DRUGS FOR THE TREATMENT OF DIABETES MELLITUS

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• DRUGS FOR THE TREATMENT OF DIABETES MELLITUS

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DIABETES MELLITUS

• One of the leading cause of death by diseases
  (cardiovascular problems, stroke)
• One of the leading cause of blindness
• One of the leading cause of renal failure
• One of the leading cause of impotence (males)
• Risk of foot amputation

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N.B. IDDM insulin dependent diabetes
mellitus. NIDMM non-insulin dependent diabetes
mellitus.
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Characteristic Type 1 ( 10 ) Type 2 (90)
Onset (Age) Usually lt 30 Usually gt 40
Type of onset Abrupt Gradual
Nutritional status Usually thin Usually obese
Clinical symptoms Polydipsia, polyphagia, polyurea, weight loss Often asymptomatic due to insulins presence
Ketosis Frequent (acetone aroma) Usually absent
Endogenous insulin Absent Present, but relatively ineffective
Related lipid abnormalities Hypercholesterolemia frequent, all lipid fractions elevated in ketosis Cholesterol triglycerides often elevated carbohydrate- induced hypertriglyceridemia
Insulin therapy Required Required in 20 - 30 of patients (for postprandial hyperglycemia)
Hypoglycemic drugs Should not be used Clinically indicated
Diet Mandatory with insulin Mandatory with or without drug (can be controlled by diet exercise)
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Effects of insulin
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Insulin deficiency
?K uptake by cells
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Some notes
Glucose is reabsorbed in the kidney tubules in
the form of glucose 6 phosphate. In diabetic
patients glucose filtration floods the renal
tubules exceeding 180 g/dl, threshold for
glucoses reabsorption, leading to the appearance
of glucose in the urine (glucosuria). This
results in osmotic dragging of water into the
tubules resulting in polyuria with subsequent
polydypsia.
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Insulin Degradation

• Hydrolysis of the disulfide linkage between
• a ß chains.
• Metabolism of insulin
• Endogenous 60 in liver 40 in kidney
  (because it goes directly to the liver by the
  portal circulation).
• Exogenous 60 kidney 40 liver
• Half-Life 5-7min (endogenous insulin)
• Delayed-release form( injected one)
• Pregnant women with type II or gestational DM
  should take insulin by injection and avoid taking
  oral hypoglycemics.

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contd

• Category B (not teratogenic)
• The site of injection should be changed every
  once in a while,
• (Injection in same place ? hypertrophy to
  subcutaneous tissue ? ? absorption)
• Should be stored in refrigerator warm up to
  room temp before use.
• Must be used within 30 days.

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Fast action of insulin in the abdomen
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TYPES OF INSULIN PREPARATIONS

• A) Insulin used to control postprandial (after
  meals) hyperglycemia and emergency ketoacidosis
• Ultra-short-acting ( e.g. insulin lispro, insulin
  aspart)
• Short-acting -Regular- (e.g. Novolin R, Humulin
  R)
• B) Insulin used for maintenance treatment of type
  I DM
• Intermediate-acting (NPH, Lente insulin)
• 4. Long-acting (Glargine ,Ultralente )

Clear liquid
Turbid suspension ???
N.B. NPH Neutral protamine Hagedorn
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Short-acting (regular) insulins e.g. Humulin R, Novolin R
Uses Designed to control postprandial hyperglycemia to treat emergency diabetic ketoacidosis
Physical characteristics Clear solution at neutral pH
Chemical structure Hexameric analogue ? dimeric ? monomeric
Route time of administration S.C. 30 45 min before meal I.V. in emergency (e.g. diabetic ketoacidosis)
Onset of action 30 45 min ( S.C )
Peak serum levels 2 4 hr
Duration of action 6 8 hr (thus creating a risk of nocturnal hypoglycemia)
Usual administration 2 3 times/day or more or when you need
Ultra-Short acting insulins e.g. Lispro, aspart, glulisine
Similar to regular insulin but designed to overcome the limitations of regular insulin
Clear solution at neutral pH
Monomeric analogue
S.C. 5 min (no more than 15 min) before meal I.V. in emergency (e.g. diabetic ketoacidosis)
0 15 min ( S.C )
30 90 min
3 4 hr (less risk of nocturnal hypoglycemia)
2 3 times / day or more or when you need
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Advantages of Insulin Lispro (ultra-short) vs
Regular Insulin (short acting)

1. Rapid onset of action ( patients will not wait
   long before they eat ).
2. Its duration of action is no longer than 3-4 hrs
   regardless of the dose.
3. Decreased risk of postprandial hypoglycemia
4. Decreased risk of hyperinsulinemia

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????? ??????
In emergency you can use either ultra-short or
regular insulin (no difference in the duration of
action because it is given IV)
In postprandial hyperglycemia you can use both but
Ultra-short has less duration of action ? no
hypoglycemia
Use ultra-short, wait for 5 minutes before
having a meal while in regular, wait for 30
minutes
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3. Intermediate - acting insulins

• Isophane (NPH) (Humulin N Novolin N, etc.)
• Turbid suspension (shaken before use)
• Injected S.C. (Only)
• Onset of action 1 - 2 hr
• Peak serum level 5 - 7 hr
• Duration of action 13 - 18 hr
• Insulin mixtures
• 75/25 70/30 50/50 ( mix isophane with
  ultra-short or short acting insulin).

Isophane (NPH)
Ultra-short or short acting
Insulin mixture is given to patients with high
postprandial hyperglycemia
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(contd.)
Lente insulin (Humulin L Novolin L).
Turbid suspension Mixture of 30 semilente
insulin small crystals rapidly acting
70 ultralente insulin
large crystals slow acting with
prolonged duration Injected S.C. (only) Onset
of action 1 - 3 hr Peak serum level 4 - 8 hr
Duration of action 13 - 20 hr
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Contd

• Lente and NPH insulins
• have the same effect.
• given once or twice a day.
• N.B They are not used during emergencies
• (e.g. diabetic ketoacidosis).

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4. Long acting insulins

• e.g. Glargine ( Lantus )
• Insulin glargine
• Onset of action 2 hr
• Absorbed less rapidly than NPH or Lente insulins
• Duration of action up to 24 hr
• Advantages
• Constant circulating insulin over 24 hr with no
  pronounced peak (see next slide)
• Safer than NPH Lente insulins ( less risk of
  nocturnal hypoglycemia)
• Clear solution (does not require resuspension
  before administration)

Designed to overcome the disadvantages of
intermediately acting insulins
Nocturnal ????? ?????
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Profile of Insulin Glargine vs NPH
NPH
Glargine
glargine (plateau )
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• In the previous figure NPH gives a peak
  risk of
• hypoglycemia
• But glargine doesnt give a peak risk of
  hypoglycemia
• N.B intermediate long acting use for
  maintenance of blood sugar during 24 hr in type I
  DM

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Glargine
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Methods of Adminisration

• Insulin Syringes (most common)
• Pre-filled insulin pens (expensive)
• External insulin pump
• Under Clinical Trials
• Oral tablets
• Inhaled aerosol (still undergoing trials)
• Intranasal, Transdermal
• Insulin Jet injectors (needle less)
• Ultrasound pulses

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COMPLICATIONS OF INSULIN THERAPY
1. Severe Hypoglycemia (lt 50 mg/dl )
life-threatening 2. Weight gain
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Contd
3. Local or systemic allergic reactions (rare)
4. Insulin resistance (when the patient needs
more than 200 units/day) (IgG anti-insulin
antibodies, infection, expired insulin(rare)).
5. Lipohypertrophy at injection sites 6.
Hypokalemia
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Severe insulin reaction (Hypoglycemic Shock) Diabetic coma (Diabetic Ketoacidosis)
Onset Rapid Slow- Over several days
Insulin Excess Too little
Acidosis dehydration No Ketoacidosis
Signs and symptoms Signs and symptoms Signs and symptoms
B.P. Normal or elevated Subnormal or in shock
Respiration Normal or shallow Deep air hunger
Skin Pale Sweating Hot dry
CNS Tremors, mental confusion, sometimes convulsions General depression
Blood sugar Lower than 70 mg/100cc Elevated above 200 mg/100cc
Ketones Normal Elevated
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Oral Hypoglycemics

• All taken orally in the form of tablets.
• Patients with type II diabetes have two
  physiological defects
• Abnormal insulin secretion (most important)
• Resistance to insulin action in target tissues
  associated with decreased number of insulin
  receptors

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Oral Anti-Diabetic Agents

1. Sulfonylureas e.g. Tolbutamide, Glyburide.
2. Meglitinides e.g. Repaglinide, Nateglinide.
3. Biguanides e.g. Metformin.
4. Alpha-glucosidase inhibitors e.g. Acarbose.
5. Thiazolidinediones e.g. Pioglitazone.
6. Dipeptidyl peptidase-4 inhibitors e.g.
   Sitagliptin, vildagliptin

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More selective an smaller dose
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FIRST GENERATION SULPHONYLUREA COMPOUNDS
Tolbutamide short-acting Acetohexamide intermediate-acting Tolazamide intermediate-acting Chlorpropamide long- acting (not preferred)
Absorption Well Well Slow Well
Metabolism Yes Yes Yes Yes/no
Metabolites Inactive Active Active Inactive
Half-life 4 - 5 hrs 6 8 hrs 7 hrs 24 40 hrs
Duration of action Short (6 8 hrs) Intermediate (12 20 hrs) Intermediate (12 18 hrs) Long ( 20 60 hrs)
Excretion Urine Urine Urine Urine
Good for patients with renal impairment
Patients with renal impairment can expect long
t1/2 Chlorpropamide isnt well
metabolized N.B. All 1st G Metabolized in liver.
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SECOND GENERATION SULPHONYLUREA COMPOUNDS
Glipizide Short- acting Glibenclamide (Glyburide) Long-acting Glimepiride Long-acting
Absorption Well Well Well
Metabolism Yes Yes Yes
Metabolites Inactive Inactive Inactive
Half-life 3 4 hrs Less than 3 hrs (hit and run) 5 - 9 hrs
Duration of action 10 16 hrs 12 24 hrs 12 24 hrs
Excretion Urine Urine Urine
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MECHANISM OF ACTION OF SULPHONYLUREAS (SU)
1) Release of insulin from ß-cells (hence, no
use in type 1 DM). 2) Reduction of serum glucagon
concentration.(in long term use) 3) Potentiation
of insulin action on target tissues.
- SUs binds to k channel ? no efflux ?
depolarization? Opening of voltage gated Calcium
channel ? insulin release
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Sulphonylureas ( Cont.)

• CLINICAL USE
• Approved for monotherapy and in combination with
  metformin or thiazolidinediones in type II DM
• Taken before each meal, 1-2 times/day

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SIDE EFFECTS OF SULPHONYLUREAS
1) Nausea, vomiting, abdominal pain, diarrhea 2)
Hypoglycaemia 3) Dilutional hyponatraemia water
intoxication (Chlorpropamide) because it ?ADH 4)
Disulfiram-like reaction with alcohol
(Chlorpropamide) contain sulfur Disulfiram R
Ingestion of chlorpropamide with alcohol ?
hyperemic flush 5) Weight gain alcoholism
Disulfiram is a drug used to support the
treatment of chronic alcoholism by producing an
acute sensitivity to alcohol.
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CONTRAINDICATIONS OF SULPHONYLUREAS
1) Type 1 DM ( insulin dependent)
2)
Parenchymal disease of the liver or kidney.
metabolism
excretion 3) Pregnancy,
lactation (due to the physiologic stress, not
teratogenicity) 4) Major stress.
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DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF
SULPHONYLUREAS
Sulfonamides (increase insulin secretion)
Warfarin (displace the drugs ? ?t1/2 )
Salicylates (displace the drugs ? ?t1/2
) Propranolol (mask the hypoglycemia) Alcohol
(acute) Liver enzymes inhibitors? ?SU conc.
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DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF
SULPHONYLUREAS
Thiazide diuretics (a K opener?
hyperpolarization? no release of
insulin) Corticosteroids
Epinephrine Liver enzymes inducers e.g.
alcohol (in chronic alcohlic patients )
?sensitivity of insulin
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MEGLITINIDES e.g. Repaglinide, Nateglinide (SU
without sulfur)

• PKs
• Taken orally
• Rapidly absorbed ( Peak approximately 1hour )
• Metabolized by liver
• t1/2 1 hr
• Duration of action 4-5 hr

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MEGLITINIDES (Contd.)
MECHANISM OF ACTION Bind to the same KATP
Channel as do Sulfonylureas, to cause insulin
release from ß-cells.
They bind to K channels ? no K efflux ?
depolarization of ß cells ? opens Ca channel ?
influx ? release of insulin
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MEGLITINIDES (Contd.)
CLINICAL USE Approved for monotherapy and in
combination with metformin in type 2
diabetes Taken before each meal, 3 times /
day Does not offer any advantage over
sulfonylureas SIDE EFFECTS Hypoglycemia Weight
gain( less than sulfonylureas ) Caution in
patients with renal hepatic impairement.
We can use it if the patient is allergic to
sulfonylurea
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BIGUANIDES

• e.g. Metformin
• PKs
• Given orally
• Do not bind to plasma proteins
• Not metabolized
• Excreted unchanged in urine
• t 1/2 2 hr

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BIGUANIDES (Contd.) MECHANISM OF ACTION
1. Increase peripheral glucose utilization
(increase insulin receptor sensitivity thus is
insulin dependent) 2. Inhibits gluconeogenesis 3.
Impaired absorption of glucose from the gut
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• Advantages of Metformin over SUlfonylurea
• Does not cause hypoglycemia because they dont
  stimulate the release of insulin from pancreas ?
  no hypoglycemia
• Does not result in weight gain because they
  ?appetite.

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BIGUANIDES (Contd.) SIDE EFFECTS
1. Metallic taste in the mouth 2.
Gastrointestinal (anorexia, nausea, vomiting,
diarrhea, abdominal discomfort) 3. Vitamin B 12
deficiency (prolonged use) 4. Lactic acidosis (
rare 01/ 30,000-exclusive in renal failure)
(they ?anerobic glycolysis ? ?lactic acid) this
phenomenon is treated with NaHCO3.
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BIGUANIDES (Contd.) CONTRAINDICATIONS

• Hepatic impairment
• Heart failure
• 3. Renal impairment
• 4. Alcoholism

In these situations the body is more sensitive to
lactic acidosis
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BIGUANIDES (Contd.) INDICATIONS

• Obese patients with type II diabetes
• 2. Alone or in combination with sulfonylureas or
  meglitinides.

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a-GLUCOSIDASE INHIBITORS

• e.g. Acarbose
• PKs
• Given orally.
• Not absorbed from intestine except small amount
  (hence, no systemic effect).
• t1/2 3 - 7 hr.
• Excreted with stool.

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a-GLUCOSIDASE INHIBITORS (Contd.)
MECHANISM OF ACTION
With the use of drugs, there is no sharp rise in
blood sugar (?????? ????? ??? ?????)
They delay the absorption but dont inhibit it
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a-GLUCOSIDASE INHIBITORS
(Contd.)

• It is a competitive inhibitor of glucosidase
  enzyme (has more affinity than sugar ).
• It used as supportive not as treatment .
• Also can be used in border line patients.
• It can be use with type I DM but not alone.

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a-GLUCOSIDASE INHIBITORS (Contd.)
SIDE EFFECTS

• Flatulence
• 
  sugar fermentation
• Loose stool or diarrhea results in gas
  formation
• Abdominal pain
• Alone does not cause hypoglycemia

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a-GLUCOSIDASE INHIBITORS (Contd.)
INDICATIONS
Patients with Type II inadequately controlled
by diet with or without other agents( SU,
Metformin) Can be combined with insulin to
reduce postprandial hyperglycemia Maybe
helpful in obese Type II patients (similar to
metformin) a-GLUCOSIDASE INHIBITORS can also be
used with type I DM with meals.
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THIAZOLIDINEDIONE DERIVATIVES
e.g. Pioglitazone PKs

• 99 absorbed
• Metabolized by liver
• 99 of drug binds to plasma proteins
• T1/2 3 4 h
• Eliminated via the urine 64 and feces 23

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THIAZOLIDINEDIONE DERIVATIVES (Contd.)
MECHANISM OF ACTION

• Increase target tissue sensitivity to insulin by
• reducing hepatic glucose output increase
  glucose uptake oxidation in muscles adipose
  tissues.
• They do not cause hypoglycemia (similar to
  metformin and acarbose ) .

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THIAZOLIDINEDIONE DERIVATIVES (Contd.)
ADVERSE EFFECTS

• Mild to moderate edema
• Weight gain
• Headache
• Myalgia (muscle pain)
• Hepatotoxicity ? Thus a liver function test is
  done before giving this drug.
• Congestive heart failure?
• Alone does not cause hypoglycemia.

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THIAZOLIDINEDIONE DERIVATIVES (Contd.)
INDICATIONS
Type II diabetes alone or in combination with
metformin , sulfonylurea or insulin in
patients resistant to insulin treatment.
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Dipeptidyl peptidase-4 inhibitors (DPP- 4
inhibitors) e.g. Sitagliptin, vildagliptin

• Mechanism of action

Incretin (gastrointestinal hormone) ? ?release of
insulin from pancrease
inactivate
Dipeptidyl pepidase (enzyme)
incretin
DPP-4 inhibitors
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Clinical uses

• Used in type II DM as an adjunct to diet
  exercise as a monotherapy or in combination with
  other antidiabetic drugs. Is also used in
  borderline patients.
• Adverse effects
• Nausea, abdominal pain, diarrhea
• Nasopharyngitis

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