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Tay Ju Lee MD
INTI
Diploma Pharmacology
The Endocrine System
We will be reviewing relevant
pathophysiology & drugs related to
 Pancreas
 Sex Hormones
 Uterus related Hormones
 Thyroid
 Adrenal gland
Today’s objectives

Pancreas & Pancreatic Islet Hormones

Insulin

Control of Blood Glucose

Diabetes Mellitus

Insulin Treatment

Oral Hypoglycemics
The Pancreas
Pancreas
is
exocrine
AND
endocrine
Pancreatic Islet of Langerhans Hormones
Four main cell types
secreting peptide
hormones
 A cells – glucagon
 B cells – insulin
 D cells – somatostatin
 PP cells – pancreatic
polypeptide (unknown
function)
Other hormones briefly…

Glucagon
 Fuel-mobilising hormone - gluconeogenesis and
glycogenolysis – increase blood glucose.
 Lipolysis and proteolysis.
 Increases the force of contraction of the heart.

Somatostatin
 Inhibits release of insulin and of glucagon
 Centrally inhibit growth hormones
 Octreotide is a long-acting analogue of somatostatin
○ Treatment of acromegaly & other several other endocrine
tumors
Clinical Uses of Glucagon
Glucagon can be given intramuscularly
or subcutaneously as well as
intravenously.
 Treatment of hypoglycaemia in
unconscious patients (who cannot drink)
 Treatment of acute cardiac failure
precipitated by β-adrenoceptor
antagonists

Insulin is required for all animal life
(excluding certain insects)
Insulin synthesis in B cells
Preproinsulin (RER)
Proinsulin (GA)
Insulin &
C- peptide
B
l
o
o
d
Factors stimulating insulin





B cells respond both to the absolute glucose
concentration and to the rate of change of blood
glucose.
Insulin release include amino acids (particularly
arginine and leucine),
Fatty acids
Parasympathetic nervous system
Peptide hormones for the gut





gastrin
secretin
cholecystokinin
gastric inhibitory polypeptide (GIP)
glucagon-like peptide (GLP)
Diagram
of factors
effecting
insulin
secretion
• Glucose enters B cells via
Glut-2 - glucokinase
makes glucose-6-phosphate
traps glucose In cell.
• As glucose metabolism
proceeds, ATP is produced
in the mitochondria.
• Intracellular ATP closes KATP
• Membrane depolarises – K +
cannot leave.
• Voltage-dependent calcium
channels open - Ca2+ influx
• Insulin exocytosis
B cell action
Glut-4 on muscle and fat cells
Actually….
it’s much
more
complicated
..\Pharmacody
namics &
Pharmacokine
tics
2011\Insulin
Signaling
(Signal
Pathways).flv
http://dolly.biochem.arizona.edu/Bioc462b_Honors_Spring_2009/abhik/MyoC1%20GLU
T4.html
Effects of insulin on carbohydrate, fat
and protein metabolism
Type of
metabolism
Carbohydrate
metabolism
Liver cells
Fat cells
Muscle
↓Gluconeogenesis
↑Glucose uptake
↑Glucose uptake
↓Glycogenolysis
↑Glycerol synthesis
↑Glycolysis
↑Glycolysis
↑Glycogenesis
Effects of insulin on carbohydrate, fat and protein metabolism
↑Glycogenesis
Fat metabolism
↑Lipogenesis
↓Lipolysis
↑Synthesis of
triglycerides
↑Fatty acid synthesis
↓Lipolysis
Protein metabolism ↓Protein breakdown -
↑Amino acid uptake
↑Protein synthesis
Why is Blood Glucose controlled?

BRAIN – glucose is obligatory source
of energy for the brain
 Physiological control reflects need to
maintain adequate fuel supplies
 Intermittent food intake
 Variable metabolic demands

Excess stored as glycogen(safe shortterm storage) or fat(long-term storage)
Two phase release to continuous
glucose infusion.
Long-term effects of insulin
Insulin has long-term actions via altered enzyme
synthesis.
 An important anabolic hormone during fetal
development
 Stimulates cell proliferation
 Implicated in somatic and visceral growth and
development
Mitogenic actions of insulin are of great concern in the
development of insulin analogues, because these are intended for
long-term use and because mammary tumours develop in rats
given one long-acting insulin analogue known as B10-asp insulin.
Diabetes Mellitus

Chronic metabolic disorder characterised by a
high blood glucose concentration hyperglycaemia
 fasting plasma glucose > 7.0 mmol/l,
 plasma glucose > 11.1 mmol/l 2 hrs postprandial

Caused by insulin deficiency, often combined
with insulin resistance.
It’s a Communication Breakdown
Diabetes is often described as
“starvation in the midst of plenty”
Extracellular glucose is abundant but the missing
insulin causes:
Pancreas cannot says to cells to “take glucose in”
 Muscle cells say “we cannot make glycogen”
 Hepatic cells think everyone’s starving “let’s make
more glucose”
 Fat cells “let’s burn fat”

Then…
Threshold for renal glucose reabsorption
exceeded - glycosuria (sugar in urine)
 Glycosuria causes osmotic diuresis –
polyuria
 Polyuria results in dehydration, thirst &
increased drinking - polydipsia
 No insulin - muscle wasting
 Diabetic ketoacidosis (DKA) due to
breakdown of fat in DM1 - emergency

Types of Diabetes

Type 1
 Autoimmune destruction of B cells - absolute
deficiency of insulin.
 Usually onset young (children or adolescent) notobese

Type 2
 Accompanied both by insulin resistance
 Impaired insulin secretion later.
 Associated with obesity and usually present in adult
life
Complications of DM

Macrovascular disease
 Due to dysfunction vascular endothelium
○ Oxygen-derived free radicals
○ Advanced glycation end (AGE) products
 Accelerated atheroma & thrombotic complication

Microvascular disease
 Retina – Blindness, Glaucoma
 Kidneys - DM commonest cause of chronic renal
failure (prevented by ACE & ARB)
 Peripheral nerve damage - Diabetic neuropathy
caused by active metabolites of glucose by aldose
reductase
Treatment overview
Type 1
 Normalizing plasma glucose prevents
diabetic complications.
Type 2
 Optimal control of BG rarely achieved
 Tight glucose control do not give as
much benefit as in Type 1 - important in
preventing microvascular complications
 Diet and increased exercise important
Insulin

Insulin used to be porcine or bovine but
is now almost entirely human (made by
recombinant DNA technology)

Porcine and bovine insulins differ from
human insulin in their amino acid
sequence, and are liable to elicit an
immune response.
Pharmacokinetics

Insulin is destroyed in the gastrointestinal
tract, and must be given parenterally
 Subcutaneous
 Intravenous
 Occasionally intramuscularly in emergencies.

Not currently used
 Inhaled insulin - not cost effective
 Intranasal insulin – 2010?
 Oral insulin – 2011?
Insulin Administration
Pharmacokinetics
Different formulations vary in timing, peak effect
and duration of action
 Soluble insulin – rapid and short
 Less soluble insulin (Insulin + protamine/zinc)
– longer acting
 Isophane insulin

Mixtures of different forms in fixed proportions
are available
Comparison of Human Insulins and Analogues
Insulin
Preparations
Onset of
Action
Duration of
Action
Peak
Lispro/Aspart
5-15 minutes
1-2 hours
3-5 hours
Human
Regular
30-60 minutes
2-4 hours
4-8 hours
Human
NPH/Lente
1-4 hours
4-12 hours
10-20 hours
Human
Ultralente
6-8 hours
Unpredictable
16-20 hours
Glargine
2-3 hours
Flat
~24 hours
The time course of action of any insulin may vary in different individuals, or at different times in the
same individual. Because of this variation, time periods indicated here should be considered general
guidelines only.
6-
Unwanted effects

Hypoglycaemia
 Treated with taking a sweet drink or snack

Rebound hyperglycaemia - Somogyi effect
 Follows insulin-induced hypoglycaemia in
early morning before breakfast
 Causes release of counter-regulatory
hormones.
 What would you do?

Allergy to human insulin - rare
Oral Hypoglycemics

Biguanides
 Metformin

Sulfonylureas and other drugs that
stimulate insulin secretion
 Tolbutamide, Glibenclamide, Nateglinide

Thiazolidinediones
 Rosiglitazone, Pioglitazone

α-Glucosidase inhibitor
 Acarbose
Biguanides
Sulfonylureas
Thiazolidinediones
α-Glucosidase inhibitor
Biguanides - Metformin
Biguanides lower blood glucose by
mechanisms that are complex and
incompletely understood.
 Increase glucose uptake and utilisation in
skeletal muscle (reduce insulin resistance)
 Reduce hepatic glucose production
 Does not cause hypoglycaemia
 Reduces LDL and VLDL
 Half-life of about 3 hours and is excreted
unchanged in the urine
Metformin – Unwanted effects
GI disturbance – anorexia, diarrhoea, nausea usually transient
 Lactic acidosis
 Contraindicated in patients with








Renal disease
Hepatic disease
Hypoxic pulmonary disease
Heart failure
Shock
Pregnancy
Long-term use may interfere with absorption
of vitamin B12
Metformin - Clinical Uses
Does not stimulate appetite - decreases
appetite
 First-line in obese Type 2 DM patients

 It
can be combined with
sulfonylureas, glitazones or insulin

Prevent onset
Biguanides
Sulfonylureas
Thiazolidinediones
α-Glucosidase inhibitor
Sulfonylureas
The sulfonylureas were developed
following the chance observation
that a sulfonamide derivative (used
to treat typhoid) caused
hypoglycaemia
Sulfonylureas - MOA
Principal action of sulfonylureas is on B
cells:
 Stimulating insulin secretion
 High-affinity receptors for sulfonylureas
are present on the KATP channels
 Block by sulfonylurea drugs of
KATP channel activation causes
depolarisation, Ca2+ entry and insulin
secretion.
Sulfonylureas – Pharmacokinetics
 Well
absorbed orally
 Most reach peak plasma concentrations
within 2-4 hours
 All bind strongly to plasma albumin and
are implicated in interactions with other
drugs.
 Most sulfonylureas (or their active
metabolites) are excreted in the urine
 Cross the placenta and enter breast milk
Drug
Relative
potencya
Duration of
action and
(half-life)
(hours)
Pharmacokinetic aspectsb
General
comments
Tolbutamide
1
6-12 (4)
Some converted in liver to weakly
active hydroxytolbutamide; some
carboxylated to inactive compound.
Renal excretion.
A safe drug; least
likely to cause
hypoglycaemia.
May decrease iodide
uptake by thyroid.
Contraindicated in
liver failure.
Glibenclamidec
150
18-24 (10)
Some is oxidised in the liver to
moderately active products and is
excreted in urine; 50% is excreted
unchanged in the faeces.
May cause
hypoglycaemia.
The active
metabolite
accumulates in renal
failure.
Glipizide
100
16-24 (7)
Peak plasma levels in 1 hour.
May cause
Most is metabolised in the liver to
hypoglycaemia.
inactive products, which are excreted Has diuretic action.
Only inactive
products accumulate
in renal failure. in
urine; 12% is
excreted in faeces
Sulfonylurea - Unwanted effects
Hypoglycaemia – can be severe & prolonged
 Stimulates appetite – causing weight gain
 GI upset

 Allergic
skin rashes can occur
 Bone marrow damage rare – can be severe
 Avoid in post-myocardial infarction patient
Sulfonylurea - Drug Interactions
Drugs that augment hypoglycaemic effect, due to
competition with CYP2C9 & albumin binding
 NSAIDs
 Coumadin
 Alcohol
 MAO inhibitors
 Antibacterial – sulfonamides, trimethoprim &
chloramphenical
 Uricosuric drugs – sulfinpyrazone
 Antifungals
Agents that decrease the action of sulfonylureas on
blood glucose include high doses of thiazide diuretics
and corticosteroids.
Other Insulin Secretagogues
Repaglinide and Nateglinide
 Stimulating insulin
 By blocking the sulfonylurea receptor
on KATP channels in pancreatic B cells
 Rapid absorption (55 minutes after an
oral dose)
 Elimination (half-life approximately 3
hours), lead to short duration of
action.
Biguanides
Sulfonylureas
Thiazolidinediones
α-Glucosidase inhibitor
Thiazolidinediones – PPARγagonist
Thiazolidinediones (or glitazones)
were developed following the
chance observation that a clofibrate
analogue, ciglitazone, which was
being screened for effects on lipids,
unexpectedly lowered blood
glucose
Glitazones have serious side-effects
Ciglitazone caused liver toxicity,
 Troglitazone – liver toxicity take off
market (90 cases of liver failure (70
resulting in death or transplantation)
before it was withdrawn in March, 2000)
 Rosiglitazone - 41,000 and 205,000
excess casualties may have resulted
from cardiovascular events
 Pioglitazone – Bladder cancer risk?

Glitazones - MOA

Glitazones are exogenous agonists that
 Bind to a nuclear receptor the peroxisome
proliferator-activated receptor-γ (PPARγ
agonist)
 producing products important in insulin
signaling e.g Glut-4.
 Differentiation of adipocytes
 Increases lipogenesis – update FA & glucose
 Promotes Na+ reabsorption
Glitazones - Effects
 Maximum
effect being achieved after
only 1-2 months of treatment
 Reduce hepatic glucose output
 Increase glucose uptake into muscle
 Reductions in circulating insulin and
free fatty acids – Triglycerides
 Weight gain 1-4 kg due to fluid
retention stabilizing in 6-12 mths
 Anemia due to haemodilution
Glitazones - Pharmacokinetics
Rosiglitazone and Pioglitazone
 Rapidly and nearly completely absorbed
 Peak plasma concentration <2 hrs
 99% plasma protein bound
 Elimination half-life <7 hrs parent drug
 Metabolised to metabolites with longer
half-lives by
 CYP3A4(150hrs) - urine
 CYP2C(24hrs) - bile
Glitazones – Unwanted effects
Hepatic toxicity
 Weight gain
 Fluid retention – precipitate/worsen
heart failure
 Headache, fatigue, GI disturbance
 Contraindicated in pregnant/breastfeeding women & in children.

α-Glucosidase inhibitors - Acarbose
An inhibitor of intestinal α-glucosidase
 Delays carbohydrate absorption,
reduce post-prandial blood glucose
 Unwanted effects - flatulence,
diarrhoea, abdominal pain & bloating
 May be coadministered with
metformin
Summary

Biguanides (e.g. metformin):
 have complex peripheral actions in the presence of residual
insulin, increasing glucose uptake in striated muscle and
inhibiting hepatic glucose output and intestinal glucose
absorption
 cause anorexia and encourage weight loss
 can be combined with sulfonylureas.

Sulfonylureas and other drugs that stimulate insulin
secretion (e.g. tolbutamide, glibenclamide,
nateglinide):
 can cause hypoglycaemia (which stimulates appetite and
leads to weight gain)
 are effective only if Bcells are functional
 block ATP-sensitive potassium channels in Bcells
 are well tolerated but promote weight gain.
Summary

Thiazolidinediones (e.g. rosiglitazone,
pioglitazone)
 increase insulin sensitivity and lower blood
glucose in type 2 diabetes
 can cause weight gain and oedema
 are peroxisome proliferator-activated
receptor-γ (a nuclear receptor) agonists.

α-Glucosidase inhibitor: acarbose
 reduces carbohydrate absorption
 causes flatulence and diarrhoea.
References





Lessons from the glitazones: a story of
drug development
Second time a farce, Rosiglitazone &
Regulators
http://www.fda.gov/Safety/MedWatch/Safet
yInformation/SafetyAlertsforHumanMedical
Products/ucm226257.htm
Insulin Therapy – Thomas Repas DO
Rang et al (2007) Rang & Dale’s
Pharmacology 6th Ed.