Upper GI role in normaglycemia

• Produces Hormones such as Glucagon-Like-Peptide-1 (which INC insulin secretion by acting on Beta Cell in Pancreas)

Pancreas Role in Normoglycemia

• Primary site for glucose regulation (glucose is primary stimulation for insulin secretion)
• ALPHA cells-secrete glucagon
• BETA cells-secrete Insulin
• Epinepherine acts on BETA cell to DEC insulin secretion

Fat Role in Normoglycemia

• Facilitates tissue uptake of glucse for storage
• DEC Lipolysis-insulin secretion gets glucose stored in fat therefore dec the amount of fat being brokedown (more fat for storage!!)

Muscle Role in Normoglycemia

• 80-90% of insulin mediated glucose uptake occurs in muscle!!
• MOST important insulin dependent - need this for energy!

Liver Role in Normoglycemia

• Can Store, Synthesize, or Secrete glucose
• Insulin converts glucose to glycogen
• Glucagon converts glycogen to blucose

DM Pathophysiology-Pancreas

Hypoglycemia bc:

• DEC insulin secretion from Beta cells in islet of langerhans (leads to Beta Cell exhaustion over yrs to decades)
• INC glucagon secretion from Alpha Cells due to DEC GLP-1 stimulation

DM Pathophysiology-Liver

Hyperglycemia bc:

• INC hepatic glucose production and secretion due to glucagon(from alpha cells) stimulation of stored glycogen conversion to glucose

DM Pathophysiology-Kidney

Hyperglycemia bc:

• Maximal Glucose reabsorption
• Glucosuria observed at Glucose Blood Levels>180mg/dL (anything above 180 lets glucose get into urine)

DM Pathophysiology-Muscle

Hyperglycemia bc: 

"Insulin Resistence" aka glucotoxicity-inability of glucose to get into insulin dependent tissues

• Observed when insulin levels elevated
• maybe due to DEC insulin receptors or post-receptor defects
• Evolving need for greater amounts of insulin w/ time

DM Pathophysiology-GI  Tract

Hyperglycemia bc: 

• DEC glucagon-like-peptide-1 released

S/S of DM

• Polyphagia, Polydypsia, Polyuria(not perceived as problem by patient)
• Lethargy, Fatigue
• Weight loss(type I) or Obesity(typeII)

Type I DM

• Autoimmune destruction, approx 5%
• NO insulin secretion
• Before age 30 (typ 17)
• Abrupt onset:days to months
• Usually NOT obese
• insulin resistence usually Absent

Type II DM

• type 2 is about 95%
• Usually assocciated w/ Metabolic syndrome
• Insulin secretion is HIGH early and LOW late
• Dx usually at 40 yo
• Gradual onset: years to decades
• obese usually 85%
• Insulin resistence usually present

Pathogenesis of Type I DM

Pathogenesis of type 2 DM

• Metabolic syndrome/obesity can lead to pre-diabetes(FBG:100-125;PPG:140-199, >50% prediabetes lead to T2DM w/i 10 yrs) which can lead to T2DM(FBG:>126;PPG>200; A1c>6%)
• Insulin Resistence starts long before Dx w/ T2DM(can be 20 yrs)
• Pancreas secretes more insulin to compensate then apoptosis lead to dec insulin secretion
• CVD starts well before Dx
• Uncontrolled/poorly controlled hyperglycemia, bc BG elevatres over time(T1-months, T2-Years)

Drug need to Tx:

Both Post-Prandial and Basal Hyperglycemia

(As PPG and Basal G inc-hyperglycemia-tissue injury and lesions-Diabetic complications)

Diabetic Complications

Macrovascular:

• Lipid disorders-atherosclerosis; 75% t1die of CVD
• Hypertension-need stricter BP goals than for non-diabetics

Microvascular:

• Retinopathy- 80-90% have some eye complication
• Neuropathy-vascular anomoly;foot ulcerations, loss of nerves in feet
• Diabetic Neuropathy-caused mostly by DM, second cause is HTN
• Gestational diabetes-babies born obese and have high risk for T2DM; Mothers have inc risk of T2DM w/i 10yrs
• Impotence

Monitoring T2DM-FBG and PPG

• FBG: norm=70-99/ pre-dm=100-125/ T2DM=>/=126
• Post-prandial glucose: norm=<140/ pre-DM=140-199/ T2DM>/=200
• Ketones start coming out when FBG=250:BAD-ketoacidosis

Monitoring of T2DM-Hemoglobin A1c

• HbA1c formed slowly snd almost irreversible during the 120 day lifespan of RBC
• accumulation of HbA1c depends on ave conc of gulcose in plasma during the preceding 3 months
• Normal: 4-6%, goal is <7%
• Diabetic: >7.5% (highest seen 14%)

Insulin Lispro-Humalog

• Immediate Onset; better than short insulin
• Quick onset and peak, but short duration
• Insulin Analog-newer
• Controls post prandial spikes use regular .5hrs before eat and they change their mind too late the drugs already in their system, but with immediate better compliance
• ADVANTAGES: less potential for HYPOGLYCEMIA bc inj immediately before meals, so in kids if

Regular,Humulin R, Novolin R

• Short acting
• supposed to be for post prandial peaks
• OLD- recombinant insulin
• quick onset but takes a while to peak, so you missthe spike of blood glucose
• has slightly longer diration than the immediate

NPH-Neutral Protamine Hagadorn

• Intermediate acting
• Old-recombinant insulin, not so good
• Basal control
• Ok onset, late peak and long duration

Insulin Glargine-Lantus

• Long acting
• only 1 inj at night and controls BASAL elevations throughout all next day
• Very good drug
• no big control w/ post prandial
• long onset and NO peak
• but 24+hrs duration!!
• Less potential for hypoglycemia bc NO peak

Premixed Insulins

• Combination products, 2 inj/day
• HumuLIN 70/30 or 50/50: NPH/Regular-when given 2 inj get too much insuin (intermeal and nocturnal hypoglucemia
• HumuLOG 75/25: NPH like/Lispro-still get 2 areas of hypoglycemia but not as much!
• ok onset  ok peak and long duration

Metformin-Glucophage

• Biguanide
• Anti-Hyperglycemic agent (doesnt secrete insulin), NOT hypoglycemic agent, Insulin sensitizer; therefore less possibility for hypoglycemia
• Preferred in Obese diabetics bc has side effect of Weight LOSS
• Most effect on liver-less glucose production and secretion, so less glucose in blood stream!
• Enhances Insulin-Stimulated glucose utilization in skeletal muscle, fat, intestinal tissue
• Improves lipid profile: Dec TC, Dec LDL, INC HDL, Dec TG

Tolbutamide-Orinase

• First Generation Sulfonylureas-Insulin Secretagogues
• Mainly Stimulate release of endogenous Insulin form functional beta cells; closes ATP-dependent K+channels which lead to longer Calcium channel opening, therefore longer duration of Insulin Secretion
• Not used at much bc oversecretion of beta cells, kills beta cells and if only have 10% beta cells left these drugs not very efficacious
• ADR: Marked Hypoglycemia w/ CNS and autonomic abnormalities

Chlorpropamide-Diabinese

• First Generation Sulfonylureas-Insulin Secretagogues
• Stimulate Beta cell to secrete insulin
• Not used at much bc oversecretion of beta cells, kills beta cells and if only have 10% beta cells left these drugs not very efficacious
• ADR: Marked Hypoglycemia w/ CNS and autonomic abnormalities

Glyburide-Diabeta,Micronase, or Glynase

• Second Generation Sulfonylureas-Insulin Secretagogues; more potent, quicker onset, longer duration, less PPB
• Mainly Stimulate release of endogenous Insulin form functional beta cells; closes ATP-dependent K+channels which lead to longer Calcium channel opening, therefore longer duration of Insulin Secretion
• Not used at much bc oversecretion of beta cells, kills beta cells and if only have 10% beta cells left these drugs not very efficacious
• ADR: Marked Hypoglycemia w/ CNS and autonomic abnormalities

Glipizide-Glucotrol or Glucotrol XL

Glimepiride-Amaryl

Pioglitazone-Actos

• better than avandia bc dont have acular ADR
• Peroxisome Proliferator Activated Recepter (PPAR) Agonist
• TZD; Antihyperglycemic agent(insulin sensitizer-get BG out of blood and into cells); Only active in presence of insulin
• Binds to Nuclear PPAR, complex w/ DNA and initiate New Protein synthesis
• Glycemic actions bc PPAR gamma stimulation: DEC insulin resistence-inc glucose uptake into insulin dependent tissues

Muscle and Fat: enhance TRANSLOCATION of GLUT-4 from cytoplasm to plasma membrane

Adipose: ADIPONECTIN: INC FFA uptake into adipose cells, INC storage of TG, DEC fat breakdown, INC adiponectin Secretion

• Cardioprotective and antiatherogenic actions bc PPAR alpha stimulation:
• lipids: DEC TG, INC HDL and LDL shift from small dense to large fluffy(which are better)
• Dec Atherosclerosis and dyslipidemiasto DEC CV complications

Rosiglitazone-Avandia

• Not as good as actos bc Has ocular ADR
• Peroxisome Proliferator Activated Recepter (PPAR) Agonist
• TZD; Antihyperglycemic agent(insulin sensitizer-get BG out of blood and into cells); Only active in presence of insulin
• Binds to Nuclear PPAR, complex w/ DNA and initiate New Protein synthesis
• Glycemic actions bc PPAR gamma stimulation: DEC insulin resistence-inc glucose uptake into insulin dependent tissues

Muscle and Fat: enhance TRANSLOCATION of GLUT-4 from cytoplasm to plasma membrane

Adipose: ADIPONECTIN: INC FFA uptake into adipose cells, INC storage of TG, DEC fat breakdown, INC adiponectin Secretion

• Cardioprotective and antiatherogenic actions bc PPAR alpha stimulation:
• lipids: DEC TG, INC HDL and LDL shift from small dense to large fluffy(which are better)
• Dec Atherosclerosis and dyslipidemiasto DEC CV complications
• ADR: distorted vision, Dec color sensitivity, dec dark adapt, macular edema

Exenatide-Byetta

• Incretin Hormone Mimetic(Mimics GLP-1)
• Used to control PPG
• GLP-1 receptor agonist:

stimulates insulin release from beta cells and inc production of New-insulin producing betaq cells!

DEC glucagon secretion; Dec glucose secretion from liver

DEC gastric emptying

INC satiety and DEC food intake

DEC FBG(some), DEC PPG(MAIN), DEC A1c, DEC weight!

GLP-1 Effects

• Secreted from intestinal cells
• Acts on Pancreas to enhance glucose dependent insulin secretion and Increase Beta cell mass and function
• Acts on Brain to suppress glucagon secretion in pancreas and brain slows gastric emptying in stomach(feel full, dont get PPG spike!!)

Sitagliptin-Januvia

• Dipeptidyl Peptidase IV(DPP-IV) Inhibitors
• Not as efficacious as mimetics or agonists
• DPP-IV is NOT specific for GLP-1, could lead to ADR(inc immune problems)
• Oral incretin enhancer
• Inhibits DPP-IV which dec GLP-1 Inactivation so GLP-1 sticks around longer and more available but ptnts w/ GI diseases have less GLP-1 secretion therefore this drug would be less efficacious

Endocrine Transmission and cellular regulation

• Endocrine transmission is slow and diffuse(unlike NT-fast and discrete)
• Types cellular regulation: Autocrine-release hormone for self/ Paracrine-release hormone for nearby cell/ Endocrine-hormone released for far away cell!

Major Endocrine Hormones

• Secreted by-Hormone
• Post Pit-ADH/Oxytocin
• Ant Pit-Growth H/prolactin/FSH/LH
• Pancreas-Insulin/Glucagon/Somatostatin
• Parathyroid-PTH
• Thyroid-T3/ T4/ Calcitonin
• Adrenal-Catecholamines/ Aldosterone/ Cortisol
• Ovary-Estradiol/progesterone
• Ovary,Testes-Testosterone

Hypothalamic-Pituitary-Target Organ Axis

• Primary Hyperthyroidism: problem w/ thyroid gland
• Secondary Hyperthyroidism: Problem with pituitary
• Tertiarty Hyperthyroidism: problem with hypothalamus

Overview of hormones-target organs-functions

Hypothyroidism

• Decrese in Metabolic Rate
• sluggish depressed
• dry, course skin/hair
• unexplained, excessive weight gain
• feel cold
• constipation
• Muscle cramps
• more frequent period, inc menstral flow
• Infertility

Hyperthyroidism

• Increased metabolic rate
• nervousness, irratability
• inc sweating, inc HR
• thinning akin, fine brittle hair
• muscle weakness, shaky hands
• more frequent bowel movements
• lighter, less frequent periods
• exophthalmos
• infertility

Hypothyroidism-pathophys

• Chronic Autoimmune Thyroiditis(hashimotos): T lymphocytes attack proteins, stimulate B cells to produce antibodies against normal Thyroid tissue(directed against peroxidase enzyme system, thyroglobulin, and thyrotropin receptor)
• Myxedema: end stage-long time uncorrected hypothyroidism; lethargy, stupor, hypothermia, delerium-coma-death(rare)

Levothyroxine, L-thyroxine, T4-Synthroid

Used for hypothyroidism

Pharmacology:

1. growth and development-need daily

2. Calorigenic effects-inc basal metabolic rates and oxygen consuption

3. Cardiovascular effects - tachycardia, INC cardiac hypertrophy, inc pulse pressure

4. Metabolic effect - INC fat breakdown, metabolize lipoproteins

Methimazole-Tapazole and Propylthiouracil-PTU

• PTU-radioactive iodide 131- standard tx, B emiiter to kill thyroid cells bc easier to ablate and then tx w/ T4 supplement than to tx w/ drops
• Indications: Graves disease-autoimmune production of thyroid stimulating antibodies(IgG) which attach and stim thyrotropin receptors on surface of thyroid; activates intracellular path like TSH, Inc T3/T4; 75% have some ocular involvement
• Pharmacology: Inhibits biosynthesis of thyroid hormones by irreversibly inactivating peroxidase enzyme system in thyroid follicular cells

Ca2+ Physiology

Elemental calcium essential for: NT release, Muscle contract, blood coagulation, second messengers, etc

Bone: major storage for ca2+, 99%

     Osteoblasts-bone formation

     Osteoclasts-bone breakdown(influenced by drugs, hormones,vitamins, etc)

PTH: secretion inc Ca2+

When Blood Ca2+ is low:

    Bone breakdown to secrete stored Ca2+

    Kidney inc tubular reabsoption from urine

    GI inc Ca2+ absoption

Pathophysiology - Osteoporosis

• DEFN: Loss bone mass, structural bone disruption, skeletal fragility
• Signs: shorter height, fractures, pain, vertebral body collapse, and widows hump
• Primary regulators of adult bone mass: Physical activity/Ca2+ intake/ reproductive, hormonal endocrine status/ genetics
• ETIOLOGY: drug induced(steroids)/ estrogen deficiency(inc bone breakdown)/ Calcium absorption dec w/ age/ Dec sun exposure/ dec kidney/liver function/ Older, white women 

Calcium:

Calcium Carbonate-Tums, Viactiv chews

Calcium Posphate-Posture

• 25-35% of diet Ca2+ absorbed normally, absorption inc w/ excess vit D
• Daily Ca2+ requirements inc with age
• Body cannot absorp more than 500-600mg elemental Ca2+ at one time
• USES: prevent/tx osteoporosis and neutralize stomach acid
• DI: impairs absorption of antibiotics

Alendronate-Fosamax

• Bisphosphates - DOC!!
• Take one/yr w/ IV, assoc w/ ostenecrosis of jaw
• USE: prevent/tx osteoporosis and corticosteroids induced osteoporosis and Pagets disease-disorder of bone remodeling (inc bone formation,large bones, but poor quality, inc fractures, abnormal structure results in deofrmity and pain)
• PHARM: Inhibits bone breakdown by SUPRESS OSTEOCLAST ACTIVITY/ INC bone mass by combining w/ bone and becming a permanent part of bone structure, which is resistant to enzymatic hydrolysis by pyrophosphatases (stays 7-10 yrs, reverses deterioration)
• DI: dont take w/ any other meds w/i 1/2-1hr; drug will bind to anything, so also need to take on an empty stomach and standing up

Risendronate-Actonel

Calcitonin-Miacalcin (nasal spray) or Calcimar (IV)

• USE: ppl who cant take orals/ Post menapausal tx of osteoporosis/ hypercalcemia
• Pharmacology: Synthesized and secreted by thyroid parafollicular cells/ Drug DEC calcium to inhibit osteoclast activity, DEC breakdown

Factors to consider when selecting Tx option for osteoporosis

Gonadal Hormone Axis

Progesterone: Stimulatory factors(visual,olfactory,stress)-Hypothal(GnRH)-pituit-LH/FSH-Theca cells-Produce PROGESTERONE

EGG: Stimulatory factors(visual,olfactory,stress)-Hypothal(GnRH)-pituit-LH/FSH-Ovaries-Produce Egg

Estradiol: Stimulatory factors(visual,olfactory,stress)-Hypothal(GnRH)-pituit-LH/FSH-Granulosa Cells-Produce estrogen/estradiol

Estrone: Stimulatory factors(visual,olfactory,stress)-Hypothal(GnRH)-pituit- ACTH at adrenal glands - Testosterone- Adipose cells - aromatase turns testosterone into Estrone

Estrogens

Physiologic Effect:

    Female maturation- growth female reproductive sexual development

    CV system - pre-menopausal benefit, improves lipid profile

    Bone - Blocks bone breakdown, inc calcium absorption from intestines

Menopause: ovaries shutting down (no more eggs)

    last episode of uterine bleeding, lack of cylcing, loss of physiological reproduction(can still do invitro to get prego)

    happens over period of years

    Decline in estrogen and progesterone secretion by ovary - slow/gradual

    typ early 50's(start at 45yo)

    Symptoms: irritable, hot, night sweats

Effects of Estrogen LOSS

• CV: inc heart disease
• Skeletal: bone loss
• Skin: dry, loss elasticity
• Genitourinary: vagina dry/atrophy, urinary incontinence, vaginal/urinary infections
• CNS: vasomotor symt, insomnia, emotional lability, change in cognitive function

17B Estradiol-Estrace, EsteraderM, vivelle, Climera, Estring, or Fempatch

• NATURAL estrogen replacement
• canbe oral, vaginal cream or transdermal
• Most physiological similar to real estrogen
• But body needs more than just estrogen

Phytoestrogens

• Natural estrogen supplements
• Soy, black cohosh, dates, mexican yams, red clover
• mimic estrogen activity
• some releive of symptoms but low efficacy

CEE-Premarin

• CEE=conjugated Equine Estrogen
• Conjugated estrogen replacement
• Primarily estrone, but it is a mixture of 10+ different estrogenic substances
• 1st to come out, they used to be thought of as good but noe realize not
• Oral, IM vaginal cream
• From Pregnant Mares urine

Ethinyl Estradiol-Estinyl, Feminone, Ortho, Novium

• Synthetic Estrogen replacement
• Modified estradiol, used usu for BC not PMW
• Oral
• BCPs

Raloxifene-Evista

• SERM=Selective Estrogen Receptor Modulators - posses tissue SELECTIVE estrogen agonist and antagonist effects
• SERMS bind with different affinity to different estrogen receoptors in different organs
• USE: osteoporosis; hormone replacement Therapy (HRT); breast cancer prevention

Tomoxifen-Nolvadex

compare Effects of Premarin/Estrogen, Tamoxifen, and Raloxifene

Progestins Physiological EFFECTS

Secreted by CORPUS LUTEUM during LUTEAL PHASE of Menstraul cycle

   Inhibits secretion of Pituitary gonadotropin (main LH) - this prevents FOLLICLE DEVELOPMENT in luteal phase

    Prepares ENDOMETRIUM for embryo implantation post ovulation and fertilization

    Makes endocervical secretions DEC in volume and viscous

PROGESTERONE blunts or opposes estrogen in many cells

    therefore DEC setrogen drinven endometrial proliferation

Maintains Pregnancy: DEC uterine contractability and INC proliferation of mammary glands

Medroxyprogesterone-Provera, Cycrin, Amen, Curretab

• 21 Carbon Skeleton Derivative - most similar to endogenous progesterone, highly selective for progesterone receptors
• Oral Hormone REplacement Therapy
• Progestin:

  Secreted by CORPUS LUTEUM during LUTEAL PHASE of Menstraul cycle

     Inhibits secretion of Pituitary gonadotropin (main LH) - this prevents FOLLICLE DEVELOPMENT in luteal phase

      Prepares ENDOMETRIUM for embryo implantation post ovulation and fertilization

      Makes endocervical secretions DEC in volume and viscous

  PROGESTERONE blunts or opposes estrogen in many cells

      therefore DEC setrogen drinven endometrial proliferation

  Maintains Pregnancy: DEC uterine contractability and INC proliferation of mammary glands

Norethindrone-Micronor, NorQD, Aygestin,Ortho-Novum

• 19-Nor Derivatives - resemble testoserone; MORE androgenic effect
• Progestin used more commonly for BCP

• Secreted by CORPUS LUTEUM during LUTEAL PHASE of Menstraul cycle

     Inhibits secretion of Pituitary gonadotropin (main LH) - this prevents FOLLICLE DEVELOPMENT in luteal phase

      Prepares ENDOMETRIUM for embryo implantation post ovulation and fertilization

      Makes endocervical secretions DEC in volume and viscous

  PROGESTERONE blunts or opposes estrogen in many cells

      therefore DEC setrogen drinven endometrial proliferation

  Maintains Pregnancy: DEC uterine contractability and INC proliferation of mammary glands

Progestins Pharmacology and USES

PHARMACOLOGY: Progestins bind to progesterone receptors in many different cells, this antagonizes estrogen induced endometrial hypertrophy in uterus

Ovarian suppression used for endometriosis: suppress pituitary output of FSH and LH causing DEC endogenous stimulation of endometrial cells

USES:

Pose menapausal replacement therapy: if woman has uterus use estrogen and progestins

Contraceptive w or w/o estrogen

Endometriosis - Progesterone therapy

Estrogen can cause endometrial cancer, progesterone keeps this in check

Hormonal therapy in Women

• W/O uterus- Estrogen Alone, raloxifene
• W/ uterus-Estrogen +progestin, prempro
• Pre-menopausal estrogen seen to prevent major disease states while post menapausal estrogen replacement sig DEC menapausal symptoms but INC many disease states!!
• Conjucated estrogens: INC abs risk at 5yrs:CHD. Pulmonary embolism, Stroke, Breast cancer
• Conjugates estrogens: DEC abs risk at 5 yrs: endometrial caner, colorectal cancer, hip fractures!

Prempro-Conj estrogen and Medroxyprogesterone

• Hormonal therapy combo product
• Oral
• Inc risk of breast cancer and CVD btu not as muchinc risk as estrogen alone!
• DEC risk of endometrial cancer which is much better than the inc with estrogen
• DEC osteoporosis/fractures about the same as estrogen

Physiology of Androgens

• Androgen Production: Testosterone by 5alpha reductase turns into DHT in prostate gland, seminal vesicles
• Testosterone and DHT ANDROGENIC effects: male maturation, virilization, sex drive, inc aggression
• T and DHT ANABOLIC actions: INC protein synthesis, muscle and bone growth; stimulates erythropoeisis, NEG effect on lipid profile

Testosterone-Depo-Testosterone, Testoderm TTS

• androgenic:anabolic= 1:1
• abuse potential
• Pharacology: T and DHT bind to intracellular androgen receptors in target cells all over body
• T dec in men w age but DONT supplement
• USES: androgen replacement for growth and development in boys, male hypogonadism/ Protein anabolic effect (if need to inc muscle mass after trauma)
• ADR: masculinization (edema, Na+retention, neg lipid profile), hepatic dysfunction, CNS (paranoia, mania, Roid Rage), Sterility (if chronic use dec T produced, causes infertility)

Finasteride-Proscar

• Antiandrogens - takes months to take effect
• PHARM: synthetics analog of testosterone, acts as competitive inhib of 5alpha reductase - LESS DHT produced-reduce prostate hyperplasia(growth)
• USES: BPH (benign prostate hyperplasia) when used in combo w, flomax(alpha 1 antag), Alopecia (propecia)
• BPH is not prostate cancer, recently proscar shown to dec Prostate cancer!!