Pharmacology of Hormones Endocrine Pancreas

1
Pharmacology of HormonesEndocrine Pancreas

• Martin Sterba, PharmD.,PhD.
• Dept. of Pharmacology

2
Glucagon

• Polypeptide hormone (29AA)
• Secreted by pancreatic a-cells
• Secretion is
• stimulated by low plasma glucose, high plasma
  AA
• secretion is inhibited by high plasma glucose,
  insulin, somatostatin
• Mechanism of Action binds on Glucagon receptors
  (GPCR type) on hepatocytes ? increased cAMP ?PK A
  ?? glycogen phosphorylase ?release of glucose
  from glycogen
• Metabolic effects catabolic hormone - increased
  glycogenolysis and gluconeogenesis result in
  increased plasma glucose levels

3
Pharmacological use of glucagon

• All parenteral routes of administration are
  feasible
• i.v., i.m., s.c.
• Main indication vital first aid in hypoglycemia
• When patient is unconsciousness (cannot take
  glucose syrup orally)
• When i.m./s.c. route of drug administration is
  needed e.g., acute first aid provided by
  non-medical personnel or i.v. route is not
  available
• The response is relatively rapid (within 2 min
  after i.v. glycemia increases promptly), duration
  of action 10-20 min.

4
Pharmacological use of glucagon

• Other indications
• treatment of b-blocker-induced overdose
  associated with severe bradycardia, heart failure
  or hypotension
• indirect antagonisms of decreased cAMP leads to
  restoration of contractility a normal HR
• High doses needed!
• Compare half-lives for b-blockers (2-12h) and
  glucagon (5-15min)
• used empirically in emergency setting to overcome
  severe myocardial depression non-responding to
  standard treatment
• Adverse effects
• generally acceptable
• headache, nausea, hyperglycemia

5
Insulin and pharmacology of diabetes mellitus

• Insulin biochemistry
• polypeptide hormone (51AA)
• Synthesized and released by
• ß-cells representing 60-80
• of Islet of Langerhans cells
• Biosynthesis in following steps
• 1. preprosinsulin
• 2. proinsulin
• 3. insulin
• C-peptide plasma marker
• of insulin secretion

6
Factors regulating insulin secretion
INTESTINE
Digested food
BLOOD
Glucose
Amino acids
Fatty acids
Sulfonylureas
GIT hormones
Parasympathetic nerves (on muscarinic receptors)
D cell
Somatostatin
B cell
Glucagon
A cell
Sympathetic nerves and adrenaline (on
a2-adrenoceptors)
PANCREATIC ISLET
Amylin
Insulin
7
Endocrine effects of insulin
EFFECT ON LIVER Reversal of catabolic reactions - Inhibits glycogenolysis - Inhibits gluconeogenesis - Inhibits conversion of fatty acids and amino acids to ketoacids Anabolic action - Stimulates glycogen sythesis - Increases triglyceride synthesis and very-low-density lipoprotein formation
EFFECT ON MUSCLE Increased protein synthesis - Increases amino acid transport - Increases ribosomal protein synthesis Increased glycogen synthesis - Increases glucose transport - Induces glycogen synthase and inhibits phosphorylase
EFFECT ON ADIPOSE TISSUE Increased triglyceride storage - Lipoprotein lipase is induced to release triglycerides from lipoproteins - Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport - Intracellular lipase is inhibited by insulin
8
The effect of hormones on blood glucose
Main stimulus for secretion
Main effect
Main actions
Hormone
Main regulatory hormone Insulin
? Glucose uptake
? Glycogen synthesis
Acute rise in ? Blood
? Glycogenolysis
blood glucose
glucose ?
Gluconeogenesis
Main counter-regulatory hormones Glucagon
? Glycogenolysis
? Gluconeogenesis
Adrenaline ?
Glycogenolysis
? Glucose uptake Glucocorticoids ?
Glyconeogenesis ? Glucose uptake and
utilisation Growth hormone ? Glucose uptake
Hypoglycaemia (i.e. blood glucose lt 3 mmol/l)
e.g. with exercise, stress, high protein meals,
etc.
? Blood glucose
9
Insulin receptors

• Insulin receptors are cell surface receptors with
  protein kinase activity
• They are responsible for both physiological and
  pharmacological action of insulin and its
  analogues

10
Diabetes mellitus

• - Diabetes is not a single disease
• It is rather a heterogeneous group of syndromes
  characterized by an elevation of blood glucose
  and metabolic perturbation caused by a relative
  or absolute insulin deficiency
• Main types
• Type I insulin-dependent DM
• Type II non-insulin-dependent DM
• Other types
• Maturity-onset DM of the young (MODY)
• Gestational diabetes

11
Diabetes diagnosis and glycemia

• Fasting Plasma Glucose (FPG)
• lt5.6 mmol/l normal glycemia
• 5.6 - 6.7 mmol/l impaired glucose tolerance
  
• gt 6.7 (7) mmol/l diabetes mellitus
• Glucose tolerance test (2h postprandial glucose)
• gt 11 mmol/l diabetes mellitus

12
Type I DM

• 5-10 of all patients diagnosed with DM
• Strong genetic background
• Typical onset juvenile (around puberty), but
  may occur at any age
• Pathogenetic mechanisms loss of ß-cells or
  their function due to the autoimmune mechanisms,
  toxic damage etc.
• Endocrine pancreas fails to respond to increased
  glucose levels by insulin secretion
• insulin levels are very low
• It results into the acute or chronic
  hyperglycemia
• Symptoms marked polyuria, polydipsia, weight
  loss

13
Type I DMPharmacotherapy

• Appropriate substitution therapy with exogenous
  insulin or insulin analogues is a must (IDDM) to
  avoid
• acute complications
• diabetic ketoacidosis (potentially
  life-threatening)
• chronic complications
• peripheral neuropathies,
• microangiopathies (nephropathies, retinopathies)
• macroangiopathies (accelerated atherosclerosis
  which leads into myocardial ischemia, cerebral
  ischemia, lower extremity ischemia)

14
Type I DM Pharmacotherapy

• AIM to maintain blood glucose as close to normal
  as possible, and to avoid wide swings in their
  levels (that contribute to long-term
  complications).
• Deserves adherence to special diet and regular
  living habits
• Compliance is essential!
• Standard therapy twice daily
• Intensive therapy 3 or more daily doses
• Usually combination of short acting insulin
  (mimic post prandial insulin secretion) and long
  acting preparations (basal secretion, antagonize
  glucose released from the liver)
• Therapy monitoring blood glucose
  (self-monitoring improves compliance), glycated
  hemoglobin (HbA1c).

15
Type II DM (NIDDM)

• Much more frequent than Type I!
• Besides genetic component, living habits, obesity
  and aging play an important role
• Typical onset in elderly
• Pathogenesis
• B-cells are not destroyed (at least not
  primarily)
• Insulin secretion impairment and/or loss of
  tissue sensitivity to insulin (insulin
  resistance) are the key issues here
• This leads to inability to maintain proper
  glucose homeostasis
• The symptoms and complications are similar to DM
  type I, but less acute/severe and obvious
• E.g. marked ketoacidosis is rare

16
Type II DM (NIDDM)Pharmacotherapy

• AIM To maintain blood glucose within normal
  limits and to prevent the development of chronic
  complications.
• Diet weight reduction pharmacological
  approach
• Important part of complex therapeutic approach to
  Metabolic syndrome
• Drugs in Type II DM
• oral hypoglycemic agents standard treatment!
• insulin (rather in specific situations
  only)
• acute complications (stress, infection, surgery,
  disease, pregnancy)
• when the disease is finally worsening beyond
  manageability with oral hypoglycemics

17
Release of insulin that occurs in response to the
constant infusion of glucose in normal subjects
and diabetic patients
Normal subjects
80
Type 2 diabetes
40
Plasma concentration of insulin (mg/mL)
Type 1 diabetes
0
0 5
10
Minutes
Infusion of glucose
(according to Lippincotts Pharmacology, 2006
18
Comparison of Type 1 and Type 2 diabetes.
Type 1 Type 2
Age of onset Usually during childhood or puberty Frequently over age 35
Nutritional status at time of onset Frequently undernourished Obesity usually present
Prevalence 5 to 10 percent of diagnosed diabetics 90 to 95 percent of diagnosed diabetics
Genetic predisposition Moderate Very strong
Defect of deficiency b cells are destroyed, eliminating the production of insulin Inability of B-cells to produce appropriate quantities of insulin insulin resistance other defects
(according to Lippincotts Pharmacology, 4th
ed., 2009)
19
Duration of non-insulin-dependent (type 2)
diabetes mellitus, sufficiency of endogenous
insulin, and recommended sequence of therapy
Impaired glucose tolerance
Normal
Type II diabetes
5 15 years
0 5 years
More than 15 years
Relative ability to secrete insulin
No treatment
Diet
Combina-tion therapy
Multiple injections of insulin
Diet plus sulfonyl-urea
Increasing severity of disease
(according to Lippincotts Pharmacology, 2006)
20
INSULIN AND ITS ANALOGUES in DM treatment

• Original sources of insulin animal pancreatic
  tissue
• Slightly different structure
• Troubles with purity, allergic reactions,
  potency, Ab-formations
• Not used anymore!
• Nowadays only HUMAN insulins are used
• Produced biotechnologically by recombinant
  technology in high purity
• Human gene for insulin is being introduced into
  the E. Coli and its expression is stimulated
• Insulin analogues
• Produced biotechnologically using recombinant
  technology
• Several AA were changed in human insulin to alter
  its physico-chemical properties esp. ability to
  dissociate from hexamer to monomer, which is
  absorbed
• Specifically altered pharmacokinetic profile
  (absorption!!!)
• Same pharmacodynamic as human insulin
  (equipotent)

21
Insulin and its analogues Route of
administration/absorption

• Parenteral route (injectables)
• i.v. administration
• Rather rare
• Used only in emergency situations mostly via
  infusions
• Suitable only for soluble human insulin
  regular!
• Mainly s.c.!!!
• Typically single dose administration (but s.c.
  infusion is also possible)
• Different body areas and devices topic for
  seminar
• Rate of absorption determines onset of actions,
  drug concentrations and duration of action
• Insulin hexamer, which is administered, must be
  dissociated to monomers to be absorbable
• Rate of dissociation largely determines
  absorption and thereby onset and duration of
  clinical effect
• i.m. also possible
• less used, when more rapid onset needed

22
Insulin and its analogues Parenteral route
(injectables)

• Factors having impact on drug absorption and
  onset/duration of action
• site of injection
• blood supply
• temperature
• physical activity

23
Alternative routes?

• A chase for non-invasive insulin
• Oral
• common approach unfeasible denaturation,
  digestion and/or poor absorption
• Inhalation
• Nanodispersed powder in gas
• impractical inhalers
• Efficacy issue
• not better rather worse than standard insulin
  preparations
• Safety issue lung fibrosis or cancer?
• Very expensive poor cost-effectiveness
• Future??? Pfizer discontinued production
• Other routes are under evaluations

24
Insulin and its analoguesPharmacokinetics - DME

• Distribution mainly into the extracellular volume
• Insulin receptors are on cell membranes
• Cannot cross membranes by passive diffusion
• does not cross placenta to affect fetus
• Vd0.3 l/kg?
• Metabolism/Elimination
• more than 90 metabolic elimination degraded by
  insulinases in the liver and kidney
• less than 10 excretion in urine
• Half-life of elimination is quite short (aprox.
  10 minutes only)
• Plasma concentration fluctuations (considerable
  intra- and inter-individual) complicate the
  situation

25
Insulin and its analoguesAdverse reactions

• HYPOGLYCEMIA
• Most frequent and important one
• Symptoms
• sympathetic nervousness, sweating, tremor,
  intense hunger, palpitation
• CNS related - speaking difficulties, weakness
• Advanced CNS function impairment - confusion,
  drowsiness, changes in behavior, coma, and
  seizure.
• Reasons
• Non-compliance - too high dose (or medication
  error), meal was not taken at the time,
  unexpected physical activity
• Liver/kidney failure, infections etc.
• Solution sweet syrup or drink when patient is
  consciousness, otherwise glucagon i.m/s.c. or
  glucose sol i.v.
• LIPODYSTROPHY, HYPERSENSITIVITY

26
Adverse effect observed with insulin
(according to Lippincotts Pharmacology, 2006
27
Insulin preparations

• Rapid/ultra short-acting insulines
• Insulin lispro, insulin aspart and insulin
  glulisine
• Short-acting insulines
• Regular insulin
• Intermediate-acting insulines
• Isophan (NPH) insulin
• Long-acting
• Glargine and detemir insulins
• Pre-mixed preparations
• lispro/NPH (e.g., 30/70)
• lispro/glargine etc

28
Ultra short-actinginsulin analogues

• Rapid onset and ultra short duration of action
• Better stimulate prandial insulin secretion to
  avoid hyperglycemia
• the lowest variability of absorption
  (approximately 5) of all insulin
• Possibility of more flexible treatment regimens
• ? Risk of hypoglycemia (meal timing!)
• Lispro
• lysine/proline switch at the position 28/29
• More rapidly dissociate and is absorbed after
  s.c. admin.
• Given 15 min before the meal to substitute
  postprandial insulin secretion
• Aspart- substitution of the B28 proline with
  aspartic acid
• Glulisine double substitution
• Similar profiles
• Often combined with other insulin types

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Short-actinginsulin

• Regular insulin (Humulin R, Novolin R)
• short-acting, soluble, crystalline zinc insulin
• Usually s.c. (i.v. in emergencies severe
  ketoacidosis)
• rapidly decreases blood glucose
• Effect - within 30 min peaks between 2 - 3
  hours after s.c. injection lasts 5-8 hours
• Should be injected 30-45 min before the meal to
  minimize the mismatching
• the pharmacokinetics and pharmacodynamics of
  small doses of regular insulin differ greatly
  from those of large doses.

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Intermediate-actinginsulin

• Isophane (NPH) insulin suspension (Humulin N,.
  Novolin N)
  
• Neutral protamine Hagedorn (NPH) insulin (also
  called isophane insulin)
• Suspension of crystalline zinc insulin combined
  with polypeptide, protamine
• Intermediate duration of action due to the
  delayed absorption of the insulin
• complex with protamine is less-soluble
• onset cca 2-5 hours duration of 4-12 hours
• Only s.c. (never i.v.).
• Use in all forms of diabetes except diabetic
  ketoacidosis or emergency hyperglycemia
• Usually given along with regular lispro, aspart,
  or glulisine insulin Given 2-4 times daily in
  patients with type 1 diabetes

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Effect of subcutaneous administration of lispro
insulin and regular insulin on (A) serum insulin
concentrations, and (B) the rate of glucose
infusion necessary to maintain normal blood
glucose levels in 10 normal subjects.
A Serum insulin levels B
Rate of glucose infusion
120
450
Lispro insulin
400
100
Lispro insulin
350
80
Regular insulin
300
Serum insulin (?U/ml)
250
Glucose infusion rate (mg/min)
60
200
Regular insulin
40
150
100
20
50
0
0
0 1 2 3 4 5 6 7 8 9 10
11 12
0 1 2 3 4 5 6 7 8 9 10
11 12
Hours
Hours
32
Long-acting insulin analogues

• Insulin glargine
  
• Precipitation at the injection site
• ? prolonged absorption and longer action.
• Slower onset than NPH insulin, (1-1.5 hours)
  maximum effect after 4-6 hours
• flat, prolonged hypoglycemic effect (i.e., it has
  no peak).
• This maximum activity is maintained for 11-24
  hours or longer.
• Must be given s.c.
• Insulin detemir
• - Fatty-acid side chain attached
• - There is an increased propensity for
  selfagreggation after s.c. administration and
  reversible albumin binding
• - Properties similar to insulin glargine
• - Has the most reproducible effect of the
  intermediate- and long-acting insulins, and its
  use is associated with less hypoglycemia than NPH
  insulin.
• - Dose-dependent onset of 1-2 hours
• - Duration of action of more than 24 hours
• - Given twice daily to obtain a smooth
  background insulin level

33
Onset and duration of action of human insulin
and insulin analogues.
Aspart insulin, lispro insulin
Glulisine insulin
Regular insulin
NPH insulin
Extended zinc insulin
Glargine insulin
Relative plasma insulin level
0 6
12
18 24
Hours
(according to Lippincotts Pharmacology, 2006)
34
A. Effect of tight glucose control on
hypoglycemic episodes in a population of
patients receiving intensive or standard therapy.

B. Effect of standard and intensive care
on the long-term complications of diabetes.
B
A
Many clinicians believe the increased risk of
hypoglycemia that accompanies intensive therapy
is justified by the substantial decrease in the
incidence of long-term complications, such as
diabetic retinopathy and nephropathy.
Intensive therapy results in a three fold
increase in the frequency of hypoglycemia.
100
Intensive therapy
60
Hypoglycemic episodes per 1000 patient months
Standard
Percentage of patients with complications
Standard therapy
30
Intensive
0
0
0 1 2 3 4 5 6 7 8 9
(according to Lippincotts Pharmacology, 2006)
Year of study
35
Examples of two regimens that provide both
prandial and basal insulin replacement. B
breakfast L lunch S supper
A
B
Morning Afternoon Evening Night
Morning Afternoon Evening Night
Lispro Lispro Lispro
Regular Regular Regular
NPH
NPH
Insulin effect
Insulin effect
B L S Bedtime
B L S Bedtime
(according to Lippincotts Pharmacology, 2006)
36
Insulin preparation Onset Peak Duration
Short-acting insulins (regular ins) Actrapid HM Humulin R Insuman Rapid 30 min 20 30 min 30 min 1,5 3,5 h 1 3 h 1 4 h 7 8 h 5 7 h 7 9 h
Intermediate-acting insulins (isophane) Insulatard HM Insuman Basal Humulin N within 1,5 h within 1 h 1 2,5 h 4 12 h 3 4 h 4 12 h 24 h 11 20 h 12 16 (20) h
Rapid-acting insulins (analogues) lispro/Humalog aspartat/Novorapid glulisin/Apidra 10 15 min 10 15 min 10 15 min 30 60 min 40 50 min 55 min 3 4 h 3 5 h 3 5 h
Prolong-acting insulins (analogues) glargin/Lantus detemir/Levemir 1 2 h 1 2 h 24 h 20 h
Mixtures Onset Peak Duration Humulin
M3 (30 regul. 70 isophane) 30 min 1
9 h 14 15 h Novomix 70 (70 aspart
30 protamine-aspart) 10 20 min 1 4 h
14 24 h Novomix 30 (30 aspart 70
protamine-aspart)
37
Oral hypoglycemic agents (OHA)

• Used in Type II DM only
• why?
• biguanides as the exception
• Best response
• in younger patients (around 40 years old)
• in the first 5 years after onset
• Advanced stage Type II DM may require
• combination of oral hypoglycemic agents
• combination with insulin (loss of ß-cells due to
  the aging and disease)

38
Classification of OHAaccording to the mechanism
of action

• Insulin secretagogues
• sulfonylureas (1st and 2nd generation)
• meglitidines
• Insulin senzitizers
• biguanides
• thiazolidindiones
• Alpha-glucosidase inhibitors
• acarbose
• miglitol
• Other agents - incretin mimetics
• - exenatide

39
OHA - Insulin secretagoguesI. Sulfonylureas

• Promote insulin release from the ß-cells
• Additional effects ?
• they reduce serum glucagon levels
• they block K channels in extrapancreatic tissues
• Mechanism of action
• they bind to sulfonylurea receptor on
  ATP-sensitive K channels
• binding of the drug make the channel close
• depolarization opens Ca2 channels, which drives
  the insulin exocytosis

40
OHA - Insulin secretagoguesI. Sulfonylureas

• Pharmacokinetic aspects
• oral administration
• peak concentrations within 2-4 hours
• high protein binding
• cross placenta to fetus and enter mother's milk
• contraindicated in pregnancy and lactation
• liver metabolism may take place metabolites can
  be active (glibenclamide, glimepiride)
• excretion mainly by kidney (be careful in
  renal/hepatic failure) or liver
• Duration of action
• I. gen - 6-12h tolbutamide
• - up to 60 hours chlorpropamide!
• II. gen - 10-24h
• PK drug interactions plasma protein binding
  and CYP interactions NSAIDs, warfarin, IMAO,
  sulfonamides, chloramphenicol

41
OHA - Insulin secretagoguesI. Sulfonylureas

• I. Generation
• Tolbutamide
• good absorption, but rapid hepatic metabolism
• shorter duration of action
• safe in elderly
• devided dose
• Chlorpropamide
• very long half-life and duration of action
• active metabolites
• not safe in elderly (hypoglycemia is likely)
• renal excretion (20-30 as unchanged) drug
• consider renal function!!!
• disulfiram-like effect, ADH-like effect, rare
  hematotox.

42
OHA - Insulin secretagoguesI. Sulfonylureas

• II. Generation
• More frequently prescribed
• More potent, fewer adverse reactions,
  interactions...
• Liver metabolisms consider liver disease
• glibenclamide (glyburide in USA)
• avoid even in mild renal dysfunction
  hypoglycemia is likely
• glipizide
• should be taken at least 30 min before breakfast
  (food slows absorption)
• shorter half-life - lower risk of hypoglycemia
• glimepiride
• once daily administration (good compliance)
• the most potent analogue

43
OHA - Insulin secretagoguesI. Sulfonylureas

• Adverse effects
• hypoglycemia
• most frequent adverse reaction
• consider - dose, patient's age, kidney/liver
  dysfunction, half-life of the drug, drug
  interactions
• most often in chlorpropamide and glibenclamide
• increased appetite and weight gain
• insulin secretion-related effects
• a trouble in obese patients with metabolic
  syndrome
• GIT disturbances
• disulfiram-like effects
• they should by replaced with insulin for few days
  after MI

44
Oral Hypoglycaemic sulfonylurea drugs
Duration of action and (half-life) In hours
Drug Relative
potency
Pharmacokinetic aspects
General comments
A safe drug least likely to cause hypoglycaemia M
ay decrease iodide uptake by thyroid Contraindicat
ed in liver failure
Tolbutamide 1
Some converted in liver to weakly active
hydroxy- tolbutamide some compound Renal
excretion
6 12 (4)
May cause hypogly- caemia. The active metabolite a
ccumulates in renal failure
Glibenclamide
Some is oxidised in the liver to modetrately
active products and is excreted in urine 50 is
excreted unchaged in the faeces

150
18 24 (10)
100
Glipizide
May cause hypoglycaemia Has diuretic action Only
inactive products accumulate in renal failure
Peak plasma levels in 1 hour. Most is metabolised
in the liver to inactive products, which are
excreted in urine 12 is excreted in faeces.

16 24 (7)
45
OHA - Insulin secretagoguesII. Meglitinides

• repaglinide and nateglinide
• mechanism of action as in SU drugs
• more selective to ß-cells than SU?
• 2 binding sites on K channel
• 1st same as for SU drugs, 2nd unique
• Rapid onset and short duration of action
• this is in contrast to SU drugs
• postprandial glucose regulators
• minimal effect on overnight or fasting glucose
  levels
• administration shortly before meals
• Often combined with biguanides or
  thiazolidindiones

46
OHA - Insulin secretagoguesII. Meglitinides

• Adverse reactions
• hypoglycemia
• less frequent, less severe than in SU
• nateglinide
• likely the lowest risk from all secretagogues
• renal failure is usually not a trouble
• liver dysfunction makes it more likely
• weight gain
• rather less than in SU
• Drug interactions (CYP inhibitors/inducers)
• repaglinide metabolized by CYP3A4
• nateglinide - metabolized by CYP2C9 a 3A4

47
OHA- Insulin sensitizersI. Biguanides

• Metformin
• the only drug from this group used
• phenformin discontinued - risk of lactate
  acidosis
• mechanism of action complex and still not fully
  understood
• reduces tissue insulin resistance
• increases glucose uptake and utilization in the
  skeletal muscle
• inhibits hepatic gluconeogenesis
• slowing of intestinal absorption of glucose and
  stimulation of glycolysis in enterocytes
• reduction of plasma glucagon levels
• reduction of plasma LDL and VLDL
• euglycemic effect rather than hypoglycemic

48
OHA- Insulin sensitizersI. Biguanides - metformin

• Pharmacokinetics
• not bound to plasma proteins
• not metabolized
• excreted by the kidney as the parent active
  compound
• Clinical use
• in obese type II DM patients
• esp. in metabolic syndrome to overcome tissue
  resistance
• administered usually once daily with breakfast
• proven to reduce chronic complications
• in combinations with secretagogues and
  thiazolidindiones

49
OHA- Insulin sensitizersI. Biguanides - metformin

• Adverse reactions and toxicity
• GIT disturbances
• anorexia, nausea, vomiting, abdominal discomfort,
  diarrhea
• the most frequent adverse reactions in up to
  20 patients
• dose related
• onset rather at the beginning may be transient
• vitamin B12 deficiency (decreased absorption)
• lactate acidosis
• rare but potentially fatal toxic effects
• contraindication in kidney/liver disease,
  alcoholism, hypoxic pulmonary disease, heart
  failure (predisposing factors)
• NO HYPOGLYCEMIA they are rather euglycemic
  agents

50
OHA- Insulin sensitizersII. Thiazolidindiones

• Rosiglitazone, pioglitazone
• Mechanism of action
• agonists on PPAR-? nuclear receptors
• peroxisome proliferator-activated receptor ?
• located in adipocytes, myocytes, hepatocytes
• modulate expression of genes involved in lipid
  and glucose metabolism, insulin signal
  transduction and adipocyte metabolism
• reduce hepatic gluconeogensis
• increase glucose uptake in the muscle/adipocytes
• enhance effectiveness of both endogenous and
  exogenous insulin

51
OHA- Insulin sensitizersII. Thiazolidindiones

• Clinical effects and use
• glucose lowering effect is slow in onset
• maximum achieved in 1-2 months!!!
• euglicemics rather than hypoglycemics
• effective in 70 of new patients
• dyslipidemia correction (metabolic syndrome)
• diabetes prevention?
• reduction of diabetic incidence in patients with
  pre-diabetes
• Pharmacokinetics
• well absorbed and highly bound to plasma proteins
  (gt99)
• metabolized to active metabolites with long
  half-life
• CYP interactions - pioglitazone

52
OHA- Insulin sensitizersII. Thiazolidindiones

• Adverse effects
• weight gain
• fluid retention
• may worsen or precipitate heart failure
  contraindication
• overall effects on cardiovascular morbidity and
  mortality?
• headache, fatigue, GIT disturbances
• Toxic effects
• hepatotoxicity
• troglitazone and ciglitazone
• severe development stopped
• role of quinone metabolite?
• hepatotoxicity of newer drugs was not observed
• monitoring is recommended
• cardiotoxicity??? Outcomes of clinical trials

53
OHA - Alpha-glucosidase inhibitors

• Acarbose and miglitol
• disaccharides and oligosaccharides must be
  cleaved enzymatically in the gut to be absorbable
• alpha-glucosidases are the enzymes responsible
  for this reaction
• alpha-glucosidase inhibitors
• decrease digestion of starch and disaccharides
  and thus decreas post-prandial glucose levels
• taken just before ingestion of first portion of
  the meal
• often used in combination with SU
• Adverse effects GIT disturbances flatulence,
  diarrhea, abdominal pain (glucose fermentation)
  may diminish
• hypoglycemia (combinations) use glucose not
  sucrose!

54
Other HA Incretin mimetics

• Incretin effect higher insulin secretion
  after oral than i.v. glucose!
• GIT hormones involved
• Exenatide
• synthetic analogue of Glucagon-like peptide 1
  (GLP-1)
• peptide!
• s.c. adminsitration!
• adjunctive therapy to inadequate therapy with SU
  or metformin
• it seems to
• potentiate insulin secretion
• decrease postprandial glucagon release
• slow gastric emptying
• increase ß-cell mass

55
Summary of oral agents used to treat diabetes.
little or no change
Drug class Mechanism of action Effect on plasma insulin Risk of hypo-glycemia Comments
First-generation sulfonylureas Tolbutamide Stimulates insulin secretion Yes Well-established history of effectiveness. Weight gain can occur.
Second-generation sulfonylureas Glipizide Glyburide Glimepiride Stimulates insulin secretion Yes Well-established history of effectiveness. Weight gain can occur.
Meglitinides Nateglinide Repaglinide Stimulates insulin secretion Yes (rarely) Short activation with less hypoglycemia either at night or with missed meal. Post-prandial effect.
Beguanides Meformin Decreases endogenous hepatic production of glucose No Preferred agent for Type 2 diabetes. Well-established history of effectiveness. Weight loss may occur. Convenient daily dosing. Many contraindications. Monitor renal function.
(according to Lippincotts Pharmacology, 4th ed.,
2009)
56
Summary of oral agents used to treat diabetes.
little or no change
Drug class Mechanism of action Effect on plasma insulin Risk of hypo-glycemia Comments
Thiazolidinediones (Glitazones) Pioglitazone Rosiglitazone Binds to peroxisome proliferator-activated receptor-g in muscle, fat and liver to decrease insulin resistance No Effective in highly insulin-resistant patients. Once-daily dosing for pioglitazone. Monitor liver function.
a-glucosidase inhibitors Acarbose Miglitol Decreases glucose absorption No Taken with meals. Adverse gastrointestinal effects.
DPP-IV inhibitors Sitagliptin Vildagliptin Increases glucose-dependent insulin release, decreases secretion of glucagon No Once-daily dosing. May be taken with or without food. Well tolerated.
(according to Lippincotts Pharmacology, 4th ed.,
2009)