DM pharmacology.pptx

Anti-diabetic
Drugs
Sewasew Amsalu (MD) DM Pharmacology

Diabetes
Mellitus
Diabetes Mellitus is a disease that occurs as a result of absolute or
relative deficiency of insulin that results in metabolic and vascular
abnormalities.
2 major categories:
• Type- I or Insulin Dependent Diabetes Mellitus (IDDM)
 Selective B cell destruction and severe or absolute insulin deficiency.
• Type- II or Non-Insulin Dependent Diabetes Mellitus (NIDDM)
 Insulin is produced by the B cells, it is inadequate to overcome the resistance, and the
bloodglucose
rises.
• Gestational Diabetes (GDM) is defined as any abnormality in glucose levels noted for the

Treatment Goals of
DM
• To achieve best possible control of plasma glucose conc.
• To relieve the immediate signs and symptoms of diabetes
• Improve quality and quantity of life by preventing and/or slowing the
onset and progression of the diabetes-associated complications.

Antidiabetic
agents
• Insulin analogs
• Oral hypoglycemic
agents

Insuli
n

Insulinrelease
• Insulin release from the pancreatic B cell by glucose and by
sulfonylurea drugs.

liver
Insulin
…
Pharmacodynamics
 Affects all major metabolic pathways
• carbohydrate, fat, protein
 Major target tissues are
• Liver, adipose, and skeletal muscle
 Actions:
• -Insulin lower blood glucose level through increasing utilization of glucose by
peripheral tissue and promoting synthesis and storage of glycogen
• Net effect is to cause hypoglycemia and increase fuel storage in muscle,
fat tissue and

Insulin
….
Pharmacokinetics
• Ineffective orally
• Given parenterally; SC or I/M; I/V in
emergency
 Sources of commercial insulin
• Animal (beef or pork)
• Human (recombinant )

Principal Types and Duration of Action of Insulin
Preparations
• Four principal types :
(1)Rapid-acting: with very fast onset and short
duration;
(2)Short-acting: with rapid onset of action;
(3)Intermediate-acting: and
(4)Long-acting: with slow onset of action

• Goal of subcutaneous insulin therapy
• is to replace the normal basal (overnight, fasting, and between meal) as
well as prandial (mealtime) insulin.
• Current regimens generally use intermediate- or long-acting
insulins to provide basal or background coverage, and rapid-
acting or short-acting insulin to meet the mealtime requirements.
• The latter insulins are given as supplemental doses to correct high blood
sugars.

Types ofInsulin….
• Rapid-acting: Insulin Lispro, Insulin aspart and, inhaled form.
• Short-acting: Regular, semilente
• Intermediate acting: NPH (Neutral Protamine Hagedorn) and
Lente
• Long-acting: Ultralente, glargene

Rapid acting
Insulin
Onset of Action Peak Action Duration of Action
Insulin
Lispro
<15 min 0.5-1.5 hours 4-6 hours
Insulin
Aspart
5-10 min 1-3 hours 4-6 hours
Taken just (10 – 15 mins) before eating.
These are insulin analogues produced by rDNA technology.

Short-Acting
Insulin
Onset of
Action
Peak Action Duration of
Action
Regular (soluble)
insulin
0.5-1 hours 2- 4 hours 6-8 hours
Prompt insulin
Zinc suspension
or semilente
0.5-1 hours 3 - 6 hours 12 – 18 hours
Taken 30 minutes before eating, Useful in diabetes emergencies,
given via IM, IV, SC routes
Semilente: an amorphous precipitates of insulin with zinc ions in
acetate buffer that has relatively short onset.

Intermediate-Acting
Insulin
Onset of
Action
Peak Action Duration of
action
NPH or Isophane
Insulin
1-2 hours 8-10 hours 20 – 24 hours
Insulin zinc
suspension/ Lente
1 - 2 hours 8 -10 hours 20 – 24 hours
Taken usually 1-2 times per day,
NPH: suspension of insulin with protamine, which delays onset of
action.
Lente: 30: 70 mixture of amorphous and crystalline zinc insulin
complex in a suspension. This provides a relatively rapid onset with
sustained action.

Long-Acting
Insulin
Onset of
Action
Peak
Action
Duration of
Action
Extended insulin zinc
suspension (crystalline) or
Ultralente
4 – 6
hours
14 – 18
hours
20-24 hours
Protamine zinc insulin 4 – 6
hours
14 – 20
hours
24 – 36
hours
Given usually once daily with soluble insulin but Protamine zinc
insulin bind with the soluble insulin when mixed in the same
syringe.
Ultralente: a poorly soluble crystals of zinc insulin that has a
delayed onset and prolonged duration of action

Insulin
Regimens
• Choice of regimen depends on desired degree of glycemic
control, the patients lifestyle, and his or her ability to adjust
insulin dose.
• Once daily injections are rarely satisfactory.

Insulin
Regimens
• 2 shots: most commonly used regimen
• Rapid + intermediate acting (1:2)
• 2/3rd of dose to be given in the morning and the remaining
in the evening.
e.g -10 units of regular and 15 units of NPH insulin in the morning
and 5 units of regular and 5 units of NPH in the evening.

• Advantages:
Controls Postprandial glycaemia at breakfast and dinner.
• Disadvantages:
 Pre-breakfast hyperglycemia is common.
Increased risk of nocturnal hypoglycemia in attempt to control pre-
breakfast hyperglycemia.

Intensive Insulin therapy (3 shots & 4
shots)
• 3 shots
• Rapid/short + intermediate at breakfast
• Rapid/short acting at supper (evening meal)
• Intermediate at bedtime
e.g. 10 units of regular insulin mixed with 10 units of NPH in the
morning, 8 – 10 units of regular insulin before the evening meal, and 6
units of NPH insulin at the bedtime.

Insulin
Regimens
• 4 shots
• Rapid/short acting at breakfast, lunch and
supper
• Long acting at bedtime

Intensive Insulin therapy (3 shots & 4
shots)
• Advantages:
- Controls PP glycemia. Allows flexibility of meal schedule and quantity.
- Tight glycemic control possible with least risk of hypoglycemia.
• Disadvantages
- Pumps( insulin syringe) are expensive, add risk of skin infections and pump
failure.

Some important guidelines for insulin
therapy
• Initiate with the daily dose with 0.3 U/kg (16 – 20 U/d), increasing to
1 U/kg
• Adjust the dose according to the usual monitoring of blood glucose
• Daily increment should not be more than 4 Units
• Peakaction of insulin injected should coincide with the postprandialrise in
blood glucose.
Aim of therapy:
* Blood glucose level of 90 – 130 mg/dl before meal, and after overnight

Factors Affecting
Absorption
• Absorption depends on :
• Blood flow to site,
- Site of injection,
Abdomen>Arm>Buttock>Thigh
• Exercise will increase absorption, as will local
massage

Therapeutic Uses of
Insulin
• Type I diabetes
• Type II diabetes when pregnant
• Type II diabetes under stress
• Type II diabetes poorly controlled by diet and oral agents
• Complications of diabetes (ketoacidosis, gangrene of
extremities)

or
Complication of Insulin
Therapy
I. Hypoglycemia (systemic): tachycardia, palpitation, trembling, anxiety, coma,
convulsion, confusion, drowsiness, incoordination, sweating, nausea, hunger
Treatment
• Patient should never miss a meal
• They should carry a packet of table sugar, candy etc.
• An ampoule of glucagon (1 mg) should be provided to every diabetic receiving
insulin therapy.
• Glucose (dextrose) iv. 20 – 50 ml of 50% sol. can be given for unconscious
patient
• If no response is shown, it may be due to cerebral edema treat with iv

ii. Lipodystrophy  atrophy of subcutaneous fatty tissue leading to depressed
areas at the site of injection.
result from an immune reaction
iii. Lipohypertrophy (accumulation of extra fat) (local)
 seen as a consequence of pharmacological effect of insulin
Other:
• Insulin resistance (activating antibodies, tissue unresponsiveness due to
excess insulin)
• Weight gain

Oral Hypoglycemic
Agents

Oral hypoglycaemic
agents
1. Sulfonylureas
• First generation
• Tolbutamide
• Chlorpropamid
e
• Tolazamide
• acetohexamid
e
• Second generation
• Glibenclamide
• Glipizide
• Gliclazide
• Glimepiride
2.
Biguanid
es
Phenformin,
Metformin
3. Meglitinide
analogues
Repaglinide, Nateglinide
5. Thiazolidinedion
es
Rosiglitazone, Pioglitazone
6. Αlpha glucosidase
inhibitors
Acarbose, Miglitol

1.
Sulfonylureas
• Classified as insulin secretagogues
Promote insulin release from the βcells of the pancreas.
• The sulfonylureas in current use are the
Second-generation drugs: glyburide, glipizide,
and glimepiride
• All are orally active
• All bound to plasma protein (90-99%)

Sulfonylureas…
Mechanism of action
• hypoglycemic action is due to Stimulation of insulin release from
βcell, Depression of glucagon secretion,
Extra-pancreatic action
• Increase the concentration of insulin receptors on the target
cells
• Increase peripheral insulin sensitivity
• Inhibits gluconeogenesis in liver
Use: Type-II DM only

Sulfonylureas…
Adverse effects
• Weight gain
• Hyperinsulinemia and Hypoglycemia
• Use with caution in hepatic or renal insufficiency
• Glipizide or glimepiride are safer options in renal dysfunction
and in elderly patients.
• Glyburide has minimal transfer across the
placenta
-

2.
Biguanides
• Drugs: Metformin and phenformin (withdrawn due to serious lactic acidosis)
• Metformin: insulin sensitizer; ↑es glucose uptake and use
• It does not stimulate insulin release or cause hypoglycemia
o Hyperinsulinemia is not a problem: risk of hypoglycemia is far less than
that with
sulfonylureas.
• Does not bind plasma proteins
• Excreted unchanged in urine
• Often combined with sulfonylurea drugs

Biguanides…
- Mechanism of action
- Reduce hepatic production of glucose-The main mechanism of action of
metformin
is reduction of hepatic glucose output, largely by inhibiting hepatic
gluconeogenesis.
- Other minor actions may include
- Increases glucose uptake by skeletal muscle and
- Increase peripheral utilization of glucose by enhancing anaerobic glycolysis.
- Weight loss may occur because metformin causes loss of appetite.

Biguanides…
Use: Type II DM
o Drug often preferred for obese patient as it stimulates weight loss in
patients not
controlled by diet and exercise????

Biguanides…
 Adverse effects – largely GI side effects
• Nausea, abdominal discomfort, diarrhea, metallic taste, anorexia more
common
• Lactic acidosis (rare)  contraindicated in renal dysfunction
• Vitamin B12 deficiency: interfere with absorption
 Biguanides are contraindicated in patients with renal disease, alcoholism,
hepatic disease, or conditions predisposing to tissue anoxia (eg, chronic
cardiopulmonary dysfunction) because of the increased risk of lactic
acidosis induced by these drugs.

Management OfTypeIIDM

Principles of Comprehensive Managementof
Type2 Diabetes
1.Lifestyle modifications
2.Individualized approach
3.Address both FPG & PPG
4.Minimize risk of hypo & weight gain
5.Major cost comes from complications and not from
medications
6.Combination therapy usually required
7.Comprehensive BP and Lipid Management
8.Initial regimen should be simple

Comprehensive DiabetesCare
•Lifestyle Modifications
•Healthy Diet
•Regular Exercise
• Maintain
Ideal
Weight
•No Smoking
• Alcohol use:
• Avoid alcohol
• Decrease to max recommended amount(1
drink per day for women,3 drinks per day
for men) Sewasew Amsalu (MD) DM Pharmacology

Exercise Recommendations for Type 2
DM
• Exercise daily for 30 minutes (min 5 days/wk)
• Intensity should be individualized
• In type 2 DM, exercise-related hypoglycemia is less
common but can occur in individuals taking either insulin
or insulin secretagogues.
Sewasew Amsalu
(MD)
DM
Pharmacology

Sewasew Amsalu
(MD)
DM
Pharmacology
First line: Metformin
• o Initial dose 500mg to 1000mg/day daily or in two
divided doses with meals.
• o Titrate dose every two weeks depending on the
fasting blood sugar
• o Maximum dose = 2000mg/day (1000mg BID)

Sewasew Amsalu
(MD)
DM
Pharmacology
• Add on to Metformin: If glycemic target is not achieved
by metformin alone after three months, add
o Sulfonylureas : Glibenclamide, Glimepiride, Gliclazide
Initiating two oral agents at diagnosis
oPatients withsevere hyperglycemia at presentation
(Fasting blood sugar >
250mg/dl or HbA1C>10%)

DM pharmacology.pptx

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