11 - Drugs to Treat Diabetes Flashcards
(48 cards)
1
Q
What is Diabetes?
A
Diabetes: a chronic disease characterized by elevated blood
levels of glucose (i.e. sugar).
- Normally glucose is efficiently
reabsorbed in the proximal
tubule of the kidney so it is not
found in urine - In untreated diabetes, blood
glucose rises so high that the
transporters that reabsorb it are
saturated and significant
amounts of glucose are found in
the urine. - diabetes used to be diagnosed by the sweet smell AND TASTE of the urine
- High blood sugar in diabetes results from either 1) not enough insulin
produced in the body or because 2) the body’s cells do not respond to the
insulin that is produced - Insulin is a hormone produced by the pancreas that is involved in regulating blood glucose.
- Diabetes occurs when insulin levels are too low or when the body’s cells
are resistant to the effects of insulin
2
Q
Symptoms of Diabetes
A
- polyuria (increased urination)
- polydipsia (increased thirst)
- polyphagia (increased hunger)
- weight loss
3
Q
What is Insulin?
A
Insulin: a peptide hormone synthesized by the β (beta) cells of the islets of Langerhans (middle) of the pancreas.
- Insulin is rapidly released from the pancreas into the blood in response to
increases in blood glucose (after eating a meal) - When insulin is secreted, it causes glucose uptake into muscle, liver, and fat cells.
→ Liver cells - glucose uptake
results in glycogen synthesis
(a storage form of glucose).
→ Muscle cells - glucose is used as energy and promotes protein
synthesis
→ Fat cells - insulin causes increased synthesis of fatty acids, which results
in increased triglyceride synthesis.
- Extracellular potassium is important as it helps insulin to drive glucose into the cell
- Islets contain 3 types pf cells
1) Beta Cells: produce insulin
2) Alpha Cells: produce glucagon
3) Delta Cells (dont need to know)
4
Q
The Healthy Pancrease
A
- when we eat, our stomach is able to turn the food into glucose
- glucose is absorbed and enters bloodstream
- when it enters bloodstream, pancreas secretes insulin into bloodstream
- insulin drives glucose out of blood and in to tissues
- basic function of normal pancreas is to maintain normal glucose levels
5
Q
Types of Diabetes
A
Diabetes can be classified into 3 distinct groups:
1. Type I diabetes – Also called insulin dependent diabetes mellitus
- Type II diabetes – Also called non-insulin dependent diabetes
mellitus. - Gestational diabetes – Diabetes that occurs in pregnancy.
6
Q
1) Type I Diabetes
A
- ~10% of people with diabetes have type I diabetes.
- usually diagnosed in children or adolescents but symptoms may not appear until early adulthood.
- caused by an autoimmune reaction where the body’s own immune cells attack and destroy insulin secreting β cells.
- As a result, the body makes too little or no insulin at all
→ requires insulin replacement. - Type I diabetes is not preventable and it is not caused by eating too much
sugar
7
Q
Process of Type 1 Diabetes
A
- Stomach converts food to glucose
- Glucose enters bloodstream
- Pancreas produces little or no insulin
- Glucose unable to enter body effectively
- Glucose levels increase
8
Q
2) Type II Diabetes
A
- ~ 90% of people with diabetes have type II diabetes (more common than type 1)
- pancreas makes sufficient insulin, but, the insulin produced is resistant to use.
- Over the course of the disease, insulin synthesis can decrease.
Risk factors for developing type II diabetes:
→ age,
→ having a family member with diabetes
→ previous gestational diabetes
→ lack of exercise
→ heart disease
→ obesity
→ ethnicity (African and Native descent
are at higher risk).
- preventable with proper diet and exercise
- 80% of all patients in Canada with type II diabetes are obese or overweight
→ primary strategy is decreasing obesity to prevent type II - typically diagnosed later in life but there is a trend towards younger people getting the disease
9
Q
Process of Type 2 Diabetes
A
- Stomach converts food to glucose
- Glucose enters bloodstream
- Pancreas produces sufficient insulin but it is resistant to effective use
- Glucose unable to enter body effectively
- Glucose levels increase
10
Q
Type 1 VS. Type 2 Diabetes
A
Type 1
- pancreas produced INSUFFICIENT insulin
- little or no insulin produces
- increased glucose levels
Type 2
- pancreas produced SUFFICIENT insulin
- insulin produced is resistant to use
- increased glucose levels
11
Q
3) Gestational Diabetes
A
- Gestational diabetes first starts during pregnancy.
- Usually begins ~ halfway through
pregnancy. - All pregnant women should have an oral glucose tolerance test between weeks 24-28 of pregnancy to test for
gestational diabetes. - Usually diet and exercise are sufficient
to keep blood glucose levels within
normal ranges. - Pregnant women with gestational diabetes tend to have larger babies and
babies with hypoglycemia in the first few days of life. - After birth, the blood sugar of the mother usually returns to normal
however; blood glucose should be continually monitored as many patients
develop diabetes 5 – 10 years later.
12
Q
Complications and Diagnosis of Diabetes
A
- Cognitive Impairment
- Depression
- Cerebrovascular disease
- Visual Impairment
- Cardiovascular Disease
- Nephropathy (kidney disease)
- Weight loss
- Urinary Incontinence
- Peripheral Vascular Disease
- Peripheral Neuropathy (contributes to falls)
- Foot Ulcers
13
Q
Diabetic Retinopathy
A
- Diabetic retinopathy is the most common cause of blindness in people under the age of 65.
- Hyperglycemia causes damage to retinal capillaries.
- Tightly controlling blood sugar minimizes the risk of retinopathy
- Patients with type I or type II
diabetes should have an eye exam once a year.
14
Q
Diabetic Nephropathy
A
- Diabetic nephropathy is characterized by things that happen to kidney in response to hyperglycemias
1) proteinuria (protein in the urine),
2) decreased glomerular filtration
3) increased blood pressure - Earliest sign: proteinuria
- leading cause of morbidity and mortality in patients with type I diabetes.
- Tight control of blood glucose both delays and reduces the severity of diabetic nephropathy.
- ACE inhibitors and ARBs are useful in
preventing diabetic nephropathy - it is suggested that patients with type I diabetes take an ACE inhibitor or ARB regardless of their blood pressure.
15
Q
Cardiovascular Disease (CVD)
A
- CVD including heart attack and
stroke are the leading causes of
morbidity and mortality in patients
with type II diabetics. - Atherosclerosis develops much
earlier in patients with diabetes. - CVD in diabetes results from a
combination of hyperglycemia and
altered lipid metabolism. - Statins reduce cardiovascular
events in patients with diabetes,
regardless of their LDL cholesterol
levels.
16
Q
Diabetic Foot Ulcers
A
- The most common cause of
hospitalization for people with
diabetes. - Diabetes accounts for approximately
1/2 of all lower limb amputations
every year due to infection. - diabetics should have regular foot exams
17
Q
Diagnosis of Diabetes
A
- Diabetes is diagnosed when plasma glucose levels are elevated.
4 tests used to diagnose diabetes:
1. Fasting Plasma Glucose Test
2. Casual Plasma Glucose Test
3. Oral Glucose Tolerance Test (OGTT)
4. Glycosylated Hemoglobin
18
Q
Test #1 - Fasting Plasma Glucose Test
A
- Patients fast for at least 8 hours and then have a blood sample drawn to
measure blood glucose. - If the fasting plasma glucose is > 7.0 mmol/L = diabetes is diagnosed.
- preferred test for diagnosing
diabetes
19
Q
Test #2 -Casual Plasma Glucose Test
A
- Advantage: Blood can be drawn at any time no matter what the interval was since the
last meal - For a diagnosis of diabetes, the casual plasma glucose is > 11.1 mmol/L
AND the patient displays classic signs of diabetes including polyuria,
polydipsia and weight loss. - If an initial casual plasma glucose test suggests diabetes, it is often
followed up by a fasting plasma glucose test.
20
Q
Test #3 - Oral Glucose Tolerance Test (OGTT)
A
- used when the other tests are unable to definitively diagnose diabetes (if fasting plasma glucose levels are close to but not over 7)
- Patients are given an oral 75 gram dose of glucose and plasma glucose is
measured 2 hours later. - If plasma glucose is > 11.1 mmol/L = diagnosed with diabetes
21
Q
Tets #4 - Glycosylated Hemoglobin
A
- when blood glucose levels are elevated in the blood for a long time, glucose interacts with hemoglobin to form glycosylated derivatives -most common form is HbA1C.
- Glycosylated hemoglobin is
useful in providing an index of the average blood glucose levels over the previous 2-3 months. - Measuring glycosylated hemoglobin is a good determinant of how well a patient is responding to therapy
- The target for management of diabetes is to maintain HbA1C < 7% of total hemoglobin
22
Q
Treatment Goals and Lifestyle Modifications
A
- complications of diabetes arise from
prolonged elevations of plasma glucose
→ so, the primary goal of diabetes therapy is to maintain tight control of plasma glucose levels. - “Tight control” means keeping plasma glucose levels in the normal range for the entire day.
The targets for plasma glucose are:
→ Pre-meal plasma glucose 4.0 - 7.0
mmol/L
→ Peak post-meal glucose 5.0 - 10 mmol/L
→ HbA1C < 7%
23
Q
Other Treatment Goals
A
- As diabetes is closely associated with cardiovascular disease and
nephropathy, it is also crucial to decrease these risk factors:
Cardiovascular Risk
→ Blood pressure – systolic < 130, diastolic < 80
→ Lipids – LDL < 2.6 mmol/L, triglycerides < 1.7 mmol/L, HDL (men) > 1.0 mmol/L, HDL (women) > 1.3 mmol/L.
Kidney Function
→ Urine albumin to creatinine ratio < 30 mg/g (albumin/creatinine)
tells us how much albumin is getting excreted into urine (albumin should not be found in urine if kidney is excreting properly)
24
Q
Lifestyle Modifications – Type I Diabetes
A
Diet
→ Most patients with type I diabetes are thin = goal is to maintain weight, not lose it.
→ Total caloric intake should be split throughout the day with meals 4-5 hours apart.
Exercise
→ Exercise increases the cellular response to insulin and increases glucose tolerance
→ Strenuous exercise can cause hypoglycemia so close patient monitoring is required.
Insulin
→ Survival requires insulin.
→ Blood glucose levels must be monitored 3 or more times per day
25
Lifestyle Modifications – Type II Diabetes
Diet
→ Dietary modifications alone (i.e. caloric restriction) often normalize insulin release and decrease insulin resistance.
→ Patients with type II diabetes are often obese so losing weight is a
treatment goal
Exercise
→ Exercise stimulates glucose uptake and should be encouraged
26
Insulin
- effects of insulin were discovered by Sir Frederick Banting (Canadian)
- Before the discovery of insulin, patients diagnosed with diabetes would die within 2- 3 years of diagnosis
27
Metabolic Actions of Insulin
- Insulin is anabolic (i.e. “building up” or conservative).
→ the actions of insulin promote energy storage and conservation.
Insulin’s anabolic actions include:
→ Cellular uptake of glucose into liver, muscle, and fat.
→ Glucose uptake (out of blood) results in the formation of glycogen (in liver and muscle) and triglycerides (adipose tissue)
- glycogen: body makes it to store
glucose
→ Decreased hepatic gluconeogenesis (i.e. new glucose synthesis in liver).
→ Cellular uptake of amino acids (mostly into muscle).
→ Amino acid uptake results in increased protein synthesis.
28
Insulin - Overview of Actions
- when insulin is released from pancreas, it enters tissue and results in increased # of transporters on surface of membranes
→ result: increased glucose uptake
1. Insulin causes conversion of glucose into fatty acids
→ fatty acids are taken up into adipose tissue to form triglycerides
2. Insulin promotes glucose uptake into adipose tissue into the liver and muscle
3. Insulin mediates the uptake of amino acids in muscle which form protein
29
Insulin Deficiency
- Insulin deficiency puts the body into a catabolic (“breaking down”) state.
→ the body favours the breakdown of complex molecules into simpler substances.
Catabolic effects seen in insulin deficiency include:
→ Glycogenolysis – conversion of glycogen (stored form) to glucose
→ Gluconeogenesis – new glucose synthesis.
→ Decreased glucose utilization.
- All of these effects contribute to the signs and symptoms of diabetes.
- These catabolic effects all act to RAISE blood glucose!
30
Insulin Therapy
- There are 7 main types of insulin
available to treat diabetes.
- The different types of insulin differ
in their appearance, time course of
action, and route of administration.
Insulins can be separated based on time course of actions:
1) Short duration-rapid acting
→ act quickly, short-lived
2) Short duration-slower acting
→ slower acting, short-lived
3) Intermediate duration
4) Long duration
31
1) Short Duration Rapid Acting Insulin
This class includes 3 different types of insulin:
1. Insulin lispro
2. Insulin aspart
3. Insulin glulisine
- This class of insulin is administered in association with meals to control
the postprandial (i.e. after eating) rise in glucose
- The route of administration is subcutaneous (IV can be used if required)
- All 3 types are a clear solution
32
2) Short Duration Slower Acting Insulin
- The only type of short duration slower acting insulin is unmodified human insulin.
Use
1) can be injected before meals to control postprandial rises in glucose
2) infused to provide basal control of blood glucose.
- can be administered subcutaneously or IM (rare)
- Following subcutaneous injection, the insulin molecules form small aggregates (i.e. dimers), which slows absorption
- Supplied as a clear solution
33
3) Intermediate Duration Insulin
There are 2 intermediate duration insulins:
1. Neutral Protamine Hormone (NPH) insulin
2. Insulin Detemir
-The onset of action of both of these are delayed, so they may not be used
at mealtime to control postprandial rises in blood glucose.
→ Instead they are injected once or twice daily to control blood glucose
between meals and in the evening.
Why are the actions delayed?
- NPH insulin – insulin conjugated to protamine (a large protein).
→ The protamine makes the molecule less soluble and decreases the
absorption
- Insulin Detemir – Insulin detemir molecules bind strongly to each
other which delays absorption
- Both NPH insulin and insulin detemir are administered by subcutaneous
injection.
- NPH insulin is supplied as a cloudy suspension
- Insulin detemir is a clear solution
34
Long Acting Insulin
Insulin glargine is the only type of long acting insulin.
- Advantage: insulin glargine is its
long duration of action therefore, it is
administered by subcutaneous injection only 1x daily at bedtime.
- The long duration is attributed to its low solubility at pH's
→ When it’s injected, it forms
microprecipitates that slowly dissolve and release insulin glargine in small
amounts over an extended time.
- Insulin glargine is supplied as a clear solution.
35
Mixing Insulins
- Sometimes insulin therapy requires combining a short acting insulin with a
longer duration insulin.
- It is optimal to be able to mix these insulins into a single syringe to avoid
2 injections.
Rules for mixing insulins include:
→ Only NPH insulin can be mixed with short acting insulins.
→ When the mixture is prepared, the short acting insulin should be
drawn into the syringe first.
→ Mixtures are stable for 28 days
36
Complications of Insulin Therapy
- The primary complication of insulin treatment is hypoglycemia (blood
glucose < 3mmol/L).
Blood Glucose levels decrease RAPIDLY = SNS effects
- Rapid decreases in blood glucose, such as in overdose, result in
activation of the sympathetic nervous system which causes:
→ Tachycardia
→ Palpitations
→ Sweating
→ Nervousness
Blood Glucose levels decrease GRADUALLY = CNS effects
- When blood glucose levels decrease more gradually, CNS symptoms
such as headache, confusion, drowsiness, and fatigue occur.
- If hypoglycemia is severe coma, convulsions, or death can occur
37
Management of Hypoglycemia
- Rapid treatment of hypoglycemia is crucial to prevent irreversible brain
damage.
- If patients are conscious, fast acting oral sugar should be used.
→ ex. glucose tablets, orange juice, corn syrup, honey and pop (not diet)
- If the patient is unconscious, IV glucose may be required
- Diabetic patients are recommended to keep the hormone glucagon on hand
38
Glucagon
- Glucagon is a hormone
produced by the (alpha cells of) pancreas.
- Glucagon causes the conversion of
glycogen to glucose (opposite action
to insulin) = effective treatment for hypoglycemia
→ pancreas secretes glucagon, glucagon converts glycogen into glucose to raise blood sugar
- Most often used when a hypoglycemic patient is unconscious
→ Once the patient regains consciousness, oral sugar solutions should be used
- For unconscious patients, IV glucose
is preferred to glucagon but is
impractical outside of medical
supervision.
- Glucagon is ineffective in starving or
malnourished patients
→ bc malnourished / starving patients do not have any glycogen stores
to begin with (glycogen is not available in the liver to be converted)
39
Oral Antidiabetic Drugs
- Oral antidiabetic drugs are used to treat type II diabetes
- are mostly ineffective in type I diabetes (bc they rely on insulin and type 1 diabetics have little/no insulin)
6 classes of oral antidiabetic drugs:
1. Biguanides
2. Sulfonylureas
3. Meglitinides
4. Thiazolidinediones (glitazones)
5. Alpha-glucosidase inhibitors
6. Gliptins
40
1) Biguanides
- Biguanides are often the drug of choice for treating type II diabetes.
- Biguanides lower blood glucose in 3 separate ways:
1. Increases the sensitivity and number of insulin receptors.
2. Decreases hepatic gluconeogenesis
→ decreases new glucose synthesis
3. Reduces intestinal glucose absorption
Advantage: they do NOT increase insulin levels, so they pose no risk of hypoglycemia
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Adverse Effects of Biguanides
1. Nausea
2. Decreased appetite
3. Diarrhea
4. Decreased absorption of vitamin B12 and folic acid
5. Lactic acidosis is rare but serious (mortality in ~ 50% of patients that get
it).
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2) Sulfonylureas
- Act primarily by stimulating release of insulin from the pancreas.
- They inhibit glycogenolysis (the breakdown of glycogen to glucose)
- There are “1st generation” and “2nd generation” sulfonylureas.
→ The difference between the 2 generations is that 2ndgeneration sulfonylureas are much more potent and cause fewer drug interactions.
- Adverse effect: hypoglycemia
→ due to increased insulin that may be circulating the blood
- Prolonged use may cause pancreatic burnout (i.e. the pancreas has a
reduced capacity to synthesize insulin)
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3) Meglitinides
- Meglitinides stimulate insulin release from the pancreas (same mechanism of action as sulfonylureas)
- Meglitinides differ from sulfonylureas in that they:
→ Have a short half life so they are effective for treating postprandial
rises in glucose.
→ Less likely to cause hypoglycemia
→ Less likely to cause pancreatic burnout
- if hypoglycemia and pancreatic burnout are caused by sulfonylureas, switch patient to Meglitinides
44
4. Thiazolidinediones (Glitazones)
- Glitazones act by increasing insulin sensitivity in target tissues and decreasing hepatic gluconeogenesis.
- Glitazones activate the PPARγ (gamma) receptor, which is an intracellular receptor.
- Activation of (nuclear receptor) PPARγ turns on genes that regulate carbohydrate metabolism.
→ result is increased sensitivity to insulin by increases in the # of
glucose transporters on cells
- Glitazones also increase HDL and decrease triglyceride levels via
activation of PPARα (alpha)
Adverse effects include:
1. Fluid retention/edema
→ should not be used in patients with heart failure
2. Headache
3. Myalgia
45
5) Alpha-Glucosidase Inhibitors
- Act at the intestine to delay carbohydrate absorption.
- In order to be absorbed, complex
carbohydrates in our diet must be
broken down into monosaccharides
(single sugar molecules)
→ This process is mediated by alpha-glucosidase (enzyme in the intestine)
- Alpha-glucosidase inhibitors block the
enzyme and therefore cause a
decrease in complex carbohydrate
metabolism
→ This reduces the postprandial rise in glucose
- Adverse effects are limited to the
intestine since alpha-glucosidase
inhibitors are poorly absorbed
- Adverse effects include:
1. Flatulence
2. Cramps
3. Abdominal distention
4. Diarrhea
5. Decreased iron absorption
46
6) Gliptins
- Gliptins act to inhibit an enzyme called dipeptidyl peptidase 4 (DPP-4)
- DPP-4 breaks down the incretin hormones GLP-1 and GIP
- Incretin hormones, GLP-1 and GIP, are released from the GI tract
after a meal
GLP-1 and GIP cause:
1. Increased release of insulin
2. Decreased release of glucagon
→ By inhibiting DPP-4, gliptins allow more GLP-1 and GIP to reach the
pancreas therefore causing increased insulin release and suppression of
glucagon release
- Gliptins have no known major adverse effects
47
Gliptins Mechanism of Action
- when we eat food, our intestine releases incretin hormones
- incretin hormones are metabolized by DPP-4
- in diabetes, not enough reach the pancreas
- gliptin drugs inhibit the enzyme DPP-4, which results in excess incretin hormones reaching the pancreas and causing insulin release and suppressing glucagon release
48
7) Incretin Mimetics
- Incretin mimetics are synthetic incretin analogs that mimic the actions of incretin hormones (not oral antiobiotic drugs)
- Therefore incretin mimetics cause an
increase in insulin release and a
decrease in glucagon release.
- Incretin mimetics are administered by
subcutaneous injection and are used
as adjunctive therapy with biguanides
or sulfonylureas.
Adverse effects include:
1. Hypoglycemia
2. Pancreatitis
- Incretin mimetics do the same things as incretins
→ act to stimulate insulin release
→ inhibit glucagon release
= lower blood glucose
