Endocrinology Slides

Diabetes Mellitus

Terminology

  • Use correct medical terminology for:

    • Diabetes mellitus

    • Thyroid disorders

    • Adrenal disorders

    • Diabetes insipidus

Recommended Readings

  • Insulin and diabetes mellitus: ALL sections, Chapter 16 Endocrine System Disorders in Gould’s pathophysiology for the health professions (7th ed.).

Learning Outcomes

  1. Describe the regulation of blood glucose by hormones in the body.

  2. Describe the pathophysiology, etiology, clinical manifestations, monitoring tests and parameters, complications, and treatment of type 1 and type 2 diabetes mellitus.

  3. Describe drugs in the following classes according to their generic and brand names, place in therapy, mechanism of action, pharmacokinetics, pharmacodynamics, precautions and contraindications, adverse effects, and auxiliary labels:

    • Insulin

    • Biguanides

    • Sodium-Glucose Cotransporter 2 Inhibitors (SGLT-2I)

    • Incretins

      • Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA)

      • Dipeptidyl Peptidase-4 Inhibitors (DPP-4I)

    • Alpha-glucosidase Inhibitors

    • Insulin Secretagogues

      • Sulfonylureas

      • Meglitinides

    • Thiazolidinediones (TZDs)

    • Glucagon

Insulin and Diabetes Mellitus

  • The fundamental problem in diabetes mellitus is inadequate insulin (hormone) effects in receptor tissues caused by:

    1. Deficit of insulin secretion AND/OR

    2. Cellular insulin resistance

  • Diabetes results in abnormal carbohydrate, protein, and fat metabolism.

  • Deficit in protein and glycogen (storage of glucose) production.

  • Alterations in the transport of glucose and amino acids into cells.

Regulation of Blood Glucose

  • Blood glucose is normally maintained at:

    • 3.9 mmol/L3.9 \, \text{mmol/L}

      • Fasting

    • 6.6 mmol/L6.6 \, \text{mmol/L}

      • Postprandial (1 to 2 hours after the start of a meal),

  • Insulin and glucagon are peptide hormones secreted from endocrine cells in the islets of Langerhans in the pancreas.

  • Insulin is secreted from beta cells in response to high blood glucose levels.

    • Insulin lowers blood glucose, and glucose is transported into cells.

  • Glucagon is secreted from alpha cells in response to low blood glucose levels.

    • Glucagon raises blood glucose and converts stored glycogen into usable sugars.

Other Hormones Involved in Blood Glucose Control

  • Incretins act on the beta cells of the pancreas to stimulate insulin secretion.

    • Secreted by endocrine cells in the small intestine in response to glucose. yes to insulin

  • Amylin slows gastric emptying, suppresses glucagon secretion, and modulates appetite. decrease insulting

    • Secreted from beta cells along with insulin in response to elevated blood glucose levels.

  • Epinephrine and cortisol both antagonize the effects of insulin and increase blood glucose levels.

    • Epinephrine increases blood glucose levels and inhibits insulin secretion.

    • Cortisol (stress hormone) increases blood glucose levels to provide fuel and building blocks during adaptation and stress.

  • > better if more blood glucose so more fuel and use pgycogen storage

Types of Diabetes Mellitus

  • Type 1 Diabetes (DM1) either born with it or an autoimmune disease (usually much younger, found out before their birthday

    • Autoimmune destruction of beta cells

    • Absolute insulin deficiency

  • Type 2 Diabetes (DM2) (progressive disease, moniter the patients glucose levels to be

    • Insulin resistance and/or insulin deficiency

    • Usually, the beta cells are capable of secreting insulin, but secretion is impaired and eventually stops

  • Gestational Diabetes (GD)

    • Glucose intolerance with onset of pregnancy

    • People with GD have an increased risk of developing type 2 diabetes

Type 1 Diabetes

  • Etiology is an autoimmune destruction of beta cells in the pancreas

  • Absolute insulin deficit in the body

  • Insulin replacement required

  • Acute onset in children and adolescents

  • Not linked to obesity

  • Genetic factors may play a role

Type 1 Diabetes (DM1) 10% of people have this one

  • Metabolic changes:

    • Catabolism of fats and proteins

    • Excessive amounts of fatty acids and metabolites

    • Ketones in the blood (product of fat breakdown)

    • Ketonuria

    • Decrease in pH of body fluids (ketones are acidic)

    • Decreased serum bicarbonate

    • Ketones are excreted in urine (acidic byproduct in the body, which can cause diabetic keotonacidosis (has a fruity smell of the breathe) which is why some people do hte keto diet )

    • Decompensated metabolic acidosis

    • Medical emergency required

Type 2 Diabetes (DM2) (progressive disease)

  • 90% of people with diabetes (lack of excercise, diabetes, genetics, eating habits)

  • Etiology is: dont make enough insulin , dont respond enough to insulin, and or too much glucose production in the liver)

    • Decreased production of insulin

    • Increased resistance by body cells to insulin

    • Increased production of glucose by the liver

  • Onset is slow and insidious, usually in those older than 50 years

  • Associated with obesity

  • Component of metabolic syndrome

  • Increasing incidence in teens and young adults

DM1 vs DM2 Characteristics & Symptoms *****

Feature

DM1

DM2

Onset Age

Usually < 30 yrs; peak 12-14 yrs

Usually > 40 yrs; increasing prevalence among obese children

Etiology

Autoimmune destruction of beta cells in the pancreas

Familial, lifestyle, environmental factors, obesity

Clinical Presentation

Rapid onset; symptoms more severe and include weight loss and ketoacidosis

Symptoms are milder compared to Type I

Body Weight

Thin

Obese

Percentage of People w/ DM

10%

90%

Pancreatic (β-cell) Function

Usually none

Insulin present in low, normal, or high amounts

Treatment

Insulin + nutrition, physical activity, amylin mimetics (synthetic compounds that mimic the effects of the natural hormone amylin)

Oral antihyperglycemic agents + nutrition, physical activity, insulin, amylin mimetics

Pathophysiology of Insulin Deficit / (urine sweeter?, pee more, hungrier, DEHYDRATED )

  • Decreased transportation < 🚎 and use of glucose 🍦 in many cells causes: =

    • Hyperglycemia – blood glucose levels rise

    • Glucosuria – excess glucose in urine

      • Glucose in the filtrate exceeds the capacity of the renal tubules to resorb it

    • Polyuria – large urine volume

      • Osmotic pressure due to glucose load

    • Polydipsia – dehydration causes thirst

    • Polyphagia – lack of nutrients in cells stimulates appetite

    • Dehydration – fluid loss through urine

      • Accompanying losses of sodium and potassium

  • 3 Ps!

    • Polyuria

    • Polydipsia

    • Polyphagia

Progressive Manifestations

  • If insulin deficits are severe or prolonged: 🫥

    • Lack of glucose in cells = the body uses fats and proteins for energy

    • Metabolite of fat catabolism = ketones (acetone + 2 organic acids)

    • Eventual decrease in body pH (ketones are acidic)

    • Ketonuria – ketones are present in urine

    • Buffers are eventually overwhelmed, and dehydration is occurring (from polyuria), leading to a decompensated metabolic acidosis

    • Diabetic ketoacidosis (DKA)

      • Treatable, but very dangerous and can be life-threatening

Diagnostic Tests

  • Fasting blood glucose level

    • 8 hours since food

    • ≥7.0 mmol/L\geq 7.0 \, \text{mmol/L}

      • Diagnostic level + not producing enough insulin

  • Glucose tolerance test

    • Oral glucose tolerance test (OGTT) – 2 hours after 75 gram of oral glucose

    • ≥11.1 mmol/L\geq 11.1 \, \text{mmol/L}

      • Diagnostic level + if they dont come down to 11.1, most likely diabetic

  • Glycosylated hemoglobin test

    • Glycosylated hemoglobin (A1C) = HbA1C must used test

    • Average glucose control over 8-12 weeks

    • ≥6.5%\geq 6.5\%

      • Diagnostic level

Targets for Glycemic Control

HbA1C (blood test, lab tests it and gives the result)

Fasting or Preprandial Glucose

2-hour Postprandial Glucose

DM 1 and 2

< or = 7%

4.0–7.0 mmol/L4.0 – 7.0 \, \text{mmol/L}

5.0–10.0 mmol/L5.0 – 10.0 \, \text{mmol/L}

(if A1C targets not being met 5.0–8.0mmol/L5.0 – 8.0 \text{mmol/L})

Normal Range

< or = 6%

4.0–6.0 mmol/L4.0 – 6.0 \, \text{mmol/L}

5.0–8.0 mmol/L5.0 – 8.0 \, \text{mmol/L}

Treatment Principles

  • Lifestyle modification

    • Diet and exercise under the guidance of health professionals

  • Treatment goals are to maintain blood glucose levels in the normal range

  • DM1 patients require insulin

  • DM2 patients may require initiation of insulin, other antihyperglycemic pharmacotherapy, or lifestyle modifications alone

Self-Monitoring of Blood Glucose

  • Conducted by the patient at home using a blood glucose monitor

  • Frequency of testing is dependent on the patient

  • DM1

    • Recommended that testing occur ≥3\geq 3 times per day

      • 2 hours after lunch

      • 2 hours after dinner

      • Bedtime

    • Frequent testing guides lifestyle and food choices and pharmacological therapy

    • Illness/infection warrants more frequent testing (will change insulin requirements)

  • DM2

    • Frequency of testing not as clear for individuals managed with lifestyle and/or oral antihyperglycemics

    • If taking insulin frequency should be the same as that recommended for type 1 DM

Insulin Types

  • Basal Insulins (once daily)

    • Ultra-long-acting

    • Long-acting

    • Intermediate-acting

  • Bolus (Mealtime) Insulins (take at meat times to reduce spikes)

    • Fast-acting

    • Regular-acting

  • Premixed Insulin (long and short acting in them)

Basal-Bolus Secretion

  • Goal of insulin therapy is to mimic physiological levels of insulin:

    • Basal secretion - the pancreas constantly secretes small amounts of insulin throughout the day

    • Bolus secretion - the pancreas secretes a larger amount of insulin response to a meal

  • Insulin therapy in type 1 diabetes combines different types of insulin with different durations of action to mimic basal-bolus secretion

Insulin Products

  • All insulin preparations in Canada are prepared using recombinant DNA technology (use recombinant DNA to chemically copy the insulin in a human’s body)

  • MOA

    • Structurally identical to human insulin

    • Preparations are classified based on their duration of action, time of onset, and peak actions

  • Kinetics and Dynamics

    • Insulin analogues which are modified to change their pharmacokinetics

    • Most common route of administration is subcutaneous

    • Regular insulin can be given intravenously in hospital settings

Subcutaneous Administration

  • Site should be rotated within the same anatomical region

  • Absorption is:

    • Fastest from the abdomen

    • Intermediate in the arm

    • Slowest from the thigh Ex. 1 basal in the morning, 3 bolus during the day

Insulin Packaging

  • Commercially available as:

    • Vials

      • 10 mL

      • Use needles and syringes to draw insulin out of vials

    • Cartridges (also called Penfills)

      • 3 mL x 5 per box (15 ml in total)

      • Used with reusable insulin pens and disposable needle tips (pen tips)

    • Pre-filled disposable pens ( after usage once, okay for 28? days)

      • 3 mL x 5 per box (15 mL in total)

      • Used with needle tips (pen tips) and then discarded when empty

  • Insulin is dosed in units

    • 100 unit/mL standard concentration for most insulins

    • Concentrated solutions are available in hospital and are denoted “U200”, “U300”, or “U500”

    • Caution: potential for lethal errors

  • Wegovy and ozempic are insulin like drugs, weekly injectable, diff type of meds but same type of giving out

Insulin Considerations

  • ROLLING/SHAKING

    • Insulins that are CLEAR do NOT need shaking prior to use

    • Insulins that are CLOUDY DO need rolling to mix prior to use

    • SHAKE GENTLY MIXING INSULINS

  • Some insulins (like Lantus® and Levemir®) form a precipitate in subcutaneous tissue after injection and these can NEVER be mixed with other insulins

    • Injection sites should be well spaced from other insulins

  • STORAGE AND STABILITY

    • Most insulins are stored at 2oC to 8oC at the pharmacy and before first use

    • KEEP IN FRIDGE; DO NOT FREEZE,,, after first use can stay outside

    • Once brought to room temperature, insulins can usually be used for one month (refer to product monograph)

    • CALCULATE BEYOND USE DATE WHEN DISPENSED

Relative Insulin Effects over Time

  • The relative effects of rapid, short, intermediate, and long-acting insulins over time are visually represented in a graph.

Basal Insulin Ultra-Long-Acting

  • Products

    • degludec (Tresiba®)

      • U100 and U200

    • glargine (Toujeo® U300),

  • Kinetics and Dynamics

    • SC dose once daily HS or BID (split a dose)

    • Duration of action is 36 to 42 hours

  • Precautions and Adverse Effects

    • Clear insulin = DO NOT SHAKE

    • Do not mix with other insulins

    • STORE IN THE FRIDGE; DO NOT FREEZE

    • CALCULATED BUD AT ROOM TEMPERATURE (usually a month)

Basal Insulin Long-Acting

  • Products

    • glargine (Lantus®); biosimilar glargine (Basalglar®)

    • detemir (Levemir®)

  • Kinetics and Dynamics

    • SC dose once daily HS or BID

    • Duration of action is ∼24\sim 24 hours

  • Precautions and Adverse Effects

    • Clear insulin = DO NOT SHAKE

    • Do not mix with other insulins

    • STORE IN THE FRIDGE; DO NOT FREEZE

    • CALCULATED BUD AT ROOM TEMPERATURE (usually a month)

Basal Insulin Intermediate-Acting

  • Products CLoudy INSULINE SHAKE GENTLY

    • insulin isophane (Humulin® N)

    • insulin isophane (Novolin® ge NPH)

  • Kinetics and Dynamics

    • SC dose once daily HS or BID

  • Precautions and Adverse Effects

    • Cloudy insulin = SHAKE GENTLY

    • STORE IN THE FRIDGE; DO NOT FREEZE

    • CALCULATED BUD AT ROOM TEMPERATURE (usually a month)

Bolus (Mealtime) Insulin Fast-Acting

  • Products CLEAR INSULIN = DO NOT SHAKE

    • insulin aspart (Fiasp®)

      • Ultra-fast acting! Onset of action is 4 minutes

    • insulin aspart (NovoRapid®); biosimilar aspart (Trurapi®)

    • insulin glulisine (Apidra®)

    • insulin lispro (Humalog®); biosimilar lispro (Admelog®)

      • Humalog U100 and U200

  • Kinetics and Dynamics

    • SC dose 0 to 15 minutes before (or within 20 min of) a meal

    • Insulin lispro, glulisine, and aspart can be used in insulin pumps (pump insulin into body and put into blood stream)

  • Precautions and Adverse Effects

    • Clear insulin = DO NOT SHAKE

    • STORE IN THE FRIDGE; DO NOT FREEZE

    • CALCULATED BUD AT ROOM TEMPERATURE (usually a month) 28 days based on monograph, (KNOW which insulins fit into each category)

Bolus (Mealtime) Insulin Regular-Acting

  • Products

    • insulin regular (Humulin® R) (Novolin® ge Toronto)

  • Kinetics and Dynamics

    • SC dose 30 to 45 minutes before a meal

    • Onset of action is 30 minutes

  • Precautions and Adverse Effects

    • CLEAR insulin = DO NOT SHAKE

    • STORE IN THE FRIDGE; DO NOT FREEZE

    • CALCULATED BUD AT ROOM TEMPERATURE (usually a month)

Premixed Insulins

  • Products CLOuDY = SHAke Gently

    • cinsulin lispro/​lispro protamine (Humalog® Mix25, Mix50)

    • insulin aspart/​aspart protamine (NovoMix® 30)

  • Kinetics and Dynamics

    • SC dose BID 0–15 min before or within 20 min of a meal

  • Precautions and Adverse Effects

    • Cloudy insulin

    • SHAKE GENTLY

    • STORE IN THE FRIDGE; DO NOT FREEZE

    • CALCULATED BUD AT ROOM TEMPERATURE (usually a month)

Insulin Pumps

  • Insulin pumps provide a continuous supply of insulin to mimic basal secretion and allow for bolus doses in association with meals

  • A reservoir within the pump contains fast-acting insulin

    • Insulin lispro, glulisine, or aspart

  • An infusion set is used to deliver insulin into subcutaneous tissue

  • Some pumps can be interfaced with blood glucose monitors

Precautions and Adverse Effects

  • Hypoglycemia (too much = drops blood sugar)

  • Lipohypertrophy at the site of injection

  • Rare hypersensitivity reactions

  • Drugs that affect glycemic control

    • Beta-blockers

      • Mask symptoms of hypoglycemia

    • Alcohol

      • Acutely, blood glucose will drop (when the liver is processing alcohol, it stops releasing glucose)

      • Over time, excessive alcohol consumption (> 3 drinks a day) can reduce the overall effectiveness of insulin = higher HbA1C

    • Drugs that increase blood glucose:

      • Sympathomimetics (mimics sympathetic nervous system?), strenuous exercise

      • Corticosteroids

      • Thiazide and loop diuretics

      • Niacin

      • Estrogens

    • know which wh insulins fall in what category, main things about storage, clody vs clear*

Antihyperglycemic Agents

  • Biguanides

  • Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2I)

  • Incretin Mimetics

    • Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA)

    • Dipeptidyl Peptidase-4 Inhibitors (DPP-4I)

  • Alpha-glucosidase Inhibitors

  • Insulin Secretagogues

    • Sulfonylureas

    • Meglitinides

  • Thiazolidinediones (TZD)

Management of DM2

  • Initial management generally depends on the HbA1c

    • In patients with an HbA1c at or near their target

      • Nonpharmacologic therapy alone (e.g., diet and exercise) for 3 months

      • If targets are not met in 3 months:

        • Monotherapy with metformin (Brings down A1c, very common , but causes stomach irritation, and slowly introduce it with meals) is the drug of choice, or

        • Combination of oral agents and/or insulin

    • In patients with an HbA1c well above their target

      • Pharmacotherapy is started immediately (along with diet and exercise)

      • Combination therapy (metformin combined with another drug, possibly hs insulin)

      • The goal of pharmacotherapy is to reach their HbA1c target within 3 to 6 months

      • Dosage titration and/or addition of other agents

Nonpharmacological Management

  • Self-management education is vital for patients to be full participants their own care

  • Nutritional management with a registered dietitian to personalize goals and tailor a dietary plan

  • Blood glucose monitoring is essential to manage diabetes well

  • Exercise

    • Physical activity can improve cardiovascular function, enhance insulin sensitivity, and lower blood pressure and lipid levels

    • Encourage aerobic exercise totaling ≥150\geq 150minutes per week with resistance training at least twice a week,,, Eye exams every year

  • Ongoing monitoring of other organ systems

    • Blood pressure measurements, foot examinations, bloodwork to monitor renal function and lipid profiles, ophthalmologist/optometrist for eye examinations

Biguanides

  • Products FIRST LINE TO USE

    • metformin (Glucophage®)

    • metformin SR (Glumetza®)

      • DO NOT CRUSH OR CHEW AND TAKE WITH FOOD

    • many combination products

  • Place in Therapy

    • First choice for patients with a new and uncomplicated DM2 diagnosis

  • MOA

    • Primarily, it decreases hepatic glucose production

    • It also lowers glucose absorption and enhances insulin-mediated glucose uptake (decreases glucose production in the liver)

  • Kinetics and Dynamics

    • Oral medications

  • Drug interactions:

    • Alcohol = Increased risk of lactic acidosis and potentiates hypoglycemic effects

    • Renal contrast dyes

  • Precautions and Adverse Effects

    • Minimal risk of hypoglycemia when used as monotherapy

    • Significant nausea, diarrhea, metallic taste

      • “Start low and go slow” to minimize GI side effects

    • TAKE WITH FOOD

    • Does not promote weight gain (weight neutral)

    • Lactic acidosis (rare)

    • Contraindicated in patients with hepatic impairment, severe renal impairment or previous lactic acidosis

Sodium-Glucose Cotransporter 2 Inhibitors (SGLT-2I)

  • Products

    • canagliflozin (Invokana®)

    • dapagliflozin (Forxiga®)

    • empagliflozin (Jardiance®)

  • Place in Therapy

    • Well tolerated option in DM2 with minimal risk of hypoglycemia

    • Proven cardiorenal benefits in high-risk populations

  • MOA

    • Prevent glucose reabsorption in the kidneys, leading to increased excretion of urinary glucose and a lowering of blood glucose

  • Kinetics and Dynamics

    • Oral medications

  • Many drug interactions: SGT-2Is are strong CYP enzyme inducers (lowers to increase?) peeing glucose out, leving the body = less fat = weight loat)

  • Precautions and Adverse Effects

    • Increased risk of genitourinary infections

    • Reduced intravascular volume = hypotension (especially with loop diuretics)

    • Hyperkalemia

    • Risk of diabetic ketoacidosis

    • Some weight loss is associated with SGLT-2Is

Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA)

  • Products

    • Short acting (works on post-prandial glucose = given with meals)

      • exenatide subcut bid (Byetta®)

      • lixisenatide subcut daily (Adlyxine®)

    • Long-acting (without regards to meals)

      • dulaglutide subcut weekly (Trulicity®)

      • liraglutide subcut daily (Victoza®)

      • semaglutide subcut weekly (Ozempic®),, mtizaritide?,

    • Oral

      • semaglutide oral once daily (Rybelsus®)

        • Daily on an EMPTY STOMACH upon waking, with only MINIMAL WATER and NOTHING ELSE FOR 30 MINUTES (no other food, drink or medications)

  • Place in Therapy

    • Well tolerated option in DM2 with minimal risk of hypoglycemia

    • Proven cardiorenal benefits in high-risk populations

  • MOA

    • Mimic the actions/agonist of GLP-1 (an endogenous incretin hormone) that is secreted in response food ingestion

    • GLP-1 increases insulin secretion, suppresses glucagon secretion, slows gastric emptying, and increases satiety

  • Kinetics and Dynamics

    • Gradual dose increase over weeks to months

  • Precautions and Adverse Effects

    • Significant nausea, and possible vomiting and diarrhea

    • Rare acute pancreatitis

    • Caution in patients with arrhythmias and severe renal impairment

    • Causes weight loss (slows gastric emptying = feel full longer)

Dipeptidyl Peptidase-4 Inhibitors (DPP-4I)

  • Products

    • alogliptin (Nesina®)

    • linagliptin (Trajenta®)

    • saxagliptin (Onglyza®)

      • Saxagliptan (Onglyza®) must be avoided in patients with heart failure; ++ interactions

    • sitagliptin (Januvia®)

  • Place in Therapy

    • Well tolerated option in DM2, decrease HbA1C with minimal risk of hypoglycemia

    • CV safety but NO proven cardiorenal benefit

  • MOA

    • Increases the availability of GLP-1 (by preventing the enzyme that breaks it down)

    • GLP-1 increases insulin secretion, suppresses glucagon secretion, slows gastric emptying, and increases satiety

  • Kinetics and Dynamics

    • Drug interactions – only with saxagliptan (Onglyza®)

    • Taken orally once daily with or without food

  • Precautions and Adverse Effects

    • Nasopharyngitis

    • Hypersensitivity reactions

    • Rare pancreatitis and severe joint pain

    • Saxagliptin (Onglyza®) must be avoided in patients with heart failure

Alpha-Glucosidase Inhibitors

  • Products

    • acarbose (Glucobay®)

  • Place in Therapy

    • Well tolerated option in DM2; minimal risk of hypoglycemia so monitored, 3-4th line agent for dm2

    • CV safety but NO proven cardiorenal benefit

  • MOA

    • Inhibits the intestinal enzyme alpha-glucosidase which breaks down complex polysaccharides into simple sugars

    • Acarbose delays the absorption of carbohydrates which improves postprandial glucose control

  • Kinetics and Dynamics

    • Taken orally with the first bite of each meal (tid)

    • Start low and titrate slowly to minimize GI adverse effects!

    • Potentiate the effect of other antihyperglycemics

  • Precautions and Adverse Effects

    • Flatulence, diarrhea, abdominal pain, cramps, and nausea

    • Contraindicated in irritable bowel syndrome and inflammatory bowel disease ((USE glucose to treat hyperglycema)

Secretagogues: Sulfonylureas

  • Products

    • glicazide (Diamicron®, Diamicron MR®)

      • MR (long acting) = DO NOT CRUSH OR CHEW

    • glyburide (generics)

  • Place in Therapy

    • Agents have CV safety, but NO proven cardiorenal benefits

    • Risk of hypoglycemia

  • MOA

    • Enhance secretion of insulin by pancreatic beta cells

    • Stimulate both basal and mealtime insulin release

    • Must have functioning beta cells for these drugs to work! (no dm1, it would not work)

  • Kinetics and Dynamics

    • Given orally once or twice daily

    • Hypoglycemic effects are potentiated by salicylates, sulfonamides, MAOIs, and other oral antihyperglycemics

  • Precautions and Adverse Effects

    • TAKE WITH FOOD

    • Hypoglycemia

    • Weight gain

    • Avoid in / constraindicated in those with sulfa allergy and with decreased kidney function

Secretagogues: Meglitinides

  • Products

    • repaglinide (GlucoNorm®)

  • Place in Therapy

    • Agents have CV safety, but NO proven cardiorenal benefits

    • Risk of hypoglycemia

  • MOA

    • Enhance secretion of insulin by pancreatic beta cells

    • Stimulate both basal and mealtime insulin release

    • Must have functioning beta cells for these drugs to work!

  • Kinetics and Dynamics

    • Given orally 0 to 30 minutes before meals

    • More rapid onset and shorter duration of action compared to sulfonylureas

    • Useful in individuals who have irregular mealtimes

    • Affected by drugs that induce or inhibit CYP3A4 = many interactions

  • Precautions and Adverse Effects

    • Hypoglycemia (especially if not taken a meal)

    • TAKE WITH FOOD

    • Weight gain

Thiazolidinediones (TZD)

  • Products

    • pioglitazone (Actos®)

    • rosiglitazone (Avandia®)

      • Health Canada requires that physicians counsel patients and obtain their written consent for all new and renewed rosiglitazone prescriptions because of the increased risk of MI (heart attack)

  • Place in Therapy

    • Agents have a risk of heart failure and cause weight gain

  • MOA

    • Insulin ‘sensitizers’

    • Influence gene expression in the cell leading to enhanced insulin sensitivity, and lower levels of blood glucose and circulating insulin

  • Kinetics and Dynamics

    • Potentiates effects of other antihyperglycemic agents

      • Gemfibrozil inhibits metabolism and increases plasma levels

    • Insulin (associated with increased incidence of edema and worsening of heart failure)

  • Precautions and Adverse Effects

    • Weight gain

    • Edema

    • Worsening of heart failure

    • Macular degeneration

    • Rosiglitazone: significantly increases the risk of heart attack; requires consent in Canada

    • Pioglitazone: Increased risk of fractures; may increase risk of bladder cancer

QUICK REVIEW:

Basal = long acting, continual secretion throughout the day

bolus = immediate in response to food / calories

  1. sc administration rotated around in the same site. thigh/glutes slowest, stomach/abdomen fastest

  2. standard concentration for most insulins = 100U/mL

  3. Premixed insulins which are cloudy need gentle shaking before administration like insulin isophane

  4. 3 bolus insulins that are fast acting, given aroind 15 minutes before meals, aspart / flasp/ novorapid, trurapi, apidra, humalog, admelong

Complications of Diabetes Mellitus

  • Describe the complications of diabetes mellitus, including hypoglycemia, diabetic ketoacidosis, microangiopathy, macroangiopathy, infections, and cataracts

  • Complications are directly related to duration and extent of abnormal blood glucose levels

  • Acute complications

    • Hypoglycemia and diabetic ketoacidosis (DKA) (low blood glucose)

  • Chronic complications

    • Macrovascular, microvascular, and infection (high blood glucose)

Hypoglycemia (Low blood glucose)

  • More common with insulin treatment

  • Can occur with some hypoglycemic drugs

  • Excess insulin in circulation = glucose deficit in blood

  • Can be life-threatening or cause brain damage if untreated (below 3?,,,

  • Causes

    • Strenuous exercise

    • Dosage error

    • Vomiting

    • Skipping meal after taking insulin

Pathophysiology of Hypoglycemia

  1. Excess insulin in blood

  2. Increased transport of glucose into cells

  3. Hypoglycemia

    • Decreased CNS function = little to no glucose in the blood

  4. Stimulates SNS

    • Clinical signs:

      • Weakness, confusion

      • Pallor

      • Diaphoresis

      • Tremors

  5. Increased gluconeogenesis (making glucose out of other particles, like fat proteins and muscles)

  6. Excess insulin transports glucose into cells (IF there is a glucose intake, return to normal state)

  7. No glucose intake

  8. Blood glucose levels decrease further

  9. Neurons cannot function

  10. Coma and death

Signs & Symptoms of Hypoglycemia

  • Disorientation and change in behavior

    • May appear impaired

  • Anxiety or decreased responsiveness

  • Decreased blood glucose level

  • Decreased BP, increased heart rate

  • Decreasing level of consciousness

  • Immediate administration of glucose is required to prevent brain damage

Treatment of Hypoglycemia

  • Check blood glucose immediately

    • No meter? Treat the symptoms anyway!

  • Eat or drink a fast-acting carbohydrate (15 grams of glucose)

    • 125 mL (1/2 cup) of juice or regular soft drink

    • 15 mL (1 tablespoon) of honey or jam/jelly

    • 15 mL (3 teaspoons) or 3 packets of table sugar dissolved in water

    • 6 Life Savers® (hard candies are not preferred due to choking risk)

  • Wait 10 to 15 minutes, then check the blood glucose again

    • If it is still low: treat again!

    • If the next meal is more than one hour away (or physical activity is anticipated) eat a snack with 15 grams of carbohydrate and a protein source

      • Like a half-sandwich or cheese and crackers

    • If unconscious, call 911

      • Give nothing by mouth

      • IV glucose is required

    • **DIABETIC KETOACIDOSIS = high blood glucose also causes a loss of consciousness, assessment should be done to check the cause

Glucagon

  • Products

    • glucagon (powder for reconstitution for subcut, im or iv injection)

  • Place in Therapy

    • Emergency treatment of severe hypoglycemia in unconscious patients treated with insulin

  • MOA

    • Hormone that causes an increase in blood glucose by converting liver glycogen to glucose

  • Kinetics and Dynamics

    • Patients typically respond within 10 minutes of subcut or im injection

  • Precautions and Adverse Effects

    • Severe adverse reactions are very rare

    • Nausea, vomiting, or hypokalemia may occasionally occur

Diabetic Ketoacidosis (DKA)

  • Occurs most commonly in DM1, can occur in DM2 if insulin dependent

  • The cause is insufficient insulin in blood which cause hyperglycemia (high sugar in the blood)

  • May result from error in dosage (underdosage), serious infection, change in diet, alcohol intake, exercise, or prolonged stress

  • The body mobilizes and uses lipids and proteins to meet cellular needs, which results in the production of ketoacids

Development of DKA

DKA Signs amd Symptoms

• Thirst

• Dry oral mucosa and skin

• Rapid pulse (but may be weak)

• Blood pressure is low (vascular volume decreases, vasodilation)

• Kussmaul respirations – fast, deep respirations

• Sweet, fruity-smelling breath – caused by acetone in the blood

• • Indicates depression of the central nervous system

Headache, lethargy and decreased responsiveness

• • Electrolyte imbalances cause abdominal cramping, nausea, and weakness

• Compensatory mechanisms to conserve fluid in the body begin Polyuria, then oliguria

Pathophysiology and Treatment of DKA

Ketones bind with bicarbonate ions in the blood

buffering system

• Decreased blood bicarbonate

As dehydration progresses the renal buffering

systems become overwhelmed, and acidosis

worsens

• Decreased blood pH

• Decompensated metabolic acidosis

• Coma is possible

Intravenous Treatment

• Extracellular fluid volume contraction

• Correct potassium deficit

• Insulin administration

• Correct serum osmolality

Vascular complications of DM microangiopathy

• Basement membrane of capillaries and small arteries become thick and hard

Leads to obstruction or rupture = tissue necrosis and loss of function

Eyes = retinopathy, Microaneurysms, neovascularization, and fibrosis in the retina

• Leads to blindness

Kidneys: nephropathy: Vascular degrenation in the kidney glomeruli, leads to chronic renal failure, some antihyperglycemics and antihypertensives have acardiorenal benefits (some of thesese are GLP -1RA, SGLT-21, ACEIs, ARBs)

Nerves: Neuropathy which is peripheral and autonomic: • Ischemia of neurons, as well as metabolic abnormalities that

cause myelin degeneration change nerve conduction

• Peripheral • Impaired sensation in extremities

• Burning, tingling, weakness, and muscle wasting

• Autonomic • Impaired gastric motility

• Erectile dysfunction

• Urinary incontinence

Vascular Complications of DM Macroangiopathy

  • Atheroscelerosis in large arteries, related to hyperlipidemia, hypertension, and DM related changes to the arterial intima, I.E. myocardial infarction, strokes, peripheral vascular disease like ischemia, necrosis, and gangrene can lead to lower limb amputation

  • Statistically: 60-80% of people with DM die of heart disease, the risk of stroke is 50% higher in persons with diabetes, and is the leading cause of non-traumatic leg amputations

Other complkcations of Diabetes Mellitus

  • Infections, are more frequent nd more severe, infections in lower body caused by vasucalr and neurologic impairment , candida fungal infections, rurinary tract infections, dental caries, gingivitis, and periodontitis

  • Cataracts: abnormal metabolism of glucose causes damage to the lens

  • Complications in Pregnancy: in both mother and fetus may occur, more chance of miscarriage, infants may have increased size and weight and may experience hypoglycemia in first hours postnatally

Thyroid Disorders

  • thyroid gland (in the throat) traps iodine and uses it to create two thyroid hormones, t# and t4 = thyroixine

  • release in response to TSH from pituitary, disroders may result from pituitary or thyroid gland dysfunction

  • start teratment when its high, so increase dose to decrease tsh more as its too high

Goiter

  • Goiter is an enlargement of the thyroid gland caused by hypo OR hyper thyroid conditions

    • Endemic goiter (Hypothyroid condition in regions with low iodine levels in soil and food, dietary deficiency leads to hyperplasia and hypertrophy in the thyroid gland

    • Goitrogens (foods and drugs that block synthesis of triiodothyroxine and thyroxine

    • Toxic goiter (hyoerthyroid condition caused by an overactive thyroid gland)

Hyperthyroid Graves disease

  • related to autoimmune factor most common in females over 30

  • hypermetabolism and increased stimulation of SNS (intolerance to heat, increasemetabolism, thin with increased appetite, flushed and warm skin, tachycardia, restless tremors and insomnia )

  • toxic gioter

  • expophthalamos (presence of protruding staring eyes, decreased blink and eye movement, result of increased tissue mass in the orbit, may result in visual impairment)

Treatment of hyperthyroidism

  • surgical removal of the thyroid gland and or administartion of radioactive iodine, induces hypo thyroidism

  • pharmacotherapy:

    • thioamides or iodine can be used to suppress thyroid function

    • beta blockers are used to suppress sympathetic overstimulation

    • corticosteroids are used tin treatment resistant cases

Thioamides

• • • Preferred agent

methimazole (Tapazole®)

• • Only used in the 1st trimester of pregnancy

propylthiouracil (PTU)

Products

• • Antithyroid drugs are used to make people euthyroid (either long-term or before surgery)

Place in Therapy

• • Decrease the production of T3 and T4; PTU also inhibits peripheral conversion of T4 to T3

MOA

• • Rash, allergic reaction, or agranulocytosis

• Rare hepatotoxicity or nephrotoxicityPrecautions and Adverse Effects

Hypothyroidism

Possible causes:

• Mild hypothyroidism is common

• • Iodine deficit

• Hashimoto thyroiditis (an autoimmune disorder)

• • Surgical removal or treatment of gland, 131I treatment, drugs such as

lithium, amiodarone, and sulfonylureas

Iatrogenic

• Pituitary dysfunction

• Congenital

Signs and Symptoms of hypothyroidism

• Intolerance to cold

• • Weight gain with decreased appetite

Decreased metabolism

• Skin is pale and cool

• Bradycardia, enlarged heart

• Lethargic, slow CNS functioning

• Goiter (if cause is endemic iodine deficiency)

• SEVERE CASES: myxedema coma

• Facial puffiness and thick tongue (due to edema)

• Hypotension, hypoglycemia, hypothermia

Treatment of hypothyroidism

• The treatment goal is to normalize TSH

• • Levothyroxine (L-T4)

• Liothyronine (T3)

• Desiccated thyroidPharmacotherapy with thyroid hormones

Levothyroixine

• • levothyroxine (Eltroxin®, Synthroid®) (controversy regarding the interchangeability of synthroid and eltroxin, patients should be maintained on one brand through dose adjustments)

Products

• • Levothyroxine is the treatment of choice for hypothyroidism

Place in Therapy

• • Hormone replacement therapy

MOA

• Dosage adjustments are made at 6-week intervals (6 weeks to steady

state)

• • • “Either ALWAYS take it on an empty stomach (preferred), OR ALWAYS take it with food”

Food and drink CAN significantly change absorption so EMPTY STOMACH; BUT the

monograph also suggests CONSISTENCY WITH REGARDS TO MEALS

Absorption may be reduced by antacids, calcium salts, cholestyramine

(separate administration by 6 hours), colestipol, and iron salts

Kinetics and Dynamics

Precautions and Adverse Effects

• • Symptoms of hyperthyroidism if overtreated!

• Other disease conditions may vary when thyroid is regulated (e.g.

anticoagulation with warfarin, glycemic control with diabetes)

Lopthyroine (T3)

  • Cytomel / triiodothyronine

  • Place in therapy: Short term management of patients with thyroid cancer in preparation of treatments

  • Moa: hormone replacement therapy

  • • • • Not ideal in monotherapy

    Triiodothyronine (T3) is a very short-acting preparation

    • Absorption may be reduced by antacids, calcium salts,

    cholestyramine (separate administration by 6 h), and colestipol

    Kinetics and Dynamics

  • • • Symptoms of hyperthyroidism if overtreated!

    • Other disease conditions may vary when thyroid is regulated (e.g.

    anticoagulation with warfarin, glycemic control with diabetes)Precautions and Adverse Effects

Desiccated thyroid

  • products desiccated thyroid (thyroid)

  • PLace in therapy: Rarely used because LEVOTHYROXINE has more reliable dosing

  • MOA: hormone replacement therapy ,,, is derived from porcine thyroid glands and may not be acceptable for patients who are vegan or those who do not consume pork/pig

  • kinetics and dynamics: dosage adjustments are made at 4-6 week intervals, Absorption may be reduced by antacids, calcium salts,

    cholestyramine (separate administration by 6 h), and colestipol

  • Precautions and adverse effects: Symptoms of hyperthyroidism if overtreated!

    • Other disease conditions may vary when thyroid is regulated (e.g.

    anticoagulation with warfarin, glycemic control with diabetes)

Cushing Syndrome

  • Collection of signs and symptoms due to prolonged

    exposure to glucocorticoids (cortisol)

    • • Adrenal adenoma

    • Pituitary adenoma

    • Ectopic carcinoma

    • Iatrogenic conditions, such as large doses of glucocorticoids

    over time for inflammatory and other conditionsMany causes, including:

Signs and symptoms of cushing syndrome

  • Change in person’s appearance: • Truncal obesity and weight gain

    • Round face (moon face)

    • Fat pad between scapulae

    (buffalo hump)

    • Fragile, thin skin with striae

  • Retention of sodium and water

  • Hypertension and edema

    • Immune response suppression

    • Delayed healing

    • Cataracts and glaucoma

    • • Emotional lability and euphoria

    • Insomnia

    Mood disturbances

    • • Osteoporosis

    Increased catabolism of bone and

    protein

    • • Hyperglycemia

    Increased insulin resistance and

    possible glucose intolerance

these are also the adverse effects of systemic corticosteroids

Addision Disease

  • Deficiency of adrenocorticoid secretions usually caused by an autoimmune reaction

  • Sign and symptoms: Fatigue, decreased blood glucose levels, inadequate stress response, weight loss, frequent infections, low serum sodium concentration, decreased blood volume, hypotension, high potassium levels

Treatment of Addison Disease

  • Pharmacotherpay

  • glucocorticoid replacement (hydrocortisone, alternative = predinisolone)

  • Mineralocorticoid Replacement (fludrocortisone)

Glucocorticoids

  • Products

    • hydrocortisone (Cortef)

    • prednisone (generics)

  • Place in therapy

    • treatment with glucocorticoids and mineralocorticoids is critically necessary for patients with addison disease

  • MOA

    • replacement of adrenal cortex hormones

  • Kinetics and Dynamics

    • Hydrocortisone is taken po bid to tid

    • Prednisone is taken po once or twice daily

  • Precautions and Adverse Effects (as with cushing syndrome)

    • Change in person’s appearance (truncal obesity and weight gain, round face (moon face), fat pad between scapulae (buffalo hump), fragile/thin skin

      • Retention of sodium and water (hypertension and edema)

      • Immune response suppression

      • Delayed healing

      • Cataracts and glaucoma

      • Mood disturbances (emotional lability and euphoria, insomnia)

      • Increased catabolism of bone and protein (osteoporosis)

      • Increased insulin resistance and possible glucose intolerance (hyperglycemia)

Mineralocorticoids

  • Products

    • Fludrocortisone (florinef)

  • Place in therapy

    • treatment with glucocorticoids and mineralocorticoids is critically necessary for patients with addison disease

  • MOA

    • replacement of adrenal cortex hormones

  • Kinetics and Dynamics

    • fludrocortisone is taken po once daily

  • Precautions and Adverse Effects

    • Oral tabs are stored at 2-8 degrees celsius

    • KEEP IN THE DRIGE

    • adverse effects as with glucocorticoids, in addition to fluid and electrolyte disturbances

Diabetes Insipidus

  • Kidneys are unable to conserve water

  • Two Types

    • Central diabetes insipidus

      • Lack of antidiuretic hormone (ADH) from the pituitary

    • Nephrogenic Diabetes Insipidus

      • Failure of the kidneys to respond to ADH

      • Nephrogenic may be drug induced (Lithium or amphotericin B)

  • Signs and Symtoms (2)

    • excessive thirst

    • excessive urination

Treatment of diabetes insipidus

• • • Oral tablet, orally disintegrating tablet, and nasal spray

desmopressin (DDAVP®, generics)

Products

• • First-line treatment for central diabetes insipidus

Place in Therapy

• • Analogue of ADH; increases water resorption in the renal

tubules

MOA

• • • DISSOLVE TABLET UNDER THE TONGUE

Recommended dose is given tid sublingually

Kinetics and Dynamics

• • Headache, nausea, and abdominal pain

Precautions and Adverse Effects

• DDVAP® is

indicated for

nocturnal

enuresis

(bedwetting)

• MELTS are given 1

hour before

bedtime for up to

3 months