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 imidazolecarcoxamide

Cytarabine (2- chlorodeoxyyadenosine, 2-CDA, leustatin)

-treatment of acute myelogenous leukemia and CML

Fludarabine (2- f-ara-amp, fludara)

-available as the phosphate salt in a 50 mg vial for IV use

-used for chronic lyphocytic leukemia, hairy cell leukemia and non- hodgkins lymphoma

Mercartopurine (6-MP, mercapropurinum, purinthol)

-available as a 50 mg tablet for oral use

-used to treat lymphoblastic leukemia, acute lymphocytic leukemia and chronic disease

Pentostatin (2- deoxyroformycin,nipent, DCF)

-available in 10 mg vials for IV use

- used to treat leukemias such as hairy cell leukemia, chronic lymphocytic leukemia and lyphoblastic leukemia

Methotrexate (MTX, abitrexate, mexate, folex)

-available in 50.100, 200, 100 mg vials for IV use

-used to treat several types including breast cancer.bladder, colorectal cancer and head and neck cancer

Pemetrexed (Mta, alimta)

-available in 100mg sterile vial for IV use


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-effective against range tumors including mesothelomia, NSCLC, colorectal cancer, bladder cancer and lung cancer

Trimetrexate (TMTX, neutrexin)

-available as a lyophilized powder in 5 or 30 mg vials for IV use

-used to treat colorectal cancer, head and neck cancer as well as NSCLC

Dactinomycin (Act- o, actinomycin- d, cosmegen)

-available in vials containing 0.5 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, Kaposi sarcoma and testicular carcinoma

Doxorubicin hydrochloride( ADM, ADR,ADRIA, adriamycin)

-available as both the conventional dosage form and liposomal preparation, both of which are administed by infusion

-used to treat various cancer including leukemias

Daunorubicin hydrochloride (daunomycin, DNM, 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- 26, VUMON)

-available in 50mg ampules with cremophor El for IV administration in the treatment of of acute lymphocyticleukemia. The agent is more potent as an inhibitor of topoisomerase II

Irinotecan hydrochloride (CPT 11, camptosar)

-available in 100 mg or 5ml vials for IV administration and is used in combination with S-FU and leucoyorin as a firstline treatment of metastatic colon cancer

ALKALOIDS:

Vinbastine sulfate (VCB,velban,velsar)

-a powder in 10 mg vials and as a solution in 10 and 25mg vials for IV administration in the treatment of various cancersincluding hodgkins disease, lymphocytic lymphoma, histiocytic lymphoma, advanced mycosis fungoides, , advanced testicular

carcinoma, Kaposi sarcoma-the elimination half life is 25 hour

Vincristine sulfate- LCR, VCR, leurocristine,oncovin)

-used to treat rhabdomyosarcoma,neuroblastoma, testicular,cancer,liver cancer, head and neck cancers

-elimination occurs primarily in the bile with aterminal elimination half life of 23 to 85 hours

Vinorelbine ditartrate (VNB, VRL, 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- life is 27 to 43 hours

TAXANES:

Paclitaxel (tax, taxol)

-available in single dose vial of 30mg per 5 ml for IV administration in the treatment of breast ,ovarian, AIDS-relatedKaposi sarcoma

-elimination occurs primarily eliminate in the feces with a terminal hal-l;ife of 11 hours

Docetaxel (azaepothilone, 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


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Mitomycin c (MITC, MTC, mutamycin)

-available in 5, 20 vials for IV administration in the treatment of cancers of the stomach and pancreas when othertreatments have failed

-adverse effects include dose limiting myelosuppression, mild nausea and vomiting, mucositis,anorexia, and fatigue.

PROTEIN KINASE INHIBITORS:

Imatinib mesylate (STI-571,gleecvec)

-available in 100 and 400 mg capsules for oral administration and is indicated for the treatment of CMI, 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- life is 18 hours for the parent and 40 hours of the N-desmethyl

metabolite

-severe side effects include heart burn, pulmonary edema, neutropenia and thrombocfytopenia

Lapatinib ditosylate (GSK 572016, TYKERB)

-available as 250 mg tablets for oral administration and is used in treatment of breast cancer for the patient that overexpress the type 2 EGF-R and who have previously received taxane, anthracycline, and trastuzumab therapy

-the half- life of the agent increases upon repeated dosing, taking 6 days to reach steady state that gives an effectivehalf- life of 24 hours

Dasatinib (BMs- 354825, sprycel)-available in 20, 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, bioavailability is more lower values with ranging between between 14to 34%

-is 95% protein bound with a terminal halflife of 3-5 hours

Erlotinib hydrochloride (CP_358-774, larcena)

-available as 25, 100, and 150 mg tablets for oral and is used after failure of the first line therapy in metastatic NSCLCand in first line therapy in combination with gemcitabine in the treatment of metastatic pancreatic cancer and in malignant gliomas

- the metabolites are primarily eliminated in the feces and the terminal half- life of 36 hours

Gefitinib (2D1389, iressa0

-available as 25mg tablets for oral administration in the treatment of NSCLC for those patients who have failed torespond 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- life of 48 hours

Sunitinib (Su11248, sutent) -available in 25 and 50 mg capsules for oral administration in treatment of advance RCC

-the terminal elimination half- life for the parent N-desemethyl derivative are 40- 60 hours, and 8- 10 hours respectively

ph.chem2 - coverage for finals (3 topics)

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