Pharmacology High Yield

1. Insulin Pharma Lecture Notes
Compiled by Shivankan Kakkar, MD
Diabetes mellitus (DM) is diagnosed when:
• Fasting blood glucose exceeds 126 mg/dl or
• Postprandial glucose > 200 mg/dl or
• HbA1c > 6.5g%.
Type I DM (IDDM) is treated only by insulin whereas in the treatment of
type II DM (NIDDM), orally active drugs are tried first in uncomplicated cases.
INSULIN
It was discovered by Banting and Best in 1921. It consists of 51 amino acids arranged in two
chains; A (21 amino acids) and B (30 amino acids).
SECRETION OF INSULIN
Glucose is the main stimulus for release of insulin. It enters beta cells via GLUT-2. Within
beta cells, glucose is metabolized and generates ATP that inhibits ATP sensitive K channels.
As K+ is not able to go out, beta cells getslightly depolarized. This triggers opening of
Ca2+ channels resulting in secretion of insulin.

2. Secretion of insulin

3. • Somatostatin and α2 agonists inhibit the release of insulin whereas glucagon, vagus and
β2 receptor activation stimulates the release of insulin.
Actions
1. It decreases blood glucose by
• Stimulating the entry of glucose in muscle and fat (by increasing the
synthesis of GLUT 4).
• Inhibiting glycogenolysis (by inhibiting phosphorylase) and gluconeogenesis (by
inhibiting phosphoenol pyruvate carboxykinase). These processes are inhibited
at lower concentration of insulin.
• Increasing glycolysis (by stimulation of glucokinase) and glycogenesis (by
stimulating glycogen synthase). These require more concentration of insulin.
2. It inhibits lipolysis and thus favors triglyceride deposition.
3. It increases the synthesis and inhibits the breakdown of proteins.

4. Routes of administration
• All preparations can be given by s.c. route on abdomen (except 2
inches around umbilicus), thigh, buttocks, or dorsal arms.
• Only regular (crystalline zinc) insulin can be given i.v.
• Inhalational insulin (exubera) had lead to lung cancers and
fibrosis. In june 2014, a new inhalational insulin (Afrezza) was
approved by FDA for type-1 DM. It should not be used in patients
with chronic lung diseases like asthma.
Insulin injection sites

5. • Site of injection (most rapid from abdomen followed by arm, buttock and thigh).
• Type of insulin (Fast with regular, aspart, lispro and glulisine)
• Subcutaneous blood flow (rate increases with massage, hot bath or exercise).
• Depth of injection (faster with IM than with SC route)
Complications of insulin therapy
• Most common complication is hypoglycemia that can be treated by glucose (oral or IV) or
glucagon (IV).
Factors affecting insulin absorption
• Lipodystrophy at the injection site can occur with conventional preparations and the chances
are less with highly purified and recombinant forms of insulin.
• Allergic reactions like lipoatrophy can occur with conventional preparations.
• Sodium and water retention leading to edema has been rarely reported. Drug interactions
• Use of non-selective beta blockers in patient on insulin therapy delays the recovery from
hypoglycemia (less chances with cardioselective beta blockers). These drugs may also mask the
warning signs of hypoglycemia i.e. palpitations, tremors and anxiety. All the warning signs may be
masked except sweating (It is mediated by sympathetic cholinergic fibres and not by beta
receptors)
• Acute consumption of alcohol can precipitate hypoglycemia.
• Drugs elevating blood glucose (diuretics, corticosteroids, oral contraceptives and
diazoxide etc.) decrease the effectiveness of insulin.

6. Indications of insulin therapy
• All cases of IDDM
• NIDDM patients
– Not controlled on OHA
– In pregnancy
– In complications like diabetic ketoacidosis and hyperosmolar coma (regular insulin i.v. is
preferred).
– To tide over stressful conditions like infections and surgery etc.
• Acute hyperkalemia
Preparations
Conventional preparations are obtained from pork and beef. Addition of zinc makes it long
acting.

7. Type
Insulin Onset Duration Comment
Rapid Acting
Lispro 15-20 min 3-4 hours Present as monomers
Apart 15-20 min 3-4 hours Most rapidly acting
Glulisine 15-20 min 3-4 hours
Short Acting
Regular 30-60 min 5-8 hours Regular insulin can be given
i.v.
Semi-Lente 1-2 hours 8-12 hours
Intermediate Acting
NPH or Isophane 2 hours 16-18 hours
Lente
(30% amorphous + 70%
crystalline)
2 hours 16-20 hours
Long Acting
Ultra–Lente 4-6 hours 20-36 hours
Glargine 4-6 hours 15-24 hours Supplied at pH = 4
Detemir 2-4 hours 20-24 hours
Degludec 2-4 hours 24-40 hours