Pancreatic Pharmacology.ppt.......................

kkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkkk

1. DRUGS FOR DIABETES MELLITUS
(Insulin & Glucagon)
Dr. Amon Agaba
Semester II 2010/11

2. Diabetes Mellitus (DM)
•Chronic metabolic disorder characterized by hyperglycemia due to:
–absent or ↓ insulin secretion or
– impairment of insulin action.
•Insulin is a hormone secreted by the β-cells of the pancreatic islet of Langerhans.
•Etiology of DM: genetic and environmental factors
•Associated with Complications, if not well controlled:
–Microvascular disease (esp. heart, kidney, brain, eyes)
–Neuropathy
–Increased susceptibility to infection
–Complicated pregnancy

3. Impaired glucose tolerance in DM
Normal and abnormal glucose tolerance tests

4. Types of DM
Type Characteristics
1. Insulin-Dependent DM (IDDM),
[Type 1], [Juvenile onset],
[ketosis-prone]
↓ levels or no endogenous insulin; abnormal
immune response -cell destruction. Onset
mostly <30 yrs. Multi-factorial genetic linkage.
2. Non-Insulin-Dependent DM
(NIDDM), [Type 2]
[Adult-onset], [Maturity onset]
Resistance to insulin with relative ↓insulin;
Onset mostly >30yrs; 60% patients are obese;
strongly genetic (concordancy in 100%
monozygotic twins)
3. Secondary DM (“Other”) Identifiable cause e.g. hormonal or pancreatic
dx, drug/chemical toxicity, etc.
4. Gestational DM Onset in pregnancy (d/t placenta & placental
hormonesinsulin resistance)

5. Diabetogenic agents (Be aware in 2
o DM)
Affect insulin secretion or action
•Hormones
–Epinephrine
–Thyroid hormone
–Growth hormone
–Corticosteroids
•Drugs
–Phenytoin
–Diuretics
–Steroids
–Diazoxide
•Pesticides
–DDT
–Fluoride
•Psychopharmacologic
agents
–Ethanol
–Opiates

6. Insulin Therapy
•Cornerstone treatment for type I DM, also used in other types.
•Forms of insulin:
–Animal-derived (beef, pork)
–Biosynthetic human insulin
•Human insulin:
–Produced by recombinant DNA techniques (in E.coli or yeast)
–Differs in amino acid sequence from pork (by 1) and beef (by 3)
–Less immunogenic
–More rapidly absorbed
–Commonly used
•Animal insulin:
–Beef more antigenic than pork; no longer in use
–Pork still available, but requires special ordering

7. Chemistry of Insulin
•A small protein with MW (in humans) of 5808
•Contains 51 amino acids arranged in 2 chains (A & B),
linked by disulfide bonds.
•processed as pro-insulin within the Golgi apparatus
packaged into granules, where it is hydrolysed into
insulin and the C-peptide
•stored within granules in the β cell (in form of zinc
crystals)

8. Structure of Insulin

9. Characteristics of Insulin preparations
Formulations Constituents/propertiesOnset of
action (hr)
Duration
(hr)
RAPID-ACTING
-Lispro (humalog),
-Aspart
-recombinant human insulin 5-15min
10-20min
3-5
3-5
SHORT-ACTING
-Regular Humulin
(Soluble)
-crystalline zinc insulin (CZI)
(only type suitable for I.V admin)
0.5-1 5-8
INTERMEDIATE-ACTING
-NPH
-Lente
-Protamine zinc, phosphate buffer
-Amorphous, acetate buffer
1.5
2.5
10-14
10-14
LONG-ACTING
-Ultralente
-Glargine (soluble ‘peakless”)
-Amorphous & crystalline mix
-CZI (reproducible 24hr pattern)
8-14
1.5
18-24
11-24
PREMIXED
-%NPH/%Regular NPH 70%, regular 30% 1-2 4-14

10. Peak effect and duration of action of Insulins

11. Insulin Regimens

12. Effects of Insulin
•Major target organs: liver, muscle, and adipose tissue
•Receptor Mechanism: Activation of cell membrane tyrosine kinase
series of IC phosphorylations of IRS activation of 2
o
messenger
pathways e.g. translocation of glucose transporters (esp. GLUT-4) to
the cell membrane
–↑ glucose uptake;
–↑glycogen synthase activity ↑glycogen formation
–↓plasma glucose
•Other effects:
–Enhanced DNA synthesis & ↑cell growth & division
–Altered lipid metabolism
–Altered protein metabolism

13. Cellular mechanism of Insulin

14. Insulin: Effects and Control Reflex Loop
Fed-state metabolism

15. Pharmacokinetics
•Factors that ↑ insulin absorption
–↑ S.C. blood flow (exercise, massage, heat),
–IM injection
–abdominal wall injection
•Factors that ↓ insulin absorption
–↓ SC blood flow (shock, cold),
–intradermal injection,
–lipohypertrophy,
•Insulin Clearence
–Hepatic & renal

16. Side Effects
•Hypoglycemia
–(know the mechanisms, the signs, and how it is treated?)
•Lipodystrophy at injection sites
–Atrophy of SC fatty tissue [older insulins]
–Hypetrophy “ “ “ [newer insulins]
•Orthostatic hypotension
–Direct vasodilation  ↓cerebral perfusion
•Immune reactions
–Insulin Allergy [immediate type, IgE-mediated]
–Immune insulin resistance [IgG anti-insulin antibodies]

17. Insulin Delivery Systems
•Intensive conventional therapy
–Multiple daily injections [MDI]; (SC, IV, IM)
–Portable pen injectors
•Continuous subcutaneous insulin infusion (CSII) devices
–Insulin pumps [most physiologic method of insulin replacement]
•Experimental
–“closed-loop” artificial endocrine pancreas
–Islet transplantation
–i.p. (portal insulin delivery)
–Inhaled
–liposomal

18. GLUCAGON
•A 29 amino acid peptide (MW 3485)
•Synthesized in the A () cells of the pancreatic islets
of Langerhans
•Effects:
–Dominate in Fasting State Metabolism
–Prevents hypoglycemia by  cell production of glucose
–Liver is primary target organ
•Causes G
s
protein-linked ↑ adenylyl cyclase - ↑cAMP
•↑gluconeogenesis and ketogenesis

19. Glucagon Action on Cells
Endocrine response to hypoglycemia

20. Clinical Uses of Glucagon
•Severe hypoglycemia
•beta-blocker overdose
•Aid in bowel radiology
•Diagnosis of endocrine disorders

21. DRUGS FOR DIABETES MELLITUS (ORAL
HYPOGLYCEMICS)
Semester II 2008/09
Dr. Amon Agaba

22. Categories
Category Mechanism of action
1. Insulin Secretagogues
-Sulfonylureas
-Meglitinides
-D-phenylalanines
 the release of insulin from the
pancreas
2. Biguanides Several: ↓hepatic gluconeogenesis,
↑glycolysis, ↓glucose absorption,
↓plasma glucagon
3. Thiazolidinediones↑target tissue sensitivity to insulin
4. -Glucosidase Inhibitors↓glucose absorption from the gut

23. Sulfonylureas
•Mechanism:
–close K+ channels in the pancreatic B cell membrane depolarization
↑insulin release.
–↓serum glucagon levels (d/t insulin & somatostatin that inhibit A cells)
•Classification: according to generations
Generation:Examples Duration of
action (hr)
Remarks
1
st
Chlorpropamide
Tolbutamide
Tolazamide
60
6-12
10-14
-Prolonged hypoglycemia
-safest in elderly
-
2
nd
Glyburide
Glipizide
Glimepiride
10-24
10-24
12-24
-All more potent than 1
st

generation; in overdose
cause hypoglycemia

24. Mechanism of action of Sulfonylureas

25. 1
st
Generation Sulfonylureas
•Tolbutamide
–Short duration of action with t
1/2 of 4-5 hrs
–Administered in divided doses
–Safest sulfonylurea in elderly diabetics
•Chlorpropamide
–Long duration of action with t
1/2 of 32 hrs
–Average maintenance dose 250mg, given o.d. in the morning
– other S/E: disulfiram-like effect, hepatotoxicity
–C/I in renal or hepatic insufficiency

26. 2
nd
Generation Sulfonylureas
•More frequently prescribed than 1
st
generation coz of fewer adverse effects
•Glyburide
–Causes disulfiram-like effect
–C/I in renal insufficiency & hepatic impairment
•Glipizide
–Has the shortest t
1/2 of 2-4 hrs
–Less likely to serious hypoglycemia
–C/I in renal insufficiency & hepatic impairment
•Glimeperide
–Long duration of action (12-24 hr) and t
1/2 (5hrs) that permits o.d dosing
–Very potent agent (doses as low as 1mg daily effective in some patients)
–Can be combined with insulin

27. Example Duration of
action (hr)
Remarks
1. Meglitinides
(Repaglinide)
4-5
-Approved for use in 1998
2. D-phenylalanines
(Nateglinide )
4 -latest insulin secretagogue
approved
•Relatively new class of insulin secretagogues
•Mechanism:
-close K+ channels in the pancreatic B cell membrane
depolarization ↑insulin release.
•Have rapid onset of action: good for control of postprandial glucose
excursions
•Metabolised by CYP3A4
Meglitinides & D-phenylalanines

28. Biguanides
•Mechanism: Specific mechanism not clear, but has several effects:
–↓hepatic gluconeogenesis, ↑glycolysis, ↓glucose absorption, ↓plasma glucagon.
•Phenformin (an older biguanide), was discontinued because of risk of lactic
acidosis:
Example Duration of
action (hr)
Remarks
1. Metfomin 10-12 Side effects:
-GI distress (nausea, diarrhea)
-lactic acidosis in renal insufficiency
-inhibition of Vit B12 absorption
*Unlikely to cause Hypoglycemia

29. Metformin
•Clinical Use
–Considered a “euglycemic” agent
–Is an insulin sparing drug
–Very useful in patients with insulin resistance
–↓risk of macro- & micro-vascular diseases
–Prevention of type 2 DM in high risk patients (obese, impaired
GTT)
•Contraindications
–Renal or hepatic disease, alcholism -  risk of lactic acidosis

30. Thiazolidinediones
•Mechanism:
–Stimulate the peroxisome proliferator-activated receptor-gamma (PPAR- receptor); a nuclear receptor
which regulates the transcription of genes encoding proteins involved carbohydrate and lipid metabolism.
–↑glucose uptake in the liver, muscle & adipose tissue, ↓hepatic gluconeogenesis, affect body fat
distribution.
Examples Duration Remarks
Troglitazone Withdrawn from market coz of hepatotoxicity
Pioglitazone
Rosiglitazone
15-24
>24
-”euglycemic”
*Unlikely to cause Hypoglycemia
-↓LDL, HDL cholesterol
-can be combined with insulin, biguanides, or
sulfonyureas
-Side effects: edema, mild anemia

31. Example Duration of action
(hr)
Remarks
1. Acarbose 3-4 Adverse effects: flatulence, diarrhea,
& abdominal pain.
2. Miglitol 3-4
Mechanism:
-carbohydrate analogs; act within the intestine to inhibit -glucosidase, an
enzyme necessary for conversion of complex sugars to monosaccarides (form
that is readily absorbed).
-Glucosidase Inhibitors