Anti-Diabetic Drugs

Question 1

Insulin Analogs (rapid acting and basal) vs Human Insulin preparations (Regular and NPH). What are some differences between the two?

Answer 1

1. Insulin analogs mimic physiologic insulin profiles more closely than human insulin preparations
2. Rapid acting insulin analogues are absorbed more rapidly than regular human insulin, attaining a quick peak and short duration of action, more similar to physiologic prandial beta cell insulin secretion
3. Regular human insulin has to be given 30 minutes before a meal whereas rapid acting insulin analogs can be administered just before a meal
4. Rapid acting analogs are associated with improved postprandial glycemic control
5. Basal Analogs provide levels of glycemic control comparable to NPH insulin
   - -in summary treatment regiments based on both rapid and long acting insulin analogs have resulted in improvements of HbA1C levels, better glycemic control and reduced hypoglycemia compared with regular insulin

Question 2

What is the onset, peak and duration of rapid acting insulin?

Answer 2

Lispro: 0.25 ; 0.5-1.5 ; 2-5
Aspart: 0.25 ; 0.6-0.8 ; 3-5
Glulisine: 0.25 ; 0.5-1.5 ; 1-2.5

Question 3

What is the onset, peak and duration of short acting insulin?

Answer 3

Regular Soluble (Crystalline): 0.5-0.7 ; 1.5-4 ; 5-8

Question 4

What is the onset, peak, and duration of intermediate acting insulin?

Answer 4

NPH: 1-2 ; 6-12 ; 18-24

Question 5

What is the onset, peak, and duration of long acting insulin?

Answer 5

Glargine: 2-5 ; no peak ; 18-24
Detemir: 1-2 ; no peak ; greater than 24

Question 6

What are the various insulin administration methods?

Answer 6

SQ injection – standard
Use: conventional disposable needles and syringes, portable pen injectors and pumps
If IV needed then use regular human insulin

Question 7

A new type of insulin administration is inhaled insulin, what are some features of this type of insulin method?

Answer 7

Dry powder formulation of regular human insulin
–after inhalation peak levels are reached in 12-15 minutes and decline to baseline in 3 hours.
Dont give to COPD and asthma and smokers

Question 8

Now the goal of SQ insulin therapy is to replace the normal basal (overnight, fasting and between meals) as well as bolus or prandial (mealtime) insulin. How does insulin release work in a non diabetic person?

Answer 8

Pancreas secretes boluses of insulin in response to snacks and meals
–between meals and throughout the night, the pancreas secretes small amounts of insulin that are sufficient to suppress lipolysis and hepatic glucose output

Question 9

What two methods are used to achieve similar pattern of insulin release in a diabetic person?

Answer 9

1. Basal Bolus Insulin Regimens: consisting of once to twice daily doses of basal insulin coupled with pre meal doses of rapid or short acting insulin
2. Insulin Pump Therapy

Question 10

The regimen that most closely mimics physiological insulin release, besides the use of an insulin pump, is what?

Answer 10

SID basal insulin such as insulin glargine or insulin detemir
–provide basal insulin levels throughout the day, along with doses of regular insulin, insulin lispro, insulin aspart or insulin glulisine before meals.
Long acting insulin can be given at bedtime or in the morning

Question 11

The use of an insulin pump is the most precise way to mimic normal insulin secretion. How does the pump work?

Answer 11

Program the pump to deliver predetermined amounts of insulin from a reservoir to a SQ inserted catheter or needle

• -deliver various basal amounts of insulin over 24 hours as well as meal related boluses
• -rapid acting insulin analogs are used

Question 12

Hypoglycemia is a common adverse effect for long term diabetics why?

Answer 12

Do not produce adequate amounts of counterregulatory hormones (glucagon, epinephrine, cortisol and GH) that normally provide effective defense against hypoglycemia

Question 13

Compared rapid and long acting insulin analogs in regards to hypoglycemia

Answer 13

Rapid Acting: associated with lower incidence of severe hypoglycemia than NPH insulin
Long Acting: associated with lower risk of nocturnal hypoglycemia than NPH insulin

Question 14

Another adverse effect of insulin is allergic reactions, explain the effect?

Answer 14

Immediate Type HSR

• -local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies.
• -sensitivity is due to non insulin protein contaminants; therefore human and analog insulins have markedly reduced the incidence of insulin allergy

Question 15

The last adverse effect of insulin is lipodystrophy at the injection site, what does this mean?

Answer 15

Atrophy of SQ fatty tissue may occur at the site of injection

Question 16

Moving on to drug interactions. A large number of drugs can cause hypoglycemia or hyperglycemia or may alter the response of diabetic patients. What drugs cause hypoglycemia?

Answer 16

Ethanol, Beta blockers and Salicylates

1. Ethanol: inhibits gluconeogenesis
2. Beta Blockers: blocking the effects of catecholamines on gluconeogenesis and glycogenolysis. Also mask the sympathetically mediated symptoms of hypoglycemia (palpitations and tremor)
3. Salicylates: enhance pancreatic beta cell sensitivity to glucose and potentiate insulin secretion.

Question 17

What drugs cause hyperglycemia?

Answer 17

Via direct effects of peripheral tissues that counter the actions of insulin
–epinephrine, glucocorticoids, atypical antipsychotic drugs (clozapine and olanzapine) and HIV protease inhibitors
Other drugs inhibit insulin secretion directly
–phenytoin, clonidine and CCB
Other drugs indirectly inhibit secretion of insulin by depletion of K
–Diuretics

Question 18

What is the management of diabetes in hospitalized patients?

Answer 18

Insulin is the cornerstone of treatment of hyperglycemia in hospitalized patients
–oral antidiabetic agents should be discontinued during acute illness and replaced with insulin. oral agents can be restarted when patent is discharged

Question 19

What non insulin antidiabetic agents are currently available in the US?

Answer 19

Insulin Secretagogues: Sulfonylureas and Meglitinides 
Biguanides 
Thiazolidinediones (TZDs)
Alpha Glucosidase Inhibitors 
Incretin Analogs 
Inhibitors of DPP-IV
Analogs of Amylin 
Bile ACID Sequestrants 
--first four groups are referred to as oral hypoglycemics

Question 20

Starting off on the anti-diabetics agents first up is Sulfonylureas (oral). For use in type 2 DM. Effective at reducing fasting plasma glucose (FPG) and HbA1C. What is the MOA?

Answer 20

Stimulation of insulin release from beta cells
–bind to the SUR1 subunit and block ATP sensitive K channels in the beta cell membrane and inhibit efflux of K resulting in depolarization, this then opens calcium channels resulting in Ca influx and release of preformed insulin
Reduction of serum glucagon levels: indirect inhibition due to increased release of insulin and somatostatin, which inhibit alpha cell secretion

Question 21

The only first generation Sulfonylurea is Chlorpropamide. What are some features?

Answer 21

Metabolized in the liver
Dosages in excess of 500mg daily increase risk of jaundice
Tolbutamide is contraindicated in elderly patients

Question 22

What are the AE of Chlorpropamide?

Answer 22

1. Hyperemic Flush: when alcohol is ingested. Accompanied by increased blood acetaldehyde concentrations; flushers eliminate acetaldehyde more slowly, suggesting a difference in aldehyde dehydrogenase activity. And it has been suggested that alcohol is a non competitive inhibitor of aldehyde dehydrogenase.
2. SIADH: potentiate the action of vasopressin and can elicit apparent syndrome of inappropriate secretion of ADH. causes hyponatremia. This drug can be used in central diabetes insipidus
3. Hematologic Toxicity: transient leukopenia

Question 23

Moving on to the second generation Sulfonylureas. These are 100 x more potent than first generation agents and lack some of the AE and drug interactions. They have replaced first generation agents. What are these agents and some features of each?

Answer 23

Glyburide (Glibenclamide): results in hypoglycemia in up to 20-30% of users
Glipizide: shortest half life of more potent agents.
Glimepiride: causes hypoglycemia in only 2-4% of patients. approved for SID as monotherapy or with metformin or insulin

Question 24

What are the pharmacokinetics, Uses and AE of the second generation Sulfonylureas?

Answer 24

Pharmacokinetics:
–given orally and metabolized by the liver
Uses:
–indicated as adjunct to diet and exercise to improve glycemic control in patients with type 2 DM
AE:
–hypoglycemic reactions including coma
–renal impairment or hepatic disease can cause elevations in sulfonylurea blood concentrations and hepatic disease can impair gluconeogenic capacity.
–weight gain

Question 25

Some patients who respond initially to sulfonylureas become secondary failures aka they fail to maintain a good response to sulfonylurea therapy. Why?

Answer 25

Change in drug metabolism, progression of beta cell failure, change in dietary compliance or misdiagnosis of a patient with slow onset type 1 DM
–most of these patients will eventually require insulin

Question 26

The second group of Insulin Secretagogues is Meglitinides (Glinides). Which includes Repaglinide (more effective) and Nateglinide. What are some features of these drugs?

Answer 26

MOA: stimulate insulin release by binding to SUR1 and thus inhibiting the beta cell ATP sensitive K channels
Not as effective as sulfonylureas or metformin in reducing fasting plasma glucose and HbA1C levels.
Rapid onset and short duration of action (postprandial glucose regulators)
Must be taken before each meal due to the rapidly absorbed and rapidly cleared
Metabolized in the liver by CYP3A4 and excreted in bile
Use in caution in hepatic impairment
NO sulfur so consider for patients with allergies

Question 27

What are the uses and adverse effects of Meglitinides (Glinides)?

Answer 27

Use: 
--approved as monotherapy or in combination with metformin or a thiazolidinedione to improve glycemic control in adults with type 2 DM
AE:
--major of repaglinide is hypoglycemia 
--right of weight gain