Endocrine pharmacology

Primary MMed Course

2006
Endocrine pharmacology
drugs used in diabetes
thyroid and anti-thyroid drugs
corticosteroid replacement therapy
Drugs used in diabetes mellitus

2006
Insulin
stimulates
uptake of glucose by liver, muscle, and adipose tissue
storage of glucose in the liver as glycogen and in adipose
tissue as triglycerides
storage of amino acids in muscle as protein
these pathways are enhanced by feeding
inhibits
breakdown of triglycerides, glycogen and protein, and the
conversion of amino acids to glucose in the liver
(gluconeogenesis)
these pathways are enhanced during fasting and in
diabetic states
Insulin receptor
a large transmembrane glycoprotein
composed of 2 subunits and 2 subunits
and a member of ligand-activated tyrosine
protein kinase
subunits are linked by disulphide bonds to form
a --- heterotetramer
the subunits are extracellular and contain the
insulin binding domain
the subunits are transmembrane proteins
that possess tyrosine protein kinase activity
Insulin - mechanism of action
insulin glucose
transporter
insulin glucose
receptor

translocation
Insulin
receptor
substrate 1
Insulin
receptor
substrate-PO4
Insulin - mechanism of action
binding of insulin to the subunits of the
receptor leads to receptors aggregation
and rapid internalisation of the receptors
aggregation is essential for signal transduction
after internalisation, the receptor may be
degraded or recycled back to the cell surface
Insulin - mechanism of action
activated receptor tyrosine protein kinase
initiates a cascade of events by first
phosphorylating a protein called insulin
receptor substrate-1 (IRS-1)
cascade of events include translocation of the
adipocyte and muscle cell glucose transporter
and attendant increase in glucose uptake
Treatment of hyperglycaemia
insulins
short-, intermediate-, and long-acting insulins
oral hypoglycaemic agents
sulphonylureas
biguanides
sulphonylurea & biguanide combination
thiazolidinediones
-glucosidase inhibitors
meglitinides
Preparations of insulin therapy
classified according to
duration of action
short-, intermediate-, and long-acting
species of origin
human (biosynthetic)
porcine
bovine
mixture of bovine and porcine
Preparations of insulin therapy
biosynthetic human insulin
produced by recombinant DNA
porcine insulin
differs from human insulin by one amino acid (alanine
instead of threonine) at the carboxy terminal of the B
chain (position B30)
bovine insulin
differs by 2 additional alterations of the A chain,
threonine and isoleucine, at position A8 and A10, are
replaced by alanine and valine, respectively
Preparations of insulin therapy
physicochemical properties
human insulin, produced by recombinant DNA, is
more soluble than porcine insulin in aqueous
solution owing to the presence of threonine (in
human insulin), with its extra hydroxyl group
all preparations supplied in neutral pH
improves stability and permits storage for several
days at a time at room temperature
Insulin therapy
unitage
doses and concentrations are expressed in units (U)
historical, when preparations of the hormone was impure,
it was necessary to standardise them by bioassay
one unit of insulin is equal to the amount required to
reduce the concentration of blood glucose in a fasting
rabbit by 2.5 mmol/L
all commercial preparations are supplied in solution or
suspension at a concentration of 100 U/ml
Short- or rapid-acting insulins
types
regular, crystalline zinc insulin dissolve in a buffer at
neutral pH
has rapid onset of action but shortest duration

after injection, there is a rapid fall in blood glucose

concentration, trough in 20-30 minutes

semilente insulin (prompt insulin zinc suspension), only
available as bovine or porcine insulins, rarely used now
has a longer duration of action

administration
subcutaneous, intramuscular, intravenous
Short- or rapid-acting insulins
with a single dose, without sustained infusion
the hormone is rapidly cleared
counter-regulatory hormones (glucagon, epinephrine,
norepinephrine, cortisol, and growth hormone) restore
plasma glucose to baseline in 2-3 hours
without normal counter-regulatory response, plasma
glucose will remain suppressed for many hours following
insulin bolus of 0.15 U/kg, because cellular actions of
insulin are prolonged far beyond its clearance from
plasma
Short- or rapid-acting insulins
infusions
for patients with ketoacidosis
for situations where requirements for insulin may change
rapidly
during perioperative period, labour and delivery, in

intensive care situations

buffered formulations are less likely to crystallise in the
tubing during slow infusion
in stable metabolic conditions
regular insulin usually given subcutaneously in combination
with intermediate- or long-acting preparations
Short- or rapid-acting insulins
side effects
local reactions and fat hypertrophy at injection
site
hypoglycaemia
Short- or rapid-acting insulins
insulin lispro
recombinant human insulin analogue
sequence of Lys (B28) and Pro (B20) has been
reversed
has shorter duration of action then soluble
insulin
convenient for patients to control plasma
glucose concentrations shortly before and
after a meal
 Properties of insulin preparations
Added Buffer Action in hours
Type Appearance protein pH 7.2-7.4 onset peak duration
Short or rapid
Regular clear none none 0.3-0.7 2-4 5-8sc
(crystalline) < 0.1 0.5iv
Semilente cloudy none acetate 0.5-1.0 2-8 12-16

Intermediate
NPH (isophane) cloudy protamine phosphate 1-2 6-12 18-24
Lente cloudy none acetate 1-2 6-12 18-24

Long or Slow
Ultralente cloudy none acetate 4-6 16-18 20-36
Protamine zinc cloudy protamine phosphate 4-6 14-20 24-36
Intermediate-acting insulins
formulated so that they dissolve gradually when
administered subcutaneously
duration of action is longer
types
neutral protamine Hagedorn (NPH) insulin (isophane
insulin suspension)
a suspension of insulin in a complex with zinc and

protamine in a phosphate buffer

lente insulin (insulin zinc suspension)
a mixture of crystallised (ultralente) and amorphous

(semilente) insulins in an acetate buffer, which

minimises the solubility of insulin
Intermediate-acting insulins
pharmacokinetics
human insulins have a more rapid onset and shorter
duration of action than do porcine insulins, due to
hydrophobic nature of human insulin

human and porcine insulins may interact differently

with protamine and zinc crystals

may create a problem with optimal timing for evening

therapy
side effects
similar to short-acting soluble insulins
protamine may cause allergic reactions
Long-acting insulins
types
ultralente insulin (extended insulin zinc
suspension)
protamine zinc insulin suspension
Long-acting insulins
duration of action
very slow onset and a prolonged relatively flat peak of
action, provide a low basal concentration of insulin
throughout the day
bovine-porcine ultralente has an even more prolonged
course of action than human ultralente insulin
long half-life makes it difficult to determine optimal
dosage, since several days are required before a steady
state concentration of circulating insulin is achieved
protamine zinc insulin rarely used because of its very
unpredictable and prolonged course of action
Receptor interactions
insulin secretion suppressed by
activation of K(ATP) channels, 2
adrenoreceptors
Oral hypoglycaemic agents

2006
 sulphonylurea drugs,
repaglinide
- (blocks, depolarises)
K+ channel

K+
glucose
ATP
transporter Ca++ channel

glucose metabolism Ca++

myosin insulin
filament granules

insulin
 O
R1 SO2NH-CNH
Sulphonylureas R2

all are substituted arylsulphonylureas

first generation
tolbutamide, acetohexamide, tolazamide, and
chlorpropamide
second generation
glibenclamide, glipizide, and gliclazide
third generation
glimepiride
Sulphonylureas mechanism of
action
stimulate insulin release by blocking an
ATP-sensitive K+ channel in pancreatic
cell membrane resulting in the opening of
voltage-gated Ca++ channels
influx of Ca++ elicits release of insulin from
storage vesicles
stimulate release of somatostatin, which
may suppress the secretion of glucagon
slightly
glucagon release from A cells is inhibited
and subsequently both muscle and liver
cells increase their sensitivity to insulin
inhibit hepatic clearance of insulin
Sulphonylureas mechanism of
action
glimepiride therapy associated with
increased plasma adiponectin
concentration, leading to
decreasing FFA and tissue triglyceride
content and improved insulin sensitivity
enhanced insulin-stimulated tyrosine
phosphorylation of signalling molecules
Chronic administration
plasma insulin concentrations decrease to
pretreatment concentrations, but plasma glucose
concentrations are low
possibly
low plasma glucose concentration allow circulating insulin
to have more pronounced effects on its target tissue;
and chronic hyperglycaemia per se impairs insulin
secretion
lead to down regulation of cell surface receptors for
sulphonylureas on the pancreatic cell, if administration
is discontinued, pancreatic cell responsiveness to acute
administration is restored
Sulphonylureas -
pharmacokinetics
absorption
all are effectively absorbed from the gut
hyperglycaemia per se inhibits gastrointestinal motility
and thus can retard absorption of the drug
decrease in presence of food
sulphonylureas with short half-lives may be more

effective when taken 30 minutes before eating

distribution
90%-99% bound to protein, especially albumin
plasma protein binding is least for chlorpropamide and
greatest for glibenclamide
Vd of most are about 0.2 L/kg
Sulphonylureas -
pharmacokinetics
clearance
all are metabolised in the liver and excreted in the urine
half-life of acetohexamide is short, but its active
metabolite has a half-life similar to tolbutamide and
tolazamide (4-7 hours)
chlorpropamide has a long half-life (24 to 48 hours),
metabolism of chlorpropamide is incomplete, 20% is
excreted unchanged
caution in renal or hepatic insufficiency

2nd generation agents are approximately 100 times more

potent than those in the first generation
half-lives are short (1.5 to 5 hours), but their

hypoglycaemic effects are evident for 12 to 24 hours

Sulphonylureas -
pharmacokinetics
side effects
hypoglycaemia
the longer the half-life (chlorpropamide,
glibenclamide), the more likely an agent will cause
hypoglycaemia
due to inhibition of metabolism or excretion
displacement from binding proteins by other
sulphonamides, clofibrate, dicumarol, salicylate,
phenylbutazone
Sulphonylureas -
pharmacokinetics
side effects
nausea, vomiting
cholestatic jaundice
agranulocytosis, aplastic anaemia,
generalised hypersensitivity reactions, dermatologic
reactions
alcohol-induced flush with chlorpropamide
chlorpropamide may induce hyponatraemia by
potentiating effects of anti-diuretic hormone on renal
collecting ducts
less frequent with glibenclamide and glipizide
Biguanides
metformin
main action appears to be
an increase in insulin action in peripheral tissues,
inhibition of gluconeogenesis
reduction in absorption of glucose from intestine
Biguanides
metformin
rarely associated with lactic acidosis
given alone or in combination with a
sulphonylurea improves glycaemic control and
lipid concentrations in patients who respond
poorly to diet control or to a sulphonylurea
alone
pharmacokinetics
absorbed mainly in small intestine
stable, does not bind to plasma protein
excreted unchanged in the urine
half-life of 1.3 to 4.5 hours
Biguanides
metformin
contraindicated in conditions that might
predispose to lactic acidosis
renal failure
hepatic disease
cardiac failure
myocardial infarction
shock
severe dehydration
history of lactic acidosis
chronic hypoxic lung disease
Biguanides
metformin
acute side effects
diarrhoea, abdominal discomfort, nausea, metallic
taste, and anorexia, which can be minimise by
increasing the dose gradually and taking with meals
chronic side effects
decreased absorption of B12 and folate with chronic
administration
Biguanides
phenformin
withdrawn in 1970s due to association with
lactic acidosis
Other hypoglycaemic agents
thiazolidinediones
ciglitazone, pioglitazone, rosiglitazone
augment insulin action in insulin-resistance by
stimulating peroxisome proliferator-activated
receptors (PPARs) involved in transcription of insulin-
responsive genes resulting in increased number of
glucose transporters and sensitisation of target
tissues to insulin, with increased glucose uptake in
liver, skeletal muscle, and adipose tissue, and
decreased gluconeogenesis
do not cause hypoglycaemia in diabetic or
normal persons
Other hypoglycaemic agents
-glucosidase inhibitor (acarbose)
reduce post-prandial plasma glucose concentrations
reduce intestinal absorption of starch, dextrin,
disaccharides by inhibiting the action of intestinal brush
border -glucosidase
competitively inhibit glucoamylase and sucrase, but has
weak effects on pancreatic -amylase
associated with a significant reduction in the risk of
cardiovascular disease and hypertension
poorly absorbed in gut
side effects
malabsorption, flatulence, abdominal bloating, diarrhoea
Other hypoglycaemic agents
meglitinides
repaglinide (Prandin) and nateglinide (Starlix),
rapid onset, short acting non-sulfonylurea
insulin secretogogues which stimulate the
glucose-dependent release of insulin from
functioning pancreatic cells, by the same
mechanism as sulphonylureas
extremely expensive, the cost is 3-5 times that
of the commonly used sulfonylurea agents
Other hypoglycaemic agents
repaglinide
closes ATP-dependent potassium channels in
the pancreatic B cell membrane by binding at
specific sites; potassium channel blockade
depolarizes the B cell, which leads to an opening
of calcium channels; the resulting increased
calcium influx induces insulin secretion
the ion channel mechanism is highly tissue
selective with low affinity for heart and
skeletal muscle
Other hypoglycaemic agents
repaglinide
rapid onset and short duration
after oral administration, rapidly and completely
absorbed from the gastrointestinal tract; peak plasma
drug levels (C max ) occur within 1 hour (T max ),
mean absolute bioavailability is 56%, more than 98%
bound to albumin
rapidly eliminated from the blood stream with a half-
life of approximately 1 hour
Other hypoglycaemic agents
repaglinide
metabolism
phase I reaction: completely metabolized by oxidative
biotransformation (CYP 3A4), N-dealkylation to form
an oxidized dicarboxylic acid, followed by oxidation to
form aromatic amine (60%)
II reaction: direct conjugation with glucuronic acid to
form inactive acyl glucuronide
90% excreted in the faeces, 8% in the urine,
0.1% of the dose is cleared in the urine as
parent compound, less than 2% of parent drug
recovered in faeces.
Duration of action of oral hypoglycaemic drugs

Drugs duration (h) Drugs duration (h)

Sulphonylureas Thiazolidinediones
chlorpropamide up to 60 pioglitazone 15-24
tolbutamide 6-12 rosiglitazone 6>24
glipizide 10-24 -glucosidase inhibitors
Miglitinides acarbose 3-4
repaglinide 1-3 miglitol 3-4
Biguanides
metformin 10-12
Treatment of hypoglycaemia

glucagon
diazoxide

2006
Glucagon
hormone from pancreatic A cells
increases blood sugar concentration via
increased cAMP
used in hypoglycaemia and as an antidote
for beta-blocker overdose
commercial preparation
extracted from bovine and porcine pancreas
sequence is identical to human glucagon
Glucagon - mechanism of action
Liver 6-phosphofructo-2-kinase/
fructose-2,6-biphosphatase
+P
ATP cAMP -
ketogenesis glycolysis
protein kinase

transcription of gene for

phosphorylase glycogen synthase
phosphoenolpyruvate
+P +P
carboxykinase
-
glycogenolysis glycogen synthesis
gluconeogenesis

glucose
Glucagon
other actions
adipose tissue - stimulates adenylyl cyclase and
increase lipolysis
heart - increases contractility
gastrointestinal tract - relaxation
Glucagon
indications
treat severe hypoglycaemia when intravenous
glucose is not available
1mg iv / im /sc, effect within 10 minutes, but duration
transient, may be inadequate if hepatic glycogen
stores are depleted
used by radiologist for relaxation of the gut
treat spasm associated with acute
diverticulitis, biliary tract disorders, sphincter
of Oddi
treat impaction of oesophagus and
intussusception
Glucagon
indications
diagnosis test for phaeochromocytoma
releases catecholamines
used as cardiac inotrope for treatment of
cardiogenic shock, in presence of -receptor
down regulation
Glucagon
Diazoxide
antihypertensive, antidiuretic
benzothiadiazine derivative with potent
hyperglycaemic actions
action
inhibits insulin secretion
inhibit peripheral glucose utilisation by muscle
stimulates hepatic gluconeogenesis
Diazoxide
mechanism of action
interacts with an ATP-sensitive K+ channel and
either prevents its closing or prolongs the open
time
this effect is opposite to that of sulphonylureas
does not inhibit insulin synthesis, and thus
there is an accumulation of insulin within
pancreatic cell
Thyroid and thyroid inhibitors

2006
Thyroxine - 3,5,3,5-
tetraiodothyronine

5 5
I I

HO O CH2CHCOOH

NH2
I I
3 3
Sites of action of some antithyroid drugs

thyroid gland
peroxidase
I- I- Io
-
I- transport iodides, MITDITT3T4
thioamides -
proteolysis iodides

peripheral
tissues
T3,T4 T3,T4
iodides, -
thioamides, blood
T3
beta-blockers
Thyroxine - metabolic pathways
DIT MIT, DIT

T3 rT3 T2s T1s ether cleavage T2s T1s

deiodination deiodination
T4 T3
conjugation conjugation
oxidative
T4 sulphate T3 sulphate
decarboxylation
T4 glucuronide T3 glucuronide

T4 pyruvic acid T3 pyruvic acid

Tetraiodothyroacetic acid Triiodothyroacetic acid

3,5,3,5 substitution and potency
5 5
I I
less potent
HO O CH2CHCOOH

NH2
I I
3 3
5
I

more potent
HO O CH2CHCOOH

NH2
I I
3 3
Thyroid hormone replacement
therapy
thyroxine (levothyroxine) sodium
treatment of choice for maintenance therapy
liothyronine sodium
similar action to thyroxine, but rapidly
metabolised
effects develop after a few hours and last for
24 to 48 hours
use in severe hypothyroid states when rapid
response is desired
intravenous administration for hypothyroid coma
 Mechanism of action
1. dissociate from binding protein in blood
2. entry of hormone
3. hormone interacts with intracellular
receptor
4. activation of H:R complex 3,4 6
5. translocation of H:R into nucleus
6. binding of H:R to acceptor site on 5
2 3,4 7
chromatin 1
7. transcription of gene (RNA)
8. protein synthesis
8
9. biological response 9
Thyroxine
absorption
only 50-80% oral dose is absorbed
occurs in small intestine and is variable and
incomplete
absorption increased if taken on an empty
stomach
interference with absorption by sucralfate,
cholestyramine resin, iron supplements, and
aluminium hydroxide
Thyroxine
considerations
half-life of thyroxine (7 days)
a new steady state concentration of thyroxine will not
be achieved until 4-6 weeks after a change in dose
determination of serum TSH concentration not within
4-6 weeks
aim to achieve TSH concentration in normal
range
over-replacement of thyroxine suppresses TSH
concentration to subnormal range, and may lead to
osteoporosis, and cardiac dysfunction
death from arrhythmias
Thyroid hormone replacement
therapy
side effects
anginal pain, arrhythmias, palpitation,
tachycardia
skeletal muscle cramps, muscle weakness
vomiting, diarrhoea
tremors, restlessness, excitability, insomnia,
headache, flushing, sweating
excessive loss of weight
Thyroid hormone replacement
therapy
considerations
in pregnancy, dose need to be increased
increased serum concentration of thyroid-binding
globulin induced by oestrogen
pregnancy may unmask hypothyroidism in patients
with pre-existing auto-immune thyroid disease or
iodine deficiency
Thyroid inhibitors
anti-thyroid drugs
interfere directly with synthesis of thyroid
hormone
thioamides (propylthiouracil)

ionic inhibitors
block the iodide transport mechanism
thiocyanate, perchlorate (ClO ), fluoborate
4-

(BF4-), lithium
Thyroid inhibitors
high concentration of iodine
inhibit the incorporation of iodine into thyroglobulin
molecule
decreases the release of thyroid hormones from the
gland
reducing vascularity of the gland before thyroidectomy
radioactive iodine, 131I

damages the gland with ionising radiation

iodinated radiocontrast media, ipodate
blocks conversion of T4 to T3
reduces release of thyroxine from the gland
rapid and effective treatment of thyroid storm
Adjuvant therapy with thyroid
inhibitors
categories
inhibitors of peripheral deiodination of
thyroxine to active hormone, triiodothyronine
-blockers
Ca++ channel blockers
Anti-thyroid drugs
thioamides
propylthiouracil (prototype), methimazole
aniline derivatives
majority are sulphonamides
polyhydric phenols
resorcinol
other drugs with anti-thyroid effects
thiopentone, sulphonylureas, dimercaprol,
aminoglutethimide, lithium salts, amiodarone
Thioamide drugs
mechanism of action
inhibit thyroid peroxidase, only when the haem
of the enzyme is in the oxidised state
inhibit oxidation of iodide ion and iodotyrosyl groups
to the active state
interfere with incorporation of iodine into tyrosyl
residues of thyroglobulin
inhibit coupling of iodotyrosyl residues (MIT, DIT) to
form iodothyronines (T4, T3)
deplete iodinated thyroglobulin store
inhibit peripheral deiodination of thyroxine to
tri-iodothyronine
Thioamide drugs
propylthiouracil
methimazole
carbimazole
a carbethoxy derivative of methimazole
a prodrug, metabolised to methimazole
Pharmacokinetic features
propylthiouracil methimazole
plasma protein binding 75% nil
plasma half-life 75 minutes 4-6 hours
volume of distribution 20 litres 40 litres
metabolism of drug in
severe hepatic disease normal decreased
severe renal disease normal normal
transplacental passage low more
concentrations in breast milk low more
 Inhibition of organification of
iodine in thyroid gland

8 propylthiouracil 24 methimazole
duration of effect (hours)

duration of effect (hours)

(more potent)
7 x
20
6
5 16
4 12
3 x 8
2
1 4
x
0 0
100 200 300 400 500 0.5 5 10 15 20 25
dose (mg) dose (mg)
Thioamide drugs
side effects
agranulocytosis
most serious complication
with methimazole, it is dose-dependent
because agranulocytosis can develop rapidly, periodic
white cell count is of little help
sore throat, fever usually herald onset
reversible upon discontinuation of the drug and
institution of recombinant human granulocyte colony-
stimulating factor (G-CSF)
Thioamide drugs
side effects
granulocytopenia
purpuric, urticarial papular rash
often subsides spontaneously
either administer anti-histamine or change to another drug
pain, stiffness in joints, paraesthesia, headache, nausea,
skin pigmentation, loss of hair
drug fever, hepatitis, nephritis
rare
abnormal liver function tests with higher doses of
propylthiouracil
Ionic inhibitors
agents are monovalent, hydrated anions, of a size
similar to that of iodide
thiocyanate
inhibits organification of iodine
produced following enzymatic hydrolysis of certain plant
glycosides (cabbage), cigarette smoking, administration
of sodium nitroprusside
perchlorate (ClO4-)
ten times as active as thiocyanate, treatment of Graves
disease and amiodarone-induced thyrotoxicosis
can cause fatal aplastic anaemia
Ionic inhibitors
fluoborate (BF4-)
as effective as perchlorate
lithium
decreased secretion of thyroxine and
triiodothyronine
Iodide - mechanism of action
limit its own transport
acute inhibition of synthesis of iodotyrosines and
iodothyronines (the Wolff-Chaikoff effect)
transient, 2-day effect
observed only above critical concentrations of
intracellular rather than extracellular concentration of
iodide
may involve inhibition of inositol phosphate signalling
pathways within the thyrocyte
escape from inhibition is associated with adaptive
decrease in iodide transport and lowered intracellular
iodide concentration
Iodide - mechanism of action
inhibition of release of thyroid hormone
action is rapid and efficacious in severe
thyrotoxicosis
effect is exerted directly on thyroid gland
can affect both euthyroid and hyperthyroid
patients
inhibit thyrocyte proliferation
mediated by actions of iodide on crucial
regulatory points in cell cycle
Iodide
indications
preoperative preparation for thyroidectomy
together with anti-thyroid drugs and
propranolol, for treatment of thyrotoxic crisis
protect the thyroid from radioactive iodine
fallout following a nuclear accident
uptake of radioactive iodine is inversely proportional
to the serum concentration of stable iodine,
administration of 30 to 100 mg of iodide daily will
markedly decrease the thyroid uptake of
radioisotopes of iodine
Iodide - side effects
sensitivity to iodide or to organic preparations
that contain iodine when administered
intravenously
may occur immediately or several hours after
administration
angioedema, swelling of larynx
multiple cutaneous haemorrhages
manifestations of serum-sickness type of
hypersensitivity such as fever, arthralgia, lymph node
enlargement, eosinophilia, thrombotic thrombocytopenia
purpura, fatal periarteritis nodosa
Iodide - side effects
iodism (chronic intoxication with iodide)
simulates a head cold
unpleasant brassy taste, burning in the mouth and throat,
soreness of teeth and gums, increased salivation, coryza,
sneezing, irritation of eyes with swelling of eyelids,
frontal sinus headache, productive cough from irritation
of mucous glands of respiratory tract, pulmonary oedema
parotid and submaxillary glands may become enlarged and
tender, inflammation of pharynx, larynx, and tonsils
Iodide - side effects
iodism (chronic intoxication with iodide)
skin lesions, acneform, fatal eruptions
(ioderma)
gastric irritation, diarrhoea, sometimes bloody
fever, anorexia, depression
symptoms resolve when iodide is withdrawn
renal excretion of I- can be increased by
procedures that promote Cl- excretion
osmotic diuresis, chloruretic diuresis, salt loading
Radioactive iodine

131I

half-life of 8 days, over 99% of radioactivity

expanded within 56 days
radioactive emissions include both rays and
particles
123 I
primarily a -emitter with a half-life of only 13
hours, expanded within 91 hours
permits brief exposure to radiation during
thyroid scans
131I - effects on thyroid gland
rapidly and efficiently trapped by thyroid
gland, incorporated into iodoamino acids,
deposited in the colloid of the follicles, and
from which it is slowly liberated
destructive particles originate within the
follicles and act almost exclusively upon
the parenchymal cells of the thyroid with
little damage to surrounding tissue
necrosis of follicular cells, followed by
disappearance of colloid and fibrosis of the
gland
131I - disadvantages
high incidence of delayed hypothyroidism
eventual rate exceeds 80%
possibly a natural progression of Graves disease
long period of time required before
hyperthyroidism is controlled
worsening of ophthalmopathy after treatment
controversial
thyroid storm
extremely rare
131I - contraindications
pregnancy
first trimester, radiation on fetal tissues
after first trimester, fetal thyroid would
concentrate the isotope and suffer damage
Corticosteroid replacement
therapy

2006
Corticosteroid replacement
therapy
adrenal cortex normally secretes
hydrocortisone (cortisol) which has
glucocorticoid activity and weak
mineralocorticoid activity
aldosterone
in deficiency states
physiologic replacement best achieved with
combination of hydrocortisone and
fludrocortisone (for mineralocorticoid effect)
Corticosteroid replacement
therapy
indications
acute adrenocortisol insufficiency
hypopituitarism
adrenalectomy
hypophysectomy
Corticosteroid replacement
therapy
immediate effects
via interaction with specific membrane-bound
receptor proteins in target tissues
Corticosteroid replacement
therapy
delayed effects
via interaction with specific nuclear receptor
proteins in target tissues to regulate the
expression of corticosteroid-responsive genes
(by increasing or decreasing transcription of
target genes), thereby changing the array of
proteins synthesized by the various target
tissues
time is required for changes in gene expression and
protein synthesis, beneficial effects are not
immediate, but become apparent after a few hours
Corticosteroid receptors, GR
members of superfamily of structurally
related proteins, the nuclear proteins
transduce the effects of small hydrophobic
ligands (steroid hormone, thyroid hormone,
vitamin D and retinoids)
2 domains:
ligand-binding dormain at the carboxy terminus
2 zinc-binding dormains (zinc-fingers) - a region
essential for the interaction of the receptor
with specific DNA sequences
Glucocorticoid receptor, GR
resides predominantly in the cytoplasm in
an inactive form, until it binds the
glucocorticoid steroid ligand
steroid binding results in receptor activation
and translocation to the nucleus
the inactive GR is found as a complex with
other proteins, heat shock protein (HSP)
90, HSP 70, and immunophilin
immunophilin binds the immunosuppressive
agents cyclosporine and tacrolimus
Glucocorticoid receptor, GR
HSP90
a member of the heat shock family of stress-induced
proteins
through interactions with steroid-binding dormain, may
facilitate folding of GR into an appropriate conformation
that is believed to be essential to ligand binding
following binding of steroid ligand,
HSP90 and other associated proteins dissociate, and the
GR is directed into the nucleus, where it can interact
with specific DNA sequences with the regulatory regions
of the affected genes
Glucocorticoid receptor, GR
the short DNA sequences that are
recognised by the activated GR are termed
glucocorticoid-responsive elements (GREs)
provide specificity to the induction of gene
transcription by glucocorticoids
may be negatively regulated, an important
component of negative feedback regulation
Glucocorticosteroids
-mechanism of 1
action
2
1. glucocorticoid steroid (S)
enter cell
2. S interacts with GR 3
3. dissociation of heat shock
protein (HSP) and
immunophilin (IP) followed by
conformational change of GR 4
4. GR translocation into nucleus
5. binding to glucocorticoid 6
responsive element (GRE)
5
6. activation of transcription of
target gene
7. splicing and removal of 7
introns and assembly of
exons into mRNA
8. protein synthesis
Mineralocorticoid receptor, MR
similar to GR
MR is a ligand-activated transcription factor
binds to similar or identical hormone-responsive elements
associated with HSP 90,
activates the transcription of discrete sets of genes
within target tissues
but
the principal sites are in kidneys (distal cortical tubule,
cortical collecting duct), colon, salivary glands, sweat
glands, and hippocampus
Relative potencies and equivalent anti-
inflammatory doses of corticosteroids
anti- sodium
inflammatory retention biological equivalent
Compound potency potency half-life (h) dose (mg)

cortisone 0.8 0.8 8-12 25

hydrocortisone 1 1 8-12 20
fludrocortisone 10 125 8-12 #

prednisone 4 0.8 12-36 5

prednisolone 4 0.8 12-36 5
6-methylprednisolone 5 0.5 12-36 4
triamcinolone 5 0 12-36 4

betamethasone 25 0 36-72 0.75

dexamethasone 25 0 36-72 0.75

# not for glucocorticoid effects

Glucocorticoid therapy
treating diseases that result from
undesirable immune reactions
humoral immunity such as urticaria
cellular immunity such as transplant rejection
Anti-inflammatory and
immunosuppressive effects
inhibit production by multiple cells of factors that
are critical in generating inflammatory response
decrease release of vasoactive and chemoattractive
factors
diminished secretion of lipolytic and proteolytic enzymes
decreased extravasation of leukocytes to areas of injury
decrease number and alter immune responses of
circulating lymphocytes
decreased fibrosis
 Glucocorticoid effects on
macrophages and monocytes
arachidonic acid and its production inhibited by
derivatives glucocorticoid induction of
(prostaglandins, and lipocortin that inhibits
leukotrienes) phospholipase A2
cytokines: interleukin production and release
(IL)-1, IL-6, TNF- blocked, resulting in
inhibition of:- activation of
T cells, and stimulation of
fibroblast proliferation
acute phase reactants production blocked, reducing
the third component of
complement
 Glucocorticoid effects on
endothelial cells
endothelial leukocyte inhibition of ELAM-1 and
adhesion molecule-1 ICAM-1 which are critical
(ELAM-1), and for leukocyte localisation
intracellular adhesion
molecule-1 (ICAM-1)
arachidonic acid and its
derivatives same as for macrophages
cytokines: IL-1 and monocytes
acute phase reactants
 Glucocorticoid effects on
basophils
histamine IgE-dependent release
leukotriene C4 inhibited
 Glucocorticoid effects on
fibroblasts
arachidonic acid and its same as for macrophages and
derivatives monocytes
also suppress growth factor-
induced DNA synthesis and
fibroblasts proliferation
 Glucocorticoid effects on
lymphocytes
cytokines (IL-1, IL-2, same as for macrophages and
IL-3, IL-6, TNF-, monocytes
granulocyte-
macrophage-colony
stimulating factor
(GM-CSF),
interferon-)
Glucocorticoids -
pharmacokinetics
absorption
hydrocortisone and congeners including
synthetic analogues are effective when taken
orally
water-soluble esters of hydrocortisone and its
synthetic analogues can be administered
intravenously to achieve high concentrations of
drug rapidly in body fluids
prolonged effects are obtained by
intramuscular injections
Glucocorticoids -
pharmacokinetics
absorption
minor change in chemical structure may
markedly alter rate of absorption, time of
onset of effect and duration of action
also absorbed systemically from sites of local
administration (synovial spaces, conjunctival
sac, skin, respiratory tract)
prolonged administration or absorption from a large
skin surface area of application may be sufficient to
cause systemic effects, including suppression of HPA
axis
Glucocorticoids -
pharmacokinetics
distribution
90% or more of cortisol is bound to plasma
proteins
corticosteroid-binding globulin (CBG, also called
transcortin), an -globulin secreted by the liver that
has relatively high affinity for steroids, but low total
binding capacity
albumin, low binding affinity but relatively large
binding capacity
only unbound fraction can enter cells to
mediate corticosteroid effects
Glucocorticoids -
pharmacokinetics
distribution
at higher steroid concentrations, protein-
binding capacity is exceeded
corticosteroids compete with each other for
binding sites on CBG
CBG has relatively high affinity for cortisol and most
of its synthetic congeners, but low affinity for
aldosterone and glucuronide-conjugated steroid
metabolites
during pregnancy or oestrogen treatment, CBG,
total plasma cortisol and free cortisol increase
several fold
Glucocorticoids -
pharmacokinetics
metabolism
all biologically active adrenocortical steroids
and synthetic analogues have a double bond in
the 4,5 position and a ketone group at C3
phase I reactions
reduction of 4,5 double bond occurs at both hepatic
and extra-hepatic sites, yielding inactive compounds;
subsequent reduction of the 3-ketone substituent to
3-hydroxyl derivative forming tetrahydrocortisol
occurs in the liver
Glucocorticoids -
pharmacokinetics
metabolism
phase II reactions
most of the A ring-reduced steroids are conjugated
through the 3-hydroxyl group with sulphate or
glucuronide in the liver and to a lesser extent, in the
kidney
elimination
resultant sulphate esters and glucuronides are
excreted in the urine
neither biliary nor faecal excretion is of
quantitative importance
Glucocorticoids -
pharmacokinetics
metabolism
11-hydroxysteroid dehydrogenase
in mineralocorticoid-responsive tissues, protects the
mineralocorticoid receptor by oxidising the 11-
hydroxyl group of cortisol to cortisone, an inactive
metabolite
in liver, one of the 11-OH-steroid dehydrogenase
isozymes reduces synthetic steroids with 11-keto
substituent (such as cortisone and prednisone), to
11b-OH derivative, making the compound biologically
active
Structural activity relationships
Structural activity
relationships
essential for
glucocorticoid mineralocorticoid
Ring activity activity
4,5 double bond A
3-ketone group A
11b-OH group C
OH group at C21 D
Structural activity
relationships
increases
glucocorticoid mineralocorticoid
Ring activity activity
17-OH group D
1,2 double bond A
fluorination at 9 B
CH3 at C16 D 0
CH3 at C6 B (for
6-methylcortisol,
but not for
6-methylprednisolone)
Structural activity
relationships
increase lipophilicity to enhance topical to
systemic potency ratios
introduction of acetonide between hydroxyl
groups at C16, C17
esterification of the hydroxyl group with
valerate at C17
esterification of hydroxyl groups with
propionate at C17 and C21
substitution of hydroxyl group at C21 with
chlorine
Structural activity
relationships
achieve local glucocorticoid activity while
minimising systemic effects by formation
of analogues that are rapidly inactivated
following absorption
C21 carboxylate or carbothioate glucocorticoid
esters, which are rapidly metabolised to
inactive 21-carboxylic acid
Glucocorticoids - side effects
withdrawal of therapy
acute adrenal insufficiency
Glucocorticoids - side effects
continued use of supraphysiological doses
fluid and electrolyte abnormalities,
hypertension, hyperglycaemia
increased susceptibility to infection
osteoporosis, avascular necrosis of femoral
head
myopathy, muscle wasting
behavioural changes: serious paranoid state,
depression, euphoria
cataracts
Glucocorticoids - side effects
continued use of supraphysiological doses
suppression of hypothalamus-pituitary-adrenal
axis, and adrenal atrophy
growth arrest (in children)
Cushings syndrome: fat redistribution, striae,
acne, ecchymoses, hirsuitism
peptic ulceration
taken during pregnancy, may affect fetal
adrenal development
Mineralocorticoids - side
effects
hypertension, sodium and water retention,
potassium loss
most marked
fludrocortisone
significant
cortisone, hydrocortisone, corticotrophin,
tetracosactrin
slight
methylprednisolone, prednisolone, prednisone,
triamcinolone
negligible
glucocorticoids, betamethasone, dexamethasone