Endo/ReproDrugs

• low-sugar diet
• insulin replacement

• DM-1
• early onset
• loss of beta cells-->absolute dependence on insulin
• ketoacidosis prone!

• diet modify
• exercise (lose weight)
• oral hypoglycemics
• insulin replacement

• DM-2
• adult onset
• decrease response to insulin--> diet-->oral hypoglycemics +/- insulin
• NOT ketoacidosis prone! more Hyperosmolar coma from hyperglycemia

• Glucose
• Sulfonylureas
• M-agonists
• B2-agonists

Alpha-2 agonists

• Bind insulin receptor (RTK)--> autophosphorylate tyr-kinase--> bind/ phosphorylate IRS-1--> bind/phosphorylate SH2-domain proteins-->-->
• activate phosphatases, induce gene expression of LPL, FA-sythase, Glucokinase...

• rapid acting insulin (IV!)
• -bind insulin receptor
• -Liver: increase glucose stored as glycogen
• -Muscle: increase glycogen synthesis, K+ uptake
• -Fat: increase TG storage

• USE- DM-1, DM-2
• life-threatening hyperkalemia
• stress induced hyperglycemia

SE- hypoglycemia

• rapid acting insulin (IV)
• -bind insulin receptor
• -Liver: increase glucose stored as glycogen
• -Muscle: increase glycogen synthesis, K+ uptake
• -Fat: increase TG storage

• USE- DM-1, DM-2
• life-threatening hyperkalemia
• stress induced hyperglycemia

SE- hypoglycemia

• rapid acting insulin
• -bind insulin receptor
• -Liver: increase glucose stored as glycogen
• -Muscle: increase glycogen synthesis, K+ uptake
• -Fat: increase TG storage

• USE- DM-1, DM-2
• life-threatening hyperkalemia
• stress induced hyperglycemia

SE- hypoglycemia

• intermediate acting insulin
• -bind insulin receptor
• -Liver: increase glucose stored as glycogen
• -Muscle: increase glycogen synthesis, K+ uptake
• -Fat: increase TG storage

• USE- DM-1, DM-2
• life-threatening hyperkalemia
• stress induced hyperglycemia

SE- hypoglycemia

• long acting insulin analog
• -NO peak!
• -supply constant background level insulin
• -NO risk of hypoglycemia

USE-DM-1, DM-2(?)

• long acting insulin analog
• -NO peak!
• -supply constant background level insulin
• -NO risk of hypoglycemia

USE-DM-1, DM-2(?)

• Ketones: (made from high ATP from burning fat)
• beta-hydroxybutyric acid--> NADH + 2 acetyl-CoA
• acetoacetate--> 2 acetyl-CoA
• acetone--> breath out (fruity breath)

• Symptoms:
• -polyuria, polydipsia
• -nausea, fatigue
• -Kussmaul breathing (wanna rid of acidosis!)
• -dehydration
• -elevated serum K+, low intracellular K+ (b/c acidosis, and low insulin)

• Rx- IV regular Insulin!
• -give w/ glucose to prevent hypoglycemia
• -give w/ K+ to prevent hypokalemia!!

• lip/tongue tingling
• lethargy
• confusion
• sweat
• tremor
• tachycardia
• coma
• seizures

• RX- oral glucose, IV-dextrose (if unconscious)
• glucagon (IM or inhalation)
• - IM glucagon in non-medical setting, or IV dextrose in medical setting. but NOT IM-glucose!

eat-->glucose--> go thru GLUT-2 (low affinity) in pancreas beta cell--> increase ATP--> close ATP-dependent K-channel--> depolarize--> open vol-Ca channel--> Ca in--> exocytosis of insulin

• first gen Sulfonylurease (secretologue)
• -close ATP-dep K channel in beta cells--> depol--> Ca influx--> insulin release
• -decrease glucagon release
• -increase insulin receptor sensitivity (?)
• (useless in DM-1)

USE-DM-2

• SE- long acting!! watch out in renal disease pt
• -weight gain, hypoglycemia
• -drug interactions w/ Cimetidine (induce cyps), Salicylates, Sulfonamides

• first gen Sulfonylurease (secretologue)
• -close ATP-dep K channel in beta cells--> depol--> Ca influx--> insulin release
• -decrease glucagon release
• -increase insulin receptor sensitivity (?)
• (useless in DM-1)

USE-DM-2

• SE -NO worries for kidney!
• -weight gain, hypoglycemia
• -drug interactions w/ Cimetidine (induce cyps), Salicylates, Sulfonamides

• first gen Sulfonylurease (secretologue)
• -close ATP-dep K channel in beta cells--> depol--> Ca influx--> insulin release
• -decrease glucagon release
• -increase insulin receptor sensitivity (?)
• (useless in DM-1)

USE-DM-2

• SE- long acting!! watch out in renal disease pt
• -disulfram-like effects! SIADH!
• -weight gain, hypoglycemia
• -drug interactions w/ Cimetidine (induce cyps), Salicylates, Sulfonamides

• second gen Sulfonylureas
• -close ATP-dep K channel in beta cells--> depol--> Ca influx--> insulin release
• -decrease glucagon release
• -increase insulin receptor sensitivity (?)
• (useless in DM-1)

USE-DM-2

• SE- watch out in liver disease pt
• -weight gain, hypoglycemia
• -drug interactions w/ Cimetidine (induce cyps), Salicylates, Sulfonamides

• second gen Sulfonylureas (secretologue)
• -close ATP-dep K channel in beta cells--> depol--> Ca influx--> insulin release
• -decrease glucagon release
• -increase insulin receptor sensitivity (?)
• (useless in DM-1)

USE-DM-2

• SE- active metabolite! watch out in kidney disease
• -weight gain, hypoglycemia
• -drug interactions w/ Cimetidine (induce cyps), Salicylates, Sulfonamides

• second gen Sulfonylureas (secretologue)
• -close ATP-dep K channel in beta cells--> depol--> Ca influx--> insulin release
• -decrease glucagon release
• -increase insulin receptor sensitivity (?)
• (useless in DM-1)

USE-DM-2

• SE-weight gain, hypoglycemia
• -drug interactions w/ Cimetidine (induce cyps), Salicylates, Sulfonamides

• Euglycemic (Biguanides)
• -decrease postprandial glucose (decr liver glucose!)
• -does NOT cause hypoglycemia or weight gain!
• inhibit intracellular enzymes
• -decrease gluconeogenesis
• -increase glycolysis
• -increase glucose uptake by GLUT-4 in SKM (insulin sensitivity)
• (maybe activate PPAR transcription factors)

• USE- (oral) monotherapy or combo DM-1, DM-2 can be used in pts w/out islet fxn.
• -synergistic w/ sulfonylureas!

• SE- Lactic acidosis!! , GI distress
• DO NOT use in renal failure!!

• alpha-glucosidase inhibitor
• -block intestinal brush-border alpha-glucosidase
• -decrease glucose absorption-->decrs postprandial glucose-->insulin demand
• -NO hypoglycemia!

USE-monotherapy or combo for DM-2

SE- GI! diarrhea (osmotic), hepatotoxity

• alpha-glucosidase inhibitor
• -block intestinal brush-border alpha-glucosidase-decrease glucose absorption-->decrs postprandial glucose-->insulin demand
• -NO hypoglycemia!

USE-monotherapy or combo for DM-2

SE- GI! diarrhea (osmotic), hepatotoxity

• Glitazone/ Thiazolidinedione
• -insulin sensitizer (like metformin)
• -bind PPAR-gamma transcription factor (nuclear receptor) for insulin-response genes (bypass insulin-receptor/signaling)--> sensitize to insulin
• -decrease liver gluconeogenesis
• -increase insulin receptor #s!
• -increase HDL

USE- monotherapy for DM-2 or combo

• SE- less hypoglycemia than sulfonylurease
• -weight gain, edema
• -CV toxicity, hepatotoxicity
• -bone fractures..

• Glitazone/ Thiazolidinedione
• -insulin sensitizer (like metformin)
• -bind PPAR-gamma transcription factor for insulin-response genes (bypass insulin-receptor/signaling)--> sensitize to insulin
• -decrease liver gluconeogenesis
• -increase insulin receptor #s!
• -increase HDL

USE- monotherapy for DM-2 or combo

• SE -less hypoglycemia than sulfonylurease
• -weight gain, edema
• -CV toxicity, hepatotoxicity
• -bone fractures..

• ultimately decreases resistance to insulin!
• -increase Adiponectin (cytokine sec by fat cells)
• -increase FA transport protein
• -increase Insulin receptor substrate
• -increase GLUT-4

• released by L-cells in GI in response to food
• -GPCR--> Gs--> cAMP!
• induce satiety
• decrease gastric emptying
• increase insulin release
• -very short half life, so GLP-1 meds are analogs

• GLP-1 (incretin) receptor agonist
• -normally: eat--> SI-->GLP-1-->pancreas--> increase insulin release, decrease glucagon--> decrease glucose
• -enhance glucose-dependent insulin secretion

• USE- (injected) DM-2
• -decrease appetite!! great for losing weight too.

SE- nausea, vomiting, hypoglycemia w/sulfonylureas, pancreatitis!

• GLP-1 enhancer
• -block DPP-4 (dipeptidyl peptidase)--> inhibit breakdown of endogenous GLP-1

USE- DM-2

SE- not much..

• synthetic amylin
• -slow GI absorption
• -decrease glucagon
• -decrease appetite

• USE- DM-2
• -decrease appetite!

SE- hypoglycemia, nausea, diarrhea

• Insulin!
• oral hypoglycemic meds are generally avoided in GDM b/c risk of fetal hyperinsulinemia and hypoglycemia.

Inhibit glucose absorption: Acarbose, Miglitol

Inhibit glucose production: Metformin, Pioglitazone, Rosiglitazone

Enhance glucose uptake: Metformine, Pioglitazone, Rosiglitazone

Increase insulin release: Sulfonylureas, Exenatide, Sitaglipin

vomiting, abdominal pain, weight loss, anorexia, hypotension, hypoglycemia, hyperpigmentation

Rx-Corticosteroids (stress dose of hydrocortisone)!!

• thioamide
• -block thyroid peroxidase
• -high dose block 5'deiodinase
• -block organification of iodied and coupling of thyroid hormone synthesis
• -cross placenta, but highly protein bound, so safer

USE- hyperthyroidism

SE- maculopapular rash, aplastic anemia, agranulocytosis (rare)

• thioamide
• -block thyroid peroxidase
• -block organification of iodied and coupling of thyroid hormone synthesis
• -cross placenta, high free form, so do NOT use in pregnancy. Use Proplthiouracil

USE- hyperthyroidism

SE- maculopapular rash, teratogen, aplastic anemia, agranulocytosis (rare)

• nonselective beta blocker
• -also blocks 5'deiodinase (block T3-->T3)

USE-hyperthyroidism

SE- sedation, bradycardia, AV block, hypotension, bronchospasm, vasospasm.. (look at b-blockers)

• block Na/Iodide symporter on thryoid follicular cell (basolateral side)
• -competative inhibition

• KI + I2 (Lugol's solution)
• -inhibit release of T3 and T4 from Thyroglobulin
• -decrease thyroid gland size, vascularity

USE- preOP use in thyrotoxicosis

SE- no long term use b/c thyroid gland "escapes" from effect afte 2wks..

• Propylthiouracil
• Glucocorticoids
• Amiodarone (hypothyroidism in iodine sufficient regions, thyrotoxicosis in iodine defficient regions)
• Iopanoic acid
• Propranolol (non selective beta-blockers)

• Glucocorticoids!
• -decrease severity of inflammation and decrease extraocular volume.
• -conventional antithyroid drugs do NOT improve opthalmopahty (edema+ lympthocyte, mac infiltration+ fibroblasts make too much PGs)

• Thyroxine analog
• replace thyroxine

USE- hypothyroidism, myxedema

SE- tachycardia, heat intolerance, tremor, arrhythmia

• Thyroxine analog
• replace thyroxine

USE- hypothyroidism, myxedema

SE- tachycardia, heat intolerance, tremor, arrhythmia

Hypothalamic/pituitary drug

USE-GH deficiency, Turner syndrome

Hypothalamic/ Pituitary drug

USE-Acromegaly, Carcinoid syndrome, Gastrinoma, Glucagonoma

Hypothalamic/Pituitary drug

USE- Stimulate labor, uterine contractions, Milk let-down, Uterine hemorrhage.

ADH analog

• USE- central diabetes incipidus
• -Hemophlia A, vWF disease (stimulate endothelial release of vWF + VIII)
• -Enuresis!
• -not much effect on V1 receptors so no vasoconstiriction

• ADH antagonist
• -member of tetracycline

USE- SIADH (syndrome of inappropriate ADH)

SE- Nephrogenic diabetes insipidus, Photosensitivity, bone + teeth abnormalities

• Glucocorticoids!
• -inhibit PLA2, block expression of COX-2
• -decrease production of leukotriens and Prostaglandins

USE-Addison's disease, inflammation, immune suppression, asthma

• SE- Iatrogenic Cushing's syndrome- buffalo hump, moon facies, truncal obesity, muscle wasting, think skin, easy bruisability, osteoporosis adrenocortical atrophy, peptic ulcers, diabetes ( if chronic)
• -Adrenal insufficiency if drug is stopped after chronic use!

• GnRH analog
• -agonist properties when used in pusatile fashion
• -antagonist properties when used continuously.

• USE- infertility (pusatile)
• - Prostate cancer (continuous, use w/ Flutamide)
• -Uterine fibroids, Endometriosis, DUB (continuous)

SE- Antiandrogen, nausea, vomiting

Androgen receptor agonist

• USE- Hypogonadism, pormote development of secondary sex characteristics
• -stimulate anabolism for recovering burns, injury
• -treat ER-positive breast cancer (exemestane)

• SE- masculinization in females, reduce intratesticular testosterone in males (inhibit LH release)--> gonadal atophy
• -Premature closure of epiphyseal plates
• -increase LDL, decrease HDL

• 5apha-reductase inhibitor
• -block Testosterone--> DHT

USE- BPH, hair growth

to prevent male patterin hair loss, give a drug that'll promote female breast growth

• testosterone, DTH receptor blocker
• nonsteroidal, competitive inhibitor of androgens

USE- Prostate carcinoma

• Inhibit steroid synthesis
• -block Desmolase

USE- PCOS (polycystic ovarian syndrome) to prevent Hirsutism

SE- gynecomastia, amenorrhea

• K-sparing diuretic
• -block Aldosterone receptor
• -also block other androgen receptors

USE- PCOS to prevent hirsutism

SE- gynecomastia, amenorrhea

Estrogen receptor agonists

• USE-hypogonadism, ovarian failure, mesntrual abnormalities, HRT in postmenopausal women
• -Men: androgen dependent prostate cancer

• SE-increase risk for endometrial cancer, bleeding in postmenopausal women
• -DES exposure in utero--> clear cell carcinoma of vagina
• -hypercoagulability
• DO NOT use in ER-positive breast cancer, History of DVT!

• SERMs (selective estrogen receptor modulators)
• Estrogen partial agonists in hypothalamus
• -prevent normal feedback inhibition
• -increase release of LH and FSH--> ovulation

USE- infertility, PCOS

SE- hot flashses, ovarian enlargement, multiple simultaneous pregnancies, visual disturbances

• Estrogen partial agonists
• SERM
• -antagonist on breast tissue -partial agonist in bone, endometrium
• USE-

• Estrogen partial agonist
• SERM
• -agonist on bone
• -reduce bone resorption

USE- Osteoporosis

• USE-relief or prevention of menopausal symptoms
• (hot flashes, vaginal atrophy)
• -Osteoporosis (increase Estrogen, decrease osteoclast)

• SE- unopposed estrogen replacement therapy increase risk of endometrial cancer (so add progesterone)
• -possible increase of CV risk

aromatase inhibitors

USE- postmenopausal women w/breast cancer

• -progesterone receptor agonist
• -increase vascularization of endometrium

• USE- oral contraceptive addjunct
• - endometrial cancer
• -abnormal uterine bleeding

• -competitive inhibitor of Progestins
• -block progesterone receptor

• USE- Termination of pregnancy
• -given w/ Misoprostol (PGE1-analog: PG cause uterine contraction + cervical dilation)

SE- heavy bleeding, GI effects ( nausea, vomiting, anorexia), abdominal pain (b.c anti-pregestin effects stimulate release of endogenous prostaglandins and sensitize myometrium to effects of hormone)

• Synthetic progestin+ estrogen
• -prevent estrogen surge, LH surge does NOT occur--> NO ovulation

Advantages- reliable, decrease rick of endometrial, ovarian cancer, decrease incidence of ectopic pregnancy, decrease pelvic infections, regulation of meses

Disadvantages- taken daily, NO protection against STDs, Increase TGs, Depression, weigh gain, nausea, HTN, hypercoagualability

Do NOT use in smokers>35 y.o (increase CV events), hx of DVT, stroke or hx of estrogent-dependent tumor!!

• PGE2 analog
• -cause cervical dilaiton, uterine contraction

USE- induce labor

• beta-2 agonist
• -relax urterus

USE- reduce premature uterine contractions

• alpha-1 blocker
• -inhibit smooth muscle contraction
• -selective for alpha-1 A,D receptors in prostate!
• (vascular- alpha-1 B)

USE- BPH

• block cGMP PDE--> increase cGMP
• -relax smooth muscle of corpus cavernosum
• -increase blood flow, penile erection

USE- erectile dysfunction

SE-headache, flushing, dyspepsia, impaire blue-green color vision, risk of life-threatening hypotension if on nitrates!!

• block cGMP PDE--> increase cGMP
• -relax smooth muscle of corpus cavernosum
• -increase blood flow, penile erection

USE- erectile dysfunction

SE-headache, flushing, dyspepsia, impaire blue-green color vision, risk of life-threatening hypotension if on nitrates!!