Flashcards in Anti-Diabetic Drugs Deck (27):
Insulin Analogs (rapid acting and basal) vs Human Insulin preparations (Regular and NPH). What are some differences between the two?
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
What is the onset, peak and duration of rapid acting insulin?
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
What is the onset, peak and duration of short acting insulin?
Regular Soluble (Crystalline): 0.5-0.7 ; 1.5-4 ; 5-8
What is the onset, peak, and duration of intermediate acting insulin?
NPH: 1-2 ; 6-12 ; 18-24
What is the onset, peak, and duration of long acting insulin?
Glargine: 2-5 ; no peak ; 18-24
Detemir: 1-2 ; no peak ; greater than 24
What are the various insulin administration methods?
SQ injection -- standard
Use: conventional disposable needles and syringes, portable pen injectors and pumps
If IV needed then use regular human insulin
A new type of insulin administration is inhaled insulin, what are some features of this type of insulin method?
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
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?
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
What two methods are used to achieve similar pattern of insulin release in a diabetic person?
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
The regimen that most closely mimics physiological insulin release, besides the use of an insulin pump, is what?
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
The use of an insulin pump is the most precise way to mimic normal insulin secretion. How does the pump work?
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
Hypoglycemia is a common adverse effect for long term diabetics why?
Do not produce adequate amounts of counterregulatory hormones (glucagon, epinephrine, cortisol and GH) that normally provide effective defense against hypoglycemia
Compared rapid and long acting insulin analogs in regards to hypoglycemia
Rapid Acting: associated with lower incidence of severe hypoglycemia than NPH insulin
Long Acting: associated with lower risk of nocturnal hypoglycemia than NPH insulin
Another adverse effect of insulin is allergic reactions, explain the effect?
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
The last adverse effect of insulin is lipodystrophy at the injection site, what does this mean?
Atrophy of SQ fatty tissue may occur at the site of injection
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?
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.
What drugs cause hyperglycemia?
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
What is the management of diabetes in hospitalized patients?
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
What non insulin antidiabetic agents are currently available in the US?
Insulin Secretagogues: Sulfonylureas and Meglitinides
Alpha Glucosidase Inhibitors
Inhibitors of DPP-IV
Analogs of Amylin
Bile ACID Sequestrants
--first four groups are referred to as oral hypoglycemics
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?
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
The only first generation Sulfonylurea is Chlorpropamide. What are some features?
Metabolized in the liver
Dosages in excess of 500mg daily increase risk of jaundice
Tolbutamide is contraindicated in elderly patients
What are the AE of Chlorpropamide?
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
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?
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
What are the pharmacokinetics, Uses and AE of the second generation Sulfonylureas?
--given orally and metabolized by the liver
--indicated as adjunct to diet and exercise to improve glycemic control in patients with type 2 DM
--hypoglycemic reactions including coma
--renal impairment or hepatic disease can cause elevations in sulfonylurea blood concentrations and hepatic disease can impair gluconeogenic capacity.
Some patients who respond initially to sulfonylureas become secondary failures aka they fail to maintain a good response to sulfonylurea therapy. Why?
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
The second group of Insulin Secretagogues is Meglitinides (Glinides). Which includes Repaglinide (more effective) and Nateglinide. What are some features of these drugs?
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