What effect do glucocorticoids have on cabohydrate metabolism?

a) increase gluconeogenesis 

b) increase glycogenolysis 

c) Both A and B 

Answer: A) increases gluconeogenesis 

It have NO EFFECT on glycogenolysis!

It does increase the synthesis of glucose in the liver, thus raising serum glucose.  

- facilitate action of lipolytic hormones 

- these hormones increase fat redistribution

(POT BELLY, buffalo hump and moon face in humans) 

Has anti-obesity applications via "anti-cortisol" actions, by decreasing the release of cortisol and following effects.

The principle cells of the distal tubule and collecting duct are effected by ALDOSTERONE which causes an increase in the translation of AIPs (aldosterone induced proteins).

This makes more sodium channels, proton pumps, and Na-K pumps.

NET EFFECT: Increased retention of Na+ at the expense of K+

Intercalated cells of the distal tubule and collect ducts will respond to ALDOSTERONE, and increase Aldosterone Induced Proteins (NA-K ATPase, Proton pump, sodium channels) 

NET EFFECT: Increased retention of Bicarb (HCO3) at the expense of H+ and Cl-

Decreased ADH causes PU/PD 

Decreased reabsorption of Ca2+ (gut and renal) = Hypocalcemia

Increased effects on cardiovascular system, which causes increased GFR, which increases excretion of Na and H20

What effect does glucocorticoid have on calcium?

What is the mechanism of action?

Causes HYPOCALCEMIA

Decreased Renal and Gut reabsorption of Ca2+ 

causes decreased plasma Ca2+, which increases PTH secretion.  This results in bone resorption and Osteoporosis. 

Osteobalsts also undergo apoptosis, decreasing bone formation = more OSTEOPOROSIS. 

Increase in Glucocorticoids leads to excitation and euphoria

Decrease = depression = Addison's disease where nerves have decreased excitability. 

Low levels of Glucocorticoids also increase memory, where high levels harm this!

Increased Mineralocorticoids will decrease excitability.

This occurs because it causes a decrease in K+ in ECF, causing a hyperpolarization, thus reduced excitibility of nerves. 

Increases vasomotor responces and mycardial contractions: 

- Increased expression of alpha receptors of the vasculature, and beta receptors of the heart.

- Conversion of NE to EPI 

- increased angiotensin

- increase ACE, which decreases bradykinin from increased breakdown

Increases vasomotor reponses and myocardial contractions.

This is done by increasing Na+ in ECF, which increases blood pressure. Also mineralocorticoids decrease K+ in ECF which increases myocardial Ca2+ needed for contractions.

Works similar to digitalis

Decreased K+ causes the blocked Na+/K+ pumps, causing an increase in Na+.  This allows for more Na/Ca exchange, resulting in an increased Ca2+ concentration in myocardium. 

Mineralocorticoids cause hyperkalemia, which will block Na/K pumps causing increased Ca2+

When digitalis is added, it further blocks the Na/K pumps and can cause cardiac arrhythmia

Bronchodilation - from increased Beta2 receptors

Anti-inflammatory - from decreased autocoids (Histamine and bradykinin) 

Decongestion - from decreased vascular permeability from vasoconstriction (alpha 1 receptors)

** do not work right away (need time for protein production)** 

Glucocorticoids work on nuclear receptors which increases the expression of proteins that will have therapeutic effects. So it will take a while for the effects to be seen clinically, and wouldnt be effective in emergency cases.

Use EPI instead.

* Need small concentrations for proper function *

Excessive glucocorticoids cause weakness from wasting of muscle mass. But weakness will also be seen if there is a deficiency of glucocortcoids because of the hypoglycemia and poor circulation.

* Small concentrations are needed for proper function * 

Excessive mineralocorticoids cause weakness from hypokalemia, but deficiency also causes weakness from hypoglycemia and poor circulation.

Increased RBCs = polycythemia, from decreased phagocytosis - tx of hemolytic anemia

Increased Neutrophils (Neutrophilia), monocytes = increased bone marrow release 

Increased PLATELETS

Decreased function of WBCs

Decreased circulating lymphocytes - from apoptosis

Decreased eosinophils, basophils - sequestered in marrow

Decreased size of lymph nodes and thymus

can be used in chemotherapy for LYMPHOMAS, 

will increase the appetite of the patient for generally improved well being. BUT it causes IMMUNE SUPPRESSION. 

It decreases the IL1 & IL2 production from macrophages 

= decreased B cells prolliferation, IgG, T cell activation, & phagocytosis

Humoral - urticaria (hives) 

Cellular - transplant rejection

Decreases the amount of collagen fibers and fibroblasts 

Causes decreased Hair and Skin Growth!

Large crystals slow down absorption, 

thus increasing the duration of action 

What type of insulin is Humulin R ?

When is it used?

Used in cases of extreme hyperglycemia 

it is a fast acting insulin - onset of less than an hour, and lasts for 5-8 hours 

It is also a human product 

Bovine - 

but it not available to sell 

Vetsulin

Onset of 2 hours and has a duration of 18-24 hours.

FDA pulled this off the market 

Insulin Zinc suspension 

Humulin 70/30 *cheaper

ONset of about 7 hours, can last up to 36 (rec for 24 hours) 

PZI - 90% bovine, 10% P (Protamine Zinc Insulin)

NOW - Prozinc which is human insulin for cats, less concentrated but expensive 

Extended zinc suspension (Humulin U) more concentrated 

(dilute with phosphate buffer) 

Insulin glargine 

What happens to Insulin glargine at a pH of 4?

pH of 7.4?

pH = 4: soluble 

pH = 7.4: no longer soluble and forms micropercipitates that cause extended slow release of insulin.

It is due to stress, or an infection which is stress.  

The insulin is no longer able to preform its job and more needs to be given. 

Stress hormones cause it.

It is a rare condition that is due to Antibody induction.

it can cause degradtion of insuli, insulin receptors or post receptor defects 

- relief of immunosuppression 

- no Na+ rentention or other electrolyte effects 

- No carbohydrate or protein effects 

What is the half-life of short-acting corticosteroids?

intermediate acting corticosteroids?

long acting corticosteroids?

Short- acting: less than 12 hours 

Intermediate- acting: 12 -36 hours 

Long- acting: 36 - 72 hours 

Administer at an alternate-day therapy.

The best to use for this would be Intermediate acting corticosteroids, that have a half-life of 12-36 hours. 

The alternate day approach allows the pituitary to have a break!

When should alternate-day corticosteroid therapy be applied?

What type of corticosteroids should be used?

CHRONIC - long term therapies: Allergies and cancer

Use intermediate-acting drugs like prednisone, methylpredisolone, etc.

(T1/2 of 12-36 hours)

immediate relief of hypersensitivity 

Topical treatments 

DO NOT use for long term control of allergies 

Cat and Horse - of course

Prednisone is is poorly absorbed when given orally to horses.

Prednisolone

prednisone needs to be converted to prednisolone to work

Rank these in order of highest mineralocorticoid potency to lowest?

a) desoxycorticosterone 

b) cortisol

c) corticosterone 

d) aldosterone

Highest mineralocorticoid potency 

Aldosterone

desoxycorticosterone

corticosterone

cortisol

Lowest mineralocorticoid potency

Rank these in order of highest glucocorticoid potency to lowest?

a) Cortisol 

b) prednisone

c) fluoroprednisolone

d) methylprednisolone

Highest glucocorticoid potency 

Fluoroprednisolone

methylprednisolone

prednisolone

Cortisol 

lowest glucocorticoid potency

Prednisone - has a Keto group

Prednisolone - has a OH group 

Cortisone = keto group 

cortisol = OH group 

Rank these in order of highest glucocorticoid potency to lowest?

a) triamcinolone

b) dexamthasone

c) cortisol

Highest glucocorticoid potency 

Dexamethasone 

trimcinolone

Cortisol

Lowest glucocorticoid potency 

3-Keto

4,5-Delta

11Beta - OH

17 alpha - OH

Naturally occurring compounds 

(Cortisol, corticosterone, aldosterone, fluoroprednisolone) 

this is because they are subject to the first pass effect!!

Succinate & phosphate forms, or if in polyethylene glycol

because this makes them WATER SOLUBLE!

Water insoluble drugs like acetate and pivalate

depo-medrol 

CBG (Cortisol Binding Globulin): High affinity, low capacity - also binds to other corticosteroids and progesterones (not specific)

Albumin: low affinity, high capacity 

1) Delta groups reduced to inactivate them (1st phase)

2) =O reduction (to -OH) 

3) OH group conjugation (2nd phase)

4) Excretion of conjugates (in urine and feces) 

Steroid conjugates (after 2nd phase metabolism) 

are excreted into urine and feces 

What are the two KINDS of side effects of corticosteroids?

ie. why they cause side effects 

1) withdrawl after continued use

2) extension of pharmacological effects 

Decreased wound healing

increased susceptibility to infection

fluid and electrolyte imbalance -> edema

thrombosis (from increased platelets) 

Myopathy 

osteoporosis 

GI ulcers 

Hepatotoxicity (micronodular cirrhosis & hepatomegaly)

Glaucoma 

Diabetes Mellitus 

Abortion

CHF in cats 

laminitis in horses

Birds can be easily overdosed.

Birds have endogenous Corticosterone that has 1/3 the activity of cortisol! This means they will be easily overdosed.

By giving them a mammalian dosage, side effects would be amplified, and their immunity would be severely inhibited.

Uncontrolled infections 

diabetes mellitus 

corneal ulcers 

cardiac disorders 

burns

late pregnancy 

Glucocorticoids cause decreased GI & Renal reabsorption of Ca causing hypocalcemia. 

The low plasma calcium causes the secretion of PTH, 

which causes the reabsorption of bone.

ALSO glucocorticoids cause increased apoptosis of osteoblasts  thus resulting in decreased bone formation 

= lower bone density = OSTEOPOROSIS 

making the bones more susceptible to fracture!

There may be decreased ACTH production.

= hypoadrenocorticism.

(Iatrogenic addisons disease)

CRH (Corticotropin releasing hormone) will cause ACTH to:

Increase or Decrease?

Glucocorticoids (cortisol and corticosterone)

What effect does ACTH have on the adrenal cortex?

It increases the growth! 

So it can produce more hormones - like cortisol and aldosterone

O,P-DDD 

(Mitotane, Lysodren) 

Destroys the zona fasciculata and reticularis 

What is the function of O,P'-DDD ?

(trade names: Mitotane, Lysodren) 

Irreversible inhibitor of corticosteroid secretion - 

DDT analog (pesticides eww) that destroys the zona fasciculata and zona reticularis 

*may need to have replacement for glucocorticoids 

SIDE EFFECTS: hypoadrenocorticism, hepatotoxicity

LONG HALF LIFE 

What is the function of ketoconazole?

How about relating to corticosteroid secretion?

It is an antifungal drug!

Reversible inhibitor of corticosteroid secretion, 

works by inactivating cytochrome P450 thus inactivating steroidgenesis 

SIDE EFFECTS: GI & Repro disturbances, hepatotoxicity

**many drug interactions**

What is 3Beta- hydroxysteroid dehydrogenase?

It is an enzyme - the only one of corticosteroid production that is not a member of the cytochrome P450 family.

Converts:

pregnenolone to progesterone

DHEA to androstenedione

androstenediol to testosterone

**INhibited by Trilostane (reversibly)

It is a reversible inhibitor of corticosteroid secretion.

Inhibits 3Beta-hydroxysteroid dehydrogenase - which inhibits the synthesis of sex steroids.  

**safer than mitotane and ketoconazole**

Reversible corticosteroid secretion inhibitor.

Used to treat hyperadrenocorticism.

Inhibits ACTH secretion by decreasing MAOB (enzyme that breaks down DA) thus increasing DA and NE accumulation

ALSO decreases DA reuptake (from the synapse)

D2 receptor agonist 

EMETIC - activates chemoreceptor-trigger zone 

Used to treat impotence

The"No-sun tanning drug"

Used for treatment of impotence 

What is the mode of action of VIAGRA (sidenafil)?

It is a phosphodieastease type 5 inhibitor

This causes an increase in cGMP resulting in vasodilation.

This is short acting treatment of pulmonary hypertension, and getting grandpa ready....

PU/PD, polyphagia, potbelly, muscle weakness, recurrent urinary tract infections.

This is often accompanied by truncal alopecia, thin skin, bruising, pyoderma, dermal atrophy and hyperpigmentation.

GnRH is a secretagogue of what hormones?

(ie. it will cause the release of what hormones?)

GnRH products:

Gonadorelin (GnRH, Ovacyst, cystorelin) 

Desorelin (sucromate)

It is a secapeptide, released from the brain and hypothalamus.  It is secreted in a pulsatile manner. 

It's release can be stimulated by Estrogen - but the ultimate goal in females is to induce ovulation, and in males it increases libido.

Females: To increase conception rates - by stimulating the secretion of FSH and LH, which induces ovulation

Also used to treat follicular cysts.

Males: increase libido

= stimulates development of follicules 

(lol, it IS follicular stimulating hormone...)

increases estrogen production in granulosa

the estrogens then increase FSH receptors in follicle = increased follicular development! 

Estrogen has a mechanism of negative feedback on FSH.

True or False

FALSE 

The estrogens will increase the number of FSH receptors in the follicle - thus it is a POSTIVE feedback for FSH

The net result of this is follicular development.

Put the following hormones in order from longer plasma halflife to shortest:

HCG

LH

FSH

ECG

Longest plasma halflife

ECG (24 hours)

HCG (8 hours)

FSH (1 hour)

LH (30 minutes)

It will increase diameter of seminiferous tubules, 

increase speratozoa development 

increased androgen-binding protein and TGFb from sertoli cells cause spermatids to develop to spermatozoa

it causes ovulation and luteinization

increased progesterone and estrogens 

increase testosterone synthesis in thecal cells 

LH > follicle > thecal cells > cholesterol conversion > progesterone > testosterone > granulosa cell 

= these actions result in the production of what hormone?

Estradiol 

The major sex steroid

It stimulates the proliferation of Leydig cells which will increase testosterone! 

LH secretion can be stimulated by females (in estrus) releasing pheromones. 

(this is the mechanism for ALL glycoprotein hormones)

they activate Gs-adenylyl cyclase system

increases cAMP

PKA (protein kinase A) activated

CREB (cAMP response element binding protein) activated 

= MORE mRNA 

= more protein 

= "trophy" (hypertrophy of trophic hormones)

Where is HCG produced? How is it excreted?

What does it do?

Produced in the placenta (hence it is human chorionic gonadotropin)

Excreted in urine 

FUNCTION: LH -like activity (increase progesterone and estrogen)

Yes... in humans.

It can be used immunoassay in weeks 1-10 after conception

Ovulation control 

treatment of follicular cysts 

treatment of cryptorchidism 

treatment of persistant infertility in females 

HCG: Human placenta, LH like activity, highest in first 1-12 weeks of of pregnancy

ECG: Equine placenta, FSH-like activity, highest in 40th - 140th day of pregnancy

Equine Chorionic Gonadotropin 

secreted from placenta (highest in plasma in 40-140th day of pregnancy) 

HAS FSH-LIKE activity 

Control breeding - can stimulate follicular development = estrus 

Superovulation

Treatment of male infertility by increasing libido and sperm counts

Which hormone could be used to treat infertility in females:

LH or FSH?

LH 

"ladies hormone"

Which hormone could be used to treat infertility in males:

LH or FSH?

The presence of carbohydrates increase the resistance hormone breakdown.

True or False?

TRUE

the more carbohydrates, the longer the plasma half-life because it will take longer to break down

Which hormone has the most amount of carbohydrate composition?

HCG

FSH

ECG

LH

ECG has the highest - 47% 

this will make it more resistant to breakdown, so it will have the longest half-life in plasma

Adding a sialic acid to a glycoprotein hormones will decrease the plasma half-life of the hormone.

True or False?

FALSE 

Removing sialic acid from glycoprotein hormones will decrease the plasma half-life 

Sialic acid 

and carbohydrates

Could be caused by early neutering of ferrets (1-3 months) 

this causes the overproduction of sex hormones by the adrenal gland > overstimulation by FSH and LH!

Another idea is a prolonged photoperiod which causes an increase in GnRH.

What is Leuprolide acetate (Lupron Depot)?

When is it used clinically?

It is a partial GnRH receptor agonist.

Downregulates GnRH receptors 

It is used for the treatment of ACD in ferrets where there is an overproduction of sex steroids by the adrenal. 

Most circulating estrogens are bound to plasma proteins.

True or False?

TRUE 

About 90% of circulating estrogens are found bound to plasma proteins.

Half life of estradiol in plasma = 30 minutes

What plasma proteins can estrogens be found bound to?

What are the differences between them?

SSBG (sex steroid binding globulin) -

high affinity, low capacity 

Albumin low affinity, high capacity

What is the metabolism of estradiol?

(ie. Half-life and excretion)

Estradiol has a plasma half-life of 30 minutes 

Conjugates are then excreted in urine

Found in pregnant mare urine 

Estrone SO4 + Equilin SO4 

Used in humans to eliviate symptoms associated with menopause.

Increased growth - hyperemia and hypertrophy 

Primes the myometrium to oxytocin

Dilates the cervix

increases sexual receptivity

(Estrus induced in spayed cows and mares)

in Ruminants: luteoLYTIC

In swine: luteoTROPIC

Luteolytic 

increase of PGF2alpha released from endometrium 

Luteotropic

CL is retained 

(this causes an increase in mammary tissue growth)

Increased bone mass - from decreased IL6 and IL11 (which decreases osteoclasts)

Decreased bone growth - epiphyseal plate ossification most significant in human women

It has anabolic effects on protein.

this causes 10% faster growth & 10% better feed conversion

Estradiol and non steroidal

brands liek SYNOVEX can be used as ear implants

What is the major difference between:

Synovex-H

Synovex-S

Synovex-C?

Synovex-H = heifer (estradiol + testosterone)

Synovex-S = steer (estradiol + progesterone)

Synovex-C = calf (estradiol + progesterone)

the one for calves is a half concentration and shouldnt be used in bulls for breeding, veal, or under 45 days 

What are the treatment methods for a ferret with ACD?

What are the differences?

Leuprolide acetate - down regulate GnRH receptors 

Left ADX - remove adrenal thats making sex hormones

mitotane - destroys adrenal cortex, can be over aggressive and destroy entire cortex

ZERANOL (Ralgro) 

Cattle: 0 Days 

Sheep: 40 days 

Increased mRNA for muscle protein

increased GH secretion 

Increased GH receptors 

increased IGF-1 secretion

increased IGF-1 receptors 

increased IGF-1 binding proteins

What are some clinical uses for estrogens?

Anabolic

estrus induction in bitches (DES) - not recommended, can you imagine a bitch in heat...

Estrus induction in mares (E2 + P4)

mismating therapy (abortion) in bitches - also not recommended 

Spay induced incontinence, vaginitis, dermatitis in dogs

Prostatic hyperplasia - not recommended

Finasteride - 5a inhibitor (enzyme for dihydrotestosterone formation) 

CASTRATION (dur..)

Vaginal/rectal prolapse

abortion (oh no add it to the list)

Follicular cysts 

Bone fractures (from increased density)

APLASTIC ANEMIA- dogs, cats, ferrets

pyometritis

No

for serious? 

If its topical then its topical to anything with skin and can be absorbed into their bloodstream and hormonal effects will occur.

Tamoxifen is used in humans -

what does it do, how does it work?

It is an estrogen receptor antagonist 

Used to treat early breast cancer in humans 

(controversial use in dogs - seriously just have them spayed)

Tamoxifen is an estrogen receptor antagonist, can cause:

PYOMETRA in dogs 

GI disturbances

menstrual disorders in humans 

increased risk of endometrial cancer in women, since receptors are still activated (although not by estrogen)

Progesterone

Megesterol acetate (Ovaban)

Altonerogest (Regu-mate, Matrix)

Melengestrol acetate (MGA)

medroxyprogesterone acetate (MPA)

CL (ovaries), Placenta (of mare, ewe, human), 

adrenal cortex 

What is progestin bound to in plasma?

What is its half-life in plasma?

CBG (like corticosteroids)

and albumin

T1/2 = 30 mins

Increased glandular growth 

densensitization to Oxytocin

Progesterone with estrogen will cause sexual receptivity to:

increase or decrease?

What are some clinical uses for progestins?

Estrus synchronization 

tx of habitual abortion and implantation failure

contraception in bitches - no one wants a pregnant bitch

Contraceptive in women and men

last attempt for aggressiveness and inappropriate urination 

Progestins can be used to treat aggressiveness and inappropriate elimination, but only as a last resort. 

What drugs should be tried first?

ANTIDEPRESSANTS

like clomipromine

Endometrial hyperplasia

endometritis

glucocorticoid activity effects:

diabetes decreased ACTH

MIFEPRISTONE

very effective abortifacient 

effective partutition inducing agent 

has antiglucocorticoid activity

testosterone

methyltestosterone 

stanozolol

boldenone

trenbolone

All androgens are Schedule IV controlled substances.

True or False?

FALSE - in two ways 

First: they are Schedule III drugs, but are still controlled.

Second: Implants are not considered controlled substances

How much of testosterone is bound in plasma?

Bound by what?

How long does it last in plasma?

How is it excreted?

90% bound by plasma proteins

SSBG (sex steroid binding globulin) high affinity, low capacity 

Albumin - low affinity, high capacity 

Plasma T1/2 = 20 mins

Excreted in urine

Masculinizing - sex hormone growth, increased gonadotropins (increased spermatogenesis)

Anabolic - increased growth of bone, cartilage, muscle

Increased retention of Na+, K+, P, N

Increased erythropoietin synthesis

THERIO: tx of impotence, infertility, induction of teaser cows, tx of chryptorchidism, tx of mammary gland tumors

Growth promotion: Muscle build up (anabolic)

reversal of tissue depletion (arthritis, CRF, degenerative myelopathy)

Anemia: decreased RBC apoptosis, increased RBC precursors

EPO

Increased Erythropoietin production:

Causes decrease in RBC apoptosis 

Increase in RBC precursors

DHEA

Dehydroepiandrosterone

converted to andreostenedione to testosterone

When given orally, it doesnt cause an increase in plasma testosterone, instead causes increased estradiol levels and decreased HDL.  

(this is because testosterone can be converted to estradiol)

Infertility 

liver disorders

masculinization of females 

mineralocorticoid activity (water retention)

What is Finesteride,

 how does it work, and

what is it used for?

It is an anti-androgen that blocks the formation of 5a-dihydrotestosterone (the more potent one)

Used to treat prostatic hyperplasia, human baldness, female hirsutism, and acne

Which anti-androgen has been recommended for Joel?

Why?

Finasteride 

Because it has been used to treat human baldness 

(trade name = propecia)

Finasteride

Cimetidine

Ketoconazole 

Trilostane

What is Cimetidine, 

How does it work

What is it used for?

An anti-androgen that blocks androgen receptors.

AS well as being an H2 receptor antagonist.

Used clinically for its anti-histamine properties such as reducing gastric secretions for peptic ulcer formation, and skin disorders.

Inducing labor at term 

tx of uterine inertia

control post partum hemorrhage and atony

induce abortion (after 1st trimester)

expel uterine contents (blech...)

Muscle stimulants (autocoids, cholinergics, Ca2+)

Poisons (like lead)

Volatile oils (oil of turpentine)

Hormones, oxytocin and vasopressin

PGE2, PGF 2a

glucocorticoids (because they increase PGF2a)

Ergot alkaloids (ergonovine)

Use substances that inhibit progesterone production or progesterone receptors:

- antiprogesterones (Mifepristone)

- Dopamine agonists (bromocriptine, cabergoline)

A delicious champagne, celebrations like valentines day and New years eve.

Ok - really its a D2 receptor antagonist that increases the secretion of prolactin.  This will increase milk production. 

Used to treat fescue toxicosis in prepartum mares, induces foaling. 

Does not cross the blood-brain barrier.

SEX HORMONES

Autonomic nervous system (Alpha AR= contraction, Beta AR = relaxation, M3 - ARs)

FETAL ACTH, cortisol

CRH increases which causes an increase in fetal ACTH > increased pregnenolone > increased E2, fetal cortisol.

the fetal cortisol increases the synthesis of PG causing luteolysis!

It causes uterine contractions, it is a galactagogue, and helps with sperm transport. 

It is released in accordance with reflexes from the genital tract and mammary glands. 

The effect of Oxytocin is enhanced by estrogens, but decreased by progesterone.

induction of labor (mares and women - because they have no CL)

Can be used to treat dystocia (cervix must be open)

Milk induction

tx of placental infections, placental retention

Alpha-Adrenergic receptor agonist

Used to control postpartum hemorrhage and uterine involution.

Excitation 

hypernea

colic 

GI disturbances

Which is more resistant to break down:

dinoprost or cloprostenol?

Cloprostenol

(PGF2a analog)

(IN ALL SPECIES BUT SWINE!)

causes VASOCONSTRICTION > blood supply to CL cut off > apoptosis of CL (Luteolysis) > decreased plasma P4 > increase in GnRH, FSH = estrus

Which species does PGF2a take longer to induce labor:

Sows or Horses? Why?

SOWS 

this is because horses have no CL so the effects take less time. 

Abortion

Luteolysis

Estrus synchronization (not swine)

labor induction 

tx of pyometra 

expulsion of mummified fetuses, retained placenta

tx of high incidence of uterine infections

tx of postpartum infections in bitches. Bitches be infected!

tx of ovarian cysts

tx of pseudopregnancy, gactational anestrus in bitches (bitches got milk!)

Retention of placenta (?? used to treat it too??)

Dystocia in mares (because they hate their lives)

ACute systemic effects: colic, tachycardia, tachypnea, resp distress, sweating, hypersalivation, itching, vomiting

Dexamethasone injection = will increase PGF2a synthesis in the endometrium 

labor will be induced within 48 hours of injection. 

Regimen = dex, then PGF2a in 40 hours = calving will occur within 2-5 hours

Cause endometrial hyperplasia and endometritis, which increases the chance for bacteria to move it 

= thus pyometra

Why can progestins cause Diabetes Mellitus?

In humans tamoxifen is a FULL estrogen receptor agonist.

In dogs it is only a partial agonist, and could cause an increase instead - so it is contraindicated.

Oxytocin is a:

Galactogague or Galactopoietic?

Galactogogue

It increases the RELEASE of milk 

Milk let down effect

Prolactin is a:

Galactogogue or Galactopoietin?

GALACTOPOIETIN

it increased the PRODUCTION of milk 

Galactogogue: increases milk let down 

Galactopoietin: increases milk production

What are bromocriptine and cabergoline?

What is their function in theriogeniology?

They are both D2 receptor agonists

Can be used in small animals to terminate pregnancy

(inhibits prolactin production causing luteolysis)

Can hydrocortisone be used to induce parturition?

Why or why not?

NO it cannot 

because it is NOT a long-acting glucocorticoid, so it is not potent enough to penetrate the placenta where it needs to cross to be effective. 

HORSES 

because they dont have a CL.

The CL in other species will inhibit the action of oxytocin.

1) Direct uterine contraction effect 

2) Luteolytic effect 

NO 

PGF2a cannot be used to synchronize estrus cycle in swine because the pig CL will not respond to PGF2a until day 14 or 15 which is too late. Other species will respond by day 5.

Not really a question - 

but know it...

Just...know it...

Hashimoto's (Lymphocutic thyroiditis) 

It is an autoimmune process where antibody is formed against thyroglobulin - this antibody is also used to diagnose it in dogs

True like 99% 

Plasma protein binding is higher in which:

Dogs or Humans?

Humans

TBG is 4X higher in humans than dogs

Thyroxine-binding globulin - high affinity, low capacity

transthyretin - an albumin precursor

T4 in humans: T1/2 = 7 days

T4 in dogs: T1/2 = 8-16 hours

MIT + DIT = ??? 

What is produced?

T3 and RT3

DIT + DIT = ???

What is produced?

Uptake of iodide 

Iodination and coupling to TG

Endocytosis and secretion

Because dogs require 1/4 of what humans do!

Humans: 50-150 micrograms/day

Dogs less than 20 micrograms a day

Estrogens: increase TBG synthesis 

Liver disease: decreased production of plasma proteins

Kidney disease: plasma proteins lost in urine

Albumin binding site competitors: NSAIDS, CNS drugs

Type 1 (5'DI) - increases T3, liver and kidney

Type 2 (5'DII) - increases T3, brain, pituitary, brown fat 

Type 3 (5DI) - increases RT3, placenta and brain

What is the effect of Type 1 deiodinase (5'DI)?

Where is it made?

Increases conversion of T4 to T3 

Found liver and kidney

It increases the conversion of T4 to T3 

It is found in Brown fat, brain, pituitary

Increase in T4 conversion to RT3 

Found in the placenta and brain

The rate of conversion of T4 to T3 in HYPOthyroidism is:

Increased or Decreased?

DECREASED

this is a compensatory action of the body, because of the excess of T3

What are the results of T4 metabolism?

How is it excreted?

30-40% is made into T3

50% is made into RT3 

15-20% is made into conjugates 

Excretion: conjugates enter bile (from liver) and into gut then excreted in feces. The conjugates are hydrolyzed in the gut  So T3 and T4 are absorbed into the ECF

They have T3 receptors, which become activated (by NE/EPI release from "stress" of cold), increasing the expression of uncoupling protein (Type II deiodinase). This uses oxidative phophorylation to uncouple and requires energy (they have lotsof mitochondria - lots of ATP). The energy loss is released as heat!

ALSO - cold works on the hypothalamus to increase TRH secretion causing more TSH = more T4.

Increased T3 and T4 allow more uncoupling to occur = more heat generated!!!

T3 is 3 -5 times more active than T4 

(T4 is also the "prohormone" for T3)

Thyroid hormones increase the secretion and action of GH

Critical for development and maintenance of neural tissues - we need to eat salt to pass vet school :P

Deficiency in young can cause cretinism, mental retardation

TSH (Thyroid stimulating hormone) - stimulates synthesis pathway

cAMP is formed - because TSH receptors are coupled to Gs

Iodide is needed for synthesis 

Because the salt is iodinized, and chips have TONS of salt.  The Iodide is needed to synthesize thyroid hormones, which increase GH needed to maintain neural tissue - and keep you smart 

HA! You though this was a pointless question :P

Increased heat generation

increased O2 consumption

(Increased Basal Metabolic Rate)

= from increased cellular work (Na+/K+ ATPase activity)

Where is the calorigenic action of thyroid hormones seen?

Where are they not seen (what cells are NOT effected)?

Effected: heart, skeletal muscle, liver, kidney

NOT IN: Adult brain, lymph nodes, spleen, gonads

INCREASED!!!!

increased Cardiac Output (to keep up with increase O2 consumption)

Increased expression of Beta and alpha1 receptors 

increased expression of a-myosin HEAVY chain

Increased expression of myocardial Ca2+ channels

= will clinically present with tachycardia in hyperthyroidism

INCREASED conversion of cholestrol into bile acids - because effect of liplytic hormones are increased

(hypothyroid will have increased cholesterol)

Needed for the TURNOVER of hair & skin

Hyperthyroidism = alopecia

Hypothyroidism = thickened skin, hair coat dryness, bilateral alopecia

Increased synthesis of proteins for nuromuscular activity

= more Na+/K+ ATPase, Ca2+ channels, A-myosin Heavy chains!

Hypothyroid patient will have CNS depression, muscle paralysis 

Need them for normal GI motility and Repro function 

In hypothyroidism: Infertility, constipation, galactorrhea, testicular atrophy, decreased libido

BECAUSE TRH increases the secretion of prolactin, which can cause luteolysis - thus anestrus and infertility

the increase in prolactin can also cause galactorrhea

2 reasons:

1) T3 has a shorter half-life 

2) T4 will still increase the amount of T3, because it is a "prohormone", but this also allows to regulate how much is being converted - especially important with brain concentrations.

Agents blocking iodide transport: ClO4, SCN-, NO3- (but need toxic doses and can cause aplastic anemia)

Thioureyelenes (methamizole)

Iodide in HIGH doses 

NaI 131 (SC)

Beta blockers (like propanolol, atenolol)

Blocks the Iodination and coupling of TG ! 

Prevents synthesis of thyroid hormones

What drug is more potent: Methamizole or Propylithiouracil? 

Which is overall a better drug, and why?

METHAMIZOLE

Methamizole is 10 times more potent than PTU

Has less side effects (PTU can cause HEMOLYTIC ANEMIA - who wants that?!?!)

Anorexia, vomiting, lethargy, hepatopathy

Possible Type 2 hypersensitivity reaction:

eosinopenia, lymphocytosis, severe SCRATCHING, Thrombocytopenia, granulocytopenia

(Ab-Ag complexes damage blood cells)

How does ¹³¹ I work as an anti-thyroid agent?

Why is it particularly effective?

This radioactive isotype emits radiation that destroys follicular cells that are secreting the excessive thyroid hormones. 

SINCE only follicular cells have mechanisms that actively transport iodide ion, the radioisotope is concentrated and specific for follicular cells, and not effecting other parts of the body.

Well, excessive thyroid hormones can cause the OVEREXPRESSION of Beta 1 receptors on the heart - catecholamines can active these recetors causing increased heart rate (even arrhythmia).

This can be prevented with BETA BLOCKERS (like propanolol) that can stabilize cardiac activity. 

Thyroid hormones cause an increase in expression of cardiac beta2 receptors, which can be activated by catecholamines, causing INCREASED HEART RATE. 

This can progess to arrhythmia = tyroid toxicosis 

What are the 2 types of diabetes mellitus?

Which one is more common?

Type 1 (Insulin-dep, IDDM, Juvenile onset)

Type 2 (Non-insulin-dependent, NIDDM, Adult onset)

Type 2 is 90% of Diabetes Mellitus cases 

Patients do not secrete insulin

Juvenile onset (because they can only go so long without insulin) - VERY SEVERE - autoimmune disease (where ab is made against Beta cells) - typically triggered by a virus

It is an autoimmune disease where ab is made against beta cells that normally secrete insulin 

(so insulin is not secreted)

this is often triggered by a viral infection (Coxsackie)

Although it is called NON-insulin dependent - there is still functioning Beta cells, they have just been desensitized to glucose.

Beta cell can also be destroyed by high plasma levels of glucose. 

Basically if you eat like a fat ass and there is too much SUGAR intake - your beta cells give up, like you should

...diabetes

vascular damages: kidney, limbs, etc

Increased LDL

Glycosylation of proteins - increased matrix of endothelial cells = vascular damage

Eye and brain damage - from sorbitol accumulation (cataracts)

Sulfonylureas 

Glyburide (micronase)

glipizide (glucotrol)

Biguanides

metformin (glucophage)

thiazolidinediones 

pioglitazone (actos)

DPP-4 inhibitors

sitagliptin

You can check the level of the C peptides

(this is what links the A and B chains)

Glucose, amino acids, fatty acids, Ca2+, cAMP, GI hormones (gastrin, CCK, secretin, glucagon, GIP, GLP1)

Glucose -> ATP 

the ATP then blocks K+ channels causing an increase of K inside the cell, causing depolarization which opens Ca2+ channels.  The influx of Ca into cells increases exocytosis of insulin. 

This blocks the K channels (that would normally be done with the ATP from glucose).

Since the K channels are blocked, there is an increase in K+ in the cell, cell depolarizes, opening Ca2+ channels, allowing Ca into the cell which 

causes EXOCYTOSIS OF INSULIN

Which are the more dominant influence on insulin secretion: Alpha2 or beta2 agonists?

What is the net result of this?

Alpha2 agonists - which cause an increase in Gi, thus decreasing cAMP and inhibiting insulin secretion

(beta2s increase Gs, which increase cAMP and stimulate insulin secretion, but they are so weak, cant handle the strength of the mighty ALPHA 1s!!!!)

Increases glucose transport to muscle and fat cells

(increased translocation of GLUT4)

Increased synthesis of glycogen (storage glucose) in liver and muscle 

Decreased glycogenolysis (break down of glycogen into glucose), and decreased gluconeogenesis 

thus decreased hepatic glucose output.

= more glycogen (more stored), less glucose 

Glucose Transporter type 4 

insulin regulated glucose translocater - only in fat and striated muscle cells 

Increased lipid synthesis 

decreased lipolysis 

Increased K+ concentrations intracellularly

= hyperkalemia with diabetes

This is from the increased activity of the Na+/K+ ATPase pump. 

Peripheral effects:

sweating, weakness, hunger, tachycardia, inner trembling (from catecholamine release)

CNS signs:

depression, coma, convulsions

What is the half-life of insulin?

How is it excreted?

IN plasma T1/2 = 9 minutes

(it is not bound to plasma proteins)

Destroyed by the liver, kidney and blood proteases

Exogenous insulin is given by injection or infusion.

Why not orally?

PORCINE

(piggies !)

this is a diluted protamine solution. 

Protamine is added to form insulin complexes that decrease absorption rate and increase duration of effectiveness of the exogenous insulin 

How would a "fast acting" insulin be classified?

What drugs are these?

When are they used?

INSULINS that have an onset in less than an hour, but last for only 5-8 hours.

This would be HumalinR (regular insulin injection)

Used to treat hyperglycemic crisis 

Insulin preps with onset of 2 hours, duration of 18-24 hours

Examples: isophane insulin suspension (NPH insulin), Humulin 70/30 (70 NPH, 30 regular)

Insulin Zinc Suspension (vetsulin)

Insulin preps with onset of 7 hrs, duration of 36 hours 

Examples: 

PZI vet - Protamine Zinc Insulin, prozinc 

Insulin extended zinc suspension

insulin glargine (lantus)

What is Insulin Glargine (Lantus)?

It is a recombinant human insulin, 

it is soluble at pH of 4, 

but at 7.4 it forms microprecipitates that make it insoluble and cause slow extended release 

(thats what she said)

A) 

NPH is an intermediate actinginsulin preparation,

and only lasts 18-24 hours at the most.

NPH is made with isophane, which is a dilute protamine solution, so it only slows the absorption down a little.

B) 

Insulin glargine (recombinant human insulin) 

is insoluble at blood pH of 7.4 and forms microprecipitates, this causes a slower, more extended release.

That is why there is a lower by longer curve on the graph.

ACUTE 

often caused by stress and the release of stress hormones.

A Rare condition 

it is from the induction of Ab - either to insulin, insulin receptors, or post receptor defects. 

What is the cause of "false insulin resistance"?

POOR INSULIN MANAGMENT 

ie. insulin is not being given properly or insulin has gone bad, not stored properly 

When can Glipizide be used in vet med?

What is it, what does it do?

It can be used in moderately hyperglycemix diabetic cats.

It is a hypoglycemic agent - it raises insulin secretion by blocking K channels (which the ATP from glucose does).

this causes an increase in K, causing hyperpolarization, which opens Ca2+ channels and Ca influx stimulated insulin exocytosis 

What are biguanides (like metaformin, glucophage)?

How do they work?

These are anti-hyperglycemic (but NOT hypoglycemic) agents used experimentally in diabetic cats.

It decreases the GI absorption of glucose and decreases hepatic gluconeogenesis.  

it is not hypoglycemic because it will not decrease glucose that is there already, just prevent more from being brought in.

What are thiazolidinediones?

How do they work?

Example: Exenatide (from gila monster saliva)

GLP1 causes an increase in insulin secretion in the treatment of diabetes 

Used in the treatment of diabetes.

Inhibit the enzyme dipeptidyl peptidase 4 (DPP4) which breaks down GLP1.  With an more GLP1 there is an increase in insulin secretion.

Examples: Sitagliptin, Vildagliptin, Saxagliptin

**hint they all have GLIP in the name - get it? GLP!**

It is caused by an insulin overdose!

this causes a HYPOglycemia, 

so hypoglycemia-associated hormones are released (like glucagon and catecholamines). Theses hormones do their job and "rebound" the blood to normal glucose levels.