PHARMACOLOGY OF THE ENDOCRINE SYSTEM: INTRODUCTION TO THE ENDOCRINE SYSTEM

The Endocrine System: Review

 The endocrine system consists of various glands that secrete hormones, which are chemical messengers
released in response to a change in the body’s internal environment. Hormones attempt to return the
body to homeostasis

 Endocrine glands include:

 Pineal gland
 Hypothalamus
 Pituitary
 Thyroid
 Parathyroid
 Thymus
 Pancreas
 Adrenal glands
 Gonad

 After secretion, hormones enter the blood and are transported throughout the body. Some hormones
(e.g. insulin) have receptors on nearly every cell in the body. Others, have receptors on only a few
specific cell typesc
 In the endocrine system, it is common for one hormone to control the secretion of another hormone. It is
also common for the last hormone secreted in the pathway to provide negative feedback to turn
off the secretion of the first hormone

Drugs targeting the Endocrine System

 Water soluble endocrine hormones: Action is mediated through an extracellular surface receptor because
they are unable to pass through the lipid bilayer
 Cell surface receptors may be G-protein coupled receptors and leads to the manufacture of second
messengers (e.g. cAMP or IP3) which alter cell functions
- Norepinephrine
- Epinephrine
- Vasopressin
- Oxytocin

 Cell surface receptors may activate protein kinases directly (no 2nd messengers)
- Insulin
- Growth hormone

 Fat soluble endocrine hormones: May pass through lipid bilayers and affect cellular activity directly
 Form a complex with their intracellular receptor and bind to DNA, acting as a transcription factor
 Note: these drugs must travel through the blood stream bound to a transport protein
- Estrogen
- Testosterone
- Progesterone
- Thyroid hormone
- Cortisol & Aldosterone

1
 PHARMACOLOGY OF THE ENDOCRINE SYSTEM 1:
DRUGS FOR PITUITARY, THYROID, AND ADRENAL DISORDERS

The Hypothalamus and Pituitary

 The hypothalamus and the pituitary gland regulate the function of numerous endocrine
glands. Therefore, if an individual has dysfunction of the hypothalamus or pituitary we will
see massive
disruption of the endocrine system and metabolism
 Note that these perturbations will manifest in different clinical symptoms depending on the life
stage of the individual (i.e. childhood vs. adulthood)

 Hypothalamus and Anterior pituitary effects:

 Control of hormone release:
1. The hypothalamus produces releasing hormones in response to perturbations in homeostasis
2. Releasing hormones stimulate the anterior pituitary to secrete hormone
3. Hormones from the anterior pituitary target tissues to produce a biological effect or
secrete another hormone

 Hormones and target tissues

- Adrenalcorticotropic Hormone (ACTH)  adrenal cortex  glucocorticoids
- Thyroid Stimulating Hormone (TSH)  thyroid gland  T3 and T4
- Growth Hormone (GH)  bone, muscle, and other tissues
- Prolactin (PRL)  mammary glands
- Follicle-Stimulating Hormone (FSH) and Lutenizing Hormone (LH)  testes and Ovaries 
testosterone, estrogen and progesterone

 Hypothalamus and Posterior pituitary effects:

 Control of hormone release
1. The hypothalamus sends neuronal signals to the posterior pituitary in response to perturbations
in homeostasis
2. The posterior pituitary secretes hormones

 Hormones and target tissues

- Antidiuretic Hormone (ADH)  kidney
- Oxytocin  prostate gland in males, uterus and mammary gland in females

Pharmacological Management of Pituitary Disorders

 Although many different hormones are produced by the pituitary, but only a few are used clinically.
Why?
 The pituitary affects many systems. Therefore, if we mess around at this level of the system, we
many accidently affect other processes that occur downstream. Therefore, in many cases it is
simply
effective to give drugs that directly affect the secretion of hormones from the secreting organ or
affect the function of the target tissue directly
 Some hormones can only be obtained from natural sources and are very expensive.

2
Growth Hormone (Somatotrophin)
Endogenous hormone effects
 Released by: The posterior pituitary
 Normal effect: Stimulates growth and metabolism
 Cellular mechanism of action: binds to receptors on the cell membrane (is water soluble) which
activate kinases directly
Deficiency State
Caused by  Hypopituitarism which may result from various adenomas of the pituitary
and associated brain regions, trauma, autoimmune disorders, or stroke
Key Features  Short stature (in children)
 Decreased energy
 Decreased lean muscle mass and increased fat mass
 Decreased bone density
Treatment Somatrophin
Mechanism of action  Full agonist of somatotrophin receptors
Route of administration  Parenteral
Effects  Can induce up to 15 cm of growth in deficiency children.
 Used to increase height in patients with short stature associated with
genetic disease, and in adults as replacement therapy
 Increases protein synthesis, bone density, lipid mobilization from fat
stores, and improves lipid profiles
Safety precautions  Client must undergo regular assessment of glucose tolerance and thyroid
function.
Other considerations  Somatrophin is often abused (e.g. by body builders); however, these have
multiple effects can be dangerous
 In a child who doesn’t have a genetic/biological defect, somatrophin will
not have any beneficial effects (and will actually cause more problems
than it solves)
Hyper-secretion State: Acromegaly (medical term for
gigantism) Caused by  Benign tumors
Key Features  Headache (caused by abnormal growth of the frontal lobe and there is less
room for the brain to grow)
 Visual disturbances (due to pressure in occipital lobes)
 Enlarged heart, hands, tongue, nose, and lips
 Fatigue (the metabolism is in overdrive and all energy has gone toward
growth; therefore the individual feels tired because they do not have energy
for other metabolic processes)
 Excessive sweating (increased metabolism increases internal
body temperature)
Treatment Octreotide
Mechanism of action  Growth hormone antagonist  Inhibits the release of growth hormone (i.e.
it does not work at the level of the tissue/receptors)
 Pharmacologically related to somatostatin (GH releasing-inhibiting factor)
but with a prolonged duration of action
Effects  Can improve/reverse some of the symptoms associated with acromegaly
Treatment Pegvisomant
Mechanism of action  Growth hormone receptor antagonist (works at the level of the tissue to
prevent growth hormone from binding to its receptor)
Effects  Can improve/reverse some of the symptoms associated with acromegaly

3
 Antidiuretic hormone (Vasopressin)
Endogenous hormone effects
 Released by: The posterior pituitary when the hypothalamus detects a decrease in plasma volume or
an increase in blood osmolarity.

 Normal effects:
- Vasopressin stimulates the kidneys to increase water resorption.
- When secreted in large amounts, it will also increase blood pressure because it is a
potent vasoconstrictor
- Clinical considerations: Sometimes ADH is used in GI bleeding because of its affects on the vascular
system

 Cellular mechanism of action:

- Binds to V2 receptors in the cell membrane (is water soluble) in the kidney. V2 is a Gs-protein
coupled receptor  increases the production of cAMP, which increases the activity of protein
kinase A, which stimulates the insertion of water channels in the apical membrane of the
kidneys,
facilitating the reabsorption of water)
- At high doses, binds to V1 receptors in vascular smooth muscle, mediating vasotensive
effects Deficiency State: Diabetes insipidus
Caused by  Rare condition
Key Features  Dilute urine
 Constant thirst
 Note: diabetes actually refers to “constant thirst”. These individuals have no
problem with blood glucose
Treatment: Desmopressin
Mechanism of action  Agonist
Route of administration  Nasal spray
 Subcutaneous
 Intravenous
 Oral
Effects  Causes up to 90% of water excreted in the urine to be conserved
 Does not exert the same effect on blood pressure
Safety precautions  Blood pressure  although desmopressin is not a vasoconstrictor, the
increase in body resorption which it causes can increased blood volume and
thus an increase in blood pressure
 Body weight (twice a week)  used to assess fluid intention
 Fluid intake and urine output  we want to encourage the patient to
consume normal amounts of fluid (they are used to consuming excess
amounts)
 Monitor neurological status of client for water intoxication

Pharmacological Management of Thyroid Disorders

Thyroid Hormones: Thyroxine (T4) and Triiodothyronine
(T3) Normal effect
 Released by: the anterior pituitary in response to a fall in circulating thyroid hormone levels.
1. The hypothalamus senses a fall in thyroid hormone levels and produces thyrotropin-releasing
hormone (TRH)

2. TRH stimulates the anterior pituitary to produce thyroid stimulating hormone (TSH)

3. TSH induces the follicular cells to produce and secrete Thyroxine T4 (90%) and triiodothyronine
T3 (10%)

4
 -
T4 and T3 are derived from the amino acid tyrosine and the element iodine
-
Clinical considerations: Individuals who are iodine insufficient will be unable to produce
sufficient levels of thyroid hormones. This is seen clinically with the presentation of thyroid
hypertrophy and the development of a goiter. In the Western world, iodine deficiency is rare
due to the fact that salt is now iodized.

4. Increased levels of T4 and T3 negatively feedback to the hypothalamus and anterior pituitary to
turn off secretion of TRH and TSH

 Normal effect: Thyroid hormones regulate the basal metabolic rate, temperature, help to maintain
blood pressure, and regulate growth and development

 Cellular mechanism of action:

- Binds to intracellular receptors (is lipid soluble). The hormone-receptor complex affect cellular
responses by acting as transcription factor
- Note: T3 is ten times more potent than T4, however, the thyroid predominately produces T4. At the
level of the tissues, T4 is converted to T3 by enzymatic cleavage. T3 then enters the cells and binds
to intracellular receptors within the nucleus.

 Clinical considerations:
- Menopausal women are more likely to have thyroid disorders. It is important to distinguish
between symptoms caused by menopause and those caused by a thyroid condition
- Since the effects of impaired thyroid are so diffuse and varied, it may take several months before
a patient presents to a physician with complaints
Deficiency State: Hypothyroidism
Types & causes  Primary: Inactive thyroid gland commonly caused by an autoimmune
disease “Hashimoto’s thyroiditis”
- In addition to attacking the virus, the body also attacks the cells of the
thyroid gland. This destruction and damage of the gland causes the
decrease in hormone secretion

 Secondary: Caused by low secretion of TSH by the anterior pituitary. In

this case, thyroid function is normal
Key Features  Decreased metabolic rate!!
 Pale, cool, puffy skin
 Sensation of being cold,
 Bradycardia, decreased stroke volume, cardiac output, and pulse pressure
 Pleural effusions, hypoventilation, and CO2 retention
 Reduced appetite
 Lethargy, general slowing of mental processes
 Stiffness, decreased deep tendon reflexes
 Infertility, decrease libido, impotence, oligospermia (amenorrhea is
common)
 Weight gain
 Maternal hypothyroidism is associated with low IQ/developmental delays
in children (thyroid hormone is critical to fetal development)
Treatment: Levothyroxine (Synthroid)
Mechanism of action  Synthetic form of thyroxine (T4) (i.e. agonist) with a longer half-life  thus,
synthroid only needs to be administered once daily
Route of administration  Oral
Effects  Reverse the effects of hypothyroidism: Increases metabolism, weight loss,
improved tolerance to environmental temperatures, increased activity
levels, increased pulse rate

5
Safety precautions  Regular monitoring of serum TSH levels are required because levothyroxine
has a narrow therapeutic induce and can induce hyperthyroidism
(thyrotoxicosis)  nervousness/anxiety, weight loss, diarrhea, intolerance
to heat, tachycardia (see below for additional information)

Hyper-secretion State: Hyperthyroidism (thyrotoxicosis)

Types & causes  Primary: Overactive thyroid caused by an autoimmune disorder (Grave’s
disease)
- The body develops antibodies that activate the TSH receptor (i.e.
the antibodies act as full agonists)
- TSH levels will be low, despite high thyroid levels

 Secondary: Caused by thyroiditis, pituitary tumours, and thyroid cancer

- Relatively uncommon

 Treatment is complex! The immunological damage may be so significant

and the antibodies at such a high concentration that you need to remove
or destroy some of the thyroid gland
Key Features  Increased metabolic rate!!
 Warm, moist skin
 Sweating, heat intolerance
 Tachycardia, increased stroke volume, cardiac output, and pulse pressure
 Dyspnea
 Increased appetite
 Nervousness, hyperkinesias, tremor
 Weakness, increased deep tendon reflexes
 Menstrual irregularity, decreased fertility
 Weight loss
 Exophthalmos (Grave’s disease)
Treatment Propylthiouracil (PTU)
Mechanism of action  Inhibits the synthesis of T3 and T4 in the thyroid gland and disrupts
the conversion of T4 to T3 in target tissues
Route of administration  Oral
Effects  Can induce remission in cases of Grave’s disease
Safety precautions  Regular monitoring of serum TSH levels is required
Other considerations  Therapeutic effect can take 3-4 weeks
 PTU doesn’t always work!
Treatment Sodium Iodide-131 (Radioactive iodine)
Mechanism of action  Used to permanently destroy the follicular cells of an overactive thyroid
gland

The thyroid cells take up iodine for the purpose of synthesizing T3 and
T4; however, since the iodine is radioactive, it will damage the thyroid
gland.

The goal is to destroy just enough follicular cells so that thyroid
function returns to normal levels
Safety precautions  If too much radioactive iodine is administered and too much of the thyroid
is destroyed you may induce hypothyroidism
Additional considerations  Single exposure usually sufficient
 Commonly used in cases of thyroid cancer
Treatment Surgical removal: is indicated in cases of adenoma of the thyroid or illness
that is unresponsive to pharmacotherapy

6
 Pharmacology of the Endocrine System
1: Drugs for the Pituitary, Thyroid and Adrenal
Disorders

Pharmacological Management of Adrenal Disorders

Adrenal corticosterioids
Endogenous hormone effects
 Glucocorticoids (Cortisol)
- Normal effect: Increases blood glucose levels, increases the breakdown of lipids and proteins,
suppresses immune and inflammatory responses, increases vascular smooth muscle sensitivity to NE
and angiotensin II, affects mood and CNS excitability, decreases bone density

- Normal release:
1. Corticotropin-releasing factor (CRF) produced by the hypothalamus as a result of
circadian rhythms and/or stress
2. Adrenocorticotropic hormone (ACTH) produced by the anterior pituitary
3. Cortisol produced by the adrenal cortex
4. Increased levels of cortisol negatively feedback to the hypothalamus and anterior pituitary
to turn off secretion of CRF and ACTH

- Cellular mechanism of action: Binds to intracellular receptors (is lipid soluble). The
hormone- receptor complex affect cellular responses by acting as transcription factor

 Mineralocorticoids (Aldosterone)
- Normal effect: Regulates sodium and potassium re-absorption in the kidney

- Cellular mechanism of action: Binds to intracellular receptors (is lipid soluble). The
hormone- receptor complex affect cellular responses by acting as transcription factor
Deficiency State: Adrenal Insufficiency
Types & causes  Inadequate secretion of ACTH from the anterior pituitary

 Addison’s disease: Primary adrenal insufficiency resulting from the

autoimmune destruction of both adrenal glands. Results in high ACTH, low
cortisol, and low aldosterone

 Secondary adrenal insufficiency: Caused by chronic, long-

term glucocorticoid therapy leading to adrenal atrophy.
Key Features  Hyposecretion of cortisol and aldosterone resulting in hypoglycemia,
fatigue, hypotension, anorexia, diarrhea, dehydration, decreased plasma
sodium levels
Treatment: Glucocorticoid replacement therapy
Mechanism of action  Agonists
Route of administration  Multiple different routes of admin
Effects  Induce cortisol’s normal effects
Safety precautions  Patients discontinuing glucocorticoid therapy (after protracted systemic
use) should have their doses tapered slowly, over the course of several
months, to allow recovery of normal adrenal function. Why? Corticosteroid
therapy results in adrenal gland atrophy. Gradual withdrawal allows
adrenal glands to resume normal function. Sudden withdrawal leads to
acute adrenal insufficiency, hypotension, lethargy, renal failure, asthenia,
and nausea/vomiting

 May have negative effects when combined with other drugs:

- Will increase blood glucose  May decrease the effectiveness of
anti- diabetic drugs
- Will increase secretion of hydrogen ions in the stomach  May

7
 Pharmacology of the Endocrine System
1: Drugs for the Pituitary, Thyroid and Adrenal
Disorders

increase the risk of peptic ulcers if administered with ASA or NSAIDs

- If the glucocorticoid used has mineralcorticoid activity
administration of non-potassium sparing diuretics may lead to
hypocalemia and hypokalemia
Additional considerations  If the patient has primary adrenal insufficiency and is not producing
sufficient mineralcorticoids, we will want to give a drug that has some
mineralcorticoid activity (e.g. fludrocortisone, hydrocortisone). However, if
we are treating a glucocorticoid deficiency only, we will want to use drugs
with minimal mineralcorticoid activity so as not to affect blood pressure

 Glucocorticoids possess potent anti-inflammatory and immunosuppressive

actions and are prescribed for many conditions other than adrenal
insufficiency such as arthritis, allergies, asthma, lupus, inflammatory
bowel disease, Crohn’s disease, post-transplant rejection, cancers, skin
disorders (rashes, eczema). The route of administration, glucocorticoid
drug choice
and drug depends on the severity of illness. We want to chose the lowest
possible dose, and the shortest duration for what we want to treat (we can
choose short-acting, intermediate acting or long acting drugs). Additionally,
if possible, we will try to limit systemic circulation by applying the
glucocortioid topically.
Hyper-secretion State: Cushing’s Syndrome
Caused by  Excessive secretion of adrenocorticoid steroids
 Most commonly due to 1) increased amounts of ATCH or 2) prolonged,
high dose, systemic glucocorticoid therapy
Key Features  Adrenal atrophy
 Osteoporosis
 Increased risk of infection/decreased wound healing
 Redistribution of body fat to the face, shoulders, trunk and abdomen
 Mood and personality changes
Treatment Surgery – if caused by dysregulation of ACTH
Treatment Slow and gradual reduction of glucocorticoid dose – if caused by therapy

8
 Pharmacology of the Endocrine System
2: Drugs for the Management of Diabetes
Mellitus

PHARMACOLOGY OF THE ENDOCRINE SYSTEM 2:

DRUGS FOR THE MANAGEMENT OF DIABETES MELLITUS

Diabetes Mellitus
□ Statistics:
□ How many people are affected by diabetes?
- 2.8 million (6.8%) Canadians
- 25.8 million (8.3%) American
- 366 million (8.3%) Worldwide

□ Who are these people? Where do they live?

- In 2011, the countries with the most people affected by diabetes were 1) China, 2) India, 3) U.S.A,
4) Russia, 5) Brazil, 6) Japan, 7) Mexico, 8) Bangladesh, 9) Egypt, and 10) Indonesia

- However, by 2030, it is predicated that the top ten countries will be 1) China, 2) India, 3) U.S.A,
4) Brazil, 5) Bangladesh, 6) Mexico, 7) Russia, 8) Egypt, 9) Indonesia, and 10) Pakistan

□ What is the nurse’s role?

□ Education:
- Educate yourself. Informed decision making improves care
- Educate the patient. They need to understand treatment options, adverse effects,
monitoring efficacy, identifying adverse events and therapeutic duplication.
□ Know what is “best practice”: Best practice guidelines, Medical directives, Policies and procedures
□ Talk to your patient: Engage, listen, inquire, and learn their story
□ Advocate: Advocate for the patient and for the provider (i.e. for new, novel, better treatment)

Insulin
Endogenous hormone effects
□ Released by: The beta cells in the Islets of Langerhans in the pancreas in response to elevated
glucose levels

□ Normal effect: Insulin affects carbohydrate, lipid, and protein metabolism of most cells in the body.
- Because it moves glucose out of the circulation and into the tissues, insulin has a glucose lowering, or
“hypoglycemic” effect

□ Cellular mechanism of action: binds to receptors which activate kinases directly

- The insulin receptor is a receptor tyrosine kinase. Activation leads to internal cellular
mechanisms that regulate the number and operation of the protein molecules in the cell
membrane that transport glucose (i.e. GLUT4)
Type 1 Diabetes
Previously referred to as □ Juvenile onset diabetes
- However, this name was abandoned because in some cases, type
1 diabetes does not appear until adulthood.
- Additionally, cases of type 2 diabetes were beginning to be seen
in children
□ Insulin dependent diabetes mellitus
- This name was abandoned because some forms of type 2 diabetes
are also insulin-dependent
Caused by □ Auto-immune destruction of pancreatic beta cells, causing an absolute lack
of insulin secretion
□ Thought to be an interaction of genetic, immunological, and environmental

9

Key Features
appetite Additional information
Treatment
Mechanism of action
diabetes Route of administration
you eat +
Effects
Safety precautions
Additional considerations
Type 2 Diabetes
Previously referred to as
factors
□ Polyuria: excessive urine
□ Polydypsia: excessive thirst
□ Polyphagi: excessive hunger or
□ Sudden onset
□ Typically occurs in childhood or teen years (although not always)
□ Family history is uncommon
□ Only 10% of diabetes mellitus diagnoses are for Type 1 diabetes
Exogenous insulin
□ There are multiple types!
□ Mimics the effects of endogenous insulin.
□ Basal insulin:
- Background insulin that addresses hepatic glucose production
- Administered once daily.
- Doesn’t have a “peak action”
- Starts to work within 60-90 minutes and works for up to 24 hours
- Used to be referred to as “cloudy” insulin □ this was because the
excipients bound to it made it cloudy. However, these days, it
isn’t necessarily cloudy
□ Bolus/prandial insulin:
- Secreted in response to energy intake and glucose.
- Is administered with/just before meals (depending on how “rapid”
acting it is □ previously, you would administer insulin first and then
eat 20-30 minutes later. However, the newest forms can be given at
the same time as eating)
- Used to be referred to as “clear” insulin
□ Premixed insulin:
- Contains short and long-acting insulin.
- Patients only need 2 injections daily instead of 4
- However, premixed insulin is not best practice for type 1
□ Subcutaneous injection: inject multiple times per day (when
background/basal injections)
□ Continuous Subcutaneous Insulin Infusion (CSII): Administers
insulin hourly
□ Inhaled insulin: not commercially available yet. Only replaces quick acting
insulin, cannot replace long-acting insulin
□ Same as those of endogenous insulin
□ Insulin administration has a high risk of inducing hypoglycemia
□ Inhaled insulin cannot be given to patients with compromised
pulmonary status (e.g. smokers, COPD, asthmatics)
□ Multiple daily injections (MDI) of basal-bolus insulin or CSII are the best
insulin regimens for type 1 diabetes.
□ Insulin regimens should be tailored to the individual
□ All individuals with type 1 diabetes should be counselled about the
risk, prevention and treatment of hypoglycemia
□ Adult onset diabetes
- However, this name was abandoned because more recently, we
are seeing type 2 diabetes in adolescents
□ Non-insulin dependent diabetes mellitus
- This name was abandoned because some forms of type 2 diabetes
are also insulin-dependent
10
Caused by □ Affected by lifestyle and age
- Perfect storm of obesity, sedentary lifestyle, and an aging population
- Canadian Practice Guidelines address lifestyle modifications: 1)
healthy eating, b) increasing physical activity, c) smoking cessation,
and d) stress management
- Evidence demonstrates an ability to prevent/delay type 2 diabetes
- Drastic lifestyle changes are not a cure; however, they may
improve insulin sensitivity and enable people to come off their
medications (remission)... It is never too early to start modifying
lifestyle!
□ May also be a secondary condition caused by other drugs/health
conditions (e.g. cancer, or sterioid use)
Key Features □ Characterized by
- Insulin resistance
- An insulin secretory defect that is not auto-immune-mediated
- An increase in glucose production by the liver (leaky liver)
- Clinical considerations: As type 2 diabetes progresses, more
exogenous insulin will be required.
□ May or may not have symptoms or complications
- Symptoms are more subtle: lethargy, decrease in eye
sight Additional information □ Gradual onset
- Often, it is “brewing” in the background for 10-15 years before we have
an onset of diabetes, and even then, it make take an addition 10 years
to be diagnosed
□ Typically occurs in adults > 40 (although not always)
□ Family history is common
□ 90% of diabetes mellitus diagnoses are for Type 2 diabetes
Treatment (General ferent mechanism. Combination therapy will address multiple
considerations) pathophysiological defects
□
r □ When deciding on an appropriate treatment, consider the effects of the
e treatment on:
a - The blood glucose lowering efficacy (assessed by % decrease in HbA1C)
t and durability
m - Risk of inducing hypoglycemia
e - Effect on weight
n - Contraindications and/or side effects
t - Cost/insurance coverage
s
□ When deciding on an appropriate treatment, also consider the patient’s
a
characteristics:
c
- Degree of hyperglycemia
t
- Risk of hypoglycemia
b
- Overweight or obese
y - Co-morbidities (renal, hepatic tissues)
m - Preferences or access to treatment
u
lt □ The higher the baseline 1AC levels, the greater reduction there is with
i therapy □ 1% higher baseline A1C = 0.5% greater reduction in A1C after 6
p months of therapy (regardless of drug class or dose)
l
e □ The benefit of any drug is most apparent in the first 6 months of treatment.
d - Speaks to the durability of treatment and the idea of combining
i therapies
f
□ Timely adjustments to and/or addition of antihyperglycemic agents should

11
 be made to attain target A1C levels within 6-12 months. If changes are not
being seen within 2-3 months, additional medications and insulin should be
added
Treatment: Alpha-glucosidase inhibitors (AGI)
□ Acarbose (Glucobay)
Mechanism of action □ Inhibits the action of pancreatic alpha-amylase and intestinal alpha-
glucosidase, thus delaying/limiting carbohydrate
absorption Route of administration □ Oral
□ Administered with
meals
Effects □ Lowers A1C by < 1.0%
□ Study results: doses of 150 mg/day or higher achieved a 1% reduction
in A1C
Safety precautions □ Risk of hypoglycemia is negligible when used as a monotherapy because it
does not stimulate insulin secretion/action
□ Side effects are predominately gastrointestinal
Treatment Anti-obesity agent
□ Orlistat (Xenical)
Mechanism of action □ Inhibits lipase in the intestine, thus delaying/inhibiting fat absorption.
- Dyslipidemia is associated with decreased insulin sensitivity
- Weight loss is associated with increased insulin
sensitivity Route of administration □ Oral
□ Administered 3x daily with meals
Effects □ Lowers A1C by < 1.0%
Safety precautions □ Risk of hypoglycemia is negligible when used as a monotherapy because it
does not stimulate insulin secretion/action
□ Side effects are predominately gastrointestinal
Treatment Biguanide
□ Metformin (Glucophage, Glumetza)
Mechanism of action □ Enhances insulin sensitivity in liver and peripheral tissues by activation of
AMP-activated protein kinases
- Decreases hepatic glucose production
- Enhances sensitivity of peripheral
tissues Route of administration □ Oral
Effects □ Lowers A1C by <2.0%
□ Study results: doses of 1500 mg/day achieved a 1% reduction in A1c
Safety precautions □ Risk of hypoglycemia is negligible when used as a monotherapy because it
does not stimulate insulin secretion; however, it may induce hypoglycemia
when used in combination with other drugs
□ Side effects are predominately gastrointestinal. Some patients report
a metallic taste
Additional considerations □ Should not be prescribed in renal insufficiency
- Metformin is eliminated by the kidneys in a primarily unchanged form.
Thus, one of the most important risk factors for elevated metformin
concentrations is the inability to clear the drug effectively
□ Should not be prescribed in patients with hepatic failure
- Metformin acts predominately on the liver to decrease hepatic
glucose production.
- Metformin reduces lactate clearance and is implicated in lactic
acidosis (although there is some debate in the literature)
□ May cause B12 deficiency
- Metformin affects calcium-dependent membrane action. The
B12- intrinsic factor complex is known to be calcium dependent
Treatment Bile Acid Sequestrants (BAS)
□ Colesevelam (Welchol)

12
 Mechanism of action □ Impedes intestinal re-absorption of bile
- Lowers LDL □ Lowered LDL has positive effects on insulin sensitivity
Route of administration □ Oral
Effects □ Lowers A1C by <1.0%
Safety precautions □ Risk of hypoglycemia is negligible when used as a monotherapy because it
does not stimulate insulin secretion/action
□ Side effects include constipation and dyspepsia
Treatment Dopamine agonist
□ Bromocriptine-QR (Cycloset)
Mechanism of action □ Activates hypothalamic dopaminergic receptors that regulate peripheral
fuel metabolism
Route of administration □ Oral (may have quick release formulations)
Effects □ Lowers A1C by <1.0%
Safety precautions □ Risk of hypoglycemia is negligible when used as a monotherapy because it
does not stimulate insulin secretion/action
□ Side effects include nausea, orthostasis, and nasal congestion
Treatment Dipeptidyl peptidase-4 inhibitor (DPP-4)
□ Sitagliptin (Januvia)
□ Saxagliptin (Onglyza)
□ Linagliptin (Trajenta)
Mechanism of action □ Amplifies incretin pathway activation by inhibiting the enzymatic
breakdown of GLP-1 and GIP
- Incretins are hormones secreted by the intestine following a meal
when glucose is elevated which signal the pancreas to increase insulin
secretion and the liver to stop glucose production. GLP-1 also slows
glucose absorption in the intestine.
- Diabetic patients are unable to secrete incretins in adequate amounts.
- The normal function of DPP-4 is to break down incretins such as GLP-
1 and GIP. Thus, DPP-4 inhibitors reduce the destruction of incretins,
increases incretin levels, increases insulin secretion and decrease/slow
glucose absorption
Route of administration □ Oral: Sitagliptin and Saxagliptin
□ Subcutaneous injection: Liraglutide
Effects □ Lowers A1C by <2.0%
□ Study results: doses of 100 mg/day or higher achieved ~1% reduction
in A1C
Safety precautions □ Risk of hypoglycemia is negligible when used as a monotherapy
□ Pancreatitis has been observed, but the mechanism for this effect is unclear
□ The table from the lecture suggests that this drug class should not be
used in patients with renal disorders
Additional considerations □ New approach (just developed in the last 4-5 years)
Treatment Glucagon like peptide-1 (GLP-1) receptor agonist
□ Exenatide (Byetta), Liraglutide (Victoza)
Mechanism of action □ Activates the incretin pathway by utilizing a DPP-4 resistant analogue to
GLP-1
- Slows down the digestive system and the rate of glucose absorption
- Remember the Gila monster which can go for months without
eating and not have low blood sugar
Route of administration □ Subcutaneous injection
Effects □ Lowers A1C by <2.0%
Safety precautions □ Risk of hypoglycemia is negligible when used as a monotherapy
□ Side effects include nausea and vomiting, weight loss,
pancreatitis, parafollicular cell hyperplasia
- Contraindicated in individuals with a family history of medullary

13

Treatment
Mechanism of action
protein Route of administration
Subcutaneous
Effects
Safety precautions
Additional considerations
□ Prolonged diabetes depletes insulin reserves, forcing many patients to go
Treatment Insulin secretagogues – Sulfonylureas and Meglitinides
Mechanism of action
Route of administration
Effects
Safety precautions
Additional considerations
Treatment
Canagliflozin Mechanism of action □ Inhibits renal glucose re-absorption
Route of administration
Effects
Safety precautions
Treatment
Mechanism of action
Route of administration
Effects
thyroid cancer or multiple endocrine neoplasia syndrome
□ The table from the lecture suggests that this drug class should not be
used in patients with renal disorders
Insulin
□ Binds to the insulin receptors to regulate the metabolism of carbohydrate,
fat and
□
□ Insulin pump: delivers insulin via a pliable catheter to subcutaneous
tissues in the abdomen
□ Lowers A1C by < 2.5%
□ Significant risk of hypoglycemia
- This risk is increased with the short and intermediate acting insulin
□ Side effects include weight gain
□ Is sometimes cheaper than other therapies
on insulin. Having to go on insulin should not be perceived as a failure
□ Glyburide (Diabetes, Euglucon), Glimepiride (Amaryl),
Gliclazide (diamicron/MR), nateglinide (Starlix), Repaglinide
(Gluconorm)
□ Activates the sulfonylurea receptor on beta-cells to stimulate endogenous
insulin secretion (the textbook notes that sulfonylureas also increase the
sensitivity of insulin receptors on target cells)
- Sulfonylureas have a more rapid and pronounced effect (helps the
body to secrete insulin)
- Meglitinides are “more gentle” (tutorial – we learned that
meglitinides help actually make insulin)
□ Oral
□ Lowers A1C by < 2.0%
□ Study results:
- Glimepiride: doses of 8 mg/day or higher achieved a 1.25%
reduction in A1C
- Nateglinide: doses of 360 mg/day achieved a 0.75% reduction in A1C
□ Moderate to significant risk of hypoglycemia
□ Would need to eat
□ Side effects include weight gain
□ It is possible to adjust the dose of these medications
□ Should be used with caution in patients with renal and/or hepatic
issues and in the elderly
Sodium glucose co-transporter-2 inhibitor (SGLT-2)
□ Dapagliflozin, Sergliflozin, Remagliflozin,
□ Oral
□ Lowers A1C by < 2.0%
□ Risk of hypoglycemia is negligible when used as a monotherapy
□ Side effects include polyuria and increased genital and urinary
tract infections
Thiazolidinediones (TZD)
□ Pioglitazone (Actos), Rosiglitazone (Avandia)
□ Enhances insulin sensitivity in peripheral tissues and liver by activation of
peroxisome proliferator-activated receptor-gamma (PPAR) receptors
- Inhibits hepatic gluconeogenesis
□ Oral
□ Lowers A1C by < 2.0%
□ Study results:
14
 - Rosiglitazone: 8 mg/day achieved a 1.25% reduction in A1C
- Pioglitazone: 30 mg/day achieved a 1.0% reduction in A1C
Safety precautions □ Risk of hypoglycemia is negligible when used as a monotherapy
□ Side effects include weight gain (2-4 kg, in part due to fluid retention),
edema, congestive heart failure (due to effects on fluid retention), macular
edema, fractures, myocardial infarction, and possible increase in cancer
risk
Additional considerations □ Has been in the news a lot in the last 5-8 years
□ Has received the “black label” from Health Canada
□ Liver function tests should be performed because this class of drugs may
be hepatotoxic

15
 PHARMACOLOGY OF THE ENDOCRINE SYSTEM 3:
DRUGS FOR THE FEMALE REPRODUCTIVE SYTEM

Regulation of Female Reproductive Hormones

□ Recall hypothalamus and anterior pituitary effects:
1. The hypothalamus releases Gonodotrophin releasing hormone (GnRH)

2. GnRH stimulates the anterior pituitary to release Luteinizing

hormone (LH) and Follicle Stimulating Hormone (FSH)

3. LH and FSH stimulate the release of sex sterioids (progesterone,

estrogen, and androgens), produced in the gonads

4. Sex steroid have many affects in the body:

- Increase sex drive (libido) (especially testosterone)
- Secondary sexual characteristics (body hair, muscle growth
etc... depends on gender)
- Affect the ovaries and uterus in the menstrual cycle

5. There is negative feedback of the sex hormones to the pituitary

and hypothalamus

□ Hormonal changes during the ovarian and uterine cycles

1. The hypothalamus releases GnRH which stimulates the anterior pituitary to produce and release
LH and FSH □ stimulate follicle maturation

2. LH and FHS stimulates the release of estrogen □ ultimately leads ovulation

16
 - Initially, estrogen has positive local control (feeds back on cells producing estrogen to
increase the number of LH and FSH receptors) and negative central control (decreases the
release of GnRH, LH and FSH, which prevents further growth of less developed follicles)
- Right before ovulation, when the estrogen concentration has been high for at least 2 days,
the central negative feedback switches to central positive feedback and there is an increase
in the production of LH and FSH causing ovulation

3. At the end of ovulation:

- The central positive feedback is switched back to central negative feedback, decreasing the
levels of GnRH, LH and FSH
- The corpus luteum stimulates the secretion of progesterone and estrogen
- Increased estrogen and progesterone production promote endometrial vascularation
and thickening. (Note: the effects of progesterone dominate at the level of the uterus)

4. Onset of menstruation
- As the corpus luteum degrades, estrogen and progesterone secretion is inhibited (also note
that GnRH, LH and FSH levels have also dropped off). This causes the endothelial lining of
the endometrium to shed □ onset of menstruation

Estrogens
Endogenous hormone effects
□ Estradiol
- The major ovarian estrogen produced by the reproductive female
- Most potent of all 3 estrogens (10x more potent than estrone)
- Arises from the action of aromatase on testosterone (i.e. it is produced from the metabolism
of testosterone)

□ Estrone
- Is also produced by the reproductive female, but to a lesser extent. Estrone predominates during
menopause (is well stored in and released from fat □ this is, in part, why we see changes to body
fat in menopause)
- Arises from the action of aromatase on androstenedione

□ Estriol
- Primary circulating form of estrogen during pregnancy
- Is produced by the placenta

□ Released by: the ovaries in response to LH and FSH as discussed above

□ Biological effects:
- Growth and maturation of female reproductive
organs o Proliferation of the uterine
endometrium
o Thickening of the vaginal mucosa
Clinical considerations: Young women have a less thick vaginal mucosa that is more
susceptible to micro-tears and thus makes young women more susceptible to STDs and
infection as compared to older women. Older women have a thicker mucosa which is more
resistant to the friction and pressure of penetration
- Female pattern of fat deposition (breast, buttocks, thighs)
- Increased bone deposition
- Increased vascularity of the skin (women look “freshest/brightest” when they are young and
fertile and in particular when they are ovulating)
- Inhibits LDL formation and increases HDL cholesterol

17
 - Enhances coagulation via increased production of clotting factors
- Production of thin, clear, watery and elastic cervical mucus (facilitates the movement of sperm)

□ Cellular mechanism of action: Binds to intracellular receptors (is lipid soluble). The hormone-
receptor complex affect cellular responses by acting as transcription factor
Progestins
Endogenous hormone effects
□ Progesterone is the most active endogenously

□ Released by: the ovaries in response to LH and FSH as discussed above

□ Normal effects
- Increases mucus thickness and prevents sperm entry
o After ovulation, we want to decrease the risk of a second ovulation [this is also why FSH and
LH levels drop] or fertilization
o The thick mucus also helps to prevent/limit infection
- Limits and stabilizes endometrial growth (receptive and quiet to a pregnancy)
- Inhibits myometrial contractions
- Increases body temperature

□ Cellular mechanism of action: Binds to intracellular receptors (is lipid soluble). The hormone-
receptor complex affect cellular responses by acting as transcription factor

□ Clinical considerations: Progesterone is completely metabolized in the gut. Therefore, we cannot

give progesterone (in its naturally occurring form) orally. Thus, in order to see a physiological
effect, we always administer synthetic progestins
Oral Contraceptives
Intervention Combination Contraceptives
□ Contain a synthetic estrogen (longer half-life) and progestin (which
remain active when administered orally).
□ With some formulations you take the same dose every day (monophasic).
With other preparations you take different doses each week (tri-phasic)
Mechanism of action □ Estrogen and progesterone agonists. However, we manipulate the normal
concentrations of these hormones and administer larger quantities than
would be present naturally to “trick the body into thinking that it is already
pregnant”
Route of administration □ Most combination preparations involve taking 21 days of hormone followed
by 7 days without hormones to allow for menstruation

□ Some exceptions:
- Seasonique: Extended regimen oral contraceptive □ 84 days
of hormone therapy, 7 days of placebo

- Ortho-Evra: Transdermal patch changed once per week (takes

advantage of the fact that estrogen and progestin are fat
soluble)
o Clinical considerations: Excellent choice for female clients seeking a
dosage regime that does not involve daily administration

- NuvaRing: Inserted into the vaginal canal for 3 weeks (takes

advantage of the fact that estrogen and progestin are fat soluble)
o Clinical considerations: Excellent choice for female clients seeking a
dosage regime that does not involve daily administration
Effects □ Suppress the release of GnRH, resulting in low LH and FSH levels □ thus
inhibiting ovulation

18

Safety precautions
pregnant Additional considerations □ Estimated failure rate of 0.7 per 100 women years
Treatment
Mechanism of action
Route of administration
Effects
implantation Safety precautions
□ Produces a thick cervical mucus that inhibits sperm migration
□ Creates a “hostile” endometrium (i.e. the endometrium is not in the
secretory phase (it is atrophic and thin) thus it does not allow the zygote
to implant)
□ Thromboembolism
- Estrogen increases the risk of thromboembolic events such as
stroke MI, deep vein thrombosis (DVT), and pulmonary embolism
- These risks are specially increased in women who smoke (and are
>35 years of age) and in women with a history of these conditions
□ Breast cancer
- No increase in lifetime risk, but some evidence suggests that it
may cause estrogen-dependent breast cancer to manifest earlier in
life.
□ Other: breakthrough bleeding, nausea, vomiting, weight changes, breast
tenderness, migraine headaches (may exacerbate pre-existing
conditions), depression (may exacerbate pre-existing conditions)
□ You should not take oral contraceptive when you are actually
- One or two missed pills may be sufficient to cause proliferation of
the endometrium and ovulation
- Adherence must be high to ensure efficacy
□ Clinical considerations: Administering estrogen on its own would actually
be sufficient to confer efficacy. However, unopposed, estrogen increases the
risk of endometrial cancer in women. Thus, if a woman has an intact uterus,
estrogen only therapy is not an option
□ Clinical considerations: Because these drugs are administered orally,
they are not recommended for patients with GI illnesses... For the same
reason, even though some antibiotics will up-regulate, down-regulate, or
not affect P450 activity and metabolism of estrogen and progesterone, we
would not trust the efficacy of oral contraceptives in patients taking
antibiotics due to their effect on the gastrointestinal bacteria and drug
absorption.
Progestin only contraceptives
□ Progesterone agonist
□ Oral formulation
- Contains a synthetic progestin
- Must be taken every day (within 3 hours, no breaks)
□ Depo-Provera
- Injectable (intramuscular) medroxyprogestrone acetate
- Provides contraception for 3 months
- Administered 5 days after the onset of menstruation
- Clinical considerations: Good choice for individuals with
poor adherence.
□ Creates a thick and scanty cervical mucus, preventing the movement of
sperm across the cervix
□ Endometrium is kept in an atrophic state, inhibiting zygote
□ Low dose formulations may not reliably inhibit ovulation!
- If a dose is taken 3 or more hours late, it is recommended that the
client use a barrier method of contraception for 48 hours after the
missed pill
- If a single day is missed, a barrier method of birth control is required
for the rest of the cycle. The client cannot take 2 pills to make up for
a
19
 missed pill and expect contraceptive coverage
- Clinical considerations: Not a good choice for clients with
poor adherence

□ General adverse effects: Irregular menstrual cycle, breast

tenderness, nausea, stomach cramps, acne, bloating and weight gain

□ Depro-provera specific risks

Additional considerations
- Mean time to pregnancy after cessation of therapy is 10 months
- Long-term use associated with a reduction in estrogen levels leading
to bone loss. Thus, this drug should not be used for longer than 2
years
□ Oral formulations have a failure rate of 1.2 per 100 women years. However,
this is predominately associated with adherence. Injectable formulations
have a failure rate of 0.3 failures per 100 women years

□ There are no side effects associated with estrogen (bc there isn`t any!)
- Good choice for women with increased risks of blood clots
- Also a good choice for breastfeeding mothers because it
doesn`t interfere with lactation (estrogen inhibits milk
production)

□ Clinical considerations: Metabolism will be affected the negative effects

of antibiotics on gastrointestinal flora.
Post-coital (emergency) contraceptives
Treatment Estrogen or estrogen + progestin combination
therapy Mechanism of action □ Estrogen and progestin agonists
Route of administration □ Oral
□ High dose estrogen therapy
- Must be administered within 72 hours of intercourse and
continued twice daily for 5 days

□ Estrogen and progestin combination therapy

- Two doses of ethinyl estradiol plus levonorgestrel within 72 hours
of intercourse, plus two more doses 12 hours later
Effects □ Massive amounts of hormones inhibit ovulation and implantation
Safety precautions □ Side effects of high-dose estrogen therapy include nausea, vomiting,
dizziness, headache, edema, hypertension and breast tenderness
- Clinical considerations: These drugs are often co-administered with
an antiemetic drug to help prevent the patient from vomiting up the
drug
Treatment Antiprogestins
□ RU486 (Mifepristone) (aka the morning after
pill) Mechanism of action □ Blocks the affects of progesterone
Route of administration □ Oral
□ Administered in a single dose within 3 days of intercourse to
prevent pregnancy (note: medical definition of pregnancy is
fertilization + implantation)
Effects □ Leads to endometrial shedding
Additional considerations □ Chemical abortion can be accomplished up to 9 weeks after conception by
co-administration of misoprostol to cause or supplement uterine
contraction
Menopause
Caused by □ Decreases in natural hormone levels
Key features □ Insomnia
□ Hot flashes
□ Vaginal atrophy

20
 □ Mood disturbances and irritability
□ Osteoporosis
Treatment Hormone replacement therapy
□ Combination estrogen and progestin hormone replacement therapy
first used to treat ovarian failure and symptoms of
Mechanism of action □ Hormone receptor agonists
Route of administration □ Oral
Effects □ Replaces endogenous hormone levels
Safety precautions □ Replacing endogenous estrogen does not confer long-term health benefits.
In contrast, the results of the WHI trial (2002) indicate that HRT is
associated with a small but significant increase risk of coronary artery
disease, stroke, breast cancer, and deep vein thrombosis in menopausal
women
- The level of risk depends on the individual – health history,
age, number of years since start of menopause
- Clinical considerations: The only benefit of HRT is relief of
menopausal symptoms. Thus, if it is possible to treat these symptoms
locally rather than systemically, we should try this first. HRT should
only be prescribed if it interferes with quality of life.

□ HRT should not be administered for more than 5 years and should not
be prescribed to women over the age of 59 years

21
 PHARMACOLOGY OF THE ENDOCRINE SYSTEM 4:
DRUGS USED IN PREGNANCY

□ Contraction of uterine smooth muscle

- Requires the release of calcium from the sarcoplasmic reticulum in smooth muscle cells
- Initiated by the stimulation of
o Gi protein coupled receptors □ inhibits the activity of adenyl cyclase and the conversion
of ATP to cAMP □ inhibits protein kinases □ inhibits the phosphorylation of the Ca2+ on
the sarcoplasmic reticulum □ inhibits calcium sequestering □ more calcium available for
contraction
o Gq protein coupled receptors □ stimulates the activity of phospholipase C □ stimulates
the cleavage of PIP to IP3 and DAG □ IP3 binds to the sarcoplasmic reticulum □
stimulates Ca2+ release

- Initiated by the inhibition of

o Gs protein coupled receptors □ inhibits the activity of adenyl cyclase (same cascade
as above)

Oxytocin
Endogenous hormone effects
□ Released by:
- The placenta and mother’s posterior pituitary due to uterine stretching
1. As the baby gets larger, stretching of the uterine muscle induces the release of estrogen
2. Estrogen induces oxytocin receptors on the uterus initiates a positive feedback loop
3. Stimulates the release of oxytocin from the placenta and the mother’s posterior pituitary

- Posterior pituitary due to suckling of the newborn

1. Suckling stimulates nerves in the breast
2. Nerve impulses sent to the hypothalamus
3. Hypothalamus sends impulse to the posterior pituitary
4. Posterior pituitary releases oxytocin

□ Normal effects:
- Increases the frequency and force of uterine contractions
- Stimulates the placenta to make prostaglandins □ stimulate more vigerous contractions of
the uterus + thinning of cervix (ripening) □ initiates a positive feedback cycle
- Oxytocin stimulates the muscle of the mammary gland to contract □ squeeze out milk

□ Cellular mechanism of action: Gq protein coupled receptor □ increases conversion of PIP to IP 3 and DAG
□ IP3 binds to the sarcoplasmic reticulum and stimulates Ca2+ released □ muscle contraction

□ Other considerations:
- Oxytocin only binds to receptors in the uterus to stimulate contraction. This is in contrast to other
hormones or drugs such as ergonovine which binds to Gq protein coupled receptors all over the
body (e.g. alpha1 adrenoreceptor) and may induce contraction

- Oxytocin receptors are only present on the uterus in the second half of pregnancy.
Stimulation of Uterine Contraction □ Oxytocins
□ Oxytocics refer to any agent that is used to stimulate the uterus to contract
□ Are used for the induction of labour and to control postpartum hemorrhage
- Clinical considerations: Oxytocins are always used – even with “natural birth” – because they facilitate
contraction and clot formation and thus prevent uncontrolled uterine hemorrhage after delivery

22
Treatment
Mechanism of action
Route of administration
Effects
Safety precautions
Additional considerations
Treatment
Mechanism of action
vessels Route of administration□ Intramuscular
Effects
Safety precautions
Additional considerations
Treatment
Mechanism of action
Route of administration
Effects
Pitocin, Syntocin
□ Oxytocin receptor agonists □ stimulates Gq
□ IV infusion: Uterine response occurs almost immediately and subsides
within one hour.
□ IM injection: Uterine response occurs within 3 to 5 minutes and persists
for 2 to 3 hours
□ IV infusion: Used for induction (to start labour) and augment (enhance
contractions) during labour. Dose is increased every 15-60 minutes until
a normal labour pattern is established (3 contractions of about 45
seconds each per 10 minutes)
□ IM injection: Used to prevent post-partum hemorrhage
□ Oxytocin binds to the ADH receptor (at high concentrations) and possesses
an anti-diuretic effect. This may lead to pulmonary edema, heart failure
and water intoxication. Clinical considerations: Monitor the patient for
signs of edema and trouble breathing
□ Oxytocin infusion should be terminated if contractions are less than 2
minutes apart and last longer than 90 seconds as these are signs of
uterine hypertonus, i.e. contracting too hard and too fast. This can lead
to uterine damage or rupture and fetal oxygen deprivation (i.e.
asphyxiation).
□ Fetal distress and maternal complications are also indications for
stopping oxytocin infusion.
□ Clinical considerations: Oxytocin receptors do not appear on the uterus until
the second half of gestation (at which point there is a 100-200 fold
increase). Therefore, if you administer an oxytocic drug in the first half of
gestation, it will not have an effect on the uterus
Ergot Alkaloids
□ Ergonovine
□ Binds to Gq protein coupled prostaglandin E1 receptors in the uterus and α-
1 adrenoceptors in blood
□ Intramuscular administration produces contractions of uterine smooth
muscle within 1-5 minutes that persist for 3 hours
□ Also causes contraction of the vascular smooth muscle
□ Must monitor the patient for significant increases in blood pressure
□ Used primarily for post-partum hemorrhage control; however, due to the
risks associated with this drug class, we generally avoid its use in North
America (it is still used in other countries because its cheap)
□ Due to risk of uterine hypertonus, ergonovine should not be given to
induce labour
Prostaglandins
□ Dinoprostone
□ Misoprostol/Cytotech
□ Bind to Gi and Gq protein coupled prostaglandin receptors
□ Misoprostol binds to Gi linked prostaglandin E1 receptors and uterine
EP3 receptors
□ Commonly administered vaginally
- Clinical considerations: Patients should be instructed not to take a
bath as this will dilute the gel
□ Dinoprostone: Causes cervical ripening (causes the cervix to thin and open),
initiation of labour, abortificient
□ Misoprostol: Causes cervical ripening (greater efficacy than
dinoprostone), controls postpartum hemorrhage (not in North America),
abortificient
23
Safety precautions □ May cause nausea, vomiting, headache, diarrhea, hypertension and
bronchospasm due to stimulatory effect on smooth muscle
□ Due to risk of hypertonus, contraindicated in women with:
- Previous caesarean section
- Previous uterine surgery
- Previous history of uterine hypertonus
- Ruptured membranes
- In combination with other oxytocics
□ Should not be used for augmentation of labour (induction only!)
Additional considerations □ Semen contains prostaglandins! Can help to stimulate cervical ripening
□ Generally, we don’t use prostaglandins to prevent post-partum
hemorrhage in North America because of adverse effects associated with
this drug class. However, they are still clinically relevant in other
countries because they are cheap!
Inhibition of Uterine Contraction: Tocolytics
□ Tocolytics refer to any agent that inhibits uterine contraction (i.e. induces relaxation of the
uterine muscles) by decreasing intracellular calcium levels

□ Commonly used for preterm labour, cephalic version, or relief of uterine hypertonus when a patient
has received too much of an oxytocic drug
- Clinical considerations: If the uterine is contracting too much during labour (uterine hypertonus),
there could be occlusion of blood vessels. This can decrease oxygen delivery to the fetus and
cause developmental issues. Forceful contractions may also cause the uterus to rupture

□ Cannot suppress myometrial contractions in cases of high irritability or strong stimulation of the
myometrium □ almost nothing will prevent an irritable uterus from contracting – our best hope is
to slow it down and improve the overall outcome of the fetus
- Tocolytics are administered in cases of preterm labour to delay delivery for up to 48 hours. This
allows for the administration of glucocorticoids and delivery at a facility with access to a neonatal
ICU

□ Should only be used:

- Between 23 and 32 weeks of pregnancy. Complications at birth are unlikely after 34 weeks and
thus tocolytic drugs should not be used at this stage
- When the patient is experiencing regular contractions that last longer than 45 seconds and occur 2
to 10 minutes apart
- When the cervix is dilated more than 2 cm and has begun to efface (thin)

□ Side note on glucocorticoids:

- Not tocolytics
- Glucocoticoid therapy is recommended for women between 23 and 34 weeks of pregnancy who
are likely to deliver a premature baby within 7 days.
- Steroids help speed up the development of the lungs (increase surfactant) significantly
improving outcome
- Reduces complications associated with respiratory distress syndrome (RDS), bleeding in the
brain, necrotizing entercolitis, and sepsis by 50%
- Bethamethasone – 12 mg every 24 hrs (2 doses)
Treatment Beta2 Adrenergic
Agonists
□ Ritodrine hydrochloride
Mechanism of action □ Stimulates Gs protein couple B2-adrenergic receptors □ stimulates
adenylyl cyclase □ induces phosphorylation and sequestration of calcium
□ decrease uterine contraction
Effects □ Smooth muscle relation of the uterus (and peripheral vasculature)
Safety precautions □ May induce reflex tachycardia due to dilation of peripheral blood vessels

24
Additional considerations □ Used when attempting cephalic version
Treatment Oxytocin Receptor Antagonists
□ Atosiban
Mechanism of action □ Antagonises the binding of oxytocin at its receptor site □ inhibits Gq
Effects □ Smooth muscle relaxation of the uterus and breast myoepithelial cells
Safety precautions □ Few side effects: nausea, headache, vomiting
Additional considerations □ Demonstrates the same clinical efficacy as beta2-adrenergic agonists,
without the associated cardiovascular effects. Thus, are the gold
standard! However, they are very expensive
Treatment Calcium Channel Blockers
□ Nifedipine
Mechanism of action □ Blocks the entry of exogenous calcium into the myometrium
Effects □ Prevents smooth muscle contraction
Safety precautions □ Possibly fewer effects compared to beta-agonists, but can still cause
headache, hypotension
Additional considerations □ Most commonly used for the treatment of angina
□ May be used for pregnancy-induced hypertension

25
 PHARMACOLOGY OF THE ENDOCRINE SYSTEM 4:
DRUGS USED FOR THE TREATMENT OF OSTEOPOROSIS

Bone Health & Calcium

□ Bone is mineralized connective tissue that functions as
1. Structural support for the body, and
2. A reservoir for calcium, phosphate (phosphorus), sodium, magnesium, and carbonate

□ Calcium:
□ Metabolic functions of calcium: Adequate levels of calcium are required for almost all
physiological functions, including:
- Building and maintaining healthy bones and teeth
- Cell membrane permeability & function
- Neuronal excitability & transmission of electrical impulses
- Contraction of cardiac, skeletal & smooth muscle
- Conduction of electrical impulses in the heart
- Blood coagulation
- Platelet adhesion
- Hormone secretion
- Enzymatic activity
- Catecholamine release from adrenal medulla
- Release of chemical mediators (e.g. histamines from mast cells)

□ Clinical consequences: If normal serum calcium levels are not kept in balance, diseases often result
- Hypercalcemia (calcium levels are too high) □ decreased sodium permeability across
cell membranes □ impaired nerve conduction (sodium influx is required for nerve
condition)
o Signs include: drowsiness, lethargy, weakness, headache, anorexia, nausea and vomiting,
increased urination and thirst

- Hypocalemia (calcium levels are too low) □ cell membranes are hyper-excitable □ may result
in muscle spasms or convulsions
o Signs include: seizures, muscle spasms, facial twitching, paresthesia

□ Calcium Storage
□ 99% of calcium in the body is located in teeth and bone.
- Within the bone, calcium is in the form of calcium carbonate, calcium phosphate and a
small amount of unbound, ionized calcium (Ca2+).
□ The extra 1% of calcium in the body is in the extracellular space and soft tissues

□ Calcium homeostasis:
□ During an individual’s lifetime, bones are constantly formed and then broken down in a
process called remodelling. During this process, calcium continuously shifts between bone and
serum, as bones cycle through the process of deposition and resorption.
- Deposition: Calcium from the diet moves from the intestine into the bone.

- Resorption: When serum calcium become low, the unbounded ionized calcium (Ca2+) stored
in the bone will be taken up and moved into the serum to compensate.

26
 □ In normal bone homeostasis, the rate of deposition will be roughly equal the rate of resorption.
During childhood, adolescents and early adulthood, bone formation usually exceeds breakdown as
the individual attains adult height and peak bone mass. After 35 years of age, the rate of bone
resorption becomes greater than the rate of deposition. This shift in bone remodelling is a normal
process of aging.

□ Dietary Calcium:
□ To keep our bones healthy, calcium is obtained through diet. However, only 30-50% of
consumed calcium is absorbed in the intestine, the rest is lost in feces.
- The absorption of calcium in the intestine is increased in the presence of vitamin D,
Lactose, moderate amounts of fat, high protein intake, and physiological need.
- The absorption of calcium in the intestine is impaired in instances of vitamin D deficiencies,
high fat diets, or diarrhea.

□ Daily calcium requirement

- Adults: 1000 mg
- Growing children: 1200 mg
- Pregnant & Lactating women: 1200 mg
- Postmenopausal women (no HRT): 1500 mg

□ Dietary Sources
- Milk and milk products (3 * 250 ml/day contain the amount of calcium needed for
healthy calcium. This is an important source bc it also contains vitamin D and lactose)
- Vegetables (e.g. broccoli, spinach, kale)
- Shellfish (e.g. oysters, clams)
- Excessive intake of zinc-rich foods (nuts, legumes, seeds, sprouts, and tofu) may
decrease calcium absorption

Osteoporosis
□ Osteoporosis is a systemic skeletal disorder characterized by decreased bone mass density
(BMD) leading to:
1. Diminished stature
2. Bone fragility
3. Increased risk of bone fracture Clinical considerations: Osteoporosis usually isn’t diagnosed until
a bone has been fractured. The public health and clinical importance of osteoporosis lies in the
fractures associated with the disease

□ Note: In healthy adult women, bone strength and density begins to decline after 35 (bone is lost
more quickly than it is replaced). However, osteoporosis causes severe bone loss and risk, at a rate
much faster than normal loss.

□ Risk factors:
□ Modifiable risk factors: Unfortunately, these are only minor risk factor
- Smoking: increases calcium excretion via kidneys
- Calcium and Vitamin D deficiency: increases bone resorption
- Increased sodium (i.e. salt) or protein intake: increases calcium excretion via the kidneys
and increases bone resorption
- Increased caffeine and alcohol: cause dieresis, leading to increased calcium excretion via the
kidneys

27
 - Lack of exercise/sedentary lifestyle: exercise helps bone retain calcium and increase
bone density. Immobilization will also increase risk.
- Clinical considerations: There is a significant opportunity for patient education to improve health.
Changes to diet and regular a exercise regiment can substantially decrease risk of osteoporosis
especially if implemented in childhood and early adulthood when bone density is still increasing

□ Unmodifiable risk factors: Unfortunately, many of these are major risk factors for the disease
- Female gender
- Advanced age
- Prolonged amenorrhea
- Early Menopause: During menopause, estrogen secretion declines and bones become weak
and fragile. Normal levels of estrogen limit the activity of osteoclasts. When estrogen levels
drop, osteoclast activity is no longer inhibited, and the rate of bone resorption increases,
resulting in a substantial loss in bone mass density
- Fragility fractures in women > 40 years
- Ancestry: Women of Northern European (Caucasian) & Asian decent have a higher risk
of osteoporosis than those of African descent. However, postmenopausal women in all
ethnic groups are at increased risk
- Small & lean frame: Suggests small bones and therefore less bone mass
- Family history of disease: A family history of osteoporosis (especially in the maternal side of
the family), confers an increased risk for osteoporosis
- Glucocorticoids (> 3 months): chronic glucocorticoid administration inhibits bone
deposition and increases bone resorption

□ Clinical considerations:
- Osteoporosis is a preventable disease if the associated risks are identified early and
appropriate patient education is implemented (i.e. diet, exercise).
- Unfortunately, once a diagnosis has been made, lifestyle changes on their own will not
be sufficient to prevent further fractures and pharmacological therapy will be required

□ Statistics and Prevalence:

□ In Canada, 1 in 4 women and 1 in 8 men have osteoporosis
□ Caucasian women have a remaining lifetime risk of 40% for hip, vertebra or wrist fractures
□ Osteoporosis is a major health problem worldwide, and its incidence is increasing because of
our aging population □ 25% of the population will be 65 and older by 2014. Thus, the incidence
of osteoporosis is expected to increase significantly over the next few decades.

□ Health Care Burden:

□ There is a 1/6 lifetime risk of developing osteoporosis. This is actually greater than the 1/9 risk
of developing breast-cancer.
□ The death rate associated with hip fracture is considerably higher than the death rate associated
with breast-cancer
□ 50% of women with fractures are unable to return to their previous functional state and
become dependent on other for daily activities (20% require long term care)
□ Given that 25% of th Cnd pop will be 65 or older in 30 years, this is concerning

□ Nursing Interventions:
□ All adult patients over 50 (including men) should be assessed for major and minor risk factors.

28
 □
□
□ Public Health initiatives highlighting the importance of regular weight bearing exercise and a
calcium and Vitamin D rich diet throughout all life stages must be made a priority – especially in
young children

Bone Mass Density Testing

□ All post-menopausal over than 50 should be assessed for the presence of minor and major risk factors
for osteoporosis. Then, those with 1 or more of the following major risk factors (65 years of age and
older; fragility fracture after the age of 40; family history of osteoporotic fracture; or systemic
glucocortricoid therapy for > 3 months) should receive a bone mass density (BMD) test

□ Bone mass density tests are preformed using dual energy x-ray absorptiometry. This test scans the
lumbar region and one hip and takes about 10 minutes. The exposure to radiation is low and testing
has high sensitivity for diagnosis of osteoporosis

□ Possible results of bone mass density testing:

□ Normal bone mass density □ Repeat test every 2 -3 years to monitor for changes
□ Moderate loss of bone mass density (i.e. Osteopenia) □ Evaluate patient (based on their risk
factors) for preventative therapy (life style changes and pharmacotherapy)
□ Severe loss of bone mass density (i.e. Osteoporosis) □ Initiate treatment to increase bone
mass density and mediate the risks of fragility fractures

Hormonal Regulation of Calcium Metabolism and Drugs for the Treatment of Osteoporosis
Calcium Metabolism
Endogenous Hormone Effects
□ There are three endocrine hormones that regulate calcium and bone metabolism – parathyroid
hormone, calcitonin, calcitriol. These hormones control
- Absorption of dietary calcium from the gastrointestinal tract
- Movement of calcium from the bone to the serum
- Excretion of calcium via the kidneys

□ Parathyroid hormone
- Released by: The parathyroid gland when serum calcium levels fall below the normal range.
Release is inhibited by normal or high serum calcium levels

- Normal effects: Increases serum calcium levels

o Bone: Stimulates the activity of osteoclasts (a type of bone cells that resorb bone) □ rate of
bone resorption increases □ movement of calcium from bone to serum to increase calcium
level
o Kidney: Increases the reabsorption of calcium in the renal tubules □ reducing the amount
of calcium excreted in the urine □ raising serum calcium levels
o Intestine: Stimulates themetabolism of vitamin D to its active form, calcitriol. Calcitriol the
acts to increase absorption of calcium from food

- Cellular mechanism of action: Not discussed

□ Calcitonin
- Released by: Released by the thyroid glands when serum levels of calcium are high Release
is inhibited by normal serum calcium levels

- Normal effects: Decreases serum calcium levels

o Bone: Inhibits the activity of osteoclasts, thereby stimulating the rate of bone deposition, such

29
 that calcium moves from serum into bone
o Kidney: inhibits the re-absoprtion of calcium in the renal tubules □ increase excretion

- Cellular mechanism of action: Not discussed

□ Calcitriol
- Is the active form of vitamin D
o Vitamin D is a fat soluble vitamin that contains 2 forms. Ergocalciferol obtained in the diet,
and cholecalciferol synthesized from the skin from cholesterol in response to UV light
o Vitamin D is not physiologically active in the body. It must first be converted into an
intermediate form calcifediol (in the liver) and then into its active form calcitriol (in the
kidney)

- Released by: Vitamin D is converted to its active form in the kidney, caclitriol, in response
to parathyroid hormone which is released due to decreased serum calcium levels.
o Clinical considerations: Clients with extensive kidney disease are unable to adequately synthesize
calcitriol.

- Normal effects:
o Intestine: Enhances the intestinal absorption of calcium.

- Cellular mechanism of action: Two cellular receptors

o Membrane receptor: Activated L-type calcium channels □ modules calcium influx across
the membrane
o Intracellular receptor: Calcitriol-receptor complex enters the nucleus and acts to up-regulate
genes involved in calcium binding proteins □ calcium binding protein modulates the
systemic effects

- Vitamin D deficiency: Results in inadequate absorption of calcium □ low serum levels of calcium
□ stimulation of PTH secretion □ increased bone resorption. If left untreated, vitamin D deficiency
can lead to a loss of bone mass and osteoporosis
Pathophysiological state: Osteoporosis
Caused by □ The rate of bone resorption exceeding the rate of bone deposition □ loss of
bone mass, bone density and structural integrity □ increased fragility
and risk of fracture

□ Low serum calcium levels (i.e. calcium deficiency) due to:

- Inadequate dietary intake/poor diet
- Inadequate calcium absorption
- Vitamin D deficiency
- Hormonal alterations
o Hypersecretion of parathyroid hormone
o Hyposecretion of
calcitonin
- Medications (e.g.
corticosteroids)

Clinical considerations: Low serum levels of calcium will cause calcium to

move from the bone into the serum, even if this compromising bone’s
integrity and function and health because calcium is important to so many
physiological processes.

□ When bone resorption exceeds deposition, there is loss of bone mass.

This causes a loss of structural function and fragility which can lead to
osteoporosis
Key Features □ Fractures
- The vertebrate of the lower dorsal and lumbar spine, the wrists, and
the hips are particularly vulnerable.

30

Treatment
□
□ Combination therapy is not recommended because there is little evidence that drugs work synergistically
□ All drugs should be administered with calcium and vitamin
supplementation Treatment Calcium and Vitamin D supplements
Mechanism of action
Route of administration
Additional considerations
Treatment
Mechanism of action
Route of administration
Effects
Safety precautions
Additional considerations
Treatment
Risedronate Mechanism of action □ Structural analog of
pyrophosphate
Route of administration
Effects
Safety precautions
- Occur most frequently after common bending or lifting movements,
or after slips, trips and falls
□ May also result in:
- Shortened stature (measurable loss of height)
- Back pain
- Spinal deformity
□ Exogenous calcium supplementation helps to increase serum calcium levels
and decrease further bone resorption
□ Vitamin D supplementation helps to increase calcium absorption from
the intestine
□ Oral
- 1000 mg/day calcium
- 800 IU/day vitamin D
□ Calcium and vitamin D supplementation is not sufficient as a sole treatment,
but may be used as an adjunct to therapy with pharmacological agents used
to treat osteoporosis
Hormone Therapy
□ Estrogen inhibits the activity of osteoclasts and reduces bone resorption.
Progestin is added to the combination because it helps decrease the risk of
uterine/endometrial cancers.
□ Oral
□ Transdermal
□ Estrogen therapy prevents the loss of bone mass in menopausal women and
increase bone mass density in patients with pre-existing osteopenia or
osteoporosis.
□ Use of HRT is associated with increased risk of breast cancer, heart disease
and stroke
□ Hormone therapy should not be prescribed solely for the prevention and
treatment of osteoporosis due to its associated health risks (breast cancer,
heart disease, and stroke). The effect of HRT on bone health may be
considered as a positive secondary benefit of HRT prescribed for the
treatment of the treatment of moderate to severe symptomatic menopause
due to hot flashes, night sweats, disrupted sleep pattern and fatigue
Bisphosphonates
□ Etidronate, Alendronate,
□ Inhibits osteoclast activity and reduces bone resorption
□ Can be administered either daily or in a once a week preparation (have a
long duration of action). Fewer side effects are reported with weekly
administration
□ Increases bone mass density and significantly reduces the risk of fragility
fractures in high risk women with osteoporosis. Effects are typically
seen after 1-3 months of treatment
□ Side effects are rare and generally gastrointestinal. These side effects
include esophageal irritation, nausea, vomiting, and abdominal pain.
- To minimize esophageal irritation, bisphosphonates should be taken
with a full glass of water and the client should remain in an
upright position for 30 minutes
□ Are generally poorly absorbed □ should be taken on an empty stomach and
31
 no other foods, beverages or medications should be taken during this time
to increase absorption.
Additional considerations □ Most common drug class used for both the prevention and treatment of
osteoporosis
Treatment Selective Estrogen Receptor Modulators (SERMs)
□ Raloxifene
Mechanism of action □ Acts as an agonist or antagonist of the estrogen receptor; however, its
effects depend on the receptor subtype
- Acts as an estrogen receptor agonist at beta-estrogen receptors in bone
□ inhibits osteoclast activity and reduces the rate of bone resorption
- Acts as an estrogen receptor antagonist at alpha-estrogen receptors
in breast tissue □ no increase in breast cancer risk
Safety precautions □ Adverse effects (minimal) include leg cramps, hot flashes and venous
thromboembolism. Thromboemobolism is reported in Canada infrequently
(3.32 events per 1000 women years) and the risk is similar to that of
traditional hormone therapy
Additional considerations □ Confer the same positive effects as hormone therapy without risk of breast
cancer. As such, this class of drugs is recommended for the prevention
and treatment of osteoporosis in asymptomaic menopausal and
postmenopausal women
□ Currently, raloxifene is the only drug in this class approved for
the prevention and treatment of osteoporosis.
Treatment Calcitonin
Mechanism of action □ Exogenous calcitonin mimics the effects of endogenous calcitonin produced
by the thyroid gland and acts on ostoclasts to inhibit bone resorption
Route of administration □ Has poor oral absorption. Therefore, is administered either subcutaneously
or intranasally
Effects □ Effects are equivalent to those of daily calcium and vitamin D
supplementation
Safety precautions □ Very few side effects because it is also produced by the body. Some patients
report rhinorrhea (runny nose) with the nasal form of the drug.
Additional considerations □ Approved for the treatment of osteoporosis, but not for its prevention.
□ In clinical trials, it has been shown to improve bone mass density and
decrease pre-tibial fractures, and effects similar to vitamin d and
calcium supplementation
Treatment Parathyroid hormone
□ Teriparatide
Mechanism of action □ Parathyroid hormone leads to excessive bone resorption if is presented
chronically (as would be the cases such as hyperparathyroidism). However,
it has been found that intermittent treatment with parathyroid hormone
stimulates bone deposition (builds new bone!). The exact mechanism
unknown but it is suggested to stimulate the activity of osteoblasts
Route of administration □ Intermittent subcutaneous administration
Effects □ Increases bone formation
Safety precautions □ Cannot be administered for longer than 18 months, since osteosarcoma was
reported in animals given high doses for long periods. No cases in human
trials, but the longest human trial was only 2 years
□ Has few adverse effects (nausea, dizziness and leg cramps)
Additional considerations □ Recommended in severe osteoporosis in those who have no responded
adequately to other treatments.
□ Should also be administered with calcium and vitamin D supplementation
□ After an 18-month course of teriparatide, bisphosphonate enhances and
maintains the bone mass gained with teripartide. In the absence of
follow- up therapy, much of the bone mass gained is lost after one year.

32
33