anti-diabetics, insulin ppn in type 2 DM, oral hypoglycemic agents, hormones of pancreatics gland and related drugs

1. Anti-Diabetic
Agents
Dr. Harshika Patel
KeMU
PHRM 400
Pharmacology and therapeutics II

2. •Pancreatic hormones
(insulin and glucagon)
•Anti-diabetic drugs

3. Diabetes Mellitus
•A chronic systemic disease
characterized by metabolic and
vascular abnormalities
•Disorder of carbohydrate
metabolism
•Results from inadequate
production or underutilization of
insulin

4. Cont’d…
•Characterized by glucosuria and
hyperglycemia
•Four forms—Type 1 and Type 2, others,
and gestational diabetes mellitus
•Type 1—patient secretes no insulin. Cause
is felt to be autoimmune.
•Type 2- patient secretes insufficient
amounts of insulin and insulin receptors
are resistant to existent circulating
insulin
https://www.diabetes.org.uk/diabetes-the-basics/types-of-diabetes

5. Cont’d…

7. •Reuqired Medical intervention is necessary
otherwise, significant complications will
ensue.
•In both form need careful attention to diet,
fasting and postprandial blood glucose
concentrations, and serum concentrations of
hemoglobin A1c, a glycosylated hemoglobin
(marker of glycaemia)
•Include: retinopathies, glaucoma,
neuropathies, cardiovascular disease (PVD).
•Increased incidence of toxemia of pregnancy.
Cont’d…

8. IMPORTANCE OF EACH BIOCHEMICAL
TEST
•Fasting BS
•Post-prandial BS
•OGTT
•HBA1C concentration
•Learn this biochemistry

10. Brief Pathophysiology
•Insulin secreted by beta cells
•Insulin binds with and activates 80% of cells
•Liver, muscle, and fat cells are primary tissues for
insulin action
•With insulin receptor binding, cell membranes
permeable to glucose into the cells (see the next
slide)
•Increased cell permeability also allows for amino
acids, fatty acids and electrolytes to enter cells
•Changes cause anabolism and inhibit catabolism

11. Cont’d.
•Various glucose transporters are available for this
purpose:
•Examples:
•GLUT 1
•GLUT 2
•GLUT 3
•GLUT 4
•SGLT 1 (intestine  to blood stream (transfer
through GLUT 2))
•SGLT2 (in kidney  glucose transfer through
GLUT 2 /3  REABSORB)
Basically insulin bind on
insulin receptors and
activates these transporters
and allows glucose to enter
into the cell

12. Endogenous Insulin
•It is synthesized as a pro-hormones (proinsulin  86-
amino-acid single-chain polypeptide)
•Which cleaved and formed 2-chain 51-peptide insulin
molecule + a 31-amino-acid residual C-peptide
•Proinsulin and c-peptide have no physiological role
•Glucose is the major stimulus of insulin secretion
•Oral glucose is more effective than intravenous glucose
because glucose in digestive tract increases the release
of gastrin, secretin, cholecystokinin, and gastric
inhibitory peptide
•Also stimulates vagal activity

13. Cont’d…
Other hormones that
raise blood glucose
levels include:
•Cortisol
•Glucagon
•Growth hormone
•Epinephrine
•Estrogen
•Progesterone
Factors that inhibit
insulin secretion
include:
• Hypoxia
• Hypothermia
• Stimulation of
alpha-2 receptors

14. Classification of Two Types of Diabetes
Type 1 diabetes results from an
autoimmune disorder that destroys
pancreatic beta cells
Usually has sudden onset
Associated with high incidence of
complications
Requires exogenous insulin
10% of those with diabetes are type I
Associated with diabetic ketoacidosis

15. Diabetic Ketoacidosis (DKA)
•Life-threatening complication occurs with
insulin deficiency
•Glucose cannot be used by body cells
for energy so fat is mobilized for this
purpose
•Mobilized fat is then extracted by liver and
broken down into glycerol and fatty acids
•Fatty acids further broken down into
ketones

16. Cont’d…
•Accumulation of ketones results in
academia:
1. Attempts to buffer acidic H+ occurs by ionic
exchange, intracellular potassium exits cells.
H+ ions enter cells. Result is excretion of
potassium in urine electrolytes imbalance
2. Kidneys attempt to buffer by excreting
ketones
3. Pulmonary attempt to buffer by Kussmaul
breathing
• Blood and urine is concentrated with
ketones  need immediate treatment

17. Clinical symptoms of DKA
•Kussmaul breathing
•Nausea and vomiting
•Thirst
•Polydipsia, polyphagia and polyuria
•Hypotension
•Tachycardia
•Shock

18. Type 2 Diabetes Mellitus
•Characterized by hyperglycemia
and insulin resistance
•Results from increased production of
glucose by liver and decreased uptake
of glucose in liver, muscle and fat cells
•Insulin resistance—higher than usual
concentrations of insulin are required

19. Type 2 Diabetes Mellitus
Occurs at any age
Gradual onset
Less severe symptoms initially
Easier to control
 higher incidence of MIs and strokes
90% of those with diabetes are Type 2
multifactorial

20. Hyperosmolar hyperglycemia non-
ketotic coma (HHNC)
•Occurs in Type 2 Diabetes
•Because patient has some endogenous
insulin, no ketosis develops
•Blood sugars can be >800-1000 mg/dL
•Can result in hypovolemic shock,
renal problems, stroke, coma and even
death

21. Metabolic Syndrome or Syndrome X
Comprised of a set of risk factors which
include:
1. Central abdominal adiposity (men waist
size greater than 40 inches, women
greater than 35 inches
2. Fasting triglycerides greater > or equal to
150 mg/dl (in adults),
3. HDL cholesterol (less than 40 in men,
less than 50 mg/dl in women

22. Cont’d...
4. Blood pressure greater than or equal
to 130/85
5. Fasting glucose greater than or equal
to 110mg/dl
Also possess prothrombotic and
proinflammatory tendencies

23. Metabolic Syndrome cont.
•All factors are interrelated
•Obesity and lack of exercise tend to lead to
insulin resistance
•Insulin resistance has a negative effect on lipid
production. Increase VLDL, LDL, TG and
decreasing the HDL.
•Insulin resistance leads to increased insulin and
glucose levels in blood.

24. Pharmacotherapy of Hypoglycemic
Drugs- Insulin
•Insulin lower glucose levels by
increasing glucose uptake by cells
•Indicated for Type 1 DM often, in Type
2 DM, in those with chronic
pancreatitis, in those on TPN, to treat
hyperkalemia (infusion with dextrose
and insulin)
•Available insulin's are from pork and
human

25. Age-Related considerations
Type 1 DM in children
•Consistent diet, blood glucose
monitoring, insulin injections and
exercise
•Blood sugar control essential to
maintain normal growth and
development
•Infections and illnesses can cause
wide fluctuations

26. Cont’d...
•Children highly susceptible to
dehydration
•Rotation of sites is very important
•Avoiding hypoglycemia is a major goal
in infants and young children which
affects the growth and development
•s/s of hypoglycemia include: hunger,
sweating, tachycardia, irritability and
lethargy

27. Age related considerations in older
adults
•Close monitoring of blood glucose levels
•Visual impairment may affect their ability
to self administer medication
•May have renal insufficiency so caution
with certain anti-diabetic drugs
•Caution with metformin if renal
impairment
•Glitazones can predispose to fluid
retention and heart failure

28. Insulin
• History:
• Insulin was discovered in 1921 by Banting and Best
(just done demonstration on extracted pancrease)
• first obtained in pure crystalline form in 1926
• The chemical structure was fully worked out in 1956
by Sanger
• Human insulin is chemically identical to endogenous
insulin but it is not derived from the human pancreas
• Cannot be given orally.
• Insulins differ in onset and duration of action. Ultra-
short, short, intermediate and long acting.

29. Regulation of insulin secretion
•By three different mechanisms:
•Chemical
•Hormonal and
•Neuronal

30. Action of insulin
1. Insulin facilitates glucose transport across cell membrane;
skeletal muscle and fat are highly sensitive.
• However, glucose entry in liver, brain, RBC, WBC and renal
medullary cells is largely independent of insulin
• Exercise has insulin sparing effect.
2. Intracellular utilization of glucose is its phosphorylation to
form glucose-6-phosphate  which is enhanced by insulin
through increased production of glucokinase.
3. Insulin facilitates glycogen synthesis from glucose in liver,
muscle and fat by stimulating the enzyme glycogen synthase.
4. It also inhibits glycogen degrading enzyme phosphorylase →
decreased glycogenolysis in liver

31. Cont’d…
5. Insulin inhibits gluconeogenesis (from protein, FFA and
glycerol) in liver
6. Insulin inhibits lipolysis in adipose tissue and favors
triglyceride synthesis  fat is broken down due to free
action of lipolytic hormones (glucagon, Adr, thyroxine,
etc.) → increased FFA and glycerol in blood. (check DKA)
7. Insulin enhances transcription of vascular endothelial
lipoprotein lipase and thus increases clearance of VLDL
and chylomicrons
• Most of the above metabolic actions are exerted within seconds or minutes
 called the rapid actions.
• Others involving DNA mediated synthesis of glucose transporter and some
enzymes of amino acid metabolism have a latency of few hours  called
intermediate actions.
• Exerts major long-term effects on multiplication and differentiation of
many types of cells.

32. Mode of action - Insulin

33. Fate of Insulin
•Oral administration – is not possible  as it is
peptide and get degrade in GIT
•Extracellular distribution – only possible
•Metabolized  primarily in liver and to a smaller
extent in kidney and muscles
•During biotransformation the disulfide bonds
are reduced—A and B chains are separated 
Further broken down to the constituent amino
acids.
•The plasma t½ is 5–9 min.

34. Insulin preparations
•Old ppn were obtained from beef and
pork pancreases which had ~1% other
proteins  and this proteins are
antigenic in nature
•Replace by newer highly purified
pork/beef insulin/recombinant
human insulin/insulin analogues

36. Ultra-short acting insulin
•Insulin lispro (Humalog) or insulin
aspart (Novolog) are very short acting
insulins
•More effective in decreasing post-
prandial hyperglycemia
•Less likely to cause hypoglycemia
before the next meal
•Onset is 15min, peaks in 1-3 hours,
duration is 3-5 hours

37. Short acting Insulin
1. Regular Iletin II, Humulin R, Novolin
R
2. May be given SC or IV
3. May be given as a continuous IV drip
4. The only insulin that may be given IV
5. Onset is ½-1 hour, peak is 2-3 hours
and duration is 5-7 hours

38. Intermediate-acting Insulin
•Isophane insulin suspension (NPH, NPH
Iletin II, Humulin N, Novolin N)
•Onset is 1-1.5 hours, peaks in 8-12 hours
and duration is 18-24
Long-acting Insulin
•Extended insulin zinc suspension
•Onset is 4-8 hours, peaks in 10-30 hours
and duration is 36+ hours

39. Insulin Mixtures
•NPH 70/30 (Humulin or Novolin 70/30)
•Durations of actions same as individual
components
Cont’d…

40. Highly purified insulin preparations
• More stable and cause less insulin resistance or injection site
lipodystrophy.
• Immunogenicity of pork mono-component (MC) insulin is
similar to that of recombinant human insulin.
• Regular (soluble) insulin: injected ½-1 hour before a meal (thr’
SC route)
• Lente insulin (Insulin-zinc suspension): two forms are available
1. large particles is crystalline and practically insoluble in water  long-
acting
2. Smaller particles and is amorphous  has short acting.
• Isophane (Neutral Protamine Hagedorn or NPH) insulin:
• Injected s.c. twice daily before breakfast and before dinner
• Mostly combined with regular insulin (70:30 or 50:50)

41. Insulin Analogs
•Recombinant DNA products with improved
pharmacokinetics parameter on SC route with
same p. dynamics
•Has Greater stability and consistency
•Insulin Lispro:
•SC  with quick pe and rapid peak and shorter
duration of action.
•Unlike regular insulin , this one can administered
before or after the meal.
•Lower incidence of hypoglycemia
•Slightly greater reduction in HbA1c compared to
regular insulin

42. Cont’d…
•Insulin aspart:
•mimics the physiological insulin release
pattern after a meal, with the same
advantages as Lispro.
•Insulin glargine (Lantus)
•long-acting biosynthetic insulin
•Once daily dose at bedtime. Onset is 1.1
hours, peak is none, duration is 24 hours
•Must not be diluted or mixed with any
other insulin or solutions

43. Side effects
•Hypoglycemia  treated b y oral glucose / IV
in severe cases
• And also , glucagon 0.5–1 mg IV or Adr 0.2 mg SC 
when pt is not able to take glucose orally or IV ppn is
not available.
•Local reactions Swelling, erythema and stinging
sometimes occur at the injected site, especially in
the beginning.
•Allergy (rare with highly purified insulin ppn)
•Edema Some patients develop short-lived
dependent edema (due to Na+ retention) when
insulin therapy is started

44. Drug-drug interactions
•With beta blockers  prolong hypoglycemia
(symptoms, like palpitation, tremor and anxiety
are masked), also rise BP through alpha receptor.
•Thiazides, furosemide, corticosteroids, oral
contraceptives, salbutamol, Nifedipine  inc’
blood sugar level  reduced effectiveness
•With acute ingestion of alcohol cause
hypoglycemia  by depleting glycogen in liver
•Lithium, high dose aspirin and theophylline 
inc’ hypoglycemia

45. Uses of insulin
• All forms of diabetes mellitus
• Must in type 1 DM
• For post pancreatectomy diabetes
• Gestational diabetes
• In type 2, used in special conditions
• Not controlled by diet and exercise
• Primary or secondary failure of oral hypoglycemics or when
these drugs are not tolerated.
• Under weight patients.
• Temporarily to tide over infections, trauma, surgery,
pregnancy.
• Any complication of diabetes, e.g. ketoacidosis, non-ketotic
hyperosmolar coma, gangrene of extremities

47. DKA – treatment
•IV fluids to rehydrate (Normal saline is infused i.v.,)
•No use of hypotonic solutions at this time
•Potassium supplementation (KCl)  resolve the lose
of K+ during ketosis
•IV insulin drip with gradual lowering of blood sugars
• Insulin Regular insulin is used to rapidly correct the
metabolic abnormalities (bolus dose of 0.1–0.2 U/kg i.v. is
followed by 0.1 U/kg/hr infusion)
•Judicious administration of sodium bicarbonate –
correct the acidosis
•Phosphate
•Antibiotics and other supportive measures
Supportive drugs

48. ORAL
HYPOGLYCEMIC
AGENTS

49. CLASSIFICATION
A. Enhance Insulin secretion
1. Sulfonylureas (KATP Channel blockers)
First generation: Tolbutamide
Second generation: Glibenclamide (Glyburide), Glipizide,
Gliclazide, Glimepiride
2. Meglitinide/phenylalanine analogues:
Repaglinide, Nateglinide
3. Glucagon-like peptide-1 (GLP-1) receptor
agonists (Injectable drugs): Exenatide,
Liraglutide
4. Dipeptidyl peptidase-4 (DPP-4) inhibitors:
Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin,
Linagliptin

50. CONT’D…
B. Overcome Insulin resistance
1. Biguanide (AMPK activator): Metformin
2. Thiazolidinediones (PPARγ activator):
Pioglitazone
C. Miscellaneous anti-diabetic drugs
1. α-Glucosidase inhibitors: Acarbose, Miglitol,
Voglibose
2. Amylin analogue: Pramlintide
3. Dopamine-D2 receptor agonist: Bromocriptin
4. Sodium-glucose cotransport-2 (SGLT-2)
inhibitor: Dapagliflozin

51. Sulfonylureas
KATP Channel blockers
•All have similar pharmacological profile
•Reduce blood sugar level in normal
subject, type 2 DM but apply in type 1
DM
•The second generation SU are widely
used in practice bcz of  more potency
and clinically superior
•Only tolbutamide is only in practice
among all 1st generation SU, occasionally

52. Mode of Action of insulin enhancers

53. Cont’d…
•SU and meglitinide analogues  block the SUR1 
which constitutes a subunit of the inwardly
rectifying ATP-sensitive K+ channel (KATP) in the
membrane of pancreatic β cells.
•Which inhibit the inward flow of K+ ions  and
dropped the intracellular K+ conc.  and the
membrane is partially depolarized augmenting
Ca2+ channel opening with release of Ca2+ from
intracellular stores.
•The Ca2+ ions promote fusion of insulin
containing intracellular granules with the
plasma membrane  and insulin released by
exocytosis

54. Cont’d…
• Incretins such as glucagon-like peptide 1 (GLP1) and
glucose-dependent insulinotropic polypeptide (GIP) 
act on their own G-protein coupled receptors  on the β
cell membrane  activate adenylyl cyclase  generate
cAMP  inc’ Ca +2 conc  inc. release of insulin
• Exenatide and liraglutide  eg. of GLP1 receptor agonists 
have same intrinsic action.
• The incretins GLP1 and GIP are rapidly inactivated by the
capillary endothelial enzyme dipeptidyl peptidase-4 (DPP-4).
• Their action is enhanced by  eg. sitagliptin and vildagliptin
• The DPP-4 inhibitors thus markedly accentuate the insulin
response to ingested glucose/meal and attenuate postprandial
glycaemia.

55. Cont’d…
Pancreatic action:
•Provoke a brisk release of insulin
•The rate of insulin secretion at any glucose
concentration is inc’d,  even at low-glucose
concentration  inc’ the chances of severe
hypoglycemia (only in type 2 DM)
•But why SU does not cause hypoglycemia in Type
1 and pancreactomised animal?
•Extra-pancreatic action:
•Eventually, cause SUR1 receptor down regulation on
beta cell but improvement on glucose tolerance is
maintained
•It will improved overtime by improving sensitivity
and it’s number (receptors on liver)

56. Side effects
•Glyburide and glipizide  high
tendency to cause hypoglycemia
•Old agents may cause hypersensitivity
reactions, rash and other allergic
events
•Weight gain

57. Meglitinide/phenylalanine analogues:
Repaglinide, Nateglinide
•Mode of action: see the slide number
53 and 54
•They induce rapid onset short lasting
insulin release.
•Administered before each major meal
to control post prandial
hyperglycemia.

58. Glucagon-like peptide-1 (GLP-1)
receptor agonists
•A member of the incretin family of peptide hormones,
release from endocrine cell of bowel in response to food
•GLP-1 is an important incretion released from the gut
in response to ingested glucose.
•It induces insulin release from pancreatic β cells,
inhibits glucagon release from α cells, slows gastric
emptying and suppresses appetite.
•A long-acting injectable peptide analog
•Uses: with metformin or a sulfonylurea for type 2
diabetes
•Drugs available: Exenatide, Liraglutide(Victoza)

59. Dipeptidyl peptidase-4 (DPP-4) inhibitors
•DPP-4 in rapid degradation of endogenous GLP-1
•Orally active inhibitors of DPP-4 have been
developed as indirectly acting insulin
secretagogues.
•ADR: Headache, nasopharyngitis, and upper
respiratory tract infection.
•Examples: Sitagliptin, Vildagliptin, Saxagliptin

60. Drugs which overcome insulin
resistance
•Biguanide
•Phenformin higher risk of lactic acidosis
banned in many countries since 2003.
•Metformin (Glucophage) increases
insulin-mediated glucose uptake by
muscle and fat cells, decreases hepatic
glucose production, and decreases
intestinal absorption of glucose

61. Cont’d…
•Does not cause hypoglycemia
•May be used alone or in combination
•Adverse effects: Lactic acidosis, g.i.
intolerance
•Contraindicated in liver or renal
impairment. Can result in lactic acidosis.
•Must check renal function before
beginning this medication
•Caution with parenteral radiographic
contrast media containing iodine. May
cause renal failure and has been associated
with lactic acidosis.

62. Thiazolidinedione (PPAR-gamma
agonist)
• Example: Pioglitazone
• MOA: Glitazones tend to reverse insulin resistance by
enhancing GLUT4 expression and translocation.
• This nuclear receptor regulates the transcription of genes
encoding proteins involved in carbohydrate and lipid
metabolism.
• Increase the uptake of glucose into muscle and adipose
tissues
• Inhibit hepatic gluconeogenesis
• Reduce both fasting and postprandial hyperglycemia
• Rosiglitazone banned in many countries  bcz increase in
risk of myocardial infarction, CHF, stroke and death.)

63. Adverse effects:
•fluid retention  presents as mild anemia and
edema  may increase the risk of heart failure
•Routine LFT is required (C/I  in patients with liver
disease or who have ALT levels > 2.5 of normal)
•In female: increased risk of bone fractures
•Induce cytochromeP450 , CYP3A4  reducethe
serum concentrations of some drugs like, oral
contraceptives, cyclosporine)
•May be used as monotherapy or in combination with
insulin, metformin (Glucophage) or a sulfonylurea
•Caution in patients with heart failure

64. α Glucosidase inhibitors
• Example: Acarbose
• MOA: Inhibits α-glucosidases, the final enzymes for the
digestion of carbohydrates in the brush border of small
intestine mucosa.
• Taken just before a meal
• Prevent type 2 diabetes in prediabetic persons
• Adverse effects: Flatulence, abdominal discomfort and
loose stool are produced in about 50% patients due to
fermentation of unabsorbed carbohydrates
• Hypoglycemia should be treated with oral glucose
(dextrose) and not sucrose (absorption might be delayed)
• Contraindicated in cirrhosis, malabsorption, severe renal
impairment

65. Pramlintide
• An injectable (S.C.) synthetic analog of amylin, 37-
aminoacid hormone produce from pancreatic beta cells
• Control the glycemia by activating high-affinity receptors
involved in both glycemic control and osteogenesis
• Other actions:
• Suppresses glucagon release
• Slows gastric emptying
• Works in the CNS to reduce appetite
• SC route  has short duration of action
• Used with insulin to suppress the post prandial glycemia
• ADR: hypoglycemia, GIT discomfort

66. Sodium-glucose transporter 2 (SGLT2)
inhibitors
•Examples: canagliflozin and dapagliflozin
•MOA: 90% of renal glucose reabsorption 
occurs by SGLT 2  inhibition causes
glycosuria and lowers glucose levels in
patients with type 2 diabetes
•ADR: incidence of genital infections and
urinary tract infections.
•The osmotic diuresis can also cause
intravascular volume contraction and
hypotension

67. Hyperosmolar (nonketotic hypergly-
caemic) coma
• Occurs in type 2 DM.
• Uncontrolled glycosuria of DM produces diuresis resulting
in dehydration and haemo-concentration over several days
→ urine output is finally reduced and glucose accumulates
in blood rapidly to > 800 mg/dl, plasma osmolality is > 350
mOsm/ L → and can cause coma, and death
• Management
• Same as for ketoacidotic coma, (except that faster fluid
replacement is to be instituted ,Alkali is usually not
required).
• These patients are prone to thrombosis (due to hyper
viscosity and sluggish circulation)  prophylactic heparin
therapy is recommended.

68. Herbals and Dietary Supplements
that affect blood glucose levels
•Bee pollen, gingko biloba and
glucosamine are thought to increase
blood sugars or may potentially affect
beta-cell function and insulin secretions
•Basil and bay leaf, okra, black plums and
bitter guards may cause hypoglycemia
•Chromium may increase production of
insulin receptors and increase insulin
effectiveness

69. Management approaches in DM

70. Hyperglycemic agents
1. Glucagon: a single chain polypeptide hormones release from α cells
of the islets of Langerhans
• Synthetically obtained from recombinant DNA tech.
• MOS: thr’ Gs-PCR mechanism  inc. AC  release cAMP  Ca+2
cons inc’ in liver, fat cells, heart and other tissues
• PK: inactivate thr’ oral route
• Endogenous glucagon is broken down in liver, kidney, plasma and
other tissues
• Its t½ is 3–6 min
• Uses: hypoglycemia, 0.5–1.0 mg i.v. or i.m., followed by oral
glucose/sugar
• Cardiogenic shock to stimulate the heart in β adrenergic blocker
treated patients (intoxication of blockers)
• In radiographic examination of upper/lower g.i. tract by relaxing
stomach and intestines

71. Cont’d…
2. Diazoxide: related to thiazides
• It inhibits insulin release from β cells and causes
hyperglycaemia lasting 4–8 hours
• Act on ATP sensitive K+ channels of β cells is opposite to
that of Sus
• Also decreased peripheral utilization of glucose and release
of catecholamines
3. Somatostatin
• By inhibiting insulin release
4. Streptozocin
• Causes selective damage to insulin secreting β cells.