PHARMACOLOGY

Topic: Thyroid & Antibone Drugs

Chapter: 38 & 42

THYROID GLAND Biosynthesis of Thyroid Hormones (Based on Katzung 14th ed.)

 Anatomy
o A ductless endocrine gland
o Located in the anterior neck over the trachea, below the
thyroid cartilage
o Weight  15-20 grams
 Physiology
o Thyroid hormones  are essential for:
 Growth and development
 Regulation of energy metabolism
o Synthesis of thyroid hormone:
 Dependent on dietary iodine (from food,
drugs, water)  recommended daily
requirement = 150-200 µg
 Major Steps:
1) Iodide trapping
2) Oxidation of iodine & Iodination
of Tyrosine
3) Formation of T3 and T4 by
coupling
4) Secretion
5) Peripheral conversion of T4 to T3
Figure Above: Biosynthesis of thyroid hormones and sites of actions of different drugs
 Iodine Metabolism
Ingested iodine is converted to iodide and Iodide undergoes a series of enzymatic reactions that incorporate it into active
absorbed in the GIT thyroid hormone once it is taken up by the thyroid gland:
1. Transport of iodide into the thyroid gland by an intrinsic follicle cell
Principal organs involved: basement membrane protein called the Na/I- symporter (NIS)
- Thyroid  for hormone synthesis
This can be inhibited by large doses of iodides as well as anions:
- Kidney  for excretion
o Thiocyanate (SCN−)
- Liver  for metabolism
o Pertechnetate (TcO4−)
o Perchlorate (CIO4−)
Information Based on Katzung 14th Ed.:
 The normal thyroid gland secretes sufficient amounts of the thyroid 2. At the apical cell membrane a second I− transport enzyme called
hormones: pendrin controls the flow of iodide across the membrane
o Triiodothyronine (T3) Pendrin is also found in the cochlea of the inner ear
o Tetraiodothyronine (T4, thyroxine)
If pendrin is deficient or absent (SLC26A4 mutation), a hereditary
 Functions of thyroid hormones: syndrome of goiter and deafness, called Pendred syndrome
o To normalize growth and development (PDS), ensues
o To normalize body temperature
o To normalize energy levels 3. At the apical cell membrane, iodide organification happens wherein
iodide is oxidized by thyroidal peroxidase (TPO) to iodine, in which
 These hormones contain iodine as an essential part of the molecule: form it rapidly iodinates tyrosine residues within the thyroglobulin
o T3  has 59% iodine molecule to form:
o T4  has 65% iodine o Monoiodotyrosine (MIT)
o Diiodotyrosine (DIT)
Iodide Metabolism
 Recommended daily adult iodide (I−)† intake is 150 mcg 4. Two molecules of DIT combine within the thyroglobulin molecule to
o Pregnancy & Lactation  200 mcg form L-thyroxine (T4)
o Children  Up to 250 mcg o 1 MIT + 1 DIT = T3
 Iodide is ingested from food, water, or medication o 1 DIT + 1 DIT = T4
It is rapidly absorbed and enters an extracellular fluid pool
5. T4, T3, MIT, and DIT are released from thyroglobulin by exocytosis
The thyroid gland removes about 75 mcg a day from this pool for
hormone synthesis and the balance is excreted in the urine and proteolysis of thyroglobulin at the apical colloid border
6. The MIT and DIT are then deiodinated within the gland, and the
If iodide intake is ↑, the fractional iodine uptake by the thyroid is iodine is reutilized
diminished
This process of proteolysis is also blocked by high levels of
intrathyroidal iodide

7. The ratio of T4 to T3 within thyroglobulin is approximately 5:1, so that

most of the hormone released is thyroxine
8. 80% of T3 circulating in the blood is derived from peripheral
metabolism of thyroxine and the rest from direct thyroid secretion

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 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Transport of Thyroid Hormones Biosynthesis of Thyroid Hormones (Based on Manual)

 T4 and T3 in plasma are reversibly bound to protein, primarily Iodide Trapping
thyroxine-binding globulin (TBG)  Is the active transport of iodide from circulation to colloid of thyroid
o 0.04%  Free T4 (FT4) gland
o 0.4%  Free T3 (FT3)  “Iodide pump”
 Stimulated by thyrotropin (TSH)
Peripheral Metabolism of Thyroid Hormones  Inhibited by thiocyanate and perchlorate
 The primary pathway for the peripheral metabolism of thyroxine is  Autoregulated  decrease thyroid iodine will enhance uptake
deiodination by three 5′deiodinase enzymes (D1, D2, D3)
Deiodination of T4 may occur by monodeiodination of the outer
ring, producing T3  3-4x more potent than T4 Oxidation/Iodination
 Iodide is oxidized to iodine by thyroid peroxidase
 D1 enzyme  responsible for about 24% of the circulating T3  Followed by iodination of tyrosyl in the thyroglobulin
 D2 enzyme  responsible for about 64% of the circulating T3  Results:
It also regulates T3 levels in the brain and pituitary o Monoiodotyrosyl (MIT)
 D3 enzyme  produces metabolically inactive reverse T3 (rT3) o Diiodotyrosyl (DIT)
The low serum levels of T3 and rT3 in normal individuals are due  This is blocked by PTU (Propylthiouracil)
to the high metabolic clearances of these two compounds
Formation of T3 and T4 (Coupling Reaction)
 Inhibitors of 5’-deiodinase:  MIT + DIT = T3 or Triiodothyronine
o Amiodarone  DIT + DIT = T4 or Thyroxine
o Iodinated contrast media T3  is 3-5x more active than T4
o β blockers
o Corticosteroids Secretion of Thyroid Hormone
o Severe illness or Starvation
 T3 and T4 are synthesized and stored in the thyroglobulin
Inhibition results to low T3 and high rT3 levels in the serum  Secretion is initiated by endocytosis of colloid from the follicular
lumen
 The ingested thyroglobulin fuse with lysosomes containing the
proteolytic enzyme resulting to release of thyroid hormone which
then exit the cell by exocytosis
 Activated by TSH by increasing activity of the lysosomal enzymes

Peripheral Conversion T4 and T3

 Normal daily production:
o T4 = 70-90 µg
o T3 = 15-30 µg
 80% of T3 comes from conversion of T4 in peripheral tissues
o 5’-deiodinase  enzyme involved (inhibited by PTU)

Transport of Thyroid Hormone in the Blood

 T3 and T4 = bound in thyroxine binding globulin (TBG)
 Only 0.03% of total thyroxine (T4) is free
 Free T3 is 0.2-0.5%
 T3 is less firmly bound
 Only free form is active
 Pregnancy or estrogen administration causes increase TBG with
increase binding, thus decrease in free form

Degradation and Excretion

 T3 has a half-life of 2 days or less
 T4 has a half-life of 6-7 days
o In hyperthyroidism  decreased to 3-4 days
o In hypothyroidism  increased to 9-10 days
 Degradation  Liver
 Excretion  Kidney (mainly)
Stool (20-40%)

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 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

EVALUATION OF THYROID FUNCTION Additional Information from Manual:

Thyroid-Pituitary Relationships Relation of Iodine to Thyroid Functions
 TRH is secreted into capillaries of the pituitary portal venous system,  Iodine is necessary for thyroid hormone synthesis
and in the pituitary gland  If iodine intake is ↓:
 TRH stimulates the synthesis and release of TSH o Hormone production is ↓
 TSH in turn stimulates an adenylyl cyclase–mediated mechanism in o Thyroid gland hypertrophies (Goiter)
the thyroid cell to increase the synthesis and release of T4 and T3 o Vascularity ↑
 T3  acts in a negative feedback fashion in the pituitary to block the o Iodide concentrating mechanism ↑
action of TSH and in the hypothalamus to inhibit the synthesis and
secretion of TRH Sources of Iodine
 Marine life sea fish/shells  as much as 200-1000 µg/kg
Autoregulation of the Thyroid Gland  Whereas 5 kg of vegetables/fruits or 3 kg of meat or fresh water fish
 Uptake of iodide and thyroid hormone synthesis: provides only 100 µg iodine
o Independent of TSH  To provide enough Iodine:
o Mechanisms are related to the level of iodine o Other regions inject iodized oil
 Wolf-Chaikoff Block  large doses of iodine inhibit iodide o Most practical  addition of iodide or iodate to table
organification salt: 1 gm iodized salt = 100 µg iodine
 Hashimoto’s Thyroiditis  can inhibit thyroid hormone synthesis
and result in hypothyroidism Clinical Diagnosis
 Hyperthyroidism  can result from the loss of the Wolff-Chaikoff HYPOTHYROIDISM HYPERTHYROIDISM
block in susceptible individuals (eg, multinodular goiter) Deficiency in thyroid hormone: Resemble sympathetic hyperactivity even
 Congenital cretinism in children though epinephrine is not elevated
Abnormal Thyroid Stimulators  Absent or atrophic thyroid gland 2 Forms of Hyperthyroidism:
 Graves’ Disease  Post thyroidectomy 1. Diffuse Toxic Goiter (Graves’ disease)
 Post radioactive iodine therapy  Exophthalmos
o Lymphocytes secrete a TSH receptor–stimulating antibody  Young middle aged woman
 Myxedema when severe
(TSH-R Ab [stim]), also known as thyroid-stimulating  Autoimmune
immunoglobulin (TSI)  IgG antibodies to TSH
 Pretibial edema
This immunoglobulin binds to the TSH receptor and
stimulates the gland in the same fashion as TSH itself 2. Nodular Toxic Goiter
The duration of its effect, however, is much longer (Plummer’s disease)
 Older patients
than that of TSH
 Arise from long standing non-
TSH receptors are also found in orbital fibrocytes, toxic nodular goiter
which may be stimulated by high levels of TSH-R Ab Signs & Symptoms: Signs & Symptoms:
[stim] and can cause ophthalmopathy  Dwarfism  Tachycardia, full pulse
 Short extremities  Palpitation
 Mental retardation  Lid lag/Retraction
 Thick, brittle nails  Heat intolerance, warm skin
 Coarse, sparse, brittle hair  Muscle weakness
 Cold intolerance  Tremor, excessive sweating, anxiety,
 Inactive, uncomplaining, nervousness
expressionless, drowsy  Insomnia, restlessness
 Puffy face, thickened lips, half-open  Increased bowel movement
mouth, enlarged tongue  Increased appetite, increased energy
 Doughy, yellowish scaly skin, cool and expenditure, weight loss, wasting
dry to touch
 Thick subcutaneous tissue
 Low, pitch, husky voice
 Cardiomegaly, decreased HR

Summarized Table of Hypothyroidism & Thyrotoxicosis

Organ Hypothyroidism Hyperthyroidism
Skin Cool, dry Warm, moist
Eyes Drooping eyelids Exophthalmos
Heart Bradycardia Tachycardia
Lungs Hypoventilation Dyspnea
GIT Anorexia Voracious
CNS Lethargy Nervousness
Musculoskeletal ↓ Deep tendon reflex ↑ Deep tendon reflex
Renal Impaired Polyuria
Blood ↓ Erythropoiesis ↑ Erythropoiesis
Reproductive ↓ Gonadal ↑ Gonadal
Metabolic ↓ BMR ↑ BMR

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 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

CLINICAL PHARMACOLOGY Effects of Thyroid Hormones:

Thyroid Hormones  For optimal growth, development, function, and maintenance of all
Agents: body tissues
Synthetic Natural (Animal Origin  Pigs)  Excess or inadequate amounts result in the signs and symptoms of
- Levothyroxine - Desiccated thyroid hyperthyroidism or hypothyroidism, respectively (Table, page 3)
- Liothyronine - Thyroglobulin  It is critical for the development and functioning of:
- Liotrix o Nervous tissues
o Skeletal tissues
Pharmacokinetics: o Reproductive tissues
 Thyroxine (T4) is absorbed best in the duodenum and ileum  Its effects depend on protein synthesis as well as potentiation of the
o Absorption is modified by intraluminal factors such as secretion and action of growth hormone
food, drugs, gastric acidity, and intestinal flora  Thyroid deprivation in early life results in:
o Oral bioavailability of current preparations: o Irreversible mental retardation
 L-thyroxine: 70-80% Congenital cretinism
o Dwarfism
 T3: 95%  Metabolism and Endocrine:
 T4 and T3 absorption appears not to be affected by mild o It affects metabolism of drugs as well as carbohydrates,
hypothyroidism but may be impaired in severe myxedema with ileus fats, proteins, and vitamins
 These factors are important in switching from oral to parenteral o It also affects secretion and degradation rates of virtually
therapy (IV) all other hormones, including catecholamines, cortisol,
estrogens, testosterone, and insulin
Mechanism of Action:  Thyroid Hyperactivity:
 Enters the cell by the active transporters, examples are: o Resemble sympathetic nervous system overactivity
o Monocarboxylate transporter 8 [MCT8], MCT10 (especially in the cardiovascular system)
o Organic anion transporting polypeptide [OATP1C1] o ↑ in catecholamine-stimulated adenylyl cyclase activity:
Transporter mutations can result in a clinical syndrome of  ↑ numbers of receptors
mental retardation, myopathy, and low serum T4 levels  Enhanced amplification of the receptor
(Allan-Herndon-Dudley syndrome) signals
o Other clinical symptoms of excessive epinephrine activity
 Within the cell, T4 is converted to T3 by 5′-deiodinase, and the T3 (and partially alleviated by adrenoceptor antagonists)
enters the nucleus include:
 T3 then binds to a specific T3 thyroid receptor protein, a member of  Lid lag and retraction
the c-erb oncogene family  Tremor
This family also includes the steroid hormone receptors and  Excessive sweating
receptors for vitamins A and D  Anxiety
 Nervousness
 The T3 receptor exists in two forms, α and β
Mutations in α and β genes  generalized thyroid hormone Actions of Thyroid Hormone (Based on Manual)
resistance
 Regulation of growth and development  increase protein
Cigarette smoking & Environmental agents  interfere with
synthesis by controlling DNA transcription
receptor action
Differing concentrations of receptor forms in different tissues   Calorigenic effect  increased basal metabolic rate by increasing
may account for variations in T3 effect on these tissues oxygen consumption
 Cardiovascular effect  tachycardia with increase force of heart
 Most of the effects of thyroid on metabolic processes appear to be contraction and increased cardiac output due to increase in number
mediated by activation of nuclear receptors that lead to increased of myocardial beta adrenergic receptors
formation of RNA and subsequent protein synthesis (eg, ↑  Metabolic effect  increased metabolism of cholesterol and bile
formation of Na+/K+-ATPase) acids, increased lipolysis, increased utilization of carbohydrates
 Hormone-Responsive Tissues: (↑ amount of receptors)  Inhibition of secretion of TSH by the pituitary gland  thru negative
o Pituitary, liver, kidney, heart, skeletal muscle, lung, and feedback to pituitary by decreased secretion of TSH
intestine
 Hormone-Unresponsive Tissues: (↓ amount of receptors) Other Clinical Use of Thyroid Hormones
o Spleen and testes  Can be used for the treatment of:
 Brain  lacks an anabolic response to T3 o Obesity
contains an intermediate number of receptors o Abnormal vaginal bleeding
o Depression due to hypothyroidism
 In congruence with their biologic potencies, the affinity of the
receptor site for T4 is about ten times lower than that for T3 NOTE: Thyroid hormones are NOT EFFECTIVE in the
 Under some conditions, the number of nuclear receptors may be management of the aforementioned conditions and can be
altered to preserve body homeostasis detrimental IF the thyroid hormone levels are NORMAL
Starvation lowers both circulating T3 hormone and cellular T3
receptors

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 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Thyroid Preparations ANTITHYROID AGENTS

Synthetic Thyroid Hormone  Reduction of thyroid activity and hormone effects can be
 Contains T4 accomplished by:
 It is preparation of choice for thyroid replacement and 1) Agents that interfere with the production of thyroid
suppression therapy due to: hormones
o Stability 2) Agents that modify the tissue response to thyroid
o Content uniformity
hormones
o Low cost
o Lack of allergenic foreign protein 3) Glandular destruction with radiation or surgery
o Easy laboratory measurement of serum levels  Goitrogens are agents that suppress secretion of T3 and T4 to
Levothyroxine o Long half-life (7 days)  allows once daily subnormal levels  ↑ TSH  Glandular enlargement (goiter)
administration
 Antithyroid agents are mainly used for hyperthyroidism
 T4 is converted to T3 intracellularly  thus,  Subdivided into 4 categories:
administration of T4 produces both hormones and T3
administration is unnecessary
1) Thioamides or Thiourylenes
 A branded soft gel capsule (Tirosint)  had faster, more Interfere directly with thyroid hormone synthesis
complete dissolution and was less affected by gastric pH
or coffee than a tablet formulation 2) Ionic Inhibitors
 Contains T3
Block the iodide transport mechanism
 It is 3-4x more active than levothyroxine
 It is NOT recommended for routine replacement therapy
because of its: 3) Iodide
o Shorter half-life (24 hours)  requiring multiple daily Suppression of thyroid hormone synthesis when in
doses high doses
Liothyronine o Difficulty in monitoring its adequacy of replacement
by conventional laboratory tests
4) Radioactive Iodine
 T3 should also be avoided in patients with cardiac disease
Damages and destroy the gland by ionizing radiation
due to significant elevations in peak levels and a greater
risk of cardiotoxicity
 It is best used as a diagnostic test in T3 suppression and Thioamides
short-term TSH suppression Divided into 2 groups:
 A mixture of levothyroxine and iodothyronine in a ratio of  Propylthiouracil
Liotrix
4:1 (T3 & T4)
 Methimazole
NOTE: The shelf life of synthetic hormone preparations is about 2 years,
particularly if they are stored in dark bottles to minimize spontaneous
Propylthiouracil (PTU)
deiodination
 Due to severe hepatitis, PTU is reserved for use only during:
o 1st trimester of pregnancy
Natural Thyroid Hormone
 Fine powder from dessicated pig thyroid
o Thyroid storm
 Disadvantage: o Patients experiencing adverse reactions with
o Protein antigenicity Methimazole
o Product instability
o Variable hormone concentrations
Desiccated Thyroid Pharmacokinetics:
o Difficulty in laboratory monitoring  far outweigh
the advantage of lower cost  Rapidly absorbed
 The shelf life of desiccated thyroid is not known with  Peak serum levels after 1 hour
certainty, but its potency is better preserved if it is KEPT  T ½: 1.5 hrs.
DRY
 Bioavailability of 50–80% may be due to incomplete absorption or a
 Purified pig extract
Thyroglobulin  Preparation: Proloid, 32.5 and 65 mg/tab large first-pass effect in the liver
 Dose: 60-300 mg/day  Volume of distribution approximates total body water with
accumulation in the thyroid gland
 Excreted by the kidney as inactive glucuronide within 24 hrs.
 Given at 100 mg every 6-8 hrs.  can inhibit iodine organification by
60% for 7 hrs.
 PTU is preferable during the first trimester of pregnancy
This is because it is more strongly protein-bound and, therefore,
crosses the placenta LESS readily

Eltroxin  Secreted in low concentrations in breast milk but are considered safe
for the nursing infant

, Euthyroid
Continued next page…..
, Thyrar
*Those in red are additional preparations from the Manual

#LaNaAkongMoney…Hayst Page 5 of 20
 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Methimazole Anion Inhibitors

 10x more potent than PTU  Monovalent anions:
 Thiamazole or MMI o Perchlorate (ClO4−)
 DOC for adults and children o Pertechnetate (TcO4−)
 Carbimazole  a drug that is converted to methimazole in vivo o Thiocyanate (SCN−)

Pharmacokinetics:  Block uptake of iodide by the gland through competitive inhibition

 Completely absorbed but at variable rates of the iodide transport mechanism
 It is readily accumulated by the thyroid gland  Effectiveness is unpredictable because effects can be overcome by
large doses of iodides
 T ½: 6 hrs.
 Volume of distribution is similar to that of PTU
 Excretion is slower than with PTU Potassium Perchlorate
o 65–70% of a dose is recovered in the urine in 48 hours  Rarely used because it is associated with aplastic anemia
 Dose of 30 mg exerts antithyroid effect longer than 24 hrs.   Major clinical use:
management of mild to moderate hyperthyroidism o Block thyroidal reuptake of I− in patients with iodide-
 Secreted in low concentrations in breast milk but safe for the nursing induced hyperthyroidism (eg, amiodarone-induced
infant (same with PTU) hyperthyroidism)

NOTE:
 Both thioamides cross the placental barrier and are concentrated by the fetal Thiocyanate
thyroid  Very toxic and is used only for diagnostic purposes
 Both thioamides are classified as FDA pregnancy category D  In large amount  may even block organification of iodine
o Evidence of human fetal risk based on adverse reaction data from
investigational or marketing experience  This chemical is produced by enzymatic hydrolysis of certain plant
glycosides like cabbage
Pharmacodynamics of Thioamides:
 Major action: Prevent hormone synthesis by: Iodides
o Inhibiting the thyroid peroxidase-catalyzed reactions  Became the major antithyroid agent until the introduction of the
o Blocking iodine organification thioamides in the 1940s
 They block coupling of the iodotyrosines  Now rarely used as sole therapy
 They DO NOT block uptake of iodide by the gland
 Inhibits the peripheral deiodination of T4 and T3 Pharmacodynamics:
This peripheral inhibition is only seen in PTU  Inhibit organification
Methimazole DO NOT have this action  Inhibit hormone release
o Through inhibition of thyroglobulin proteolysis (dose of >6
Toxicity of Thioamides: mg/d)
 Most common adverse reaction: Maculopapular pruritic rash (4-6%)  Decrease the size and vascularity of the hyperplastic gland  this
 Adverse reactions occur in 3-12% of treated patients effect is valuable as preoperative preparation for surgery
 Early reactions: Nausea and GI distress  In susceptible individuals, iodides can induce:
 Rare adverse reactions: o Hyperthyroidism (Jod-Basedow phenomenon)
o Urticarial rash o Hypothyroidism (Wolff-Chaikoff phenomenon)
o Vasculitis  Improvement occurs within 2-7 days  valuable as therapy in thyroid
o Lupus-like reaction storm
o Lymphadenopathy
o Hypoprothrombinemia Clinical Use:
o Exfoliative dermatitis  Should be initiated after onset of thioamide therapy
o Polyserositis o Because it ↑ intraglandular stores of iodine which:
o Acute arthralgia  Delays onset of thioamide therapy
o Asymptomatic elevations in transaminase levels  Prevent use of radioactive iodine therapy for
 PTU: ↑ risk of severe hepatitis several weeks
 Methimazole:  Should NOT be used alone
o Altered sense of taste or smell o Because the gland will escape from the iodide block in 2–
o Cholestatic jaundice 8 weeks  withdrawal may produce severe exacerbation
 Most dangerous complication: Agranulocytosis of thyrotoxicosis in an iodine-enriched gland
o Infrequent but potentially fatal  Chronic use of iodides in pregnancy should be avoided
o Occurs in 0.1–0.5% of patients but ↑ risk in older patients o Since they cross the placenta and cause fetal goiter
and those receiving >40 mg/d of Methimazole  Can protect the gland from subsequent damage if administered
o Rapidly reversible when the drug is discontinued before radiation exposure in radiation emergencies
o Broad-spectrum antibiotic therapy may be necessary for
complicating infections Toxicity:
o Colony-stimulating factors (eg, G-CSF) may hasten  Acneiform rash (similar to that of bromism), swollen salivary glands,
recovery of the granulocytes mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug
 Do not switch drugs (PTU and Methimazole) in patients with severe fever, metallic taste, bleeding disorders, and anaphylactoid reactions
reactions
o Due to cross-sensitivity of about 50%

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 PHARMACOLOGY NOTE: Study smart on
Topic: Thyroid & Antibone Drugs
Clinical Pharmacology
Chapter: 38 & 42

Radioactive Iodine CLINICAL PHARMACOLOGY OF THYROID & ANTITHYROID DRUGS

 131
I: is the only isotope used for treatment of thyrotoxicosis Hypothyroidism
o Administered orally in solution as sodium 131I  A syndrome resulting from deficiency of thyroid hormones and is
o it is rapidly absorbed, concentrated by the thyroid, and manifested largely by a reversible slowing down of all body functions
incorporated into storage follicles  In infants and children:
 Therapeutic effect depends on emission of β rays o Striking retardation of growth and development 
o T ½: 5 days dwarfism and irreversible mental retardation
o Penetration range: 400-2000 µm  Can occur with or without thyroid enlargement (goiter)
o Few weeks after  Destruction of the thyroid  Laboratory diagnosis in the adult:
parenchyma: o Combination of low free thyroxine and elevated serum
 Epithelial swelling and necrosis TSH levels
 Follicular disruption  Hashimoto thyroiditis
 Edema o An immunologic disorder in genetically predisposed
 Leukocyte infiltration individuals
Advantages Disadvantages o There is evidence of humoral immunity in the presence
Easy administration Genetic damage of antithyroid antibodies and lymphocyte sensitization to
Effectiveness Leukemia thyroid antigens
Low expense Neoplasia
Absence of pain

 Restrict use only to patient 35 years old above

 Contraindication:
o Pregnancy  crosses the placenta
o Nursing mothers  goes out with milk

Adrenoceptor-Blocking Agents
 Effective agents are β-blockers without intrinsic sympathomimetic
activity: Management of Hypothyroidism:
o Metoprolol  Levothyroxine replacement therapy
o Propranolol o Infants and children: 10-15 mcg/kg/d (1-6 months old)
o Atenolol o Adult: 1.7 mcg/kg/d or 125 mcg/d
o Older adults: require less 1.6 mcg/kg/d (>65 yrs. old)
 Propranolol has been the β blocker most widely studied and used in
o Patients in suppression therapy (post-thyroidectomy for
the therapy of thyrotoxicosis
thyroid cancer): 2.2 mcg/kg/d
 Beta blockers cause clinical improvement of hyperthyroid symptoms o Patients with celiac disease & H. pylori gastritis: higher
but do not typically alter thyroid hormone levels
requirements
 Propranolol at doses >160 mg/d may also reduce T3 levels o It should be administered in an empty stomach
approximately 20% by inhibiting the peripheral conversion of T4 to o T ½: 7 days  once daily dosing
T3 o Children should be monitored for normal growth and
development
Manual Information: o Serum TSH (0.5-2.5 mIU/L) and free thyroxine should
 Many signs and symptoms of thyrotoxicosis mimic those associated always be measured at regular intervals and monitored
with sympathetic stimulation, thus agents that deplete o Steady-state level takes 6-8 weeks after administration
catecholamines (Reserpine and Guanethidine) or agents like beta  Reduced Dosaging
blockers, are useful because they impair tissue response at the o Long-standing hypothyroidism
receptor site o Older patients
 Drug of Choice  Propranolol o Patients with underlying cardiac diseases
Give 12.5-25 mcg/d for 2 weeks, increasing the daily
Iodinated Contrast Media (Based on Manual) dose by 12.5-25 mcg every 2 weeks until
 Ipodate, Iopanoic acid euthyroidism or drug toxicity is observed
 Valuable in treatment of hyperthyroidism (though it is not approved
by the FDA) o Stop or reduce dose immediately when angina pectoris or
 Rapidly inhibit the conversion of T4 and T3 in liver, kidney, pituitary cardiac arrhythmia develops
gland and brain  Toxicity
 Also inhibition of hormone release due to iodine release o Directly related to the hormone level
 Relative non-toxic  similar to iodide o In children: restlessness, insomnia, and accelerated bone
 Useful adjunct in thyroid storm maturation and growth
 Important alternative if iodides and thioamides are contraindicated o In adults: increased nervousness, heat intolerance,
 May not interfere with 131I retention as much as iodides episodes of palpitation and tachycardia, or unexplained
weight lose
o Chronic overtreatment with T4: increase the risk of atrial
fibrillation and accelerated osteoporosis

#LaNaAkongMoney…Hayst Page 7 of 20
 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Special Problems in Hypothyroidism: Hyperthyroidism (Thyrotoxicosis)

A. Myxedema and Coronary Artery Disease  Is the clinical syndrome that results when tissues are exposed to high
 Frequently occurs in older persons and associated with CAD levels of thyroid hormone
 ↓ T3 and ↑ T4  protect the heart against increasing demands that
could result in angina pectoris or MI Graves’ Disease
 Coronary artery surgery first then thyroxine administration  Considered to be an autoimmune disorder in which a defect in
suppressor T lymphocytes stimulates B lymphocytes to synthesize
B. Myxedema Coma antibodies (TSH-R Ab [stim]) to thyroidal antigens
 An end state of untreated hypothyroidism The TSH-R Ab [stim] is directed against the TSH receptor in the
 Medical emergency and should be treated in ICU due to: thyroid cell membrane and stimulates growth and biosynthetic
o Progressive weakness activity of the thyroid cell
o Stupor
o Hypothermia  Genetics, the postpartum state, cigarette smoking, and physical and
o Hypoventilation emotional stress increase TSH-R Ab [stim] development
o Hypoglycemia
o Hyponatremia Laboratory Diagnosis:
o Water intoxication  T3, T4, FT4, and FT3 are ↑and TSH is ↓
o Shock  Radioiodine uptake is usually markedly elevated as well
o Death  Antithyroglobulin, thyroid peroxidase, and TSH-R Ab [stim]
 Give all preparations IV antibodies are usually present
o Because patients absorbs poorly from other routes
o Administer with caution to avoid excessive water intake Management of Graves’ Disease:
 Levothyroxine therapy  Antithyroid drug therapy  Methimazole (preferred drug)
o Drug of choice  Destruction of the gland with radioactive iodine
o 300-400 initially IV, followed by 50-100 mcg  Surgical thyroidectomy
 IV Hydrocortisone  Adjuncts to Antithyroid Therapy
o For patients with adrenal or pituitary insufficiency o Propranolol  most commonly used
 Opioids and sedatives must be used with extreme caution o Metoprolol
o Diltiazem  control tachycardia if β-blocker is C/I
C. Hypothyroidism and Pregnancy o Barbiturates  accelerate T4 breakdown
 Hypothyroid women o Bile acid sequestrants (Cholestyramine)  increase fecal
o Have anovulatory cycles  infertile until restoration of secretion of T4
the euthyroid state
o Use of thyroid hormone for infertility although there is no Toxic Uninodular Goiter & Toxic Multinodular Goiter
evidence for its usefulness  Occur often in older women with nodular goiters
 Pregnant hypothyroid patient  Free thyroxine is moderately elevated or occasionally normal, but FT3
o Extremely important that the daily dose of thyroxine be or T3 is strikingly elevated
adequate because early development of the fetal brain  Single toxic adenomas can be managed with:
 Increase the thyroxine dose about 30-50% to normalize serum TSH o Surgical excision of the adenoma
level during pregnancy o Radioiodine therapy
o Take an extra 25 mcg thyroxine tablet as soon as they are  Toxic multinodular goiter is usually associated with a large goiter and
pregnant is best treated by preparation with:
o Separate thyroxine from prenatal vitamins and calcium by o Methimazole (preferable) or PTU
at least 4 hrs. o Followed by subtotal thyroidectomy
o ↑ maternal TBG levels  ↑ total T4 levels 
maintenance of TSH (0.5 and 3.0 mIU/L) and total T4 at or Subacute Thyroiditis
above the upper range of normal  During the acute phase of a viral infection of the thyroid gland, there
is destruction of thyroid parenchyma with transient release of stored
D. Subclinical Hypothyroidism thyroid hormones
 ↑ TSH level and normal T3 and T4 in 4-10% of the general population  A similar state may occur in patients with Hashimoto’s thyroiditis
 Increases to 20% in women >50 years of age  These episodes of transient thyrotoxicosis have been termed
 Thyroid hormone therapy in patient with: spontaneously resolving hyperthyroidism
o TSHL >10 mIU/L  Supportive therapy is usually all that is necessary, such as:
o Close TSH monitoring for those with lower TSH elevations o β-blocking agents without intrinsic sympathomimetic
activity (eg, propranolol) for tachycardia
E. Drug-Induced Hypothyroidism o Aspirin or NSAIDs to control local pain and fever
 Levothyroxine therapy o Corticosteroids may be necessary in severe cases to
o If offending agent cannot be stopped control the inflammation
o Amiodarone-induced hypothyroidism

#LaNaAkongMoney…Hayst Page 8 of 20
 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Special Problems  Neonatal Graves’ Disease

 Thyroid Storm o May be due either to passage of maternal TSH-R Ab [stim]
o Also called thyrotoxic crisis through the placenta, stimulating the thyroid gland of the
o Sudden acute exacerbation of all of the symptoms of neonate
thyrotoxicosis, presenting as a life-threatening syndrome If caused by maternal TSH-R Ab [stim], the disease is
o Vigorous management is mandatory usually self-limited and subsides over a period of 4–12
o Propranolol  DOC weeks

 Ophthalmopathy o May be due to genetic transmission of the trait to the

o Rare and difficult to treat fetus
o 15–20% risk of aggravating severe eye disease may occur o If with severe metabolic stress  Therapy includes:
following RAI  Propylthiouracil
o Management:  Lugol’s solution
 Total surgical excision  Propranolol
 131I ablation of the gland plus oral prednisone  Oral prednisone
therapy
 Local therapy Subclinical Hyperthyroidism
Example:  Defined as a suppressed TSH level (below the normal range) in
Elevation of the head to diminish periorbital conjunction with normal thyroid hormone levels
edema and artificial tears to relieve corneal  Cardiac toxicity (eg, atrial fibrillation), especially in older persons and
drying due to exophthalmos those with underlying cardiac disease, is of greatest concern
 Amiodarone-Induced Thyrotoxicosis
 Smoking cessation
o 3% of patients receiving this drug will develop
 Prednisone  if with severe inflammatory
hyperthyroidism (instead of hypothyroidism)
reaction o 2 types of amiodarone-induced thyrotoxicosis:
If C/I, then do irradiation of the posterior 1) Iodine-induced (type 1)
orbit using well-collimated high-energy X-
Often occurs in persons with underlying
ray therapy
thyroid disease (eg, multinodular goiter,
Graves’ disease)
 Eyelid or Eye muscle surgery  to correct Treatment: Thioamides
residual problems after the acute process has
subsuded 2) Inflammatory thyroiditis (type 2)
Occurs in patients without thyroid disease
 Dermopathy due to leakage of thyroid hormone into the
o Also called pretibial myxedema circulation
o Often respond to topical corticosteroids applied to the Treatment: Glucocorticoids
involved area and covered with an occlusive dressing
Nontoxic Goiter
 Thyrotoxicosis during Pregnancy  Is a syndrome of thyroid enlargement without excessive thyroid
o When in childbearing period with severe disease, ideally, hormone production
should have definitive therapy prior to pregnancy with:  Enlargement of the thyroid gland is often due to TSH stimulation from
 131I
inadequate thyroid hormone synthesis
 Subtotal thyroidectomy  The most common cause of nontoxic goiter worldwide is iodide
o Propylthiouracil deficiency
 Less placental transfer and T4 to T3 But in the United States, it is Hashimoto’s thyroiditis
conversion
 Fewer teratogenic risks than methimazole  Other causes include:
 Can be given in 1st trimester o Germ-line or Acquired mutations in genes involved in
 Dosage kept to the minimum necessary for hormone synthesis
control of disease (<300 mg/d) o Dietary goitrogens
 May affect fetal thyroid gland function o Neoplasms
o Methimazole  Management:
 Can be given for the remainder of pregnancy Cause of Nontoxic Goiter Treatment
to avoid potential liver damage Goiter due to iodide deficiency Iodide
 Potential alternative Elimination of the goitrogen
Goiter due to ingestion of
Adding sufficient thyroxine to
 Possible risk of fetal scalp defects goitrogens in the diet
shut off TSH stimulation
o Thyroidectomy in mid-trimester Adequate thyroxine therapy will
o Thyroid supplement suppress pituitary TSH and result
Hashimoto’s thyroiditis and
o Definitive therapy after delivery in slow regression of the goiter as
dyshormonogenesis
well as correction of
hypothyroidism

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 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Thyroid Neoplasm
 May be benign (adenomas) or malignant
 Diagnostic test: fine needle aspiration biopsy & cytologic
examination
 Benign lesions:
o Monitored for growth or symptoms of local obstruction
o Surgical excision
o Levothyroxine therapy  not recommended especially in
iodine sufficient areas
 Thyroid carcinomas:
o Requires a total thyroidectomy
o Postoperative radioiodine therapy
o Lifetime replacement with levothyroxine

#LaNaAkongMoney…Hayst Page 10 of 20
 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

BONE MINERAL HOMEOSTASIS DRUGS Disturbance in Structural Support:

Introduction  Osteoporosis
Bone: A decrease in bone mass/density with decrease in strength
 It is the principal reservoir of the minerals: predisposing to fractures due to various causes like decrease in
o 98% of the 1-2 kg of Calcium estrogen in menopausal women or due to aging
o 85% of the 1 kg of Phosphorus
 Principal structural support of the body  Rickets
 Provides space for hematopoiesis A defective mineralization or calcification of bones before
epiphyseal closure in children due to impaired metabolism of
Bone Homeostasis: vitamin D, phosphorus or calcium or their deficiency resulting to
bone deformity or fractures

 Osteomalacia
A similar condition occurring in adults also due to vitamin D
deficiency but occurs after epiphyseal closure, with osteoid
production but no mineralization

Average Diet:
 600-1000 mg of calcium per day
Approximately 100-250 mg is absorbed

 Amount of phosphorus is same as the calcium

 Absorption: duodenum & upper jejunum
 Secretion: ileum

Principal Hormone Regulators of Calcium & Phosphate:

Figure Above: Mechanisms contributing to bone mineral homeostasis  Parathyroid Hormone (PTH)
 Fibroblast Growth Factor 23 (FGF23)
Serum calcium (Ca) and phosphorus (P) concentrations are controlled
 Vitamin D (a prohormone)
principally by three hormones:
1. 1,25-dihydroxyvitamin D (D) Prohormone  means that it must be further metabolized to gain
2. Fibroblast growth factor 23 (FGF23) biologic activity
3. Parathyroid hormone (PTH)
Secondary Regulators of Calcium & Phosphate Homeostasis:
These hormones control calcium & phosphorus by their action on absorption
from the gut and from bone and on renal excretion  Calcitonin • Insulin-like growth factors
 Prolactin • Thyroid hormone
PTH and 1,25(OH)2D ↑ the input of calcium and phosphorus from bone into  Growth hormone • Glucocorticoids
the serum and stimulate bone formation  Insulin • Sex steroids

1,25(OH)2D also ↑ calcium and phosphate absorption from the gut

Non-Hormonal Agents/Drugs Affecting Bone Mineral Homeostasis:
In the kidney:  Biphosphonates (Etidronate, Pamidronate, Alendronate, Risedronate,
o 1,25(OH)2D  ↓ excretion of both calcium and phosphorus Tibudronate, Ibandronate, Zoledronate)
o PTH  ↓ calcium but ↑ phosphorus excretion
o FGF23  ↑ renal excretion of phosphate  Monoclonal antibodies (Denosumab)
 Calcimimetics (Cinacalcet)
Calcitonin (CT) is a less critical regulator of calcium homeostasis, but in
pharmacologic concentrations can ↓ serum calcium and phosphorus by  Cytotoxic antibiotic (Plicamycin/Mithramycin)
inhibiting bone resorption and ↑ their renal excretion  Diuretics (Thiazides)
 Iron (Phicorides)
Feedback may alter the effects shown; for example:
o 1,25(OH)2D ↑ urinary calcium excretion indirectly through ↑  Strontium ranelate
calcium absorption from the gut and inhibition of PTH secretion and
may ↑ urinary phosphate excretion because of ↑ phosphate CLINICAL PHARMACOLOGY (discussed in detail later)
absorption from the gut and stimulation of FGF23 production Abnormal Serum Calcium & Phosphate Levels:
 Hypercalcemia
Abnormalities in Bone Mineral Homeostasis can lead to:  Hypocalcemia
 Cellular dysfunctions:  Hyperphosphatemia
o Tetany  Hypophosphatemia
o Coma
o Muscle weakness Specific Disorders:
 Disturbance in structural support:  Primary Hyperparathyroidism • X-linked Autosomal
o Osteoporosis  Hypoparathyroidism Dominant Hypophosphatemia
 Nutritional Vitamin D Deficiency  Vitamin D-dependent Rickets
o Rickets
 Chronic Kidney Disease  Nephritic Syndrome
o Osteomalacia  Intestinal Osteodystrophy  Idiopathic Hypercalcemia
 Osteoporosis  Paget’s Disease
 Enteric Oxaluria

#LaNaAkongMoney…Hayst Page 11 of 20
 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

PRINCIPAL HORMONE REGULATORS OF CALCIUM & PHOSPHATE  Denosumab

Parathyroid Hormone An antibody that inhibits the action of RANKL, has been
 Single-chain peptide hormone composed of 84 amino acids developed for the treatment of excess bone resorption in patients
 Produced in the parathyroid gland in a precursor form of 115 amino with osteoporosis and certain cancers
acids
The excess 31 amino terminal amino acids being cleaved off  Romosozumab
before secretion Antibodies against sclerostin
In clinical trials for the treatment of osteoporosis
 Regulates calcium and phosphate flux across cellular membranes in
bone and kidney, resulting in: Vitamin D
o ↑ serum calcium  Secosteroid produced in the skin from 7-dehydrocholesterol under
o ↓ serum phosphate the influence of UV radiation
 Metabolic clearance of intact PTH is rapid  Regulates calcium, phosphate and bone metabolism
o Within minutes  Natural form: Cholecalciferol (Vit D3)
o Occurring mostly in the liver and kidney  Plant-derived form: Ergocalciferol (Vit D2)
o Inactive carboxyl terminal fragments produced by  Prohormone serves as precursor to biologically active metabolites:
metabolism of the intact hormone have a much lower o Calcifediol  2-hydroxyvitamin D (liver)
clearance, especially in renal failure o Calcitriol  1,25-dihydroxyvitamin D (kidney)
o Secalciferol  24,25-dihydroxyvitamin D (kidney)
Physiologic Effects of PTH:
Bone  Analogs:
 Indirect Effect: ↑ the activity and number of osteoclasts o Dihydrotachysterol – DHT
 Direct Effect: Acts on the osteoblast (the bone-forming cell) to induce o Calcipotriene (calcipotriol)
RANK ligand (RANKL) Synthetic analog used for psoriasis
RANKL:
o Is a membrane-bound protein o Doxercalciferol (1α-hydroxybitamin D2)
o Acts on osteoclasts and osteoclast precursors to ↑ both Treatment of secondary hyperparathyroidism in
the numbers and activity of osteoclasts = ↑ bone patients with chronic kidney disease
resorption
o Paricalcitol (19-nor-1,25-dihydroxyvtiamin D2)
 End-Effect: Promotion of both bone formation & resorption (but net Treatment of secondary hyperparathyroidism in
effect of more on resorption), by stimulating proliferation & patients with chronic kidney disease
differentiation of osteoblast or osteoclast
 It also inhibits the production and secretion of sclerostin from o Eldecalcitol
osteocytes Has been approved in Japan for the treatment of
Sclerostin is one of several proteins that blocks osteoblast osteoporosis with minimal effects on serum calcium
proliferation by inhibiting the wnt pathway
Regulation of Vitamin D:
 Excess PTH: ↑ bone resorption  Regulation involves calcium, phosphate, PTH, and FGF23
 Low and Intermittent doses of PTH: ↑ bone formation (involving o Its synthesis is stimulated by PTH & low serum
other factors such as IGF1) phosphorus
o Inhibited by FGF23
Kidney  DBP  Vitamin D-binding protein (α-globulin)
 ↑ reabsorption of calcium and magnesium o High affinity: calcifediol, secalciferol
 ↓ reabsorption of phosphate, amino acids, bicarbonate, sodium o Low affinity: vitamin D, calcitriol
chloride, & sulfate  Analogs are bound poorly
 Stimulation of 1,25-dihydroxyvitamin D [1,25(OH)2D] production o Rapid clearance
Agents Mentioned Related to PTH: o Less hypercalcemic
 Natpara  Excess vitamin D is stored in adipose tissue
A full length form of PTH (rhPTH 1-84) that has been recently  Metabolic clearance of calcitriol in humans indicates a rapid turnover
approved for treatment of hypoparathyroidism  Terminal half-life measured in hours
 Several of the Calcitriol analogs:
 Abaloparatide o Poorly bound by the DBP
The analog of PTHrP o Rapid clearance
Used for the treatment of osteoporosis
Has anabolic action of stimulating bone formation Additional Information from Manual:
 If vitamin D is ↑ = ↓ PTH
 Teriparatide  Physiologic effects of Vitamin D:
The recombinant form of PTH 1-34 o ↑ osteoclastic bone resorption with ↑ blood calcium
Used for the treatment of osteoporosis o ↑ intestinal absorption of calcium
Has anabolic action of stimulating bone formation
o ↑ tubular reabsorption of phosphate in kidney
 Its deficiency in children leads to rickets
 Its deficiency in adults leads to osteomalacia

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 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Vitamin D continued….. Interaction of PTH, Vitamin D and FGF23

Calcitriol:
 Most potent stimulant of intestinal calcium and phosphate
transport and bone resorption
 Acts on intestine by:
o Induction of new protein synthesis, examples:
 Calcium binding protein
 TRPV6
o Modulation of calcium flux across the brush border and
basolateral membrane
 Receptors:
o Exist in nearly all issues, not just intestine, bone, and
kidney
o In these “non-classic” target tissues:
 Regulation of the secretion of PTH, insulin,
and renin
 Regulation of innate and adaptive immune
function through actions on dendritic cell and
T-cell differentiation
 Enhanced muscle function; proliferation and
differentiation of a number of cancer cells
Fibroblast Growth Factor 23 (FGF23)
 Single chain protein with 251 amino acids with a 24 amino acid leader
sequence
 Hormone produced by bone
 ↑ renal phosphate excretion or ↓ reabsorption of renal phosphate
 Inhibits renal production of 1,25(OH)2D (Calcitriol)
This will result to hypophosphatemia or osteomalacia
 Three main target tissues: intestine, kidney, bone
 Net effect:
o PTH: ↑ serum calcium & ↓ serum phosphate
o FGF23: ↓ serum phosphate
o Vitamin D: ↑ serum calcium & phosphate
 Calcium is one of the principal regulator of PTH secretion:
o It binds to part of Gq protein-coupled receptor called the
Calcium Sensing Receptor (CaSR)
Employs the phosphoinositide second messenger
system to link changes in the extracellular calcium
concentration to changes in the intracellular free
calcium
 ↑ calcium = ↓ PTH
 ↑ phosphate = ↑ PTH & ↑ FGF23
Such feedback regulation is appropriate to the net effect of PTH
to ↑ serum calcium and ↓ serum phosphate levels
FGF23 = ↓ serum calcium
 ↑ calcium & phosphate = ↓ Calcitriol & ↑ Secalciferol
Calcitriol  raises serum calcium and phosphate (therefore
should be inhibited)
Secalciferol  less effect on serum calcium and phosphate

#LaNaAkongMoney…Hayst Page 13 of 20
 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42
SECONDARY HORMONAL REGULATORS OF BONE MINERAL HOMEOSTASIS
Calcitonin
 Secreted by the parafollicular cells of the mammalian thyroid
 Single-chain peptide hormone with 32 amino acids and a molecular
weight of 3600
 Disulfide bond between positions 1 and 7 is essential for biologic
activity
 MRC Units
Activity is compared to a standard maintained by the British
Medical Research Council (MRC) and expressed as MRC units
 Half-life of human calcitonin: 10 minutes
 Half-life of salmon calcitonin: 40-50 minutes  more useful clinically
 Clearance occurs in the kidney by metabolism
Effects of Calcitonin:
 ↓ serum calcium and phosphate by actions on bone and kidney
 Inhibits osteoclastic bone resorption
o Bone formation is not impaired at first after calcitonin
administration
o Formation and resorption of bone are reduced when used
chronically
 In the kidney:
o ↓ reabsorption of calcium, phosphate, sodium,
potassium, & magnesium
 In the gut:
o ↓ gastrin secretion and ↓ gastric acid output
o ↑ secretion of sodium, potassium, chloride & water
Calcitonin Secretion:
 Pentagastrin  is a potent stimulator of calcitonin secretion
 Hypercalcemia
In adults, there is no readily demonstrable problem develops in cases of:
 Calcitonin deficiency (thyroidectomy)
 Calcitonin excess (medullary carcinoma of the thyroid)
Clinical Uses of Calcitonin:
 Since it blocks resorption and lower serum calcium, it can be used
for the treatment of:
o Paget’s disease
o Hypercalcemia
o Osteoporosis
Glucocorticoids
 Alter bone mineral homeostasis by:
o Antagonizing vitamin D–stimulated intestinal calcium
transport
o Stimulating renal calcium excretion
o Blocking bone formation
 Reverses the hypercalcemia associated with:
o Lymphomas
o Granulomatous diseases such as sarcoidosis
Sarcoidosis  there is ↑ production of calcitriol
o Cases of vitamin D intoxication
 Prolonged administration of glucocorticoids is a common cause of
osteoporosis in adults and can cause stunted skeletal development
in children
#LaNaAkongMoney…Hayst
Estrogen
 Prevent accelerated bone loss during the immediate
postmenopausal period
 Transiently increase bone in postmenopausal women
 Reduce the bone-resorbing action of PTH
 Administration leads to ↑ of 1,25(OH)2D level in blood
o No direct effect on calcitriol production in vitro
o This may be due to ↓ serum calcium and phosphate with
↑ PTH
o ↑ DBP production by the liver = ↑ vitamin D metabolites
in circulation
 Estrogen receptors have been found in bone, and estrogen has direct
effects on bone remodeling
 Men who lack the estrogen receptor or who are unable to produce
estrogen because of aromatase deficiency noted marked osteopenia
and failure to close epiphyses
 Principal therapeutic application:
o Treatment/Prevention of postmenopausal osteoporosis
Selective Estrogen Receptor Modulators (SERMS):
Raloxifene
 First SERM to be approved for the prevention of osteoporosis
 Shares some of the beneficial effects of estrogen on bone without
increasing the risk of breast or endometrial cancer
It may actually ↓ the risk of breast cancer
 Shown to reduce vertebral fractures
NON-HORMONAL REGULATORS OF CALCIUM AND PHOSPHATE
Biphosphonate
 Are analogs of pyrophosphate in which the P-O-P bond has been
replaced with a nonhydrolyzable P-C-P bond
 Etidronate is seldom used
Currently Available Biphosphonates:
 Etidronate  Tiludronate
 Pamidronate  Ibandronate
 Alendronate  Zoledronate
 Risedronate
Mechanism of Action:
 Has the ability to retard formation and dissolution of hydroxyapatite
crystals within and outside the skeletal system
 ↑ bone density by inhibiting:
o 1,25(OH)2D production
o Intestinal calcium transport
o Glycolysis
o Cell growth
o Changes in acid and alkaline phosphatase activity
Pharmacokinetics:
 <10% of an oral dose of these drugs is absorbed
 Food reduces absorption even further
Therefore must be given on an empty stomach
 IV dosing also allows a larger amount of drug to enter the body and
markedly reduces the frequency of administration
Zoledronate is infused ONCE per year
 Nearly half of the absorbed drug accumulates in bone
The remainder is excreted unchanged in the urine
 The portion of drug retained in bone depends on the rate of bone
turnover
Drug in bone often is retained for months to years
Page 14 of 20
 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Biphosphonates continued….. Denosumab continued…..

Clinical Uses: Adverse Effects:
 Hypercalcemia associated with malignancy  Drug appears to be well tolerated
 Paget’s disease  3 concerns:
 Osteoporosis 1. ↑ risk of infection associated with the use of denosumab
2. ↑ risk of osteonecrosis of the jaw and subtrochanteric
Adverse Effects: fractures
 Oral forms  Risedronate, Alendronate, Ibandronate: Since suppression of bone turnover with denosumab
o Esophageal irritation is similar to that of bisphosphonates
o Gastric irritation
IV infusions of Pamidronate, Zoledronate, & Ibandronate is 3. Can lead to transient hypocalcemia, especially in patients
used with marked bone loss (and bone hunger) or
compromised calcium regulatory mechanisms, including
 Etidronate (higher doses) chronic kidney disease and vitamin D deficiency
o Induces mineralization defect Denosumab can be used in patients with advanced
renal disease, unlike the bisphosphonates, as it is NOT
 Zoledronate (high IV dose) cleared by the kidney, and it has the advantage over
o Osteonecrosis of the jaw bisphosphonates in that it is readily reversible
because it does not deposit in bone
Rare in usual doses of bisphosphonates
Frequent when the drug is used to control bone
metastases and banker-induced hypercalcemia Calcimimetics
Cinacalcet
 Others: Mechanism of Action:
o Over-suppressing bone turnover  A drug that activates the calcium-sensing receptor (CaSR)
o Subtrochanteric femur fractures (long-term treatment)  CaSR is widely distributed but has its greatest concentration in the
parathyroid gland
Contraindications: By activating the parathyroid gland CaSR, cinacalcet inhibits PTH
 Upper gastrointestinal disorder secretion
o Esophageal motility disorders
o Peptic ulcer disease Clinical Use:
 Treatment of secondary hyperparathyroidism in chronic kidney
 Decreased renal function disease
 Treatment of parathyroid carcinoma
Amino Biphosphonates:
 Alendronate & Risedronate Plicamycin (Based on Manual; Not found in Katzung 14th Ed.)
Inhibit farnesyl pyrophosphate synthase, an enzyme in the  Mithramycin
mevalonate pathway that appears to be critical for osteoclast  Cytotoxic antibiotic
survival
Clinical Uses:
Denosumab  Paget’s disease
 Fully humanized monoclonal antibody
 Hypercalcemia

Mechanism of Action:
Mechanism of Action:
 It binds to and prevents the action of RANKL
 Binds to DNA and interrupts DNA-directed RNA synthesis, thus may
By interfering with RANKL function, denosumab inhibits interrupt with bone resorption
osteoclast formation and activity
NOTE: RANKL is produced by osteoblast and it stimulates Thiazide Diuretics
osteoclastogenesis  Used to treat bone mineral disorders by reducing renal calcium
excretion via:
 As effective as the potent bisphosphonates in inhibiting bone o Increasing the effectiveness of PTH in stimulating
resorption reabsorption of calcium by the renal tubules
o Act on calcium reabsorption secondarily by ↑ sodium
Clinical Uses: reabsorption in the PROXIMAL tubule
 Treatment of postmenopausal osteoporosis o Blocking sodium reabsorption at the luminal surface in
 Treatment of some cancers (prostate and breast) the DISTAL tubule
Limit the development of bone metastases or bone loss resulting Leads to ↑ calcium-sodium exchange at the
from the use of drugs that suppress gonadal function basolateral membrane and thus ↑ calcium
reabsorption into the blood at this site
Pharmacokinetics:
 Administered SQ every 6 months  avoids GI side effects  Reduces the hypercalciuria and incidence of urinary stone
formation in subjects with idiopathic hypercalciuria
Reduction stone formation may lie in their ability to:
o ↓ urine oxalate excretion
o ↑ urine magnesium and zinc levels

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 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Fluoride CLINICAL PHARMACOLOGY

 Prophylaxis of dental caries Abnormal Serum Calcium & Phosphate Levels
 Has been evaluated for the treatment osteoporosis Hypercalcemia
o Fluoride alone, without adequate calcium  Causes CNS depression, including coma, and is potentially lethal
supplementation, produced osteomalacia  Its major causes:
If with calcium supplementation: o Thiazide therapy
It demonstrated an improvement in calcium balance, o Hyperparathyroidism
an ↑ in bone mineral, and an ↑ in trabecular bone o Cancer, with or without bone metastases
volume
 Less common causes:
o Hypervitaminosis D  require emergency ↓ of serum Ca2+
o It failed to demonstrate a reliable reduction in fractures,
o Sarcoidosis
and some studies showed an increase in fracture rate
o Thyrotoxicosis
o Fluoride is not approved by the FDA for treatment or
o Milk-alkali syndrome
prevention of osteoporosis
o Adrenal insufficiency
o Immobilization
Mechanism of Action:
 Accumulates in bones and teeth, where it may stabilize the
Treatment of Hypercalcemia:
hydroxyapatite crystal
1.) Saline Diuresis:
This may explain the effectiveness of fluoride in increasing the
 Symptomatic hypercalcemia  patients with severe hypercalcemia
resistance of teeth to dental caries, but it does not explain its
have a substantial component of prerenal azotemia owing to
ability to promote new bone growth
dehydration
Pharmacokinetics:  Rapid reduction of serum calcium is required
 Fluoride in drinking water appears to be most effective in preventing  First steps:
dental caries if consumed before the eruption of the permanent 1) Rehydration with Saline
teeth  Initial infusion: 500-1000 mL/h
o Optimum concentration: 0.5-1 ppm  Can reverse dehydration and restore urine
flow
 Topical application is most effective if done just as the teeth erupt  Can by itself substantially lower serum
calcium
Adverse Effects: 2) Diuresis with Furosemide
 Mottling of the enamel (if concentration is >1 ppm)  Enhances urine flow
 At higher doses:  Inhibits calcium reabsorption in the ascending
o Nausea & vomiting limb of the loop of Henle
o Gastrointestinal blood loss  Monitoring of central venous pressure is important to forestall the
o Arthralgias development of heart failure and pulmonary edema in predisposed
o Arthritis subjects
Such effects are usually responsive to reduction of the  If saline diuresis does not suffice to reduce serum calcium, the
dose or giving fluoride with meals (or both) following agents are available:
o Biphosphonates
Strontium Ranelate o Calcitonin
 Composed of two atoms of strontium bound to an organic ion, ranelic o Gallium Nitrate
acid o IV Phosphate
 Used in Europe for treatment of osteoporosis o Glucocorticoids
 Clinical trials demonstrated its efficacy in ↑ bone mineral density
and ↓ fractures in the spine and hip 2.) Biphosphonates:
 For treatment of hypercalcemia of malignancy
Mechanism of Action: o Pamidronate
 Appears to block differentiation of osteoclasts while promoting 60-90 mg, infused over 2-4 hours
their apoptosis, thus inhibiting bone resorption
o Zoledronate
 Appears to promotes bone formation
4 mg, infused over at least 15 mins.
Unlike bisphosphonates, denosumab, or teriparatide, this drug ↑
bone formation markers while inhibiting bone resorption
markers  Effects generally persist for weeks
o But treatment can be repeated after a 7-day interval if
necessary and if renal function is not impaired
 Adverse Effects:
o Self-limited flu-like syndrome after initial infusion
o Rare: renal deterioration and osteonecrosis of the jaw

Continued next page…..

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 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Treatment of Hypercalcemia continued….. Diseases that may respond to Glucocorticoids continued…..

3.) Calcitonin: o Vitamin D intoxication
 Ancillary treatment in some patients Reduces vitamin D-mediated intestinal calcium
 If used alone: transport but does not alter vitamin D metabolism
o Seldom restores serum calcium to normal
o Refractoriness frequently develops o Multiple myeloma and related lymphoproliferative
 Lack toxicity diseases
o Permits frequent administration at high doses (200 MRC Sensitive to the lytic action of glucocorticoids
units or more) Decrease tumor mass and activity
 Effect on serum calcium is observed within 4–6 hours and lasts for 6– Inhibits secretion or effectiveness of cytokines
10 hours
 Calcimar  Primary hypoparathyroidism DO NOT respond to glucocorticoid
therapy
A salmon calcitonin that is available for parenteral and nasal
administration
Hypocalcemia
4.) Gallium Nitrate:  Main features are neuromuscular:
 Approved by the FDA for the management of hypercalcemia of o Tetany
malignancy o Paresthesias
 MOA: inhibits bone resorption o Laryngospasm
 Dosage: 200 mg/m2 body surface area per day given as a continuous o Muscle cramps
IV infusion in 5% dextrose for 5 days o Seizures
Superior to calcitonin in reducing serum calcium in cancer  Major causes (in adults):
patients o Hypoparathyroidism
o vitamin D deficiency
 Potentially nephrotoxic o Chronic kidney disease
o Patients should be well hydrated and have good renal o Malabsorption
output before starting the infusion  Hypocalcemia can also accompany the infusion of potent
5.) IV Phosphate bisphosphonates and denosumab for the treatment of osteoporosis,
 It is probably the fastest and surest way to reduce serum calcium but this is seldom of clinical significance
 It is a hazardous procedure if not done properly  Neonatal hypocalcemia is a common disorder that usually resolves
 It should be used only after other methods of treatment without therapy
(bisphosphonates, calcitonin, and saline diuresis) have failed to  Large infusions of citrated blood can produce hypocalcemia
control symptomatic hypercalcemia secondary to the formation of citrate-calcium complexes
 Given slowly 50 mmol or 1.5 g elemental phosphorus over 6–8 hours:
Switch to oral phosphate (1–2 g/d elemental phosphorus) as soon Treatment of Hypocalcemia:
as symptoms of hypercalcemia have cleared  Mainstay of treatment: Calcium & Vitamin D
 In patients with hypoparathyroidism:
 Adverse Effects: o Teriparatide
o Hypocalcemia o Natpara (rhPTH 1-84)
o Ectopic calcification
o Acute renal failure 1.) Calcium
o Hypotension  Available for IV, IM, and oral use
 Amounts required to provide 1 g of elemental phosphorus are as IV Calcium
follows: Calcium gluceptate 0.9 mEq calcium/mL
Intravenous Calcium gluconate
In-Phos 40 mL  Preferred 0.45 mEq calcium/mL
Hyper-Phos-K 15 mL  Less irritating to veins
Oral Calcium chloride 0.68-1.36 mEq calcium/mL
Fleet Phospho-Soda 6.2 mL Oral Calcium
Neutra-Phos 300 mL Calcium carbonate
 Preparation of choice
K-Phos-Neutra 4 tablets  High calcium percentage
40% calcium
 Readily available (eg, Tums)
6.) Glucocorticoids  Low cost
 Oral Prednisone: 30-60 mg daily is generally used  Has antacid properties
 Have no clear role in the immediate treatment of hypercalcemia Calcium lactate 13% calcium
 Diseases that may respond to this drug: Calcium phosphate 25% calcium
o Chronic hypercalcemia of sarcoidosis Calcium citrate 21% calcium
Directed at reduction of sarcoid tissue results in
restoration of normal serum calcium and 1,25(OH)2D
levels Continued next page…..

#LaNaAkongMoney…Hayst Page 17 of 20
 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Treatment of Hypocalcemia continued…..  Effects of Acute Hypophosphatemia:

 Achlohydric patients o Reduction in the intracellular levels of high-energy
o Calcium carbonate should be given with meals to organic phosphates (eg, ATP)
increase absorption, or the patient should be switched to o Interfere with normal hemoglobin-to-tissue oxygen
calcium citrate, which is somewhat better absorbed transfer by decreasing red cell 2,3-diphosphoglycerate
levels, and lead to rhabdomyolysis
Severe symptomatic hypocalcemia Less severe hypocalcemia  Clinically significant acute effects of hypophosphatemia are seldom
- Oral forms of 400-1200 mg of seen, and emergency treatment is generally not indicated
- Slow infusion of 5-20 mL of 10% elemental calcium (1-3 g  Long-term effects:
calcium gluconate calcium carbonate) per day
o Proximal muscle weakness
- Rapid infusion can lead to cardiac - Dosage must be adjusted to
arrhythmias avoid hypercalcemia and
o Abnormal bone mineralization (osteomalacia)
hypercalciuria  Treatment: Oral forms of phosphate

2.) Vitamin D SPECIFIC DISORDERS INVOLVING BONE MINERAL-REGULATING

 1,25(OH)2D3 HORMONES
o Calcitriol Primary Hyperparathyroidism
o Metabolite of choice when rapidity of action is required  Signs and Symptoms:
 Dosage: 0.25-1 mcg daily o Hypercalcemia
o Raises serum calcium within 24-48 hours o Hypercalciuria
o Also raises serum phosphate late in the treatment o Osteoporosis
 Careful monitoring of these mineral levels to prevent ectopic o Kidney disease
calcification secondary to an abnormally high serum calcium-  Treatment:
phosphate product o Surgical removal of parathyroid glands
o Asymptomatic patients do not need treatment
o Cinacalcet
Hyperphosphatemia
For treatment of secondary hyperthyroidism
 Common complication of renal failure
 Also found in:
 Primary Hyperparathyroidism is often associated with ↓ levels of
o All types of hypoparathyroidism (idiopathic, surgical, and
25(OH)D
pseudohypoparathyroidism)
This suggests that mild vitamin D deficiency may be contributing
o Vitamin D intoxication
to the ↑ PTH levels  in such situation Vitamin D
o Rare syndrome of tumoral calcinosis (usually due to supplementation may be given
insufficient bioactive FGF23)
 Emergency treatment of hyperphosphatemia is seldom necessary Hypoparathyrodism
but can be achieved by:  Causes:
o Dialysis o Idiopathic hypoparathyroidism ↓ PTH levels
o Glucose o Surgical hypoparathyroidism
o Insulin infusions o Pseudohypoparathyroidism - ↑ or Normal PTH levels
 General control of hyperphosphatemia:  Findings:
o Restriction of dietary phosphorus o ↓ 1,25(OH)2D levels
o Phosphate-binding gels (Sevelamer or Lanthum carbonate) o ↓ serum calcium
o Calcium supplements o ↑ serum phosphate
 Aluminum-containing antacids should be used sparingly and only o Normal bone
when other measures fail to control the hyperphosphatemia because o Osteitis fibrosa
of their potential to induce aluminum-associated bone disease Finding in pseudohypoparathyroidism wherein there
 In patients with chronic kidney disease, large doses of calcium to is normal or ↑ PTH level
control hyperphosphatemia has waned because of the risk of ectopic
calcification  Principal therapeutic goal: Restore normal levels of Ca2+ and P
 Treatment:
Hypophosphatemia o Calcitriol
 Associated with: o Dietary calcium supplements
o Primary hyperparathyroidism o Natpara (rhPTH 1-84)
o Vitamin D deficiency Approved for the treatment of hypoparathyroidism
o Idiopathic hypercalciuria and reduces the need for large doses of calcium and
o X-linked and autosomal dominant hypophosphatemic calcitriol
↑ Bioactive FGF23 rickets
o Tumor-induced osteomalacia Nutritional Vitamin D Deficiency or Insufficiency
Renal Phosphate o Fanconi’s syndrome  Role of normal vitamin D:
wasting o Overzealous use of phosphate binders Prevents rickets, osteomalacia, fractures, diabetes mellitus,
o Parenteral nutrition with inadequate phosphate content hyperparathyroidism, autoimmune disease, cancer

 10-30 ng/mL  necessary for preventing rickets or osteomalacia

 Treatment: D2 or D3  1000-4000 IU/d or 50,000 IU/week for
several weeks

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 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Chronic Kidney Disease (CKD) Treatment of Osteoporosis continued….

 Major sequelae of CKD: o Calcitonin
o ↓ 1,25(OH)2D production Approved for use in the treatment of
o Retention of phosphate with an associated ↓ in ionized postmenopausal osteoporosis
calcium levels ↑ bone mass and reduce fractures, but ONLY in the
o Secondary hyperparathyroidism that results from the SPINE
parathyroid gland response to ↓ serum ionized calcium
and ↓ 1,25(OH)2D o Denosumab
 Signs and Symptoms: RANKL inhibitor
o Muscle weakness Given SQ every 6 months
Reduces risk of vertebral & non-vertebral fractures
o Bone pain
o Osteomalacia
o Strontium Ranelate
o Osteitis fibrosa
o Some case may show hypercalcemia, and adynamic bone Used in Europe for the treatment of osteoporosis
General dose: 2 g/d
disease (a ↓ in bone cell activity)
 Treatment:
X-Linked & Autosomal Dominant Hypophosphatemia
o Vitamin D
 Manifest in childhood as rickets and hypophosphatemia
o Analogs of Calcitriol
 X-linked and autosomal dominant hypophosphatemia:
 Doxercalciferol & Paricalcitol (in U.S)
o Biologically active FGF23 accumulates  leading to
 Maxacalcitol & Falecalcitriol (in Japan)
phosphate wasting in the urine and hypophosphatemia
 Tumor-induced osteomalacia
Intestinal Osteodystrophy
Acquired syndrome in adults that results from overexpression of
 Malabsorption of calcium & vitamin D due to GIT or liver disease
FGF23 in tumor cells
 Results to:
o Osteoporosis
 Treatment:
o Osteomalacia
o Oral phosphate
 Treatment:
o Calcitriol
o Calcitriol
o FGF23 antibodies
o Calcifediol
Vitamin D-dependent Rickets
Osteoporosis
 Pseudovitamin D–deficiency rickets is due to an isolated deficiency
 Abnormal loss of bone predisposing to fractures
of 1,25(OH)2D production caused by mutations in 25(OH)-D- 1α-
 Most common in postmenopausal women but also occurs in
hydroxylase (CYP27B1)
 Most commonly associated with loss of gonadal function as in: o Treatment  Calcitriol
o Menopause
 Hereditary vitamin D–resistant rickets (HVDRR) is caused by
o Long-term administration of glucocorticoids or other
mutations in the gene for the vitamin D receptor
drugs, including those that inhibit sex steroid production
o Treatment  High dose of Calcitriol
 May be a manifestation of:
 Calcium and phosphate infusions have been shown to correct the
o Thyrotoxicosis or hyperparathyroidism
rickets in some children
o Malabsorption syndrome
o Alcohol abuse and cigarette smoking
Nephrotic Syndrome
o Idiopathic (no obvious cause)
 Lose vitamin D metabolites in the urine  presumably by loss of the
 Treatment:
vitamin D–binding protein
o Estrogen
 Cannot be treated by vitamin D supplementation
For postmenopausal form of osteoporosis
Idiopathic Hypercalciuria
o Biphosphonates  Characterized by hypercalciuria and nephrolithiasis with normal
Inhibits bone resorption serum calcium and PTH levels
↑ bone density & ↓ risk of fractures  Divided into 3 groups:
Approved agents: 1) Hyperabsorbers: ↑ intestinal absorption of calcium,
Alendronate, Risedronate, Ibandronate, Zoledronate resulting in high-normal serum calcium, low-normal PTH,
and a secondary ↑in urine calcium
o SERMs (Raloxifene) 2) Renal Calcium Leakers: ↓ in renal reabsorption of
Prevent the risk of breast and uterine cancer filtered calcium, leading to low-normal serum calcium
associated with estrogen while maintaining the and high-normal serum PTH
benefit to bone 3) Renal Phosphate Leakers: ↓ in renal reabsorption of
It protects against SPINE fractures but NOT hip
phosphate, leading to ↑ 1,25(OH)2D production, ↑
fractures—unlike bisphosphonates, denosumab, and
intestinal calcium absorption, ↑ ionized serum calcium,
teriparatide, which protect against both
low-normal PTH levels, and a secondary ↑ in urine
calcium
o Teriparatide
 Treatment:
Recombinant form of PTH 1-34
Stimulates new bone formation o Hydrochlorthiazide or Chlorthiazide– recommended
Given SQ for only 2 years of use o Allopurinol – alternative to thiazide

#LaNaAkongMoney…Hayst Page 19 of 20
 PHARMACOLOGY
Topic: Thyroid & Antibone Drugs
Chapter: 38 & 42

Paget’s Disease Enteric Oxaluria

 A localized bone disorder characterized by uncontrolled osteoclastic  Patients with short bowel syndromes and associated fat
bone resorption with secondary increases in poorly organized bone malabsorption can present with renal stones composed of calcium
formation and oxalate
 Cause  Measles-related virus  Such patients characteristically have:
 Diagnosis: o Normal or ↓ urine calcium levels
o ↑ serum alkaline phosphatase o ↑ urine oxalate levels
o ↑ urinary hydroxyproline  Reasons for the development of oxaluria:
 Goal of Treatment: 1) In the intestinal lumen, calcium (which is now bound to
o Reduce bone pain fat) fails to bind oxalate and no longer prevents its
o Stabilize or prevent progressive deformity, fractures, absorption
hearing loss, high-output cardiac failure, and 2) Enteric flora, acting on the increased supply of nutrients
immobilization hypercalcemia reaching the colon, produce larger amounts of oxalate
 Treatment:  Treatment:
o Calcitonin & Bisphosphonates  1st line agents o Calcium supplementation (Calcium carbonate)
o Currently approved bisphosphonates: ↑ intestinal calcium binds the excess oxalate and
 Etidronate, Alendronate, Risedronate, & prevents its absorption
Tiludronate, Pamidronate
o Treatment of bisphosphonates should not exceed 6
months per course (but may be repeated after 6 months) References:
 Toxicity:  Basic & Clinical Pharmacology by Katzung
o Etidronate  osteomalacia, bone fractures, bone pain (14th ed.)
 Pharmacology Lecture Guide (2020)
o Alendronate  gastric irritation

#LaNaAkongMoney…Hayst Page 20 of 20
 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

THE ENDOCRINE PANCREAS

 Consists of approximately 1 million islets of Langerhans interspersed
throughout the pancreatic gland
Within the islets, at least five hormone producing cells are
present

 Hormone products:
o Insulin
The storage and anabolic hormone of the body
Figure Above: Structure of human proinsulin and insulin
o Islet amyloid polypeptide (IAPP or amylin)
Proinsulin (C-peptide plus A and B chains)
Modulates appetite, gastric emptying, and glucagon
Insulin is shown as the shaded (orange color) peptide chains, A and B
and insulin secretion

 Granules within the beta cells store the insulin in the form of crystals
o Glucagon
consisting of two atoms of zinc and six molecules of insulin
Hyperglycemic factor that mobilizes glycogen stores
 The entire human pancreas contains up to 8 mg of insulin,
representing approximately 200 biologic units
o Somatostatin
Originally, the unit was defined on the basis of the hypoglycemic
A universal inhibitor of secretory cells
activity of insulin in rabbits
o Pancreatic peptide
 With improved purification techniques, the unit is presently defined
A small protein that facilitates digestive processes by
on the basis of weight, and present insulin standards used for assay
a mechanism not yet clarified
purposes contain 28 units per milligram
o Ghrelin
Insulin Secretion
A peptide known to increase pituitary growth
hormone release  Insulin is released from pancreatic beta
 Stimulants of Insulin Release:
o Glucose – major
o Other sugars (eg, mannose)
o Gluconeogenic amino acids (eg, leucine, arginine)

 Amplifiers of Glucose-Induced Insulin Release: (Hormones)

o Glucagon-like polypeptide 1 (GLP-1)
o Glucose-dependent insulinotropic polypeptide (GIP)
o Glucagon
o Cholecystokinin
o High concentrations of fatty acids
o β-adrenergic sympathetic activity

 Stimulatory Drugs:
o Sulfonylureas
o Meglitinide & Nateglinide
o Isoproterenol
o Acetylcholine
INSULIN
Chemistry
 Inhibitors of Insulin Release:
 A small protein with a molecular weight in humans of 5808
o Neural: α-sympathomimetic effect of catcholamines
 It contains 51 amino acids arranged in two chains (A and B) linked
o Humoral: somatostatin, leptin
by disulfide bridges
o Drugs: diazoxide, phenytoin, vinblastine, colchicine
There are species differences in the amino acids of both chains
Insulin Degradation
 Proinsulin, a long single-chain protein molecule, is processed within
 Endogenous insulin (coming from the pancreas):
the Golgi apparatus of beta cells and packaged into granules, where
o Liver – 60% of endogenous insulin is cleared
it is hydrolyzed into insulin and C-peptide
o Kidney – 35-40% of endogenous insulin is cleared
C-peptide is a residual connecting segment as a result of removal
of four amino acids
 In insulin-treated diabetics receiving SQ insulin injections:
o Kidney – 60% of exogenous insulin is cleared
 Insulin and C-peptide are secreted in equimolar amounts in response
o Liver – 30-40% of exogenous insulin is cleared
to all insulin secretagogues; a small quantity of unprocessed or
partially hydrolyzed proinsulin is released as well
NOTE: You will notice that the ratio is reversed if the insulin is
 Proinsulin may have some mild hypoglycemic action
coming from an exogenous source
 C-peptide has no known physiologic function
 Insulin Half-life: 3-5 minutes

#ThankYouFrontliners Page 1 of 13
 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Circulating Insulin Metabolism

 Basal serum insulin values 5–15 μU/mL (30–90 pmol/L)  Glucagon is extensively degraded in the:
 Peak rise  60–90 μU/mL (360–540 pmol/L) during meals o Liver
o Kidney
Effects of Insulin on its Targets o Plasma
 Insulin affects many organs: o Tissue receptor sites
o It stimulates skeletal muscle fibers  Glucagon Half-life: 3-6 minutes (similar with insulin)
o It stimulates liver cells
o It acts on fat cells Pharmacologic Effects of Glucagon
o It inhibits production of certain enzyme A. Metabolic Effects
In each case, insulin triggers these effects by binding to the  The first six amino acids at the amino terminal of the glucagon
insulin receptor molecule bind to specific Gs protein–coupled receptors on liver cells
↓
↑ in cAMP, which facilitates catabolism of stored glycogen and ↑
gluconeogenesis and ketogenesis
↓
↑ blood glucose at the expense of stored hepatic glycogen

 There is NO effect on skeletal muscle glycogen, presumably because

of the lack of glucagon receptors on skeletal muscle
 Pharmacological amounts of glucagon causes:
o Release of insulin from normal pancreatic beta cells
o Release of catecholamines from pheochromocytoma
o Release of calcitonin from medullary carcinoma cells

B. Cardiac Effects
 Glucagon has a potent inotropic and chronotropic effect on the heart
(mediated by the cAMP mechanism )
 Thus, it produces an effect very similar to that of β-adrenoceptor
agonists without requiring functioning β receptors

C. Effects on Smooth Muscles

 Large doses of glucagon produce profound relaxation of the
intestine

Clinical Uses
 Severe Hypoglycemia
The major clinical use of glucagon is for emergency treatment of
severe hypoglycemic reactions in patients with type 1 diabetes
Recombinant glucagon is currently available in 1-mg vials for
parenteral (IV, IM, or SC) use (Glucagon Emergency Kit)

 Endocrine Diagnosis
The Insulin Receptor Several tests use glucagon to diagnose endocrine disorders

 Beta-Adrenoceptor Blocker Overdose

Glucagon is sometimes useful for reversing the cardiac effects of
an overdose of β-blocking agents because of its ability to ↑ cAMP
production in the heart independent of β-receptor function
NOT clinically useful in the treatment of heart failure

GLUCAGON  Radiology of the Bowel

Chemistry Glucagon has been used extensively in radiology as an aid to x-ray
 It is synthesized in the alpha cells of the pancreatic islets of visualization of the bowel because of its ability to relax the
Langerhans intestine
 It is a peptide—identical in all mammals—consisting of a single chain
of 29 amino acids, with a molecular weight of 3485 Adverse Reactions
 Selective proteolytic cleavage converts a large precursor molecule of  Transient nausea & occasional vomiting
approximately 18,000 MW to glucagon
 Glicentin Contraindication:
A precursor intermediate which consists of a 69-amino-acid  Patients with pheochromocytoma
peptide and contains the glucagon sequence interposed between
peptide extensions

#ThankYouFrontliners Page 2 of 13
 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

DIABETES MELLITUS Laboratory Findings

Diabetes Mellitus:
 An elevated blood glucose associated with absent or inadequate
pancreatic insulin secretion, with or without concurrent impairment
of insulin action

Classification:
 Type 1 Diabetes Mellitus
 Type 2 Diabetes Mellitus
 Gestational Diabetes Mellitus
 Other Specific Type of Diabetes Mellitus

Type 1 Diabetes Mellitus

 Selective beta cell (B cell) destruction and severe or absolute insulin Additional Information from Manual:
deficiency ADA CRITERIA FOR THE DIAGNOSIS OF DIABETES (2018)
 Further subdivided: FPG >/=126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for
o Type 1a – immune mediated (most common) at least 8 h.*
o Type 1b – idiopathic cause OR
 <30 years of age at the time of diagnosis 2-h PG >/=200 mg/dL (11.1 mmol/L) during OGTT. The test should be
But the onset can occur at any age performed as described by the WHO, using a glucose load containing the
equivalent of 75-g anhydrous glucose dissolved in water.*
 Highest incidence is in people from: OR
o Northern Europe A1C >/=6.5% (48 mmol/mol). The test should be performed in a laboratory
o Sardinia using a method that is NGSP certified and standardized to the DCCT assay*
 At the time of diagnosis they have: OR
o One or more circulating antibodies to glutamic acid In a patient with classic symptoms of hyperglycemia or hyper glycemic
crisis, a random plasma glucose >/=200 mg/dL (11.1 mmol/L)
decarboxylase 65 (GAD 65)
*In the absence of unequivocal hyperglycemia, results should be confirmed by repeat
o Insulin autoantibody testing
o Tyrosine phosphatase IA2 (ICA 512)
o Zinc transporter 8 (ZnT8) Pathogenesis of Type 2 Diabetes (Based on Manual)
These antibodies facilitate the diagnosis of type 1a diabetes I. Ominous Octet
and can also be used to screen family members at risk for
developing the disease

 Latent Autoimmune Diabetes of Adulthood (LADA)

Up to 10–15% of “type 2” patients may actually have this milder
form of type 1 diabetes (LADA)

Type 2 Diabetes Mellitus

 A heterogenous group of conditions characterized by tissue
resistance to the action of insulin combined with a relative deficiency
in insulin secretion
 A given individual may have more resistance or more beta-cell
deficiency, and the abnormalities may be mild or severe
 Although the circulating endogenous insulin is sufficient to prevent
ketoacidosis, it is inadequate to prevent hyperglycemia
 Patients with type 2 diabetes can be controlled with:
o Diet II. Egregorious Eleven
o Exercise
o Oral glucose lowering agents
o Non-insulin injectables
o Insulin therapy
Used only when there is progressive beta cell failure

Gestational Diabetes Mellitus

 Abnormality in glucose levels noted for the first time during
pregnancy
 The placenta and placental hormones create an insulin resistance
that is most pronounced in the last trimester

Other Specific Types of Diabetes Mellitus

 The “other” designation refers to multiple other specific causes of an
↑ blood glucose: pancreatectomy, pancreatitis, nonpancreatic
diseases, drug therapy

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

III. Dirty Dozen  Colesevelam is a novel 2nd generation bile acid sequestrant which
In 2013, Kalra et al took a further step, describing the “Dirty was observed to mediate modest reduction in glucose in T2DM when
Dozen” in diabetes with 4 additions to the octet: Dopamine, used as an adjunct to other agents. The exact mechanism of action is
Vitamin D, Testosterone, and Renin Angiotensin System not yet identified and potential mechanism include effect on bile acid
receptors in the intestine as well as in the liver to reduce endogenous
Dopamine glucose production
 Dopamine is a neurotransmitter in the brain which has lower plasma
levels during insulin-resistant state and increased to normal following Gut Microbiota
restoration of the insulin-sensitive state  Role of colonic microbiome on pathogenesis of diabetes
 Bromocriptine administration in insulin-resistant animals lead to a  Patients with type 2 diabetes exhibited a moderate intestinal
decreased in elevated ventromedial hypothalamus noradrenergic dysbiosis, which included decrease in butyrate produce Roseburia
and serotonergic levels with a decline in hepatic gluconeogenesis, intestinalis and F. prausnitzii, while healthy control samples were
reduced adipose lipolysis, and improved insulin sensitivity enriched with various butyrate producing bacteria (Clostridiales sp.,
 It is postulated that hypothalamic dopamine is decreased in the early Eubacterium rectale, F. prausnitzii, R. intestinalis)
morning in diabetic patients causing increased hepatic  It is postulated that the gut dysbiosis exert enrichment in membrane
gluconeogenesis and lipolysis resulting in glucose intolerance, transport of sugars, branched chain amino acid and sulfate reduction,
insulin-resistance and dyslipidemia decrease butyrate biosynthesis and modifications in the secretion of
the incretin and possibility of an increase in oxidative stress response
Vitamin D
which may represent a link to the pro-inflammatory observed in
 Vitamin D has been shown to stimulate insulin secretion by regulating T2DM patient
intracellular calcium, modulating pancreatic beta-cell insulin release
and prevention of apoptosis
MEDICATIONS FOR HYPERGLYCEMIA
Insulin Preparations
Testosterone
 Human insulin is dispensed as:
 Low serum testosterone levels is associated with T2DM and o Regular (R) formulation
metabolic syndrome o Neutral protamine hagedorn (NPH) formulations
 Androgen replacement in hypogonadal men has shown to improve  There are 6 analogs of human insulin
insulin sensitivity and glycemic levels, reduce insulin requirements o 3 of which are rapidly acting:
and improvement in the other metabolic parameters 1) Insulin glargine
2) Insulin detemir
Renin Aldosterone System 3) Insulin degludec
 Renin aldosterone system (RAS) blockage with ACE inhibitor (ACEI)  Animal insulins are available in other parts of the world (not in U.S.)
and Angiotensin receptor blockers (ARBs) plays a major role in o Pork and beef preparations:
management of diabetic nephropathy  Isophane, neutral, 30/70
 Postulated mechanism for RAS blockage resulting in improved insulin  Lente
sensitivity include; improvement of blood flow & microcirculation in  All the insulins are available in a concentration of 100 units/ML
skeletal muscles and facilitating insulin signaling at cellular level and (U100) and dispensed as:
improvement of insulin secretion by pancreatic beta cells o 10-mL vials
o 0.3-mL cartridges
IV. Unlucky Thirteen o Prefilled disposable pens
 As the Dirty Dozen doesn’t complete the full spectrum of Several insulins are also available at higher
pathogenesis of diabetes, a proposed 13th mechanism in the concentrations in the prefilled disposable pen form:
pathogenesis of diabetes  the role of gut in diabetes mellitus  Insulin glargine 300 units/mL (U300)
 Insulin degludec (U200)
Gut in Diabetes Mellitus  Insulin lispro 200 units/mL (U200)
 The primary driver in the diabetic pandemic across the world is an  Regular insulin 500 units/mL (U500)
increase in mean caloric intake. Hence it is appropriate that this is
also the 13th unlucky pathophysiologic mechanism Principal Types of Insulin
 The only class of drug which utilize this mechanism for treatment of 1.) Short-Acting Insulin Preparations
diabetes is Alpha Glucosidase Inhibitor  It includes:
o Drugs: Acarbose, Voglibose, Miglitol o Regular human insulin
o AGIs delay carbohydrate absorption from proximal small o 3 rapidly acting insulin analogs
intestine and thus have a lowering effect on postprandial  All are clear solutions at neutral pH
blood glucose and insulin levels  The insulin molecules exist as dimers that assemble into hexamers in
 Sodium Glucose Co-transporter 1 (SGLT-1) is the transporter the presence of two zinc ions
responsible for glucose absorption and SGLT-1 is also involved in 10% The hexamers are further stabilized by phenolic compounds such
of renal glucose reabsorption as phenol and meta-Cresol
 Combined SGLT-1/SGLT-2 inhibitor LX4211 (Sotagliflozin) has shown
to increase urinary glucose excretion, delay intestinal glucose  The mutations engineered into the rapidly acting insulin analogs are
absorption, and increase circulating GLP-1 levels designed to disrupt the stabilizing intermolecular interactions of the
dimers and hexamers, leading to more rapid absorption into the
circulation after SQ injection

Continued next page…..

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Short-acting Insulin Preparations….. Long-acting Insulin Preparations…..

 Regular Insulin  Insulin glargine
o Short-acting o Soluble
o Soluble crystalline zinc insulin o “Peakless” (having a broad plasma concentration plateau)
o Onset: 30 minutes o Long-acting insulin analog
o Peak: 2 hours o Two arginine molecules are attached to the B-chain
o Duration: 5-7 hours carboxyl terminal and glycine is substituted for
o Should be injected 30-45 minutes before meal asparagine at the A21 position
o Administered IV This created an analog that is soluble in an acidic
Useful in diabetic ketoacidosis and during the solution but precipitates in the more neutral body pH
perioperative management of insulin-requiring after SQ injection
diabetics
o Individual insulin molecules slowly dissolve away from
 Rapidly-acting Insulin Analogs the crystalline depot and provide a low, continuous level
o Insulin lispro (Humalog) of circulating insulin
An insulin analog in which the proline at position B28 o Onset: 1-1.5 hours
is reversed with the lysine at B29 o Maximum effect: 4-6 hours
o Duration: 11-24 hours or longer
o Insulin aspart (Novolog) o Given once a day
A single substitution of proline by aspartic acid at
position B28  Insulin detemir
o The terminal threonine is dropped from the B30 position
o Insulin glulisine (Apidra) and myristic acid (a C-14 fatty acid chain) is attached to
Differs from human insulin in that the amino acid the B29 lysine
asparagine at position B3 is replaced by lysine and the These modifications prolong the availability of the
lysine in position B29 by glutamic acid injected analog by:
 Increasing both self-aggregation in
o Taken 15 minutes before meals subcutaneous tissue
o Preferred for use in continuous SQ infusion devices  Reversible albumin binding
o Quickly dissociate into monomers
o Absorbed very rapidly o Its affinity is 4-5x lower than that of human soluble
o Peak: 1 hour insulin
o Available in powder form for alveolar absorption o Injected SQ
 Human insulin recombinant inhaled o Administered once or twice a day
o Duration: about 17 hours
 The rapidly acting analogs are commonly used in insulin pumps
 Insulin aspart has been approved for IV use (eg, in hyperglycemic  Insulin degludec
emergencies) o The threonine at position B30 has been removed and the
But there is NO advantage in using insulin aspart over regular lysine at position B29 is conjugated to hexadecanoic acid
insulin by this route via a gamma-l-glutamyl spacer
o In the vial, in the presence of phenol and zinc, the insulin
is in the form of dihexamer
But when injected SQ, it self-associates into large
multihexameric chains consisting of thousands of
dihexamers

o The chains slowly dissolve in the subcutaneous tissue,

2.) Long-acting Insulin Preparations and insulin monomers are steadily released into the
 NPH (neutral protamine Hagedorn, or isophane) insulin systemic circulation
o An intermediate-acting insulin whose absorption and o Injected SQ
onset of action are delayed by combining appropriate o Administered once or twice a day
amounts of insulin and protamine so that neither is o Half-life: 25 hours
present in an uncomplexed form (“isophane”) o Onset: 30-90 hours
o After SQ injection, proteolytic tissue enzymes degrade o Duration: >42 hours
the protamine to permit absorption of insulin
o Onset: 2-5 hours  Mixtures of Insulin
o Peak: 4-10 hours o Premixed insulins (70% NPH and 30% regular insulin)
o Duration 4-12 hours o Neutral protamine lispro (NPL) + Insulin lispro = Human
Mix 75/25, Humalog Mix (50/50)
More rapid onset of glucose-lowering activity, can be
given within 15 minutes before or after starting a
meal

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Mixtures of Insulin continued….. Insulin Delivery Systems

o 70% insulin degludec + 30% insulin aspart (injected once
or twice daily)
o Insulin glargine or insulin detemir CANNOT be mixed
with either regular insulin or the rapid-acting insulin
analogs
 Insulin Syringes and Needles
 Insulin Pens
Eliminate the need for carrying insulin vials and syringes.
Facilitate multiple SQ injections
 Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin
Pumps)
Encouraged for individuals who are unable to obtain target
control while on multiple injection regimens & where excellent
glycemic control is desired, such as during pregnancy
Velosulin (reg. insulin) & insulin aspart and lispro

 Inhaled Insulin
Have rapid route and a relatively short duration of action
Used to cover mealtime insulin requirements to correct high
glucose levels

Factors that Affect Insulin Absorption

 Site of injection: abdomen, buttock, anterior thigh, or dorsal arm
 Type of insulin
 Subcutaneous blood flow: massage, hot baths, or exercise
 Smoking
 Regional muscular activity at the site of the injection
 Volume & concentration of injected insulin
 Depth of injection

Complications of Insulin Therapy

 Hypoglycemia
o Mechanism and diagnosis
 Result from a delay in taking a meal
 Unusual physical exertion
 Dosage error
o Clinical Manifestations
 Tachycardia, palpitations, sweating,
Insulin Time Action Curve:
tremulousness, hunger, nausea, convulsion,
coma
o Treatment
 Glucose administration
 Glucagon 1 mg SQ or IM
 Honey or syrup

 Immunopathology of Insulin Therapy

o Insulin Allergy
 An immediate type of hypersensitivity (IgE-
antibodies)
 Tx: antihistamines, corticosteroids &
desensitization
Figure Above:
o Immune Insulin Resistance (IgG antibodies)
Extent and duration of action of various types of insulin as indicated by the
glucose infusion rates (mg/kg/min) required to maintain a constant glucose  (+) circulating antibodies that neutralize the
concentration. The durations of action shown are typical of an average dose action of insulin to a small extent
of 0.2–0.3 U/kg. The durations of regular and NPH insulin increase  Tx: switching to a lesser antigenic purified
considerably when dosage is increased insulin
 Lipodystrophy at injection site
Additional from Manual: o Injection of animal insulin preparations sometimes led to
Species of Insulin atrophy of subcutaneous fatty tissue at the site of
Beef & Pork Insulin Human Insulin injection
- The beef insulin differs by 3 amino acids - Less expensive, less immunogenic
o Since the development of human and analog insulin
- The pork insulin differs by 1 amino acid - Production by recombinant DNA
- The beef hormone is most antigenic techniques preparations of neutral pH, this type of immune
complication is almost never seen
 Purity of Insulin  chromatography o Hypertrophy of subcutaneous fatty tissue remains a
 Concentrations: 100 units, 500 units problem if injected repeatedly at the same site 
Corrected by avoidance of that specific site

#ThankYouFrontliners Page 6 of 13
 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

MEDICATIONS FOR TREATMENT OF TYPE 2 DIABETES DOA T½

Sulfonylurea Dosage S/E
Several categories of glucose-lowering agents are available for patients with type (Hrs.) (Hrs.)
2 diabetes: 2nd Generation
Glyburide 10-24 5-10 mg/d Hypoglycemia, flushing
 Sulfonylureas, Meglitinides, d-phenylalanine derivatives
Glipizide 10-24 2-4 (shortest) 5-20 mg/d Hypoglycemia
Agents that bind to the sulfonylurea receptor and stimulate Glimepiride 12-24 5-9 1 mg/d
insulin secretion Gliclazide 10 40-320 mg/d

 Biguanides, Thiazolidinediones Meglitidine Analogs

Agents that lower glucose levels by their actions on liver, muscle,
 Repaglinide
and adipose tissue
o 1st member of the meglitinide group of insulin
secretagogues
 α-glucosidase inhibitors
o MOA: Modulate beta-cell insulin release by regulating
Agents that principally slow the intestinal absorption of glucose
potassium efflux through the potassium channels
o No direct effect on insulin exocytosis
 GLP-1 receptor agonists, Dipeptidyl peptidase 4 [DPP-4] inhibitors
o Peak concentration & peak effect: within 1 hour
Agents that mimic incretin effect or prolong incretin action o Fast onset & duration of action: 5-8 hrs.
o T ½: 1 hour
 Sodium-glucose co-transporter inhibitors (SGLTs) o Hepatically cleared by CYP3A4
Agents that inhibit the reabsorption of glucose in the kidney o Indication: controlling postprandial glucose excursions
o Dosage: 0.25-4 mg
 Pramlintide, Bromocriptine, Colesevelam o S/E: hypoglycemia
Agents that act by other or ill-defined mechanisms o Caution: hepatic & renal impairment

Drugs that Primarily Stimulate Insulin Release by Binding to the  Mitiglinide

Sulfonylurea Receptor (Insulin Secretagogues) o Benzylsuccinic acid derivative
Sulfonureas o Binds to the sulfonylurea receptor and is similar to
Mechanism of Action: repaglinide in its clinical effects
 To increase insulin release from pancreatic B cells o Approved for use in Japan
 Sulfonylureas bind sulfonylurea receptor that is associated with a
beta-cell inward rectifier ATP-sensitive potassium channel  D-Phenylalanine Derivative
inhibits efflux of K+  depolarization  opens a voltage-gated Ca2+  Nateglinide
channel  results in Ca2+ influx and the release of preformed insulin o Stimulates rapid and transient release of insulin from
 Reduction of serum glucagon concentrations beta cells through closure of the ATP-sensitive K+ channel
Chronic administration of sulfonylureas to type 2 diabetics o May suppress glucagon release early in the meal and
reduces serum glucagon levels result in less endogenous or hepatic glucose production
 Potentiation of insulin action on target tissues o Has minimal effect on overnight or fasting blood glucose
levels
1st Generation Sulfonylureas o Ingested just prior to meals
 Tolbutamide o Absorption: within 20 minutes
 Tolazamide o Peak concentration: <1 hour
 Chlorpropamide o Metabolized by CYP2C9 & CYP3A4
 Acetohexamide o T ½: 1.5 hours
o Duration: <4 hours
2nd Generation Sulfonylureas
o S/E: Hypoglycemia (lowest)
 Glyburide o Advantage: sage in those with renal impairment & elderly
 Glipizide
 Gliclazide Drugs that Primarily Lower Glucose Levels by their Action on the Liver,
 Glimepiride Muscle & Adipose Tissue
Biguanides
DOA T½
Sulfonylurea Dosage D/I S/E  Drugs:
(Hrs.) (Hrs.)
o Metformin – The only biguanide currently available
1st Generation
Dicumarol, o Phenformin – Discontinued due to lactic acidosis
0.5-2 Phenylbutazo Skin rash,
Tolubutamide 6-12 4-5
gm/dose ne, hypoglycemia Mechanism of Action:
Sulfonamides
 Reduce hepatic glucose production through activation of the enzyme
500 mg in/
Tolazamide 10-14 7 Hypoglycemia AMP-activated protein kinase (AMPK)
doses
Hypoglycemia,  Impairment of renal gluconeogenesis
Dicumarol, jaundice,  Slowing of glucose absorption from the GIT, with increased glucose
250 mg phenylbutazo hyperemic flush, to lactate conversion by enterocytes
Chlorpropamide 60 32
daily ne, transient
sulfonamide leukopenia,  Direct stimulation of glycolysis in tissue
thrombocytopenia  With increased glucose removal from blood
Acetohexamide 8-24 4-6
0.25-0.5  Reduction of plasma glucagon levels
g/d

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Biguanides continued…..  Major site of action: adipose tissue  promotes glucose uptake and
Metabolism & Excretion: utilization and modulate synthesis of lipid hormone or cytokines and
 Half-life: 1.5-3 hours other proteins involved in energy regulation
 Duration of action: 10-12 hours  Have slow onset and offset of activity
 Not bound to plasma proteins
 Not metabolized Drugs:
 Excreted by the kidneys as active compound  Pioglitazone
 May impair the hepatic metabolism of lactic acid  Rosiglitazone
 Troglizatone – withdrawn from the market due to hepatic toxicity
Clinical Uses:
 1st line therapy for type 2 diabetes Pioglizatone Rosiglizatone
 Refractory obesity whose ↑ blood sugar is due to ineffective insulin Actions Have PPAR-α and PPAR-γ activity PPAR-γ activity
action (insulin resistance syndrome) Rapid
Absorption Within 2 hours
Highly protein bound
Only anti-diabetic drug that has been proven to reduce the
Metabolism CYP2C8 and CYP3A4 CYP2C8 & CYP2C9
complications of diabetes, as evidenced in a large study of
Dosage 15-30 mg 4-8 mg
overweight patients with diabetes (UKPDS, 1998)
Frequency o.d o.d or b.i.d
Oral contraceptive Used as monotherapy or in
 Use as in combination with sulfonylureas or thazolidinediones in Used as monotherapy or in combination with
T2DM in whom oral monotherapy is inadequate Interaction combination with sulfonylureas, sulfonylureas, metformin &
 Useful in prevention of T2DM metformin & insulin insulin
 Dosage: 500 mg TID
Advantages:
Toxicities:  Thiazolidinedione + Metformin  advantage is no hypoglycemia
 Anorexia, nausea, vomiting, abdominal discomfort, and diarrhea  Improves the biochemical and histologic features of nonalcoholic
 Interferes with the calcium-dependent absorption of vitamin B12– fatty liver disease
intrinsic factor complex in the terminal ileum  Have positive effect on endothelial function
Vitamin B12 deficiency can occur after many years of metformin
use  peripheral neuropathy, macrocytic anemia Specific Side Effects:
 Pioglitazone:
 Lactic acidosis (rare) o ↓ triglycerides
o ↑ HDL cholesterol
Contraindications: o No effect on total cholesterol and LDL cholesterol
 Renal diseases o ↓ neointimal proliferation after coronary stent
 Hepatic diseases placement
 Alcoholism  Rosiglizatone:
 Chronic cardiopulmonary dysfunction o ↑ total cholesterol, HDL cholesterol, and LDL cholesterol
o No significant effect on triglycerides
o ↓ microalbuminuria
Thiazolidinediones
 Act to decrease insulin resistance
Adverse Effects:
↑ the sensitivity of muscle, fat & liver to endogenous &
 ↑ risk of angina pectoris and MI – Rosiglitazone
exogenous insulin (“insulin sensitizers”)
 Fluid retention
 Macular edema
 They are ligands of peroxisome proliferator-activated receptor
 Loss of bone mineral density
gamma (PPAR-γ)
↑ atypical extremity bone fractures in women  due to
They bind to and activate the gamma isoform of the PPAR-γ
decreased osteoblast formation
PPAR-γ  is a member of the steroid thyroid nuclear receptor
superfamily, and is found in adipose tissue, cardiac and skeletal
muscle, liver and placenta  Anemia
 Weight gain
Observed Effects:  Bladder tumors – Pioglitazone
 ↑ GLUT-1 and GLUT-4  Fatal liver failure - Troglitazone
 ↓ free fatty acid levels
 ↓ hepatic glucose output Contraindications:
 ↑ adiponectin  Pregnancy
 ↓ release of resistin from adipocytes  Significant liver disease
 ↑ differentiation of preadipocytes to adipocytes  Heart failure
 ↓ levels of the following:
o Plasminogen activator inhibitor type 1
o Matrix metalloproteinase 9
o C-reactive protein
o IL-6

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Drugs that Affect Absorption of Glucose Glucagon-like Peptide-1 (GLP-1) Receptor Agonists
α-glucosidase inhibitors Drugs:
 Competitively inhibit the intestinal α-glucosidase enzymes  Exenatide
 Reduce post-meal glucose excursions by delaying the digestion and  Liraglutide
absorption of starch and disaccharides  lowering post-meal  Albiglutide
glycemic excursions (45-60 mg/dL) and creating an insulin-sparing  Dulaglutide
effect
Exenatide
Drugs:  Derivative of the exendin-4 peptide in Gila monster venom
 Acarbose Has 53% homology with native GLP-1 and a glycine substitution to
 Miglitol reduce degradation by DPP-4
 Voglibose – available in Japan, Korea, India
 Approved as an injectable, adjunctive therapy in persons T2DM
Action: treated with metformin or metformin + sulfonylureas who still have
 Acarbose & Miglitol suboptimal glycemic control
o Potent inhibitors of glucoamylase, α-amylase, and  Dispensed as fixed-dose pens (5 mcg and 10 mcg)
sucrase but have less effect on isomaltase and hardly any  Injected SQ within 60 minutes before breakfast and dinner
on trehalase and lactase  Given twice daily
 Peak concentration: 2 hours
Pharmacokinetics:  Duration: 10 hours
 Taken in doses of 25-100 mg just prior to ingesting the first portion  Exenatide LAR
of each meal Once-weekly preparation that is dispensed as a powder (2 mg)
 Both are absorbed from the gut
 A/E: nausea (major), ↓ HbA1c, weight loss
Adverse Effect:
 Flatulence, diarrhea, abdominal pain
Liraglutide
Contraindications:  Soluble fatty acid-acylated GLP-1 analog
 Chronic or inflammatory bowel disease  T ½: 12 hours
 Renal impairment  Once daily dosing
 Hepatic disease (Acarbose)  Approved in patients with T2DM who achieve inadequate control
with diet and exercise and are receiving concurrent treatment with
Drugs that Mimic Incretin Effect or Prolong Incretin Action metformin, sulfonylureas, or thiazolidinediones
 An oral glucose load provokes a ↑ insulin response compared with  Also approved for weight loss (3 mg daily)
an equivalent dose of glucose given IV  A/E: nausea (28%), vomiting (10%), ↓ HbA1c, weight loss
This is because the oral glucose causes a release of gut hormones
(“incretins”): Albiglutide
 GLP-1  Human GLP-1 dimer fused to human albumin
 Glucose-dependent insulinotropic peptide (GIP)  T ½: 5 days
Incretins amplify the glucose-induced insulin secretion  Steady state is reached after 4-5 weeks of once weekly
administration
 GLP-1 infusion  stimulates insulin release  ↓ glucose levels  Usual dose: 30 mg weekgly (SQ injection)
GLP-1 effect is glucose dependent in that the insulin release is  A/E: nausea, injection-site erythema, weight loss (less common)
more pronounced when glucose levels are elevated but less so
when glucose levels are normal  Therefore lower risk of Dulaglutide
hypoglycemia (compared with sulfonylureas)  Consists of two GLP-1 analog molecules covalently linked to an Fc
fragment of human IgG4
 Additional Effects of GLP-1:  It has amino acid substitutions that resist DPP-4 action
o Suppresses glucagon secretion  T ½: 5 days
o Delays gastric emptying  Usual dose: 0.75 mg weekly (SQ injection)
o Reduces apoptosis of human islets in culture  A/E: nausea, diarrhea, vomiting
o Inhibits feeding by a CNS mechanism
T2DM on GLP-1 therapy are less hungry Common Adverse Effects:
 ↑ risk of pancreatitis
 GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) and
 Persistent severe abdominal pain
other enzymes such as endopeptidase 24.11
 Renal impairment
 It is cleared by the kidney Exenatide
 Acute renal injury
 Stimulate thyroidal C-cell (parafollicular) tumors (Exenatide &
Liraglutide)

Contraindications:
 Medullary thyroid cancer
 Multiple endocrine neoplasia (MEN) syndrome type 2

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Dipeptidyl Peptidase 4 (DPP-4) Inhibitors Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors

Drugs:  SGLT2 accounts for 90% of glucose reabsorption
 Sitagliptin  SGLT2 inhibition causes glycosuria  ↓ glucose levels in patients
 Saxagliptin with T2DM
 Linagliptin It ↓ glucose levels by changing the renal threshold and not by
 Alogliptin insulin action
 Vildagliptin (available in Europe)
Drugs:
Sitagliptin  Canagliflozin
 Given Orally  Dapagliflozin
 100 mg, once daily  Empagliflozin
 Bioavailability: 85%
 Peak concentrations: 1-4 hours Canagliflozin
 T ½: 12 hours  ↓ the threshold for glycosuria from a plasma glucose threshold of
 Excreted in urine approximately 180 mg/dL to 70–90 mg/dL
 Hepatic metabolism is limited and mediated by:  ↓ HbA1c (0.6-1.0%) when used alone or in combination with other
o CYP3A4 oral agents or insulin
o CYP2C8  Dosage: 100 mg daily
 It is used as monotherapy and in combination with metformin,  A/E: modest weight loss (2-5 kg)
sulfonylureas, and thiazolidinediones
 ↓ HbA1c (0.5-1.0%) Dapagliflozin
 A/E: nasopharyngitis, upper respiratory infections, headaches,  ↓ HbA1c (0.5-0.8%) when used alone or in combination with other
hypoglycemia (if combined with insulin or insulin secretagogues), oral agents or insulin
acute pancreatitis, severe allergic & hypersensitivity reactions  Dosage: 10 mg daily, 5 mg (if with hepatic failure)
 A/E: modest weight loss (2-4 kg)
Saxagliptin
 Given Orally Empagliflozin
 2.5-5 mg, daily  ↓ HbA1c (0.5-0.7%) when used alone or in combination with other
 Maximum concentration: within 2 hours (4 hours- active metabolites) oral agents or insulin
 Minimally protein bound  Dosage: 10-25 mg daily
 Hepatic metabolism – CYP3A4/5  A/E: modest weight loss (2-3 kg), death from CVS cause
 Excreted renal and hepatic
 T ½: 2.5 hours (3.1 hours- active metabolites) Contraindications:
 Approved as monotherapy and in combination with biguanides,  Canagliflozin & Empagliflozin  not used if with GFR <45 mL/min per
sulfonylureas, and thiazolidinediones 1.73m2
 ↓ HbA1c (0.4-0.9%)  Dapagliflozin  not used if with GFR <60 mL/min per 1.73 m2
 A/E: ↑ rate of infections (upper respiratory and urinary tract),
headaches, hypersensitivity reactions (urticaria, facial edema), Adverse Effects:
hypoglycemia (if combined with insulin or insulin secretagogues),  ↑ genital infections & UTI
heart failure  Intravascular volume contraction & hypotension
 ↑ in LDL – Canagliflozin & Empagliflozin
Linagliptin  Breast & bladder cancer – Dapagliflozin
 ↓ HbA1c (0.4-0.6%) when added to metformin, sulfonylurea, or  ↓ bone mineral density at the lumbar spine & hip – Canagliflozin
pioglitazone  ↑ risk of fractures – Canagliflozin
 Dosage: 5 mg daily, orally  Diabetic ketoacidosis
 Primarily excreted in bile
 A/E: nasopharyngitis, hypersensitivity reactions (urticaria, OTHER HYPOGLYCEMIC DRUGS
angioedema, localized skin exfoliation, bronchial hyperreactivity), ↑ Pramlintide
risk of pancreatitis  An islet amyloid polypeptide (IAPP, amylin) analog
IAPP is a 37-amino-acid peptide present in insulin secretory
Alogliptin granules and secreted with insulin
 ↓ Hb1ac (0.5-0.6%) when added to metformin, sulfonylurea, or
pioglitazone  Has approximately 46% homology with the CGRP and physiologically
 Dose: 25 mg daily, orally acts as a negative feedback on insulin secretion
 A/E: Hypersensitivity reactions (anaphylaxis, angioedema, Stevens-
Johnson syndrome), hepatic failure Effects:
 Reduces glucagon secretion, slows gastric emptying by a vagally
Vildagliptin mediated mechanism, and centrally decreases appetite
 ↓ HbA1c (0.5-1.0%) when added to the therapeutic regimen of
patients with T2DM Clinical Use:
 Dosage: 50 mg orally, once or twice daily  Approved for use in insulin-treated type 1 and type 2 patients who
 A/E: upper respiratory infections, nasopharyngitis, dizziness, and are unable to achieve their target postprandial blood glucose levels
headache, hepatitis

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 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Pramlintide continued…..  Mediterranean-style eating pattern  a diet supplemented with

 Rapidly absorbed after SQ injection before eating walnuts, almonds, hazelnuts, and olive oil
 Peak level: 20 minutes It has been shown to improve glycemic control and lower
 Duration: <150 minutes combined endpoints for cardiovascular events and stroke
 Metabolized & excreted renally
 Modulated postprandial glucose levels in T1DM & T2DM  Caloric restriction and weight loss is an important goal for the obese
patient with type 2 diabetes
Adverse Effects:
 Hypoglycemia Education
 Nausea & vomiting  The patient should be informed about the kind of diabetes he or she
 Anorexia has and the rationale for controlling the glucose levels
 Self-monitoring of glucose levels should be emphasized, especially if
Colesevelam Hydrochlorine the patient is on insulin or oral secretagogues that can cause
hypoglycemia
 Bile acid sequestrant
 The patient on insulin therapy should understand the action profile
 A cholesterol-lowering drug
of the insulins
 He or she should know how to determine if the basal insulin dose is
Clinical Use:
correct and how to adjust the rapidly acting insulin dose for
 Approved as an antihyperglycemic therapy for persons with T2DM
carbohydrate content of meals
who are taking other medications or have not achieved adequate
 Insulin adjustments for exercise and infections should be discussed
control with diet and exercise
 The patient and family members also should be informed about the
signs and symptoms of hypoglycemia
Mechanism of Action:
 Presumed to involve an interruption of the enterohepatic circulation
Glycemic Targets
and a ↓ in farnesoid X receptor (FXR) activation
 The American Diabetes Association criteria for acceptable control
FXR is a nuclear receptor with multiple effects on cholesterol,
glucose, and bile acid metabolism. Bile acids are natural ligands include:
of the FXR o HbA1c of less than 7% (53 mmol/mol)
o Pre-meal glucose levels of 90–130 mg/dL (5–7.2 mmol/L)
 It may also impair glucose absorption o <180 mg/dL (10 mmol/L) one hour and 150 mg/dL (8.3
 ↓ HbA1c (0.3-0.5%) mmol/L) two hours after meals
 While the HbA1c target is appropriate for individuals treated with
Adverse Effects: lifestyle interventions and euglycemic therapy, it may need to be
 Constipation modified for individuals treated with insulin or insulin secretagogues
due to their increased risk of hypoglycemia
 Indigestion
 Flatulence  Less stringent blood glucose control also is appropriate for children
as well as patients with a history of severe hypoglycemia, limited life
 Exacerbate hypertriglyceridemia
expectancy, and significant microvascular and macrovascular
disease. For the elderly frail patient an HbA1c greater than 8% may
Bromocriptine be appropriate
 Dopamine agonist
 ↓ HbA1c (0-0.2%) Treatment
 The mechanism by which it lowers glucose levels is not known  Treatment must be individualized on the basis of the type of diabetes
and specific needs of each patient
Adverse Effects:
 Nausea Type 1 Diabetes
 Fatigue  At least 3 or 4 insulin injections a day are necessary for safe and
 Dizziness effective control of glucose levels
 Vomiting  A combination of rapidly acting insulin analogs and long-acting
 Headache insulin analogs allow for more physiologic insulin replacement

MANAGEMENT OF THE PATIENT WITH DIABETES Type 2 Diabetes

Diet
 A well-balanced, nutritious diet remains a fundamental element of
therapy for diabetes
 It is recommended that the macronutrient proportions
(carbohydrate, protein, and fat) be individualized based on the
patient’s eating patterns, preferences, and goals
 Limiting the carbohydrate intake and substituting some of the
calories with monounsaturated fats, such as olive oil, rapeseed
(canola) oil, or the oils in nuts and avocados, can lower triglycerides
and increase HDL cholesterol
 Normalization of glucose levels can occur with weight loss and
improved insulin sensitivity in the obese patient with T2DM
 A combination of caloric restriction and increased exercise is
necessary if a weight reduction program is to be successful
 Non-obese patients with T2DM frequently have ↑ visceral
adiposity—the so-called metabolically obese normal weight patient
There is less emphasis on weight loss in such patients, but
exercise is important

#ThankYouFrontliners Page 11 of 13
 PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

Type 2 Diabetes Treatment continued….. Treatment:

 Hypoglycemia:
o Glucose administration
 DKA:
o IV hydration
o Insulin therapy
o Maintenance of K+ and other electrolyte levels
 HHS:
o Rehydration
o Restoration of glucose
o Electrolyte homeostasis

Chronic Complications of Diabetes

 Pathologic changes that involve:
o Small and large blood vessels
o Cranial and Peripheral nerves
o Skin
Figure Above: Suggested algorithm for the treatment of type 2 diabetes o Lens of the eye
The seven main classes of agents are metformin, sulfonylureas (includes  These lesions lead to:
nateglinide, repaglinide), pioglitazone, GLP-1 receptor agonists, DPP-4 o Hypertension
inhibitors, SGLT2 inhibitors, insulins. o End-stage chronic kidney disease
α-Glucosidase inhibitors, colesevelam, pramlintide, and bromocriptine NOT o Blindness, autonomic and peripheral neuropathy
included because of LIMITED EFFICACY and SIGNIFICANT ADVERSE EFFECTS o Amputations of the lower extremities
o Myocardial infarction
Acute Complications of Diabetes o Cerebrovascular accidents
 Hypoglycemia
 In patients with type 1 diabetes, complications from end-stage
Are the most common complication of insulin therapy. It can also chronic kidney disease are a major cause of death
occur in any patient taking oral agents that stimulate insulin
 In patients with type 2 diabetes, they are more likely to have
secretion (eg, sulfonylureas, meglitinide, d-phenylalanine
analogs), particularly if the patient is elderly, has renal or liver macrovascular diseases leading to myocardial infarction and stroke
disease, or is taking certain other medications that alter as the main causes of death
metabolism of the sulfonylureas (eg, phenylbutazone, Cigarette use adds significantly to the risk of both microvascular
sulfonamides, warfarin). It occurs more frequently with the use of and macrovascular complications in diabetic patients
long-acting sulfonylureas

 Diabetic Coma References:

o Diabetic Ketoacidosis  Basic & Clinical Pharmacology by Katzung
Diabetic ketoacidosis (DKA) is a life-threatening (14th ed.)
medical emergency caused by inadequate or absent  Pharmacology Lecture Guide (2020)
insulin replacement, which occurs in people with type
1 diabetes and infrequently in those with type 2
diabetes. It typically occurs in newly diagnosed type 1
patients or in those who have experienced
interrupted insulin replacement, and rarely in people
with type 2 diabetes who have concurrent unusually
stressful conditions such as sepsis or pancreatitis or
are on high-dose steroid therapy

o Hyperosmolar Hyperglycemic Syndrome

Hyperosmolar hyperglycemic syndrome (HHS) is
diagnosed in persons with type 2 diabetes and is
characterized by profound hyperglycemia and
dehydration. It is associated with inadequate oral
hydration, especially in elderly patients; with other
illnesses; with the use of medication that elevates the
blood sugar or causes dehydration, such as phenytoin,
steroids, diuretics, and calcium channel blockers; and
with peritoneal dialysis and hemodialysis. The
diagnostic hallmarks are declining mental status and
even seizures, a plasma glucose >600 mg/dL, and a
calculated serum osmolality >320 mmol/L
Persons with HHS are NOT acidotic unless DKA is also
present

#ThankYouFrontliners Page 12 of 13
PHARMACOLOGY
Topic: Antidiabetic Drugs
Chapter: 41

#ThankYouFrontliners Page 13 of 13
 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

TYPES OF STEROID HORMONES

 Glucocorticoids: Cortisol is the major representative in most
mammals
 Mineralocorticoids: Aldosterone being most prominent
 Androgens: Such as testosterone
 Estrogens: Including estradiol and estrone
 Progestogens: (Also known as “progestins”) Such as progesterone

ADRENAL GLAND
Figure Above: HPA Axis
Control of Endocrine Activity
 The physiologic effects of hormones depend largely on their
concentration in blood and extracellular fluid
 Almost inevitably, disease results when hormone concentrations are
either too high or too low, and precise control over circulating
concentrations of hormones is therefore crucial

Steroid Hormones
 Located above the kidney, retroperitoneally
 Combined weight: 7-10 g
 3 different zones of adrenal cortex:
o Outer zona glomerulosa  mineralocorticoid aldosterone
o Middle zona fasciculata  corticosteroid cortisol
o Inner zona reticularis  DHEA and its sulfated derivatives
(androgens)
 Adrenal medulla: 20% norepinephrine; 80% epinephrine
 All steroid hormones are derived from cholesterol and differ only in
the ring structure and side chains attached to it
 All steroid hormones are lipid soluble
 Pregnenolone is the major precursor of corticosterone and
aldosterone
 17-hydroxypregnenolone is the major precursor of cortisol

Adrenal Cortex
Outer Zone (Zona Glomerulosa)
 Secretes mineralocorticoids (aldosterone)
ACTH (pituitary release of corticotropin) produces moderate
stimulation of its release

 Aldosterone is under the influence of angiotensin

Angiotensin attaches to receptors for angiotensin II and express
aldosterone synthase  aldosterone synthesis

 Do not atrophy in the absence of ACTH

Inner Zone (Zona Fasciculata & Reticularis)

 Secrete glucocorticoids and adrenal androgens respectively Steroid Hormone Production
 Absence of ACTH results in atrophy  Rate limiting step  conversion of cholesterol to pregnenolone
 Sources of cholesterol:
Adrenocorticotropic Hormone (ACTH) o Circulating cholesterol (LDL)
 A peptide of 39 amino acids o Cholesterol esterase
 Amino acids 15-18: high affinity binding o De novo biosynthesis
 Amino acids 6-10: receptor activation
 Lack of:
 Synthesized from pro-opiomelanocortin (POMC)
o 21-β-hydroxylase (CYP21A2)  virilization
o 11-β-deoxycorticosterone (CYP11β1)  hypertension
Physiologic Effect:
o 17-α-hydroxypregnenolone (CYP17)  hypogonadism
 Stimulates the synthesis and release of adrenocortical hormones
 Human ACTH – G-protein coupled receptor  activates adenylyl
Steroidogenic Enzymes
cyclase  ↑ intracellular cAMP (2nd messenger for most
steroidogenesis) Common Name “Old” Name Current Name
Side-chain cleavage enzymes;
P450SCC CYP11A1
desmolase
Regulation of ACTH secretion
3 beta-hydroxysteroid
 Hypothalamic-Pituitary-Adrenal axis (HPA axis) dehydrogenase
3 beta-HSD 3 beta-HSD
 3 levels of regulation: 17-α-hydroxylase/17,20 lyase P450C17 CYP17
1. Diurnal rhythm in basal steroidogenesis 21-hydroxylase P450C21 CYP21A2
2. Negative feedback regulation 11-β-hydroxylase P450C11 CYP11B1
Aldosterone synthase P450C11AS CYP11B2
3. Marked increases in steroidogenesis in response to stress
Aromatase P450aro CYP19

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40
Adrenocorticosteroids
Classification:
 Mineralocorticoids
 Glucocorticoids
 Adrenal Androgens (DHEAs)
This now follows the flow of information from the Katzung 14 th Ed.
NATURAL-OCCURING GLUCOCORTICOIDS
Cortisol (Hydrocortisone; Compound F)
Pharmacokinetics:
 Cortisol is synthesized from cholesterol (See page 8 for pathway)
 In the absence of stress, 10-20 mg of cortisol is excreted daily
 Rate of secretion follows a circadian rhythm
 In plasma, cortisol is bound to circulating proteins:
o 90% is bound to Corticosteroid-binding globulin (CBG)
o 5% is free
o 5% is bound to albumin
 Half-life: 60-90 minutes
 Metabolized in the liver
Many cortisol metabolites are conjugated with glucuronic acid or
sulfate at the C3 and C21 hydroxyls
 Elimination:
o 1% excreted in the urine
Measured as 17-hydroxysteroid
o 20% of cortisol is converted to cortisone by 11-
hydroxysteroid dehydrogenase in the kidney
 CBG (transcortin)
o α2 globulin synthesized by the liver
o Elevated:
Pregnancy, hyperthyroidism, estrogen administration
o Diminished:
Hypothyroidism, protein deficiency, genetic defects
Pharmacodynamics:
 MOA: Diffusion of glucocorticoid across the membrane of the target
cell to bind to a glucocorticoid-receptor heat-shock-protein complex
in the plasma
o Release of heat-shock protein and transport of the
hormone-receptor complex into the nucleus
o Binding of the hormone-receptor complex to specific
nucleotide sequences along the DNA called the
glucocorticoid response elements (GREs)
o Decreased or increased accumulation of mRNA, within
the target cell (alteration of transcription)
o Changes in the rate of synthesis of specific patterns that
carry the biological actions of the hormones
MOA based from Manual:
Binds to glucocorticoid receptors (cytosol)
(Steroid-receptor complex)
↓ 
Interact with promoter and regulates transcription (Hsp 90)
↓ nucleus
Alters gene expression by binding to glucocorticoid-response
element (GREs) and other transcription factors (e.g. API and NF-
κβ) which act on non-GRE containing promoters
↓
Contribute to the regulation of transcription of their responsive
genes causing regulation of growth factors, proinflammatory
cytokines and mediate anti-growth, anti-inflammatory and
immunosuppressive effects of glucocorticoids
#RoadToVNeck
Physiologic Effects:
 Widespread effects because they influence the function of most cells
in the body
 The major metabolic consequences of glucocorticoid secretion or
administration are due to direct actions of these hormones in the cell
However, some important effects are the result of homeostatic
responses by insulin and glucagon
 Permissive effects (this means that without cortisol  normal function
becomes deficient):
o Diminished catecholamine response in vascular and
bronchial smooth muscle
o Attenuated lipolytic response to catecholamine ACTH
and GH in the absence of glucocorticoids
Metabolic Effects:
 Glucocorticoids have important dose-related effects on
carbohydrate, protein, and fat metabolism
 Glucocorticoids stimulate and are required for gluconeogenesis and
glycogen synthesis in fasting state
 Glucocorticoids increase serum glucose levels  thus stimulate
insulin release but inhibit the uptake of glucose by muscle cells 
stimulate hormone-sensitive lipase and thus lipolysis
From Manual:
Carbohydrate Metabolism
o Protect glucose-dependent tissues from starvation
o Stimulate gluconeogenesis, glycogen synthesis in the fasting
state  ↑ glucose  lipolysis ↑ FFA  insulin release 
periphery: ↓ glucose utilization and lipogenesis (fat
deposition)
Muscle Catabolism
o ↑ protein breakdown (amino acids
o Stimulate phosphoenol pyruvate carboxylase, G6-
phosphatase and glycogen synthase
o Catabolic effects: ↓ muscle mass, atrophy of lymphoid
tissue, negative nitrogen balance, thinning of the skin
Lipid Metabolism:
o Redistribution of body fat (buffalo hump, moon facies,
supraclavicular are with loss of fat in the extremities)
o Induce lipolysis in adipocytes (FFA and glycerol)
o Lipogenesis
Electrolyte:
o ↑ Ca2+ excretion by the kidneys (antagonize vitamin D effect
on Ca2+ absorption)
Catabolic and Antianabolic Effects:
 Glucocorticoids stimulate RNA and protein synthesis in the liver
o Catabolic and antianabolic effects in lymphoid and
connective tissue, muscle, peripheral fat, and skin
 Supraphysiologic amounts of glucocorticoids lead to ↓ muscle mass
and weakness and thinning of the skin
Catabolic and antianabolic effects on bone – causes osteoporosis in
Cushing’s syndrome
Major limitation in the therapeutic use of glucocorticoids
 Children  glucocorticoids reduce growth
Page 2 of 21
 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40
Cortisol continued…..
Anti-Inflammatory and Immunosuppressive Effects:
 Glucocorticoids dramatically reduce the manifestations of
inflammation
Suppressive effects on inflammatory cytokines, chemokine and
other mediators of inflammation
 Glucocorticoids also inhibit the functions of tissue macrophages and
other antigen-presenting cells
 Glucocorticoids influence the inflammatory response by inhibiting
phospholipase A2
↓ synthesis of arachidonic acid (the precursor of prostaglandins
and leukotrienes) and of platelet-activating factor
 Glucocorticoids reduce expression of cyclooxygenase 2 (the
inducible form of this enzyme) in inflammatory cells
↓ amount of enzyme available to produce prostaglandins
 Glucocorticoids cause vasoconstriction when applied directly to the
skin, possibly by suppressing mast cell degranulation
 ↓ capillary permeability by ↓ amount of histamine released by
basophils and mascells
 ↓ antibody production (large doses >20 g/d prednisone)
 Inhibits complement activation
 The anti-inflammatory and immunosuppressive effects of these
agents are widely useful therapeutically but are also responsible for
some of their most serious adverse effects
#RoadToVNeck
Other Effects:
 Glucocorticoids have important effects on the nervous system
o Adrenal insufficiency – causes marked slowing down of
alpha rhythm of EEG: associated with depression
o Initial behavior disturbance is insomnia and euphoria,
then depression
 Large doses:
o ↑ intracranial pressure – pseudotumor cerebri
o Large doses also associated with development of peptic
ulcer
o Vitamin D antagonist on Ca2+ absoprtion
 Important effects of hematopoietic system – effect on leukocyte but
also may increase platelets and RBC
 Glucocorticoids play a role in the development of fetal lungs
The structural and functional changes in the lungs near term
including the production of pulmonary surface-active material
required for air breathing (surfactant), are stimulated by
glucocorticoids
 Chronic use: suppress pituitary release of ACTH, GH, TSH, LH
Page 3 of 21
 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Synthetic Corticosteroids Adrenocortical Hypo- and Hyperfunction

Chemistry/Pharmacokinetics:  Congenital Adrenal Hyperplasia
 Source: Synthesized from cholic acid (from cattle or steroid o Group of disorders characterized by specific defects in the
sapogenins in plants synthesis of cortisol
o Most common defect: decrease in or lack of P450c21 (21-
 Disposition:
α-hydroxylase) activity
o Most rapidly and completely absorbed when given by
 Diversion of steroid precursors to the
mouth
androgen-producing pathway:
o Alterations in the glucocorticoid molecule influence its
↑ adrenal androgens
affinity for glucocorticoid and mineralocorticoid receptor
↓ glucocorticoids & ↓ mineralocorticoid
 Characterized by virilization of women, early
Pharmacodynamics:
acceleration of linear growth & early
 MOA: They bind to specific intracellular receptor proteins and
appearance of pubic hair
produce the same effects but have different ratios of glucocorticoid
o If defect is 11-hydroxylation – large amounts of
to mineralocorticoid potency (See table page 3)
deoxycorticosterone are produced
 Because this has mineralocorticoid activity 
Clinical Pharmacology:
hypertension with or without hypokalemic
 Diagnosis and Treatment of Disturbed Adrenal Function:
alkalosis may occur
o Adrenocortical Insufficiency
o If defect in 17-hydroxylation is detected in the adrenals
o Adrenocortical Hypo & Hyperfunction
and gonad  hypogonadism is present
o Congenital Adrenal Hyperplasia
 Increase 11-hydroxylation may occur due to
o Cushing’s Syndrome
the steroid precursors being diverted to the
o Aldosteronism
mineralocorticoid pathway
o Primary generalized glucocorticoid resistance (Chrousos
 Symptoms of glucocorticoid deficiency may
Syndrome)
also occur
 Stimulation of lung maturation in the fetus
o Management:
 Treatment of Non-Adrenal disorders
 Infant with adrenal crisis due to CAH:
 IV hydrocortisone in stress dose
Adrenocortical Insufficiency  Electrolyte solution to correct
 Chronic (Addison’s Disease) imbalance
o Can be caused by autoimmune destruction of the adrenal  Once patient is stabilized, treatment is:
cortex or certain infections  Oral hydrocortisone 12-18
o Characterized by: mg/m2/day in 2 unequally divided
 Weakness doses (2/3 in am, 1/3 in pm)
 Fatigue  Dosage should be adjusted to allow
 Weight loss normal growth and bone
 Hypotension maturation
 Hyperpigmentation
 Cushing’s Syndrome
 Inability to maintain the blood glucose level
o Result of bilateral adrenal hyperplasia secondary to ACTH-
during fasting
secreting pituitary adenoma (Cushing’s disease)
o Management: 20-30 mg of hydrocortisone daily, with
o Occasionally is due to tumors or nodular hyperplasia of
increased amounts during period of stress
adrenal gland or ectopic production of ACTH by other
 Acute tumors
o Management: o Signs & Symptoms:
 Large amount of IV hydrocortisone +  Rounded, plethoric face and trunk obesity are
correction of fluid and electrolyte striking in appearance
abnormalities + treatment of precipitating  Muscle wasting; thinning, purple striae, and
factors easy bruising of the skin; poor wound healing;
 Hydrocortisone sodium succinate or and osteoporosis
phosphate in doses of 100 mg IV every 8 hours  Mental disorders, hypertension, and diabetes
until patient is stable – gradually reduce dose, o Treatment:
achieving maintenance dose within 5 days  Surgical removal of tumor-producing ACTH or
 Administration of salt-retaining hormone is cortisol resection of adrenal
resumed when the total hydrocortisone  Irradiation of pituitary tumors
dosage has been reduced to 50 mg/day  Resection of 1 or both adrenals
 Patients should receive doses of up
to 300 mg soluble hydrocortisone
or continuous IV on day of surgery
(to prevent adrenal crisis)
 Dose must be slowly reduced to
normal replacement levels
(to prevent withdrawal symptoms,
e.g, fever, joint pain)

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40
Adrenocortical Hypo- and Hyperfunction continued…..
 Primary Generalized Glucocorticoid Resistance
o a.k.a. Chrousos Syndrome
o Rare, sporadic or familial genetic condition due to
inactivating mutations of the glucocorticoid receptor
gene
o The HPA axis hyperfunctions in an attempt to compensate
for the defect
 ↑ ACTH leads to high-circulating levels of
cortisol and cortisol precursors eg,
corticosterone, 11-hydroxycorticosterone
with mineralocorticoid activity as well as
androgens
 Signs and Symptoms:
 Hypertension with or without
hypokalemic alkalosis
 Hyperandrogenism (virilization and
precocious puberty in children;
acne, hirsutism, male pattern
baldness and menstrual
irregularities in women)
 Treatment:
 High doses of synthetic
glucocorticoids
(e.g, dexamethasone)
Glucocorticoids for Diagnostic Purposes
 Suppress the production of ACTH to identify the source of a particular
hormone or establish whether production influenced by the
secretion of ACTH
 Dexamethasone Suppression Test
o Used for diagnosis of Cushing’s Syndrome
o Used also in:
 Differential diagnosis of depressive psychiatric
state
 Differentiating between hypercortisolism due
to anxiety, alcoholism (pseudo-Cushing
syndrome) and bona fide Cushing’s syndrome
o Screening is given orally at 11 pm, plasma sample is
obtained in the following morning:
 Normal individual morning cortisol: <3 mcg/dL
 Cushing’s syndrome: >5 mcg/dL
o Combined test
 Carried out by giving dexamethasone (0.5 mg
orally every 6 hrs. for 2 days) followed by
standard corticotropin-releasing hormone
(CRH) test (1 mg/kd given as bolus IV infusion
2 hours after last dose of dexamethasone)
Corticosteroid & Stimulation of Lung Maturation in Fetus
 Treatment of mother with large doses of glucocorticosteroid reduces
the incidence of respiratory distress syndrome (RDS) in infants
delivered prematurely
 Betamethasone 12 mg IM followed by additional dose of 12 mg 18-
24 hours later
 Betamethasone is chosen because maternal protein binding and
placental metabolism is less than that of cortisol  allows ↑ transfer
across the placenta to the fetus
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Non-Adrenal Disorders
 Synthetic analog of cortisol are useful in the treatment of diverse
group of diseases unrelated to any known disturbance of adrenal
function
Toxicity of Glucocorticoids
 Insomnia
 Behavioral changes (primary hypomania)
 Acute peptic ulcers
 Acute pancreatitis is rare but serious adverse effects of high dose
glucocorticoids
 Iatrogenic Cushing’s Syndrome
o Metabolic effects that occur when administering daily
dose of hydrocortisone or more, for >2 weeks
o Signs & Symptoms:
 Round, puffiness, fat deposition of face (moon
facies)
 Fat redistribution from the extremities to the
trunk, back of neck and supraclavicular fossa
 Punctate acne
 Insomnia & increased appetite
o Other complications:
 Bacterial and mycotic infection
 Severe myopathy is more frequent in patients
treated with long-acting glucocorticoids
 Hypomania or acute psychosis
 Depression
 Development of subcapsular cataracts
 ↑ intraocular pressure; glaucoma
 Benign intracranial hypertension
 Growth retardation in children given doses of
45 mg/m2/d or more hydrocortisone or
equivalent
 Sodium and fluid retention
Complications: edema, heart failure
 Loss of potassium
Hypokalemic, hypochloremic alkalosis
↓
↑ blood pressure
o Adrenal Suppression
 >2 weeks administration leads to adrenal
suppression
 Corticosteroid should be tapered slowly
 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Precautions ADRENOCORTICAL ANTAGONISTS

 Carefully monitoring for development of: Synthesis Inhibitors & Glucocorticoid Antagonist
o Hyperglycemia  Block conversion of cholesterol to pregnenolone
o Glycosuria  Causes reduction in the synthesis of all
o Sodium retention hormonally active steroid
o Edema Clinical Use:
o Hypertension  Used in conjunction with dexamethasone or
 Dosage should be kept as low as possible and intermittent hydrocortisone (eliminate estrogen production
in breast CA)
administration (alternate day)
Aminogluthetimide  Used in conjunction with metyrapone or
 Contraindications: ketoconazole to reduce steroid secretion in
o Observe great caution with peptic ulcer disease, heart patients with Cushing’s syndrome due to
disease or hypertension with heart failure, certain adrenocortical cancer who do not respond to
mitotane
infectious diseases (such as Varicella, TB)
o Psychosis, DM, osteoporosis, or glaucoma  Dosage: 1 g/d (well tolerated)
 Toxicity: Lethargy and skin rash are common
effects in higher doses
MINERALOCORTICOIDS
 Antifungal imidazole derivative
Aldosterone, Deoxycorticosterone (DOC), Fludrocortisone
 Potent and rather nonselective inhibitor of
 Most important mineralocorticoid is aldosterone adrenal and gonadal steroid synthesis
 Small amounts of DOC (Deoxycorticosterone) are also formed and Clinical Use:
released  Used for treatment of patient with Cushing’s
Ketoconazole
 Fludrocortisone syndrome due to several causes
o Synthetic corticosteroid  Dosage: 200-1200 mg/d
 Toxicity: Hepatotoxic (should be started with
o Most commonly prescribed salt retaining hormone
200 mg/d slowly increased by 200 mg/d every 2-
3 days to total daily dose of 1000 mg)
Mineralocorticoids  Used for induction of general anesthesia and
 Synthesized mainly in zona glomerulosa of sedation
adrenal cortex  At subhypnotic doses of 0.1 mg/kg/h this drug
 Secreted at rate of 100-200 mcg/d in normal Etomidate inhibits adrenal steroidogenesis at the level of
individual with moderate dietary salt intake 11β-hydroxylase
 Electrolyte-balance regulating, salt-retaining  Used as parenteral medication available in the
activity treatment of severe Cushing’s syndrome
 Promotes reabsorption of Na+ from the DCT and  Relative selective inhibitor of 11-hydroxylation,
PCT; loosely coupled with K+ and H+ ions interfering with cortisol and corticosterone
Aldosterone excretion synthesis
 ↑ Na+ reabsorption in sweat, salivary glands,  Dosage: 0.25 mg 2x daily to 1g 4x daily
gastric mucosa
Clinical Use:
 MOA: binds with mineralocorticosteroid
 It is the only adrenal-inhibiting medication that
receptor
can be administered to pregnant women with
 Half-life: 15-20 minutes
Cushing’s syndrome
 Excretion: 5-15 mcg/24 hr appearing in the urine
 Commonly used for test of adrenal function
as conjugated tetrahydroaldosterone
Metyrapone  Pituitary function may be tested by
 Precursor of aldosterone administering metyrapone, 2–3 g orally at
 Secreted in amounts of 200 mcg/d midnight and by measuring the level of ACTH or
 Half-life: 70 minutes 11-deoxycortisol in blood drawn at 8 am or by
Deoxycorticosterone (DOC)  Concentration in plasma is approximately 0.03 comparing the excretion of 17-
mcg/dL hydroxycorticosteroids in the urine during the
 Secretion is ↑ patients with adrenocortical 24-hour periods preceding and following
carcinoma & congenital adrenal hyperplasia administration of the drug
 Potent steroid with both glucocorticoid and
 Adverse Effect: transient dizziness, GI
mineralocorticoid activity
disturbances, salt and water retention,
 Widely used mineralocorticoid
Fludrocortisone  Oral dose: 0.1 mg (2-7x weekly)  Is a 3β-17 hydroxysteroid dehydrogenase
inhibitor
 Used in the treatment of adrenocortical
insufficiency associated with mineralocorticoid  Interferes with the synthesis of adrenal and
Trilostane
deficiency gonadal hormones and is comparable to
aminoglutethimide
 Adverse Effects: predominantly GI disturbance
ADRENAL ANDROGENS  Newest of the steroid synthesis inhibitors to be
 Adrenal cortex secretes: approved
o Large amounts of DHEA  Blocks 17α-hydroxylase (P450c17) and 17,20-
o Small amounts of androstenedione & testosterone lyase
Abiraterone
 Reduces synthesis of cortisol in the adrenal and
 They do not stimulate or support major androgen-dependent gonadal steroids in gonads
pubertal changes in humans  Clinical Use: Treatment of refractory prostate
 Used in SLE and women with adrenal insufficiency cancer

Continued next page…..

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Synthesis Inhibitors & Glucocorticoid Antagonist Clinical Pharmacology: Hyperaldosteronism

 11β-aminophenyl-substituted 19-norsteroid  Primary Aldosteronism (Conn Syndrome)
 Pharmacologic antagonist at the steroid o Excessive production of aldosterone by adrenal adenoma
receptor (blocks glucocorticoid receptor)
o Result in abnormal secretion by hyperplastic glands or
 Has strong antiprogestin activity and initially
was proposed as a contraceptive-contragestive from a malignant tumor
agent o Can also be caused by enzyme defects that increase
Mifepristone (RU-486)  Causes generalized glucocorticoid resistance synthesis of steroid precursors with mineralocorticoid
Clinical Use: activity (eg, DOC, corticosterone)
 Given orally to several patients with Cushing’s o Clinical findings:
syndrome due to ectopic ACTH production or  Hypertension
adrenal carcinoma who have failed to respond
 Hypokalemia
to other therapeutic manipulations
 Related to the DDT class of insecticides  Weakness
 Non-selectively cytotoxic action on adrenal  Tetany are related to the continued renal loss
cortex in dogs and to a lesser extent in humans of potassium
Mitotane  Clinical Use: 12 g/daily results in reduction in  Alkalosis
tumor mass in patients with adrenal carcinoma
 Hypernatremia
 Toxicity: diarrhea, nausea, vomiting,
depression, somnolence, and skin rashes
 Secondary Aldosteronism
Mineralocorticoid Antagonist o These patient have high levels of plasma renin activity and
 7α-acetylthiospironolactone angiotensin II
 Onset- Slow
 Effect – lasts for 2-3 days after drug is  Treatment:
discontinued
o Fludrocortisone (0.2 mg 2x daily orally for 3 days), or
Clinical Uses: o Deoxycorticosterone acetate (20 mg/d IM for 3 days)
 Used in treatment of primary aldosteronism
o Aldosterone antagonists (eg, spironolactone)
Dose: 50-100 mg/d
 When used diagnostically for the detection of
aldosteronism in hypokalemic patients with
hypertension
Spironolactone Dose: 400-500 mg/d for 4-8 days
 Useful in preparing patients for surgery
Dose: 300-400 mg/d for 2 weeks to reduce
incidence of cardiac arrhythmias
 Hirsutism and acne in women
Dose: 50-100 mg/d (effects in 2 months)
Toxicity:
 Gyncomastia (in males), menstrual irregularities
(in females), hyperkalemia, cardiac arrhythmia,
sedation, headache, GI disturbances, & skin
rashes
 Aldosterone antagonist
 Approved for treatment of hypertension and
heart failure
 It is more selective than spironolactone and has
Epleronone no reported effects on androgen receptors
 Reduces mortality in heart failure
 Dosage in hypertension: 50-100 mg/d
 Toxicity: Hyperkalemia (mild)
 Progestin
Drospirenone  An oral contraceptive
 Antagonizes the effect of aldosterone

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Figure Above: Outline of major pathways in adrenocortical hormone biosynthesis

The major secretory products are underlined. Pregnenolone is the major precursor of corticosterone and aldosterone, and 17-hydroxypregnenolone is the major precursor
of cortisol. The enzymes and cofactors for the reactions progressing down each column are shown on the left and across columns at the top of the figure. When a particular
enzyme is deficient, hormone production is blocked at the points indicated by the shaded bars

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

#RoadToVNeck Page 9 of 21
 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

OVARY Menstrual Cycle

 The ovary has important gametogenic functions that are integrated  Vesicular follicles (each containing an ovum) enlarge responding to
with its hormonal activity FSH
 In childhood:  Follicles granulose cells multiply
o The ovary is quiescent during rapid growth & maturation o Estrogen synthesis (LH influence) and release rate ↑
 Puberty: o Estrogen inhibits FSH release (estrogen causes
o Begins a 30- to 40-year period of cyclic function called regression of smaller, less mature follicles)
the menstrual cycle because of the regular episodes of  Corpus luteum cells produce (for the remainder of the cycle or
bleeding longer if pregnancy occurs):
 Menopause o Estrogen
o Failure to respond to gonadotropins and cessation of o Progesterone
cyclic bleeding

Puberty
 Onset of ovarian function at the time of puberty is thought to be
neuronal in origin
Immature gonad can be stimulated by gonadotropins already
present in the pituitary and because the pituitary is responsive to
exogenous hypothalamic GnRH

Disturbance in Ovarian Function

 Secretion of GnRH is regulated by:  Minor causes:
o Kisspeptin o Inflammatory or neoplastic processes the influence
o Neurokinin B function of the ovaries, uterus or pituitary
o Dynorphin neuron (KNDy) system Leads to periods of amenorrhea or anovulatory cycles
Recently, makorin ring finger protein 3 (MKRN3) was
 Often associated with environmental or emotional stress
also implicated in pubertal onset by contributing to
the regulation of the KNDy system  Anovulatory cycles are also associated with:
o Eating disorders (bulimia, anorexia nervosa)
 Gonadarche  This is the change of ovarian function at puberty o Severe exercise (distance running & swimming)
 Result in:  Common causes:
o Removal of hypothalamic median eminence cellular o Pituitary prolactinomas and syndromes
inhibition  permitting pulsed GnRH release  resulting o Tumors characterized by excessive ovarian or adrenal
to stimulation of FSH and LH release androgen production
 FSH and LH release (initially small amounts) inducing estrogen Normal ovarian function can be modified by
androgens produced by the adrenal cortex or tumors
secretion (in small amounts) cause:
arising from it
o Breast development
o Changes in adipose tissue distribution (fat distribution)
 The ovary also gives rise to androgen-producing neoplasms such as
o Growth spurt (ending in epiphyseal closure- long bones)
arrhenoblastomas, as well as to estrogen-producing granulosa cell
 One year later:
tumors
o ↑ estrogen levels induce:
 Endometrial change
 Periodic bleeding (Menarche)
o After the first few irregular cycles, which may be
anovulatory, normal cyclic function is established

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

ESTROGENS Pharmacokinetics continued…..

 Catechol Estrogens: neurotransmitters
Natural Estrogens
 Major estrogen produced by the ovary o Converted to 2- and 4-methoxy derivatives by catechol-O-
Estradiol (E2) methyltransferase
 Estradiol-17β
 Some are produced in the ovary  Estrogen is secreted in small amounts in breast milk
Estrone (E1)  Produced in the liver from estradiol or from peripheral tissues  High biliary excretion and intestinal reabsorption (enterohepatic
from androstenedione and other androgens
circulation) leads to significant hepatic : peripheral effect ratio
 Produced in the liver from estradiol or from peripheral tissues
Estriol (E3)
from androstenedione and other androgens
o Significance: hepatic concentration  undesirable actions
may result:
Nonsteroidal Agents with  ↑ clotting factor synthesis
Synthetic Estrogen  ↑ plasma renin substrate
Estrogenic Activity
 Etinyl estradiol  Dienestrol o To minimize enterohepatic effects
 Quinesterol  Diethylstilbestrol  Estrogen to be used for peripheral actions
 Mestranol  Benzestrol (postmenopausal women): use different route
 Hexestrol that avoids first-pass effect:
 Methestrol  Vaginal route
 Methallenestril  Transdermal route
 Chlorotrianisene  Injection route

 Immediate precursors: Androstenedione, Testosterone Mechanism of Action

 Ovaries  principal source of circulating estrogen  MOA: Primarily by regulating gene expression
 Estrogen dissociates from SHBG and enter cells and bind to a receptor
Significant Sources of Estrogen:  Receptors
 Liver o Superfamily of steroid, thyroid, retinoic acid and vit D
o Estrone, estriol from estradiol o Located in the nucleus
 Peripheral tissues o Hormone + receptor interaction causes a conformational
o From androstenedione & other androgens change with release of associated, stabilizing proteins
 Pregnancy o Bind to specific sequence of nucleotides: influence gene
o Fetoplacental unit (fetal adrenal zone, secreting transcription
androgen precursor, placenta) Diagram from Manual:
 Stallions SHBG-bound estrogens
o They liberate more estrogen than the pregnant mare or ↓
pregnant woman Dissociate & enter cell
 Equine Estrogen ↓
o Recovered from urine Bind to their receptor
o May be used for medical applications ↓
o Equilenin Receptor-hormone complex
o Equilin ↓
Bind to Estrogen Response Elements (EREs)
[EREs are specific sequence of nucleotides]
Pharmacokinetics ↓
 Binds strong to an α2 globulin (sex hormone–binding globulin Regulate gene transcription
[SHBG]) and with lower affinity to albumin
 Only free E2 is physiologically active Physiologic Effects
 E1 and E3 have low receptor affinity 1.) Female Maturation
 Required for the normal sexual maturation and growth of the female
 Stimulate the development of vagina, uterus and uterine tubes
 Breast development  stromal development & ductal growth
 Accelerated growth phase and closure of epiphysis
 Axillary and pubic hair
 Alter distribution of fat to produce typical female body contours
 Regional pigmentation of axilla, areola & genital area

2.) Endometrial Effects

Conversion Steps:
 Estradiol is converted by the liver and other tissues to estrone and
estriol and their 2-hydroxylated derivatives and conjugated
metabolites
 Lipid insolubility leads to biliary excretion but then these conjugates
will undergo hydroxylation in the intestine to be activated and be
reabsorbed
 Reabsorption from the intestine results to the undesirable effects in
the enterohepatic circulation
 Development of endometrial lining
 Continuous exposure to estrogens for prolonged periods leads to
hyperplasia of the endometrium that is usually associated with
abnormal bleeding patterns
3.) Metabolic and Cardiovascular Effects
 ↓ rate of bone resorption
 ↑ leptin production from adipose tissues
 ↑ plasma TAG, HDL; ↓ LDL, total plasma cholesterol
 ↓ hepatic oxidation; ↑ synthesis of TAGs

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

4.) Blood Coagulation o But following estrogen replacement:

 Enhances blood coagulability  ↓ total cholesterol
 ↑ factors II, VII, IX, and X  ↓ LDL cholesterol
 ↑ plasminogen levels  ↑ HDL cholesterol
 ↓ antithrombin III  50% reduction in myocardial infarction
 ↓ platelet adhesiveness frequency
 As much as 40% reduction in fatal stroke
5.) Other Effects: frequency
 Induce synthesis of progesterone receptors  Management of hot flushes and sleep disturbance
 Influence behavior and libido o Symptomatic relief-use lowest estrogen dose possible
 Promotes sense of well-being to estrogen-deficient women  Limited period of treatment to reduce breast
 Facilitate the loss of intravascular fluid into the extracellular space, cancer risk
producing edema  Following hysterectomy
 Retention of sodium and water by the kidney o Symptoms relieved by estrogen replacement
 Modulate sympathetic nervous system control of smooth muscle o Hot flushes, sweating, insomnia, atrophic vaginitis
function o Symptoms which may or may not be relieved by estrogen
replacement
 Psychopathological conditions, including
Clinical Uses
depression
 Primary Hypogonadism
 Atrophic vaginitis
o Estrogen replacement therapy
o Estrogen deficiency due to: o Topical treatment: not subject to first-pass effect
 Primary failure of ovarian development  Cancer
 Castration o Estrogen monotherapy causing ↑ risk of endometrial
 Premature menopause carcinoma
 Menopause o Progesterone (Progestational agent) + Estrogen:
o Treatment of primary hypogonadism prevents endometrial hyperplasia; markedly reduce
 Initiation time: 11-13 years of age cancer risk
 Stimulation of secondary sex characteristics  Combinations: estrogen + progestin
and menses (medroxyprogesterone)
 Stimulation of growth  Reduced risk (protocol: estrogen first 25 days
 Prevent osteoporosis of the month; progestin medroxyprogesterone
 Avoiding psychological effects of the delayed (10 mg/d) added during last 10-14 days of
puberty month)
o Agent used  Cyclic bleeding may occur: eliminated with
 Conjugated estrogen (0.3 mg) treatment combining conjugated equine
 Ethinyl estradiol (5-10 µg) estrogens + medroxyprogesterone; this
combination will also:
o When growth is completed  chronic therapy with both  Control vasomotor symptoms
estrogens and progestins  Prevent genital atrophy
 Maintain bone density
Postmenopausal Hormonal Therapy:  Promote favorable lipid profiles
 Changes associated with menopause: those that may influence  Other uses:
health/well-being of postmenopausal women: o Estrogen + Progestins
 Accelerated bone loss (osteoporosis) predisposing to:  Suppress ovulation in patients with intractable
o Wrist, vertebral, hip fracture dysmenorrhea
o Factor influencing osteoporosis development  Suppression of ovarian function is used in the
 Amount of initial bone present treatment of hirsutism and amenorrhea due
 Calcium intake to excessive secretion of androgens by the
 Physical activity ovary
o Risk highest
 Smokers who are thin; Caucasian; inactive Adverse Effects
women with low calcium intake; strong family  Uterine Bleeding
history; depression Estrogen therapy is a major cause of postmenopausal uterine
o Estrogen replacement bleeding  patients should be treated with the smallest amount
 Conjugated estrogen or ethinyl estradiol of estrogen possible
effective Endometrial Hyperplasia  add progesterone to prevent it
 Cardiovascular effects:
o Lipid changes due to estrogen may contribute to  Cancer
acceleration of atherosclerotic cardiovascular disease ↑ risk of endometrial carcinoma, breast cancer,
o Following oophorectomy or menopause, estrogen falls adenocarcinoma of vagina
causing:
 ↑ plasma cholesterol + LDL  Other Effects
 ↓ LDL receptors Nausea, breast tenderness, hyperpigmentation, migraine
 +/- HDL headaches, cholestasis, gallbladder disease, hypertension

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Contraindications PROGESTINS
 Estrogen-dependent neoplasm (eg, endometrial carcinoma) Progesterone
 Those at higher risk for or with breast carcinoma  Natural progestins
 Undiagnosed genital bleeding  Most important human progestin
 Liver disease o Precursor to estrogen, androgens, and adrenocortical
 History of thromboembolic disorder steroids
 Heavy smokers  Synthesized in the ovary (corpus luteum), testis, and adrenal cortex
(from circulating cholesterol) and placenta (during pregnancy)

Synthetic Progestins: Physiologic Effects

 Most closely related, pharmacologically and chemically to  Stimulates lipoprotein lipase
progesterone  Promotes fat deposition
 21-carbon agents  Significant effect in carbohydrate metabolism
o Hydroxyprogesterone o ↑ basal insulin level
o Medroxyprogesterone o ↑ insulin response to glucose
o Megestrol o ↑ glycogen storage
o Dimethisterone o ↑ ketogenesis
 Newer “third-generation” synthetic progesterones o ↓ Na reabsorption (compete with aldosterone)
o Components of oral contraceptives with lower  ↑ body temperature
androgenic activity  ↑ ventilator response to CO2
o “19-nor, 13-ethyl” steroids  Depressant & hypnotic effects
 Desogestrel  Sexual characteristics:
 Gestodene o Breast: alveolobular development of the secretory
 Norgestimate apparatus
o Endometrium: maturation & secretory changes
Pharmacokinetics o Important in the maintenance of pregnancy
 Rapidly absorbed  ↓ plasma amino acid levels  ↑ urinary nitrogen excretion
 T ½: approximately 5 minutes
 Small amounts are stored temporarily in body fat Synthetic Progestins:
 Extensive first-pass metabolism  Induces Na retention (competes with aldosterone)
o Ineffective when administered orally  “19-nortestosterone” third-generation agents:
 Hepatic metabolism o Produce a decidual change in the endometrial stroma
o Metabolized to pregnanediol o Do not support pregnancy in test animals
o Urinary excretion product: pregnanediol glucuronide o Effective gonadotropin inhibitors
(used in assessing progesterone secretion) o May have minimal estrogenic and androgenic or anabolic
o Other metabolites formed in small quantities activity

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Synthetic Progestins Physiologic Effect continued….. HORMONAL CONTRACEPTION

o They are sometimes referred as “impeded androgens”  Two types of preparations are used for oral contraception:
o Progestins WITHOUT androgenic activity: 1. Combinations of estrogens and progestins
 Desogestrel 2. Continuous progestin therapy without concomitant
 Norgestimate administration of estrogens
 Gestodene  The combination agents are further divided into:
o Monophasic forms (constant dosage of both components
Clinical Uses during the cycle)
Major Uses: o Biphasic or triphasic forms (dosage of one or both
 Hormone replacement therapy components is changed once or twice during the cycle)
 Hormonal contraception Special Contraceptive Preparations:
Other Uses:  Implantable:
 Introduction of long-ovarian suppression and may be used to treat: o Etonogestrel  available in the subcutaneous implant
o Dysmenorrhea, endometriosis, & hirsutism  Vaginal rings
o Bleeding disorders (Where estrogen is contraindicated)  Intrauterine devices
o Treatment of premenstrual syndrome (PMS) and women  IM injection of large doses of medroxyprogesterone also provides
with difficulty of conceiving contraception of long duration
Diagnostic Uses:
 Used as a test of estrogen secretion Mechanism of Action
o Progesterone (150 mg/d) or Medroxyprogesterone (10  Estrogen + Progestin contraception:
mg/d) for 5–7 days  withdrawal bleeding in o Selective inhibition of pituitary function that results in
amenorrheic patients (when stimulated by estrogen) inhibition of ovulation
o Estrogen + Progestin  test the responsiveness of the o Change in the cervical mucus, in the uterine
endometrium in patients with amenorrhea endometrium
o Change in motility and secretion in the uterine tubes
Contraindications, Cautions & Adverse Effects All of these decrease the likelihood of conception and
 Progestational compounds alone and with combination oral implantation
contraceptives indicate that the progestin in these agents may
 NOTE: The continuous use of progestins alone does NOT always
increase blood pressure in some patients
inhibit ovulation
 The more androgenic progestins also reduce plasma HDL levels in
 They are very effective in general
women
 Failure is observed in some patients with:
 When used with estrogen, may increase the risk of breast cancer
o One or more missed doses
o Concomitant use of phenytoin - ↑ catabolism of
OTHER OVARIAN HORMONES
contraceptive compounds
 Small amount produced o Antibiotics which alter enterohepatic cycling of
 Physiological significance  may be partly responsible for metabolites
normal hair growth at puberty, for stimulation of female
Testosterone libido, and, possibly, for metabolic effects
 Ovarian androgen production markedly increased in some Pharmacologic Effects
abnormal states, usually in association with hirsutism and  Inhibits ovulation
amenorrhea
 Chronic use of Estrogen/Progesterone combinations:
 Peptides with multi-dimeric forms o Ovarian function depression
 α and β subunits Ovary
o Minimal follicular development
o Inhibin (αβ subunit combination) inhibits FSH secretion o Absence of: Corpus lutea, Larger follicles, Stromal
Inhibin & Activin
o Activin (ββ subunit combination) increases FSH edema
secretion  Cervix – hypertrophy and polyp formation
 Physiologic roles are not fully understood  Endometrium – decidual stroma and glandular atrophy
 Peptide related to growth-promoting peptides (stromal-glandular dissociation)
 Similar to insulin  Following prolonged use:
 Localization: Ovary, Blood, Uterus, Placenta o Possible cervical hypertrophy
 Relaxin – synthesized in corpus luteal granulosa cells o Polyp formation
 Several other nonsteroidal substances such as corticotropin o Changes in cervical mucus
releasing hormone, follistatin, and prostaglandins are Uterus
 Resemble postovulation mucus
produced by the ovary. These probably have paracrine  Thick and less copious
effects within the ovary  Estrogen/Progesterone combinations
 Physiologic Effects: o Result to stromal deciduation at cycle end
o ↓ uterine contractility  Combination agents contain 19-nor progestins
Relaxin
o ↑ glycogen synthesis & water uptake by myometrium o Increased glandular atrophy
o Changes in the mechanical characteristics of pubic o Less bleeding
ligaments and cervix promoting delivery  Decrease motility
o In women, relaxin has been measured by immunoassay Fallopian Tubes
 Altered secretion
o Levels were highest immediately after the LH surge and
 Intermediate cells predominate
during menstruation Vagina
 Increase vulvovaginitis
o Have been conducted in patients in premature labor and
 Suppress lactation
during prolonged labor
o When applied to the cervix of a woman at term, it  Stimulation of breast and some enlargement
facilitates dilation and shortens labor Breast  Happens when administered estrogen or estrogen/
progesterone combination
 Only small amounts of compounds cross the milk

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

 Mood, affect, and behavior changes are low  Withdrawal bleeding – sometimes may fail to occur
 Estrogen: decrease threshold of excitability o Sometimes may fail to occur
CNS  Progesterone: increase threshold of excitability o Most often seen with combination preparations
 Progesterone and Synthetic progestins: Thermogenic effect o May cause confusion with pregnancy
(possibly mediated in the CNS) o Remedy: change in formulation
Effects of Estrogen:  Breakthrough bleeding
 ↓ FSH & LH o Most common problem in using progestational agents
 Change in adrenal structure and function alone for contraception
 ↑ corticosteroid-binding globulin concentration in plasma  Weight gain
 Changes in RAAS o More common with combinational agents containing
Endocrine o ↑ plasma renin activity androgen-like progestins
o ↑ aldosterone secretion  Increased skin pigmentation
 ↑ thyroxine binding globulin (TBG) o Though to be exacerbated by vitamin B deficiency
 ↑ plasma thyroxine (T4) levels  Acne
 ↑ sex hormone-binding globulin (SHBG) o Improved by contraceptives containing large estrogen
 ↓ free androgen plasma levels content
 ↑ risk of thromboembolic phenomena Moderate  Hirsutism
o Aggravated by the “19-nortestosterone” derivatives
 Inconsisten alteration in blood coagulation times
o ↑ factors VII, VIII, IX, and X (7,8,9,10)  Ureteral dilatation
o ↓ antithrombin III o Associated with bacteriuria
Blood o ↑ Coumarin anticoagulants amounts required to ↑  Vaginal infection
prothrombin time in patient on oral contraceptives o More common
 ↑ serum iron and total iron-binding capacity o More difficult to manage n patient taking oral
contraceptives
 Some develop folic acid deficiency anemia
 Amenorrhea
 ↓ serum haptoglobulins
o Prolactin levels should be measured
 Changes in hepatic drug excretion/metabolism
o Many have prolactinomas
 Delayed clearance of sulfobromophthalein
o May require discontinuance of oral contraceptives
Hepatic  Reduced bile flow
 Vascular disorders:
 Proportion of cholic acid in bile acids is ↑
o Venous Thromboembolic Disease
 Proportion of chenodeoxycholic acid is ↓
o Myocardial Infarction
 ↑ risk for cholelithiasis o Cerebrovascular Disease
 Estrogen  GI: cholestatic jaundice with progestin-containing oral
o ↑ serum TAGs, free and esterified cholesterol Severe contraceptives
Lipid o ↑ phospholipids  Depression
Metabolism o ↑ HDL
 Cancer
o ↓ LDL
o Risk reduction: endometrial and ovarian cancer
 Progestin antagonizes theses estrogen effects o ↑ risk in breast cancer of young women
 Decrease glucose tolerance  Alopecia
 Effects are similar to those observed in pregnancy Other Adverse  Erythema miltiforme
 ↓ GI tract carbohydrate absorption  Erythema nodosum
Carbohydrate Effects
 Progesterone: increases basal insulin; increases insulin rise  Other skin disorders
Metabolism induced by carbohydrates
 Reduced carbohydrate tolerance associate with long-term
potent progestin use (e.g, norgestrel) – effect reversible Contraindications & Caution
Cardiovascular  ↑ systolic BP, diastolic BP, HR, CO  Thrombophlebitis, thromboembolic phenomena, & cardiovascular
 ↑ pigmentation (chloasma) & cerebrovascular disorders
o Enhanced by exposure to UV light  They should not be used to treat vaginal bleeding with unknown
o Enhanced in women with darker complexion
cause
Skin  Acne – androgen-like progestins caused increased sebum
o However, since ovarian androgen is suppressed, many  They should be avoided in patients with known or suspected tumors
patients note ↓ sebum production, acne, and terminal of the breast or other estrogen-dependent neoplasms
hair growth  They should be avoided or used with caution in patients with liver
disease, asthma, eczema, migraine, diabetes, hypertension, optic
Clinical Uses neuritis, retrobulbar neuritis, or convulsive disorders
 Most important use of combined estrogens and progestins is for oral  Caution in patients with heart failure
contraception Because oral contraceptives may produce edema
 They are also useful in the treatment of endometriosis,
dysmenorrhea, acne, hirsutism  Estrogens increase rate of growth of fibroids
Therefore, for women with these tumors, agents with the
Adverse Effects smallest amounts of estrogen and the most androgenic
 Usually reversible progestins should be selected
 Nausea, mastalgia (breast pain), edema, breakthrough
bleeding  Contraindicated in adolescents in whom epiphyseal closure has not
o Remedy: smaller amounts of estrogen or agents yet been completed
containing progestins with more androgenic effects
 Changes in serum protein  Antimicrobial drugs that interfere with normal GI flora and may
Consider when evaluating thyroid function, pituitary reduce the efficacy of oral contraceptives
Mild function, adrenal function test results Normal gastrointestinal flora increase the enterohepatic cycling
(and bioavailability) of estrogens
 Increase sedimentation rates (ESR) secondary to increased
fibrinogen levels
 Headache: mild, transient
 Rifampin, Phenytoin  increase liver catabolism of estrogens or
 Migraine – often worsened by treatment progestins and diminish their efficacy

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

ESTROGEN AND PROGESTERONE INHIBITORS AND ANTAGONISTS

Drug Properties
 Competitive partial agonist – inhibitor of estradiol at
estrogen receptors
 First SERM (Selective estrogen receptor modulator) to be
introduced
 MOA: Recruitment of different coregulators to the estrogen
receptor when it binds tamoxifen rather than estrogen,
differential activation of heterodimers (ERα-ERβ) versus
homodimers, competition of ERα by ERβ and others
Clinical Use:
 Palliative treatment of breast cancer in postmenopausal
women
 Approved for chemoprevention of breast cancer in high-risk
women
Drug Properties
 Potent experimental progesterone inhibitor
Lilopristone  Abortifacient in doses of 25 mg twice daily
(ZK 98734)  Like mifepristone, it also appears to have antiglucocorticoid
activity
 Isoxazole derivative of ethisterone (17α-ethinyltestosterone)
 Weak progestational, androgenic, and glucocorticoid
activities, is used to suppress ovarian function
MOA:
 Inhibits the midcycle surge of LH and FSH and can prevent
the compensatory increase in LH and FSH following
castration in animals
 But it DOES NOT significantly lower or suppress basal LH or
FSH levels in normal women

Good Effects: Pharmacodynamics:

Tamoxifen
 Prevention of the expected loss of lumbar spine bone density  It binds to androgen, progesterone, and glucocorticoid
and plasma lipid changes consistent with a reduction in the receptors  translocate the androgen receptor into the
risk for atherosclerosis nucleus  initiate androgen-specific RNA synthesis
 It does not bind to intracellular estrogen receptors
Pharmacokinetics:  It does bind to sex hormone–binding and corticosteroid-
 Nonsteroidal; orally active binding globulins
 Peak plasma levels within hours  It inhibits the following:
 T ½: 7-14 hrs. o P450scc (the cholesterol side chain–cleaving enzyme)
 Excreted by the liver o 3β-hydroxysteroid dehydrogenase
Adverse Effects: o 17α-hydroxysteroid dehydrogenase
 Hot flushes o P450c17 (17α-hydroxylase)
 Nausea and vomiting o P450c11 (11β-hydroxylase)
 Stimulates the endometrium; increasing endometrial CA risk o P450c21 (21β-hydroxylase)
– due to its agonist property  It does not inhibit aromatase
 Similar to Tamoxifen  It ↑ mean clearance of progesterone
Toremifene
 Ethiserone  major metabolite – with progestational and
 Partial estrogen agonist-antagonist at some but not all Danazol
mild androgenic effects
tissues
 It has estrogenic effects on lipids and bone but appears NOT Pharmacokinetics:
to stimulate the endometrium or breast  Slowly metabolized
 T ½: >15 hours
Pharmacokinetics:
Raloxifene  Highly concentrated in the liver, adrenals, kidneys
 Very large volume of distribution
 Excreted in both feces and urine
 Long half-life (>24 hours), so it can be taken once a day
Clinical Use:
Clinical Use:
 Inhibitor of gonadal function
 Used for the prevention of postmenopausal osteoporosis
 Major use in the treatment of endometriosis
 Prophylaxis of breast cancer in women with risk factors
 Treatment of fibrocystic disease of the breast and
 Newer SERM developed
hematologic or allergic disorders, including hemophilia,
 In combination with conjugated estrogens, is approved for
Bazedoxifene Christmas disease, idiopathic thrombocytopenic purpura,
treatment of menopausal symptoms and prophylaxis of
and angioneurotic edema
postmenopausal osteoporosis
 Older partial agonist Adverse Effects:
Clomiphene  A weak estrogen  Weight gain, edema, ↓ breast size, acne and oily skin, ↑ hair
(discussed further next growth, deepening of the voice, headache, hot flushes,
 Also acts as a competitive inhibitor of endogenous estrogens
page) changes in libido, and muscle cramps
 Used as an ovulation-inducing agent
 “19-norsteroid” that binds strongly to the progesterone and  Mild to moderate hepatocellular damage
glucocorticoid receptors and inhibits the activity of  Adrenal suppression
progesterone and that of glucocorticoids
 Has luteolytic properties in 80% of women when given in the Contraindication & Caution:
midluteal period  Should be used with great caution in patients with hepatic
dysfunction
Pharmacokinetics:  Pregnancy and breast-feeding  urogenital abnormalities in
 Long half-life: (20-40 hrs.) may prolong progesterone offspring
receptor and makes it difficult to be used continuously as a ANASTRAZOLE & LETROZOLE
contraceptive  Selective nonsteroidal inhibitor of aromatase (the enzyme
Clinical Use: required for estrogen synthesis)
Mifepristone  Effective emergency postcoital contraceptive  Effective in some women whose breast tumors have become
(RU-486)  Has antiglucocorticoid activity resistant to tamoxifen
 May be useful in the treatment of endometriosis, Cushing’s EXEMESTANE
syndrome, breast cancer, and possibly other neoplasms such  Steroid molecule, is an irreversible inhibitor of aromatase
as meningiomas that contain glucocorticoid or progesterone Aromatase  Like anastrozole and letrozole, it is approved for use in
receptors Inhibitors women with advanced breast cancer
 Major use: terminate early pregnancies FADRAZOLE
 Oral nonsteroidal (triazole) inhibitor of aromatase activity
Adverse Effects:
 As effective as tamoxifen
 Prolonged bleeding
 In addition to their use in breast cancer, aromatase inhibitors
 If with vaginal pessary (prostaglandin E1 or misoprostol):
have been successfully employed as adjuncts to androgen
o Vomiting
antagonists in the treatment of precocious puberty and as
o Diarrhea
primary treatment in the excessive aromatase syndrome
o Abdominal or pelvic pain

#RoadToVNeck Page 16 of 21
 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Drug Properties TESTIS

 Pure estrogen receptor antagonist  Function:
 It is somewhat more effective than those with partial agonist o Gametogenic – onset controlled largely by FSH secretion
effects in some patients who have become resistant to
tamoxifen
o Endocrine – high concentration of testosterone are locally
required for continuing sperm production in the
Clinical Use:
 Approved for use in breast cancer patients who have
seminiferous tubules
Fulvestrant
become resistant to tamoxifen  Secretes small amounts of:
o Dihydrotestosterone (potent androgen)
ICI 164,384 o Weak androgens:
 Is a newer antagonist
 Androstenedione
 it inhibits dimerization of the occupied estrogen receptor
and interferes with its binding to DNA  Dehydroepiandrosterone
GnRH and its  GnRH analogs  NAFARELIN, BUSERELIN o Pregnenolone
analogs  They important in both stimulating and inhibiting ovarian o Progesterone and 17-hydroxylated derivatives
function
Sertoli Cells
Clomiphene Citrate  Located in the seminiferous tubules
 Partial estrogen agonist
 May be the source of estradiol produced in the testes via
 Closely related to the estrogen chlorotrianisene aromatization of locally produced testosterone
 Synthesize and secrete a variety of active proteins including:
Pharmacokinetics:
o Mullerian duct inhibitory factor
 Well absorbed when taken orally o Inhibin and Activin
 T ½: 5-7 days  Inhibins A and B
 Excreted in the urine  α subunit + one of the β subunit
 Exhibits significant protein binding and enterohepatic circulation and  In conjunction with testosterone
is distributed to adipose tissues and dihydrotestosterone  are
responsible for feedback inhibiton
Mechanism of Action: of pituitary FSH secretion
 Partial agonist at estrogen receptors  Activin
 It leads to an increase in the secretion of gonadotropins and  Composed of two β subunits (βAβB)
estrogens by inhibiting estradiol’s negative feedback effect on the  Stimulates pituitary FSH release
release of gonadotropins
Interstitial Cells of Leydig
Effects:  Found in the spaces between seminiferous tubules
 It has the ability to stimulate ovulation in women with  LH stimulation  testosterone production
oligomenorrhea or amenorrhea and ovulatory dysfunction
 Used in patients with polycystic ovary syndrome (characterized by ANDROGENS
gonadotropin-dependent ovarian hyperandrogenism associated with Testosterone
anovulation and infertility)  Most important androgen
 Clomiphene probably blocks the feedback inhibitory influence of  Synthesized from progesterone and dehydroepiandrosterone (DHEA)
estrogens on the hypothalamus, causing a surge of gonadotropins,  8 mg is produced daily
which leads to ovulation  Leydig cells production – 95%
 Adrenal cells production – 5%
Clinical Uses:
 Treatment of disorders of ovulation in patients who wish to become Pharmacokinetics
pregnant  65% are bound to sex hormone-binding globulin (SHBG)
 Dose of 100 mg/d for 5 days: rise in plasma LH and FSH o Factors that ↑ SHBG:
 Thyroid hormone, Estrogen, Liver Cirrhosis
Adverse Effects: o Factors that ↓ SHBG:
 Hot flushes (most common; mild and disappear when drug is  Androgen, Growth Hormone, Obesity
discontinued)  33% are bound to albumin
 Eye symptoms (rare)  2% are Free and they enter the cells and bind to intracellular
 Headache, constipation, allergic skin reactions, and reversible hair receptors
loss Mechanism of Action
 Ovarian enlargement  At intracellular target sites:
 A/E usually associated with hormonal changes in cycle (instead of o Converted to 5α-dihydrotestosterone (primary
caused by the drug): androgen) by 5α-reductase in certain tissues:
o Nausea & vomiting, ↑ nervous tension, depression, Skin, Seminal Vesicles, Epididymis, Prostate
fatigue, breast soreness, weight gain, urinary frequency,
 Testosterone/Dihydrotestosterone:
heavy menses
o Binds to cytosolic androgen receptor
Contraindications: o Subsequent process is similar to that for
 Enlarged ovaries estradiol/progesterone  growth differentiation, and
 Patients with visual symptoms  drug makes driving more hazardous synthesis of various enzymes and other functional
proteins

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Physiologic Effects Clinical Uses

 Changes during puberty in male (Adrenarche)  Androgen Replacement Therapy in Men
o Penile & scrotal growth Replacement or augmentation of endogenous androgen
 Testosterone & 5α-dihydrotestosterone secretion in men with hypogonadism
o Skin changes  pubic, axillary & beard hair; more active o Preferred in pituitary deficiency except when normal
sebaceous glands (thicker & oilier skin) spermatogenesis is to be achieved
 Androstenedione, DHEA o In patients with hypopituitarism:
o Larynx  vocal cords thicker  low pitch voice  Not added to treatment regimen until puberty
 Skeletal growth is stimulated and epiphyseal closure accelerated  Instituted in gradually increasing doses to
 Increase lean body mass achieve:
 Male development (Secondary sexual characteristics)  Growth spurt
o Stimulate development & maturation of sperm  Development of secondary
o Stimulate development of the epididymis, vas deferens, hormones
seminal vesicles, scrotum, penis, prostate o Therapy started with long-acting agents (e.g,
 Anabolic effects on muscle & bone mass testosterone enanthate or cypionate)
o Increase protein synthesis, decrease protein breakdown  Dose: 50 mg IM initially every 4 week  every
o Measured by ↓ urine nitrogen secretion 3 weeks  finally every 2 weeks
 Masculinization in females Each change taking place at 3-month
 Metabolic effects: interval
o ↓ hormone binding and other carrier proteins
o ↓ HDL  Doubled to 100 mg every 2 weeks until
o ↑ liver synthesis of clotting factors completion of maturation
o ↑ triglyceride lipase  Finally changed to adult replacement dose of
o ↑ α1-antitrypsin 200 mg at 2-week intervals
o Stimulate renal erythropoietin secretion o Testosterone propionate
 Potent and short-acting
Synthetic Steroids with Androgenic & Anabolic Action  Not practical for long-term use
o Testosterone undecanoate
 Administered PO in large amounts (e.g, 40
mg/d) BID
Not recommended because oral
testosterone is associated with liver
tumors

o Transdermal testosterone
 Skin patches or gels available for scrotal or
other skin area application
 Two applications daily usually required for
replacement therapy
 Implanted pellets and other longer-acting
preparation understudy
o Development of polycythemia or hypertension
 May require some reduction in dose

 Gynecologic Disorders
o Occasional use in the treatment of certain gynecologic
 Used for their anabolic effects
disorder
 Treatment of testosterone deficiency
 Used with great caution because of pronounce
undesirable effects in women
 Rapidly absorbed when administered by mouth
 Largely converted to inactive metabolites (only 1/6 of o In conjunction with estrogens:
administered dose available is in active form)  Reduce breast engorgement during
 Can be administered parenterally but has more postpartum
Testosterone
prolonged absorption time due to greater activity in  Postmenopausal period to eliminate
propionate, enanthate, undecanoate, and cypionate
endometrial bleeding
ester forms: hydrolyzing the release of free testosterone
at injection site  Enhance libido
Methyltestosterone  Testosteron derivative alkylated at 17 position  Breast tumors in premenopausal women
Fluoxymesterone  Active when given orally o Danazol  weak androgen used in the treatment of
endometriosis

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Clinical Uses continued….. Adverse Effects

 Use as Protein Anabolic Agents  Masculinizing effects
o In conjunction with dietary measures and exercises:  In women
 Reverses protein loss after trauma, surgery, o Administration of >200-300 mg testosterone per month
or prolonged immobilization and in patients is usually associated with:
with debilitating diseases  Hirsutism
 Acne
 Anemia  Amenorrhea
o Large doses of androgens employed in treatment of  Clitoral enlargement
refractory anemias such as:  Deepening of voice
 Aplastic anemia  Progestational activity of some androgenic steroids  endometrial
 Fanconi’s anemia bleeding upon discontinuation
 Sickle cell anemia  Alter serum lipids
 Myelofibrosis  Conceivably increase susceptibility to atherosclerotic disease in
 Hemolytic anemia women
Recombinant erythropoietin replaced  Not used in infants
androgens for this purpose o Administration in early life may have profound effects on
maturation of CNS centers governing sexual development
 Osteoporosis  Administration in pregnant women may lead to either:
o Androgens and anabolic agents + estrogens o Masculinization of female external genitalia
 Have been used in the treatment of o Undermasculinization of male fetus external genitalia
osteoporosis  Sodium retention and edema
 Largely replaced by biphosphonates o Not common
o Carefully watched for in patients with heart and kidney
 Growth Stimulation disease
o Stimulate growth in boys with delayed puberty  Hepatic dysfunction
 If used carefully: o Reversible upon cessation of therapy
Expected adult height will probably  In older males:
achieved o Prostatic hyperplasia  urinary retention
 Effects of replacement therapy in men
 If treatment is too vigorous: o Acne
Patient may grow rapidly at first but will o Sleep apnea
not achieve full predicted full stature o Erythrocytosis
because of accelerated epiphyseal closure o Gynecomastia
↓ o Azoospermia
 Difficult to control such type of therapy o Decrease in testicular size
adequately even with frequent X-ray  Effects of high-dose 17-alkylated androgens
examination of epiphysis o Peliosis hepatica
 Action of hormones in epiphyseal centers may o Cholestasis
continue for many month after o Hepatic failure
discontinuation  ↓ plasma HDL
 ↑ plasma LDL
 Abuse in Sports  Hepatic adenomas and carcinomas
o Use of anabolic steroid has received worldwide attention  Behavioral effects:
 In doses: 10-200 times larger than daily normal o Psychological dependence
physiologic production: o Increased aggressiveness
 Increase strength and o Psychotic symptoms
aggressiveness  improves
competitive performance Contraindications & Cautions
 Unequivocally demonstrated only
 Pregnant women or women who may become pregnant
in women
 Male patients with prostate or breast carcinoma
o Adverse effects of these drugs clearly make their use
 Infants and young children  CNS effects
inadvisable
 Renal & cardiac disease  predisposed to edema
 Methyltestosterone associated with creatinuria
 Aging
 Patients with aplastic anemia treated with androgen anabolic
o Androgen production
therapy  hepatocellular cancer
 Falls with age in men
 Many contribute to decline in muscle mass,
strength and libido
o Androgen replacement in aging males with low androgen
levels:
 ↑ in lean body mass and hematocrit
 ↓ bone turnover

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

ANDROGEN SUPPRESSION Ketoconazole continued…..

 Used for the treatment of advanced prostatic carcinoma
 Achieved by:
o Sustained nonpulsatile doses of GnRH analogs (preferred)
E.g, goserelin, nafarelin, buserelin, leuprolide
o Orchietomy
Adverse Effect: Psychological disturbance
o Large doses of estrogen to reduce available endogenous
androgen
Adverse Effect: Gynecomastia
ANTIANDROGENS
Figure on Left: Control of
androgen secretion and
activity and some sites of
action of antiandrogens:
1.) Competitive inhibitors of
GnRH receptors
2.) Stimulation (+, pulsatile
administration) or inhibition
via desensitization of GnRH
receptors (-, continuous
administration)
3.) Decreased synthesis of
testosterone in the testis;
4.) Decreased synthesis of
dihydrotestosterone by
inhibition 5α-reductase
5.) Competition for binding
for binding to cytosol
androgen receptors
 Does not appear to be clinically useful in women with increased
androgen levels because of the toxicity associated with prolonged
use of the 400–800 mg/d required
 Experimentally used to treat prostatic carcinoma
 Adverse effect: reversible gynecomastia
Inhibition of Conversion of Steroid Precursors to Androgens
Abiraterone
 MOA: Inhibit the 17-hydroxylation of progesterone or
pregnenolone  ↓ active androgens
 It is a newer 17α-hydroxylase inhibitor
 Approved for use in metastatic prostate cancer
Finasteride
 5α-reductase inhibitor
 An orally active enzyme inhibitors that decreases
dihydrotestosterone levels
 Effects starts within 8 hours and lasts after 24 hours
o Half-life: 8 hours
o Dose: 5 mg/day
 Uses:
o May be moderately effective in reducing prostate size in
men with BPH
o Hirsutism in women
o Early male pattern baldness in men
Dutasteride
 A similar orally active steroid derivative with a slow onset of action
and a much longer half-life than finasteride
 Dose: 0.5 mg/day
 Used for the treatment of BPH
Receptors Inhibitors
Flutamide
 A substituted anilide
 MOA: Behaves like a competitive antagonist at the androgen
receptor
 Rapidly metabolized
Clinical Use:
 A potent antiandrogen that has been used in the treatment of
prostatic carcinoma
 Also useful in the management of excess androgen effect in women

Adverse Effects:
 Often causes mild gynecomastia
Antiandrogens:
 Mild reversible hepatic toxicity
 Drugs that are available that acts on different sites of the androgen
pathway
 Used for treatment of patients producing excessive amounts of Bicalutamide, Nilutamide, & Enzalutamide
testosterone  Potent orally active antiandrogens
 Administered as a single daily dose
Steroid Synthesis Inhibitors
Ketoconazole Clinical Use:
 Used in patients with metastatic carcinoma of the prostate
 Used primarily for fungal diseases
o Bicalutamide is recommended (to reduce tumor flare) +
 MOA: Inhibitor of adrenal and gonadal steroid synthesis WITHOUT
GnRH analog  may have fewer GI side effects than
affecting ovarian aromatase BUT reduces human placental
flutamide
aromatase activity
o Nilutamide or Enzalutamide for use following surgical
 ↑ estradiol:testosterone ratio
castration
By displacing estradiol and dihydrotestosterone from sex
hormone-binding protein

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 PHARMACOLOGY
Topic: Steroids & Gonadal Drugs
Chapter: 39 & 40

Receptor Inhibitors continued…..

Cyproterone & Cyproterone Acetate
 Effective antiandrogens that inhibit the action of androgens at the
target organ
 The acetate form has a marked progestational effect that suppresses
the feedback enhancement of LH and FSH, leading to a more
effective antiandrogen effect

Clinical Use:
 Hirsutism in women
o Dose: 2 mg/day
o Co-administered with estrogen
o Doubles as contraceptive
 Reduction of sexual drive in men
 It has orphan drug status in the U.S.

Spironolactone
 Competitive inhibitor of aldosterone
 It also competes with dihydrotestosterone for the androgen
receptors in target tissues
 It also reduces 17α-hydroxylase activity, lowering plasma levels of
testosterone and androstenedione

Clinical Use:
 Treatment of hirsutism in women
Appears to be as effective as finasteride, flutamide, or
cyproterone in this condition

Chemical Contraception in Men

 An effective oral contraceptive for men has not been found
 Options:
o Testosterone/testosterone enanthate 400 mg/month
produces azoospermia
 Toxicity: Gynecomastia, Acne
o Testosterone + Danazol was well tolerated but no more
effective than testosterone alone
o IM testosterone enanthate + levonorgestrel (oral) also
produces azoospermia (94% of men)
o Cyproterone acetate, a very potent progestin and
antiandrogen, also produces oligospermia  but DOES
NOT cause reliable contraception
o Testosterone + GnRH  reversible azoospermia in
nonhuman primates

Gossypol
 Cottonseed derivative (Chinese study)
 This compound destroys elements of the seminiferous epithelium
but does NOT significantly alter the endocrine function of the testis
 99% of men developed sperm counts below 4 million/mL
Recovery (return of normal sperm count) following
discontinuance of gossypol administration is more apt to occur in
men whose counts do not fall to extremely low levels and when
administration is not continued for >2 years

 Major adverse effect: Hypokalemia  leads to transient paralysis

References:
 Basic & Clinical Pharmacology by Katzung
(14th ed.)
 Pharmacology Lecture Guide (2020)

#RoadToVNeck Page 21 of 21
 PHARMACOLOGY
Topic: Dietary Supplements & Herbal Medicine
Chapter: 64

OBJECTIVES OF THE LECTURE History & Regulatory Factors

 Describe the current regulation and legal status of herbal and dietary  Under the DSHEA, dietary supplements are not considered over-the-
supplements counter drugs in the USA but rather food supplements used for
 Understand the various chemical diverse constituents commonly health maintenance
present in dietary supplements  Legally, dietary supplements are intended to supplement the diet
 Describe the intended clinical use of dietary supplements and their But consumers may use them in the same fashion as drugs and
proposed mechanism of action, recommended dosage, potential side even use them in place of drugs or in combination with drugs
effects, common drug interactions, and contraindications  In 1994, US Congress passed the DSHEA. The DSHEA required the
establishment of Good Manufacturing Practice (GMP) standards for
OUTLINE the supplement industry:
 Botanical Substances o 2007 – FDA issued a final rule on the proposed GMP
o Echinacea (Echinacea Purpurea) standards
o Garlic (Allium Sativum) This 13-year delay allowed supplement manufacturers
o Ginkgo (Ginkgo Biloba) to self-regulate the manufacturing process and
o Ginseng resulted in many instances of adulteration,
o Milk Thistle (Silybum Marianum) misbranding, and contamination
o St. John’s Wort (Hypericum Perforatum)
o Saw Palmetto (Serenoa Repens or Sabal Serrulata) o Therefore, much of the criticism regarding the dietary
 Purified Nutritional Supplements supplement industry involves problems with botanical
o Coenzyme Q10 misidentification, a lack of product purity, and variations
o Glucosamine in potency and purification, which continue to be
o Melatonin problematic even with GMP standards in place
 In 2006, Dietary Supplement and Non-Prescription Drug Consumer
INTRODUCTION Protection Act was approved
 Limited existing research available for each dietary supplement This law requires manufacturers, packers, or distributors of
supplements to submit reports of serious adverse events to the
ingredient
FDA
o Evidence-based resources should be used to evaluate
claims and guide treatment decisions
Clinical Aspects of the Use of Botanicals
o Pharmacist’s Letter/Prescriber’s Letter Natural Medicines
 Many consumers have embraced the use of dietary supplements as
Comprehensive Database
a “natural” approach to their health care
Unbiased and regularly updated compendium of basic
and clinical reports regarding botanicals Unfortunately, misconceptions regarding safety and efficacy of
the agents are common
o National Standard
Another evidence-based resource  The fact that a substance can be called “natural” does not of course
(www.naturalstandard.com) guarantee its safety
This is because botanicals may be inherently inert or toxic
Dietary Supplements vs. Prescription Drugs
Dietary Supplements Prescription Drugs  If a manufacturer does not follow GMP  results in intentional or
 Available without a prescription  Derived from plants (morphine,
unintentional plant species substitutions (eg, misidentification),
 Legally considered dietary supplements digitalis, atropine, etc)
rather than drugs  Needs to have proof of efficacy and adulteration with pharmaceuticals, or contamination
 There is NO need for proof of efficacy and safety prior to marketing  Adverse effects have been documented for a variety of dietary
safety prior to marketing  Are tested for dose-response supplements
It places the burden of proof on the relationships or toxicity
However, underreporting of adverse effects is likely since
FDA to prove that a supplement is  They have adequate testing for
harmful before it can be removed mutagenicity, carcinogenicity, and
consumers do not routinely report, and do not know how to
from the market or its use can be teratogenicity report an adverse effect if they suspect that the event was caused
restricted by consumption of a supplement

 Are NOT tested for dose-response  Chemical analysis is rarely performed on the products involved
relationships or toxicity
This leads to confusion about whether the primary ingredient or
 There is a LACK of adequate testing for
mutagenicity, carcinogenicity, and an adulterant caused the adverse effect
teratogenicity
 In some cases, the chemical constituents of the herb can clearly lead
Dietary Supplement Health & Education (DSHEA) to toxicity
 They define dietary supplements as vitamins, minerals, herbs or  An important risk factor in the use of dietary supplements is the lack
other botanicals, amino acids or dietary supplements used to of adequate testing for drug interactions
supplement the diet by increasing dietary intake, or concentrates, Since botanicals may contain hundreds of active and inactive
metabolites, constituents, extracts, or any combination of these ingredients, it is very difficult and costly to study potential drug
ingredient interactions when they are combined with other medications

#OneLastPush Page 1 of 6
 PHARMACOLOGY
Topic: Dietary Supplements & Herbal Medicine
Chapter: 64

#OneLastPush Page 2 of 6
 PHARMACOLOGY
Topic: Dietary Supplements & Herbal Medicine
Chapter: 64

Botanical Substance Dose
 Alcohol extract or Fresh
pressed Juice
 Taken within the first 24 hours
Echinacea
of cold symptoms
(Echinacea Purpurea)
 Should not be used on a
continuous bases for longer
than 10-14 days
 Powdered garlic in enteric-
coated formulations
o Contain 1.3% alliin
o 600-900 mg/d
Garlic
 Garlic bulb – contain 1.8% alliin
(Allium Sativum)
 Doses of AGE (Aged garlic
extract):
o 600-1800 mg/d
o Up to 7200 mg/d is safe
Chemistry
 3 Most Common Species:
o E purpurea
o E pallida
o E angustifolia
 Flavinoids
 Lipophilic constituents
o Alkamides
o Polyacetylenes
 Water soluble polysaccharides
 Water soluble caffeoyl conjugates
o Achinacoside – E pallida &
E angustifolia
o Cichoric acid – E purpurea
o Caffeic acid
 Pharmacologic activity involves a
variety of organo-sulfur compounds
which are standardized to allicin or
alliin content
 Allicin  responsible for the
characteristic odor of garlic
 Alliin  chemical precursor of
allicin
 Dried powdered formulations are
often enteric-coated (protects them
from the enzyme allinase)
Allinase converts alliin  allicin
Aged Garlic Extract (AGE)
 Contains no alliin or allicin and is
odor-free
 Has water-soluble organosulfur
compounds
BOTANICAL SUBSTANCES
Pharmacological Effects Adverse Effects Drug Interactions & Precautions
 Immune modulation
o ↑ phagocytosis, total circulating monocytes,
neutrophils, and natural killer cells
o It inhibited the ↑ in pro-inflammatory
cytokines and IL-6 and -8
o It inhibited mucin secretion caused by
exposure to rhinovirus type 1A in a 3D tissue
model of human airway epithelium
 Immune deficiency disorders
 Anti-inflammatory effects
o eg, AIDS, cancer
o Inhibition of cyclooxygenase, 5-lipoxygenase,
and hyaluronidase may be involved  Autoimmune disorders
 Unpleasant taste
o eg, multiple sclerosis, rheumatoid
 Antibacterial, antifungal, antiviral and antioxidant  Gastrointestinal upset
arthritis
effects  Allergic reactions (eg, rash)
o Used to enhance immune function in  Persons taking immunosuppressant
individuals who have colds and other medications
respiratory tract infections o eg, organ transplant recipients
o It has also been used as an adjunct in the
treatment of urinary tract and vaginal fungal
infections
o Not effective in treating recurrent genital
herpes
 Investigational
o Used as an adjunct in the treatment of urinary
tract and vaginal fungal infections
 Cardiovascular Effects
o Inhibit HMG-CoA reductase (involved in
cholesterol biosynthesis)  ↓ total serum
cholesterol, LDL
o Exhibit antioxidant properties
o Has antiplatelet effects through inhibition of
thromboxane synthesis or stimulation of nitric
oxide synthesis
o Enhance fibrinolytic activity
o May be used in patients with atherosclerosis
o It affects blood vessel elasticity and blood
pressure
 Breath and body odor (20-40%)
 Endocrine Effects
 Nausea (6%)  Patients using anticlotting medications
o Organosulfur constituents in garlic  has
 Hypotension (1.3%) o eg, warfarin, aspirin, ibuprofen
hypoglycemic effects in nondiabetic animal
 Allergy (1.1%)  Reduce bioavilability of saquinavir – an
models
 Bleeding (rare) antiviral protease inhibitor
 Antimicrobial Effects  Contact dermatitis (if handling raw
o Allicin: have in vitro against gram (+) & (-) garlic)
bacteria, fungi (C. albicans), protozoa (E.
histolytica) & certain viruses
MOA: Inhibition of thiol-containing
enzymes needed by these microbes
o Used for prevention of cold
 Antineoplastic Effects:
o Inhibits procarcinogens for colon, esophageal,
lung, breast, and stomach cancer, possibly by
detoxification of carcinogens and reduced
carcinogen activation

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 PHARMACOLOGY
Topic: Dietary Supplements & Herbal Medicine
Chapter: 64
Botanical Substance
 Dried leaf extract:
Ginkgo
(Ginkgo Biloba)  Daily dose:
Ginseng
 1-2 g/d of the crude of P.
(Panax ginseng:
Chinese/Korean variety)
 200 mg P. ginseng extract = 1 g
(Panax quinquefolium:
American variety)
#OneLastPush
Dose
o 24% flavone glycosides
o 6% terpene lactones
o 120-240 mg dried extract
in 2-3 divided doses
ginseng
crude root
BOTANICAL SUBSTANCES
Chemistry Pharmacological Effects Adverse Effects Drug Interactions & Precautions
 Cardiovascular Effects
o ↑ blood flow, ↓ blood viscosity, and promote
vasodilation, thus enhancing tissue perfusion
o Enhances endogenous nitric oxide effects &
antagonism of platelet-activating factor (PAF)
o For mild-moderate occlusive peripheral artery
disease: standard extract lacked benefit for this  Have antiplatelet properties
indication o Should not be used in combination
 Metabolic Effects with antiplatelet or anticoagulant
o Antioxidant & radical-scavenging properties medication
 Part used: Leaves (superoxide dismutase-like activity)  Nausea  Ginkgo + Efavirenz = virologic failure
o Flavinoid fraction – have antiapoptotic properties  Headache  Ginkgo + Trazodone = sedation
Active Constituents:
o Protective effect in limiting free radical formation  Stomach upset, diarrhea  Ginkgo + Risperidone = priapism
 Flavone glycosides
in ischemic injury  Allergy  Ginkgo + Valproic acid/Phenytion =
 Terpenoids
o ↓ markers of oxidative stress in CAB surgery  Anxiety seizure
o Ginkgolide A, B, C, J  Insomnia  Seizure is a toxic effect of gingko
o Bilobalide  CNS Effects  Bleeding complications o Uncooked ginkgo seeds are
o Used in treatment of cerebral insufficiency and epileptogenic due to the presence
dementia in Alzheimer type of ginkgotoxin
 Miscellaneous Effects (under study) o Avoided in patients with seizure
o Schizophrenia, tardive dyskinesia disorders
o Used in allergic and asthmatic bronchoconstriction
o Short term memory in healthy, non-demented
adults
o Erectile dysfunction
o Tinnitus and hearing loss
o Macular degeneration
 Modulation of immune function
o Induced mRNA expression of IL-2 & α-IF, GMCSF,
activated B- & T-cells, NK cells, macrophages
 CNS Effects
o ↑ proliferating ability of neural progenitors
o ↑ central levels of acetylcholine, serotonin,
norepinephrine, and dopamine in the cerebral Precaution:
cortex  Irritability, sleeplessness, and manic
Active Constituents:  Antioxidant behavior in psychiatric patients (if
 Triterpenoid saponin glycosides:  Anti-inflammatory taking phenelzine, lithium,
 Vaginal bleeding
o Ginsenosides or Panaxosides  Anti-stress (stimulation of pituitary-adrenocortical neuroleptics)
 Mastalgia
system)  Immunocompromised individuals, who
 CNS stimulation (insomnia,
 Eleutherococcus senticosus:  Analgesia (substance P inhibition) are taking immune stimulants
nervousness)
Siberian ginseng  Vasoregulatory effects (↑ NO, ↓ prostacyclin)  Autoimmune disorders
 Hypertension in higher doses
Contains Eleutherosides  Cardioprotective activity (↓ ventricular remodeling &
(>3 g/dL)
cardiac hypertrophy) D/I:
 Pfaffia paniculata: Brazilian ginseng  Antiplatelet  Estrogenic medications
 ↑ glucose homeostasis (↑ insulin release, receptor  Hypoglycemic medications
number & sensitivity; ↓ death of pancreatic B cells)  Warfarin
 Anti-cancer properties (↓ tumor angiogenesis, ↑
tumor cell apoptosis)
 Claimed to help improve physical and mental
performance or to function as an “adaptogen,” an agent
that helps the body to return to normal when exposed to
stressful or noxious stimuli
Page 4 of 6
 PHARMACOLOGY
Topic: Dietary Supplements & Herbal Medicine
Chapter: 64

BOTANICAL SUBSTANCES
Botanical Substance Dose Chemistry Pharmacological Effects Adverse Effects Drug Interactions & Precautions
 Liver Disease
o Limits hepatic injury associated with variety of
toxins
Amanita mushrooms, galactosamine,
carbon tetrachloride, acetaminophen,
radiation, cold ischemia, ethanol

o ↓ lipid peroxidation; scavenger free radicals,

 Contain a lipophilic mixture of
flavonolignans known as silymarin
 Silymarin comprises 2–3% of the dried
herb and is composed of 3 primary
isomers:
Milk Thistle  280-420 mg/day in 3 divided o Silybin – most potent &
(Silybum Marianum) doses prevalent
Also called silybinin or
silibinin
o Silychristin (silichristin)
o Silydianin (silidianin)
 Dried hydroalcoholic extract
 Hypericin
(flowers) standardized to 2-5%
o Marker of standardization for
St. John’s Wort hyperforin
currently marketed products
(Hypericum  Mild to moderate depression:
o Though to be the primary
Perforatum) 900 mg of dried extract/day in
antidepressant constituent
3 doses
 Hyperforin
 Effect may take 2-4 weeks
enhances glutathione & superoxide dismutase
levels
o Contribute to membrane stabilization
o ↓ toxin entry
o Anti-inflammatory
o Inhibition of leukocyte migration
 In Animal Models
o ↓ collagen accumulation – may play a role in
hepatic fibrosis  Gastrointestinal upset
o Dose-dependent stimulatory effects on bile flow  Dermatologic problems
– beneficial in cholestasis  Headaches
 At high doses (>1500 mg), it can  No drug-drug interactions
 Chemotherapeutic Effects
have a laxative effect caused by
o Induction of apoptosis in variety of malignant
stimulation of bile flow and
human cell lines (melanoma, prostate, colon,
secretion
leukemia, transient-cell papilloma cells,
hepatoma)
o ↓ cell growth & proliferation by inducing G1 cell
cycle arrest in breast & prostate CA
 Lactation
o Used by herbalists and midwives to induce
lactation in pregnant or postpartum women
o ↑ prolactin production (female rats) – clinical
data lacking for indication on human breast milk
production
 Used in Europe as antidote to Amanita phalloides
mushroom poisoning
 Clinical Trials
o For chronic & acute viral hepatitis
o For alcoholic liver disease
o For toxin-induced liver injury
 Antidepressant  Avoid use with anti-depressant drugs
o Hypericin – has MAO-A & B- inhibitor properties & stimulants (Due to risk of Serotonin
o Hyperforin – (-) terminal reuptake of serotonin,  Photosensitization – advised to Syndrome)
NE, dopamine use sunscreen and eye  Herb may induce hepatic CYP enzyme
 Clinical Trials protection & P-glycoprotein drug transporter
o Efficacy: St. John’s Wort = SSRI (mild to  Mild GI symptoms
moderate depression)  Fatigue, sedation, restlessness, Subtherapeutic levels of the ff. drugs:
 Antiviral and Anticarcinogenic effects dizziness, headache, and dry  Digoxin, birth control drugs (and
o Hypericin is photolabile; can be activated by mouth subsequent pregnancy), cyclosporine,
certain wavelengths of visible or UVA light  Hypomania, mania, and HIV protease and nonnucleoside
o Used investigationally to treat HIV infection autonomic arousal reverse transcriptase inhibitors,
(given IV) and basal and squamous cell warfarin, irinotecan, theophylline, and
carcinoma (given by intralesional injection) anticonvulsants

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 PHARMACOLOGY
Topic: Dietary Supplements & Herbal Medicine
Chapter: 64

BOTANICAL SUBSTANCES
Botanical Substance Dose Chemistry Pharmacological Effects Adverse Effects Drug Interactions & Precautions
Most common:
 Promoted for treatment of BPH  Abdominal pain
 Berries contain: o In vitro inhibition of 5α-reductase  Nausea
o Phytosterols (β-sitosterol) o Additional effects in vitro: inhibition of prostatic  Diarrhea
Saw Palmetto o Aliphatic alcohols growth factors, blockade of α1 adrenoceptors, and  Fatigue
o Polyprenic compounds inhibition of inflammatory mediators produced by  Headache
(Serenoa Repens
 160 mg orally BID o Flavonoids the 5-lipoxygenase pathway  ↓ libido  No drug-drug interactions
or  Marketed preparations are dried o No effect on prostate-specific antigen (PSA) levels,  Rhinitis
Sabal Serrulata) lipophilic extracts  standardized a marker that is typically reduced by enzymatic
to contain 85-95% fatty acid and inhibition of 5α-reductase Rare
sterols o Clinical trials have no significant improvement in  Pancreatitis
most urologic symptoms  Liver damage
 ↑ bleeding risk

PURIFIED NUTRITIONAL SUPPLEMENTS

Supplement Properties Clinical Uses & Dosage Adverse Effects Drug Interactions
 Hypertension
o Clinical trial – small but significant reductions in systolic and diastolic
BP
 Also known as CoQ, CoQ10 and ubiquinone
 Heart Failure
 Found in the mitochondria of many organs including
o Adjunct treatment in heart failure
heart, kidney, liver and skeletal muscle
 Ischemic Heart Disease  Rarely leading to adverse effects
o Coenzyme Q10  Ubiquinol at doses as high as 3000 mg/d  Structural similarity with vitamin K
Coenzyme Q10 o Modest effect on coronary artery disease (CAD) and chronic stable
o Coenzyme Q10 – potent antioxidant – role in  GI upset, including diarrhea,  CoQ10 + Warfarin = ↓ warfarin
angina
maintaining healthy muscle function nausea, heartburn, & anorexia
 Prevention of Statin-Induced Myopathy
 ↓ CoQ10 in serum levels are reported with Parkinson’s
Dose:
disease
 30 mg
 Cardiac effect: 100-600 mg/d in 2-3 divided dosage (↑ endogenous levels
2-3 mcg/mL)
 Used for production of glycosaminoglycans and other proteoglycans in
articular cartilage  Very well-tolerated
 Found in human tissue  substrate for production of  Osteoarthritis – rate of production of new cartilage exceeded by the rate  Mild diarrhea
articular cartilage  cartilage nutrition of degradation of existing cartilage  ↑ INR (international normalized ratio)
 Abdominal cramping
Glucosamine  Derived from crabs and other crustaceans o Clinical Trials: significant improvement in overall mobility range of in patients taking warfarin  ↑ risk
 Nausea
 Dietary supplement for pain associated with knee motion and strength in patients with OA for bruising and bleeding
 Cross-allergenicity in people
osteoarthritis
Dose: with allergies to shellfish
 500 mg 3x a day or 1500 mg once daily
 Most commonly used to prevent jet lag
o Dosage: 5-8 mg on evening of departure for 1-3 nights after arrival at
Drugs that alter Melatonin levels:
new destination
 NSAIDs
 Insomnia 
 Serotonin derivative produced by pineal gland Well-tolerated  Antidepressants
o Dosage: 0.3-16 mg once nightly may be used repeatedly up + 30
 Responsible for regulating sleep-wake cycle  Next-day drowsiness  β-adrenoceptor agonists and
minutes up to maximum of 10-20 mg
 Release coincides with darkness (begins around 9 pm and  Fatigue antagonists
 For pre- and postoperative anxiety in adults
lasts until 4 am)  Dizziness  Scopolamine
 Female Reproductive function
Melatonin  Suppressed by daylight  Headache  Sodium valproate
o Can be used as an adjunctive therapy in the treatment of infertility
 Studied for other functions such as contraception,  Irritability
during in vitro fertilization by reducing oxidative stress and thereby
protection against endogenous oxidants, prevention of  Transient depressive symptoms  It may decrease prothrombin time and
improving the quality of oocytes and embryos during ovulation
aging, treatment of depression, HIV infection, and a
induction and egg retrieval  Dysphoria may theoretically decrease the effects
variety of cancers
o ↓ prolactin release – should not be used while nursing  May ↑ or ↓ BP of warfarin therapy
 May interact with nifedipine  ↑ BP
 Male Reproductive function
and HR
o Findings: ↑ sperm motility and early apoptosis was inhibited
 Often used in preference to over-the-counter “sleep-aid” drugs

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