Hyperglycaemic Medication (Insulin).pptx

Pharmacology Lecture Notes
ANTI-DIABETES AGENTS
BY
MR. AZI BULUS SAMUEL (BNSC, PDE, MSC)
5/6/2023 Hyperglycaemic Medication (Insulin) 1

DIABETES MELLITUS
 Diabetes mellitus is defined as an elevated blood glucose associated with
absent or inadequate pancreatic insulin secretion, with or without concurrent
impairment of insulin action.
 The disease states underlying the diagnosis of diabetes mellitus are now
classified into four categories:
type 1,
 type 2,
other, and
gestational diabetes mellitus.

Type 1 Diabetes Mellitus
 The hallmark of type 1 diabetes is selective beta cell (B cell) destruction
and severe or absolute insulin deficiency.
 Type 1 dia betes is further subdivided into immune-mediated (type 1a) and
idiopathic causes (type 1b).
 The immune form is the most common form of type 1 diabetes. Although
most patients are younger than 30 years of age at the time of diagnosis, the
onset can occur at any age.
 Type 1 diabetes is found in all ethnic groups, but the highest incidence is in
people from northern Europe and from Sardinia.
 Susceptibility appears to involve a multifactorial genetic linkage, but only
10–15% of patients have a positive family history.

Type 1 Diabetes Mellitus Cont…
 Most patients with type 1 diabetes have one or more circulating
antibodies to glutamic acid decarboxylase 65 (GAD 65), insulin
autoantibody, tyrosine phosphatase IA2 (ICA 512), and zinc
transporter 8 (ZnT8) at the time of diagnosis.
 These antibodies facilitate the diagnosis of type 1a diabetes and can
also be used to screen family members at risk for developing the
disease.
 Most type 1 patients with acute symptomatic presentation have
significant beta cell loss and insulin therapy is essential to control
glucose levels and to prevent ketosis.

Type 1 Diabetes Mellitus Cont…
 Some patients have a more indolent autoimmune process and initially
retain enough beta cell function to avoid ketosis.
 They can be treated at first with oral hypoglycemic agents but then
need insulin as their beta cell function declines.
 Antibody studies in northern Europeans indicate that up to 10–15% of
“type 2” patients may actually have this milder form of type 1 diabetes
(latent autoimmune diabetes of adult hood; LADA).

Type 2 Diabetes Mellitus
 Type 2 diabetes is a heterogenous group of conditions characterized by
tissue resistance to the action of insulin combined with a relative
deficiency in insulin secretion.
 A given individual may have more resistance or more beta-cell
deficiency, and the abnormalities may be mild or severe.
 Although the circulating endogenous insulin is sufficient to prevent
ketoacidosis, it is inadequate to prevent hyperglycemia.
 Patients with type 2 diabetes can initially be controlled with diet,
exercise and oral glucose lowering agents or non-insulin injectables.
 Some patients have progressive beta cell failure and eventually may
also need insulin therapy.

Other Specific Types of Diabetes Mellitus
 The “other” designation refers to multiple other specific causes of an
elevated blood glucose: pancreatectomy, pancreatitis, non pancreatic
diseases, drug therapy, etc, of which coverage is beyond the scope of this
lectures

Gestational Diabetes Mellitus
 Gestational diabetes (GDM) is defined as any abnormality in glucose levels
noted for the first time during pregnancy.
 Gestational diabetes is diagnosed in approximately 7% of all pregnancies in
the United States.
 During pregnancy, the placenta and placental hormones create an insulin
resistance that is most pronounced in the last trimester.
 Risk assessment for diabetes is suggested starting at the first prenatal visit.
 High-risk women should be screened immediately.
 Screening may be deferred in lower-risk women until the 24th to 28th week
of gestation.

Laboratory Findings (Plasma or Serum Glucose)
 A plasma glucose level of 126 mg/dL (7 mmol/L) or higher on more than
one occasion after at least 8 hours of fasting is diagnostic of diabetes
mellitus (Table 41–4). Fasting plasma
 glucose levels of 100–125 mg/dL (5.6–6.9 mmol/L) are associated with
increased risk of diabetes (impaired fasting glucose tolerance).
 If the fasting plasma glucose level is less than 126 mg/dL (7 mMol/L) but
diabetes is nonetheless suspected, then a standardized oral glucose
tolerance test may be done (Table 41–4).
 The patient should eat nothing after midnight prior to the test day.
 On the morning of the test, adults are then given 75 g of glucose in 300
mL of water; children are given 1.75 g of glucose per kilogram of ideal
body weight.

Laboratory Findings (Plasma or Serum Glucose)
 The glucose load is consumed within 5 minutes. Blood samples for
plasma glucose are obtained at 0 and 120 minutes after ingestion of
glucose.
 An oral glucose tolerance test is normal if the fasting venous plasma
glucose value is less than 100 mg/dL (5.6 mmol/L) and the 2-hour value
falls below 140 mg/dL (7.8 mmol/L).
 A fasting value of 126 mg/dL (7 mmol/L) or higher or a 2-hour value of
greater than 200 mg/dL (11.1 mmol/L) is diagnostic of diabetes mellitus.
 Patients with 2-hour value of 140–199 mg/dL (7.8–11.1 mmol/L) have
impaired glucose tolerance.

Laboratory Findings (Hemoglobin A1c Measurements)
 When plasma glucose levels are in the normal range, about 4–6% of
hemoglobin A has one or both of the N terminal valines of their beta chains
irreversibly glycated by glucose—referred to as hemoglobin A1c (HbA1c).
 The HbA1c fraction is abnormally elevated in people with diabetes with
chronic hyperglycemia.
 Since red cells have a lifespan of up to 120 days, the HbA1c value reflects
plasma glucose levels over the preceding 8–12 weeks.
 In patients who monitor their glucose levels, the HbA1c value provides a
valuable check on the accuracy of their monitoring.

Laboratory Findings (Hemoglobin A1c Measurements)
 In patients who do not monitor their glucose levels, HbA1c measurements are
essential for adjusting treatment.
 HbA1c can be used to diagnose diabetes.
 An HbA1c of 6.5% or greater if confirmed by repeat testing is diagnostic of
diabetes.
 Less than 5.7% is normal, and patients with levels of 5.7–6.4% are considered
at high risk for developing diabetes

Laboratory Findings (Urine or Blood Ketones)
 Qualitative detection of ketone bodies can be accomplished by nitroprusside
tests (Acetest or Ketostix).
 Although these tests do not detect beta-hydroxybutyric acid, which lacks a
ketone group, the semiquantitative estimation of ketonuria thus obtained is
nonetheless usually adequate for clinical purposes.
 Many laboratories now measure beta-hydroxybutyric acid, and meters are
available (Precision Xtra; Nova Max Plus) for patient use that measure beta-
hydroxybutyric acid levels in capillary glucose samples.
 Beta hydroxybutyrate levels >0.6 mmol/L require evaluation.
 A level >3.0 mmol/L, which is equivalent to very large urinary ketones, will
require hospitalization.

Self-Monitoring of Blood Glucose
 Capillary blood glucose measurements performed by patients themselves,
as outpatients, are extremely useful.
 In type 1 patients in whom “tight” metabolic control is attempted, they are
indispensable. Several paper strip methods and a large number of blood
glucose meters are now available for measuring glucose on capillary blood
samples.
 All are accurate, but they vary with regard to speed, convenience, size of
blood samples required, reporting capability, and cost.
 Some meters are designed to communicate with an insulin pump.
 A number of continuous glucose monitoring (CGM) systems are also
available for clinical use.

Self-Monitoring of Blood Glucose Cont…
 The systems utilize a subcutaneous sensor that measures glucose
concentrations in the interstitial fluid for 3–7 days.
 Studies show that adult type 1 patients who use continuous systems have
improved glucose control without an increased incidence of hypoglycemia.
 There is great interest in using continuous glucose monitoring systems to
automatically deliver insulin by continuous subcutaneous insulin infusion
pump.
 The first artificial pancreas system has been approved by the U.S. Food and
Drug Administration (FDA) and will become available in 2017.
 With this system, the continuous glucose monitor readings are used to
automatically adjust the basal insulin dosing by the insulin pump

Medications for Hyperglycemia (Insulin Preparations)
 Human insulin is dispensed as regular (R) and neutral protamine
hagedorn (NPH) formulations. There are also six analogs of human
insulin.
 Three of the analogs are rapidly acting:
insulin lispro,
insulin aspart, and
insulin glulisine; and
 three are long acting:
insulin glargine,
insulin detemir, and
insulin degludec.

Medications for Hyperglycemia (Insulin Preparations)
 All the insulins in the United States are available in a concentration of
100 units/ML (U100) and dispensed as 10-mL vials or 0.3-mL
cartridges or prefilled disposable pens.
 Several insulins are also available at higher concentrations in the
prefilled disposable pen form: insulin glargine 300 units/mL (U300);
insulin degludec (U200); insulin lispro 200 units/mL (U200); and
regular insulin 500 units/mL (U500).

Summary of Bioavailability Characteristics of the Insulins.

Short-Acting Insulin Preparations
 The short-acting preparations include regular human insulin and the three
rapidly acting insulin analogs.
 All are clear solutions at neutral pH.
 The insulin molecules exist as dimers that assemble into hexamers in the
presence of two zinc ions.
 The hexamers are further stabilized by phenolic compounds such as phenol
and meta-Cresol.
 The mutations engineered into the rapidly acting insulin analogs are
designed to disrupt the stabilizing intermolecular interactions of the dimers
and hexamers, leading to more rapid absorption into the circulation after
subcutaneous injection.

Regular Insulin
 Regular insulin is a short-acting, soluble crystalline zinc insulin whose
hypoglycemic effect appears within 30 minutes after subcutaneous injection,
peaks at about 2 hours, and lasts for 5–7 hours when usual quantities (ie, 5–
15 U) are administered.
 For very insulin-resistant subjects who would otherwise require large
volumes of insulin solution, a U500 preparation of human regular insulin is
available both in a vial form and a disposable pen.
 If the vial form is used, it is necessary to use a U100-insulin syringe or
tuberculin syringe to measure doses.

Regular Insulin Cont…
 The physician should then carefully note dosages in both units and volume to
avoid overdosage.
 The disposable pen avoids this conversion issue and dispenses the regular
U500 insulin in 5-unit increments.
 Intravenous infusions of regular insulin are particularly useful in the
treatment of diabetic ketoacidosis and during the perioperative management
of insulin-requiring diabetics.

Rapidly Acting Insulin Analogs
 Insulin lispro (Humalog) is an insulin analog in which the proline at position
B28 is reversed with the lysine at B29. Insulin aspart (Novolog) is a single
 substitution of proline by aspartic acid at position B28.
 Insulin glulisine (Apidra) differs from human insulin in that the amino acid
asparagine at position B3 is replaced by lysine and the lysine in position B29
by glutamic acid.
 When injected subcutaneously, these three analogs quickly dissociate into
monomers and are absorbed very rapidly, reaching peak serum values in as
little as 1 hour.
 The amino acid changes in these analogs do not interfere with their binding to
the insulin receptor, with the circulating half-life, or with their
immunogenicity, which are all identical to those of human regular insulin.

 Clinical trials have demonstrated that the optimal times of preprandial subcutaneous
injection of comparable doses of the rapid-acting insulin analogs and of regular
human insulin are 15 minutes and 45 minutes before the meal, respectively.
 Although the more rapid onset of action has been welcomed as a great convenience
by patients with diabetes who object to waiting as long as 45 minutes after injecting
regular human insulin before they can begin their meal, patients must be taught to
ingest adequate absorbable carbohydrate early in the meal to avoid hypoglycemia
during the meal.
 The analogs also have lowest variability of absorption: approximately 5%.
 This compares with 25% for regular insulin.
 Another desirable feature of rapidly acting insulin analogs is that their duration of
action remains at about 4 hours for most commonly used dosages.
 This contrasts with regular insulin, whose duration of action is significantly
prolonged when larger doses are used.

 The rapidly acting analogs are commonly used in insulin pumps.
 In a double-blind crossover study comparing insulin lispro with regular insulin in
insulin pumps, persons using insulin lispro had lower HbA1c values and improved
postprandial glucose control with the same frequency of hypoglycemia.
 However, the concern remains that in the event of pump failure, users of the rapidly
acting insulin analogs will have more rapid onset of hyperglycemia and ketosis.
 While insulin aspart has been approved for intravenous use (eg, in hyperglycemic
emergencies), there is no advantage in using insulin aspart over regular insulin by
this route.
 A U200 concentration of insulin lispro is available in a disposable prefilled pen.
 The only advantage of the U200 over the U100 insulin lispro preparation is that it
delivers the same dose in half the volume.

Long-Acting Insulin Preparations
 NPH (neutral protamine Hagedorn, or isophane) insulin—NPH insulin is
an intermediate-acting insulin whose absorption and onset of action are
delayed by combining appropriate amounts of insulin and protamine so that
neither is present in an uncomplexed form (“isophane”).
 After subcutaneous injection, proteolytic tissue enzymes degrade the
protamine to permit absorption of insulin.
 NPH insulin has an onset of approximately 2–5 hours and duration of 4–12
hours; it is usually mixed with regular, lispro, aspart, or glulisine insulin and
given two to four times daily for insulin replacement.
 The dose regulates the action profile; specifically, small doses have lower,
earlier peaks and a short duration of action with the converse true for large
doses.

Long-Acting Insulin Preparations (Insulin glargine)
 Insulin glargine—Insulin glargine is a soluble, “peakless” (ie, having a broad
plasma concentration plateau), long-acting insulin analog.
 The attachment of two arginine molecules to the B-chain carboxyl terminal and
substitution of a glycine for asparagine at the A21 position created an analog
that is soluble in an acidic solution but precipitates in the more neutral body pH
after subcutaneous injection.
 Individual insulin molecules slowly dissolve away from the crystalline depot
and provide a low, continuous level of circulating insulin.
 Insulin glargine has a slow onset of action (1–1.5 hours) and achieves a
maximum effect after 4–6 hours.
 This maximum activity is maintained for 11–24 hours or longer.

Long-Acting Insulin Preparations (Insulin glargine)
 Glargine is usually given once daily, although some very insulin-sensitive or
insulin-resistant individuals benefit from split (twice a day) dosing.
 To maintain solubility, the formulation is unusually acidic (pH 4.0), and
insulin glargine should not be mixed with other insulins.
 Separate syringes must be used to minimize the risk of contamination and
subsequent loss of efficacy.
 The absorption pattern of insulin glargine appears to be independent of the
anatomic site of injection, and this drug is associated with less
immunogenicity than human insulin in animal studies.
 Glargine’s interaction with the insulin receptor is similar to that of native
insulin and shows no increase in mitogenic activity in vitro.
 It has sixfold to sevenfold greater binding than native insulin to the insulin-
like growth factor 1 (IGF-1) receptor, but the clinical significance of this is
unclear.

 Insulin detemir—In this insulin the terminal threonine is dropped from the B30
position and myristic acid (a C-14 fatty acid chain) is attached to the B29 lysine.
 These modifications prolong the availability of the injected analog by increasing both
self-aggregation in subcutaneous tissue and reversible albumin binding.
 The affinity of insulin detemir is four- to fivefold lower than that of human soluble
insulin and, therefore, the U100 formulation of insulin detemir has a concentration of
2400 nmol/mL compared with 600 nmol/mL for NPH.
 The duration of action for insulin detemir is about 17 hours at therapeutically
relevant doses.
 It is recommended that the insulin be injected once or twice a day to achieve a stable
basal coverage.
 This insulin has been reported to have lower within-subject pharmacodynamic
variability compared with NPH insulin and insulin glargine.

 Insulin Degludec: the threonine at position B30 has been removed and the lysine at
position B29 is conjugated to hexadecanoic acid via a gamma-l-glutamyl spacer.
 In the vial, in the presence of phenol and zinc, the insulin is in the form of
dihexamers but, when injected subcutaneously, it self-associates into large
multihexameric chains consisting of thousands of dihexamers.
 The chains slowly dissolve in the subcutaneous tissue, and insulin monomers are
steadily released into the systemic circulation.
 The half-life of the insulin is 25 hours.
 Its onset of action is in 30–90 minutes, and its duration of action is more than 42
hours.
 It is recommended that the insulin be injected once or twice a day to achieve a stable
basal coverage.
 Insulin degludec is available in two concentrations, U100 and U200, and dispensed
in pre-filled disposable pens.

Mixtures of insulins
 Because intermediate-acting NPH insulins require several hours to reach
adequate therapeutic levels, their use in patients with diabetes usually requires
supplements of rapid- or short-acting insulin before meals.
 For convenience, these are often mixed together in the same syringe before
injection.
 The regular insulin or rapidly acting insulin analog is withdrawn first, then the
NPH insulin and then injected immediately.
 Stable premixed insulins (70% NPH and 30% regular) are available as a
convenience to patients who have difficulty mixing insulin because of visual
problems or insufficient manual dexterity.
 Premixed preparations of rapidly acting insulin analogs (lispro, aspart) and
NPH are not stable because of exchange of the rapidly acting insulin analog for
the human regular insulin in the protamine complex.

 Consequently, over time, the soluble component becomes a mixture of regular and
rapidly acting insulin analog at varying ratios.
 To remedy this problem, intermediate insulins composed of isophane complexes of
protamine with the rapidly acting insulin analogs were developed (neutral
protamine lispro [NPL]; aspart protamine).
 Premixed combinations of NPL and insulin lispro are now available for clinical use
(Humalog Mix 75/25 and Humalog Mix 50/50).
 These mixtures have a more rapid onset of glucose-lowering activity compared
with 70% NPH/30% regular human insulin mixture and can be given within 15
minutes before or after starting a meal.
 A similar 70% insulin aspart protamine/30% insulin aspart (NovoLog Mix 70/30) is
now available.
 The main advantages of these new mixtures are that (1) they can be given within 15
minutes of starting a meal and (2) they are superior in controlling the postprandial
glucose rise after a carbohydrate-rich meal.

 Insulin glargine or insulin detemir cannot be acutely mixed with either regular
insulin or the rapid-acting insulin analogs.
 Insulin degludec, however, can be mixed and is available as 70% insulin
degludec/30% insulin aspart and is injected once or twice a day are available
for reusable pens (Lilly, Novo Nordisk, and Owen Mumford).
 Disposable prefilled pens are also available for regular insulin (U100, U500),
insulin lispro, insulin aspart, insulin glulisine, insulin detemir, insulin glargine,
insulin degludec, NPH, 70% NPH/30% regular, 75% NPL/25% insulin lispro,
50% NPL/50% insulin lispro, 70% insulin aspart protamine/30% insulin
aspart, and 70% insulin degludec/30% insulin aspart

Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps)
 Continuous subcutaneous insulin infusion devices are external open-loop
pumps for insulin delivery. The devices have a user programmable pump that
delivers individualized basal and bolus insulin replacement doses based on
blood glucose self-monitoring results.
 Normally, the 24-hour background basal rates are preprogrammed and
relatively constant from day to day, although temporarily altered rates can be
superimposed to adjust for a short-term change in requirement.
 For example, the basal delivery rate might need to be decreased for several
hours because of the increased insulin sensitivity associated with strenuous
activity.

 Boluses are used to correct high blood glucose levels and to cover mealtime insulin
requirements based on the carbohydrate content of the food and concurrent activity.
 Bolus amounts are either dynamically programmed or use pre-programmed
algorithms.
 When the boluses are dynamically programmed, the user calculates the dose based
on the amount of carbohydrate consumed and the current blood glucose level.
 Alternatively, the meal or snack dose algorithm (grams of carbohydrate covered by
a unit of insulin) and insulin sensitivity or blood glucose correction factor (fall in
blood glucose level in response to a unit of insulin) can be preprogrammed into the
pump.
 If the user enters the carbohydrate content of the food and current blood glucose
value, the insulin pump will calculate the most appropriate dose of insulin.
 Advanced insulin pumps also have an “insulin on board” feature that adjusts a high
blood glucose correction dose to correct for residual activity of previous bolus
doses.

 The traditional pump (by MiniMed, Animas, Roche, Sooil)— which contains
an insulin reservoir, the program chip, the keypad, and the display screen—is
about the size of a pager.
 It is usually placed on a belt or in a pocket, and the insulin is infused through
thin plastic tubing that is connected to the subcutaneously inserted infusion set.
 The abdomen is the favored site for the infusion set, although flanks and thighs
are also used.
 The insulin reservoir, tubing, and infusion set need to be changed using sterile
techniques every 2 or 3 days. Currently, only one pump does not require tubing
(OmniPod, Insulet).
 In this model, the pump is attached directly to the infusion set (electronic patch
pump).

 Programming is done through a hand-held unit that communicates wirelessly
with the pump.
 Optimal use of these devices requires responsible involvement and
commitment by the patient.
 Insulin aspart, lispro, and glulisine all are specifically approved for pump use
and are preferred pump insulins because their favorable pharmacokinetic
attributes allow glycemic control without increasing the risk of hypoglycemia.
 A mechanical patch pump (V-Go, Valeritas) designed specifically for patients
with type 2 diabetes is available on a basal plus-bolus insulin regimen.
 The device is preset to deliver one of three fixed and flat basal rates (20, 30,
or 40 units) for 24 hours (at which point it must be replaced), and there is a
button that delivers two units per press to help cover meals.

Inhaled Insulin
 A dry powder formulation of recombinant regular insulin (technosphere insulin,
Afrezza) is now approved for use in adults with diabetes.
 It consists of 2- to 2.5-µm crystals of the excipient, fumaryl diketopiperazine,
that provide a large surface area for adsorption of proteins like insulin.
 After inhalation from the small, single-use device, pharmacokinetic studies
show that peak levels are reached in 12–15 minutes and decline to baseline in 3
hours, significantly faster in onset and shorter in duration than subcutaneous
insulin.
 Pharmacodynamic studies show that median time to maximum effect with
inhaled insulin is approximately 1 hour and declines to baseline by about 3
hours.
 In contrast, the median time to maximum effect with subcutaneous insulin
lispro is about 2 hours and declines to baseline by 4 hours.

Inhaled Insulin
 In trials, inhaled insulin combined with injected basal insulin was as effective
in lowering glucose as injected rapid-acting insulin combined with basal
insulin.
 It is formulated as a single-use color coded cartridge delivering 4, 8 or 12
units immediately before the meal.
 The manufacturer provides a dose conversion table; patients injecting up to 4
units of rapid-acting insulin analog should use the 4-unit cartridge.
 Those injecting 5–8 units should use the 8-unit cartridge.
 If the dose is 9–12 units of rapid-acting insulin pre-meal then one 4-unit
cartridge and one 8-unit cartridge or one 12-unit cartridge should be used.
 The inhaler is about the size of a referee’s whistle.

Inhaled Insulin
 The most common adverse effect of inhaled insulin was cough, affecting 27%
of trial patients.
 A small decrease in pulmonary function (forced expiratory volume in 1
second [FEV1]) was seen in the first 3 months of use, which persisted over 2
years of follow-up.
 Inhaled insulin is contraindicated in smokers and patients with chronic lung
disease, such as asthma and chronic obstructive pulmonary disease.
 Spirometry should be performed to identify potential lung disease prior to
initiating therapy.
 During the clinical trials, there were two cases of lung cancer in patients who
were taking inhaled insulin and none in the comparator-treated patients.

Immunopathology of Insulin Therapy
 At least five molecular classes of insulin antibodies may be produced in
diabetics during the course of insulin therapy:
IgA,
IgD,
IgE,
IgG, and
IgM.

 There are two major types of immune disorders in these patients:
i. Insulin allergy—Insulin allergy, an immediate type hypersensitivity, is a
rare condition in which local or systemic urticaria results from histamine
release from tissue mast cells sensitized by anti-insulin IgE antibodies.
In severe cases, anaphylaxis results.
Because sensitivity is often to non-insulin protein contaminants, the human and
analog insulins have markedly reduced the incidence of insulin allergy, especially
local reactions.

ii. Immune insulin resistance—A low titer of circulating IgG anti-insulin
antibodies that neutralize the action of insulin to a negligible extent
develops in most insulin-treated patients.
Rarely, the titer of insulin antibodies leads to insulin resistance and may be associated
with other systemic autoimmune processes such as lupus erythematosus.

Lipodystrophy at Injection Sites
 Injection of animal insulin preparations sometimes led to atrophy of
subcutaneous fatty tissue at the site of injection.
 Since the development of human and analog insulin preparations of neutral
pH, this type of immune complication is almost never seen.
 Injection of these newer preparations directly into the atrophic area often
results in restoration of normal contours.
 Hypertrophy of subcutaneous fatty tissue remains a problem if injected
repeatedly at the same site.
 However, this may be corrected by avoiding the specific injection site.

Thank you for your Time

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