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PHARMACOLOGY
‫علم األدوية‬

Dr. Ahmed Al- Akydy

Assoc. Prof.
of
Pharmacology & Therapeutics
 Antidiabetic Drugs
Insulin & Non- Insulin Antidiabetic drugs
 Diabetes Mellitus (DM)
 Definition:
 A group of chronic metabolic disorders characterized by hyperglycemia and
alterations in lipid and protein metabolism.
 Causes
1) Lack of insulin (absolute/or relative)
2) Resistance to insulin
3) Disorders of other hormones → impaired insulin secretion & action.
 Complications:
A. The short- term (acute) complications:
1. Hypoglycaemia
2. Diabetic ketoacidosis(DKA)
3. Hyperosmolar hyperglycaemic state (HHS)
B. The long – term (chronic) complications
1. Macrovascular complications:
 Fatal and result from damage to large blood vessels, such as those supplying
blood to the heart, brain and legs (IHD, stroke & PVD)
2. Microvascular complications:
 Result from damage to smaller vessels, such as those supplying blood to the eyes
and kidneys (retinopathy, nephropathy and neuropathy)
 DM - Classification
Items Type 1 Type 2
Other name IDDM, juvenile-onset DM NIDDM, adult-onset DM
Age of onset (year) < 30 (peak 12–14) > 40 (peak between 60 & 70)
Prevalence 5-10% 90- 95%
Autoimmune → β- cell
Pathogenesis Insulin resistance & β-cell dysfunction
destruction
Present in low, ―normal,‖ or high
Endogenous insulin Absent
amounts
Relative/or partial insulin receptor
Insulin deficiency Absolute
defect?
Insulin resistance Absent Present
FH (genetic) Weak (5-15%) Strong (80%)
Body built Thin Obese (majority)/or H/o obesity
Rapidly/or abrupt (days -
Onset of symptoms Slow & gradual (months - years)
weeks), & extreme
Ketosis Yes, DKA No, HHS
Diet + exercise + oral hypoglycaemic
Treatment Diet + insulin
agents + insulin (if other therapies fail)
3) Genetic Defects
 Latent Autoimmune Diabetes in Adults (LADA)
 Maturity-onset diabetes of the young (MODY)
4) Gestational Diabetes Mellitus (GDM):
 A glucose intolerance which is first recognized during pregnancy

5) Secondary DM
Disease  Example(s)
1) Exocrine  Chronic pancreatitis, Pancreatic cancer, Trauma,
pancreas diseases Cystic fibrosis, Pancreatectomy
2) Endocrine  Acromegaly, Cushing’s syndrome,
disorders Phaeochromocytoma, Thyrotoxicosis
3) Infections  CMV, Coxsackie B, Congenital rubella virus
4) Medications  Glucocorticoids, Phenytoin, Thiazide diuretics
 DM- Symptoms & Signs
1. ―The Polys‖: Polyuria, Polydipsia, Polyphagia
2. Unexplained weight loss, Fatigue
3. Blurred vision
5. Frequent infections: skin, urogenital (urethritis, pruritis vulvae, balanitis,
vaginitis)
6. Slow healing of cuts/or wounds
7. Complications
o Diabetic Ketoacidosis (DKA)/ or hyperosmolar hyperglycaemic state(HHS)
→ lethargy, weakness, stupor, coma & death
o Long term complications: vascular, heart, & renal diseases, neuropathy,
retinopathy, arthropathy.
Diagnostic criteria
Plasma tests (on > 1 occasion) mg/dL mmol/L
1. Fasting plasma glucose (FPG) ≥ 126 ≥ 7.0
2. Random plasma glucose (RPG) ≥ 200 ≥ 11.1
3. OGTT (2- h postload glucose) ≥ 200 ≥ 11.1
4. Hemoglobin A1c (Hb A1c) ≥ 6.5%
 Management of DM
A B

Pharmacological therapy

1- Insulin therapy

Non-pharmacological therapy 2- Oral hypoglycaemic therapy

Medical nutrition
Exercise
therapy (MNT)

Smoking Alcohol in
cessation moderation

Pt' education Monitoring

 Glucose transporters

1) Insulin –independent Tissue 2) Insulin –dependent Tissue

transporters transporters
o GLUT1 Brain, RBCs
o GLUT2 Pancreatic beta
cells, liver
o SGLT: reabsorb filtered renal Kidney
glucose into tubular cells SGLT2 (90%)
o GLUT2 : release glucose from SGLT1 (10%) Adipose
tubular cells to blood tissue
o SGLT1: absorb glucose from GI tract
intestinal lumen to enterocytes GLUT4
o GLUT2: release glucose from
enterocyte to blood
Muscles
o SGLT1 Eye, heart, lungs
o GLUT 3 Brain, placenta
 Endogenous insulin  Insulin synthesis
 An anabolic, polypeptide hormone, & is Preproinsulin
essential in homeostatic regulation of BG.
Proinsulin
Protease enzymes

Insulin (MW 5808 Da)

+
C-peptide (inactive)
 Insulin secretion
 Insulin function

3
K+
 Pattern of endogenous insulin secretion during 24-h profile

50
Insulin(µU/mL)
25 50%
0 Basal Insulin 1) Bolus insulin (mealtime
Breakfast Lunch Dinner (prandial)
50%  Limits hyperglycemia
150 after meals
 Immediate ↑ & sharp
1. Basal insulin
peak at 1 h
100
Glucose (mg/dL)

 Suppresses glucose
 10 - 20% (5–10 units) of
production between
total daily insulin
meals & overnight 50 need/each meal.
 50% of total daily
Basal Glucose
insulin need (1unit/h) 0
7 8 9 10 11 12 1 2 3 4 5 6 7 8 9
AM Time of Day PM

Insulin therapy mimics the pattern of endogenous insulin secretion

Insulin (the key) Insulin receptors Target cell (the lock)

Insulin’s functions & consequences of insulin deficiency

Insulin effect (s) Insulin deficiency
 ↑ Glucose uptake  ↑ FFA levels
 ↑ lipogenesis  ↑TGs
 ↓lipolysis
 ↑glycogen synthesis  Ketoacidosis (↑
 ↓Gluconeogenesis ketone bodies)
 ↑ lipogenesis (inhibits ketogenesis)
 ↑Glucose uptake  Muscle wasting
 ↑Glycogen synthesis
 ↑ protein synthesis (d/t ↑AA uptake)
 Inhibits protein breakdown
 Types of insulin preparations

1) Conventional (animal) insulin preparations

 Contain pancreatic proteins, proinsulin,
insulin fragments, can cause immunogenicity
& insulin resistance.
o Bovine (beef) insulin: differs from human
insulin by 3 AA residues
o Porcine (pig) insulin: differs from human
insulin by only one AA residue

2) Highly purified insulin preparations

 More stable, less immunogenic; cause less insulin resistance & lipodystrophy at
the site of injection
A.Monocomponent pork insulin
 Prepared by purification techniques of conventional porcine insulin
B.Human insulins:
 Produced by rDNA technology using E.coli/or yeast (e.g., human regular
insulin, human neutral protamine hagedorn (NPH) insulin)
 The commonly used insulin preparations.
 Insulin products: different in their onset, peak, & duration of action
1) Human insulin preparations
Insulin type Onset (h) Peak (h) Duration (h)
 Short- acting insulin (clear solution) ─Bolus
o Regular (soluble 0.5-1 2–4 6–8 o 30 – 45 min
crystalline zinc) before meals
o To ↓ high BG
 Intermediate - acting insulin (cloudy suspension) ─Basal
• NPH (isophane): 1- 2 8 16 - 20 o Once (bedtime)
insulin + protamine o BID (morning &
• Lente: insulin + zinc evening)
 Long –acting insulin (clear solution) ─Basal
o Ultratard 4 6-16 24-30 o Once (bedtime/or
prebreakfast)
 Mixtures (cloudy) ─Bolus + Basal
o Humulin M1 o Short (10%) & intermediate (90%)
o Humulin M3 o Short (30%) & intermediate (70%)
2) Analogue insulin preparations
Insulin type Onset (h) Peak (h) Duration (h) Adm.
1. Ultra-short (rapid)- acting insulin — (clear solution)─ Bolus
• Insulin lispro 15- 30 1-2 <5 o 0-15 min before
• Insulin aspart meals
• Insulin glulisine o To ↓ high BG
2. Long - acting insulin (clear solution)
• Insulin glargine o 2-4 o Flat o 20-24 o OD
• Insulin detemir o BID
• Insulin degludec Peakless
o > 42 o OD
3. Combination insulin products
A. Premixed insulins — cloudy o Basal + bolus
o NPA+ insulin aspart: 70%/30% o NovoLog Mix 70/30 o BID (pre-breakfast
o NPL+ insulin lispro: 75%/25% o Humalog Mix 75/25 & dinner)
o NPL + insulin lispro: 50%/50% o Humalog Mix 50/50 o OD (rarely)
o NEVER at bedtime
B. Insulin + GLP-1 receptor agonist o Single injection.
o Degludec + liraglutide
o Glargine + lixisenatide
 Oral inhalation insulin (Exubera)
o An alternative to mealtime injectable insulin
d/t has an onset of action,10 - 20 min & a
duration of action of 6 h Bolus only

o Not totally replace injectable insulin d/t long-

acting insulin injections are necessary for basal
control
o Monitoring: lung function (at baseline & 6
months’ post initiation of therapy)
o Contraindications:
• Not recommended for patients:
 with chronic lung disease (e.g., asthma,
COPD)
 who smoke/or who have stopped smoking
within the past 6 months
 Insulin delivery
 Orally, insulin not effective, d/t it is
destroyed by proteolytic enzymes in the GI
tract
A. Injections:
o SC: abdomen (avoid 5 cm radius around
the umbilicus)/or lateral, anterior thigh /or
dorsal, upper arm/or buttock
o IV: regular insulin, raid- acting (lispro,
aspart, & glulisine)
B. Oral inhalation insulin
 Insulin administration devices
1) Insulin syringes + shorter needles (4–6
mm)
2) Pen injector devices + shorter needles (4–
6 mm): refillable/or disposable, holds
1500 U total, & can injects 300 U at one
time
3) Insulin pump therapy
 A small computerized device that delivers
insulin continuously throughout 24 hours daily
 Regular/or rapid -acting insulin are used.

Advantages Disadvantages
1)Accurate dosing: maintain basal 1)Skin problems: allergic reactions to tape, &
levels & a bolus dose prior to meals infection at infusion site
2)Flexible way to deliver insulin: 2)Expensive
timing & content of meals, 3)Pump malfunction
exercise, sick-day
3)Attains excellent glucose control 4)Lack of insulin reservoir → rapidly develop DKA.
with less hypoglycemia 5)Patients need extensive training on how to use &
maintain pump.
 Adverse effects of insulin
1. Hypoglycaemia: the most common
2. Lipodystrophy [lipohypertrophy/lipoatrophy
(rare)] at the site of injection
3. Bruising: usually d/t superficial injection
4. Hypokalemia
5. Local/or systemic allergic reactions
6. Immune insulin resistance:
 A state in which patient requires > 200 U/d, d/t
antibodies → changing to a highly purified
insulin preparation
6. Weight gain & oedema: d/t salt & water
retention

 Insulin storage:
• Typically refrigerated, & most products are stable for 28d at room Temp.
• Insulin detemir can be stored at room temperature for 42 days
• The vial (s)/cartridge/or pen in current use may be stable for 4 – 6 wks.
• The injecting of cold/or refrigerated insulin is undesirable d/t it is more painful
& the insulin absorption profile is altered.
 Insulin therapy
 Insulin can be used in all types of DM
A. Short-term use B. Long-term use
1) Acute illness, stress, infections, surgery & MI 1) T1DM (the primary
2) Pregnant & breast-feeding women treatment)
3) As initial therapy in T2DM diagnosed during stress 2) T2DM
4) Marked hyperglycaemia unresponsive to
5) DKA, HHS, lactic acidosis, severe oral antidiabetics
hypertriglyceridaemia
6) Hyperkalaemia (IV+ glucose)

Before After
 Insulin units
 U-100 (100 U/mL), U-40 (40 U/mL), 200 U/mL (insulin degludec & insulin
lispro), 300 U/mL (insulin glargine) & 500 U/mL (regular insulin)
 Estimating total daily dosing (TDD) insulin requirements:
 Type 1  Initial TDD  0.5–0.6 U/kg/d
DM  Most patients  0.5 - 1 U/kg/d
 With ketosis, during illness, & growth  1–1.5 U/kg
 Type 2 DM  0.7–1.5 U/kg
 Other method:
 TDD = BW(Kg) x 0.55
o Example: TDD = 72.7 kg x 0.55 = 40U
 Percentage of basal & bolus insulin:
 50% basal, 50% bolus (20% prior to breakfast, 15% prior to lunch, & 15% prior
to supper)
o Example:
• Basal = 40 U x 50/100 = 20 U
• Bolus = 40 U x 50/100 = 20U/3 meals = 8 U prior to breakfast, 6 U prior to
lunch & 6 U prior to supper
 Insulin regimens
A. Multiple daily injections (MDI)

Intermediate

B. Continuous subcutaneous insulin infusion (CSII/or insulin pump)

 Follow up of insulin therapy
1) Portable glucometer (capillary
blood glucose)

2) By urine dipsticks (glucose in

urine)
 Amylin analogues (e.g., Pramlintide)
 A synthetic amylin analog
 Delays gastric emptying, ↓ postprandial glucagon secretion, & ↑
satiety. Bolus

 Indicated as an adjunct to mealtime insulin therapy in patients with

T1DM/or T2 DM → dose of rapid/or short-acting insulin should be ↓ by 30-
50% prior to meals to avoid a risk of severe hypoglycemia.
 Administered by SC injection, immediately prior to meals
 Not mixed in the same syringe with any insulin preparation.
 Adverse effects:
• GI upset: nausea, anorexia, & vomiting
 Contraindications: diabetic gastroparesis (delayed stomach emptying)/or a
history of hypoglycemic unawareness
 Thank you
Any question?

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