<img class="logo" alt="The University of Western Australia logo"/> THE UNIVERSITY OF **WESTERN** **AUSTRALIA** DENT 3005:Introduction to Pharmacology **Endocrine drugs: Diabetes** Dr Thuy Linh Truong thuy.truong@uwa.edu.au # **DENT 3005: Introduction to Pharmacology - Endocrine drugs: Diabetes** **Acknowledgement** of country The University of Western Australia acknowledges that its campus is situated on Noongar land, and that Noongar people remain the spiritual and cultural custodians of their land, and continue to practise their values, languages, beliefs and knowledge. **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** Artist: Dr Richard Barry Walley OAM **Learning Outcomes** **Learning objectives** 1) Understand the different types of diabetes 2) Identify and differentiate between major classes of drugs for diabetes 3) Recognise oral and dental side effects of these drugs 4) Understand drugs interactions with dental medications 5) Understand the impact of diabetes on oral health 6) Applied knowledge to clinical scenarios <img > Illustration of a medical chart for diabetes, a glucometer showing "5.5", an insulin pen, insulin vials, and a green apple. </img> # **Diabetes Mellitus** * **Diabetes mellitus: high blood glucose** * Different to diabetes insipidus * Insulin: hormone made by pancreas helps bring glucose into cells * Diabetic patients: not enough insulin or insulin not effective $\rightarrow$ glucose cannot reach the cells * Complications: eyes, kidneys, nerves, heart, cancer * **Types** * T1DM * T2DM * Insulin resistant * Gestational diabetes * Other # **Diabetes Mellitus** - **Diabetes mellitus: high blood glucose** - Different to diabetes insipidus - Insulin: hormone made by pancreas helps bring glucose into cells - Diabetic patients: not enough insulin or insulin not effective $\rightarrow$ glucose cannot reach the cells - Complications: eyes, kidneys, nerves, heart, cancer - **Types** - T1DM - T2DM - Insulin resistant - Gestational diabetes - Other **Classification of Diabetes** | Type 1 DM | Type 2 DM | Gestational | Other | | :--- | :--- | :--- | :--- | | - Autoimmune destruction of B-cells | - Insulin resistance & B-cell dysfunction | - During pregnancy in women who did not have DM | - Genetic defects of B-cell function | | - Young children & adults | - Pancreas loses ability to produce insulin | - Increase risks of mother & child developing T2DM later | - Genetic defect in insulin action | | - Life-long insulin therapy | - Obesity, physical inactivity, genetic | | - Disease of exocrine pancreas | | | | | - Endocrinopathies | | | | | - Many more | # **Classification of Diabetes** | Type 1 DM | Type 2 DM | Gestational | Other | | :--- | :--- | :--- | :--- | | - Autoimmune destruction of B-cells | - Insulin resistance & B-cell dysfunction | - During pregnancy in women who did not have DM | - Genetic defects of B-cell function | | - Young children & adults | - Pancreas loses ability to produce insulin | - Increase risks of mother & child developing T2DM later | - Genetic defect in insulin action | | - Life-long insulin therapy | - Obesity, physical inactivity, genetic | | - Disease of exocrine pancreas | | | | | - Endocrinopathies | | | | | - Many more | **Other types (Rare) (cont.)** * **Diseases of the Exocrine Pancreas** * Conditions that damage the pancreas – *pancreatitis, cystic fibrosis, hemochromatosis, pancreatic cancer* * Exocrine pancreas – responsible for producing digestive enzymes; damage to this part – impairs insulin production * **Endocrinopathies** * Hormonal disorders that affect endocrine system * E.g. *Cushing’s syndrome* (excess cortisol), *acromegaly* (excess growth hormone), *hyperthyroidism* * Cause insulin resistance – leading to hyperglycemia * **Drug/ Chemical-induced Diabetes** * Certain medications and chemicals can impair insulin secretion or action * E.g. *glucocorticoids* (used in the treatment of inflammation), *antipsychotics, immunosuppressants* – can cause hyperglycemia * *a-interferons* – used in the treatment of hepatitis, can lead to diabetes, in genetically predisposed individuals * **Infection-Related Diabetes** * Some infections damage the pancreas or lead to insulin resistance * E.g. *Rubella, cytomegalovirus* * **Uncommon forms of Immune-Mediated Diabetes** * Immune system attacks insulin or insulin-producing cells, different from Type-1 diabetes * E.g. stiff-man syndrome – antibodies attack insulin-producing cells in the pancreas * **Other Genetic syndromes associated with Diabetes** * Certain genetic syndromes have a higher incidence of diabetes due to associated insulin resistance or $\beta$-cell dysfunction * E.g. *Down syndrome, Turner syndrome, Klinefelters syndrome, Prader-Willi syndrome* * **Post-transplant Diabetes Mellitus (PTDM)** * Occur after organ transplantation – due to the use of immunosuppressive drugs like corticosteroids or calcineurin inhibitors * Cause insulin resistance or $\beta$-cell dysfunction ## **Other types (Rare) (cont.)** - **Diseases of the Exocrine Pancreas** - Conditions that damage the pancreas – *pancreatitis, cystic fibrosis, hemochromatosis, pancreatic cancer* - Exocrine pancreas – responsible for producing digestive enzymes; damage to this part – impairs insulin production - **Endocrinopathies** - Hormonal disorders that affect endocrine system - E.g. *Cushing’s syndrome* (excess cortisol), *acromegaly* (excess growth hormone), *hyperthyroidism* - Cause insulin resistance – leading to hyperglycemia - **Drug/ Chemical-induced Diabetes** - Certain medications and chemicals can impair insulin secretion or action - E.g. *glucocorticoids* (used in the treatment of inflammation), *antipsychotics, immunosuppressants* – can cause hyperglycemia - *a-interferons* – used in the treatment of hepatitis, can lead to diabetes, in genetically predisposed individuals - **Infection-Related Diabetes** - Some infections damage the pancreas or lead to insulin resistance - E.g. *Rubella, cytomegalovirus* - **Uncommon forms of Immune-Mediated Diabetes** - Immune system attacks insulin or insulin-producing cells, different from Type-1 diabetes - E.g. stiff-man syndrome – antibodies attack insulin-producing cells in the pancreas - **Other Genetic syndromes associated with Diabetes** - Certain genetic syndromes have a higher incidence of diabetes due to associated insulin resistance or $\beta$-cell dysfunction - E.g. *Down syndrome, Turner syndrome, Klinefelters syndrome, Prader-Willi syndrome* - **Post-transplant Diabetes Mellitus (PTDM)** - Occur after organ transplantation – due to the use of immunosuppressive drugs like corticosteroids or calcineurin inhibitors - Cause insulin resistance or $\beta$-cell dysfunction | Type 1 Diabetes Mellitus | Type 2 Diabetes Mellitus | | :--- | :--- | | **Autoimmune-mediated $\beta$-cell destruction** | No Autoimmune-mediated $\beta$-cell destruction; **Insulin resistance / Decline in Insulin production over time** | | **Autoantibodies like anti-GAD and Islet cell antibodies that attack pancreatic $\beta$-cells present** | **Autoantibodies absent** | | Genetic link | **Stronger genetic link** | | **Age of onset- younger** (children/adolescents/young adults) **than 25-30 years** | **Age of onset usually in adults over 40-45, but seen in younger people due to obesity** | | **Faster onset of symptoms & can be severe** – excessive thirst, frequent urination, unintended weight loss, fatigue | **Slower onset of symptoms & maybe less noticeable** | | **Lifelong insulin therapy** – as pancreas produce little to no insulin | **Diet control & oral hypoglycemic medications often sufficient for control,** Insulin therapy required if disease progresses | | **Patients often normal weight, or may experience weight loss before diagnosis** | **Most patients are overweight/obese** | | **High risk of diabetic ketoacidosis (DKA) – life threatening** | DKA is rare, but **hyperosmolar hyperglycemic state (HHS) can occur** | # **Comparison of Diabetes Types** | Type 1 Diabetes Mellitus | Type 2 Diabetes Mellitus | | :--- | :--- | | **Autoimmune-mediated $\beta$-cell destruction** | No Autoimmune-mediated $\beta$-cell destruction; **Insulin resistance / Decline in Insulin production over time** | | **Autoantibodies like anti-GAD and Islet cell antibodies that attack pancreatic $\beta$-cells present** | **Autoantibodies absent** | | Genetic link | **Stronger genetic link** | | **Age of onset- younger** (children/adolescents/young adults) **than 25-30 years** | **Age of onset usually in adults over 40-45, but seen in younger people due to obesity** | | **Faster onset of symptoms & can be severe** – excessive thirst, frequent urination, unintended weight loss, fatigue | **Slower onset of symptoms & maybe less noticeable** | | **Lifelong insulin therapy** – as pancreas produce little to no insulin | **Diet control & oral hypoglycemic medications often sufficient for control,** Insulin therapy required if disease progresses | | **Patients often normal weight, or may experience weight loss before diagnosis** | **Most patients are overweight/obese** | | **High risk of diabetic ketoacidosis (DKA) – life threatening** | DKA is rare, but **hyperosmolar hyperglycemic state (HHS) can occur** | ## Glucose metabolism pathway * The processes involved in the **utilization** and **regulation** of glucose * Glucose: primary source of energy for cells, regulated by hormones like insulin & glucagon * Stages * Digestion * Absorption * Glycolysis * Krebs cycle * Oxidative phosphorylation * Gluconeogenesis ## **Glucose metabolism pathway** - The processes involved in the **utilization** and **regulation** of glucose - Glucose: primary source of energy for cells, regulated by hormones like insulin & glucagon - Stages - Digestion - Absorption - Glycolysis - Krebs cycle - Oxidative phosphorylation - Gluconeogenesis **Insulin** * Proinsulin synthesized in the $\beta$-cells of the pancreas * consists of insulin peptide and C- peptide * In the $\beta$-cells, proinsulin is cleaved $\rightarrow$ active insulin and inactive C- peptide * Active insulin peptide released into the bloodstream to regulate blood glucose levels * Indication: Diabetes mellitus * **\*\*Not Diabetes insipidus** * Hypoglycaemia: most frequent & common serious adverse effect # **Insulin** - Proinsulin synthesized in the $\beta$-cells of the pancreas - consists of insulin peptide and C- peptide - In the $\beta$-cells, proinsulin is cleaved $\rightarrow$ active insulin and inactive C- peptide - Active insulin peptide released into the bloodstream to regulate blood glucose levels - Indication: Diabetes mellitus - **\*\*Not Diabetes insipidus** - Hypoglycaemia: most frequent & common serious adverse effect **RAPID-ACTING INSULIN** Onset **~5 minutes** Duration **4–5 hours** * **NOVORAPID®** * **HUMALOG®** * **APIDRA®** * **FIASP®** Ultra-rapid acting, can be given just after meal **SHORT-ACTING INSULIN** Onset **30 minutes** Duration **Up to 6 hours** * **ACTRAPID®** * **HUMULIN R®** **LONG-ACTING INSULIN** Onset **2–4 hours** Duration **~24 hours** (longer for Toujeo) * **TOUJEO®** * **OPTISULIN®** **PREMIX INSULIN (HUMAN)** Onset **30 minutes** Duration **10–16 hours** * **MIXTARD 30®** * **MIXTARD 50®** **PREMIX INSULIN (ANALOGUE)** Onset **5–15 minutes** Duration **10–16 hours** * **NOVOMIX30®** * **HUMALOG MIX 25®** * **HUMALOG MIX 50®** * **RYZODEG 70®** (degludec lasts >24 hours) Infusion set Continuous Glucose Monitor Insulin pump A graph illustrating the typical rapid-acting insulin profile, followed by images of insulin pens. A graph illustrating the typical short-acting insulin profile, followed by images of insulin pens. A graph illustrating the typical long-acting insulin profile, followed by images of insulin pens. A graph illustrating the typical premix insulin (human) profile, followed by images of insulin vials and pens. A graph illustrating the typical premix insulin (analogue) profile, followed by images of insulin pens. An illustration of an insulin pump and continuous glucose monitor setup on a person's abdomen. # **Types of Insulin** ### **RAPID-ACTING INSULIN** - Onset **~5 minutes** - Duration **4–5 hours** - **NOVORAPID®** - **HUMALOG®** - **APIDRA®** - **FIASP®** - Ultra-rapid acting, can be given just after meal ### **SHORT-ACTING INSULIN** - Onset **30 minutes** - Duration **Up to 6 hours** - **ACTRAPID®** - **HUMULIN R®** ### **LONG-ACTING INSULIN** - Onset **2–4 hours** - Duration **~24 hours** (longer for Toujeo) - **TOUJEO®** - **OPTISULIN®** ### **PREMIX INSULIN (HUMAN)** - Onset **30 minutes** - Duration **10–16 hours** - **MIXTARD 30®** - **MIXTARD 50®** ### **PREMIX INSULIN (ANALOGUE)** - Onset **5–15 minutes** - Duration **10–16 hours** - **NOVOMIX30®** - **HUMALOG MIX 25®** - **HUMALOG MIX 50®** - **RYZODEG 70®** (degludec lasts >24 hours) **Delivery Systems** - Infusion set - Continuous Glucose Monitor - Insulin pump <table> <thead> <tr> <th> Insulin type **(brand®)** </th> <th> Activity¹ </th> <th> Comments </th> </tr> </thead> <tbody> <tr> <td colspan="3">Ultra-short-acting (analogues)</td> </tr> <tr> <td>faster-acting insulin aspart (Fiasp)</td> <td><ul> <li>onset: 5–15 minutes</li> <li>peak: 0.5–1.5 hours</li> <li>duration: 3–5 hours</li> </ul></td> <td><ul> <li>give at start of meal, or up to 20 minutes after starting it</li> <li>clear solution</li> <li>do not mix with other insulins; inject separately</li> <li>compared to standard insulin aspart: <ul> <li>marginally faster time to effect (but unclear if this is clinically meaningful)</li> <li>may increase infusion site reactions and need for non-routine change of infusion pump</li> </ul></li> </ul></td> </tr> <tr> <td>insulin aspart (NovoRapid)</td> <td><ul> <li>onset: 10–15 minutes</li> <li>peak: 1–1.5 hours</li> <li>duration: 3–5 hours</li> </ul></td> <td><ul> <li>give immediately before meals</li> <li>clear solution</li> </ul></td> </tr> <tr> <td>insulin lispro² (Humalog)</td> <td></td> <td></td> </tr> <tr> <td>insulin glulisine (Apidra)</td> <td></td> <td></td> </tr> </tbody> </table> # **Insulin Profiles** <table> <thead> <tr> <th> Insulin type <strong>(brand®)</strong> </th> <th> Activity¹ </th> <th> Comments </th> </tr> </thead> <tbody> <tr> <td colspan="3"><strong>Ultra-short-acting (analogues)</strong></td> </tr> <tr> <td>faster-acting insulin aspart (Fiasp)</td> <td><ul> <li>onset: 5–15 minutes</li> <li>peak: 0.5–1.5 hours</li> <li>duration: 3–5 hours</li> </ul></td> <td><ul> <li>give at start of meal, or up to 20 minutes after starting it</li> <li>clear solution</li> <li>do not mix with other insulins; inject separately</li> <li>compared to standard insulin aspart: <ul> <li>marginally faster time to effect (but unclear if this is clinically meaningful)</li> <li>may increase infusion site reactions and need for non-routine change of infusion pump</li> </ul></li> </ul></td> </tr> <tr> <td>insulin aspart (NovoRapid)</td> <td><ul> <li>onset: 10–15 minutes</li> <li>peak: 1–1.5 hours</li> <li>duration: 3–5 hours</li> </ul></td> <td><ul> <li>give immediately before meals</li> <li>clear solution</li> </ul></td> </tr> <tr> <td>insulin lispro² (Humalog)</td> <td></td> <td></td> </tr> <tr> <td>insulin glulisine (Apidra)</td> <td></td> <td></td> </tr> </tbody> </table> <p>The following table provides information about different types of insulin, categorized by their action profiles.</p> <table> <thead> <tr> <th></th> <th></th> <th></th> </tr> </thead> <tbody> <tr> <td colspan="3"><strong>Short-acting</strong></td> </tr> <tr> <td>neutral insulin³ (Actrapid, Humulin R)</td> <td><ul><li>onset: 30 minutes</li><li>peak: 2–3 hours</li><li>duration: 6–8 hours</li></ul></td> <td><ul><li>give within 30 minutes before meal</li><li>soluble insulin</li><li>clear solution</li></ul></td> </tr> <tr> <td colspan="3"><strong>Long-acting</strong></td> </tr> <tr> <td>isophane insulin (Humulin NPH, Protapnane)</td> <td><ul><li>onset: 1–2.5 hours</li><li>peak: 4–12 hours</li><li>duration: 16–24 hours</li></ul></td> <td><ul><li>also known as intermediate-acting insulins</li><li>give once or twice daily</li><li>cloudy solution</li></ul></td> </tr> <tr> <td colspan="3"><strong>Long-acting (analogues)</strong></td> </tr> <tr> <td>insulin detemir (Levemir)</td> <td><ul><li>onset: 1–2 hours</li><li>peak: 6–8 hours</li><li>duration: 12–24 hours</li></ul></td> <td><ul><li>give once or, more commonly, twice daily (effect often wears off before 24 hours)</li><li>clear solution</li><li>do not mix with other insulins; inject separately</li></ul></td> </tr> <tr> <td>insulin glargine 100 units/mL (Optisulin), 300 units/mL (Toujeo)</td> <td><ul><li>onset: 1–2 hours (100 units/mL); 1–6 hours (300 units/mL)</li><li>no peak</li><li>duration: 24 hours (100 units/mL); 24–36 hours (300 units/mL)</li></ul></td> <td><ul><li>give once daily</li><li>provides a constant basal insulin level</li><li>do not mix with other insulins; inject separately</li><li>clear solution</li><li>the 2 strengths are not directly interchangeable</li></ul></td> </tr> </tbody> </table> <table> <thead> <tr> <th> Insulin type <strong>(brand®)</strong> </th> <th> Activity¹ </th> <th> Comments </th> </tr> </thead> <tbody> <tr> <td colspan="3"><strong>Short-acting</strong></td> </tr> <tr> <td>neutral insulin³ (Actrapid, Humulin R)</td> <td><ul><li>onset: 30 minutes</li><li>peak: 2–3 hours</li><li>duration: 6–8 hours</li></ul></td> <td><ul><li>give within 30 minutes before meal</li><li>soluble insulin</li><li>clear solution</li></ul></td> </tr> <tr> <td colspan="3"><strong>Long-acting</strong></td> </tr> <tr> <td>isophane insulin (Humulin NPH, Protapnane)</td> <td><ul><li>onset: 1–2.5 hours</li><li>peak: 4–12 hours</li><li>duration: 16–24 hours</li></ul></td> <td><ul><li>also known as intermediate-acting insulins</li><li>give once or twice daily</li><li>cloudy solution</li></ul></td> </tr> <tr> <td colspan="3"><strong>Long-acting (analogues)</strong></td> </tr> <tr> <td>insulin detemir (Levemir)</td> <td><ul><li>onset: 1–2 hours</li><li>peak: 6–8 hours</li><li>duration: 12–24 hours</li></ul></td> <td><ul><li>give once or, more commonly, twice daily (effect often wears off before 24 hours)</li><li>clear solution</li><li>do not mix with other insulins; inject separately</li></ul></td> </tr> <tr> <td>insulin glargine 100 units/mL (Optisulin), 300 units/mL (Toujeo)</td> <td><ul><li>onset: 1–2 hours (100 units/mL); 1–6 hours (300 units/mL)</li><li>no peak</li><li>duration: 24 hours (100 units/mL); 24–36 hours (300 units/mL)</li></ul></td> <td><ul><li>give once daily</li><li>provides a constant basal insulin level</li><li>do not mix with other insulins; inject separately</li><li>clear solution</li><li>the 2 strengths are not directly interchangeable</li></ul></td> </tr> </tbody> </table> | **Mixed (short-acting with long-acting)** | | | | :--- | :--- | :--- | | neutral insulin with isophane (Humulin 30/70) | • onset: 0.5–1 hours • peak: 2–12 hours • duration: 16–24 hours | • give within 30 minutes before meal(s) • also known as biphasic insulins • give once or twice daily • cloudy solution | | **Mixed, analogues (ultra-short-acting with long-acting)** | | | | insulin aspart with aspart protamine (NovoMix 30) | • onset: 10–15 minutes • peak: 1 hour • duration: 16–18 hours | • also known as biphasic insulins • give once or twice daily • give immediately before meal(s) • cloudy solution | | insulin lispro with lispro protamine (Humalog Mix25, Humalog Mix50) | | | | insulin aspart with degludec (Ryzodeg)$^4$ | • onset: 10–15 minutes • peak: 1.25 hours • duration: >24 hours | • also known as biphasic insulin • give once or twice daily • give immediately before largest carbohydrate meal(s) • clear solution • degludec is an ultra-long acting insulin: | | | | ∘ it provides a constant basal insulin level ∘ its glucose-lowering effect persists longer than that of insulin glargine | <table> <thead> <tr> <th> Insulin type <strong>(brand®)</strong> </th> <th> Activity¹ </th> <th> Comments </th> </tr> </thead> <tbody> <tr> <td colspan="3"><strong>Mixed (short-acting with long-acting)</strong></td> </tr> <tr> <td>neutral insulin with isophane (Humulin 30/70)</td> <td><ul><li>onset: 0.5–1 hours</li><li>peak: 2–12 hours</li><li>duration: 16–24 hours</li></ul></td> <td><ul><li>give within 30 minutes before meal(s)</li><li>also known as biphasic insulins</li><li>give once or twice daily</li><li>cloudy solution</li></ul></td> </tr> <tr> <td colspan="3"><strong>Mixed, analogues (ultra-short-acting with long-acting)</strong></td> </tr> <tr> <td>insulin aspart with aspart protamine (NovoMix 30)</td> <td><ul><li>onset: 10–15 minutes</li><li>peak: 1 hour</li><li>duration: 16–18 hours</li></ul></td> <td><ul><li>also known as biphasic insulins</li><li>give once or twice daily</li><li>give immediately before meal(s)</li><li>cloudy solution</li></ul></td> </tr> <tr> <td>insulin lispro with lispro protamine (Humalog Mix25, Humalog Mix50)</td> <td></td> <td></td> </tr> <tr> <td>insulin aspart with degludec (Ryzodeg)⁴</td> <td><ul><li>onset: 10–15 minutes</li><li>peak: 1.25 hours</li><li>duration: >24 hours</li></ul></td> <td><ul><li>also known as biphasic insulin</li><li>give once or twice daily</li><li>give immediately before largest carbohydrate meal(s)</li><li>clear solution</li><li>degludec is an ultra-long acting insulin: <ul><li>it provides a constant basal insulin level</li><li>its glucose-lowering effect persists longer than that of insulin glargine</li></ul></li></ul></td> </tr> </tbody> </table> # Metformin * First line * **MOA**: Reduces hepatic glucose production; increases peripheral utilisation of glucose * **ADR**: taste disturbance * No weight gain ☺ | Generic name | Brand Name | |---|---| | Metformin IR | Diabex, Diaformin, Metex | | Metformin MR | Diabex XR, Diaformin XR, Metex XR | **Metformin combinations** Alogliptin with metformin Dapagliflozin with metformin Empagliflozin with metformin Linagliptin with metformin Metformin with glibenclamide Saxagliptin with metformin Sitagliptin with metformin Vildagliptin with metformin # **Metformin** - First line - **MOA**: Reduces hepatic glucose production; increases peripheral utilisation of glucose - **ADR**: taste disturbance - No weight gain ☺ | Generic name | Brand Name | |---|---| | Metformin IR | Diabex, Diaformin, Metex | | Metformin MR | Diabex XR, Diaformin XR, Metex XR | ## **Metformin combinations** - Alogliptin with metformin - Dapagliflozin with metformin - Empagliflozin with metformin - Linagliptin with metformin - Metformin with glibenclamide - Saxagliptin with metformin - Sitagliptin with metformin - Vildagliptin with metformin # Sulfonylureas * MOA: Increase pancreatic insulin secretion * ADR: hypoglycaemia, weight gain * Taste alteration (metallic) # Dipeptidyl peptidase 4 inhibitors * Inhibit dipeptidyl peptidase-4 (DPP-4) * ADR: headache, musculoskeletal pain * Hypoglycemia: combination w/ insulin or sulfonylurea <table id="table-1"> <thead> <tr> <td style="text-align: left"><b>Generic name</b></td> <td style="text-align: left"><b>Brand Name</b></td> </tr> </thead> <tbody> <tr> <td style="text-align: left">Glibenclamide</td> <td style="text-align: left">Daonil</td> </tr> <tr> <td style="text-align: left">Gliclazide</td> <td style="text-align: left">Diamicron</td> </tr> <tr> <td style="text-align: left">Glimepiride</td> <td style="text-align: left">Glimepiride</td> </tr> <tr> <td style="text-align: left">Glipizide</td> <td style="text-align: left">Minidiab</td> </tr> </tbody> </table> **Dipeptidyl peptidase-4 inhibitors** * <u>Alogliptin</u> * <u>Alogliptin with metformin</u> * <u>Linagliptin</u> * <u>Linagliptin with metformin</u> * <u>Saxagliptin</u> * <u>Saxagliptin with dapagliflozin</u> * <u>Saxagliptin with metformin</u> * <u>Sitagliptin</u> * <u>Sitagliptin with metformin</u> * <u>Vildagliptin</u> * <u>Vildagliptin with metformin</u> # **Sulfonylureas** - **MOA**: Increase pancreatic insulin secretion - **ADR**: hypoglycaemia, weight gain - Taste alteration (metallic) | **Generic name** | **Brand Name** | | :--- | :--- | | Glibenclamide | Daonil | | Gliclazide | Diamicron | | Glimepiride | Glimepiride | | Glipizide | Minidiab | # **Dipeptidyl peptidase 4 inhibitors** - Inhibit dipeptidyl peptidase-4 (DPP-4) - **ADR**: headache, musculoskeletal pain - Hypoglycemia: combination w/ insulin or sulfonylurea - **Drugs** - <u>Alogliptin</u> - <u>Alogliptin with metformin</u> - <u>Linagliptin</u> - <u>Linagliptin with metformin</u> - <u>Saxagliptin</u> - <u>Saxagliptin with dapagliflozin</u> - <u>Saxagliptin with metformin</u> - <u>Sitagliptin</u> - <u>Sitagliptin with metformin</u> - <u>Vildagliptin</u> - <u>Vildagliptin with metformin</u> **Glucagon like peptide 1 analogues** * Analogues of glucagon-like peptide-1 (an incretin) * ADR: gastrointestinal sx, hypoglycaemia (+SU/insulin) | **Generic name** | **Brand Name** | | :--- | :--- | | Dulaglutide | Trulicity | | Liraglutide | Saxenda | | Semaglutide | Ozempic | **Sodium-glucose co-transporter 2 inhibitors** * Inhibit sodium-glucose co-transporter 2, reducing glucose reabsorption in the kidney (and increasing its excretion in the urine) * ADR: genital infections, polyuria, dysuria, UTI, dyslipidaemia, hypoglycaemia (+SU/insulin) | **Generic name** | **Brand Name** | | :--- | :--- | | Dapaglifozin +metformin | Forxiga Xigduo | | Empaglifozin +linagliptin +metformin | Jardiance Glyxambi Jardiamet | # **Glucagon like peptide 1 analogues** - Analogues of glucagon-like peptide-1 (an incretin) - **ADR**: gastrointestinal sx, hypoglycaemia (+SU/insulin) | **Generic name** | **Brand Name** | | :--- | :--- | | Dulaglutide | Trulicity | | Liraglutide | Saxenda | | Semaglutide | Ozempic | # **Sodium-glucose co-transporter 2 inhibitors** - Inhibit sodium-glucose co-transporter 2, reducing glucose reabsorption in the kidney (and increasing its excretion in the urine) - **ADR**: genital infections, polyuria, dysuria, UTI, dyslipidaemia, hypoglycaemia (+SU/insulin) | **Generic name** | **Brand Name** | | :--- | :--- | | Dapaglifozin +metformin | Forxiga Xigduo | | Empaglifozin +linagliptin +metformin | Jardiance Glyxambi Jardiamet | ## Other drugs for diabetes * **Acarbose** * Inhibiting alpha-glucosidase enzymes in the small intestine * ADR: flatulence, diarrhoea, abdominal pain and distension * **Pioglitazone** * Agonist of peroxisome proliferator-activated receptor gamma * ADR: peripheral oedema, weight gain, headache, dizziness +++ * **Tirzepatide** * Agonist at glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors * ADR: gastrointestinal sx, hypoglycaemia (+SU/insulin) <br> **Other drugs for diabetes** *Acarbose* *Insulins* *Metformin* *Metformin with glibenclamide* *Pioglitazone* *Tirzepatide* ## **Other drugs for diabetes** - **Acarbose** - Inhibiting alpha-glucosidase enzymes in the small intestine - ADR: flatulence, diarrhoea, abdominal pain and distension - **Pioglitazone** - Agonist of peroxisome proliferator-activated receptor gamma - ADR: peripheral oedema, weight gain, headache, dizziness +++ - **Tirzepatide** - Agonist at glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors - ADR: gastrointestinal sx, hypoglycaemia (+SU/insulin) ### **Drug List Summary** - *Acarbose* - *Insulins* - *Metformin* - *Metformin with glibenclamide* - *Pioglitazone* - *Tirzepatide* **Figure 13.49** Management of hypoglycaemia in dental practice **If the patient is conscious and cooperative:** * Stop dental treatment. * Give glucose if available: * adult: 15 g * child 5 years or younger, or up to 25 kg: 5 g * child 6 years or older, or more than 25 kg: 10 g * If glucose is not available, give a fast-acting glucose-containing food or drink [NB1]. * If after 15 minutes the blood glucose concentration has not returned to normal or the symptoms have not improved, repeat the dose of glucose. * If three or more portions of glucose are needed to restore the blood glucose concentration to normal, seek medical advice. * If symptoms have improved, the patient should eat a longer-acting carbohydrate (eg sandwich, dried fruit, yoghurt) to prevent recurrence of hypoglycaemia. * Keep the patient under observation until recovered. Do not allow them to drive home. Strongly advise medical review. **If the patient is drowsy, uncooperative or unconscious:** * Stop dental treatment. * Call 000. * If the patient is unconscious, start basic life support (for ‘Basic life support flow chart’, see **Figure 13.43**). NB1: Examples of food and drink containing 15 g of glucose include: 15 g of easily absorbed carbohydrate (eg 6 to 7 regular glucose jelly beans, 4 large glucose jelly beans); three teaspoons of sugar or honey; 125 mL of fruit juice (approximately one glass or a small popper or box); 150 mL of soft drink (not ‘diet’); 100 mL of oral glucose solution (eg Lucozade). # **Management of hypoglycaemia in dental practice** (Figure 13.49) ### **If the patient is conscious and cooperative:** - Stop dental treatment. - Give glucose if available: - adult: 15 g - child 5 years or younger, or up to 25 kg: 5 g - child 6 years or older, or more than 25 kg: 10 g - If glucose is not available, give a fast-acting glucose-containing food or drink [NB1]. - If after 15 minutes the blood glucose concentration has not returned to normal or the symptoms have not improved, repeat the dose of glucose. - If three or more portions of glucose are needed to restore the blood glucose concentration to normal, seek medical advice. - If symptoms have improved, the patient should eat a longer-acting carbohydrate (eg sandwich, dried fruit, yoghurt) to prevent recurrence of hypoglycaemia. - Keep the patient under observation until recovered. Do not allow them to drive home. Strongly advise medical review. ### **If the patient is drowsy, uncooperative or unconscious:** - Stop dental treatment. - Call 000. - If the patient is unconscious, start basic life support (for ‘Basic life support flow chart’, see **Figure 13.43**). **NB1:** Examples of food and drink containing 15 g of glucose include: 15 g of easily absorbed carbohydrate (eg 6 to 7 regular glucose jelly beans, 4 large glucose jelly beans); three teaspoons of sugar or honey; 125 mL of fruit juice (approximately one glass or a small popper or box); 150 mL of soft drink (not ‘diet’); 100 mL of oral glucose solution (eg Lucozade). # **Diabetes Dental implications** * Drug implications: not many * Hypoglycemic effects: learn management * Taste disturbance * Lowered resistance to infections * Routine dental visits * Oral manifestations * Periodontal disease * Tooth decay * Oral candidiasis * Taste disturbances * Xerostomia * Patient's considerations * Blood glucose control * Hypoglycemia # **Diabetes Dental implications** - **Drug implications**: not many - Hypoglycemic effects: learn management - Taste disturbance - **Lowered resistance to infections** - **Routine dental visits** - **Oral manifestations** - Periodontal disease - Tooth decay - Oral candidiasis - Taste disturbances - Xerostomia - **Patient's considerations** - Blood glucose control - Hypoglycemia DENT 5003:Introduction to Pharmacology **Endocrine drugs: Thyroid disorders** Dr Thuy Linh Truong thuy.truong@uwa.edu.au The University of Western Australia Logo # **DENT 5003: Introduction to Pharmacology - Endocrine drugs: Thyroid disorders** **Dr Thuy Linh Truong** thuy.truong@uwa.edu.au **Learning Outcomes** **Learning objectives** 1) Broad understanding of the pituitary gland 2) Broad understanding of thyroid disorders 3) Understand implications of thyroid disorder in the dental setting 4) Identify drugs used for thyroid disorders and recognise oral and dental side effects of these drugs 5) Understand drugs interactions with dental medications 6) Applied knowledge to clinical scenarios Cartoon image of a thyroid gland and a capsule holding hands. # **Learning Outcomes** ## **Learning objectives** 1) Broad understanding of the pituitary gland 2) Broad understanding of thyroid disorders 3) Understand implications of thyroid disorder in the dental setting 4) Identify drugs used for thyroid disorders and recognise oral and dental side effects of these drugs 5) Understand drugs interactions with dental medications 6) Applied knowledge to clinical scenarios **The pituitary gland** * RECAP $\rightarrow$ A major endocrine gland! * Produces a wide variety or hormones that travels to regulate other glands $\&$ organs in the body * Anterior lobe: GH, ACTH, TSH, FSH, LH * Posterior lobe: ADH, oxytocin **The thyroid gland** * Regulates key metabolic processes * Produces two main hormones * **Triiodothyronine (T3)** * **Thyroxine (T4)** * Controlled by **Thyroid-Stimulating Hormone (TSH)** from the anterior pituitary gland! * Proper thyroid function is crucial for metabolic balance and overall health A diagram illustrating the pituitary gland, its connection to the brain, and the hormones it secretes to regulate other glands and organs in the body (Mammary glands, Gonads, Thyroid gland, Adrenal gland, Bones/Muscles/Adipose Tissue) is shown to the right, along with a detailed illustration of the thyroid gland in the neck region, including front and back views with labeled structures: Right lobe, Left lobe, Isthmus, and Parathyroid glands (on the back view). mermaid graph LR A[Brain] --> B(Pituitary Gland) B -->|PRL| C[Mammary glands] B -->|GH| D[Bones, Muscles, Adipose tissue] B -->|ACTH| E[Adrenal gland] B -->|TSH| F[Thyroid gland] B -->|FSH & LH| G[Gonads] # **Anatomy and Physiology** ## **The pituitary gland** - RECAP $\rightarrow$ A major endocrine gland! - Produces a wide variety or hormones that travels to regulate other glands & organs in the body - **Anterior lobe**: GH, ACTH, TSH, FSH, LH - **Posterior lobe**: ADH, oxytocin ## **The thyroid gland** - Regulates key metabolic processes - Produces two main hormones - **Triiodothyronine (T3)** - **Thyroxine (T4)** - Controlled by **Thyroid-Stimulating Hormone (TSH)** from the anterior pituitary gland! - Proper thyroid function is crucial for metabolic balance and overall health A diagram illustrating the pituitary gland, its connection to the brain, and the hormones it secretes to regulate other glands and organs in the body (Mammary glands, Gonads, Thyroid gland, Adrenal gland, Bones/Muscles/Adipose Tissue) is shown to the right, along with a detailed illustration of the thyroid gland in the neck region, including front and back views with labeled structures: Right lobe, Left lobe, Isthmus, and Parathyroid glands (on the back view). ```mermaid graph LR A[Brain] --> B(Pituitary Gland) B -->|PRL| C[Mammary glands] B -->|GH| D[Bones, Muscles, Adipose tissue] B -->|ACTH| E[Adrenal gland] B -->|TSH| F[Thyroid gland] B -->|FSH & LH| G[Gonads] ``` ## Thyroid disorders * Thyroid disorders can be overactive (hyperthyroidism) or underactive (hypothyroidism) * TSH elevation $\rightarrow$ hypothyroidism * Rationale for treatment: relieve sx, restore & maintain euthyroid state * Hypothyroidism: maintain normal growth & intellectual development in children | | **Hypothyroidism** | **Hyperthyroidism** | | :--- | :--- | :--- | | **Drug Therapy** | Thyroid hormones (Levothyroxine, liothyronine) | Antithyroid drugs | | | | Levothyroxine | | | | Iodine | | | | Beta blockers: short term sx relief | ## **Thyroid disorders** - Thyroid disorders can be overactive (hyperthyroidism) or underactive (hypothyroidism) - TSH elevation $\rightarrow$ hypothyroidism - Rationale for treatment: relieve sx, restore & maintain euthyroid state - Hypothyroidism: maintain normal growth & intellectual development in children | | **Hypothyroidism** | **Hyperthyroidism** | | :--- | :--- | :--- | | **Drug Therapy** | Thyroid hormones (Levothyroxine, liothyronine) | Antithyroid drugs | | | | Levothyroxine | | | | Iodine | | | | Beta blockers: short term sx relief | <table> <thead> <tr> <td style="text-align: left;"></td> <td style="text-align: left;">**Hypothyroidism**</td> <td style="text-align: left;">**Hyperthyroidism**</td> </tr> </thead> <tbody> <tr> <td style="text-align: left;">**Symptoms**</td> <td style="text-align: left;"><ul><li>Tiredness and low energy levels</li><li>Weight gain</li><li>Constipation</li><li>Dry, coarse skin</li><li>Puffy face</li><li>Hair loss</li><li>Slowed heart rate</li><li>Muscle aches and weakness</li><li>Depression</li><li>Problems with concentration</li><li>Intolerance to cold</li></ul></td> <td style="text-align: left;"><ul><li>Rapid or irregular heartbeat</li><li>Unexplained weight loss</li><li>Increased appetite</li><li>Anxiety and irritability</li><li>Sleep problems</li><li>Sweating</li><li>Fine, brittle hair</li><li>Diarrhea</li><li>Sensitivity to heat</li><li>Weak/less frequent menstrual period</li></ul></td> </tr> <tr> <td style="text-align: left;">**Causes**</td> <td style="text-align: left;"><ul><li>The immune system attacking the thyroid gland</li><li>Damage to the thyroid during treatment for an overactive thyroid or thyroid cancer</li></ul></td> <td style="text-align: left;"><ul><li>Graves' disease</li><li>Toxic nodular goitre</li><li>Thyroiditis</li><li>Post-partum thyroiditis</li><li>Taking too much thyroid medicine</li><li>Having too much iodine in your system</li></ul></td> </tr> </tbody> </table> ## **Comparison of Thyroid Disorders** <table> <thead> <tr> <td style="text-align: left;"></td> <td style="text-align: left;"><strong>Hypothyroidism</strong></td> <td style="text-align: left;"><strong>Hyperthyroidism</strong></td> </tr> </thead> <tbody> <tr> <td style="text-align: left;"><strong>Symptoms</strong></td> <td style="text-align: left;"><ul><li>Tiredness and low energy levels</li><li>Weight gain</li><li>Constipation</li><li>Dry, coarse skin</li><li>Puffy face</li><li>Hair loss</li><li>Slowed heart rate</li><li>Muscle aches and weakness</li><li>Depression</li><li>Problems with concentration</li><li>Intolerance to cold</li></ul></td> <td style="text-align: left;"><ul><li>Rapid or irregular heartbeat</li><li>Unexplained weight loss</li><li>Increased appetite</li><li>Anxiety and irritability</li><li>Sleep problems</li><li>Sweating</li><li>Fine, brittle hair</li><li>Diarrhea</li><li>Sensitivity to heat</li><li>Weak/less frequent menstrual period</li></ul></td> </tr> <tr> <td style="text-align: left;"><strong>Causes</strong></td> <td style="text-align: left;"><ul><li>The immune system attacking the thyroid gland</li><li>Damage to the thyroid during treatment for an overactive thyroid or thyroid cancer</li></ul></td> <td style="text-align: left;"><ul><li>Graves' disease</li><li>Toxic nodular goitre</li><li>Thyroiditis</li><li>Post-partum thyroiditis</li><li>Taking too much thyroid medicine</li><li>Having too much iodine in your system</li></ul></td> </tr> </tbody> </table> # Drugs for thyroid disorders * **Thyroid hormones** * Levothyroxine T4: hypothyroidism, block-replacement regimen in hyperthyroidism * Liothyronine: severe hypothyroidism * **Anti-thyroid drugs**: block thyroid hormone synthesis * Carbimazole * Propylthiouracil: inH T4$\rightarrow$T3 conversion * **Iodine** * Transiently inhibits thyroid hormone release * Indication: short-term use before surgery for graves disease | Generic name | Brand Name | | :--- | :--- | | **Levothyroxine** | Eutroxisg, Thyroxine, Oroxine | | **Liothyronine** | Tertroxin | | **Carbimazole** | Neo-mercazole, Thirazol | | **Propylthiouracil** | PTU | | **Iodine** | Iodine sol aq | # **Drugs for thyroid disorders** - **Thyroid hormones** - Levothyroxine T4: hypothyroidism, block-replacement regimen in hyperthyroidism - Liothyronine: severe hypothyroidism - **Anti-thyroid drugs**: block thyroid hormone synthesis - Carbimazole - Propylthiouracil: inH T4$\rightarrow$T3 conversion - **Iodine** - Transiently inhibits thyroid hormone release - Indication: short-term use before surgery for graves disease | Generic name | Brand Name | | :--- | :--- | | **Levothyroxine** | Eutroxisg, Thyroxine, Oroxine | | **Liothyronine** | Tertroxin | | **Carbimazole** | Neo-mercazole, Thirazol | | **Propylthiouracil** | PTU | | **Iodine** | Iodine sol aq | **Thyroid drugs** **Dental** **implications** * Levothyroxine & Liothyronine * ADR associated w/ excessive dosages, corresponds to sx of hyperthyroidism * Manage accordingly # **Thyroid drugs: Dental implications** - **Levothyroxine & Liothyronine** - ADR associated w/ excessive dosages, corresponds to sx of hyperthyroidism - Manage accordingly **Thyroid disorder** **Dental implications** * Hypothyroidism * Affects younger population * Delayed eruption of primary and permanent teeth * Malocclusion (misalignment of teeth) * Skeletal growth retardation * Tongue enlargement (**macroglossia**) and scalloping * Hyperthyroidism * **Osteoporosis of the alveolar bone** $\rightarrow$ tooth mobility, complications with extractions, increased risk of periodontal disease * Higher incidence of **dental caries** and **periodontal disease** * Accelerated **development of jaws and teeth** in children * **Early eruption of permanent teeth** / **Early loss of deciduous teeth** * Gingival changes: **inflammation, enlargement, tenderness** # **Thyroid disorder: Dental implications** - **Hypothyroidism** - Affects younger population - Delayed eruption of primary and permanent teeth - Malocclusion (misalignment of teeth) - Skeletal growth retardation - Tongue enlargement (**macroglossia**) and scalloping - **Hyperthyroidism** - **Osteoporosis of the alveolar bone** $\rightarrow$ tooth mobility, complications with extractions, increased risk of periodontal disease - Higher incidence of **dental caries** and **periodontal disease** - Accelerated **development of jaws and teeth** in children - **Early eruption of permanent teeth** / **Early loss of deciduous teeth** - Gingival changes: **inflammation, enlargement, tenderness** THE UNIVERSITY OF WESTERN AUSTRALIA DENT 3005:Introduction to Pharmacology **Endocrine drugs: Adrenal** **insufficiency** Dr Thuy Linh Truong thuy.truong@uwa.edu.au # **DENT 3005: Introduction to Pharmacology - Endocrine drugs: Adrenal insufficiency** **Dr Thuy Linh Truong** thuy.truong@uwa.edu.au **Learning Outcomes** **Learning objectives** 1) Broad understanding of the pituitary gland $\odot$ 2) Broad understanding of adrenal insufficiency 3) Identify drugs used for adrenal insufficiency and recognise oral and dental side effects of these drugs 4) Understand drugs interactions with dental medications 5) Broad understanding of other endocrine drugs 6) Applied knowledge to clinical scenarios <img src="ADRENAL CRISIS cartoon of two adrenal glands standing upright and smiling" /> # **Learning Outcomes** ## **Learning objectives** 1) Broad understanding of the pituitary gland $\odot$ 2) Broad understanding of adrenal insufficiency 3) Identify drugs used for adrenal insufficiency and recognise oral and dental side effects of these drugs 4) Understand drugs interactions with dental medications 5) Broad understanding of other endocrine drugs 6) Applied knowledge to clinical scenarios **The pituitary Gland** * A teenie tiny gland at the base of the brain: small but mighty! * A major endocrine gland! * Produces a wide variety or hormones that travels to regulate other glands & organs in the body * Anterior lobe: GH, ACTH, TSH, FSH, LH * Posterior lobe: ADH, oxytocin <img src="The pituitary Gland's influence on various organs" alt="Diagram showing the pituitary gland sending hormones (PRL, GH, ACTH, TSH, FSH & LH) to other glands/organs like Mammary glands, Adipose, bone, and muscle, Adrenal glands, Thyroid gland, and Gonads."/> **PRL** Mammary glands **FSH & LH** Gonads **GH** Adipose, bone, and muscle **ACTH** Adrenal glands **TSH** Thyroid gland # **The pituitary Gland** - A teenie tiny gland at the base of the brain: small but mighty! - A major endocrine gland! - Produces a wide variety or hormones that travels to regulate other glands & organs in the body - **Anterior lobe**: GH, ACTH, TSH, FSH, LH - **Posterior lobe**: ADH, oxytocin - **PRL** - Mammary glands - **FSH & LH** - Gonads - **GH** - Adipose, bone, and muscle - **ACTH** - Adrenal glands - **TSH** - Thyroid gland # Adrenal Insufficiency * Adrenal insufficiency: insufficient production of cortisol & aldosterone * Hypothalamus releases CRH $\rightarrow$ anterior pituitary release ACTH $\rightarrow$ adrenal gland to produce cortisol * Function of cortisol * Regulate blood pressure, blood glucose, body's response to stress * Too much $\rightarrow$ Cushing's * Too little $\rightarrow$ Addison's or hypopituitarism <table> <thead> <tr> <th>Symptoms</th> </tr> </thead> <tbody> <tr> <td>Extreme fatigue</td> </tr> <tr> <td>Muscle weakness</td> </tr> <tr> <td>Loss of appetite and weight loss</td> </tr> <tr> <td>Low blood pressure</td> </tr> <tr> <td>Nausea and vomiting</td> </tr> <tr> <td>Abdominal pain</td> </tr> <tr> <td>Hyperpigmentation (darkening of skin) in some cases</td> </tr> <tr> <td>Salt cravings</td> </tr> </tbody> </table> ```mermaid flowchart TD A[Hypothalamus] -->|releases CRH| B(Pituitary gland) B -->|releases ACTH| C(Adrenal gland) C -->|produces| D[Cortisol] D --> E{To immune system} D --> F[The hypothalamus responds to level of cortisol] ``` # **Adrenal Insufficiency** - Adrenal insufficiency: insufficient production of cortisol & aldosterone - Hypothalamus releases CRH $\rightarrow$ anterior pituitary release ACTH $\rightarrow$ adrenal gland to produce cortisol - **Function of cortisol** - Regulate blood pressure, blood glucose, body's response to stress - Too much $\rightarrow$ Cushing's - Too little $\rightarrow$ Addison's or hypopituitarism ## **Symptoms** - Extreme fatigue - Muscle weakness - Loss of appetite and weight loss - Low blood pressure - Nausea and vomiting - Abdominal pain - Hyperpigmentation (darkening of skin) in some cases - Salt cravings ```mermaid flowchart TD A[Hypothalamus] -->|releases CRH| B(Pituitary gland) B -->|releases ACTH| C(Adrenal gland) C -->|produces| D[Cortisol] D --> E{To immune system} D --> F[The hypothalamus responds to level of cortisol] ``` Drugs for adrenal insufficiency * Corticosteroids $\bigodot$ replacement therapy * **Hydrocortisone & cortisone preferred:** glucocorticoid replacement * **Fludrocortisone:** mineralocorticoid replacement w/ one of the above * Monitor adverse effect & titrate dose accordingly * Increase dose during intercurrent illness & periods of stress * Major stress req parenteral administration | Generic name | Brand Name | | :--- | :--- | | Cortisone | Cortate | | Fludrocortisone | Florinef | | Hydrocortisone | Hysone, Solu-Cortef inj | # **Drugs for adrenal insufficiency** - Corticosteroids $\bigodot$ replacement therapy - **Hydrocortisone & cortisone preferred:** glucocorticoid replacement - **Fludrocortisone:** mineralocorticoid replacement w/ one of the above - Monitor adverse effect & titrate dose accordingly - Increase dose during intercurrent illness & periods of stress - Major stress req parenteral administration | Generic name | Brand Name | | :--- | :--- | | Cortisone | Cortate | | Fludrocortisone | Florinef | | Hydrocortisone | Hysone, Solu-Cortef inj | **Corticosteroids** **ADRs** * Infection * Delayed wound healing * Steroid rosacea * Perioral dermatitis * Skin atrophy * Bruising * Acne * Facial flushing * Pupura * Depigmentation * Telangiecstasia * Steroid induced crushing's Description of figure: Multiple images showing skin conditions such as rosacea, perioral dermatitis, and facial flushing, as well as a diagram illustrating the common face proportion versus a round face due to fat deposit buildup. # **Corticosteroids ADRs** - Infection - Delayed wound healing - Steroid rosacea - Perioral dermatitis - Skin atrophy - Bruising - Acne - Facial flushing - Pupura - Depigmentation - Telangiecstasia - Steroid induced crushing's **Adrenal insufficiency Dental** **implications** * Immunosuppression * Adrenocortical suppression * Dose & duration varies btw patients * Oral pred 10mg od >3wks → suppression * High dose inhaled, topical or intra-articular → suppression * Risks: Addisonian Crisis! * Plan morning appointments * Ensure patient is looked after for remainder of day * Seek urgent medical attention: sx of acute adrenal insufficiency # **Adrenal insufficiency: Dental implications** - Immunosuppression - Adrenocortical suppression - Dose & duration varies btw patients - Oral pred 10mg od >3wks → suppression - High dose inhaled, topical or intra-articular → suppression - Risks: Addisonian Crisis! - Plan morning appointments - Ensure patient is looked after for remainder of day - Seek urgent medical attention: sx of acute adrenal insufficiency **Adrenal insufficiency Dental management** * Non-invasive procedures: examination, impressions, diagnostic radiographs * Advise patient to take usual dose of their corticosteroid * Invasive procedure <1hr (outpatient setting) * Scale, restorative, extraction, debridement, implant * Patient at risks of suppression: req increase corticosteroid dose * Consult their medical GP for dosing strategy * Start dose on morning of procedure * Invasive procedure >1hr or requiring sedation, GA or fasting * DEFER & REFER!!! # **Adrenal insufficiency: Dental management** - **Non-invasive procedures**: examination, impressions, diagnostic radiographs - Advise patient to take usual dose of their corticosteroid - **Invasive procedure <1hr (outpatient setting)** - Scale, restorative, extraction, debridement, implant - Patient at risks of suppression: req increase corticosteroid dose - Consult their medical GP for dosing strategy - Start dose on morning of procedure - **Invasive procedure >1hr or requiring sedation, GA or fasting** - DEFER & REFER!!! Other endocrine drugs | Drugs for other endocrine disorders | | |---|---| | **Androgens** | | | | Testosterone (men) | | | Testosterone (women) | | **Antidiuretic hormone agonists and antagonists** | | | | Argipressin | | | Demeclocycline | | | Desmopressin (endocrine) | | | Terlipressin | | **Growth hormone** | | | | Somatrogon | | | Somatropin | | **Nonselective alpha-blockers** | | | | Phenoxybenzamine | | | Phentolamine | | **Somatostatin analogues** | | | | Lanreotide | | | Octreotide | # **Other endocrine drugs** | Drugs for other endocrine disorders | | |---|---| | **Androgens** | | | | Testosterone (men) | | | Testosterone (women) | | **Antidiuretic hormone agonists and antagonists** | | | | Argipressin | | | Demeclocycline | | | Desmopressin (endocrine) | | | Terlipressin | | **Growth hormone** | | | | Somatrogon | | | Somatropin | | **Nonselective alpha-blockers** | | | | Phenoxybenzamine | | | Phentolamine | | **Somatostatin analogues** | | | | Lanreotide | | | Octreotide | **Other endocrine drugs: testosterone** * Androgens aka anabolic steroids: testosterone * Men: Confirmed androgen deficiency in men due to hypothalamic-pituitary or testicular disorder, Male delayed puberty (seek specialist advice) * **Women: Postmenopausal low libido with associated distress (hypoactive sexual desire dysfunction) when other measures (eg education, addressing modifiable biopsychosocial factors) have failed** * Misuse: athletes to increase muscle mass BUT serious adverse effects! * Aggressive behaviour, psychological dependence, withdrawal symptoms, sodium and water retention, oedema * Men: Testicular atrophy, impotence or priapism * Women: amenorrhoea, clitoral enlargement, voice change, virilisation or hirsutism * Men: Androforte, Testogel, Testavan, Reandron 1000, Primiteston Depot, Sustanon inj * Women: Androfeme ## **Other endocrine drugs: testosterone** - Androgens aka anabolic steroids: testosterone - **Men**: Confirmed androgen deficiency in men due to hypothalamic-pituitary or testicular disorder, Male delayed puberty (seek specialist advice) - **Women**: Postmenopausal low libido with associated distress (hypoactive sexual desire dysfunction) when other measures (eg education, addressing modifiable biopsychosocial factors) have failed - **Misuse**: athletes to increase muscle mass BUT serious adverse effects! - Aggressive behaviour, psychological dependence, withdrawal symptoms, sodium and water retention, oedema - **Men**: Testicular atrophy, impotence or priapism - **Women**: amenorrhoea, clitoral enlargement, voice change, virilisation or hirsutism - **Brand Names** - **Men**: Androforte, Testogel, Testavan, Reandron 1000, Primiteston Depot, Sustanon inj - **Women**: Androfeme # Anti-diuretic hormones agonists & antagonists | | **Argipressin aka ADH/vasopressin** | **Demeclocycline (tetracycline AB)** | **Desmopressin** | **Terlipressin aka triglycyl-lysine-vasopressin** | |---|---|---|---|---| | **MOA** | Increase tubular reabsorption of water, vasoconstrict | Antagonises the effect of antidiuretic hormone on renal tubules, promoting excretion of free water | Increases tubular reabsorption of water; increases factor VIII and von Willebrand's factor coagulation activity. | Vasoconstrictor | | **Indication** | Central diabetes insipidus | Persistent marked SIADH resistant to fluid restriction and high salt intake | Central diabetes insipidus Nocturnal enuresis Nocturia due to idiopathic nocturnal polyuria Control of bleeding in patients with mild or moderate haemophilia and type I von Willebrand's disease | Bleeding oesophageal varices Type 1 hepatorenal syndrome | | **Brand** | Pitressin inj | Only available through SAS | Minirin, Octostim | Glypressin inj, Terlipressin inj | # **Anti-diuretic hormones agonists & antagonists** | | **Argipressin aka ADH/vasopressin** | **Demeclocycline (tetracycline AB)** | **Desmopressin** | **Terlipressin aka triglycyl-lysine-vasopressin** | |---|---|---|---|---| | **MOA** | Increase tubular reabsorption of water, vasoconstrict | Antagonises the effect of antidiuretic hormone on renal tubules, promoting excretion of free water | Increases tubular reabsorption of water; increases factor VIII and von Willebrand's factor coagulation activity. | Vasoconstrictor | | **Indication** | Central diabetes insipidus | Persistent marked SIADH resistant to fluid restriction and high salt intake | Central diabetes insipidus Nocturnal enuresis Nocturia due to idiopathic nocturnal polyuria Control of bleeding in patients with mild or moderate haemophilia and type I von Willebrand's disease | Bleeding oesophageal varices Type 1 hepatorenal syndrome | | **Brand** | Pitressin inj | Only available through SAS | Minirin, Octostim | Glypressin inj, Terlipressin inj | # Growth hormones * MOA: Promotes growth of skeletal, muscular and other tissues; stimulates protein synthesis and influences fat, carbohydrate and mineral metabolism. * Indications: As detailed in the **PBS Growth Hormone Program** # Non-selective alpha blockers * MOA: Block the effects of adrenaline and noradrenaline at alpha$_1$ and alpha$_2$ receptors * Indications: Phaeochromocytoma # Somatostatin analogues * MOA: Inhibit release of growth hormone and of various peptides of the gastro-entero-pancreatic endocrine system * Indications: Acromegaly, relief of symptoms associated with gastro-entero-pancreatic neuroendocrine tumours | Generic name | Brand Name | | :--- | :--- | | **Growth hormones** | | | Somatrogon | Ngenla inj | | Somatropin | Saizen inj | | **NSABs** | | | Phenoxybenzamine | Dibenyline | | Phentolamine | Only thru SAS | | **Somatostatin analogues** | | | Lanreotide | Mytolac inj | | Octreotide | Sandostatin inj | # **Growth hormones** - **MOA**: Promotes growth of skeletal, muscular and other tissues; stimulates protein synthesis and influences fat, carbohydrate and mineral metabolism. - **Indications**: As detailed in the **PBS Growth Hormone Program** # **Non-selective alpha blockers** - **MOA**: Block the effects of adrenaline and noradrenaline at alpha$_1$ and alpha$_2$ receptors - **Indications**: Phaeochromocytoma # **Somatostatin analogues** - **MOA**: Inhibit release of growth hormone and of various peptides of the gastro-entero-pancreatic endocrine system - **Indications**: Acromegaly, relief of symptoms associated with gastro-entero-pancreatic neuroendocrine tumours ## **Drug List** | Generic name | Brand Name | | :--- | :--- | | **Growth hormones** | | | Somatrogon | Ngenla inj | | Somatropin | Saizen inj | | **NSABs** | | | Phenoxybenzamine | Dibenyline | | Phentolamine | Only thru SAS | | **Somatostatin analogues** | | | Lanreotide | Mytolac inj | | Octreotide | Sandostatin inj | **Other Dental implications** * Androgens: worsening of sleep apnea * **Demeclocycline (applies for all tetracyclines)** * Children: teeth discolouration, enamel dysplasia * Pregnancy: discoloration od deciduous teeth in babies * **Terlipressin: drug interaction w/ erythromycin** * May trigger irregular beating of heart * **Growth hormones: watch for limping** * May indicate development of a slipped capital epiphysis $\rightarrow$ direct patient to see their MGP * **Non-selective alpha blockers: orthostatic hypotension, dizziness, drowsiness** # **Other Dental implications** - **Androgens**: worsening of sleep apnea - **Demeclocycline (applies for all tetracyclines)** - Children: teeth discolouration, enamel dysplasia - Pregnancy: discoloration of deciduous teeth in babies - **Terlipressin**: drug interaction w/ erythromycin - May trigger irregular beating of heart - **Growth hormones**: watch for limping - May indicate development of a slipped capital epiphysis $\rightarrow$ direct patient to see their MGP - **Non-selective alpha blockers**: orthostatic hypotension, dizziness, drowsiness DENT 3005: Introduction to Pharmacology **Endocrine Drugs: Drugs for Infertility** Dr Thuy Linh Truong thuy.truong@uwa.edu.au # **DENT 3005: Introduction to Pharmacology - Endocrine Drugs: Drugs for Infertility** **Dr Thuy Linh Truong** thuy.truong@uwa.edu.au **Learning Outcomes** **Learning objectives** 1) Broad understanding of drugs for infertility and their dental implications 2) Understand drugs interactions with dental medications 3) Applied knowledge to clinical scenarios A gloved hand holding a vial with a heart on it, with a baby illustration in the background. # **Learning Outcomes** ## **Learning objectives** 1) Broad understanding of drugs for infertility and their dental implications 2) Understand drugs interactions with dental medications 3) Applied knowledge to clinical scenarios **Drugs for infertility** * Highly specialist tx * Clomiphene: 1st line for anovulatory infertility * Letrozole accepted (aromatase inH) main indication for hormone receptor +ve breast cancer * Metformin: may be added in PCOS * Assisted reproductive technology (IVF) may include GnRH agonists * Progesterone: used for luteal phase support in assisted conception cycle # **Drugs for infertility** - Highly specialist tx - **Clomiphene**: 1st line for anovulatory infertility - Letrozole accepted (aromatase inH) main indication for hormone receptor +ve breast cancer - **Metformin**: may be added in PCOS - **Assisted reproductive technology (IVF)** may include GnRH agonists - **Progesterone**: used for luteal phase support in assisted conception cycle # GnRH agonists * AKA LH releasing hormone agonists * MOA: GnRH initially stimulates synthesis of FSH and LH * **Indications** * Endometriosis * Uterine fibroids * Endometrial thinning before endometrial ablation * Pituitary down-regulation to prepare for controlled ovarian stimulation * Central precocious puberty * Prostate cancer * Breast cancer | Generic name | Brand Name | | :--- | :--- | | Goserelin | Zoladex inj | | Leuprorelin | Eligard inj, Lucrin depot | | Nafarelin | Synarel nasal spray | | Triptorelin | Decapeptyl inj Dephereline inj | # **GnRH agonists** - AKA LH releasing hormone agonists - **MOA**: GnRH initially stimulates synthesis of FSH and LH - **Indications** - Endometriosis - Uterine fibroids - Endometrial thinning before endometrial ablation - Pituitary down-regulation to prepare for controlled ovarian stimulation - Central precocious puberty - Prostate cancer - Breast cancer | Generic name | Brand Name | | :--- | :--- | | Goserelin | Zoladex inj | | Leuprorelin | Eligard inj, Lucrin depot | | Nafarelin | Synarel nasal spray | | Triptorelin | Decapeptyl inj Dephereline inj | Other drugs for infertility * **Clomiphene** * MOA: Competitively antagonises estrogen receptors in the hypothalamus * Indication: anovulatory infertility * **ADR (dental implications)** * Clomiphene: dizziness * Letrozole: vertigo, dry mouth * Metformin: see diabetes lecture <table> <thead> <tr> <th>Generic name</th> </tr> </thead> <tbody> <tr> <td>Clomiphene</td> </tr> <tr> <td>Letrozole</td> </tr> <tr> <td>Metformin</td> </tr> <tr> <td>Progesterone</td> </tr> </tbody> </table> # **Other drugs for infertility** - **Clomiphene** - **MOA**: Competitively antagonises estrogen receptors in the hypothalamus - **Indication**: anovulatory infertility - **ADR (dental implications)** - **Clomiphene**: dizziness - **Letrozole**: vertigo, dry mouth - **Metformin**: see diabetes lecture |Generic name| |---| |Clomiphene| |Letrozole| |Metformin| |Progesterone| **Infertility drugs** **Dental** **implications** * Hormonal changes * Infertility medications can cause hormonal imbalances, which can affect the tissues in the mouth, making them more susceptible to inflammation and gum disease * Some patients are not comfortable taking intraoral radiographs, patient education is important but routine radiographs may have to be deferred especially if the patient has gone through a lot of difficulty to conceive they are most likely going to be extremely worried a lot of things * Triptorelin and letrozole: dry mouth * Clomiphene: Watch out for dizziness & light headedness # **Infertility drugs: Dental implications** - **Hormonal changes** - Infertility medications can cause hormonal imbalances, which can affect the tissues in the mouth, making them more susceptible to inflammation and gum disease - Some patients are not comfortable taking intraoral radiographs, patient education is important but routine radiographs may have to be deferred especially if the patient has gone through a lot of difficulty to conceive they are most likely going to be extremely worried a lot of things - **Triptorelin and letrozole**: dry mouth - **Clomiphene**: Watch out for dizziness & light headedness **References** - Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan D, Robinson E, editors. *Rang & Dale’s pharmacology*. 10th ed. Edinburgh: Elsevier; 2023 - Australian Medicines Handbook Online [Internet]. Adelaide (AU): Australian Medicines Handbook Pty Ltd;2000. Endocrine; [updated 2025; cited 2025]. Available from: UWA Onesearch - Pharmaceutical Society of Australia. Australian Pharmaceutical Formulary and Handbook: A Guide to Best Practice. 25th ed. Canberra: Pharmaceutical Society of Australia; 2021 - Ali K. Clinical dental pharmacology. 1st ed. Oxford: Wiley-Blackwell; 2023 - Bullock S, Manias E. *Fundamentals of pharmacology*. 8th ed. Frenchs Forest, NSW: Pearson Australia; 2017 - MIMS Australia. *eMIMSelite: Consumer medicine information, specific* *clinical monograph* [Internet]. Sydney: MIMS Australia; [updated 2025; cited 2025 Apr 17]. Available from: UWA Onesearch A visual representation of medical/pharmaceutical references, featuring an illustration of a person with a cold/allergies and two images of prescription bottles and loose pills. # **References** - Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan D, Robinson E, editors. *Rang & Dale’s pharmacology*. 10th ed. Edinburgh: Elsevier; 2023 - Australian Medicines Handbook Online [Internet]. Adelaide (AU): Australian Medicines Handbook Pty Ltd;2000. Endocrine; [updated 2025; cited 2025]. Available from: UWA Onesearch - Pharmaceutical Society of Australia. Australian Pharmaceutical Formulary and Handbook: A Guide to Best Practice. 25th ed. Canberra: Pharmaceutical Society of Australia; 2021 - Ali K. Clinical dental pharmacology. 1st ed. Oxford: Wiley-Blackwell; 2023 - Bullock S, Manias E. *Fundamentals of pharmacology*. 8th ed. Frenchs Forest, NSW: Pearson Australia; 2017 - MIMS Australia. *eMIMSelite: Consumer medicine information, specific* *clinical monograph* [Internet]. Sydney: MIMS Australia; [updated 2025; cited 2025 Apr 17]. Available from: UWA Onesearch [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=1|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.1]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=4|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.4]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=5|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.5]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=6|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.6]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=7|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.7]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=8|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.8]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=9|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.9]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=10|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.10]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=11|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.11]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=12|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.12]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=13|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.13]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=14|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.14]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=15|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.15]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=16|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.16]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=17|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.17]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=18|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.18]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=19|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.19]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=20|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.20]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=21|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.21]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=22|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.22]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=23|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.23]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=24|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.24]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=25|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.25]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=26|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.26]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=27|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.27]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=28|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.28]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=29|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.29]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=30|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.30]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=31|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.31]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=32|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.32]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=33|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.33]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=34|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.34]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=35|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.35]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=36|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.36]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=37|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.37]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=38|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.38]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=39|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.39]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=40|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.40]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=41|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.41]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=42|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.42]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=43|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.43]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=44|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.44]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=45|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.45]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=46|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.46]] [[L13 ENDOCRINE DIABETES THYROID ADRENAL 2025.pdf#page=47|L13 ENDOCRINE DIABETES THYROID ADRENAL 2025, p.47]]