pharma sheet # 7 - Mais Smadi

بسم الله الرحمن الرحيم
We started this lecture from slide 7 in handout 7 and we finished in slide 29 now let us start:

Slide 7:
*Factors/drugs ↑ release and Factors/drugs ↓ release of insulin:
We will talk about these factors to utilize them in certain disorders whether these disorders are hypoglycemia or hyperglycemia:
-Hypoglycemia: we use drugs which enhance release of insulin
Hyperglycemia: we use drugs which inhibit release of insulin-
*Factors/drugs ↑ release:
Most of the oral hypoglycemic agents such as sulfonylureas act by enhancing the insulin secretion from the pancreas
*Factors/drugs ↓ release:
we will concentrate only on one drug which is streptozotocin (streptozocin) bcz this drug coz irreversible damage to the β-cells of the pancreas its very dangerous drug (in healthy person single injection or 2 injections from this drug and that's it no β-cells functioning for ever and so this person will have type 1 diabetes bcz β-cells is damaged as a result there is no insulin )so any one who is working with this drug for research he has to be very careful this drug is used to induce the diabetes in animals (animal model of diabetes ) if we want to study any thing in diabetes we want to make an animal model or we use it for control the disease when we have animals (ex: rats)which have diabetes without any mean by which we induce diabetes in it maybe due to specific stress(ex: hypertension ) and these are better for studying on them bcz they have the disease naturally (not induce by us) in this case we don't use this drug to induce the diabetes(bcz its already found in them) but we use it for control the disease
This drug is used clinically in patients who have tumor affecting β-cells it's widely used as anticancer agent so its used in cancer, adenoma and insulinoma

slide8:
*insulin effects:
1- Increase glucose uptake or transport → muscles & adipocytes(its the major mechanism by which insulin produce its hypoglycemic effect)
2- Decrease hepatic gluconeogenesis (glucose synthesis)
3-increase the hepatic glycogen synthesis; decrease glycogenolysis (glucagon breakdown)
4-increase a.a uptake and protein synthesis by muscles and liver
5- Decrease lipolysis
6-decrease ketogenesis (ketonbodies formation)
Note: any mechanism by which you can decrease bld sugar level it apply to insulin and in contrast any mechanism elevate bld sugar level it apply to glucagons

Slide 9:
Insulin preparation:


-as we said in the last lecture the sources of insulin can be either human sources or animal sources (such as porcine which has 1 a.a different from human insulin or bovien which has 3 a.a different from human insulin)
-Potency:
Human > porcine > bovine
-Allergy:
Bovine > porcine > human
Allergy more frequent with bovine than porcine coz porcine has 1 a.a different from human insulin in contrast bovien which has 3 a.a different from human insulin) so whenever the diff btw a.a in animal insulin's from human insulin is more the allergy will be more
note: the substance which is responsible for most of the allergy with insulin from animal source is pro-insulin (it has 1/10 the potency of insulin) when you extract insulin from pancreas there is no way to extract insulin without a little contamination with pro-insulin (human insulin is recombinant it is free of this) so allergic rxn with human recombinant insulin is less in compared to the bovine and porcine

Slide 10:
Classification of insulin preparations:
They are classified according to duration of action (DOA)
1-ultra rapid onset very short acting (DOA about 3-4 hours)
-ex: insulin lispro
-uses of this group of insulin preparations: this is mainly used with insulin pumps, this pump inserted in the abdomen by prop which control bld sugar level and deliver insulin accordingly it has insulin inside and it deliver the insulin according to the bld sugar level up to 3-4 hours, actually this pump is very expensive and it is not that much convenient to the patient
-if this very short acting drug given as injection and patient has to inject himself every 3-4 hours this also is not convent for him at all so its not widely used in most diabetic patient specially type 2
2-rapid onest short acting (DOA about 8 hours)
-it's also known as (regular; soluble; insulin injection)
-ex: Crystalline zinc
-uses of this group of insulin preparations: its very important drugs
-for the sake of exam its the only preparation in addition to being effective subcutaneously it could be given I.V in the management of the hyperglycemic coma or sever ketoacidosis so in emergency cases of the hyperglycemic coma or sever ketoacidosis you give the patient immediately this drug I.V and put him on insulin
So again it's the only one which is used for the management of the hyperglycemic coma (very imp to know that)
-its highly effective and very quickly acting drugs the onset of rxn is 0.5 hour so in about 0.5 hour you will save the patients life
with large dose of this drug I.V: beside the increase of the peripheral tissue uptake of the glucose by insulin there is also increase in the peripheral tissues uptake of the k in response to the insulin (very imp point) so when I give insulin from I.V it will decrease the bld sugar level and it also decrease k level so it will lead to hypoglycemia and hypokalemia
Hypokalemia which occur with the large dose I.V preparation more common as compare to the subcutaneous one

Slide 11:
3-intrmediate acting and onsets (DOA about 24 hours)
-the most widely used
-ex:-Insulin zinc suspension (Lente)
-Isophane insulin suspension (NPH; Humulin)
4-long acting and slow onset (DOA about 36 hours)
ex:-Protamine zinc suspension
Mechanism: they add substance like protamine as local anesthetic effect and it form a complex with insulin reducing its absorption from subcutaneous sides
-Extended insulin zinc suspension also known as (Ultralente)

Slide 12:
-there are new insulin preparations called Insulin Glargine or Insulin detemir
-they are peakless insulin as if there is steady state the level of it in the body from the begging is the same until the end of action of this insulin
-in fact there is no over advantage of this preparation in compare to other preparations but some reports said that these insulin associated with less frequent hypoglycemic attacks
-they are more expensive than other preparations
-all of them available from both animal and human sources but nowadays human sources are the most widely used
here we should take care with respect to the potency (actually in the pharmacology we are interested in efficacy more than potency but with respect to the insulin we should take care ) bcz some patient switch from one type to another without changing the dose and as you know human insulin are more potent than animals so:
-if the patient was used to take animals insulin and then he replaced it by the human one without consult his doctor and he didn't change the dose then he will have hypoglycemia (note that potency her become important)
--if the patient was used to take human insulin and then he replaced it by animals one also without consult his doctor and he didn't change the dose then he will have hyperglycemia (the complication with the hyperglycemia are more than hypoglycemia)
So this is the important of the potency
-again as we said all insulin preparations are given S.C except regular insulin which can be given either S.C or I.V

Slide 13:
Dose of insulin:
-Insulin is given in units and dose is different from one diabetic patient to another
-how we decide that this particular diabetic patient require for example 100 units a day to control his bld sugar level?
it depend we start with small dose and measure bld sugar level therefore we advice the diabetic patient to be in contact with diabetic clinic frequently to adjust the dose ,screening for complications ,diet and other instructions
-we learn the diabetic patient how to inject himself independently , there are syringes that already filled with insulin dose
Side effects to Insulin therapy:*
1-Hypoglycemia; ↑ sympathetic activity: the major and dangerous side effect of insulin therapy bcz if it occurs it will lead to a very quick damage to the liver
2-Lipodystrophy
3-Allergy
4- induration: there will be dryness at the site of the injection this side effect happen when you learn the diabetic patient to inject himself and then each time he inject himself exactly at same site where you learn him (in another word it result from the repetitive injections at the same site) so we advice the diabetic patient to change the site of the injections each time
Note: the best site for insulin absorption is the abdomen
So he can inject himself in the abdomen or in the thigh or other site to avoid this side effect
Dr said in the exam if I ask you:
Which of the following is/are the major side effect(s) of insulin therapy?
A-hypoglycemia B-lipodystrophy C-allergy D-Induration
E-all of the above
The answer will be a
But if he asked:
Which of the following is/are the reported or common side effect(s) of insulin therapy?
A-hypoglycemia B-lipodystrophy C-allergy D- Induration
E-all of the above
The answer will be e, so be careful

Management of the diabetic patient who deliver to the emergency room with coma-
-there are two types of coma to such patients
1-hyperglycemic coma
2-hypoglycemic coma
whenever you see patient in the emergency and in coma and you know that he is a diabetic patient (from his family with him or we advice diabetic patient to have a card or any thing always with him denoting that he is a diabetic patient) so you have now diabetic patient with coma you should suspect 2 things ether he has hypoglycemic coma or hyperglycemic coma what you should do?
1-take bld sample from him and send it very quickly to the lab
2-put the patient on the glucose despite the type of the coma
3-when the result from the lab is ready see the bld glucose level then
*if the pateint has hyperglycemic coma(bld glucose level is high)we remove the glucose (don't remove the needle only remove the fluid)and put I.V regular insulin and along with it you have to give K bcz as we said before large dose of regular insulin coz hypokalemia beside the hypoglycemic effect
*if the patient has hypoglycemic coma (bld glucose level is low) continue with giving him glucose don't change it

Slide 14:
Oral hypoglycemic agents:
1-Biguanides
-ex: Metformin
-Possible MOA:
A. decrease CHO absorption
B. decrease hepatic gluconeogenesis; ↑ glycolysisb
C. decrease glucagon release
D. increase peripheral utilization of glucose
-similar actions to the insulin with the exception of decrease CHO absorption as if these actions are direct effect to the metformin (in fact its not, I will explain soon)
-this drug is widely used among the diabetic patients they like it bcz its side effects are not that much

Slide 15:
-the MOA is not direct effect to metformain it require insulin for its action so it require insulin to produce its hypoglycemic effect and so this drug doesn't reduce the bld sugar level in the individual without insulin and the prove for this that this drug is ineffective in type 1 diabetes bcz these patients are not have insulin at all
-Side effects:
1-N & V, metallic taste
2-Abdominal pain and diarrhea
3-Hypoglycemia (rare)
4-Lactic acidosis
5- Decrease vitamin B12 absorption
Note that there is nothing which is unique for this drug in these side effect all drugs produce N&V and so that as we said before this drug is widely used

: slide 16
2-Sulfonylureas:
-it's classified into 1st and 2nd generations according to the potency and the metabolic fate
-Dr said :forget about the metabolic fate and DOA ,questions in the exam will be like this:
Which of the following has the longest duration of action?
Which of the following has the shortest duration of action?
-in the 1st generation Chlorpropamide has the longest duration of action and Tolbutamide has the shortest duration of action

Slide 17:
2nd generation are more potent and they are not produce active metabolite but Dr put the (+) for Glyburide (Glibenclamide) and Glimeperide bcz as he said t1/2 for these 2 drugs is 4 or 5 hours and the DOA is 24 or 22 hours so there will be minimal production of active metabolite
-they are widely used in the diabetic patients
-Glyburide (Sulfonylureas) and insulin could be taken together (in addition to diet control), remember that number 1 management for the diabetic patient is the diet
-also a lot of the diabetic patients take metformin and Sulfonylureas and insulin together

Slide 18:
MOA of sulfonylureas:
) 1-increase insulin release from the pancreas (major MOA
So we use this drug in case when insulin is already percent in the pancreas but it doesn't release for reason or another
2- Increase no. Of β-cells and ↑synthesis of the insulin, ↑ no. of insulin receptors
3- Increase peripheral cells sensitivity to insulin effect
4- Increase insulin binding to its receptors
5- Increase insulin affinity to its receptors
6- Decrease hepatic gluconeogenesis
7- Decrease glucagon release, ↑ somatostatin release (the effect for it as we said in the previous lecture is dose dependent on the bld glucouse)
-and also any mechanism that increase the effect of the insulin
-these drugs are act through the insulin just like Biguanides so they are ineffective in type 1 diabetes its effective in the type 2 diabetes or in the patients who have insulin in the pancreas

Slide 19:
-Sulfonylureas differ in kinetic profile, potency, bioavailability, DOA, tolerance
-an imp point her regarding the kinetic of the Sulfonylureas which is the extensive binding to the plasma proteins ,its a major site of drug-drug interaction in which some drugs increase the effect Sulfonylureas (hypoglycemia) another decrease the effect of Sulfonylureas (hyperglycemia)
-Clinical uses to sulfonylureas:
1-Dabetis mallets (DM) the major clinical use of such drugs
2-Nocturnal enuresis (Glyburide → ↑ ADH release from the post. Pituitary

Slide 20:
Side effects to sulfonylureas:
1-Hypoglycemia (major side effect)
2-N & V, dizziness
3-Allergy
4-Agranulocytosis
5-Hepatic dysfunction

Slide 21:
Other orally effective drugs in DM:
1-α-glucosidase inhibitors
Ex: Acarbose
-Effective in type 2 DM
-decrease CHO absorption
-Inhibits α-glucosidase, an enzyme in the brush border of intestine responsible for breakdown of CHO to glucose, and hence ↓ glucose absorption Such inhibitors ↓ fasting and postprandial hyperglycemia

Slide 22:
-it Could be given with insulin and sulfonylureas
-Side effects: Abdominal pain and diarrhea

Slide 23:
2-Prandial glucose regulators
-ex: Repaglinide; Nateglinide and others
-increase insulin release
-MOA is similar to sulfonylureas
-Hypoglycemia is infrequent
-Taken before meals or with meals (every meal)
-Could be taken with metformin or insulin bcz Hypoglycemia is infrequent

Slide 24:
3-hiazolidinediones:
-ex: Rosiglitazone; Pioglitazone
-New drugs recently approved by FDA to be used in the non insulin dependent diabetes (NIDDM)
1-increase sensitivity of peripheral tissues to insulin effect
2-dcrease glucose exit or output from the liver
3-decrease insulin resistance
Good to patients with ↑ insulin levels and they have insulin resistance which are believed to be responsible for ↑ B.P (hypertension),↑ lipids and atherosclerosis in patients with insulin resistance
-these drugs are orally effective drugs could be of a value for the patient who has↑ insulin levels and they have insulin resistance

Slide 25:
4-Incretin hormones:
How they discover it?
-they give glucose I.V then orally they suspect that insulin secretion will be more when they glucose by I.V than when we give glucose orally but they found that that insulin secretion following oral administration of glucose is better

-note: when you give the glucose to any individual after carbohydrate rich meal the insulin secretion increase immediately in normal individuals to decrease bld sugar level to the extant that bld sugar level wont exceeded the threshold of the kidney which is 180mg/dl
-so in the normal individuals its impossible to have sugar in the urine except if there is certain abnormality and bld sugar level exceed 180mg/dl

-this difference btw insulin secretion in response to the glucose that is given I.V and orally is known as incretin effect
-they suspect that this effect induce by sth in the intestine that play role in mediating the effect of insulin or in reducing bld sugar level or in enhancing the insulin secretion by the pancreas and they found that these are polypeptides mainly 2 polypeptides responsible for the increten effect

Slide 27:
-as we can see in the slide that incrten effect in the diabetic patient is decreased bcz these patients have a certain defect in the polypeptides which is responsible for the increten effect so in order to retain the balance and enhance the increten effect to these patient we can do 2 things:
1-we give them these polypeptides (increten) either orally or by injections
OR
2-inhebetion of the metabolism of such polypeptides that are already found in the diabetic patient

Slide 25:
2-polypeptides ↑ glucose absorption by gut
1-Glucagon-like peptide-1 (GLP-1)
-Produced by the L cells in ileum and colon
-It ↑ insulin release and ↓ glucagon release following meals
-decrease gastric emptying & leads to induction of satiety

Slide 26:
. 2-Glucose-dependent insulinotropic polypeptide (GIP)
-Produced by the K cells in the proximal gut (duodenum & proximal jejunum)
-It stimulates glucose-dependent insulin release from β-cells
-Both GLP & GIP are metabolized by the enzyme dipeptidyl peptidase-4 (DPP-4) which is present in gut, liver, kidneys, lymphocytes and endothelial cells ,and the drugs which is inhibit this enzyme will increase the level of these polypeptides and so it enhance the increten effect

: slide 28
*Sitagliptin:
-Orally effective selective DPP-4 inhibitor
- increase blood levels of GLP-1, GIP insulin and C-peptide and ↓ glucagon blood levels
-it given orally
-Hypoglycemia is infrequent
Note: Dr said: the dose which is written in this slide is not important

Slide 29:
*Exenatide:
-increase insulin and ↓ glucagon blood levels
-Considered as an adjunct therapy to metformin or sulfonylureas
-it given S.C and it's not effective orally
-Hypoglycemia is infrequent


Done by :mays smadi