6/20/2016

GLUCOSE HOMEOSTASIS
Glucose
major energy source for all cells
some tissues (e.g., brain) need a
continuous delivery of glucose
Hormone regulators:
Insulin hypoglycemia
Glucagon hyperglycemia
ROWEL P. CATCHILLAR, MS

The Pancreas Glucagon

Islets of Langerhans
Endocrine portion of the pancreas
cordlike groups of cells arranged along
pancreatic capillary channels
Types:
-cells produce glucagon
-cells insulin
-cells somatostatin
F cells (PP) pancreatic polypeptide
G cells gastrin
Secreted in response to
increases in amino acid and fatty
acid levels
glucose inhibits glucagon
secretion
Secretion is augmented during
fall of glucose levels

Insulin
Mering and Minkowski
first demonstrated that
pancreatectomized dogs exhibited
signs and symptoms characteristic of
diabetes mellitus
Banting and Best
Used pancreatic extracts to reverse
these symptoms in diabetic patients
Insulin
In 1982, recombinant DNA
(rDNA) derived human insulin
was first produced and is now
widely used instead of insulin
derived from beef or pork

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Biochemical Actions of Insulin Biological Actions of Insulin

glycogenolysis Initiated following a reversible
glycogenesis binding of the hormone to a
high-affinity specific insulin
gluconeogenesis receptor on the cell membrane
lipolysis surface
promote the active transport Binds to the -subunit on the
of amino acids into cells extracellular surface of the cell
and activates tyrosine kinase
activity in the intracellular
portion of the -subunit

DIABETES MELLITUS (DM) Types of DM

abnormality in insulin production Type I DM
or action or both Insulin-dependent DM (IDDM)
metabolic disorder in which juvenile-onset diabetes mellitus
carbohydrate metabolism is
reduced while that of proteins and Pathogenesis: Autoimmune
lipids is increased destruction of the cells of the pancreas
Endpoint: Hyperglycemia
3rd leading cause of death
2nd leading cause of blindness and
renal failure

Types of DM Type I vs Type II

Type II DM Characteristics Type I Type II
Onset (age) Usually <30 Usually >40
noninsulin-dependent diabetes Type of onset Abrupt Gradual
mellitus (NIDDM) Nutritional status Often thin Often obese
adult-onset diabetes mellitus) Clinical symptoms Polydipsia, polyuria, Often asymptomatic
polyphagia
More common
Ketosis Present Usually absent
Major contributors of hyperglycemia Endogenous insulin Absent Variable
glucose-induced insulin secretion Insulin therapy Required Sometimes
increased hepatic glucose output Oral hypoglycemic Usually not effective Often effective
inability of insulin to stimulate glucose Diet Mandatory with Mandatory with or
insulin without drugs
uptake in peripheral target tissues

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METABOLIC DISTURBANCES AND

COMPLICATIONS OF THE DIABETIC STATE CLINICAL MANAGEMENT OF DIABETES
In DM: Diet
hyperglycemia Exercise
glucosuria
Protein catabolism OHAs
nitrogen excretion Insulin
gluconeogenesis For type I DM
catabolism of lipids ketone bodies For type II (refractory to OHAs)
dehydration, electrolyte abnormalities, and
acidbase disturbances
Diabetic ketoacidosis

Antidiabetic Drugs Insulin Preparations

Augment insulin supply rapid acting : 05 hours
Lispro
Insulin Aspart
Sulfonylureas short acting / Regular : 08 hours
Meglitinides Semilente (prompt insulin zinc suspension)
intermediate acting: 2 to 16 hours
Enhance insulin action NPH (Isophane insulin suspension)
Biguanides Lente (Insulin Zinc suspension)
Thiazolidinediones long acting: 4 to 36 hours
Protamine zinc
Delay carbohydrate absorption Ultra-lente (Extended Zinc suspension)
Insulin glargine
-glucosidase inhibitor

Insulin Preparations Insulin Preparations

Rapid-acting insulin analogues Short-acting or regular insulins
control postprandial hyperglycemia
Lispro supplement intermediate- and long-acting
Humalog insulin preparations
(first insulin analogue approved in the preparation of choice for glucose
US and Europe) management during surgery, trauma,
shock, or diabetic ketoacidosis
very similar actions to insulin and can be given intravenously when
similar affinity for the insulin receptor emergency diabetes management is
required (e.g., diabetes ketoacidosis)
Insulin aspart Prompt insulin zinc suspension
Novolog (Semilente)
mixed with Lente & Ultralente

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Insulin Preparations
Intermediate-acting
preparations
used to control diabetes in a variety of
situations except during emergencies
(e.g., diabetic ketoacidosis)
more delayed onset of action, but they
act longer
isophane insulin suspension
Neutral protamine Hagedorn, NPH
insulin zinc suspension
Lente
Insulin Preparations
Long-acting insulin preparations
Insulin glargine (Lantus)
does not use zinc or protamine to
modulate insulin solubility
Insulin Regimens
Semilente
Prompt insulin zinc suspension
Ultralente
Extended insulin zinc suspension
Lente insulin
30% semilente + 70% ultralente
prompt insulin zinc suspension (30%)
+ extended insulin zinc suspension
(70%)
6/20/2016
Insulin Preparations
Long-acting insulin preparations
Protamine zinc
extended insulin zinc suspension
Ultralente
Similar to protamine zinc except that it
does not contain protamine
more protamine and zinc than
isophane insulin suspension
Insulin Regimens
NPH + regular insulin
70:30 or 50:50
70/30 Humulin
70/30 Novolin
50/50 Humulin
Protamine lispro + lispro insulin
75/25 insulin
Adverse Reactions to Insulin
Therapy
Hypoglycemia
CNS symptoms as tremors, lethargy, hunger,
confusion, motor and sensory deficits, seizures,
and unconsciousness
Diabetics are aware that hypoglycemia is
developing, and prompt administration of oral
carbohydrates (e.g., fruit juice or glucose tablets)
can restore normoglycemia
Severe cases (e.g., unconsciousness, seizures),
intravenous glucose or intramuscular glucagon is
required to reverse the hypoglycemia
Weight gain
anxiety, palpitations, tachycardia, and
diaphoresis
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ORAL AGENTS FOR TREATING DM Sulfonylureas

Sulfonylureas most widely prescribed drugs in
First generation the treatment of type II diabetes
Second generation mellitus
Insulin secretagogue MOA: direct stimulation of
Meglitinide
insulin release from the
D-phenylalanine derivative
pancreatic -cells
Biguanides
-glucosidase inhibitors ineffective for the management
of type I and severe type II
Thiazolidinediones diabetes mellitus

Sulfonylureas First-Generation Sulfonylureas

The Sulfonylurea Receptor Not frequently used
Adenosine triphosphate (ATP) sensitive low specificity of action, delay in time
potassium (KATP) channel that is of onset, occasional long duration of
present on the -cell membrane action, and a variety of side effects
surface
Closure of KATP channel cell
membrane depolarization calcium
channel open calcium influx
insulin release

First-Generation Sulfonylureas Second-Generation Sulfonylureas

Acetohexamide (Dymelor) Higher specificity and affinity for
the only sulfonylurea with uricosuric
activity beneficial in diabetic patients the sulfonylurea receptor and
who also have gout more predictable
Chlorpropamide pharmacokinetics in terms of
Maintenance dose: 250 mg daily
>500 mg: risk to jaundice time of onset and duration of
S/E: dilutional hyponatremia action, and they have fewer side
Tolazamide effects
Tolbutamide
the safest sulfonylurea for elderly
diabetics

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Second-Generation Sulfonylureas Sulfonylureas

Glyburide A/E
Aka glibenclamide Hypoglycemia (especially when used
approximately 150 times as potent as as monotherapy)
tolbutamide on a molar basis and twice Weight gain
as potent as glipizide
Glipizide
Glimepiride

Insulin secretagogue: D-phenylalanine

Insulin secretagogue: Meglitinides derivative
Meglitinides Nateglinide
incapable of stimulating insulin Restores initial insulin release in
secretion in nutrient-starved -cells response to an intravenous glucose
(+) glucosethey demonstrate tolerance test
hypoglycemic effects by augmenting ingested just before meals
the release of insulin
peak effect within approximately 1
hour after ingestion

Biguanides Biguanides
does not affect insulin secretion but Metformin formulations
requires the presence of insulin to be
effective Glucovance
Phenformin Glucophage XR
Withdrawn due to severe lactic acidosis
Metformin ADR: weight loss (not weight
the only approved biguanide for the treatment of
patients with NIDDM that are refractory to dietary gain)
management alone
first-line therapy in the treatment of mild to
moderate type II overweight diabetics who
demonstrate insulin resistance
treat hirsutism in individuals with polycystic
ovarian syndrome and may enhance fertility in
these women

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Thiazolidinediones / Glitazones
Decrease insulin resistance and
enhance insulin action in target
tissues
activate the nuclear peroxisome
proliferator activated receptor
(PPAR)
-Glucosidase Inhibitors
Decrease postprandial
hyperglycemia by slowing the rate
at which carbohydrates are
absorbed from the gastrointestinal
tract
Inhibitor of -glucosidase enzymes
(glycoamylase, sucrase, maltase and
dextranase)
Unlike the sulfonylureas, insulin,
and the thiazolidinediones, -
glucosidase inhibitors do not cause
weight gain
DRUG UPDATES
SYNTHETIC AMYLIN ANALOG
INCRETIN MIMETICS
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Thiazolidinediones / Glitazones
Troglitazone (Rezulin)
Withdrawn: idiosyncratic hepatic
toxicity several deaths worldwide
Rosiglitazone
Avandia
Pioglitazone
Actos
type II diabetic with a substantial
amount of insulin resistance
-Glucosidase Inhibitors
Acarbose (Precose)
Miglitol (Glyset)
SYNTHETIC AMYLIN ANALOG
Amylin is a hormone that is
cosecreted with insulin from -cells
following food intake
delays gastric emptying, decreases
postprandial glucagon secretion,
and improves satiety
Pramlintide
Synthetic amylin analog that is indicated
as an adjunct to mealtime insulin therapy
in patients with type 1 and type 2 diabetes
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INCRETIN MIMETICS INCRETIN MIMETICS

Incretin hormones are GLP-1 receptor agonists
responsible for 60% to 70% of Effects:
postprandial insulin secretion insulin secretion
Drugs: slow gastric emptying time
Reduce food intake by enhancing
Exenatide satiety (a feeling of fullness)
Liraglutide Decrease postprandial glucagon
secretion, and promote -cell
proliferation
S/E: pancretitis, weight loss

Dipeptidyl peptidase-4 inhibitors Sodiumglucose cotransporter 2 inhibitors

DPP-4 enzyme that sodiumglucose cotransporter 2

enactivates incretin hormone (SGLT2)
Drugs responsible for reabsorbing filtered
Alogliptin glucose in the tubular lumen of the
kidney
Linagliptin
Saxagliptin Drugs
Sitagliptin Canagliflozin
Dapagliflozin

Thyroid Gland
Thyroxine
Thyroid and Anti-thyroid 3,5,3,5 tetraiodothyronine
T4
Drugs Tri-iodothyronine
3,5,3-triiodothyronine
T3
ROWEL P. CATCHILLAR, MS Calcitonin

8

negative feedback control systems
hypothalamicpituitary-thyroid
axis (HPTA)
regulate the concentration of thyroid
hormones in the blood by controlling their
synthesis and secretion by the thyroid
gland
thyroid autoregulatory system
intrinsic to the thyroid gland and acts to
ensure that an adequate supply of iodide
is extracted from the blood and made
available for thyroid hormone synthesis
despite variations in dietary iodine intake
Requirement for Iodine
Iodine is naturally present in water
and soil, although some soils
contain very low amounts
seafood is a more reliable source of
iodine than crop plants
Min: 60 g of elemental iodine
thyroid hormone synthesis
at least 100 g/day
required to eliminate thyroid follicular cell
hyperplasia and thyroid enlargement (i.e.,
iodine deficiency goiter)
Iodide Transport by Follicular Cells and
Iodine Trapping Within Follicles
Iodide is actively transported into the cell
against both a concentration gradient and
a negative potential
At the basal (blood side) follicular cell
membrane, an iodide pump actively
transports Iodide from the extracellular
fluid (pertechnetate) into the cytoplasm
and concentrates Iodide within the
follicular cell
Follicular lumen: the Iodide is rapidly
oxidized in the presence of H2O2 and TPO
and incorporated into the tyrosyl residues
in newly formed Tg to form MIT or DIT
6/20/2016
BIOSYNTHESIS, STORAGE, SECRETION, AND
METABOLISM OF THYROID HORMONES
Thyroid epithelial cells
synthesize and secrete T4 and T3 and make up the
thyroid follicles
Thyroid follicles
functional units of thyroid glandular tissue
Hollow vesicles formed by a single layer of epithelial cells
that are filled with colloid.
T4, T3, and iodine are stored in the follicular colloid
T4 and T3
derived from tyrosyl residues of the protein thyroglobulin
(Tg)
Thyroid follicular cells
synthesize and secrete Tg into the follicular lumen
remove iodide (I-) from the blood and concentrate it
within the follicular lumen
Iodide Transport by Follicular Cells and
Iodine Trapping Within Follicles
Thyroid follicular cells
transport Iodide across the cell and
secrete the precursor protein, Tg, into the
follicular lumen
these cells contain an apical membrane
bound enzyme, thyroperoxidase (TPO), and
the enzymatic machinery to produce
hydrogen peroxide (H2O2)
(+) H2O2, TPO catalyzes the incorporation
of Iodide into tyrosyl residues of Tg to form
monoiodotyrosine (MIT) and diiodotyrosine
(DIT) and the coupling of these iodotyrosyl
residues to form T4 and T3
Iodine Transport & Trapping
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Coupling of Iodotyrosines to Form
Iodothyronines
Coupling: final step in thyroid
hormone synthesis is the of two
iodotyrosines within a single
peptide chain of Tg to form the
iodothyronine T4 or T3
T4: DIT + DIT coupling
T3: MIT + DIT coupling
Secretion of Thyroid Hormones
Endocytosis
macropinocytosis or micropinocytosis
stimulated by TSH uptake of
macropinocytotic or micropinocytotic
vesicles
Migration
endocytotic vesicles migrate from the
follicular cell apical membrane toward the
basal membrane
Fusion
Lysosomes (hydrolase- & protease-
containing) fuse with the endocytotic
vesicles to form lysoendosomes
Secretion of Thyroid Hormones
During thyroidal secretion, only
T4,T3 and a small amount of I
normally reach the circulation
no Tg, MIT, or DIT escapes
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Storage of Thyroid Hormones and Iodine in
Colloid
T4, T3, MIT, and DIT are stored
outside the cell in the follicular
colloid in peptide linkage within
the Tg molecules
Secretion of Thyroid Hormones
Hydrolysis
Within the lysoendosomes, Tg is
hydrolyzed to yield peptide fragments,
iodoamino acids (MIT and DIT),
iodothyronines (T4 and T3), and other
free amino acids
Release
T4 and T3 rapidly diffuse across the
basal plasma membrane into the
pertechnetate and eventually into the
circulation
Transport Proteins
Thyroxine-binding globulin
least abundant of the three major
transport proteins
Carries about 70% of the circulating T4
and T3 by virtue of its high affinity for the
two hormones
Transthyretin
Formerly known as thyroxine-binding
prealbumin
Binds only about 10 to 15% of the
hormones.
10

Transport Proteins
Albumin
Protein that has a binding affinity for a
multitude of small molecules
lower affinity for T4 and T3 than
transthyretin, but the high plasma
albumin concentration results in the
binding of about 15 to 20% of the
circulating thyroid hormones
Thyroid Hormone Activation and
Inactivation by Selenodeiodinases
Deiodination
T4 T3 conversion by the
(monodeiodination)
major pathway in the metabolism of
the thyroid hormones
Selenium plays an important role in
thyroid hormone economy
Requires deiodinase isoenzymes
Deiodination of T4
deiodinase (D1)
Happens in the liver (80%)
most of the T3 formed is exported into the
circulation
deiodinase (D2)
catalyzes T3 from T4 for local cellular
demands independent of circulating T3
Deiodinase (D3)
sole action of this enzyme is the removal
of iodide from the inner ring of
iodothyronines
6/20/2016
Cellular Uptake and Intracellular Binding of
T3 to Nuclear Thyroid Hormone Receptors
Cell entry of T4 & T3
carrier-mediated facilitated diffusion or
active transport
After gaining access to the cell
interior, T4 may undergo 5-
monodeiodination to yield T3.
The T3 thus mixes with T3
entering the cell from the plasma
and binds to nuclear TRs.
Thyroid Hormone Activation and
Inactivation by Selenodeiodinases
removal of an iodide from the
outer ring of T4 yields T3
affinity of nuclear TRs is much
higher for T3 than T4, outer ring
monodeiodination of T4 to yield T3
produces a more active metabolite
removal of an iodide from the inner
ring of T4 yields an inactive
metabolite, rT3
T3 and rT3 further deiodinations
to yield totally deiodinated
thyronine (T0)
MECHANISMS OF ACTION OF THYROID
HORMONES
genomic or nuclear
Modification of gene transcription, are
mediated only by T3
require at least several hours to detect
nongenomic
actions are generally rapid in onset
occur in response to T4 and some T4
metabolites (e.g., rT3,T3, and T2).
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Genomic Actions of Thyroid Hormones Nongenomic Actions of Thyroid Hormone

the lipophilic T3 binds to a involve interactions with
protein receptor to form a components of the cellular signal
complex and the hormone transduction pathways
receptor complex binds to an cyclic adenosine monophosphate (cAMP)
appropriate hormone response Phosphatidyl inositol
element on DNA to alter the protein kinases
transcription of specific genes

Thyroid Disorders HYPOTHYROID STATES

Hypothyroidism exposure of body tissues to a
Dietary iodine deficiency subnormal amount of thyroid
Hyperthyroidism hormone

Primary hypothyroidism Secondary hypothyroidism

inability of the thyroid gland itself to produce
and secrete sufficient quantities of T4 and T3
pituitary hypothyroidism
accounts for most cases of hypothyroidism consequence of impaired thyroid-
pituitary THS & THS levels stimulating hormone (TSH)
enlargement of the thyroid, or goiter
secretion
Causes: less common than primary
chronic autoimmune thyroiditis hypothyroidism
Hashimotos thyroiditis
the most common cause of primary hypothyroidism in undetectable or inappropriately
iodine-sufficient areas of the world serum TSH concentrations
Idiopathic hypothyroidism
spontaneous degeneration of glandular tissue Causes
thyroid ablation with radioactive iodine uptake (131I) hypopituitarism (e.g., pituitary tumor,
total or subtotal surgical thyroidectomy postpartum pituitary necrosis, trauma).
Drugs (e.g. lithium carbonate) Patients

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S/Sx: Infantile hypothyroidism /

Tertiary hypothyroidism Cretinism
hypothalamic hypothyroidism mental and growth retardation
Rare form of hypothyroidism feeding problems
levels of serum TSH
failure to thrive
impaired TRH stimulation of
pituitary TSH Constipation
due to a disorder that damages the hoarse cry
hypothalamus or interferes with
hypothalamic-pituitary portal blood somnolence
flow, thereby preventing delivery of
TRH to the pituitary

S/Sx: Adult hypothyroidism Myxedema Coma

Somnolence
slow mentation
Hoarseness
extreme manifestation of
muscle weakness
dryness and loss of hair slow return of muscle to the
untreated hypothyroidism
increased fluid in body neutral position after a
cavities tendon jerk
low metabolic rate Constipation
tendency to gain weight menstrual abnormalities
hyperlipidemia infertility
subnormal temperature myxedema (hard edema of
subcutaneous tissue with
cold intolerance increased content of
Bradycardia proteoglycans in the fluid)
systolic and diastolic goiter (i.e., enlargement of
pulse pressure the thyroid gland)

ANTI-HYPOTHYROIDISM DRUGS Levothyroxine Sodium

Levothyroxine Sodium naturally occurring levorotatory
Liothyronine Sodium isomer of T4
Liotrix Long half-life and DOA; once
Thyroid USP and Thyroglobulin daily dosing
preparation of choice for
maintenance of plasma T4 and
T3 concentrations for thyroid
hormone replacement therapy in
hypothyroid patients

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Liothyronine Sodium Liotrix

naturally occurring levorotatory 4:1 mixture of levothyroxine
isomer of T3
not used for maintenance thyroid
sodium and liothyronine sodium
hormone replacement therapy
because of its short plasma half-life
and duration of action
recommended only in special
situations
initial therapy of myxedema and
myxedema coma
short-term suppression of TSH in patients
undergoing surgery for thyroid cancer

Thyroid USP and Thyroglobulin Adverse effects

thyroid glands Hyperthyroidism
Bovine Goiter + heart problems (angina,
Ovine cardiac arrhythmias)
Porcine
Tg (Proloid)
frozen porcine thyroid glands.
rarely used today

THYROTOXICOSIS vs HYPERTHYROIDISM Types of Hyperthyroidism

Thyrotoxicosis
body tissues are exposed to supraphysiological Most common
concentrations of thyroid hormones
ingestion of excessive quantities of thyroid hormone Graves disease
not result from excessive thyroid gland secretion toxic multinodular goiter
hyperthyroidism
overactivity of the thyroid gland. Less common
Result from overproduction of hormone by the thyroid
itself toxic adenoma
Why differentiate? Postpartum thyroiditis
only conditions caused by hyperthyroidism respond to
treatment with agents that decrease iodine uptake,
thyroid hormone production, and the release of thyroid
hormone, and only these conditions may require
permanent radioactive or surgical ablation of the gland

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Graves disease toxic multinodular goiter

most common type of hyperthyroidism older patients typically presents
autoimmune disease characterized by the
presence of TSH receptorstimulating as longstanding asymptomatic
antibodies (TSAB) that bind to the TSH multinodular goiters
receptors (TSHR) on thyroid follicular cells
TSABs mimic TSH in stimulating growth of Functional autonomy of the
the thyroid gland (diffuse goiter) and by
causing an increase in synthesis and nodules develops over time by an
secretion of T4 and T3 unknown mechanism and causes
S/Sx:
Serum concentrations of T4,T3, and TSAB the disease to move from the
TSH levels are suppressed. nontoxic to the toxic phase
infiltrative ophthalmopathy (exophthalmos)
infiltrative dermopathy

Toxic adenoma S/Sx: Thyrotoxicosis

Plummers disease increased basal Nervousness
metabolic rate Insomnia
less common and caused by one or heat intolerance
more autonomous adenomas of the change in menstrual
thyroid gland Tachycardia pattern
Widened pulse frequent bowel
autonomously secreting tumors occur pressure movements
in an intrinsically normal thyroid gland cardiac arrhythmias (occasionally diarrhea)
and result from point mutations in the weight loss despite an
TSHRs on thyroid follicular cells leading skeletal muscle increased appetite
weakness
to constitutive activation of the TSHR in retraction of the upper
the absence of TSH muscle wasting eyelid (evident as the
Tremor presence of a rim of
Continued autonomous growth sclera between the lid
results in excessive secretion of T4 and Hyperreflexia
and the limbus) and lid
T3 and thyrotoxicosis emotional instability lag

Thyrotoxic Crisis, or Thyroid Storm ANTI-HYPERTHYROIDISM DRUGS

accelerated hyperthyroidism Goal: Reducing the excessive
extreme accentuation of synthesis and secretion of thyroid
thyrotoxicosis hormones
invariably fatal Strategies
inhibiting thyroidal synthesis and
secretion with antithyroid drugs
reducing the amount of functional
thyroid tissue
Both mentioned above

15

Beta-blockers
Rationale: many of the signs and
symptoms of hyperthyroidism
reflect increased cellular
sensitivity to adrenergic
stimulation
Propranolol (Inderal)
Most widely used -blocker
effective in ameliorating many of the
manifestations of thyrotoxicosis
May impair the conversion of T4 to T3
Thionamides
Propylthiouracil
Methylthiouracil (methimazole)
MOA: interfere with peroxidase-
catalyzed reactions
activity of the enzyme TPO (required for
the intrathyroidal oxidation of Iodide)
incorporation of Iodide into Tg
coupling of iodotyrosyl residues to form
thyroid hormones
thyroid hormone synthesis (and with time,
also secretion)
Propylthiouracil, but not methimazole, also
inhibits D1 (which deiodinates T4 to T3)
Iodine and Iodine-Containing Agents
Potassium iodide (KI)
transient inhibition of the uptake and
incorporation of Iodide into Tg (Wolff-
Chaikoff effect)
high doses: inhibit the secretion of
thyroid hormone and thyroid blood flow
ideal agent for treating severe
thyrotoxicosis or thyroid crisis when a
rapid decrease in plasma T4 and T3 is
desirable
6/20/2016
Thionamides
primary drugs used to decrease
thyroid hormone production
do not inhibit secretion of
stored thyroid hormone, and
therefore, when they are used
alone, their clinical effects are not
apparent until the preexisting
intrathyroidal store of thyroid
hormone is depleted
This may take several weeks
Thionamides
used in the management of
hyperthyroidism and thyrotoxic
crisis
S/E
Hypothyroidism
Most frequent: rash
Most serious: granulocytopenia and
agranulocytosis
Iodine and Iodine-Containing Agents
Potassium iodide (KI)
With continued treatment with KI alone, the
inhibition of thyroid secretion may also
diminish
Hypersecretion of thyroid hormone and
thyrotoxicosis may return at the previous or a
more severe intensity
iodide alone is not used for the management of
hyperthyroidism
(+) propylthiouracil
management of thyrotoxic crisis to rapidly inhibit
thyroid hormone secretion
Management of preoperative preparation of
patients about to undergo total or subtotal
surgical thyroidectomy
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S/E: Iodine-Containing Agents Oral Cholecystographic Agents

intrathyroidal reactions sodium ipodate (Oragrafin),
Low dose (<25 mg/day): iodine-induced
thyrotoxicosis (Jod-Basedows phenomenon) iopanoic acid (Telepaque)
High doses (50500 mg/day): iodide goiter or
hypothyroidism tyropanoic acid (Bilopaque),
Extrathyroidal reactions iocetamic acid (Cholebrine)
relatively rare and generally not serious
Rash (acneiform) MOA: inhibit D1 and D2
drug fever useful as adjunctive therapy with
Sialadenitis (inflammation of the salivary glands)
Conjunctivitis other antithyroid drugs by
Rhinitis promoting a rapid fall in the plasma
Vasculitis T3 concentration of the seriously
leukemoid eosinophilic granulocytosis thyrotoxic patient

Radioiodine Potassium Perchlorate

131I competitive inhibitor of
thyroid ablation thyroidal Iodide transport via the
Sodium Iodide Symporter (NIS)
Ablative effect through -
particle emissions, which destroy can cause fatal aplastic anemia
thyroid tissue and gastric ulcers

Lithium Carbonate Drug interactions

inhibits thyroidal incorporation Anti-thyroid drugs decreases the
of Iodide into Tg, as well as the catabolism of vitamin K
secretion of thyroid hormones (+) coumarin: decreased
employed for temporary control effectiveness of coumarin
of thyrotoxicosis in patients who (+) insulin or OHAs: increased
are allergic to both thionamides effectiveness of OHAs
and iodide KI is an expectorant
Bipolar disorders: increase the major ingredient in many cough
effect of anti-thyroid drugs medications

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Principal regulators of Ca & PO4 homeostasis

Parathyroid Hormone, Calcitonin, parathyroid hormone (PTH),

Vitamin D, and Other Compounds fibroblast growth factor 23
Related to Mineral Metabolism (FGF23), calcitonin, and vitamin
D (D3)
Hormonal target tissues
bone, kidney, and intestine
ROWEL P. CATCHILLAR, MS maintain serum calcium levels,
extracellular calcium levels, and
bone integrity

CALCIUM HOMEOSTASIS CALCIUM HOMEOSTASIS

Calcium
principal extracellular electrolyte
Extracellular calcium
critical component of signal transduction across the plasma
membrane
muscle contraction
secretion of neurotransmitters and hormones
action of growth factors, cytokines, and protein hormones.
Intracellular calcium
important cofactor in many enzymatic reactions
Plasma calcium
ionized (50%)
protein bound (46%)
complexed to organic ions (4%)
Total plasma calcium concentration (4.5 to 5.7
mEq/L)

Hormone Regulators of Calcium Hormone Regulators of Calcium

PTH
Increase the input of calcium and phosphorus from bone Calcitonin
into the serum
Stimulate bone formation reduce serum calcium and
reduces calcium but increases phosphorus excretion phosphorus by inhibiting bone
PTH=Calcium=P=Vit.D=Calcitonin
resorption and stimulating their renal
Vitamin D
Increase the input of calcium and phosphorus from bone excretion
into the serum
increases calcium and phosphate absorption from the Calcitonin = Ca = PTH
gut
Prohormone because further metabolized to 1,25-
dihydroxyvitamin D
decreases excretion of both calcium and phosphorus

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BISPHOSPHONATES
synthetic organic compounds
that are incorporated directly
into the hydroxyapatite of bone
and then inhibit osteoclastic
bone resorption
treatment of hypercalcemia,
osteoporosis, and Pagets disease
CLINICAL USES
Osteoporosis
estrogen replacement therapy (ERT),
along with calcium supplementation
and D3
CLINICAL USES
Pagets Disease (uncommon
disorder of bone characterized by
mixed lytic and sclerotic bone
changes)
Bisphosphonates
Calcitonin
6/20/2016
CLINICAL USES
Hypercalcemia of Malignancy
bisphosphonates (most effective
Pamidronate (Aredia)
Zoledronic acid (Zometa)
Calcitonin
Plicamycin
CLINICAL USES
Renal Osteodystrophy: chronic renal
failure (hyperphosphatemia,
hypocalcemia, secondary
hyperparathyroidism, and severe
metabolic bone disease)
Calcitriol
END..
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