pharm_repro_endo_ms2

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pharm_repro_endo_ms2
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pharmacology reproductive endocrine ms2
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pharm repro endo ms2
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  1. 4 ESTROGENS
    • ESTRADIOL
    • CONJUGATED ESTROGENS
    • ETHINYL ESTRADIOL
    • DIETHYLSTILBESTROL (DES)
  2. ESTRADIOL MOA
    Natural steroidal estrogen

    ALL estrogens interact w/ intracellular receptors to alter gene tsc & thus protein synth
  3. CONJUGATED ESTROGENS MOA
    Composed of phytoestrogen

    Contains same 3 major & 6 minor estrogens as Premarin
  4. ETHINYL ESTRADIOL
    Synthetic steroidal estrogens

    Ethinyl group added to 17 position of steroid ring →rev 1st pass metab → incr:

    • --bioavailability
    • --potency
    • --t1/2
  5. DIETHYLSTILBESTROL (DES) MOA
    Synthetic non-steroidal estrogen

    • teratogenic (1st trimester)
    • --fetus: clear cell adenocarc of vagina in late teens-20s
    • --fetus: undesc testes, epidydymal cysts &
    • azoospermia
  6. PHARMACOLOGICAL EFFECTS OF ESTROGENS
    Nl sexual maturation of ♀

    Dev of 2o sex char

    Distrb fat to hips & breasts

    Accel growth phase & epiphyseal closure at puberty

    Maintenance of nL struct of skin, mucosa & blood vessels

    • Stim hepatic synth of:
    • --TBG, SHBG, transcortin, transferrin, renin substrate & fibrinogen →
    • --incr circ levels (thyroxine, estrogen, testosterone, Fe, Cu, etc.) but free conc ≤
    • nL

    Stim synth clotting factors 2, 7, 9, 10 → incr likelihood of thromboembolic disease

    • Antag PTH → decr rate of bone resorption by osteoclasts
    • --reason for postmenopausal bone loss

    Incr HDL & TG

    Decr LDL & total chol

    Facilitate mov of fluid from plasma to ECF → edema (Kidney has compensatory salt/H2O retention)
  7. PHARMACOKINETICS OF ESTROGENS
    Pharmacokinetics (of estrogens):

    1. Enterohepatic recirc → greater effect on liver than periphery

    2. Apply drugs topically (cream) for periph action to minimize hepatic effects
  8. THERAPEUTIC USES OF ESTROGENS
    Primary hypogonadism

    • Post-menopausal HRT
    • --> dec LDL & ­HDL & TGs
    • --> “Perfect” HRT:
    • ----Agonistic (+) at bone, skin & mucous membranes, CNS & plasma lipid profile.
    • ----Antagonistic or no effect at breast, uterus & liver

    • Contraception (***combo w/ progestin to prevent endometrial hyperplasia caused by
    • estrogen)

    “Morning after” contraception

    Dysmenorrhea

    Dysfunctional uterine bleeding

    OCP’s decr Sx of benign breast dz

    • Hirsuitism
    • --Combo w/ finasteride, flutamide & spironolactone may prevent
    • --Eflornithine applied topically → irrev inhb ornithine decarboxylase → prevent hair growth
  9. ADVERSE S/E OF ESTROGENS
    1. n/v

    2. Diarrhea

    3. Breast tenderness

    • 4. Endometrial hyperplasia
    • (post-meno dec via co-admin progestin)

    5. Salt & H2O retention

    6. HTN

    7. Gallbladder disease

    8. Chol jaundice (very rare)

    9. Thromboembolic disease

    10. Post-meno bleeding

    11. Headache

    • 12. Hyperpigmentation
    • (Chloasma or melasma)

    • DES:
    • teratogenic (1st trimester)
    • --♀ fetus: clear cell adenocarc of vagina in late teens-20s
    • --♂ fetus: undesc testes, epididymal cysts &
    • azoospermia
  10. CONTRAINDICATIONS FOR ESTROGEN USE
    • Relative:
    • 1. Fam hx of breast or uterine malign
    • 2. Severe varicose veins
    • 3. Hx of hepatic dz
    • 4. HTN

    • Absolute:
    • 1. Estgn-dep breast or uterine cancer
    • 2. UnDx abnl genital bleeding
    • 3. Hx of severe thromboembo dz
    • 4. Acute hepatic dz
  11. SERMS
    (selective estrogen receptor modulators)
    CLOMIPHENE

    TAMOXIFEN

    RALOXIFEN

    • Acts as estrogen agonist (+) in some tissues
    • & estrogen antagonist (-) in other tissues
  12. CLOMIPHENE MOA AND PHARM EFFECTS
    SERM

    Orally active non-steroidal

    • 1. BLOCKS estgn rec in hypothal → interrupts nl feedback inhb of GnRH &
    • gonadotropin secretn

    2. Incr GnRH secrtn → incr FSH & LH

    • 3. Incr FSH & LHgametogenesis & estgn
    • --------------------------

    Induce ovulation in ♀ w/ amenorrhea or anovulatory cycles

    (-) CNS (nl sleep & temp regltn)

    (+) liver: protein synth



  13. TAMOXIFEN MOA AND PHARM EFFECTS
    SERM

    Orally active non-steroid comptv estgn receptor antag (-) w/ partial agon (+) in some pts

    1. Estgn receptor antag (-) in BREAST

    • 2. Agonist (+) in liver & uterus*** → S/E
    • --DVT or PE in high risk pts
    • --Prolonged tx: endometrial hyperplasia → endometrial cancer

    • Pre-meno ♀: Tamox antag (-)
    • estgn receptors in hypothal & pit
    • → incr GnRH → incr LH → incr estgn → (-) tamox effects.
    • ----Prev the incr estgn w/ GnRH analog

    Post-meno ♀: Same as pre-meno but ovaries quit making estgn → doesn’t matter

    -----------------------------------------------

    • (-) breast
    • (-) CNS (nl sleep & temp regltn)
    • (-) skin/mucous membr

    • (+) bone density
    • (+) plasma lipids
    • (+) liver: protein synth
    • (+) uterus: hyperplasia***
  14. RALOXIFENE MOA AND PHARM EFFECTS
    SERM

    Estrogen receptor AGONIST (+) on:

    • 1. Bone: decr bone resorption by osteoclasts
    • 2. Plasma lipid profile
    • 3. Hepatic protein syn

    • ANTAGONIST (-) on:
    • 1. Uterus***
    • 2. Breast
    • -------------------------------------

    • (-) breast
    • (-) CNS (nl sleep & temp reg)
    • (-) skin/mucous membr
    • (-) uterus: hyperplasia***

    • (+) bone density
    • (+) plasma lipids
    • (+) liver: protein synth
  15. CLOMIPHENE THERA AND ADVERSE S/E
    SERM

    Want to be pregnant!!!!

    Induce ovulation in ♀ w/ amenorrhea or anovulatory

    • Poss:
    • 1. Multiple births
    • 2. Stillbirths
    • 3. Ovarian enlargement
    • ------------------------------------

    ADVERSE

    • 1. Ovarian enlargement
    • 2. Temp scintillating scotomata
    • (blurred spots or flashes)
    • 3. Sx of menopause (hot flashes, etc.)

    • Contraindicated in pts w/ thromboembo
    • d/o b/c acts as an estrogen receptor (+) in liver → incr clot factor synth
  16. TOMAXIFEN THERA AND ADVERSE S/E
    SERM

    1. Tx E(+) breast cancer

    2. Breast cancer prophylaxis in high risk ♀

    • 3. Post-meno: same (+) agonistic
    • (good) effect on bone density & lipids as estrogen
    • ----------------------------------

    ADVERSE

    • 1. n/v
    • 2. Hot flashes
    • 3. Less freq vag bleeding & menstrual irreg
    • 4. Comp prevents metab of warfarin → incr PT
  17. RALOXIFENE THERA AND ADVERSE S/E
    1. Decr size of uterine leiomyomas in post-meno ♀

    2. Maint post-meno bone density

    3. Decr incid of vertb fractures by 30-40% (but effctv < HRT w/ conjugated estrogens)

    4. Decr breast cancer in high risk ♀

    • 5. Decr Tc & LDL. No incr HDL
    • (like HRT w/ estgn)
    • ------------------------------------

    • ADVERSE
    • 1. Hot flashes
    • 2. Flu-like sx
    • 3. Arthralgia
    • 4. Thromboembo (inc hep clot factor synth)
    • 5. p.o. → prev bene of topical estradiol in post-meno ♀ w/ atropic vaginitis
    • (dec estrogen → vaginal itching & dryness)
  18. AROMATASE INHIBITORS
    ANASTROZOLE

    LETROZOLE

    (Block synth of ALL estrogen in body)
  19. AROMATASE INHIBITORS MOA AND PHARM EFFECTS
    Prevents conversion of androgens to estrogens

    • LH → (thecal cells) ASDN →
    • (granulosa cells) ASDN → testn → [aromatase (fat cells)] → estradiol

    • Aromatase (CYP450 enz) converts andgns → estgns (testn → estradiol & DHEA → estrone)
    • --------------------

    • ANASTROZOLE
    • LETROZOLE
  20. AROMATASE INHIBITOR THERA AND ADVERSE S/E
    Tx breast cancer in post-meno ♀:

    • 1. Estro receptor (+) cancer
    • 2. Advanced or metastatic breast cancer
    • 3. NOT responded to tamoxifen
    • 4. Been on tamoxifen for 5 years
    • ----------------------------

    ADVERSE:

    • 1. MENOPAUSAL Sx
    • 2. MSK PROBS
  21. LIST OF PROGESTINS
    PROGESTERONE

    NORETHINDRONE

    NORGESTIMATE

    NORELGESTROMIN

    DROSPIRENONE

    MEDROXYPROGESTERONE
  22. PROGESTERONE MOA
    PROGESTIN

    ANTI-MINERALOCORTICOID

    ANTI-ANDROGENIC
  23. NORETHINDRONE MOA
    PROGESTIN

    FAMILY OF DERIVATIVES OF 19-MORTESTOSTERONE

    SOME ANDROGENIC EFFECTS

    LACK ANTI-MINERALOCORTICOID ACTIVITY
  24. NORGESTIMATE & NORELGESTOMIN MOA
    PROGESTINS

    • Norelgestromin = 17-deacylated norgestimate
    • = actv metabolite of norgestimate

    • 1. Does NOT stim androgen receptors
    • → NOT (-) antagonize estrogen effect on plasma HDL conc
    • ---- NO stim of sebum prodn → good skin (No acne)

    2. Combo w/ ethinyl estradiol (OCP) → 3x incr serum conc of SHBG → 50% decr in serum free testosterone conc
  25. DROSPIRENONE MOA
    PROGESTINS

    Spironolactone derivative

    1. Stim (+) progesterone rec

    2. Blocks (-) androgen & mineralocorticoid rec

    3. Block mineralocorticoid rec → CV benefits
  26. MEDROXYPROGESTERONE MOA
    PROGESTIN

    I.M. DEPO PROVERA

    COMPLETE AMENORRHEA --> CONTRACEPTION LASTING 3 MONTHS
  27. THERAPEUTIC USES OF PROGESTINS
    Uses of OCPs

    1. Contraception: combo w/ ethinyl estradiol

    • 2. Acne
    • --Estgn inhb hypothal & pit → decr LH → decr testn
    • prodn by ovaries

    --Incr hepatic synth of SHBG → decr free testn conc

    --Decr free testn → decr sebum prodn in skin

    • 3. HRT for post-meno (esp drospirenone***)
    • --Constant estgn w/ cyclic or intermittent progestin
    • --Const estgn & progestin
    • --Ethinyl estradiol + drospirenone: Drospirenone has
    • anti-androgenic and anti-mineralocorticoid effects
  28. PROGESTIN ADVERSE EFFECTS
    • NORETHINDRONE
    • --LOW ANDROGENIC ACT --> INC SEVUM PROD --> ACNE
    • --Tx w SPIRONOLACTONE

    • MEDROXYPROGESTERONE
    • --NO RISK OF THROMBOEMBOLIC Dz BUT UNPREDICTABLE MENSTRUAL BLEEDING
  29. LIST OF PROGESTIN ANTAGONISTS
    MIFEPROSTONE (RU-486)

    ULIPRISTAL
  30. MIFEPRISTONE MOA AND THERAPEUTIC USES
    PROGESTIN ANTAG

    GLUCOCORTICOID REC ANTAG

    OUTPATIENT ABORTION OF FETUS < 49 DAYS

    • INTERRUPTS PREG
    • --2 DAYS LATER GIVE SYNTH PG DINOPROSTONE --> CONTRACTS UTERINE SMOOTH MUSC
    • ---------------------------------------

    THERA

    1. Prevent implantation of fertilized egg

    2. Alleviate sx of endometriosis

    3. Tx non-resectable meningiomas

    4. Tx uterine leiomyomas

    5. Tx Cushing’s syndrome (b/c also glucocorticoid receptor antag)
  31. ALENDRONATE & IBANDRONATE
    BISPHOSPHONATES

    INH BONE REABS BY STIM OSTEOBLASTS

    • BINDS TO REMODELING BONE SURFACES
    • --> INH OSTEOCLASTS

    • PREVENT POST-MENO BONE LOSS
    • -------------------------------------

    ADVERSE

    • Esophagitis:
    • --Pts should take drug w/ 8 oz of H2O & remain upright for 30 min.

    • --If drink too much or lie down (before 1st
    • meal of the day) → level of drug reaches LES → damage

    Osteonecrosis of the jaw (mostly w/i.v.)
  32. DRUGS FOR Tx OF THYROID Dz (5)
    levothyroxine

    propranolol

    iodide (Lugol's solution)

    propylthiouracil

    methimazole
  33. SINGLE MOST SENSITIVE TEST OF THYROID STATUS?
    TSH
  34. LEVOTHYROXINE (T4)
    Tx HYPOTHYROIDISM (HASHIMOTO'S)

    START w SMALL DOSES

    • INC SLOWLY EVERY 2 WEEKS UNTIL nL TSH
    • ----------------------------------------

    ADVERSE

    • Pts w/ CV risk factors (CAD, myocardial dysfunc)
    • MI or dysrhythmias (A fib)

    • Adults:
    • o Tachycardia
    • o Weight loss
    • o Heat intol
    • o Nervousness

    • Children:
    • o Insomnia
    • o Accel bone growth
    • o Restlessness

    • Measure TSH: will indicate if sx due to overTx w/ T4
    • (very low TSH if overdosed w/T4)
  35. Sx AND Tx OF MYXEDEMATOUS COMA
    End stage of prolonged hypothyroidism

    Medical emergency req early recogn & tx.

    • o Obtunded, confused
    • o Hypothermic
    • o Hypotensive
    • o Jaundice
    • o Eyebrows missing
    • o Puffy face, esp around eyes
    • o Enlarged tongue & lips
    • o Speaks in a hoarse whisper
    • o Slow respiration
    • o Hypercapnia
    • o Hypoglycemia
    • o Hyponatremia
    • o ~Absent DTRs
    • ---------------------------------------

    Tx

    1. Intubation & ventilation

    2. Glucose (hypoglycemia)

    3. Caution w/ i.v. fluids (already hyponatremic)

    • 4. LARGE loading dose of i.v. thyroxine:
    • Must saturate TGB binding sites before enough free T4

    • --Incr body temp & improved mental func indicate
    • adeq tx.

    --All drugs must be given i.v. b/c poor GI absorption.
  36. DRUGS THAT CAUSE HYPOTHYROIDISM (3)
    • Corticosteroids
    • --Inhb release of TRH & TSH
    • --Prevents periph conversion of T4 to T3

    • Lithium
    • --Inhb secr of T4 & T3 from thyroid gland
    • --TT4 falls 25-35%
    • -- ~ In pts w/ previous decr in thyroid func (Hashimoto’s)

    • Amiodarone: “purple man”
    • **HYPOTHYROIDISM
    • ----Inhb periph conversion of T4 to T3
    • ----Tx: p.o. thyroxine

    • **HYPERthyroidism
    • ----37% iodine by weight (substr for thyroid peroxi)
    • ----Incr synth of T4 to T3
  37. DOC FOR HYPERTHYROIDISM
    PROPRANOLOL & PTU
  38. PTU & METHIMAZOLE PHARM
    • Inhb enz thyroid peroxidase
    • → inhb conversion of iodide (I-) to iodine (Io)
    • → Prevent iodide organification

    • Block coupling of MIT & DIT
    • -- req’d to form of T3 & T4)

    • Decr synth of T4 & T­3
    • → slow onset of action (several weeks to deplete)
    • **DOES NOT BLOCK RELEASE

    • PTU Blocks periph conversion of T4 to T3
    • -- INH 5’-deiodinase
    • -- Only B-blocker to do this
  39. DOC FOR PREGO WITH GRAVE'S Dz
    PTU

    HYPERTHYROIDISM

    BABY AT RISK FROM EXCESS THYROID STIM
  40. DOC FOR THYROID STORM
    PROPRANOLOL

    LARGE DOSES po or iv

    Sx DISAPPEAR IN SEVERAL HRS
  41. PROPRANOLOL MOA AND THERAPEUTIC EFFECTS
    Tx HYPERTHYROIDISM (graves)

    • Unique β-blocker
    • --no other β-blocker has this effect
    • --Blocks 5’-deiodinase → dec periph conv of T4 to T3

    Poss initially need Lrg doses b/c rapid metab (hyperthyr)

    If β-blockers contraindicated, use diltiazem to control ♥ sx (NO effect on T3 formation)

    • Modify tissue response to excessive T4 and T3
    • --------------------------------------------

    THERA

    • Controls autonomic sx
    • (does NOT alter underlying excess T4 production)

    • tachycardia
    • palpitations
    • fatigue
    • weight loss
    • diaphoresis
    • heat intolerance
    • tremor
    • anxiety
  42. PROPYLTHIOURACIL (PTU)
    &
    METHIMAZOLE


    THERA & ADVERSE
    Tx HYPERthyroidism

    • Thioamides: main drugs to tx hyperthyroidism
    • -- PTU & METHIMAZOLE
    • -- Both accum in thyroid & given as single daily dose
    • -- PTU t1/2 = 1.5 hours
    • -- Methimazole t1/2 = 6 hours

    THERA

    3-4 weeks to deplete T4 → slow rate of onset

    NO esc phenomenon

    • After achieve euthyroid state, 20-40% pts enter remission
    • w/in 1 month – 2 years

    60-80% eventual relapse.

    • If recur, tx w/ I-131
    • ---------------------------------------------

    ADVERSE

    Reverisble agranulocytosis in < 1% pts

    PTU: anti-Vit K actvty & potentiates Warfarin effects

    Skin rash w/ itching (tx w/ anti-histamine)

    • Prego: Use PTU not Methimazole
    • --PTU highly bound to plasma proteins → less likely to cross placenta
    • --Use min effectv doses & shortest tx periods poss
    • --10% neonates dev goiter if exposed to PTU in utero
  43. IODIDE (Lugo's solution)

    MOA AND THERA
    Tx HYPERTHYROIDISM

    • Large doses of Iodide = KI
    • --Prevent proteolysis of thyroglobulin
    • --Inh release of T3 and T4
    • --Transient inh of organification of iodide by prev iodide trapping

    Dec size and vascularity of thyroid gland (2-7 days)

    • NOT used in routine tx of hyperthyroidism
    • (rarely used as single agent)
    • --------------------------------------

    Prep of thyrotoxic patients for emergency surgery not related to thyroid or subtotal thyroidectomy

    • Thyroid storm
    • --From hypothyroidism or induced by I-131
  44. IODIDE ADVERSE EFFECTS
    Tx HYPERTHYROIDISM

    • LARGE doses of Iodide:
    • --Delay action of PTU
    • --Prevents use of 131I for several wks

    • Toxicity:
    • Inflammation of salivary glands

    • “iodism” = sore gums, burning sensation in mouth &
    • throat, metallic taste, GI discomfort (very rare)

    • Allergic reaction:
    • ----skin rash with itching (Histamine release)
    • ----fever & joint pain
    • ----facial swelling
    • ----severe dyspnea (emergency)

    • Hyperthyroidism: reason that ioidide is NEVER used alone to tx hyperthy
    • ----thyroid gland escapes suppressive effect of iodide → iodide substrate to make T4 and T3

    Preg ♀: fetal goiter
  45. Sx OF THYROID STORM
    • · (E.g. hyperthyroid pt presents to ER months after dx
    • & initiating tx)

    · High fever (e.g. 104o F)

    · Thin

    · Severe musc weakness

    · Shortness of breath

    • · Dyspneic & fatigued with mild exertion (e.g. short
    • walk in exam room)

    · Tachypnea

    · Freq vomits after eating

    · Insomnia

    · Tremor

    · Hyperreflexive

    · Atrial fib

    • · Irritable: “snaps at you every time you ask a question
    • & complains that you are just as nosey as the IRS agents who are trying to make him pay his delinquent taxes”

    · Can cause death via HF and shock
  46. Sx OF DIABETES INSIPIDUS
    • · Extreme thirst
    • · Polydipsia
    • · Polyuria (e.g. 10-12 L/day)
    • · Nocturia
    • · Heavy exercise in hot weather → feel faint, worse
    • thirst
  47. · Serum Na+ conc & osmolality: high normal
    • · High serum glucose conc
    • · Urinalysis: (-) for glucose & low urine osm (< 300 mOsm)
    • · Generally healthy
    • * Normal neuro tests & BP
  48. DOC FOR COMPLETE CENTRAL AND PARTIAL DI
    DESMOPRESSIN
  49. DOC FOR COMPLETE & PARTIAL NEPHROGENIC DI
    • COMP
    • --HCTZ or INDOMETHACIN

    • PART
    • --HCTZ or LRG DOSES OF DESMOPRESSIN
  50. DOC FOR LITHIUM INDUCED DI
    AMILORIDE

    DOES NOT ALTER Li CLEARANCE
  51. DOC FOR SIADH
    DEMECLOCYCLINE
  52. RECEPTORS FOR ADH
    • V2
    • --INC ­renal water absorption in late distal tubule:
    • --AVP stim adenyl cyclase (basolat.) →cAMP kinases
    • →­ INC water channels in apical membrane →conc. urine

    • --INC release of coag FVIII & vWF
    • --DEC TPR via relax of VSM

    • V1
    • --Vasoconstriction of VSM →­ INC TPR
  53. DEFINE CENTRAL / NEPHROGENIC DIABETES AND SIADH
    • Central:
    • Lack of release of sufficient ADH from posterior pituitary → lack of response to normal stim

    • Nephrogenic:
    • Renal tubule unresponsive to ADH (complete or partial) → ADH rises in response to normal stim

    • SIADH:
    • secretion of ADH is autonomous and independent of serum osmolality → excessive retention of water causes hypervolemia & dilutional hyponatremia
  54. DESMOPRESSIN MOA
    Tx DI

    Mainly has V2 receptor activity (little V1)

    Long-acting synthetic analog of AVP (6-20hrs)

    Marked reduction in daily urine volume
  55. DESMOPRESSIN THERA AND ADVERSE
    Tx DI

    Central DI

    Partial NDI (must give larger doses)

    Nocturnal Enuresis

    • Hemophilia A & Type I vWF disease:
    • a) Maintain homeostasis during and after surgery
    • b) stop trauma-induced & spont bleeding
    • c) Tolerance devs (days) b/c of depletion of
    • preformed clotting factors
    • -------------------------------------------

    ADVERSE

    URTI: slow absorption of nasal spray

    • Toxicity:
    • · HTN (rare w/nasal spray)
    • · Hypotension w/ tachycardia (i.v./s.c.)
    • * Water intox & Hyponat w/ excessive water intake
  56. HCTZ MOA
    Tx DI

    Reduces urine volume (25-30%)

    Uniformly DEC GFR → less dilute urine formed

    • Indirectly ­INC reabsorption of water from prox tubule:
    • a) DEC of urinary volume depends on natriuresis

    b) Natriuresis→contracts ECF volume → ­INC solute & water reabsorption in prox tubule → DEC volume to distal tubule (where urine is diluted)

    • c) Inhib NaCl reabsorption in distal tubule → further
    • impairs renal dilution
  57. HCTZ THERAPEUTIC USES
    · Central DI

    · Nephrogenic DI

    • · Lithium-induced NDI:
    • a) Na depletion caused by HCTZ → DEC urinary volume by ­ INC efficiency of solute/water reabsorption in the
    • proximal tubule --> INC ­reabsorption of lithium in prox tubule (up to 90%)

    • b) DEC renal clearance → ­INC Serum Li
    • --may have to DEC Li dose to prevent tox
  58. LITHIUM MOA IN DIABETES INSIPIDUS
    · 80% reabsorbed by prox tubule

    · NOT reabsorbed by loop of henle/early DT

    • * Reabsorbed by principal cells of late DT/ CD via
    • apical Na channel
    • ------------------------------------

    ADVERSE

    • NEPHROGENIC DI
    • -- DEC ACT OF ADENYL CYCLASE PROD BY ADH STIM OF BASOLATERAL V2 REC --> UNRESPONSIVE TO ADH
    • -- Tx w AMILORIDE
  59. AMILORIDE
    Tx OF Li INDUCED NDI

    Blocks Na channels in principal cells → prevents entry of Li

    DEC urinary volume (30-40%) & ­urine Osml

    NOT greatly DEC renal clearance of Li (Li can have same effect as normal)
  60. CHLORPROPAMIDE
    Tx DI

    · Orally active

    · Induce insulin release in patients w/Type 2 DM

    • ­* release of AVP & potentiates its renal effects
    • (can lead to SIADH)

    Tx T2 DM

    CAUSES SIADH
  61. DEMECLOCYCLINE
    Tx DI

    Tetracycline Abx agent

    Inhib AVP action in collecting duct

    • Tx Hyponatremia assoc w/SIADH when:
    • a) Serum Na < 120mEq/L
    • b) Pt has severe neurological sx
  62. DRUGS THAT CAUSE SIADH
    CHLORPROPAMIDE

    CARBAMAZEPINE

    NICOTINE

    MORPHINE
  63. METABOLIC EFFECTS OF GLUCOCORTICOIDS (cortisol)
    MAINTAIN PLASMA GLUCOSE CONC FOR BRAIN

    CATABOLIZE OTHER TISSUES FOR THIS PURPOSE
  64. OBLIGATE GLUCOSE USERS
    • BRAIN
    • RBC
    • WBC
    • ADRENAL MEDULLA
  65. GLUCOCORTICOID MOA
    • GC Receptor (GR) located in cytoplasm
    • -- inh by Heat-Shock Protein (HSP 90)

    • Cortisol-GR complex migrates to nuc (inact HSP 90)
    • → transcrip regulator (+/-)

    • Stimulates:
    • --Lipocortin → inh PLA2 → inh liberation of AA & synth of PGs and LTs

    --Enzymes in gluconeogenesis

    --Glycogen synthetase in liver

    • Inhibits:
    • --CRH (hypothalamus)
    • --ACTH POMC in pituitary
    • --COX2 in leukocytes
    • --IL-1, IL-6, collagenase, and TNF in Macrophages
    • ------------------------

    • Because changes in protein synth, effects of cortisol & synthetic GCs:
    • --will develop slowly over a period of days

    -- persist much longer than the half-life of these compounds in the blood
  66. LIST OF GLUCOCORTICOIDS
    "-SONE / -LONE"

    hydrocortisone

    cortisone

    prednisone

    prednisolone

    methylprednisolone

    triamcinolone

    betamethasone

    dexamethasone

    fludrocortisone

    beclomethasone

    budesonide

    fluticasone

    ciclesonide
  67. GLUCOCORTICOID PHARM EFFECTS
    • Permissive Effects: permit organs to have normal function
    • --VSM
    • --Skel musc

    • Metabolic Effects
    • Cortisol maintains plasma gluc conc for BRAIN even if this means destroying other tissues in the process

    • Glucose Metabolism:
    • --Proteolysis of skel musc
    • --Act genes for gluconeogenesis
    • --DEC act of GLUT-2 transporters in periph
    • --Stim hep glycogen synthetase → ­glycogen storage

    • Protein Metabolism:
    • --Proteolysis in skel musc
    • --­AA uptake by liver and kidney
    • --­hep gluconeogenesis

    • Lipid Met in Hypercortisolism:
    • --redistribution of fat to thorax & abd
    • --Proteolysis of sk muscle → ­gluconeogenesis
    • --­glucose → insulin release
    • --Truncal fat cells respond to insulin → inh intracell lipase → stim of fat storage
    • --Periph fat cells respond to cortisol → stim lipolysis

    • Other Catabolic Effects:
    • --Lymph & conn tissue, musc, fat, and skin
    • --Bone → Osteoporosis
    • *----inh osteobasts
    • *----Indirectly ­inc osteoclasts
    • --Avascular Necrosis of femoral head
    • --Even small p.o. doses can dec linear growth in children

    • Immunosuppression
    • --Anti-Inflamm effects linked to immunosupp effects
    • --CNS
    • *----elevated mood
    • --Neg feedback on Hypothal:
    • a) dec CRH
    • b) dec TRH
    • c) dec GnRH
    • --Bone Marrow
    • *----Stim erythropoesis → ­RBCs and plates
    • --Lungs:
    • *----Stim fetal prod of pulm surfactant
  68. HYDROCORTISONE THERAPEUTIC USES
    Acute Adrenal Insufficiency

    • Addison’s Disease (with fludrocortisones)
    • --Treat for rest of life

    • Congenital Adrenal Hyperplasia
    • (treat aggressively at birth)
  69. CORTISONE THERAPEUTIC USES
    ADDISON'S Dz

    • CONVERTED TO ACTIVE HYDROCORTISONE:
    • --HEP 11B-HYDROXYSTEROID DEHYDROGENASE
  70. PREDNISONE: ACTIVE OR INACTIVE?
    INACTIVE

    • CONVERTED TO ACTIVE PREDNISOLONE
    • --HEP 11B-HYROXYSTEROID DEHYDROGENASE
  71. BETAMETHASONE THERAPEUTIC USES
    FETAL LUNG MATURATION

    • When delivery is expected prior to 34 wks
    • gestation

    Reduces incidence of Fetal Resp Distress Syndrome
  72. DEXAMETHASONE THERAPEUTIC USES
    Suppression test for Dx Cushing’s Dz:

    Give Dex and measure plasma cortisol conc

    If Cushing’s: suppress cortisol by at least 50%

    • IF Ectopic ACTH-sec tumor/adrenal carcinoma:
    • will NOT suppress plasma cortisol
  73. FLUDROCORTISONE THERAPEUTIC USES
    GREATEST MINERALOCORTICOID ACTIVITY

    • ADDISON'S
    • --with HYDROCORTISONE
  74. GLUCOCORT ADVERSE EFFECT ON ADRENALS?
    • Adrenal suppression
    • --must withdrawal therapy slowly

    • Use descending doses for short-term p.o. therapy
    • --must give big dose at start to get rid of prob, but then withdraw

  75. IATROGENIC CUSHING'S SYND
    P = peptic ulcers

    • R = retention of Na/H2O
    • --> hypokalemia, hypochloremia & met alk, HTN

    E = extra depots of fat in trunk & face (moon facies)

    D = diabetes mellitus & changes in Carb met

    N = neurosis & psychosis

    I = infection

    S = suppression of pit-adrenal axis

    O = osteoporosis, esp ribs & vertebrae

    • N = neg nitrogen balance w/ musc wasting
    • --may effect resp muscles

    E = eye- posterior subscapular cataracts & glaucoma
  76. GLUCOCORT DRUG INTERACTIONS
    • Furosemide & HCTZ
    • --Enhance hypokalemia
    • --Induce hep P450 inc met of glucocorticoids

    • Ways to manage toxicity of chronic use:
    • --Alternate day therapy (prednisone)
    • --Worry about osteopor
    • *----Tx w/ risedronate or ibandronate
    • --Use smallest poss doses, but remember daily doses must incr during stress
  77. AMINOGLUTETHIMIDE
    INH OF STEROID SYNTH

    Blocks conv of chol to pregnenolone

    • Blocks all adrenal & extra-adrenal steroid synth
    • → “medical adrenalectomy

    • AFTER Tx w AGT: Body responds w/ an inc in ACTH --partially overcomes blockade of adrenal steriodogenesis
    • --CO-ADMIN Dexamethasone or Hydrocortisone to suppress ACTH inc
    • -----------------------

    THERA

    • BREAST CANCER
    • --PLUS DEXAMETHASONE TO DEC ANDRO & ESTRO SYNTH

    • CUSHING'S
    • --ADRENAL CARCINOMA
  78. PLASMA CORTISOL: INC
    PLASMA ACTH: INC
    ADRENAL CORTEX SIZE: HYPER
    CORT CONC AFTER DEXA: DEC 50%
    PLASMA 11-DEOXYCORT &
    URINE 17-KETOSTERO
    AFTER METYRAPONE: INC
    • CUSHINGS
    • --PIT ADENOMA
  79. PLASMA CORTISOL: INC
    PLASMA ACTH: INC
    ADRENAL CORTEX SIZE: HYPER
    CORT CONC AFTER DEXA: NO CHANGE
    PLASMA 11-DEOXYCORT &
    URINE 17-KETOSTERO
    AFTER METYRAPONE: N.C.
    ECTOPIC ACTH TUMOR
  80. PLASMA CORTISOL: INC
    PLASMA ACTH: DEC
    ADRENAL CORTEX SIZE: ATROPIC
    CORT CONC AFTER DEXA: NO CHANGE
    PLASMA 11-DEOXYCORT &
    URINE 17-KETOSTERO
    AFTER METYRAPONE: N.C.
    ADRENAL CARCINOMA
  81. LISPRO MOA
    Tx DM -- sc

    ULTRA SHORT ACTING

    AA substitution (proline & lysine switched) prevents lispro insulin from forming hexamers

    exists as monomers --> rapid action & duration of action NOT prolonged by inc dose

    • Advantages over reg insulin:
    • o Can be given 10 min before meal
    • o Equal rate of absorption from abdominal, deltoid
    • & femoral sites
    • o Reduced postprandial hyperglycemia
    • o Lower incidence of overnight hypoglycemia
  82. REGULAR INSULIN
    Tx DM

    RAPIDLY ACTING

    Crystalline zinc-insulin complex suspended in a clear soln at neutral pH

    • Hexamers must dissociate before absorption into blood
    • ------------------------------

    • Injected 30-45min before meal
    • ·
    • Effect begins w/in 15min, peaks 2-4hrs, lasts 5-8hrs
    • ·
    • Rapidly acting

    s.c. --> dur of action inc as dose inc b/c slow rate of dissoc of hexamers

    Tx DIABETIC KETOACIDOSIS ALONG w K+
  83. ISOPHANE (NPH) INSULIN
    TX DM -- sc

    INTERMEDIATE ACTING

    Insulin complexed w/ arginine-rich peptides (protamine) in a phosphate buffer

    Enzymes degrade protamine & allow DELAYED absorption of insulin
  84. DRUGS CAUSING HYPERGLYCEMIA
    • HCTZ
    • FUROSEMIDE
    • DIAZOXIDE

    INH INSULIN RELEASE

    DIAZOXIDE WORKS ON PANCREATIC INSULINOMAS
  85. LENTE INSULIN
    TX DM - sc

    INTERMEDIATE ACTING

    30% semilente insulin (RAPID) w/70% ultralente (DELAYED) insulin
  86. ULTRA LENTE INSULIN
    Tx DM - sc

    LONG ACTING

    POORLY SOLUBLE CRYSTALS OF Zn INSULIN

    • DELAYED ONSET AND PROLONGED DURATION
    • --20 to 36 hrs
    • --BEGINS 4-8 hrs
  87. INSULIN GLARGINE
    Tx DM

    LONG ACTING

    Gly substituted for asp & 2 arg are added to C-terminus of B chain

    • Given once daily b/c abs very slowly from s.c. site & thus exhibits a very flat profile on plasma insulin w/ NO peak conc
    • ----------------------

    • DEC fasting plasma glucose & HbA1c in patients being
    • treated w/ reg insulin

    • Works as well as isophane insulin but only has to be
    • given 1/day instead of 2/day

    Glargine plus lispro insulin given w/ meals may more closely mimic nL state of plasma insulin seen in euglycemic humans
  88. DRUGS CAUSING HYPOGLYCEMIA
    • ETHANOL (inh gluconeogen)
    • SALICYLATES
    • B-BLOCKERS (mask signs of hypogly except sweating)
  89. GLYBURIDE
    &
    GLIPIZIDE
    Tx DMT2 -- SULFONYLUREA

    Block ATP sensitive K chann → Depol pancreatic βcells

    • Depol open voltage sensitive Ca channels → influx of
    • Ca → --> IP3 release Ca from SR → inc intracellular Ca → secretion of insulin & C peptide into portal circulation
    • ------------------------------------

    • Insulin release from β cell:
    • --lowers plasma gluc
    • --prevents gluc prod by liver
    • --suppresses plasma glucagon

    Does NOT potentiate actions of insulin at target tissues

    • Reduces plasma gluc conc
    • ----------------------------

    2nd generation --> very potent

    should be used w/ care in elderly & pts w/ CV dz b/c risk of hypoglycemia

    • Prescribed for pts who cannot achieve
    • normoglycemia w/diet and weight loss and tx
  90. ADVERSE EFFECTS OF SULFONYLUREAS
    Tx DM (GLYBURIDE & GLIPIZIDE)
  91. Hypoglycemia
    --esp glyburide w 24hr half life
  92. Drug/drug interactions interfere w/ clearance
    • --Ethanol
    • --Salicylates
    • --Beta-blockers
    • *--Potentiate hypoglycemic effect
  93. Tolerance develops as the ability of pancreas to secrete insulin is impaired
  94. Hypoglycemia in euglycemic people
  95. REPAGLINIDE
    Tx DMT2

    NOT SULFONYLUREA

    BUT SAME MOA

    SAME PHARM EFFECTS

    PEAK 1hr & SHORT t1/2

    TAKE 10 min BEFORE MEAL

    • Prevents postprandial hyperglycemia w/o much
    • effect on fasting plasma gluc conc

    • CAUSES Hypoglycemia via insulin release in diabetic
    • pts who are over-treated or in euglycemic humans
  96. METFORMIN MOA
    TX DMT2 -- ANTI-HYPERGLYCEMIC

    WILL NOT CAUSE HYPOGLYCEMIA

    • INC sensitivity of periph tissues to insulin
    • --NO effect in absence of insulin

    • INC sensitivity of periph & hepatic tissues to insulin resulting in:
    • --Dec hep prod of gluc
    • --DEC glycogenolysis and gluconeogen

    • --Inc insulin stimed uptake of gluc by sk musc,
    • fat, intestinal tissue & RBCs
    • (poss recruitment of GLUT-1 & GLUT-4)

    • --Inc insulin stimed periph glucose utilization via
    • anaerobic (non-oxidative) pathways --> lactic acidosis
    • ------------------------

    Fasting gluc conc falls & glucagon sec is suppressed

    Inc glycogen in liver & sk muscle

    Inc lipogenesis in adipocytes

    Inc postprandial lactate production by GI tissue

    • Improves plasma lipid profile
    • -- DEC TGs
    • --DEC VLDL, LDL, ­HDL

    Works on ALL 3 organs: liver, fat cells, skel musc

    Metformin + rosiglitazone (or pioglitazone) used together for additive effect to lower plasma gluc conc & HBA1c

    Combo w/ sulfonylurea
  97. METFORMIN ADVERSE
    • Contraindications include:
    • o Dec renal clearance (cleared by kidneys)
    • o Previous lactic acidosis of any etiology
    • o Hepatic dz
    • o Cardiac failure
  98. Dec GI absorption of folate & vit B12
  99. N/V, GI discomfort, metallic taste
  100. No weight gain or hypoglycemia
  101. PIOGLITAZONE
    &
    ROSIGLITAZONE MOA
    Tx DMT2

    "PIA & ROSY ARE LADIES THAT FIGHT RESISTANCE"

    INC sensitivity of periph tissues to insuln

    • Binding to nuclear peroxisome proliferators-activated receptor gamma (PPAR-γ) → INC gene prods for:
    • --GLUT-4 (sk musc & adipose tissue)
    • --Lipoprotein lipase (imp lipid profile)
    • --Insulin receptors in sk musc & adipose tissue

    Does NOT cause release of insulin from panc

    No effect in absence of insulin

    • May prevent islet cell degeneration in type 2 DM
    • --------------------------------------

    Monotherapy lowers plasma glucose and HbA1c

    Combo sulfonylurea lowers plasma gluc & HbA1c

    • Metformin + pio or rosi may be used together for
    • additive effect to lower plasma gluc conc & HBA1c
  102. PIOGLITAZONE
    &
    ROSIGLITAZONE

    ADVERSE
    • ROSI
    • --Heart failure due to fluid retention
    • --INC RISK MI
    • --Black box warning
  103. Pio:
    • WOMEN -- may incr fracture risk
    • (esp of distal upper limb/distal lower)
  104. Macular edema
  105. PRAMLINTIDE
    Tx DM -- sc

    AMYLIN ANALOG

    • AMYLIN
    • --INH SECRETION OF GLUCAGON
    • --DEC GASTIC EMPTYING
    • --SUPPRESS APPETITE via CNS

    Panc releases insulin & amylin (& c-pep)

    AA subs prevent self-agg of pramlintide molecules

    • PHARM:
    • -- t1/2 20-45min
    • -- Cleared by kidneys
    • -- DEC rise in plasma glucose & HbA1c after meals

    Given before meal in pts using insulin in both T1 and T2 DM

    No weight gain

    CAN INC INSULIN-INDUCED HYPOGLYCEMIA
  106. SITAGLIPTIN
    Tx DMT2

    INCRETIN MIMETIC

    • INH DPP-4
    • --GIF & GLP-1 (incretins = GI hormones)

    DEC HbA1c by about 0.6%

    Added to Tx in T2DM pts taking sulfonylureas, metformin, or glitazones

    • ADVERSE:
    • --Hypoglycemia
    • --N/V
  107. EXENATIDE
    Tx DM

    • Incretin mimetic:
    • --Originally from saliva & tail of Gila monster

    Synth chemically

    • Agonist at GLP-1 receptors
    • --INC gluc-depend insulin release
    • --DEC glucagon secretion
    • --Inhib gastric emptying
    • --DEC appetite
    • (all on top are same actions as GLP-1)

    • --DEC hepatic fat content
    • --Animal studies: promotes β-cell prolif & inhib
    • β-cell death

    Added to Tx in T2DM pts taking sulfonylureas, metformin, or glitazones

    DEC basal glucose, postprandial glucose, & HbA1c

    Promotes weight loss

    • ADVERSE:
    • --HYPOGLYCEMIA
    • --N/V

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