pharm_repro_endo_ms2

• ESTRADIOL
• CONJUGATED ESTROGENS
• ETHINYL ESTRADIOL
• DIETHYLSTILBESTROL (DES)

Natural steroidal estrogen

ALL estrogens interact w/ intracellular receptors to alter gene tsc & thus protein synth

Composed of phytoestrogen

Contains same 3 major & 6 minor estrogens as Premarin

Synthetic steroidal estrogens

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

• --bioavailability
• --potency
• --t1/2

Synthetic non-steroidal estrogen

• teratogenic (1st trimester)
• --♀ fetus: clear cell adenocarc of vagina in late teens-20s
• --♂ fetus: undesc testes, epidydymal cysts &
• azoospermia

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)

Pharmacokinetics (of estrogens):

1. Enterohepatic recirc → greater effect on liver than periphery

2. Apply drugs topically (cream) for periph action to minimize hepatic effects

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

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

• 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

CLOMIPHENE

TAMOXIFEN

RALOXIFEN

• Acts as estrogen agonist (+) in some tissues
• & estrogen antagonist (-) in other tissues

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 & LH → gametogenesis & estgn
• --------------------------

Induce ovulation in ♀ w/ amenorrhea or anovulatory cycles

(-) CNS (nl sleep & temp regltn)

(+) liver: protein synth

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***

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

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

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

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)

ANASTROZOLE

LETROZOLE

(Block synth of ALL estrogen in body)

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

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

PROGESTERONE

NORETHINDRONE

NORGESTIMATE

NORELGESTROMIN

DROSPIRENONE

MEDROXYPROGESTERONE

PROGESTIN

ANTI-MINERALOCORTICOID

ANTI-ANDROGENIC

PROGESTIN

FAMILY OF DERIVATIVES OF 19-MORTESTOSTERONE

SOME ANDROGENIC EFFECTS

LACK ANTI-MINERALOCORTICOID ACTIVITY

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

PROGESTINS

Spironolactone derivative

1. Stim (+) progesterone rec

2. Blocks (-) androgen & mineralocorticoid rec

3. Block mineralocorticoid rec → CV benefits ♥

PROGESTIN

I.M. DEPO PROVERA

COMPLETE AMENORRHEA --> CONTRACEPTION LASTING 3 MONTHS

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

• NORETHINDRONE
• --LOW ANDROGENIC ACT --> INC SEVUM PROD --> ACNE
• --Tx w SPIRONOLACTONE

• MEDROXYPROGESTERONE
• --NO RISK OF THROMBOEMBOLIC Dz BUT UNPREDICTABLE MENSTRUAL BLEEDING

MIFEPROSTONE (RU-486)

ULIPRISTAL

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)

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.)

levothyroxine

propranolol

iodide (Lugol's solution)

propylthiouracil

methimazole

TSH

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)

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.

• 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

PROPRANOLOL & PTU

• Inhb enz thyroid peroxidase
• → inhb conversion of iodide (I-) to iodine (I^o)
• → 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

PTU

HYPERTHYROIDISM

BABY AT RISK FROM EXCESS THYROID STIM

PROPRANOLOL

LARGE DOSES po or iv

Sx DISAPPEAR IN SEVERAL HRS

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

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

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

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

• · (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

• · Extreme thirst
• · Polydipsia
• · Polyuria (e.g. 10-12 L/day)
• · Nocturia
• · Heavy exercise in hot weather → feel faint, worse
• thirst

• · Serum Na+ conc & osmolality: high normal
• · High serum glucose conc
• · Urinalysis: (-) for glucose & low urine osm (< 300 mOsm)
• · Generally healthy
• * Normal neuro tests & BP

DESMOPRESSIN

• COMP
• --HCTZ or INDOMETHACIN

• PART
• --HCTZ or LRG DOSES OF DESMOPRESSIN

AMILORIDE

DOES NOT ALTER Li CLEARANCE

DEMECLOCYCLINE

• 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

• 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

Tx DI

Mainly has V2 receptor activity (little V1)

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

Marked reduction in daily urine volume

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

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

· 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

· 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

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)

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

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

CHLORPROPAMIDE

CARBAMAZEPINE

NICOTINE

MORPHINE

MAINTAIN PLASMA GLUCOSE CONC FOR BRAIN

CATABOLIZE OTHER TISSUES FOR THIS PURPOSE

• BRAIN
• RBC
• WBC
• ADRENAL MEDULLA

• 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

"-SONE / -LONE"

hydrocortisone

cortisone

prednisone

prednisolone

methylprednisolone

triamcinolone

betamethasone

dexamethasone

fludrocortisone

beclomethasone

budesonide

fluticasone

ciclesonide

• 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

Acute Adrenal Insufficiency

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

• Congenital Adrenal Hyperplasia
• (treat aggressively at birth)

ADDISON'S Dz

• CONVERTED TO ACTIVE HYDROCORTISONE:
• --HEP 11B-HYDROXYSTEROID DEHYDROGENASE

INACTIVE

• CONVERTED TO ACTIVE PREDNISOLONE
• --HEP 11B-HYROXYSTEROID DEHYDROGENASE

FETAL LUNG MATURATION

• When delivery is expected prior to 34 wks
• gestation

Reduces incidence of Fetal Resp Distress Syndrome

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

GREATEST MINERALOCORTICOID ACTIVITY

• ADDISON'S
• --with HYDROCORTISONE

• 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

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

• 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

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

• CUSHINGS
• --PIT ADENOMA

ECTOPIC ACTH TUMOR

ADRENAL CARCINOMA

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

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+

TX DM -- sc

INTERMEDIATE ACTING

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

Enzymes degrade protamine & allow DELAYED absorption of insulin

• HCTZ
• FUROSEMIDE
• DIAZOXIDE

INH INSULIN RELEASE

DIAZOXIDE WORKS ON PANCREATIC INSULINOMAS

TX DM - sc

INTERMEDIATE ACTING

30% semilente insulin (RAPID) w/70% ultralente (DELAYED) 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

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

• ETHANOL (inh gluconeogen)
• SALICYLATES
• B-BLOCKERS (mask signs of hypogly except sweating)

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

Tx DM (GLYBURIDE & GLIPIZIDE)

• Hypoglycemia
• --esp glyburide w 24hr half life

• Drug/drug interactions interfere w/ clearance
• --Ethanol
• --Salicylates
• --Beta-blockers
• *--Potentiate hypoglycemic effect

Tolerance develops as the ability of pancreas to secrete insulin is impaired

Hypoglycemia in euglycemic people

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

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

• Contraindications include:
• o Dec renal clearance (cleared by kidneys)
• o Previous lactic acidosis of any etiology
• o Hepatic dz
• o Cardiac failure

Dec GI absorption of folate & vit B12

N/V, GI discomfort, metallic taste

No weight gain or hypoglycemia

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

• ROSI
• --Heart failure due to fluid retention
• --INC RISK MI
• --Black box warning

• Pio:
• WOMEN -- may incr fracture risk
• (esp of distal upper limb/distal lower)

Macular edema

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

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

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