Made for a pharmacology presentation. includes case history, basic pathophysiology, treatment aproaches

1. MELLITUS

2. DEFINITION
DIABETES MELLITUS (DM) - a group of
heterogeneous metabolic disorders in
which there are high blood sugar levels
over a prolonged period of time
•the third leading cause of death and
second leading cause of blindness as well
as of renal failure.
•characterised by hype!rglycaemia,
glycosuria, hyperlipidemia, negative
nitrogen balance and ketonaemia.

3. HISTORY
Name - Mr. X
Reg no. 336458
Age, Sex - 35 yrs old male
Address- malvya nagar indore
Occupation- plumber
Date of admission- on 5th December 2014
Chief complaints-
• Abdominal pain for 3 days
•Nausea and vomiting for 3 days
History of presenting illness – The patient was
apparently alright 3 days back when he had complaint of
abdominal pain which was sudden in onset located in
umbilical region non radiating and dull aching type.
Pain was continuous without diurnal variation
Pain was not associated with constipation ,diarrhoea

4. Patient also complains of nausea and vomiting just after meal
for 3 days with general body weakness.
Past History
Patient has a history of diabetes mellitus type 1 for 4-5 years
for which the he has been taking subcutaneous insulin
regularly.
No history of TB , Asthma hyper/hypo thyroid ,hypertension.
No relevant surgical history.
No relevant family history.
Personal History
Bladder and bowel habits – normal
Sleep pattern – normal
Appetite decreased
No addiction
Mixed diet

5. Drug history
Patient is on 20U insulin daily in 2 divided doses before
breakfast and dinner.
Patient has no known allergy to any drug.
GENERAL EXAMINATION
Patient was well oriented to person place and time at the time
of examination.
1. BP as seen in right brachial artery – 100/70 mm of Hg
2. Pulse rate as seen in right radial artery – 84 per minute,
rhythmic, normovolumic and equal on both sides.
3. Respiratory rate – 14 per minute, rhythmic
4. Icterus is absent as seen on bulbar conjunctiva of both
eyes
5. Pallor is absent
6. Cynosis is absent
7. Lymph nodes are not palpable
8. Oedema is absent

6. INVESTIGATIONS RECOMMENDED
•Oral Glucose Tolerance test
•Fasting blood glucose monitoring
•Post prandial blood glucose monitoring
•Glycosylated haemoglobin (HbA1c) estimation
•Blood profile – CBC, ESR, lipid profile, serum
electrolytes etc.
•Liver function tests
•Renal function tests – detection of glucose, ketone
bodies

7. ROUTINE URINE EXAMINATION
Character Result Normal Value
Albumin Absent Absent
Sugar Present++ Absent
Ketone Bodies Present+++ Absent
Chemical Examination

8. GLYCOSYLATED HAEMOGLOBIN (HBA1C)
Estimated value = 10.17%
Normal value = 3-6%

9. SERUM ELECTROLYTES
Electrolyte Result Normal value
Sodium (mEq/L) 130 135-145
Potassium(mEq/L) 3.56 3.5-5
Chloride(mEq/L) 92 96-107

10. COMPLETE BLOOD COUNT
Investigation Result Normal Value Unit
Haemoglobin 14.1 Male – 13-17
Female – 11.5-
15.5
gm%
Total RBC 5.40 Male – 4.5-6.5
Female – 3.8-5.8
mill/cumm
Total WBC 9,900 4,000 – 11,000 /cumm
Neutrophils 63 40 – 70 %
Lymphocyte 32 20 – 45 %
Monocyte 04 2 – 10 %
Eosinophils 01 1 – 6 %
Basophils 00 0 – 1 %
Platelet Count 2.77 1.5 – 4.5 Lakh/cumm

11. LIPID PROFILE
Investigation Result Normal Values Unit
S. Total
Cholesterol
173 150 – 250 mg/dl
S. HDL
Cholesterol
34 35 – 60 mg/dl
S. LDL
Cholesterol
101 90 – 140 mg/dl
LDL : HDL 2.9 : 1
Serum
Triglyceride
77 60 – 170 mg/dl
NOTE : Ultrasonography report detected no significant abnormality in
abdomen

12. DIAGNOSIS
Patient suffers from diabetic
ketoacidosis superimposed by
gastrointestinal infection.

13. DIABETES MELLITUS
CLASSIFICATION
Type 1 – juvenile onset, insulin dependent
Destruction of beta cells, majority autoimmune, low
circulating insulin levels
Type 2 – maturity onset, non insulin dependent
Relative deficiency of insulin, low to high circulating
insulin, insulin resistance , majority obese

14. Gestational diabetes mellitus – 4% pregnant women,
reverts to normal but increased risk of diabetes in
future
Other types – due to genetic or acquired factors

15. SYMPTOMS
DIABETES
Fruity
Odour
Polyphagia
PolydypsiaPolyuria
Easy
fatigability

16. TREATMENT APPROACH
FOR TYPE-1 DM
Insulin has to be administered exogenously.
TREATMENT APPROACH FOR
TYPE-2 DM
Oral hypoglycaemics are more useful
initially, insulin in later stages.

17. INSULIN PREPARATIONS
Insulin is a peptide hormone secreted by beta
cells of pancreatic islets, consisting of two
chains-
A chain with 21amino acids
B chain with 30 amino acids
Joined by disulfide bonds
Insulin is synthesized after removal of
C peptide (35 amino acids) from proinsulin
Several insulin preparations are available,
produced by recombinant DNA techniques.
These are classified according to there
duration.

19. • glulisine
• Aspart
• lispro
ULTRA SHORT
ACTING
• RegularSHORT ACTING
• NPH (Neutral Protamine
Hegadron)
• Lente
INTERMEDIATE
ACTING
LONG ACTING •Glargine
•Detemir
INSULIN PREPARATIONS - CLASSIFIED
ACCORDING TO DURATION OF ACTION

20. INSULIN ANALOGUES
 Produced by DNA recombinant technology, higher
stability and consistency
 INSULIN LISPRO – produced by reversing proline
and lysine at carboxy terminus, shorter duration of
action than human insulin
 INSULIN ASPART – produced by replacing proline
of human insulin with aspartic acid
 INSULIN GLULYSINE – lysine replaces aspargine
and glutamic acid replaces lysine in human insulin

21. REGULAR (SOLUBLE) INSULIN
 It is a buffered neutral pH solution of unmodified
insulin stabilised by a small amount of zinc
 Insulin molecules aggregate around zinc – form
hexamers, slowly dissociate on subcutaneous
injection.
 Absorption rate depends upon multiple factors –
injected before meal may cause early post prandial
hyperglycaemia and late post prandial hypoglycaemia

22. LENTE INSULIN
 These are insulin zinc preparations
 Ultralente – crystalline, long acting, water insoluble form
 Semilente – amorphous form with shorter of
actionduration
 Lente insulin is a 7 : 3 ratio mixture of ultralente and
semilente, with intermediate duration of action.

23. ISOPHANE (NEUTRAL PROTAMINE
HEGADRON) INSULIN
 Protamine is added to insulin such that all molecules
of insulin are complexed and neither is present in free
form.
 S.c. injection – slow dissociation with intermediate
duration of action

24. LONG ACTING PREPARATIONS
 INSULIN GLARGINE – it is soluble at acidic pH (4)
at which it is administered, but at neutral pH
encountered on s.c. administration, it precipitates –
long duration of action with low blood levels and
peakless effect is obtained.
 INSULIN DETEMIR – binds to albumin after
injection, slowly released

25. ADMINISTRATION REGIMENS
Insulin is administered in such a way that
euglycaemia is maintained round the clock.
BASAL BOLUS REGIMEN
•One long acting + rapid
acting preparations
•3 to 4 injections
•Rapid acting given before
meals
•Long acting given before
breakfast or at bedtime,
once.

26. SPLIT MIXED REGIMEN
•Regular and NPH
insulin Mixed in ratio of
70:30
•Injected before
breakfast and dinner

27. ADVERSE EFFECTS OF INSULIN
THERAPY
1. Hypoglycemia
2. Local reactions – swelling, erythema.,
stinging sensation, lipodystrophy.
3. Allergy
4. Edema

28. ORAL HYPOGLYCAEMICS
 INSULIN SECRETAGOGUES
1. Sulfonylureas – glipizide,gliclazide(K-ATP
channel blockers)
2. Meglitinide analogues – rapaglinide, nateglinide
3. GLP-1 receptor agonist – exenatide,liraglutide
4. DPP-4 inhibitors – sitagliptin, vildagliptin

29. TO OVERCOME RESISTANCE
1. Biguanides – metformin (AMPK activator)
2. Thiazoledinediones – pioglitazone
MISCELLANEOUS DRUGS
1. Alpha glucosidase inhibitor – voglibose,
acarbose
2. Amylin analogues – pramlintide
3. D2 receptor agonist – bromocriptin
4. Sodium Glucose cotransporter -2 inhibitor -
dapagliflozin

30. ADVERSE EFFECTS OF ORAL
HYPOGLYCAEMICS
1. Hypoglycemia
2. Nonspecific – weight gain, nausea vomiting,
flatulence, diarrhea, headache , paraesthesia
3. Hypersensitivity- rashes,photosensitivity, purpura
, leukopenia

31. SULFONYLUREAS
MECHANISM OF ACTION

32. SPECIFIC ADVERSE EFFECTS
 Weight gain – due to fluid retention and edema
 Foetal hypoglycaemia –contraindicated in
pregnancy
 Disulfiram like effect with alcohol.
 Rare – photosensitivity , skin rash , cholestastic
jaundice , blood dyscrasias

33. MEGLITINIDE ANALOGUES
MECHANISM OF ACTION
 Act on the same receptors on ATP sensitive potassium
channels as sulfonyluras and increases insulin secretion.
These drugs have a rapid onset of action and hence are
given before meals – risk of hypoglycaemia is high if meal
is skipped.

34. GLUCAGON LIKE PEPTIDE-1 ANALOGUES
AND DIPEPTIDYL PEPTIDASE - 4 INHIBITORS
 GLP-1 and GIP act on their own GPCRs and
activate adenyl cyclase to generate cAMP, which
promotes exocytosis of insulin.
 Incretin GLP-1 and GIP are inactivated by capillary
endothelial enzyme DPP-4. Action of incretins is
enhanced by DPP-4 inhibitors.

36. BIGUANIDES
MECHANISM OF ACTION
 Activation of AMP dependent protien kinase, leading to
 Suppression of hepatic gluconeogenesis and glucose output
from liver
 Enhanced insulin mediated glucose uptake and disposal in
skeletal muscle and fat
 Promotion of peripheral glucose utilisation through anaerobic
glycolysis by interference with mitochondrial respiratory chain

37. CONTRAINDICATIONS
 Hypertension
 Heart failure
 Respiratory disease
 Hepatic disease
 Renal disease
 Alcoholics (risk of lactic acidosis)
ADVANTAGES OVER OTHER HYPOGLYCAEMICS
• non hypoglycaemic
•Weight loss promoting
•Prevents microvascular as well as macrovascular
complications
•No acceleration of beta cell exhaustion

38. THIAZOLIDINEDIONES (PPAR Γ AGONIST)
MECHANISM OF ACTION
THIAZOLIDINEDIONES
Bind to nuclear
PPARγ receptor
Activate insulin
responsive
genes that
regulate
carbohydrate
and lipid
metabolism
Sensitizes peripheral
tissues to insulin
Reduces
blood
glucose

39. COMPLICATIONS OF DM
 Diabetes mellitus is fatal due to its acute
and chronic complications.
ACUTE METABOLIC COMPLICATIONS
 Diabetic ketoacidosis
 Hyperosmolar nonketotic coma
 Hypoglycaemia
CHRONIC SYSTEMIC COMPLICATIONS
 Microangiopathy
 Nephropathy
 Neuropathy
 Retinopathy
 Infections

40. MANAGEMENT OF ACUTE
COMPLICATIONS
I. DIABETIC KETOACIDOSIS
 Commonly seen in type I DM
 Precipitating factors – infections, pancreatitis,
stress, inadequate dose of insulin, etc.

41. PATHOGENESIS OF DIABETIC KETOACIDOSIS
DIABETIC KETOACIDOSIS
HYPERGLYCAEMIA METABOLIC
ACIDOSIS
Osmotic Diuresis
Dehydration
Electrolyte Loss
(Sodium, Potassium)
ELEVATED
SRESS
HORMONES
Lipolysis↑
↑ Free Fatty
Acids
↑ hepatic
ketogenesis
KETOSIS
Accumulation of ketone bodies in blood

42. Management :
Insulin – bolus dose 0.1-0.2 U/kg i.v.
followed by 0.1 U/kg/hr i.v. Infusion
Infusion reduced to 2-3 U/hr when blood
glucose falls to 300 mg/dl
Maintained till patient becomes fully
conscious
Routine therapy with s.c. Insulin is instituted
KCl – hypokalaemia is due to insulin administration
(large amounts driven intracellularly).
Add 10 mEq/hr KCl to i.v. Fluid, guided by serum K
measurements and ECG.

43. Intravenous fluids – to correct dehydration – normal
saline is infused at the rate 1 L/hr, reducing
progressively to 0.5 L/4 hours.
change over to ½ N saline once BP and HR have
stabilized and renal perfusion is adequate
When blood sugar reaches 300 mg/dl, infuse 5% glucose
with ½ N saline.
Sodium Bicarbonate – 50 mEq added to i.v. Fluid only if
acidosis doesn’t subside spontaneously, blood pH<7.1.

44. Phosphates – when serum phosphate is in
low to normal range
Antibiotics and other measures to treat the
underlying cause.
2. HYPEROSMOLAR COMA
 Seen usually in type 2 patients
 Mechanism – uncontrolled glycosuria produces
diuresis, leading to dehydration and
haemoconcentration over long time, which
reduces urine output and glucose accumulates
rapidly in blood, blood osmolarity > 350
mOsm/lit precipitates coma.

45.  Treatment strategy remains same as that in diabetic
ketoacidosis, except that
 Faster fluid replacement is needed
 Alkali is not required
 Hyperviscosity and sluggish flow predisposes to thrombosis,
prophylactic heparin therapy required
3. HYPOGLYCAEMIA
Due to insulin overdose or missing a meal after injection.
More common in labile patients – insulin requirement fluctuates
unpredictably.
Treatment – glucose 0.5 – 1 mg i.v. or Adr 0.2 mg s.c.

46. DRUGS ADMINISTERED
 I.V. NS + KCl 150 ml/hr – intravenous fluid
infusion to maintain volume balance and KCl for
electrolyte balance
 I.V ns + oframax 100 ml +1 gm – ceftriaxone to
prevent and treat infection (precipitating cause)
 Tab. Pantocid 40 mg BD – pantoprazole to
reduce gastric acid secretion, to treat gastric ulcer
 i.v. zofer 4 mg SOS – ondansetron to treat
nausea and vomiting

47.  Syp. Sucrol 2 table spoon TDS – sucralfate as
ulcer protective
 S.c. mixtrad 30/70 (26 U + 20 U) – for split mixed
regimen for insulin administration.