Diabetes Mellitus 2021 PRINT
Diabetes Mellitus 2021 PRINT
Diabetes Mellitus 2021 PRINT
* Characterized by:
1- Glycogenolysis, Gluconeogenesis & ↓Uptake of glucose by tissues →Hyperglycemia → Glycosuria →
Polyuria → Polydipsia.
2- Polyphagia BUT loss of weight.
3- ↑Lipolysis & ↓ Lipogenesis →Hyperlipidemia → Ketonemia (Ketosis) → Ketonuria.
4- ↑Catabolism →Azotemia → Azoturia
5- Weakness, ↓ Immunity & Recurrent infections.
* Classification of DM:
Type l Type ll
3- Treatment with Insulin: Always necessary = IDD Usually NOT necessary NIDD
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ENDOCRINE PHARMACOLOGY DR A.E
3- Type III Diabetes: Due to multiple other specific causes either pancreatic or non- pancreatic,
endocrine diseases and drug therapy e.g.:
1- Alloxan & Streptozotocin: Selective cytotoxic effect on β-Cells.
2- Immunosuppressive: They inhibit insulin synthesis.
3- Inhibitors of Insulin Release: α-Agonists, β2-Antagonists, Thiazide diuretics, Diazoxide & Phenytoin.
4- Counter-regulating hormones e.g. Glucagon, Glucocorticoids, Growth hormone, Thyroxin , Oral
contraceptives & Catecholamines.
a-Insulin Secretagogues:
1-Sulphonylureas
2-Meglitinides
b-Insulin Sensitizers:
1- Biguanides
2-Glitazones
1-Acarbose
2-Miglitol
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ENDOCRINE PHARMACOLOGY DR A.E
Insulin
1-The pancreas contains about one million (1000’OOO) islets of Langerhans.
2-Each islet contains four types of polypeptide hormone-producing cells:
a-A “(α” Cells (20%) → Glucagon → Counter-insulin →Hyperglycemia.
b-B “β” Cells (75%) → Insulin → Synthesis & Storage.
c-D “∞” Cells (3-5%) → Somatostatin →↓↓ A cells > ↓ B cells → ↓Glucagon > ↓Insulin
d-F “PP” Cells (2%) → Pancreatic Polypeptide →↑ Digestive process
e- G Cells (1%) —> Gastrin
* Fate of Insulin:
1- NOT effective orally, used parenterally usually SC. In emergency diabetic coma soluble insulin can be given
IM & IV.
2- Extensive hepatic first pass metabolism (50%), mainly by glutathione-insulin trans-hydrogenase
( Insulinase) enzyme → Break bisulphide bridges → Inactivation.
3- Short t½ of endogenous insulin = 5 minutes.
•New administration routes e.g. intranasal for Alzheimer's dementia or mild cognitive impairment.
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ENDOCRINE PHARMACOLOGY DR A.E
.Sources of insulin
A. Human insulins: made with recombinant DNA technology using yeast or bacteria.
B. Insulin Analogs: These are insulin preparations with modified amino acid sequence or composition
prepared by the use of the recombinant DNA technology and genetic engineer. They are used mainly to
modify the pharmacokinetics of insulin.
C- Animal insulins: are isolated from beef and pig pancreas—> “foreign” proteins—> greater risk of
allergic reactions.
lnsulin preparations
Insulin Preparations
Rapid acting Insulin Aspart 5-10 min 1-3 hrs 3-5 hrs
analogues
Insulin Lispro <15 min 2-4 hrs
Short acting Regular Soluble insulin 30-60 min 2-3 hrs. 3-6 hrs.
Intermediate- Neutral Protamine Hagedorn NPH 2-4 hrs 4-10 hrs. 10-16 hrs.
acting (isophane) insulin
75% Lispro Protamine + 25% Lispro < 15 min ½-1½ hrs. and
4-10 hrs.
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ENDOCRINE PHARMACOLOGY DR A.E
Pharmacodynamics of Insulin:
A) Mechanism of Action:
1- Insulin binds to specific membrane receptors, each receptor has a & β subunits connected together
by 2 bisulphide bridges. The α subunit is outside while the β is trans-membrane and has a tyrosine
kinase activity.
Insulin binds to α subunit → Activation of tyrosine kinase activity of β subunit —> Phosphorylation of
intracellular proteins → Change in enzyme activity, gene expression and translocation of Glut-4
2-The insulin receptor complex is then rapidly internalized into the cell → Metabolism of insulin and
recycling of the receptor.
B) Actions of Insulin: see bio
Indications of Insulin :
A) Diabetes Mellitus:
2- Temporary in N.I.D.D. during STRESS periods e.g. Infection, Operation & Pregnancy.
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ENDOCRINE PHARMACOLOGY DR A.E
A) Specific reactions:
1- Hypoglycemia:
2- Somogyl Effect : Rebound morning hyperglycemia (due to excess release of counter- regulating
hormones) that follows insulin-induced hypoglycemia during night. Avoided by reducing the evening dose
of insulin .
3- Weight gain.
4- Insulin resistance due to high activity of insulinase enzyme or over production of Insulin
antibodies.
B) Non specific :
1- Hypersensitivity (Allergic) reaction either local at injection site (usually subside spontaneously)
or generalized
A) Sulfonylurea Group :
*Preparations.
A) First Generation:
1- Short acting (6-12 hours) → Tolbutamide
2- intermediate acting (12-24 hours) → Acetohexamide
3- Long acting (up to 60 hours) → Chlorpropamide
Chlorpropamide —> Potentiate ADH on Nephron → Anti diuretic effect.
B) Second Generation:
• More potent & Less side effects
• Intermediate acting → up to 24 hours
1- Glimepiride 2- Glibenclamide = Glyburide 3- Glipizide 4- Gliclazide
*Kinetics.
1- Absorbed orally.
2- Distributed all over the body and pass BBB & placental barrier
3- Metabolized in liver. Acetohexamide →Active metabolite. they should be used in caution in patients
with either renal or hepatic insufficiency
4- Excreted in urine.
*Mechanism of Action:
a- It is the main action of sulfonylureas, so their action depends on presence of preformed endogenous
insulin (about 30% functioning -cells)
2- Other actions (Extra-pancreatic): sulfonylureas may reduce hepatic glucose production and increase
peripheral insulin sensitivity.
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ENDOCRINE PHARMACOLOGY DR A.E
*Indications of Sulfonylureas:
1- Type-2 Diabetes (NIDD) after failure of Diet regulation & exercise. They are more effective in mild
diabetics with daily requirements of insulin <30 U / day.
a- Non-Obese (Sulphonylureas ↑ Appetite).
b- Non-Complicated Diabetes:
- No stress e.g. Infection, Operation or Pregnancy.
- No Major organ disease e.g. Cardiac, hepatic or renal.
- No History of diabetic ketoacidosis.
2- Chlorpropamide → Anti-diuretic → Treat Hypothalamo-pituitary Diabetes insipidus.
*Contraindications of Sulfonylureas:
NB) Glyburide is most likely to accumulate during renal dysfunction and cause hypoglycemia. Therefore,
glyburide is not recommended for patients with a creatinine clearance less than 50 ml/min.
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ENDOCRINE PHARMACOLOGY DR A.E
b-Weight gain (1-3 kg) due to improvement of glycemic control &T Appetite.
c-Failure:
2-Uncommon:
a- Cholestatic jaundice
b- Hematological: agranulocytosis, aplastic and hemolytic anemias: caution should be used in patients
with G6PD-deficiency and a non sulfonylurea alternative should be considered.
b- Hyponatremia.
5-There is a controversial concern whether this class of drugs is associated with an increase in
cardiovascular mortality.
1-Generalized and dermatological Hypersensitivity & cross-allergy with other sulfonamides e.g. Thiazides
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ENDOCRINE PHARMACOLOGY DR A.E
7- Less liable to produce hypoglycemia & weight gain and no need for dose adjustment in elderly and in
renal impairment especially repaglinide
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ENDOCRINE PHARMACOLOGY DR A.E
* Metformin
*Kinetics:
1- Absorbed orally.
1- The primary effect is to reduce hepatic glucose production by activating the enzyme AMP-
dependent protein kinase (AMPK). This leads to
stimulation of hepatic fatty acid oxidation, glucose uptake, and non-oxidative glucose metabolism
2-Other effects
C- Increases anaerobic glycolysis in peripheral tissues→ ↑ Removal of glucose from the blood BUTT
Lactic acid production.
-Type 2 (NIDD), particularly in overweight patients, when dietary management and exercise alone does
not result in adequate glycemic control.
May be used as monotherapy or in combination with other oral anti-diabetic agents, and/or insulin.
A reduction of diabetic complications has been shown in overweight type 2 diabetic patients treated
with metformin as first-line therapy after diet failure
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ENDOCRINE PHARMACOLOGY DR A.E
c- Hypoxic states e.g. Cardiac & pulmonary diseases (↑lactic acid production)
d- Advanced age
B) Thiazolidinediones (Glitazones):
1- Examples:
a- Rosiglitazone b- Pioglitazone
2- Kinetics
Absorption: oral and not affected by food and taken once daily
The onset of action of thiazolidinediones is relatively slow; maximal effects on glucose homeostasis
develop gradually over the course of 1-3 months.
Metabolism is affected by both inhibitors and inducers of the hepatic microsomal enzymes
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ENDOCRINE PHARMACOLOGY DR A.E
These receptors modulate the expression of genes involved in synthesis of cellular molecules important for
lipid and glucose metabolism, tissues differentiation and insulin signaling e.g. Lipoprotein lipase enzyme &
Glut-4.
- Reduces plasma levels of fatty acids by increasing clearance and Reducing lipolysis.
- These drugs also cause a shift of triglyceride stores from non-adipose to adipose tissues and from
visceral to subcutaneous fat depots.
- Pioglitazone reduces plasma triglycerides by 10%-15%, raises HDL cholesterol levels, and both increase
LDL cholesterol.
Type 2 (NIDD): May be used as monotherapy, in double combination therapy with a biguanide or
sulfonylurea, or in quadruple combination with a biguanide, sulfonylurea, and insulin.
2-Increased incidence of heart failure after use of these drugs for several years due to plasma volume
expansion in patients with type 2 diabetes who have an increased risk for heart failure
3- Increase incidence of osteoporosis and fracture of long bones due to decreased osteoblast
formation.
5- Although rosiglitazone and pioglitazone have not been reported to cause liver injury, they are not
recommended for use in patients with active liver disease or pretreatment elevation of alanine
aminotransferase (ALT) 2.5 times greater than normal. Liver function should be monitored
intermittently during treatment
6- Teratogenic.
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ENDOCRINE PHARMACOLOGY DR A.E
Alpha-Glucosidase Inhibitors:
Give oral glucose (not sucrose) in hypoglycemia, as they impair digestion and absorption of sucrose
2-Synthetic analogs of Glucagon like Peptide-1(GLP-l), an incretin released from GIT after
a meal → Bind to GLP-1 receptors →
1- delayed gastric emptying 2-↑ insulin release 3-↓secretion of glucagon 4- suppresses appetite
3- Used SC
4- Indicated as an adjunctive therapy to control hyperglycemia in patients with type 2 diabetes who
fail to achieve adequate glycemic control via the use of metformin and/or sulfonylureas.
6- Disadvantages:
a- Risk of hypoglycemia when used + sulfonylurea
b- Nausea common (about 40% of patients)
c-Pancreatitis, renal impairment and acute renal injury may occur
d- Delayed gastric emptying may ‘↓ absorption of some oral drugs
e- Has to be injected
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ENDOCRINE PHARMACOLOGY DR A.E
3- Inhibit Di-Peptidyl Peptidase IV (DPP-IV) enzyme (DPP-4 is an enzyme that breaks down incretin
hormones e.g. GLP-1) leading to prolongation of the action of endogenously released GLP-1 and GIP (glucose
dependent neurotropic peptide)
4- Adverse Effects:
Rhinitis, upper respiratory infections, headaches, pancreatitis, rare allergic reactions and
5- Many of them are now available in combination with insulin sensitizers as metformin and Glitazones
e.g. Janumet ( Sitagliptin + Metformin)
- A synthetic amylin analog (Amylin is a pancreatic hormone secreted from β-Islet cells and reach to
its receptors in brain by circulation )
3. decreases appetite
- Used SC as an adjunct to meal time insulin therapy in patients with Type 1 or Type 2 diabetes who have
problems with post prandial hyperglycemia.
- Adverse effects:
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ENDOCRINE PHARMACOLOGY DR A.E
Sodium-glucose transporter 2 (SGLT2) accounts for 90% of glucose reabsorption, and its inhibition causes
glycosuria and lowers glucose levels in patients with type 2 diabetes
Kinetics:
Clinical indication:
3rd line in ttt of type 2 DM who are very insulin deficient and prone to ketosis
Adverse Reactions:
1. The main side effects are increased incidence of genital infections and urinary tract infections
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ENDOCRINE PHARMACOLOGY DR A.E
N.B.) Glucagon:
2- Synthesized, stored & released from α-cells of Islets of Langerhans & from Upper GIT:
b- ↑Heart → +ve ino & +ve Chrono → Useful in heart failure induced by β-blockers.
4- Therapeutic Uses:
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