Drugs Used in the Treatment of Metabolic Disorders

Drugs Used in the Treatment of Metabolic Disorders Pharmacology 49.222 Bill Diehl-Jones RN, PhD Faculty of Nursing and Department of Zoology Agenda • Zen Review • Treatment of Diabetes – Insulin, oral hypoglycaemics • Treatment of thyroid disorders Endogenous Insulin Secretion and Blood Glucose Source: Ergun-Longmire et al, May 5, 2005. Accessed November 26, 2005. Endotext_com - Pediatric Endocrinology, Management of Type-1 and Type-2 Diabetes.htm Diabetes Mellitus • Heterogenous disease • The Problem: – high blood glucose due relative or absolute deficiency of insulin • Two types based on insulin requirement: – IDDM (20%) – NIDDM (80%) • Diabetics suffer from dysregulated glucose control The Difference Between Diabetics and Non-Diabetics Source: Ergun-Longmire et al, May 5, 2005. Accessed November 26, 2005. Endotext_com - Pediatric Endocrinology, Management of Type-1 and Type-2 Diabetes.htm Complications of Diabetes • Heart disease • Microvascular complications (Type 2) – Retinopathy – ‘stocking glove’ syndrome • Renal Disease • Edema General Approach to Diabetes • Goal-setting for the following: – – – – – Glycemia Diet and exercise modification SMBG Laboratory assessment Medications Glycaemic Control is ESSENTIAL • HbA1c is a measure of glycated hemoglobin – A better measure of longer-term blood glucose levels • SMBG is done to help clients reach blood glucose goals • Two long-term multicenter studies have shown that tight glycaemic control significantly reduces diabetes complications Pharmacologic Solutions • Insulin (for IDDM) – Many different forms (differ in solubility, speed and duration of action) • Eg: Semilente, NPH, Lente, ultralente • Oral Hypoglycemics (for NIDDM) • • • • Sulfonylureas (eg: tolbutamide) Biguanides (eg: metformin) Alpha-Glucosidase Inhibitors (eg: acarbose) Other Insulin • Rapid Acting – Humalog, Novalog • Onset 15-30 min; Peak 1-2 hours; Duration 3-5 hours • Short Acting – Humulin R, Novolin R • Onset 30-60 min; Peak 2-3 hours; Duration 3-6 hours • Intermediate acting – NPH, Lente • NPH: Onset 2-4 hours; Peak 4-6 hours; Duration 8-12 hours • Long Acting – Ultralente • Onset 6-10 hours; Peak 10-16 hours; Duration 18-20 hours Pharmacokinetics of Combination Therapy (Eg: Long-Acting and Rapid-Acting Insulins) Source: Ergun-Longmire et al, May 5, 2005. Accessed November 26, 2005. Endotext_com - Pediatric Endocrinology, Management of Type-1 and Type-2 Diabetes.htm Why Do We Use Combination Insulin Therapies? Mechanisms of Action of Oral Hypoglcaemics Agent Sulfonylureas Meglitinides Biguanides Thiazolidinedinediones α-glucoside Inhibitors Mechanism of Action Stimulate insulin secretion by blocking K+ channels As above Increase muscle glucose uptake and utilization and decrease hepatic glucose production Increases insulin sensitivity Decrease hepatic glucose production Drugs Which May Affect Glycaemic Control • Ace Inhibitors – ↓ glucose by improving insulin sensitivity • Alcohol – ↓ glucose by reducing hepatic glucose production • Diuretics – ↑ glucose by ↑ insulin resistance • Glucocorticoids – ↑ glucose by impairing insulin action • Phenytoin – ↑ glucose by ↓ insulin secretion • Beta blockers – May ↓ by ↓ insulin secretion Clinical Pearls • Sliding scales for dose/type of insulin are frequently used in hospital – Allows titration of amount of insulin • Avoids wide variations in blood glucose Clinical Pearls • Many patients are given premixed insulin – 70% NPH:30% regular or rapid-acting • Insulin glargine is a newer, recombinant insulin analog – It MUST NOT be mixed in a syringe with any other insulin – It is given once daily, HS Clinical Pearls • Adverse reactions of insulin include: – Hypoglycemia or hyperglycemia – Hyperinsulinemia – May also be localized allergic reactions • Somogyi Phenomenon – Rapid decrease in blood glucose, usually at night – This stimulates epinephrine, cortisol, glucagon – Result is elevated morning glucose Clinical Pearls • Symptoms of insulin rxn or hypoglycemia more likely in Pt. with Type 1 diabetes who has more insulin in blood than needed – Can occur due to med error, exercise, skipped meal • Symptoms include PALE, MOIST SKIN, BG<50 mg/dl, SUDDEN ONSET – This helps distinguish from DKA (see slide 20) Clinical Pearls • DKA (Diabetic Ketoacidosis) – Cells cannot get enough sugar from blood, so fat is used as energy source • Waste product is KETOACIDS • These smell ‘FRUITY’ – Plasma pH gets very low (acidic) – Can cause death – Usual cause: skipped insulin Clinical Pearls • How do you tell the difference between HYPOGLYCEMIA and DKA? – DKA: • fruity smell is key • Also: DRY warm skin, blurred vision, Kussmaul respirations, BG>300 mg/dl • Treatment differs!!! – Hypoglycemia: GIVE SUGAR (juice is good) – DKA: NO GIVE SUGAR • Need saline, K supps to correct deficits Drugs Used to Treat Thyroid Dysfunction Thyroid Disease • One of the most common endocrine problems • Often missed by both generalists (90%) and specialists (66%) • Presenting complaints are rarely classic – Dysphagia, ear pain, hoarseness, neck pain, fever, heartburn, constipation, fatigue • Hypothlamic-pituitary-thyroid axis • Thyrotropin (TSH) regulates thyroid size, cell proliferation, thyroid hormone synthesis and secretion • The effects of TSH are modulated by the iodine content of the cells •  iodine,  TSH,  thyroid size •  TSH,  colloid production,  thyroid size Zen Review TSH • • • • Normal range 0.5-5.0 mU/L 5-20 subclinical hypothyroidism > 20 overt hypothyroidism TSH is the gold standard screening tool for thyroid disease • Other tests to determine etiology: Total and free T4 and T3, antithyroid antibody titres Hypothyroidism • Second to diabetes as the most common endocrine problem • Incidence: 18 per 1000 people – 14x more common in women – 2-3% of older women • Up to 10% of post-menopausal women where it exacerbates osteoporosis and hyperlipidemia Hypothyroidism • Almost always a destructive process resulting in decreased synthesis and secretion of T3 and T4 Hypothyroidism • Causes: • Iodine deficiency (most common cause world-wide) • Hashimoto’s thyoiditis (chronic lymphocytic thyroiditis) • Iatrogenic (2º to treatment of Grave’s disease) • Hypothalmic or pituitary disorders Treatment • Levothyroxine 0.1-0.5 mg/day (start with 0.075) • Reduce the dose in the elderly • *thyroid supplementation accelerates bone loss in older women • Increased doses may be needed with Oral Contraceptives, HRT, pregnancy Hyperthyroidism Excess Production of Thyroid Hormone Signs and Symptoms of Hyperthyroidism • • • • • • • Thyroid enlargement Fatigue and weakness Weight loss Frequent soft BMs Heat intol, sweating Warm moist soft skin Soft, fine, thin hair and nails Hyperthyroidism • Incidence: 2% females • 1/10 as many males • Profile: mid 20-30’3, northern European Grave’s Disease • 60-90% of hyperthyroidism • Autoimmune disorder Thyrotoxicosis • Increased metabolic state occurring when Free T4, T3 or both are  • Can occur with all diseases of the thyroid • Thyroid storm is a severe form of thyrotoxicosis Thyrotoxicosis • TREATMENT – Beta adrenergic blocking agents to control symptoms – PTU or Methimazole to block hormone synthesis – Treat underlying cause Treatment Continued • Antithyroid drugs: PTU 75-100 mg tid • Radioactive iodine • surgery