Far Eastern University - Nicanor Reyes Medical Foundation

Department of Pharmacology
Clinical Therapeutics

3B1 Group 1
CASE 1

This is a case of a 25-year old male who came in due to a 5 days history of headache,
epigastric pain and nausea. He also noted he was thirsty all the time and frequently urinating.
He also noted fast heartbeat and breathing. These prompted consultation at the emergency
department.

Past Medical History

Type 1 DM for 15 years – maintained on Insulin Glargine 20 units SC at night but not
regularly taken
Peripheral neuropathy – maintained on Pregabalin 50mg capsule at bedtime
Hypertension for 7 years – maintained on Telmisartan 40mg tab once a day
but not regularly taken

Family History
Father - 50 years old with hypertension, dyslipidemia, post myocardial
infarction, Type 1 Diabetes mellitus
Mother- 48 years old with hypertension, dyslipidemia

Personal and Social History

Fond of fatty food and pastries. Non-smoker. Alcohol drinker consuming 3 bottles of beer 3
times a week for the past 7 years.

Pertinent Physical Examination

BP: 150/90mmHg Height: 170cm
CR: 122 beats/min Weight: 64kg
RR: 25 cycles/min BMI: 22.1
Skin: Warm and dry. No rashes, petechiae, or jaundice
HEENT: normocephalic, dry mucous membranes, no palpable lymph nodes,
no neck vein engorgement
Chest/Lungs: tachypneic, no retractions, no wheezing, no crackles, vesicular
breath sounds
Heart: Tachycardic, regular rhythm
Abdomen: epigastric tenderness, normoactive bowel sounds

Laboratory examinations
CBC:
Hemoglobin 152g/L FBS 460 mg/dl
Hematocrit 0.45 Random blood sugar 425 mg/dl
Platelet 254 Arterial Blood Gas
WBC 11 x 109 /L pH 7.06
Na 127meq/L Pco2 22mmHg
K 3.8meq/L pO2 60mmHg
HgbA1C 12% HCO3 8meq
CASE 1 Questions
1. What are the signs and symptoms present in the patient related to diabetic
ketoacidosis?
a. Headache
i. This is attributed to the dehydration of the patient. During dehydration,
the brain loses fluid volume that results in temporary contraction of the
organ which stretches the pain-sensitive structures like the blood
vessels.
b. Epigastric Pain
i. Many mechanisms have been suggested to underlie the abdominal
symptoms in DKA, namely acute hyperglycemia mediated impaired
gastrointestinal motility (esophageal, gastric and gallbladder), rapid
expansion of the hepatic capsule, and mesenteric ischemia
precipitated by volume depletion.
c. Nausea
i. As ketones accumulate in the blood, more ketones will be passed in
the urine, taking sodium and potassium salts out with them. Over
time, levels of sodium and potassium salts in the body become depleted,
which can cause nausea and vomiting.
d. Thirsty all the time and frequently urinating
i. High levels of ketones are associated with high sugar levels in the blood
and urine. More water is drawn into the urine, resulting in frequent
urination.
ii. The frequent urination causes dehydration which triggers the thirst
center or hypothalamus to drink more water.
**Glucose is an osmotically active substance
e. Tachycardic
i. Might be present to compensate for the volume depletion caused by
frequent urination.
f. Tachypneic
i. The presence of metabolic acidosis will normally generate a respiratory
response. The reduction of serum bicarbonate and pH will result in
hyperventilation and reduction in carbon dioxide (CO2), partially
preventing further fall in pH and bicarbonate concentration.
1. Extra ketones are formed and accumulate in the body. This
triggers the respiratory system to start breathing faster to expel
more carbon dioxide, which is an acidic compound in the blood.
 2. What laboratory findings support the diagnosis of diabetic ketoacidosis?

CBC Reference Range Result

Hemoglobin 140-160 152g/L

Hematocrit 0.42-0.52 0.45

Platelet 150-450 254

WBC 5.0 - 10.0 x 10^9/L 11 x 10^9 /L

CHEMISTRY Reference Range Result

Na 135-145 127 meq/L

K 3.5-5.5 3.8 meq/L

HbA1C 4 - 5.6 12%

FBS 80 -100 460 mg/dL

Random Blood sugar <200 425 mg/dL

ARTERIAL BLOOD Reference Range Result

GAS

pH 7.35-7.45 7.06

PCO2 35-45 22 mmHg

PO2 80-100 60 mmHg

HCO3 22-26 8 meq/L

ABG result: Partially compensated metabolic acidosis

According to Harrison’s Principles of Internal Medicine 20th edition, DKA is characterized by

hyperglycemia (serum glucose > 13.9 mmol/L [250 mg/dL], ketosis, and metabolic acidosis
(serum bicarbonate <15 mmol/L with increased anion gap) along with a number of secondary
metabolic derangements.

The laboratory findings in this patient such as hyperglycemia as evidenced by the markedly
elevated fasting blood sugar (460 mg/dL), elevated random blood sugar (425 mg/dL) and
elevated HbA1C (12%), together with the ABG result interpreted as partially compensated
metabolic acidosis are all consistent with the aforementioned diagnostic hallmark findings in
Diabetic Ketoacidosis.
The ABG result was interpreted as partially compensated metabolic acidosis since the pH was
decreased pointing to acidosis, HCO3 was markedly decreased which made us deduce that the
acidosis is of metabolic origin, and the patient is compensating by way of hyperventilation
leading to the decrease in PCO2. However, this is just a partial compensation since the pH was
not restored to the normal range. In DKA, ketoacidosis is also a prominent laboratory finding,
but the limited data on the electrolytes hindered us from computing the anion gap since the
Chloride result was not given.

The hyponatremia (127 meq/L) present in this patient is a consequence of hyperglycemia

because for every 100 mg/dL rise in serum glucose, sodium is reduced by 1.6 meq/L. This is
due to the property of glucose as an osmotically active substance. Hyperglycemia causes
osmotic shift of water from the intracellular to the extracellular space, causing a relative
dilutional hyponatremia. According to Harrison’s, despite a total-body potassium deficit, the
serum potassium of DKA patients at presentation may be normal or mildly elevated, secondary
to the acidosis and volume depletion. This is consistent with the potassium level of the patient in
the case which is within normal (3.8 meq/L). In addition, leukocytosis is also evident in the
patient (WBC 11 x 10^9 /L) and it was mentioned in Harrison’s that this is a common finding in
DKA patients as well.

The table below lifted from Harrison’s Principles of Internal Medicine (20th ed.) shows a
summary of the laboratory values in DKA. The boxed parameters are consistent with the
laboratory findings in the case, hence supporting our diagnosis of DKA.
3. What are the precipitating events that may lead to diabetic ketoacidosis?

● The most common precipitating factor in the development of DKA is infection. Majority
of infections are accounted for by urinary tract infections and pneumonia.
○ An infection or other illness can cause your body to produce higher levels of
certain hormones, such as adrenaline or cortisol. These hormones counter the
effect of insulin — triggering an episode of diabetic ketoacidosis.
○ As these hormones are increased, insulin secretion is reduced, glucose entry into
cells is decreased and gluconeogenesis and glycogenolysis in the liver is
increased, creating a hyperglycemic state, fostering conditions that contribute to
diabetic ketoacidosis.
● Other precipitating factors include cerebrovascular accident, alcohol abuse,
pancreatitis, myocardial infarction, trauma, and drugs.
○ Excessive alcohol consumption often causes malnourishment and people who
drink large quantities of alcohol may not eat regularly. They may also vomit as a
result of drinking too much. Not eating enough or vomiting can lead to periods of
starvation. This further reduces the body’s insulin production.
○ Poor food intake can lead to depleted glycogen levels and continued alcohol
metabolism results in diminished gluconeogenesis. Both the depletion of
glycogen and diminished gluconeogenesis lead to lower blood sugar levels.
○ As blood sugar falls, insulin secretion is reduced as well. Because insulin
restrains glucagon secretion, lower insulin secretion allows increased glucagon
secretion, setting the stage for the development of ketoacidosis.
○ This situation can be amplified if the drinker vomits repeatedly. Vomiting can lead
to dehydration and a reduced blood volume, which, in turn, increases the levels
of certain stress hormones in the blood called catecholamines. Catecholamines
further decrease insulin production and increase glucagon production.
● In addition, new-onset type 1 diabetes or discontinuation of or inadequate insulin in
established type 1 diabetes commonly leads to the development of DKA.
○ Diabetic ketoacidosis is a serious and life-threatening complication of type 1
diabetes that occurs when your body produces high levels of blood acids called
ketones.
○ The condition develops when your body can't produce enough insulin. Insulin
normally plays a key role in helping sugar (glucose) — a major source of energy
for your muscles and other tissues — enter your cells.
■ Type 1 Diabetics are also referred to as the insulin-dependent patients
because they almost rely entirely on exogenous insulin for glucose use.
○ Without enough insulin, your body begins to break down fat as fuel. This process
produces a buildup of acids in the bloodstream called ketones, eventually leading
to diabetic ketoacidosis if untreated.
○ The patient’s noncompliance and frequent missed insulin shots play as the
major precipitating factors of DKA.
 ● Drugs that affect carbohydrate metabolism, such as corticosteroids, thiazides, and
sympathomimetic agents (e.g., dobutamine and terbutaline), may precipitate the
development of DKA.
○ Steroids: The main mechanisms include increased glucose production via
hepatic gluconeogenesis and glycogenolysis, and more insulin resistance by
reducing peripheral uptake at adipose and muscle level via inhibition of GLUT4
translocation.
○ The acute effects of steroids are more distinct on glucose tolerance than is
long-term use, and there is more risk of acute events of hyperglycemia like DKA.
○ Thiazide-induced impairment of glucose tolerance is due to both reduced
glucose-stimulated insulin release and increased peripheral resistance to the
action of insulin.
● In young patients with type 1 diabetes, psychological problems complicated by
eating disorders may be a contributing factor in 20% of recurrent ketoacidosis. Factors
that may lead to insulin omission in younger patients include fear of weight gain with
improved metabolic control, fear of hypoglycemia, rebellion from authority, and
stress of chronic disease.

4. What is the pathophysiology of diabetic ketoacidosis?

Type 1 DM and/or Physiologic Stress

● With Type 1 DM, there is autoimmune destruction of insulin-producing beta cells in the
islet of langerhans which will decrease insulin levels, and is the main reason for an
absolute insulin deficiency. In the presence of physiologic stress, such as infections,
missed medication, or CVDs, insulin deficiency can occur preventing the entry and
utilization of glucose in cells, and spill over of glucose into the blood (hyperglycemia)
while cells are starved.

Metabolic Starvation
● In response to this metabolic starvation, the body increases the levels of
counter-regulatory hormones (glucagon,catecholamine, cortisol, and growth
hormone). These hormones promote gluconeogenesis and glycogenolysis in the
liver as well as proteolysis in the muscles, in which the amino acid released from the
proteolysis serves as a substrate for gluconeogenesis. These pathways occur to
increase levels of glucose in the blood. There will also be a decreased utilization of
glucose by muscles and adipocytes in response to the counter-regulatory hormones.

Hyperglycemia
● However, the glucose will just remain in the blood causing hyperglycemia. Glucose is
osmotically active and exceeds renal threshold leading to an increased urine output,
glycosuria, and polyuria, a phenomenon known as osmotic diuresis. This will lead to
dehydration and a hyperosmolar state, in which the decrease in the ECF volume will
concentrate the ketone bodies produced from ketogenesis and exacerbate acidosis.
 ○ Dehydration due to hyperglycemia will result to nausea, while the concomitant
volume depletion will result to polydipsia (from the triggering of the thirst center in
the brain), headache (brain loses fluid volume leading to temporary contraction of
blood vessels), and dry mucous membrane.
○ When the renal threshold for glucose is exceeded (∼170–200 mg/dL [∼9.4–11.1
mmol/L]), glucosuria and hyperketonemia cause osmotic diuresis, dehydration,
and electrolyte wasting (including sodium, potassium, magnesium, calcium, and
phosphate loss). It can also lead to impaired renal function or azotemia.

Lipolysis
● The pathway to ketogenesis begins with the lack of insulin being unable to suppress
lipolysis. The increase in lipolysis will lead to fatty acid release for an alternative energy
source. The fatty acids will undergo ketogenesis in the liver which will produce ketone
bodies - acetone, acetoacetic acid, and beta hydroxybutyric acid - and increase the
ketone bodies in the blood.
● Bicarbonate will try to neutralize the acidity in the blood from the ketone bodies, but
eventually the bicarbonate stores will be depleted and will be unable to neutralize the
acidity of the blood.
● The acidity of the blood will continue to increase and result in metabolic acidosis (ph <
7.3). The first presentation of metabolic acidosis involves a type of deep, labored
breathing known as Kussmaul respiration or tachypnea in an attempt to offset
acidosis by blowing off CO2. The sweet smell noticed in the breath of patients with DKA
is due to the acetone from the ketogenesis which accumulates in the blood.
○ Epigastric pain is also seen which is due to a disrupted enteric system leading to
decreased gastric emptying and pain.
○ The nausea is due to dehydration and high levels of glucose in the blood.
● Another mechanism of compensation of the acidity involves the movement of hydrogen
ions into the cell in exchange for potassium, which leads to increased potassium levels
in the blood (hyperkalemia). But as potassium becomes continuously excreted in the
urine due to osmotic diuresis, the overall potassium stored in the body is eventually
depleted.
○ Furthermore, once insulin treatment is started, the potassium will move into the
cells and can result in hypokalemia. That’s why the mainstay treatment of DKA
involves administration of both potassium and insulin to prevent the depletion of
potassium stores.
Flowchart

5. What electrolytes are likely affected in patients with diabetic ketoacidosis?

Hyperglycemia due to insulin deficiency causes an osmotic diuresis that leads to marked
urinary losses of water and electrolytes.

● Sodium- usually is low in affected patients. Urinary excretion of ketones obligates

additional losses of sodium. Serum sodium may fall due to natriuresis or rise due
to excretion of large volumes of free water. Initially, increased glucose
concentration is restricted to the extracellular space, which forces water from the
intracellular to the extracellular compartment and induces dilution of the plasma
sodium concentration.
 ● Potassium- associated with profound total body potassium depletion, ranging
from 3 to 15 mmol/kg of body weight. Urinary excretion of ketones obligates
additional losses of potassium. Despite a significant total body deficit of
potassium, initial serum potassium is typically normal or elevated because of the
extracellular migration of potassium in response to acidosis. As with sodium, the
presence of hyperglycemia leads to a shift of water and potassium from the
intracellular to the extracellular space. This shift of potassium is further enhanced
in the presence of acidosis, intracellular proteolysis and insulinopenia. Potassium
depletion is due to excessive urinary potassium loss secondary to osmotic
diuresis, and it leads to increased delivery of fluid and sodium to potassium
secretory sites in the distal nephron. Potassium levels generally fall further during
treatment as insulin therapy drives potassium into cells. If serum potassium is not
monitored and replaced as needed, life-threatening hypokalemia may develop.
● Phosphate- uncontrolled hyperglycemia is typically in negative phosphate
balance because of decreased phosphate intake, an acidosis-related shift of
phosphate into the ECF when metabolic acidosis exists, and phosphaturia
caused by osmotic diuresis. The net urinary loss of phosphate occurs because of
a transcellular shift, osmotic diuresis and reduced renal phosphate reabsorption
by the Na-Pi transporters in the renal proximal tubule due to acidosis and
hyperglycemia.
● Magnesium- At the presentation of DKA, the levels of serum magnesium are
usually normal. Excessive amounts of magnesium are excreted during acidosis,
secondary to insulin deficiency. Insulin resistance reduces magnesium
reabsorption resulting in urinary magnesium wasting.
● Calcium- The observed severe negative calcium balance occured through
diminished bone formation mediated by metabolic acidosis and increased bone
mineral dissolution and bone resorption because of severe insulin deficiency.

6. Which therapies should be provided to manage diabetic ketoacidosis?

Therapeutic Goals for DKA: to restore plasma volume and tissue perfusion,
correct blood glucose and osmolality, correct acidosis, replenish electrolyte losses, and
identify and treat precipitating factors

Assess the severity of the patient’s DKA according to his level of consciousness
serum pH level and beta-hydroxybutyrate levels.
TABLE 397-8 Management of Diabetic Ketoacidosis (Pharmacotherapy book)

Management of Diabetic Ketoacidosis

1.Confirm diagnosis (increased plasma glucose, positive serum

ketones, metabolic acidosis).

2.Admit to hospital; intensive care setting may be necessary for

frequent monitoring or if pH < 7 or unconscious.

3.Asses serum electrolytes (K+, Na+, Mg2+, Cl– , bicarbonate,

phosphate), acid–base status—pH, HCO–3 , Pco2 ,
β-hydroxybutyrate, and renal function (creatinine, urine
output).

4.Replace fluids: 0.9% saline 1 L/hour over first 1–3 hours;

subsequently, 0.45% saline at 4–14 mL/kg/hour; change to 5%
dextrose with 0.45% saline when plasma glucose reaches
250 mg/dL (13.9 mmol/L).

5.Administer regular insulin: IV (0.15 U/kg bolus followed by

0.1 unit/kg/hour infusion); check glucose hourly and double
insulin infusion until glucose level falls at steady hourly rate
of 50–70 mg/dL (2.8–3.9 mmol/L). Alternatively, could use
SC or IM routes, although dosing regimen is different.
If initial serum potassium is less than 3.3 mEq/L (3.3 mmol/L),
do not administer insulin until the potassium is corrected to
> 3.3 mEq/L (3.3 mmol/L).

6.Assess patient: What precipitated the episode (eg, nonadherence,

infection, trauma, infarction, cocaine)? Initiate appropriate
workup for precipitating events (cultures, chest x-ray, ECG).
 7.Measure chemistry (especially K+, bicarbonate, phosphate and
anion gap) every 2–4 hours until stable.

8.Replace K+:
If K+ is < 3.3 mEq/L (3.3 mmol/L), hold insulin
and give 40 mEq (40 mmol) of K+ per liter of IV fluid.

If K+ is> 5 mEq/L (5 mmol/L), do not give K+ but check level every

2 hours.

When K+ > 3.3 mEq/L (3.3 mmol/L) but < 5 mEq/L

(5.5 mmol/L), ECG normal, urine flow and normal creatinine
documented, administer 20–30 mEq/L (20–30 mmol/L) of
IV fluid to maintain K+ at 4–5 mEq/L (4–5 mmol/L).

9.Continue above until patient is stable, glucose goal is

150–250 mg/dL (8.3–13.9 mmol/L), and acidosis is resolved.
Insulin infusion may be decreased to 0.05–0.1 unit/kg/hour.

10.Administer intermediate- or long-acting insulin as soon as

the patient is eating. Allow for overlap in insulin infusion and
subcutaneous insulin injection.

Insulin Type Onset Duration

Regular/short acting 30 minutes 3 to 6 hours

Intermediate acting 2 to 4 hours 12 to 18 hours

Long acting 2 hours Up to 24 hours

Ultra-long acting 6 hours 36 hours or longer

FLUID REPLACEMENT:
After the initial bolus of normal saline, replacement of the sodium and free water
deficit is carried out over the next 24 hours ( fluid deficit is often 3-5L). When
hemodynamic stability and adequate urine output are achieved, IV fluids should be
switched to 0.45% saline depending on the calculated volume deficit. This change to
0.45% saline helps to reduce the trend towards hyperchloremia later in the course of
DKA. Alternatively, initial use of lactated Ringer’s IV solution may reduce the
hyperchloremia that commonly occurs with normal saline.

INSULIN REPLACEMENT:
The current recommendation is to give low-dose (short-acting regular) insulin after the
diagnosis of diabetic ketoacidosis has been confirmed by laboratory tests and fluid
replacement has been initiated.

Standard low-dose insulin therapy consists of an initial intravenous bolus of 0.15 units of
regular insulin per kg followed by the continuous intravenous infusion of regular insulin
prepared in normal saline or hypotonic saline solution at a rate of 0.1 unit per kg per
hour.

IV administration is usually preferred because it ensures rapid distribution and allows

adjustment of the infusion rate as the patient responds to therapy. DKA can also be
treated with SC short-acting insulin analogues. IV regular insulin should be continued
until the acidosis resolves and the patient is metabolically stable.

IV regular insulin should be continued until the acidosis resolves and the patient is
metabolically stable. As the acidosis and insulin resistance associated with DKA resolve,
the insulin infusion rate can be decreased to (0.02-0.1 units/kg per hour). Long-acting
insulin, in combination with SC short-acting insulin, should be administered as soon as
the patient resumes eating, since it facilitates transition to an outpatient insulin regimen
and reduces the length of hospital stay.

: After giving him fluids, immediately administer a 0.1 unit/kg bolus insulin dose
intravenously to the patient to prime the tissue insulin receptors. For our patient, we
would need to administer 6.4 units (IV) of bolus insulin. Afterwards, insulin doses of 0.1
unit/kg/h are continuously infused intravenously or injected intramuscularly every hour to
replace insulin deficiency. This corrects acidosis by reducing ketone production by the
liver and improves serum ketone removal. This also corrects hyperosmolality caused by
hyperglycemia by facilitating peripheral utilization of glucose, and inhibiting
gluconeogenesis and glycogenolysis. For patients who normally take insulin glargine or
insulin detemir for maintenance, such as our patient, they can be given their usual
maintenance doses during initial treatment of their diabetic ketoacidosis which will also
lower the required IV infusion and allow a smoother transition from IV insulin to
subcutaneous insulin treatment.

POTASSIUM:
During rehydration and insulin therapies for diabetic ketoacidosis, the serum potassium
concentration typically declines rapidly as potassium reenters the intracellular
compartment.

One protocol entails using insulin and intravenous fluids until the serum potassium
concentration is less than 5.5 mEq per L (5.5 mmol per L). At this time, potassium
chloride is added to intravenous fluids in the amount of 20 to 40 mEq per L. The exact
amount of potassium that is administered depends on the serum potassium
concentration.
 The goal is to maintain the serum potassium concentration in the range of 4 to 5 mEq
per L (4 to 5 mmol per L).

SODIUM BICARBONATE:
Despite a bicarbonate deficit, bicarbonate replacement is not usually necessary. In fact,
theoretical arguments suggest that bicarbonate administration and rapid reversal of
acidosis may impair cardiac function, reduce tissue oxygenation, and promote
hypokalemia. The results of most clinical trials do not support the routine use of
bicarbonate replacement, and one study in children found that bicarbonate use was
associated with an increased risk of cerebral edema.

However, in the presence of severe acidosis (arterial pH <7.0), the ADA advises
bicarbonate (50 mmol [meq/L] of sodium bicarbonate in 200mL of sterile water with 10
meq/L KCl per hour for 2 h until the pH is >7.0).

PHOSPHATE:
Phosphate replacement is seldom required unless in severe hypophosphatemia of <1
mg/dl during insulin therapy, in which case a small amount of phosphate can be replaced
as potassium salt. However, when phosphate is too rapidly replaced, it can induce
tetany. To prevent this, replace 40–50 mmol of phosphate intravenously at no more than
3–4 mmol/h in a 60–70-kg person such as our patient.

Hypomagnesemia may develop during DKA therapy and may also require
supplementation.

7. After starting continuous IV insulin infusion, which criteria would you use to
discontinue it?

Outlined on Table 397-8 from Harrison’s adapted from the American Diabetes
Association is the summary of management of diabetic ketoacidosis. Continuous IV
insulin infusion must be done until the patient becomes stable with a glucose goal of
8.3-11.1 mmol/L (150-200mg mg/dL), and until the acidosis is resolved. Insulin infusion
may now be decreased to 0.02-0.1 units/kg per hour. As soon as the patient starts
eating, we may now administer long-acting insulin allowing for 2-4 hr overlap in insulin
infusion and SC long-acting insulin injection. This facilitates transition to an outpatient
insulin regimen and reduces length of hospital stay. It is essential that insulin infusion
must be continued until adequate levels of insulin are achieved by the long-acting insulin
administration. Inadequacy of insulin administration even for short bouts of time in this
transition phase may precipitate DKA again.
8. Is bicarbonate replacement necessary with diabetic ketoacidosis?
Consensus guidelines for the management of DKA recommend administering
Sodium bicarbonate to DKA patients who present with an initial blood gas pH of less
than 7.0 and if the arterial pH is 7.0 or higher, no bicarbonate therapy shall be
administered. However several studies failed to show benefit and observed that
bicarbonate therapy did not improve morbidity or mortality of Diabetic Ketoacidosis in
both guidelines (whether pH is less or greater than 7.0). There was no evidence of
improved glycemic outcomes, no significant resolution of ketoacidosis, CSF acidosis,
electrolyte imbalance, tissue oxygenation, and duration of hospitalization. Bicarbonate
 replacement is not necessary in treating Diabetic Ketoacidosis since insulin therapy will
be sufficient in correcting metabolic acidosis and its lack of clinical benefits do not justify
its use. With regards to our patient, his blood gas pH is 7.06 therefore bicarbonate
replacement is not indicated.
There are several concerns that arise from administration of Sodium Bicarbonate.
There was a study demonstrating that Bicarbonate infusion delayed the resolution of
ketosis and led to a rise in serum ketoacid anion levels. Moreover, Bicarbonate infusion
may result in paradoxical worsening of CNS acidosis in response to an acute increase in
serum Bicarbonate level. The rationale behind this is that increased pCO2 quickly and
more readily crosses the BBB than bicarbonate. This leads to a fall in cerebral pH and
commences neurologic deterioration in patients. Randomized controlled trials in the
pediatric population also implicated Bicarbonate therapy as a risk factor for the
development of cerebral edema due to aggressive hypotonic fluid resuscitation and is
associated with prolonged hospitalization. Another concern is that given that patients in
DKA are already in hypokalemic state, implementation of bicarbonate may compound
the problem, worsen hypokalemia, and perhaps lead to fatal arrhythmia. Additionally,
acute reversal of acidosis with bicarbonate was previously linked to worsening tissue
oxygenation. Acidosis will induce the Bohr effect and reduce total hemoglobin-oxygen
affinity. However, it also lowers the concentration of 2,3-DPG in erythrocytes which leads
to a counter-active increased hemoglobin-oxygen affinity. There exists a delicate balance
in favor of the Bohr effect in the initial presentation of DKA, which theoretically can be
pushed towards lower 2,3-DPG levels with bicarbonate administration and abrupt
acidemia reversal. However, there is evidence suggesting that this may occur regardless
of bicarbonate administration, and levels of 2,3-DPG remain quite low for several days
beyond the treatment of acidosis. Finally, bicarbonate administration can lead to
post-treatment metabolic alkalosis as insulin mediated ketoacid metabolism leads to
both spontaneous bicarbonate generation and resolution of metabolic acidosis.

9. What are the different insulin regimens that can be given to the patient’s diabetes
mellitus? Give their corresponding mechanism of action, peak and duration of
action.
a. Mechanism of Insulin analogues is the same as endogenous insulin with alterations to
their pharmacokinetics to allow them to last longer
b. Bolus Insulins
I. Rapid acting
1. Aspart
a. substitution of proline by aspartic acid at B28
b. Approved for IV use but is not as superior as to the regular insulin
IV
2. Glulisine
a. B3 asparagine is replaced by lysin
b. B29 lysine is replaced by glutamic acid
3. Lispro
a. B28 proline reversed with B29 lysine
 b. These 3 are available as 100 units/mL and 200 units/mL
c. The amino acid substitutions do not alter binding with insulin
receptors
- Instead they alter the pharmacokinetics of absorption
d. Rapid acting insulins are dosed at 15 mins before or immediately
prior to a meal, usually prepared as subcutaneous injection or
insulin pumps (SQ)
e. Pharmacokinetics
- Dissociation into monomers then absorbed
- Onset of action: 5-15 minutes
- Peak of action: 1- 1.5 hours
- Effective duration: 3-4 hours
II. Regular insulin
1. Short acting, soluble crystalline zinc solution that is dissolved in neutral pH given
via subcutaneous injection,IV or IM.
a. IV infusions are given for diabetic ketoacidosis and preoperatively
for type 1 DM.
b. It is designed to cover insulin response to meals and when given
SQ, should be given 30 minutes before meals.
2. Pharmacokinetics
a. Upon SQ injection, it would form small hexamer aggregates that
would then turn into dimers then into monomers then it would be
systemically absorbed into the circulation.
- For insulin resistant subjects
b. U500 regular insulin preparation is used either as a vial form or
dispensable pen
- If a vial form is used, use a U100-insulin syringe or
tuberculin syringe to measure dose.
c. Onset of action: Delayed 30 - 60 minutes
d. Peak action: 2 hours
e. Effective duration: 6-8 hours
c. Basal insulin
I. NPH (Neutral Protamine Hagedorn, or isophane)
1. Intermediate-acting insulin whose absorption and onset are delayed by
combining appropriate amounts of insulin and protamine.Serve as a basal
insulin only when dosed at bedtime, or a basal and prandial insulin when
dosed in the morning.
2. Pharmacokinetics:
a. Preparation: Insulin + zinc + protamine + phos buffer
b. Onset of action: 2-4h
c. Peak action: 6-7h
d. Effective duration: 10-20h
II. Long acting Insulin
 1. To suppress hepatic gluconeogenesis effects and preventing glucose
levels from rising during the fasting state in insulin deficient patients
- Prevents ketogenesis
- Peakless property = Continuous and steady release of insulin that
is ideal for basal insulin at night time
a. Insulin Glargine
- Soluble, peakless insulin analog. The attachment of two
arginine molecules to B-chain carboxyl terminal and
substitution of a glycine for asparagine at the A21. Provide
solubility in acidic solution but precipitates in the more
neutral body pH after subcutaneous injection. Given once
daily. It should not be mixed with other insulins. Separate
syringes must be used to minimize the risk of
contamination and subsequent loss of efficacy
b. Insulin Detemir
- Terminal threonine is dropped from B30 position and
myristic acid is attached to B29 lysine. Injected once or
twice a day to achieve a stable basal coverage
c. Insulin Degludec
- Threonine at position B30 has been removed and the
lysine at position B29 is conjugated to hexadecanoic acid
via a gamma-L-glutamyl spacer. Given once or twice daily.

2. Pharmacokinetics:
Insulin Glargine Insulin Detemir Insulin Degludec

Onset of action 0.5-1h 0.5-1h 0.5-1.5h

Peak of action Flat or peakless Flat or peakless Flat or peakless

Effective duration 11-24 hrs or longer 17 hours >42 hours

10. Aside from insulin, what other agents can be given to the patient to improve
glucose control? Give the mechanism of action and adverse effects of the
corresponding agent/s.

A. Metformin - first line oral drug of choice in T2DM across all age groups. It is the only
biguanide currently available.
a. Mechanism of action: activates adenosine monophosphate-activated protein
kinase in the liver → hepatic uptake of glucose and inhibiting gluconeogenesis
through complex effects on the mitochondrial enzymes
b. Adverse effects:
i. gastrointestinal disturbances including diarrhea, nausea, and dyspepsia
 ii. lactic acidosis (severe renal insufficiency)
iii. Vitamin B12 and folic acid deficiency
iv. Hypoglycemia
B. Pramlintide - is an islet amyloid polypeptide (IAPP, amylin) analog. Pramlintide is
approved for use in insulin-treated type 1 and type 2 patients who are unable to achieve
their target postprandial blood glucose levels. It is rapidly absorbed after subcutaneous
administration; levels peak within 20 minutes, and the duration of action is not more than
150 minutes. It is metabolized and excreted by the kidney, but even at low creatinine
clearance there is no significant change in bioavailability. It has not been evaluated in
dialysis patients.
a. Mechanism of action: by mimicking the activity of Amylin, pramlintide acts to
improve glycemic control through modulation of the rate of gastric emptying,
prevention of postprandial rise in glucagon levels, and by increasing sensations
of satiety, thereby reducing caloric intake and potentiating weight loss.
i. Three distinct receptor complexes that bind with high affinity to amylin:
RAMP1, RAMP2, or RAMP3.
b. Adverse effects:
i. Hypoglycemia
ii. Gastrointestinal symptoms including nausea, vomiting, and anorexia
iii. Since the drug slows gastric emptying, recovery from hypoglycemia can
be problematic because of the delay in absorption of fast-acting
carbohydrates.
c. Dosage:
i. Pramlintide is injected immediately before eating
ii. Dosages range from 15 to 60 mcg subcutaneously for type 1 patients and
from 60 to 120 mcg for type 2 patients.
iii. Therapy should be initiated at the lowest dosage and titrated upward.
Concurrent rapid- or short-acting mealtime insulin dosages should be
decreased by 50% or more because of the risk of hypoglycemia.
iv. Should always be injected by itself using a separate syringe; it cannot be
mixed with insulin.
C. SGLT2 Inhibitors (Dapagliflozin,Canagliflozin, Empagliflozin)- provide
insulin-independent glucose lowering by blocking glucose reabsorption in the proximal
renal tubule by inhibiting SGLT2. It may be effective in advanced stages of T2DM when
pancreatic beta cell reserves are permanently lost
a. Mechanism of action: inhibits SGLT2 (sodium/glucose cotransporter 2) in the
proximal tubule, blocking reabsorption of filtered glucose (leading to osmotic
diuresis)
b. Adverse effects:
i. UTIs leading to urosepsis and pyelonephritis
ii. Genital mycosis
iii. Rarely cause ketoacidosis
iv. Upper limb fractures was observed in canagliflozin therapy
 3B Group 1 Members QR Codes

Aliasas, Natasha Kathrine D.

Almonte, Precedence Elwen M.

Alvarez, Vanessa Kate I.

Antonio, Faith DG.

Arban, Josef Brent B.

Cabasag, Althea Suzerane D.

Castro, Allea Lorra G.

Chan, Paul Meryll D.

Chua, Angelica A.
Chua, Kimberly Mae L.

De Leon, Christine Joy M.

Diaz, Maria Angela S.