Endocrine Pharmacology Flashcards
Explain the HPA axis and the hormones involved
Hypothalamus: Produces releasing hormones
- GnRH
- GHRH
- CRH
- TRP
- PIH/ dopamine (prolactin inhibiting hormone
- GHIH (growth hormone inhibiting hormone)
Pituitary: Produces stimulating hormones
Anterior: ACTH/TSH/FSH/LH/MSH/Prl/GH
Posterior: Oxytocin/ADH
Target Gland: releases hormones that have a negative feedback role on the hypothalamus and anterior pituitary
- Oxytocin will have a positive feedback loop with the hypothalamus
- T3/4
- glucocorticoids
- estrogen
Describe the 2 types of hormones produced by the HPA axis and how their type impacts their function.
water soluble
- bind cell membrane receptors = second messenger cascade results in impact on molecular activity
- peptide or monoamine hormones (catecholamines/eicosanoids like prostaglandin/prostacyclin/thromboxane/leukotriene/epoxyeicosatrienoic acid)
lipid soluble:
- can enter cell and act on intracellular receptors = change gene transcription
- steroids/thyroid hormones
List 4 factors that affect the action of hormones
age
reproductive status
sex
environmental factors
How are hormones secreted? What is required for secretion
non-constitutive
- impacted by seasonality/diurnal/pulsatile
require receptor binding/signal transduction/response - impact feedback control
What are 4 uses/goals for endocrine therapeutics
replacement therapy (ex. hypothyroid)
regulation (ex. hypothyroid + methimazole)
reproduction
supraphysiologic response (ex. rBST causing excess lactation in cows - illegal in CA)
What are 5 uses/goals of reproductive therapeutics
induce/synch estrus
suppress estrus
maintain pregnancy
induce parturition/abortion
expel uterine fluid/metritis/endometritis and fetal membranes
List 5 reasons why we manipulate the estrus of cows
estrus is difficult to detect
large farm sizes
improves production for dairy cows - they have more subtle signs of estrus
fixes poor conception rates
synchronizes calving
How long is the estrus cycle of a cow
21d
Describe the estrus cycle of a cow and the hormone fluctuations that occur
Estrus: high estrogen and low progesterone
Metestrus (post ovulation): decreasing estrogen and increasing progesterone
Diestrus:
1st follicular wave: estrogen increases but ovulation is suppressed by progesterone from the existing CL
2nd follicular wave: estrogen increases and stimulates the LH surge which triggers ovulation
- this occurs after luteolysis (CL degrade)
What structure is primarily responsible for making estrogen?
the follicle - follicular granulosa cells
What structure is primarily responsible for making progesterone?
corpus luteum
What structure is primarily responsible for making prostaglandin F2a?
the endometrium
What are 3 functions of prostaglandin F2a
relax the cervix
luteal regression
uterine muscle contraction
What are 4 uses for PGF2a
estrus synchronization - shorten cycle
abortion in cows between d5-130
treat endometritis/pyometra/retained fetal membranes
induce parturition
What are the adverse effects associated with prostaglandin F2a
small animals are very sensitive to the adverse effects
diarrhea
vomit
abdominal pain/colic
hyperthermia if overdosed
use gloves when administering because it can induce bronchospasm in people with asthma and miscarriages
Give 2 types of PGF2a drugs commonly used
dinoprost: natural prostaglandin
chlorpostanol: synthetic prostaglandin
What are dinoprost PGF2a labelled for? Provide 2 examples of these drugs
beef
dairy
swine
horse
ex. lutalyse/enzaprost T
What are chlorpostanol PGF2a labelled for? Provide 2 examples of these drugs
beef
dairy
swine
ex. estrumate/ bioestrovet/ alfaglandin C / planate/ cloprostenol veyx
Compare dinoprost and chlorpostanol
dinoprost: in cows it has a short t1/2 - 30m
chlorpostanol: in cows it has a longer half life = 3h
What is the function of GnRH use in estrus manipulation
it can trigger the LH surge/ovulation
induce ovulation in cows
treat cystic ovaries in cows and camelids
induce estrus in small animals
it is licensed for estrus synch and cystic ovary tx in dairy cows
What are the adverse effects associated with GnRH
safe
few effects
What are some examples of GnRH drugs
cystorelin
factrel
fertiline
ovu-gel
maprelin XP-10
What are 4 effects of estrogen
induce estrus behaviour
contribute to LH surge
increase mammary development
endometrial proliferation (anabolic steroid)
What are 2 types of estrogen
estradiol cypionate (ECP): natural estrogen
diethysilbestrol (DES): synthetic
What is estradiol cypionate used for? What species is it used in?
Cows:
- speed up uterine involution
- correct anestrus
- treat metritis and retained placentas
Dog: not recommended anymore
- urinary incontinence/palliative/prevent ovum implantation
What is diethylsilbestrol used for? What species is it used in?
urinary incontinence treatment in dogs
What are the adverse effects associated with diethysilbestrol
bone marrow suppression
increase mammary tumor risk
human carcinogen
What are the adverse effects of estrogen in SA
bone marrow suppression
endometrial hyperplasia and uterine cancer
pyometra
What are the adverse effects of estrogen in LA
prolonged estrus
cyst development
reduced lactation
What is the role of progesterone secretion on the HPA axis
negative feedback on the hypothalamus/anterior pituitary = reduce LH and FSH secretion
What is the function of progesterone
prevent ovulation and maintain endometrium/preganancy
What are 3 examples of progesterone drugs that are commonly used
CIDR
MGA
Altrenogest
Provide 3 examples of synch protocols for dairy cows. What is their function/purpose
Ovsynch
Cosynch
SelectSynch
estrus synchronization for times artificial insemination
it will can also treat follicular and luteal cysts
Explain the OvSynch protocol
Day
-12 (12d before): Presynch: give 2 prostaglandin injections 14 days apart
0: give GnRH when the cow is in diestrus to start a new wave of follicles
7: give prostaglandin to induce luteolysis and allow for a new wave of follicles to develop (reduce progesterone)
9: Give GnRH to induce the LH surge and stimulate ovulation
10: AI (won’t show estrus but can still breed)
Explain the CoSynch Protocol
Day
-12 (12d before): Presynch: give 2 prostaglandin injections 14 days apart
0: give GnRH when the cow is in diestrus to start a new wave of follicles
7: give prostaglandin to induce luteolysis and allow for a new wave of follicles to develop (reduce progesterone)
9.5: Give GnRH and AI
This will reduce the number of times ou need to handle the cows but is less efficacious vs OvSynch
Explain the SelectSynch protocol
Day
-12 (12d before): Presynch: give 2 prostaglandin injections 14 days apart
0: give GnRH when the cow is in diestrus to start a new wave of follicles
7: give prostaglandin to induce luteolysis and allow for a new wave of follicles to develop (reduce progesterone)
Allow the cow to ovulate and observe estrus - which should be between day 6-13
more labour
How do beef estrus synch protocols compare to dairy
Same basic principles but less handling
What is a CIDR?
controlled internal drug release
release progesterone over 7d
inserted into the vagina
Explain how to use a CIDR
Day
0: insert the CIDR
6: prostaglandin injection
7: remove the CIDR
8-10: heat detection/AI
What is the function of a CIDR
it can start an anestrus cow cycling again
by giving and removing progesterone it simulates a CL
The prostaglandin injection will induce luteolysis of the old follicles
What is CIDR1380? What is it used for?
1380 is the amount (mg) of progesterone in the device
it is labelled for dairy and beef in Canada
What is the withdrawal time and adverse effects of CIDR1380
milk: no withdrawal
meat - 1 d
adverse:
vaginal irritation
wear gloves because it can be absorbed across the skin
What is CIDR330 for?
sheep
What is melengestrol acetate? What is it used for?
oral progesterone
used to suppress estrus in feedlot heifers
How do you use melengestrol acetate?
0.5mg/head/d for 14d
synch estrus + cause poor quality egg and reduced conception rates
you can combine it with prostaglandin 17-19d after the last MGA feed
What is the goal of estrus manipulation in horses?
start cycling earlier
- all racehorses have a ‘birthday’ of Jan 1 so if you are born earlier = advantage
What are 3 methods of inducing estrus in horses?
increase light exposure
progesterone
sulpiride (dopamine antagonist)
What is the function of progesterone administration in horses? What drugs are commonly used
Use
- shorten transition from anestrus to estrus
- suppress estrus in performance mares
- maintain preganancy
Altrenogest aka regumate
How is altrenogest used in horses?
PO for 10-16d
they will ovulate around 10 days after treatment stops
How long is an equine estrus cycle
21d
Why is inducing ovulation important in horses
an ovulated egg will only be viable for 12h
- while sperm will live much longer
- mating should be done 1-2d pre-ovulation
When do you induce ovulation in horses
when the dominant follicle is seen on u/s
What are 2 drugs that are commonly used to induce ovulation in horses
human chorionic gonadotropin: large glycoprotein
deslorelin: synthetic GnRH analogue
When should HCG be used in horses
to induce ovulation
when the follicle is >35mm
they will ovulate within 2 days
repeated use will reduce the efficacy
What is deslorelin
a super-agonist
not licensed in CA
What 3 scenarios are repro drugs used in SA
cats: induce ovulation to stop estrous with GnRH and HCG
dogs/cats: deslorelin used as a contraceptive
- chronic GnRH causes (-) feedback and reduced FSH/LH
prostaglandin can be used to induce abortion
- lots of adverse effects
When are repro drugs used to help maintain equine pregnancies
when they are high risk
- colic/placentitis/history of pregnancy loss
must balance with the potential risk of fetal abnormalities
What is used to help maintain pregnancy in horses? Why?
progesterone - altrinogest
some mares dont make enough progesterone early (pre day 120)
- supplement until day 120 - when the placenta takes over
if they have a placentitis they may need supplementation the whole pregnancy
Explain how a normal equine pregnancy is maintained
DAY
17: implantation
- primary CL producing progesterone
40: endometrial cups form - produce equine chorionic gonadotropin (like FSH/LH)
- cause ovulation of follicles that happened earlier in pregnancy and induce lutenization of l=follicles
- induce the development of accessory CLs for increase progesterone
- beginning of placentation
120: placental progesterone is enough to maintain pregnancy
What are 4 reasons why you would induce a cows parturition
to increase the time before the next breeding
to reduce the calf size and dystocia risk
to reduce excess udder edema
to take advantage of the available foliage for lactation
What are 2 ways to induce parturition in a cow
glucocorticoids - dexamethasone
prostaglandin - PGF2a
best effect = a combo of both
What is the reasoning behind using glucocorticoids and prostaglandin to induce parturition in cows
glucocorticoids (cortisol) are released by the fetus to stimulate birth
- it would induce PGF2a and estradiol 2 release
PGF2a = causes luteolysis and relaxin release (resulting in the stretching of the pelvic ligament)
estradiol 2: causes myometrial contraction
- the increased pressure and cervical stimulation cause oxytocin release
How is parturition induced in horses
oxytocin: they will deliver within 90m
- if you use a low dose the mare won’t deliver unless she is ready
using glucocorticoids and prostaglandin are not that effective
Why do retained fetal membranes occur? What factors increases your risk for this?
collagenase fails to degrade between cotyledons and caruncles
Higher risk if…
- parturition was induced
- dystocia/fetotomy/ or c-section was performed
- immunosuppressed or nutritional deficiency
- twins
What are 7 ways to treat retained fetal membranes in a cow
- do nothing if the cow seems healthy
- systemic abx if there are clinical signs (do not use if early/healthy)
- intrauterine abx
- PGF2a
- oxytocin can be used close to calving
- collagenase (expensive)
- Ca supplement to treat underlying hypoCa
What are 5 ways to treat retained fetal membranes in a horse
oxytocin (low dose)
Ca
PGF2a
NSAID
systemic abx
How does retained fetal membranes in a cow compare to a horse
in a horse it is an emergency
- acute metritis/endotoxemia/laminitis/death
in a cow it may not be a problem
What is used to increase milk let down or uterine contractions
oxytocin
- it increases the contraction of the mammary myoepithelium
How is oxytocin administered
IV
it has a short half life so it may need to be re-dosed
should correct any hypoCa before giving
What are the adverse effects associated with oxytocin administration
overdoses can cause tetanic uterine contractions and water intoxication (has a an antidiuretic effect)
What are the cells that make up the thyroid? What are their general function
colloid: contain thyroglobulin and precursor thyroid hormone
thyroid follicular cells: synthesize thyroid hormone
Explain how thyroid hormone is made
The thyroid follicular cells uptake iodine via Na/I pumps
I is secreted into the colloid > it binds thyroglobulin
- for either diiodotyrosine or monoiodotyrosine
Thyroid peroxidase couples MIT and DIT to for with T3 (DIT+MIT) or T4 (DIT+DIT)
T3/4 is endocytosed from the colloid into follicular cells
T3/4 is released into circulation for thyroid follicular cells
- more T4 is released vs T3
How is thyroid hormone transported through the body? What does it act on?
protein bound in circulation
- only the free hormone can interact with target so there is lots of storage hormone in the blood
If there is enough dietary iodine then T4 os preferentially made
- it is converted to the more biologically active T3 at the tissue target
it is lipid soluble so it acts on intracellular receptors
What should you measure to evaluate the productivity of the thyroid?
total and free T4 is all made from the thyroid = can indicate function
T3 can be up or down regulated depending on tissues/other factors and is not reflective of thyroid function
What are 6 functions of thyroid hormones
increase metabolic rate
growth and development
increase sensitivity to catecholamines
increase protein synthesis/glycolysis/glyconeogenesis
positive inotrope
increase immunity
How is HPA regulation of thyroid hormone useful diagnostically?
T3/4 has a negative feedback on the hypothalamus (TRH) and the anterior pituitary (TSH)
if primary thyroid dysfunction
hypothyroid = high TSH
hyperthyroid = low TSH
What is the common signalment and cause of hyperthyroidism
mid/old cats
mainly due to benign thyroid hyperplasia
What are the clinical signs associated with hyperthyroidism
weight loss with a good appetite
PU/PD
hyperactivity
vomit
diarrhea
How is hyperthyroidism treated
methimazole
What is the mechanism of action of methimazole
It disrupts thyroid peroxidase mediated iodination of tyrosine on thyroglobin = no DIT/MIT formed
it acts as an alternative substrate for thyroid peroxidase
it concentrates in the thyroid
resulting in reduced T3/4 production = normal T3 and low T4
What are the adverse effects of methimazole
vomit
lethargy
pruritis
hepatomegaly
it can cross the placenta
How should methimazole be administered and monitored
start slowly at a low dose and adjust accordingly
PO or transdermal - varied bioavail
since there is lot of protein-bound thyroid hormone that acts as a storage = weeks before an effect is seen
- check total T4/CBC q2-3 weeks for 3 months
- check total T4 at 3-6 month intervals
How is methimazole metabolized
liver
What are other non-methimazole options in treating hyperthyroidism
carbimazole (prodrug of methimazole)
radioactive I
sugery
What are the clinical signs of hypothyroidism
weight gain
lethargy
hair loss
neuropathy
myxedema
What are the 2 most common causes of primary hypothyroidism
lymphocytic thyroiditis
idiopathic atrophy
How do you diagnose hypothyroidism
PE/clinical signs
total and free T4
TSH levels (high)
there can be lots of overlap between normal T4 levels and hypothyroid ranges so you need the clinical signs and TSH levels to confirm
What is used to treat hypothyroidism
levothyroxine - a lipophilic synthetic T4
What is the pharmacokinetics associated with levothyroxine
it has a high first pass effect - not all formulations have the same bioavailability
- more will be absorbed on an empty stomach
it is excreted in bile
How to administer levothyroxine
SID or BID
PO
give at a consistent time after a meal
- there will be more absorption on an empty stomach but it is easier to adjust dose if it is consistently given with or without food
What are the adverse effects of levothyroxine
iatrogenic hyperthyroidism
overdoses can cause osteoporosis in humans
How is levothyroxine monitored
1-2 months after treatment started
- measure peak total T4 (3-4 h after last dose ) = should be in the upper half of the reference range
recheck 2-4 weeks after a dose change
