Endocrine drugs

What endocrine glands do

• produce hormones that control body systems

• To work properly, just the right amount of hormone needs to be released when it is needed

Endocrine diseases

Caused by too much or too little of the hormone being produced compared to what the body actually needs

Endocrine drugs

Mimic the effects of natural hormones and in so doing correct or alter the physiology of the endocrine gland or system

Endocrin negative feedback loop

• Endocrine gland 1 detects low level of hormones

• Gland 1 send a signal to gland 2

• Gland 2 produces the hormone the body needs to produce some effect

• The same hormone also sends negative feedback to gland 1 to shut down further release of stimulatory hormone to gland 2

3 gland system for negative feelback loop

• Gland 1 = 1 hypothalamus in the brain

• Hypothalamus produces hormone 1 that stimulates gland 2

  • Gland 2 = pituitary gland

• Pituitary gland produces hormone 2 that stimulated gland 3

  • Gland 3 = target gland

• The target gland 3 produces the hormone the body needs (ex. Thyroid hormone, progesterone, etc.)

• The target gland's hormone also helps produce the negative feedback on the hypothalamus and pituitary

Exogenous compound

originating from outside of the body

Endogenous hormone

 originating from within the body

Control of endocrine hormones

• If an exogenous compound such as a DRUG that is similar to the natural endogenous hormone

  • The exogenous drug will do the same beneficial effect as the natural endogenous hormone

  • The exogenous drug will also cause the same negative feedback mechanism that the endogenous natural hormone does

• DRUGS HAVE TO BE USED CAREFULLY TO AVOID CAUSING HORMONE IMBALANCES

Normal function of thyroid gland

• Hypothalamus releases Thyrotropin-Releasing Hormone (TRH)

• TRH stimulates nearby pituitary gland

• Pituitary gland is stimulated to release Thyroid-Stimulating Hormone (TSH)

• Pituitary TSH stimulates the thyroid gland to produce triiodothyronine (T3) or Thyroxin (T4)

• T3 and T4 are released into the body and taken up by cells in the body to increase the body's metabolic rate

• T3 is the biologically active form of thyroid hormone (even though produced less than T4)

• T4 is converted by enzymes in the body tissues to T3 (removing an iodine converts T4 --> T3)

• T4 acts as a circulating precursor reservoir of hormone to be converted to T3 as needed

• T3, T4 provides negative feedback

T3

triiodiothyronine

T4

thyroxin

What thyroid disease to cats normally get?

Hyperthyroidism (high T3, T4)

What thyroid disease to dogs normally get?

hypothyroidism (low T3, T4)

What thyroid disease to horses normally get?

 hypothyroidism (not recognized much)

Primary thyroid disease

problem with the thyroid gland itself

Secondary thyroid disease

thyroid normal; problem with the pituitary gland (TSH)

Tertiary thyroid disease

thyroid, pituitary normal; problem with the hypothalamus (TRH)

Prognosis for secondary and tertiary thyroid disease

End result is the same (low or high T3/T4) but prognosis much worse for secondary and tertiary because often affects other hormones too

What is a goiter

Enlarged thyroid gland - but problem is Not with the thyroid gland itself!

Goiter

• Enlarged thyroid gland - but problem is Not with the thyroid gland itself!

• Cattle raised strictly on pasture without mineral supplementation - lack iodine

• No iodine = no T3/T4

Treatment for goiter

give supplemental iodine (this condition is rare today)

Signs of hypothyroidism

• Lethargic

• Weight gain in spite of normal consumption of food

• Heat-seeking behavior (dog lays on heat register on floor)

• Bradycardia

• Decreased growth of young animals

• Alopecia, decreased hair growth, dry scaly skin

Main function of T3 and T4

Regulation of metabolic rate and cellular metabolism

Treatment for hypothyroidism

• Most common is supplementation of thyroid hormone drugs

  • Synthetic T4 (levothyroxine)

  • Levothyroxine is the drug of choice for treatment and preferred over synthetic T3 (liothyronine)

Main advantages of T4 over synthetic T3 for treatment of hypothyroidism

• levothyroxine T4 allows each tissue to convert T4 to T3 (active hormone) based upon its metabolic need (T3 bypasses)

  • CNS has a highly metabolic rate, adipose tissue has a very low rate

Levothyroxine

synthetic T4

Liothyronine

Synthetic T3

function of levothyroxine

• returns T4 and T3 to normal; with T3, only T3 normalizes

• More closely mimics the natural negative feedback mechanism

• Has a longer half life than T3 so needs to be dosed less frequently

Brands when treating hypothyroidism

• some endocrinologist recommend using a well-known brand name because they may be more reliable

• Best rule: stick with one brand; don't be constantly switching rands based on whatever is cheapest

Thyrotoxicosis

• Clinical signs resulting from excessive thyroid hormone

  • Rarely happens in vet patients (more humans)

  • Because dogs tolerate higher levels of T4, hypothyroidism may be diagnosed by instituting 4 week regimen of T4 to see if clinical signs improve

  • Outward changes in hair, skin, weight, etc. may be subtle and not conclusive even after 4 weeks; it’s better to do lab work to diagnose hypothyroidism

Euthyroidism

Normal thyroid levels

Hyperthyroidism

• increased circulating T3/T4

• Middle aged elderly cats; hormone secreting tumor

Clinical signs of hyperthyroidism

• relate to thyrotoxicosis and increased metabolic rate for all cells in the body

  • Weight loss despite increased appetite

  • Tachycardia (exceeds 240bpm)

  • Heat intolerant (overheated easily)

  • PD, diarrhea, unkempt hair coat

  • Much more active, playful, aggressive

  • Palpable enlargement of one side of thyroid gland

4 options for treatment of hyperthyroidism

1. Surgical excision of thyroid tumor (thyroidectomy) - produces cure

2. Injection of radioactive iodine (131I) - produces cure

3. Inhibition of thyroid hormone production - control only, no cure

4. Low iodine diet - control only, no cure

Choice for treatment of hyperthyroidism is based on

• Cost

• Client ability/willingness to administer daily medication (for oral drugs)

• Anesthetic/surgical risk (for thyroidectomy)

Drugs for hyperthyroidism

• Methimazole (Felimazole, Tapazole)

• Radioactive iodine (131I)

• Idoine-limited diet

Methimazole (Felimazole, Tapazole)

• anti-thyroid drug

  • Blocks thyroid tumors ability to use iodine to produce T3/T4

  • Inexpensive, relatively safe, tolerated by old cats, but NO CURE

  • Sometimes used for reduce hyperthyroidism clinical signs to make cat a better surgical candidate (reduce tachycardia) then remove tumor by thyroidectomy

  • May be used to establish euthyroidism in older cats to check renal function

  • Small % experience liver problems, bleeding (loss of clotting factors from liver disease) , leukopenia, thrombocytopenia

Methimazole can be used to establish euthyroidism in older cats to check renal function

• Increase BP in hyperthyroidism = increased perfusion of kidneys

• If old cat has reduced renal function, the hyperthyroidism increased perfusion may cover up renal failure - once euthyroid --> signs of renal failure appear

Administration of Radioactive iodine (131I)

One time SQ or IV

Iodine

Is natural component of T3/T4 so is taken up only by thyroid tissue that is actively secreting this hormone

High T3/T4 levels from tumor

• Negative feedback on TRH and TSH production (tumor produces T3/T4 without TSH stimulation)

• Normal thyroid tissue has atrophied because no TSH

• Thyroid tumor concentrates radioactive iodine with a lethal dose of beta particle radiation (beta particles only penetrate 1-2 mm of tissue) - destroys just tumor

Using Radioactive iodine (131I)

• 131I Gamma radiation (more dangerous, penetrating) requires cat be isolated, feces and urine collected as radioactive waste - cat housed in special facility

• After 3 days - 3 weeks (by state regulations) cat is released

Iodine-limited Diet

•  prevent formation of T3/T4 by limiting iodine needed to create the hormones

  • Used for: control because it does not affect the underlying tumor causing the hyperthyroidism

  • Diet must be strictly confined to prevent other sources of iodine's from treats, snack, other foods

  • Cats requiring other prescription diets may not be able to use this diet

  • Can't be used in multiple cat households unless affected cat fed separately and prevented from eating other cats' food

Exocrine function

digestive enzymes put into small intestine

Low T3/T4 has what effect on TRH and TSH release?

The body is going to increase TRH and TSH because the body thinks it needs more

What effect does change in TSH have on thyroid gland? How does the gland respond?

The gland is going to stimulate the thyroid to make more T3 and T4

Endocrine function

Hormones

3 pancreative hormones

Insulin, glucagon, and somatostatin

What is the only pancreatic enzyme used for therapy?

Insulin

Insulin

causes cells to actively transport glucose from blood into cells

What happens without insulin

• get hyperglycemia (high blood sugar)

Effects of insulin

• causes cells to actively transport glucose from blood into cells

• causes the liver to store glucose as glycogen storage molecule

• facilitates fat deposition in adipose tissue

Lack of insulin

 diabetes mellitus characterized by hyperglycemia and glucosuria (glucose found in the urine)

Beta cells in pancreas

these cells produce insulin

Most common cause of diabetes mellitus

• Destruction of beta cells which leads to a lack of insulin

Type 1 diabetes

• Beta cell destruction and lack of enough insulin

• Insulin dependent diabetes mellitus (IDDM)

Type 2 diabetes

• Problem with the insulin receptor and beta cells are producing appropriate amounts of insulin

• Non-insulin dependent diabetes mellitus (NIDDM)

NIDDM

• Not enough insulin receptors on cells of target tissues

• Insulin receptors are present in adequate numbers, but become non-responsive to presence of insulin

Treatment for Type 1 diabetes

• Insulin must be used by injection

  • Does not exactly mimic the way body releases insulin

  • Must be coordinated with meal times and amount f food

  • Requires strong commitment of owners 365 days of the year

Reason insulin can’t be given by mouth

Insulin is a protein and would be natured by stomach acid and digested by intestinal enzymes --- and the molecules is too big to be absorbed

Classifications of the types of Insulin

1. Species from which the insulin is derived

2. Duration of action

What can reduce effectivenes of insulin injection

Species differences can generate antibodies against the insulin

Pork (porcine) insulin

Is antigenically similar to dog insulin - one of the insulins of choice for dogs and cats - porcine insulin zinc suspension (Vetsulin)

Recombinant human insulin

(Insulin glargine and insulin detemir) are created by combining strands of DNA together that do not occur in nature - antigenically similar enough to dogs and cats to be used in these species

Types of insulin by species

•  Porcine insulin zinc suspension (Vetsulin)

  • recommended and typically used for dogs and cats

• Recombinant human insulin (Insulin glargine and insulin detemir)

Short acting insulin

 regular (crystalline) insulin (only one that can be given IV)

INtermediate acting insulin

• NPH(neutral protamine Hagedorn)

• Porcine insulin zinc suspension (Vetsulin)

Long acting insulin

• protamine zinc insulins (PZI)

• Insulin glargine

• Insulin determir

Duration of action for insulin classification

• this hormone is combined into crystals with zinc or a fish protein called protamine

  • How quickly/slowly the crystal dissolves and releases insulin determines the duration of the insulin

Using insulin in canine diabetes

• Initial stabilization

  • by starting intermediate duration recombinant human NPH insulin or porcine insulin zine suspension

  • If hyperglycemia is severe enough, regular (crystalline) insulin can be given by IV to bring the glucose level down until the intermediate insulins can be used

Using insulin in cat diabetes

• Regular (crystalline) IV initially for stabilization

  • NPH doesn't last long in the cat as it does in the dog

  • Long acting PZI insulin used more commonly for controlling cats than intermediate insulins

Re-suspending Insulin

• Most insulins are suspensions

• THIS VARIES BY BRAND OF INSULIN!!!

  • Most say to re-suspend by rolling the bottle gently back and forth between hands - do NOT shake - will break apart insulin molecule!

  • Vetsulin manufacturer says its insulin "should be shaken thoroughly" to create a milky homogenous liquid - FOLLOW THE MANUFACTURER'S INSTRUCTIONS

Considerations for insulin

• Most are suspensions and need to be re-suspended before use

• Injection site

• Syringes and bottle can be U-40 or U-100

Injection sites for Insulin

• Injection SQ 3/4 to 2 inches to either side of the dorsal midline

• Any location between scapula and midlumbar

• Alternate subsequent injections from side to side

Syringes and Insulin bottle are listed as U-40 or U-100

• Means there are 40 units or 100 units per mL of insulin

• Client draws up X number of Units instead of mL

• Use the U-40 bottle with the U-40 syringe to give an accurate dose

Hypoglycemic agents

Sulfonylurea compounds like glipizide

• these lower the BG

• Oral

How oral hypoglycemic agents work

Combine with beta cells in pancreas and stimulate release of additional insulin

Canine diabetes and hypoglycemic agents

results primarily from loss of beta cells and subsequent lack of insulin - no beta cells left to be stimulated by glipizide so not very usefuk

Feline diabetes and hypoglycemic agents

Has been tried for many years - but evidence seems to point to no medical advantage or consistent improvement in feline patients - no recommended

Use of reproductive drug in food animals and equine

1. Synchronize estrous cycle (NOTE: "Estrous")

2. Delay the onset of estrus (NOTE: "Estrus")

3. Terminate pregnancies

4. Induce ovulation (with persistent follicles)

Use of reproductive drugs in cats and dogs

 to prevent pregnancy or alter the state of the uterus

Female repro endocrine drugs work by…

by blocking or enhancing the normal reproductive physiology - drugs have to be used at the appropriate phase or they will not work

the 2 general phases of Estrous

1. Follucular phase

2. Luteal phase

Common signs of Type 1 diabetes

• INcreased thirst

• Urinates more often

• Weight loss

• Doesn’t eat

• Tired, lack of energy

• Vomiting

• Cataracts (in dogs)

what time of the day is insulin given in type 1 diabetes

typically at meal time

Follicular Phases

• Controlled by ovarian follicular cells that contain the ovum (egg)

• Ends near the onset of estrus (heat) with ovulation of the egg

Luteal phase

• Controlled by corpus luteum (CL)

• Ends with lysis of CL and return to follicular phase

Hormone production during the follicular phase

• Cycle starts with neural input, presence of estrogen, or absence of progesterone

• Hypothalamus releases Gonadotropin releasing hormone (GnRH)

• Pituitary gland releases Follicle stimulating hormone

• FSH stimulates ovarian follicles developments - oocytes (egg cells)

• Follicle produces estrogen (estrus signs

• Follicle produces inhibin --> creates negative feedback on pituitary to decrease FSH

Hormones during the end of the follicular phase

• When follicle matures --- the hypothalamus releases GnRH in a different way than it did previously to signal pituitary FSH release

• GnRH now stimulates pituitary gland to release Luteinizing hormone (LH)

• LH causes the mature follicle to rupture and release the egg (oocyte)

• LH transforms the follicular cells into cells of the corpus luteum(CL) --> this ends the follicular phase and starts luteal phase

What produces progesteron

the corpus leteum

What type of insulin can you give IV

ONLY SHORT ACTING REGULAR insulin

What takes control of the estrous cycle during luteal phase

the corpus luteum

Function of progesterone

• To shut down the hypothalamus - pituitary - follicle system

• Prepare the uterus to receive, important and support a fertilized ovum

  • Causes uterine lining to thicken and secrete a nutrient rich fluid

  • Keeps uterine smooth muscle in a quiet, non-contractile state

Hormones during the end of the luteal phase

• CL is on a "timer" and degenerates after a set period of time if the egg is not fertilized and implanted in the uterus

• When CL degenerates, the progesterone production stops and negative feedback is removed from hypothalamus and pituitary gland

• Then the cycle starts over again with the hypothalamus releasing GnRH to stimulate the pituitary gland to again stimulate follicle formation

Lack of progestrone

abortion (termination of pregnancy)

Initation of parturition

At the end of pregnancy the fetus pituitary releases Adrenal corticotropic hormone (ACTH)

• ACTH stimulates adrenal gland to produce cortisol

• Cortisol causes uterus to begin to secrete estrogen and PGs

Prostaglandins in the uterus

• lyses the CL which terminates progesterone production

  • Progesterone also helps to maintain the pregnancy and keep the uterine myometrium "calm"

Estrogen from the uterus effects

• Makes the myometrium more “twitchy”

• Causes more oxytocin receptors to appear on the myometrium

Effect of fetal pressure on cervix or stimulation of nipples

causes pituitary to release surge of oxytocin --uterine contractions - LABOR

Types of reproduction drugs

1. GnRH or gonadorelins

2. Progestins, progestogens, progestational hormones

3. Estrogen compounds

4. Prostaglandins