1. Antidiabetic drugs
Dr. Hashem Mansour

2. Introduction
Diabetes mellitus (DM) It is a metabolic disorder characterized by hyperglycaemia, glycosuria, hyperlipidaemia, negative nitrogen balance and sometimes ketonaemia.
A widespread pathological changes resulting in macrovascular, microvascular and metabolic complications

3. Types of DM The ADA recognizes four clinical classifications:
Type 1 diabetes (formerly insulin- dependent D.M).
Type 2 diabetes (formerly non–insulin-dependent D.M).
Maturity onset diabetes of young (MODY).
Gestational diabetes is defined as carbohydrate intolerance with first recognition during pregnancy.
Uncontrolled gestational diabetes can lead to fetal macrosomia (abnormally large body) and shoulder dystocia (difficult delivery), as well as neonatal hypoglycemia.

4. Type 1 diabetes
Type 1 diabetes most commonly afflicts children, adolescents, or young adults, but some latent forms occur later in life.
The disease is characterized by an absolute deficiency of insulin due to destruction of β cells.
Loss of β-cell function results from autoimmune-mediated processes that may be triggered by viruses or other environmental toxins.

5. Type 2 diabetes
Type 2 diabetes accounts for greater than 90% of cases.
Type 2 diabetes is influenced by genetic factors, aging, obesity, and peripheral insulin resistance, rather than autoimmune processes.
The metabolic alterations are generally milder than those observed with type 1
The long-term clinical consequences are similar.

6. Type 1 vs type 2

8. Insulin
Is a polypeptide hormone consisting of two peptide chains that are connected by disulfide bonds.
It is synthesized as a precursor (proinsulin) that undergoes proteolytic cleavage to form insulin.

9. Actions of Insulin
It facilitates glucose transport across cell membrane and alters the activity of enzymes involved in carbohydrate, fat and protein metabolism in liver, muscle and adipose tissue to lower blood glucose level.
This action prevent rise in free fatty acid level, ketone production and protein breakdown of the diabetic state.

10. Insulin mechanism of action

11. Actions of Insulin

12. Pharmacokinetics and fate
Insulin preparations vary primarily in their onset and duration of activity.
Dose, injection site, blood supply, temperature, and physical activity can also affect the onset and duration of various insulin preparations.
Administered by S.C or I.V or continuous S.C insulin infusion called the insulin pump.
The pump is programmed to deliver a basal rate of insulin in addition to a bolus of insulin to cover mealtime carbohydrate intake.

13. Types of insulin

14. Onset of action Insulin preparations

15. Adverse reactions to insulin
Hypoglycemia is the most serious and common adverse reaction to insulin.
Weight gain.
Local injection site reactions.
Lipodystrophy, can be minimized by rotation of injection sites.
Diabetics with renal insufficiency may require a decrease in insulin dose.

16. Adverse effects

17. Insulin combinations
Various premixed combinations of human insulins, such as 70% NPH insulin plus 30% regular insulin , or 50% of each of these are also available.
Use of premixed combinations decreases the number of daily injections but makes it more difficult to adjust individual components of the insulin regimen.

18. Goal of treatment of DM
The purpose of therapy in diabetes mellitus is to restore metabolism to normal
Avoid symptoms due to hyperglycaemia and glucosuria.
Prevent short term complications (infection, ketoacidosis, etc.) and long-term squeals (cardiovascular, retinal, renal, etc.)

19. When to use of insulin in D.M
(i) Not controlled by diet and exercise.
(ii) Primary or secondary failure of oral hypoglycaemics.
(iii) Underweight patients.
(iv) Temporarily to tide over infections, trauma, surgery, pregnancy.
In the perioperative period and during labour, monitored i.v. insulin infusion is preferable.
(v) Any complication of diabetes, e.g. ketoacidosis, diabetic or non-ketotic hyperosmolar coma, gangrene of extremities.

20. Insulin resistance
This is said when requirement is increased (> 200 U/day, but physiologically > 100 U/day).
Relative insulin resistance is integral to the ‘metabolic syndrome, of which hyperinsulinemia (with latent or overt type 2 diabetes), dyslipidaemia, hyperuricaemia and hypertension are important components.
It can be overcome by increasing insulin

22. INCRETIN MIMETICS
Incretin hormones are responsible for 60% to 70% of postprandial insulin secretion.
Exenatide and liraglutide are injectable incretin mimetics used for the treatment of type 2 diabetes.

23. Mechanism of action
The incretin mimetics are analogs of GLP-1 that exert their activity by acting as GLP-1 receptor agonists.
These agents improve glucose dependent insulin secretion, slow gastric emptying time, reduce food intake by enhancing satiety, decrease postprandial glucagon secretion, and promote β-cell proliferation.
Consequently, weight gain and postprandial hyperglycemia are reduced, and HbA1c levels decline.

25. Pharmacokinetics and fate
Exenatide and liraglutide must be administered S.C.
Liraglutide has a long half-life, allowing for once-daily dosing without regard to meals.
Exenatide injected twice daily within 60 minutes prior to morning and evening meals.
A once-weekly extended-release preparation is also available.
Exenatide should be avoided in patients with severe renal impairment.
Liraglutide is the drug of choice for T2DM among CHF and CKD patients.

26. Adverse effects
The main adverse effects of the incretin mimetics consist of nausea, vomiting, diarrhea, and constipation and pancreatitis.
Patients should be advised to discontinue these agents immediately if they experience severe abdominal pain.
Liraglutide causes thyroid C-cell tumors in rodents.
However, it is unknown if it causes these tumors or thyroid carcinoma in humans.

27. Oral hypoglycemic
SULFONYLUREAS: Glyburide, Glipizide, Gliclazide, Glimepiride
BIGUANIDE: Metformin
MEGLITINIDE: Repaglinide Nateglinide
THIAZOLIDINEDIONES: Rosiglitazone Pioglitazone
α GLUCOSIDASE INHIBITORS: Acarbose
DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITOR: Sitagliptin, Vildagliptin
Sodium glucose cotransporte inhibitors SGLT2 inhibitors: canagliflusin

28. Sulfonylureas
These agents are classified as insulin secretagogues, because they promote insulin release from the β cells.
Mechanism of action: Stimulation of insulin release from the β cells of the pancreas.
Sulfonylureas block ATP-sensitive K+ channels, resulting in insulin exocytosis.
In addition, sulfonylureas may reduce hepatic glucose production and increase peripheral insulin sensitivity.

29. Pharmacokinetics and fate
Given orally
These drugs bind to serum proteins
Metabolized by the liver
Excreted in the urine and feces.
The duration of action ranges from 12 to 24 hours.

30. Adverse effects Weight gain, hyperinsulinemia, and hypoglycemia.
They should be used with caution in hepatic impairment.
Contra indicated in Renal impairment increase the risk of hypoglycemia.
Glipizide or glimepiride are safer options in renal dysfunction and in elderly patients.
Glyburide has minimal transfer across the placenta and may be an alternative to insulin for diabetes in pregnancy.

31. General adverse effects of oral hypoglycemic drugs

32. Glinides Glinides are also considered insulin secretagogues.
Mechanism of action: Stimulate insulin secretion.
They bind to a distinct site on the β cell, closing ATP-sensitive K+ channels results in the release of insulin.
Have a rapid onset and a short duration of action.
They promote release of insulin that occurs after a meal and are categorized as postprandial glucose regulators.
Glinides should not be used in combination with sulfonylureas.

33. Pharmacokinetics and fate
Glinides should be taken prior to a meal and are well absorbed after oral administration.
Both glinides are metabolized to inactive products by the liver
Excreted through the bile.

34. Adverse effects
Glinides can cause hypoglycemia and weight gain, the incidence is lower than that with sulfonylureas.
By inhibiting hepatic metabolism, the lipid-lowering drug gemfibrozil may significantly increase the effects of repaglinide, and concurrent use is contraindicated.
These agents should be used with caution in patients with hepatic impairment.

35. Biguanides
Metformin the only biguanide, is classified as an insulin sensitizer.
It increases glucose uptake by target tissues, thereby decreasing insulin resistance.
Metformin does not promote insulin secretion.
Therefore, hyperinsulinemia is not a problem, and the risk of hypoglycemia is far less than that with sulfonylureas.

36. Mechanism of action
Presence of some insulin is essential for their action.
1. Suppress hepatic gluconeogenesis and glucose output from liver: the major action.
2. Enhance insulin-mediated glucose disposal in muscle and fat.
3. Retard intestinal absorption of glucose, amino acids and vit B12.
4. Promote peripheral glucose utilization by enhancing anaerobic glycolysis.

37. Pharmacokinetics and fate
Metformin is well absorbed orally.
Is not bound to serum proteins
Is not metabolized.
Excretion is via the urine.

38. Adverse effects These are largely gastrointestinal.
Metformin is contraindicated in renal dysfunction due to the risk of lactic acidosis.
It should be discontinued in cases of acute myocardial infarction, exacerbation of heart failure, sepsis, or other disorders that can cause acute renal failure.
Metformin should be used with caution in patients older than 80 years and in those with heart failure.
It should be temporarily discontinued in patients undergoing procedures requiring IV radiographic contrast.
Decrease vitamin B12 absorption.

39. Other uses
In addition to type 2 diabetes, metformin is effective in the treatment of polycystic ovary syndrome.
It lowers insulin resistance seen in this disorder and can result in ovulation and, therefore, possibly pregnancy.

40. Thiazolidinediones
The thiazolidinediones (TZDs) are also insulin sensitizers.
The two members of this class are pioglitazone and rosiglitazone.
Although insulin is required for their action, the TZDs do not promote its release from the β cells, so hyperinsulinemia is not a risk.

41. Mechanism of action
The TZDs lower insulin resistance by acting as agonists for the peroxisome proliferator–activated receptor-γ (PPARγ), a nuclear hormone receptor.
Activation of PPARγ regulates the transcription of several insulin responsive genes, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle.

42. Pharmacokinetics and fate
Well absorbed after oral administration.
Undergo extensive metabolism by liver.
Excreted in the bile and eliminated in the feces.
No dosage adjustment is required in renal impairment.
These agents should be avoided in nursing mothers.

43. Adverse effects
Liver toxicity need periodic monitoring of liver function
Weight gain can occur because TZDs may increase subcutaneous fat and cause fluid retention.
Contra indicated in patients with severe heart failure.
Osteopenia and increased fracture risk.
Pioglitazone may also increase the risk of bladder cancer.
Other uses: As with metformin, TZDs can resume ovulation in premenopausal women with polycystic ovary syndrome.

44. Effects on cholesterol
Rosiglitazone increases LDL cholesterol and triglycerides, whereas pioglitazone decreases triglycerides.
Both drugs increase HDL cholesterol.

45. Dipeptidyl peptidase-4 inhibitors
Vildagliptin , linagliptin, saxagliptin, and sitagliptinare orally active dipeptidyl peptidase-4 (DPP-4) inhibitors used for the treatment of type 2 diabetes.

46. Mechanism of action
These drugs inhibit the enzyme DPP-4, which is responsible for the inactivation of incretin hormones such as GLP-1.
Prolonging the activity of incretin hormones increases insulin release in response to meals and reduces inappropriate secretion of glucagon.
Unlike incretin mimetics, these drugs do not cause satiety, or fullness, and are weight neutral.

47. Pharmacokinetics and fate
Well absorbed after oral administration.
Sitagliptin are mostly excreted unchanged in the urine.
Saxagliptin is metabolized to an active metabolite.
The primary route of elimination is renal.
All DPP-4 inhibitors except linagliptin require dosage adjustments in renal dysfunction.
Adverse effects: Nasopharyngitis and headache. Dizzy, diarrhea, pancreatitis has occurred with use of all DPP-4 inhibitors.

48. Sodium–glucose cotransporter 2 inhibitors
Canagliflozin and dapagliflozin are the agents in this category of drugs for type 2 diabetes.

49. Mechanism of action
The sodium–glucose cotransporter 2 (SGLT2) is responsible for reabsorbing filtered glucose in the tubular lumen of the kidney.
By inhibiting SGLT2, these agents decrease reabsorption of glucose, increase urinary glucose excretion, and lower blood glucose.
Inhibition of SGLT2 also decreases reabsorption of sodium and causes osmotic diuresis.
Therefore, SGLT2 inhibitors may reduce systolic blood pressure.

50. Pharmacokinetics and fate
These agents are given once daily in the morning.
Canagliflozin should be taken before the first meal of the day.
Metabolized by glucuronidation to inactive metabolites.
Excretion for canagliflozin is via the feces, about one-third of a dose is renally eliminated.
These agents should be avoided in patients with renal dysfunction.

51. Adverse effects
The most common adverse effects with SGLT2 inhibitors are female genital mycotic infections (for example, vulvovaginal candidiasis), urinary tract infections, and urinary frequency.
Hypotension has also occurred, particularly in the elderly or patients on diuretics.
Thus, volume status should be evaluated prior to starting these agents.

53. Implications in physiotherapy
Diabetes mellitus is associated with increased incidence of many diseases mostly cardiac, candidiasis and other infections, etc.
The most important complications of antidiabetic drugs include hypoglycemia, hyperglycemia and weight gain.
Before starting physiotherapy session the blood sugar levels must be well controlled.
This can be done by measuring blood sugar level before session and after session.

54. Implications in physiotherapy
If the blood sugar level is very low so never to start session (hypogalycemia risk is very high).
For long session you must don blood sugar level during excercise.
Patient education is another way to help patients to overcome diabetes complications.
If the blood sugar level is very high refer the patient to physician.
Sugar source should be available to overcome the problem of hypoglycemia

56. GLUCAGON
The hyperglycaemic hormone glucagon is secreted by the α cells of the islets of Langerhans in pancreas.
Blood glucose level has opposite effects on insulin and glucagon release, i.e. high glucose level inhibits glucagon secretion.
Glucagon causes hyperglycaemia primarily by enhancing glycogenolysis and gluconeogenesis in liver.
Suppression of glucose utilization in muscle and fat contributes modestly.
Glucagon increases the force and rate of cardiac contraction and this is not antagonized by β blockers.

57. Mechanism of action
Glucagon, activates adenylyl cyclase and increases cAMP in liver, fat cells, heart and other tissues; most of its actions are mediated through this cyclic nucleotide.
Uses Glucagon can be used to counteract insulin hypoglycaemia as an expedient measure, and occasionally to stimulate the heart in cardiogenic shock.