Diabetes pharm - Martin Flashcards
rapid-acting insulin drugs
insulin lispro, aspart, glulisine
short-acting insulin drugs
regular insulin
intermediate acting insulin drugs
NPH and NPL
ultra-long acting insulin drugs
Glargine insulin
insulin deetmir
Fixed – Mix Insulins
NPH / Regular (50%/50%) NPH / Regular (70%/30%) NPL / Lispro (75%/25%) NPL/ Lispro (50%/50%) Aspart protamine/aspart (70%/30%)
Hypoglycemic Agents
biguanides sulfonylureas meglitinides alpha-glucosidase inhibitors TZDs glucagon-like Peptide-1 (GLP-1) agonists dipeptidyl-peptidase-4 inhibitors (DPP-4) Amylin analog Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors
Biguanides
Metformin
Sulfonylureas
Glipizide, Glyburide, Glimepiride
Meglitinides
(“Glinides” or Non-sulfonylurea Insulin Releasers)
Repaglinide, Nateglinide
a-Glucosidase Inhibitors
Acarbose, Miglitol
TZDs
Rosiglitazone, Pioglitazone
Glucagon-like Peptide-1 (GLP-1) Agonists
Exenatide
Dipeptidyl-Peptidase-4 (DPP-4) Inhibitors
“Gliptins”
Amylin analog
Pramlintide
Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors
flozins”
Insulin: Biosynthesis and Chemistry
Biosynthesis of Insulin
cells of pancreatic islet
Preproinsulin - proinsulin - insulin
A and B chains, C peptide
Chemistry:
monomers, dimers, hexamers
Zn2+
Soluble versus semi-crystalline states of the molecule - onset and duration of action
Regulation of Insulin Secretion
Insulin secretion is tightly regulated by the interplay of: nutrients, especially glucose GI hormones pancreatic hormones autonomic neurotransmission
**Glucose is the principal stimulus of insulin secretion
Biphasic Insulin Secretion
Normal individuals have two phases of insulin secretion in response to a meal
Phase I - rapid rise and fall
Phase II - slower, more gradual increase
things that can stimulate insulin secretion
glucose, of course
amino acids, ketoacids
ach, CCK
Glucagon, GLP-1
Epi, Norepi, Somatostatin inhibit
insulin and diabetes
Type 1 diabetes mellitus
no insulin secretion
Type 2
initially, Type 2 DM patient may have elevated plasma insulin levels and tissue insulin resistance, but often 1st phase of insulin release is dysregulated
years later, beta cells fail and insulin levels are low
Distribution and Degradation of Insulin
Insulin circulates as the free monomer
Degradation in the liver operates at near maximal capacity
Degradation in the kidney after tubular reabsorption
Uptake by the muscle
t1/2 of insulin is about 5 - 15 minutes
Plasma levels measured by RIA (if necessary)
Insulin- Molecular Mechanism of Action
All cells have insulin receptors
Insulin receptor stimulates phosphorylation or dephosphorylation of cell-specific intracellular signal transduction proteins
The Insulin Receptor
The insulin receptor is an integral plasma membrane protein complex
Receptor is a heterodimer of alpha and b subunits
Intracellular beta subunits have *** tyrosine kinase enzyme activity
Insulin binding to the receptor stimulates autophosphorylation of the receptor beta subunits and activation of tyrosine kinase activity
Docking proteins bind to the receptor and recruit other mediator proteins to the plasma membrane
Regulation of Glucose Transport
Glucose transport is a crucial component of the physiological effects of insulin
Glucose is transported into cells by facilitated diffusion by means of Glucose Transporters (GLUT)
Insulin stimulates reversible translocation of glucose transporters to the plasma membrane
GLUT-4 - muscle and fat cells
GLUT-2 pancreas, liver
Insulin increases synthesis of GLUT1 and GLUT4
Regulation of Glucose Metabolism
Insulin stimulates glucose uptake
Insulin stimulates glucose storage and utilization
Insulin inhibits glycogen breakdown (glycogenolysis)
Insulin inhibits glucose synthesis (gluconeogenesis)
Central Features of Diabetes Mellitus
Insulin deficiency
Insulin resistance
Hyperglycemia
Type I vs Type II DM
Type 1- young, frequently undernourished, 10-20% prevalence, moderate genetic predisposition, beta cells are destroyed- eliminating the production of insulin
Type 2- often over age 35, obesity usually present, 80-90 percent of diagnosed diabetics, very strong genetic predisposition, inability of beta cells to produce appropriate quantities of insulin; insulin resistance; other defects
ACCORD Trial
The ACCORD Trial was a large clinical trial
in >10,000 patients with patients with Type 2 D, with or at high-risk for CV disease.
This trial found that treating patients intensively to a HbA1C target of under 6.0% did not significantly reduce the incidence of major CV events and was associated with increased all-cause mortality compared to patients treated to a target HbA1C of 7.0-7.9%
Diabetes Control and Complications Trial (DCCT)
Conclusion: Intensive therapy to attain euglycemia dramatically reduces the incidence of and severity of long-term complications
Major problem: * Hypoglycemia
The more intense the attempt to maintain “normal” glucose levels, the greater the risk of hypoglycemia
Maintenance of Intensive Insulin Therapy requires educated, motivated patient
Hemoglobin A1c
A convenient index of long-term exposure to elevated glucose. Hemoglobin becomes glycosylated t1/2 120 days Used to monitor therapeutic goals ** Recommendation: Hemoglobin A1c < 7.0%
Diagnosis of Diabetes
Classic signs and symptoms Unequivocally high FPG >126 mg/dL Random glucose of >200 mg/dL FPG of >126 mg/dL on two or more occasions Failure on Oral Glucose Tolerance Test
Typical Insulin Regimen
Example: 30 Units (U) per day
2/3 total dose before breakfast
- 2/3 NPH (14U)
- 1/3 Regular (6U)
1/3 total dose in the evening
- 1/3 Regular before dinner (3U)
- 2/3 NPH at bedtime (7U)
Adverse Reaction to Insulin Therapy: Hypoglycemia
Hypoglycemia due to: inappropriate dose mismatch of time of injection versus food intake exercise-induced glucose demand increase need for insulin
hypoglycemia- signs and symptoms, treatment
Signs and Symptoms
Sweating, hunger, paresthesias, palpitations, tremor, anxiety
confusion, weakness, drowsiness, blurred vision, loss of consciousness
** Treatment
Glucose
Glucagon
Type 2 Diabetes Mellitus
Diminished insulin secretion Tissue resistance to insulin Enhanced glucagon Enhanced gluconeogenesis Obesity
Metformin [Glucophage]
Antihyperglycemic action, ** not hypoglycemic
increases insulin action, glycolysis, uptake and utilization by muscle
DECREASES gluconeogenesis, hepatic glucose output, intestinal absorption of glucose
Metformin [Glucophage] therapy and advantages
Drug of first choice for type II diabetes
Monotherapy
or added to GLP-1 agonist, DPP-4 inhibitor, glinide, sulfonylurea, or TZD
step-up to daily divided doses
Advantages:
- no weight gain
- no hypoglycemia
- favorable lipid profile
Metformin [Glucophage] side effects
Metformin has advantages over SUs & insulin in some obese, insulin-resistant patients
Concern is lactic acidosis (but rare) especially in patients with:
- renal or hepatic insufficiency
- CV disease
Common side effects
GI: anorexia, nausea, abdominal discomfort, diarrhea
Combinations with metformin
Since most patient end up needing more than one drug a number of combination products have been introduced including: Metformin plus: Glipizide Glyburide Linagliptin Pioglitazone Repaglinide Sitagliptin Saxagliptin
Combination products simplify dosing but reduce the flexibility in adjusting doses
Oral Hypoglycemic Agents Sulfonylureas - the generations
[First Generation: No longer used- Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide]
Second Generation
- Glipizide
- Glyburide
“Third” Generation
* Glimeperide
Sulfonylureas (SUs): Mechanism of Action
Block ATP-sensitive K+ channel
Leads to depolarization and influx of Ca++
- Results in insulin secretion
- Adverse Effects: Weight gain and Hypoglycemia
Sulfonylureas- key points
- stimulate insulin release
SUs indirectly increase tissue sensitivity to insulin, i.e., help overcome insulin resistance
Help suppress hepatic glucose output
Success depends on functionality of b-cells20-25% of patients fail to respond adequately
Subsequent failures result from eventual b-cell failure
2nd or 3rd generation Sulfonylureas
Glimeperide
Glipizide
Glyburide
same mechanism, release insulin equally efficacious more potent than 1st generation most costly than 1st generation less severe/persistent hypoglycemia
Glimepiride
appears to cause * less weight gain than all the other SUs
contraindications include sulfa allergy, pregnancy, type 1 DM, ketoacidosis, renal failure, hepatic failure, and major surgery.
Once daily doses possible
Glipizide and Glyburide
Glipizide
Intermediate-acting
QD dosing, if >15 mg per day give BID
inactive metabolites, no special precautions
Glyburide
greater incidence of severe prolonged hypoglycemia than glipizide
use cautiously in elderly or anyone predisposed to hypoglycemia
Non-Sulfonylurea Secretogogues
Repaglinide & Nateglinide
Non-sulfonylurea insulin releasing agents
Blocks ATP-sensitive K+ channel
Binds at different site than sulfonylureas
* Short half-life; rapid action
* Taken right before meals
a-Glucosidase Inhibitors
Acarbose
Miglitol
Inhibit digestion of complex sugars
Decrease sugar uptake after a meal
* Cause flatulence and GI upset
- leads to poor acceptance & compliance
Watch out for hypoglycemia when used with insulin or sulfonylurea
Glucagon-like Peptide 1 (GLP-1 agonists)
Exenatide, Liraglutide, Albiglutide, Dulaglutide
GLP-1 is a peptide hormone produced from cleavage of the proglucagon precursor
- Secreted by intestinal L cells
- First discovered from saliva of the Gila monster
- Exenatide is an analog of GLP-1 that is highly resistant to inactivation by dipeptidyl peptidase-4 (DPP-4)
- Binds to GLP-1 receptor as an agonist
GLP-1 Agonists
GLP-1 agonists stimulate:
- Glucose-dependent enhancement of insulin secretion
- Inhibition of glucagon secretion
- Appetite suppression and satiety induction
- Reduction of gastric emptying
- Possible stimulation of islet cell growth, differentiation, and regeneration
*decreases HbA1c, decreases postprandial glucose, causes weight loss
* Little hypoglycemia
GI upset most common adverse effects but there appears to be some risk for pancreatitis.
GLP-1 Agonists therapy regimens
Use as monotherapy or in combination with:
- Metformin (in dual therapy)
- Metformin + TZD (triple therapy)
- Metformin + Sulfonylurea (triple therapy)
Not approved for use with insulin
Exenatide requires twice-daily SQ injections or there is an extended-release formulations that is injected once per week
Liraglutide requires only once-daily injections
Dipeptidyl Peptidase-4 Inhibitors(DPP-4 Inhibitors)- administration
Sitagliptin, Saxagliptin, Linagliptin DPP-4 hydrolyzes: Glucagon-like peptide-1 (GLP-1) Glucose-dependent insulinotropic peptide (GIP) These drugs are administered * orally*
- Monotherapy or combined with metformin, SUs, or TZD
- Increases insulin secretion, decreases glucagon and hepatic glucose production, * increases peripheral glucose uptake and utilization
DPP-4 Inhibitors side effects/ DDIs
Little hypoglycemia
because DPP-4 effects are glucose-dependent
Not approved for use with insulin
Pramlintide
Pramlintide is a synthetic analog of amylin, a peptide co-secreted with insulin from pancreatic b-cells.
The identified metabolic effects of pramlintide are:
- centrally-mediated induction of satiety
and DECREASE:
- of endogenous glucagon production, especially in the postprandial state.
- of postprandial hepatic glucose production.
- of gastric emptying time.
- of postprandial glucose levels
Used in Type 1 or type 2 diabetics already using insulin, especially those with insulin resistance requiring large doses of insulin
***Require SQ injections prior to meals and cannot be mixed with insulin
Thiazolidinediones (TZDs)
- Pioglitazone
- Rosiglitazone
- Insulin Sensitizers
Thiazolidinediones (TZDs) MOA, uses, risks
Bind to nuclear transcription factors involved in insulin action
decreased insulin resistance
increased peripheral action of insulin
increased glucose uptake, and GLUT-1 & GLUT-4
decreased hepatic glucose output
Takes several weeks to develop clinical effect
Useful effect since many Type 2 patients are “insulin-resistant”
Liver enzyme tests required - idiosyncratic hepatocellular injury
Long-term risks have been debated, * ↑ risk of MI with rosiglitazone was reported but was never substantiated; both drugs cause * weight gain; rosiglitazone was restricted in use in the USA but restriction now lifted; pioglitazone taken off the market in Germany and France because of increased risk of bladder cancer.
* Cause fluid retention and CHF (2X risk) and increase risk of
Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors
- Canagliflozin, Dapagliflozin, Empagliflozin
New drugs just approved in the last several years
Oral treatment (once per day) of Type 2 diabetes; in combination with insulin or metformin, ± sulfonylurea or pioglitazone
SGLT2 is a membrane protein expressed mainly in the kidney. It transports filtered glucose from the proximal renal tubule into tubular epithelial cells. By inhibiting SGLT2, “flozins” decrease glucose reabsorption, increase urinary glucose excretion, and lower blood glucose levels.
Flozins are modestly effective in reducing HbA1c, systolic blood pressure and weight, with a low risk of hypoglycemia.
Genital mycotic infections can occur in both men and women; long-term safety still unknown.
