Download 8. Anti-diabetics

DRUGS FOR THE TREATMENT
OF DIABETES MELLITUS
1
• 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
2
Types of
diabetes
Type I (formally
IDDM or juvenile).
Type II (formally
NIDDM or adult).
Secondary
diabetes(occur
only if there is an
underlying
disease) e,g,:
cushing disease,
pancreatectomy,
growth hormone
tumor.
Gestational
diabetes.
N.B.
IDDM: insulin dependent diabetes mellitus.
NIDMM: non-insulin dependent diabetes mellitus.
3
Characteristic
Type 1 ( 10% )
Type 2 (90%)
Onset (Age)
Usually < 30
Usually > 40
Type of onset
Abrupt
Gradual
Nutritional status
Usually thin
Usually obese
Clinical symptoms
Polydipsia, polyphagia,
polyurea, weight loss
Often asymptomatic due to
insulin’s 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; carbohydrateinduced hypertriglyceridemia
Insulin therapy
Required
Hypoglycemic drugs
Should not be used
Required in 20 - 30% of
patients (for postprandial
hyperglycemia)
Clinically indicated
Diet
Mandatory with insulin
Mandatory with or without
drug (can be controlled by
diet & exercise)
4
carbohydrates
• ↑glucose uptake.
• ↑glycogen
synthesis
(↑storage).
• ↑glycolysis (in
muscles).
• ↑conversion of
cyrbohydrate to
fat (lypogenesis).
• ↓gluconeogenesis.
fat
• ↑lypolysis.
protein
• ↑amino acid
uptake (protein
synthesis).
potassium
• ↑ K+ uptake to
cells.
↓ glucose uptake
hyperglycemia
↑amino acid mobilization
↑ lipolysis
glycosuria
↑plasma amino
acid
↑ plasma
free fatty
acid
ketosis
dehydration
Amino acid 
glucose
(gluconeogenesis)
acidosis
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 glucose’s 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.
7
Insulin Degradation
 Hydrolysis of the disulfide linkage between
α & β 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.
8
cont’d
Upper arm
(intermediate
action)
Site of injection
Abdomen (fast
action)
Thigh (slow
action)
 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.
9
Fast action
of insulin
in the
abdomen
10
TYPES OF INSULIN PREPARATIONS
A) Insulin used to control postprandial (after meals) hyperglycemia
and emergency ketoacidosis
1. Ultra-short-acting ( e.g. insulin lispro, insulin aspart)
2. Short-acting -Regular- (e.g. Novolin R, Humulin R)
Clear liquid
B) Insulin used for maintenance treatment of type I DM
3. Intermediate-acting (NPH, Lente insulin)
Turbid suspension ‫عكر‬
4. Long-acting (Glargine ,Ultralente )
N.B.
NPH = Neutral protamine Hagedorn
11
Short-acting (regular) insulins
e.g. Humulin R, Novolin R
Ultra-Short acting insulins
e.g. Lispro, aspart, glulisine
Uses
Designed to control postprandial
hyperglycemia & to treat
emergency diabetic ketoacidosis
Similar to regular insulin but
designed to overcome the
limitations of regular insulin
Physical
characteristics
Clear solution at neutral pH
Clear solution at neutral pH
Chemical
structure
Hexameric analogue  dimeric
 monomeric
Monomeric analogue
Route & time of
administration
S.C. 30 – 45 min before meal
I.V. in emergency
(e.g. diabetic ketoacidosis)
S.C. 5 min (no more than 15 min)
before meal
I.V. in emergency
(e.g. diabetic ketoacidosis)
Onset of action
30 – 45 min ( S.C )
0 – 15 min ( S.C )
Peak serum levels
2 – 4 hr
30 – 90 min
Duration of
action
6 – 8 hr (thus creating a risk of
nocturnal hypoglycemia)
3 – 4 hr (less risk of nocturnal
hypoglycemia)
Usual
administration
2 – 3 times/day or more or when
you need
2 – 3 times / day or more or when
12
you need
Advantages of Insulin Lispro (ultrashort) vs Regular Insulin (short
acting) :
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
1)
13
In emergency you
can use either
ultra-short or
regular insulin
(no difference in
the duration of
action because it
is given IV)
Ultra-short has less
duration of action  no
hypoglycemia
‫قواعد جوهرية‬
In
postprandial
hyperglycemia
you can use
both but
Use ultra-short, wait for 5
minutes before having a
meal while in regular, wait
for 30 minutes
14
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
Isophane (NPH)
Ultra-short or short acting
75/25 70/30 50/50 ( mix isophane with ultra-short or
short acting insulin).
Insulin mixture is given to patients with
high postprandial hyperglycemia
(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
16
Cont’d
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).
17
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
Designed to overcome the disadvantages
of intermediately acting insulins
Advantages
1.
2.
Constant circulating insulin over 24 hr with no pronounced peak (see next
slide)
Safer than NPH & Lente insulins ( less risk of nocturnal hypoglycemia)
Nocturnal = ‫أثناء النوم‬
3.
Clear solution (does not require resuspension before administration)
18
Profile of Insulin Glargine vs NPH
NPH
Glargine
glargine
(plateau )
19
In the previous figure NPH gives a peak
hypoglycemia
But glargine doesn’t give a peak
hypoglycemia
risk of
risk of
N.B: intermediate & long acting use for maintenance of
blood sugar during 24 hr in type I DM
20
Glargine
21
Methods of Adminisration



Insulin Syringes (most common)
Pre-filled insulin pens (expensive)
External insulin pump
Under Clinical Trials
Oral tablets
2. Inhaled aerosol (still undergoing trials)
3. Intranasal, Transdermal
4. Insulin Jet injectors (needle less)
5. Ultrasound pulses
1.
22
COMPLICATIONS OF INSULIN THERAPY
1. Severe Hypoglycemia (< 50 mg/dl ) life-threatening
Treatment of
hypoglycemia
Occurs in
Overdose
of insulin
Excessive
exercise
A meal is
missed
Give sugar
IV (dextrose)
Give
glucagon
2. Weight gain
23
Cont’d
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
N.B. In infection (stress); there is an
increase catecholamine, corticosteroid
leading to insulin resistance.
24
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
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, General depression
sometimes convulsions
Blood sugar
Lower than 70 mg/100cc
Elevated above 200 mg/100cc
Ketones
Normal
Elevated
25
Oral Hypoglycemics
All taken orally in the form of tablets.
Patients with type II diabetes have
two physiological defects:
1.
2.
Abnormal insulin secretion (most important)
Resistance to insulin action in target tissues
associated with decreased number of insulin
receptors
26
Oral Anti-Diabetic Agents
1.
2.
3.
4.
5.
6.
Sulfonylureas e.g. Tolbutamide, Glyburide.
Meglitinides e.g. Repaglinide, Nateglinide.
Biguanides e.g. Metformin.
Alpha-glucosidase inhibitors e.g. Acarbose.
Thiazolidinediones e.g. Pioglitazone.
Dipeptidyl peptidase-4 inhibitors e.g.
Sitagliptin, vildagliptin
27
sulfonylureas
Second
generation
First generation
Short acting
tolbutamide
Intermediate
acting
Acetohexamide
tolazamide
More selective
an smaller dose
Long acting
chlorpropamide
Short acting
Glipizide
gliclazide
Long acting
Glyburide
(glibenclamide)
glimepiride
FIRST GENERATION SULPHONYLUREA COMPOUNDS
Tolbutamide
short-acting
Acetohexamide
intermediateacting
Tolazamide
intermediateacting
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
Absorption
Chlorpropamide
long- acting
(not preferred)
* Good for patients with renal impairment
** Patients with renal impairment can expect long t1/2
*** Chlorpropamide
isn’t well metabolized
st
N.B. All 1 G Metabolized in liver.
29
SECOND GENERATION SULPHONYLUREA
COMPOUNDS
Glipizide
Shortacting
Absorption
Metabolism
Metabolites
Half-life
Well
Yes
Inactive
3 – 4 hrs
Glibenclamide
(Glyburide)
Long-acting
Well
Yes
Inactive
Less than 3 hrs
Glimepiride
Long-acting
Well
Yes
Inactive
5 - 9 hrs
(hit and run)
Duration of
action
Excretion
10 – 16 hrs
12 – 24 hrs
12 – 24 hrs
Urine
Urine
Urine
30
MECHANISM OF ACTION OF
SULPHONYLUREAS (SU)
1) Release of insulin from β-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.
- SU’s binds to k+ channel  no efflux  depolarization
Opening of voltage gated Calcium channel  insulin release
31
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
32
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.
33
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.
34
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.
35
DRUGS THAT ANTAGONIZE THE
HYPOGLYCEMIC ACTION OF
SULPHONYLUREAS
Thiazide diuretics (a K+ opener hyperpolarization no
release of insulin)
Corticosteroids ↓sensitivity of insulin
Epinephrine
Liver enzymes inducers e.g.
alcohol (in chronic alcohlic patients )
36
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
37
MEGLITINIDES (Contd.)
MECHANISM OF ACTION
Bind to the same KATP Channel
as do Sulfonylureas,
to cause insulin release from β-cells.
They bind to K channels  no K efflux  depolarization
of β cells  opens Ca channel  influx 
release of insulin
38
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
We can use it if the patient is allergic to sulfonylurea
SIDE EFFECTS:
Hypoglycemia
Weight gain( less than sulfonylureas )
Caution in patients with renal & hepatic impairement.
39
BIGUANIDES
e.g. Metformin
PKs:
 Given orally

Do not bind to plasma proteins

Not metabolized

Excreted unchanged in urine

t 1/2 2 hr
40
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
41
Advantages of Metformin
over SUlfonylurea
 Does not cause hypoglycemia because they
don’t stimulate the release of insulin from
pancreas  no hypoglycemia
 Does not result in weight gain because they
↓appetite.
42
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.
43
BIGUANIDES (Contd.)
CONTRAINDICATIONS
1. Hepatic impairment
2. Heart failure
In these situations the
body is more sensitive to
lactic acidosis
3. Renal impairment
4. Alcoholism
44
BIGUANIDES (Contd.)
INDICATIONS
1. Obese patients with type II diabetes
2. Alone or in combination with sulfonylureas or
meglitinides.
45
α-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.
46
α-GLUCOSIDASE INHIBITORS
(Contd.)
MECHANISM OF ACTION
They inhibit α
glucosidase
Disaccharides
will not be
converted to
monosacchari
de
With the use
of drugs,
there is no
sharp rise in
blood sugar
‫(مايشطح السكر‬
)‫بعد األكل‬
Delay
absorption
of glucose
↓post
prandial
increase in
blood
glucose
They delay
the
absorption
but don’t
inhibit it
47
α-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.
48
α-GLUCOSIDASE INHIBITORS
(Contd.)
SIDE EFFECTS
•
Flatulence
sugar fermentation
• Loose stool or diarrhea
results in gas formation
• Abdominal pain
• Alone does not cause hypoglycemia
49
α-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)
α-GLUCOSIDASE INHIBITORS
can also be used with type I DM with meals.
50
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%
51
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 ) .
52
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.
53
THIAZOLIDINEDIONE DERIVATIVES
(Contd.)
INDICATIONS
Type II diabetes alone or in combination with
metformin , sulfonylurea or insulin in patients
resistant to insulin treatment.
54
Dipeptidyl peptidase-4 inhibitors
(DPP- 4 inhibitors)
e.g. Sitagliptin, vildagliptin
Mechanism of action
Dipeptidyl pepidase (enzyme)
DPP-4 inhibitors
inactivate
incretin
55
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
56
57
If you have developed –
Tachyphylaxis – from studying
Pharma!
then we recommend you to
take some rest!!!!!
Thank You!
58