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Endocrine Pharmacology:
Part 1: Hypothalamus/Pituitary, Pineal, Thyroid/Parathyroid, Adrenals, Ovaries/Testes
Part 2: Diabetes mellitus types 1 & 2
PHRM 203 Allison Beale
A Beale PHRM 203 - Endocrine 2
Types of Diabetes • D. mellitus
– Type I (Juvenile onset) • Pancreas not producing enough insulin, must take insulin
– Type II (Non-insulin dependant diabetes mellitus, NIDDM) • Usually insulin resistance, but may be not enough insulin
• Gestational Diabetes – Placental hormones cause insulin resistance in mom
• Cystic fibrosis Diabetes – Shared characteristics with Type I and II DM
• D. insipidus – Problem with ADH (usually, pituitary or kidney issue)
A Beale PHRM 203 - Endocrine 3
Pancreas is a combination of exocrine and endocrine glands
• Ducted (exocrine) gland – Digestive enzymes secreted
into small intestine • Ductless (endocrine) gland
– Insulin • Glucose out of blood
– Glucagon • Glucose into blood
A Beale PHRM 203 - Endocrine 4
Conditions that affect glycemic control
• Hyperglycemia (⇑[gl]blood) – Excessive food intake – ↓ Physical activity – Pancreatic disease – Infection – Ischemia/infarction – Trauma – Surgery – Emotional stress – Pregnancy (2nd/3rd T) – Cirrhosis (liver disease)
• Hypoglycemia (⇓[gl]blood) – ↓ Dietary intake – ↑ Physical activity – Malabsorption – Alcohol intake – Adrenocortical
insufficiency – Renal insufficiency – Hepatic failure – Pregnancy (1st T) – Gastrectomy
Management of Hospitalized Patients with Type 2 diabetes Mellitus, SH Lilley and GI Levine, AAFP, 1 March 1998
A Beale PHRM 203 - Endocrine 5
Drugs with diabetes interactions Drug Interaction
Glucosamine May increase insulin resistance
Risperidone (Risperdal, an atypical antipsychotic) Linked to type 2 DM, pancreatitis
SSRIs Patients report hypoglycemia
Low Blood Sugar Symptoms
Headache, dizziness, hunger, confusion, trouble concentrating, weakness, nausea, blurred vision, drowsiness, rapid heart rate, sweating, tremors
Severe Hypoglycemia Symptoms
Confusion, stomach pain, trouble speaking, extreme weakness, blurred vision, sweating, tremors, seizures, coma
Hyperglycemia Symptoms Thirst, loss of appetite, nausea, increased urination, vomiting, drowsiness, dry mouth, dry skin
A Beale PHRM 203 - Endocrine 6
Drugs with diabetes interactions Drugs that ↑ blood glucose Cause HYPERGLYCEMIA
Drugs that ↓ blood glucose Cause HYPOGLYCEMIA
Glucagon Diuretics Insulin
Sympathomimetics Ethanol (chronic) Oral antihyperglycemic agents
Amphetamines Glucocorticosteroids Ethanol (acute use)
β Blockers β Agonists Pentamidine (initially)
Cyclosporins Diazoxide Management of Hospitalized Patients with Type 2 diabetes Mellitus, SH Lilley and GI Levine, AAFP, 1 March 1998
Growth hormone Niacin
Pentamidine Salicylates (hi-dose)
A Beale PHRM 203 - Endocrine 7
Drugs with possible diabetes interactions
Drugs that may ↑ blood glucose Drugs that may ↓ blood glucose
Caffeine CCBs ACE - I
Clonidine Estrogen/progestins Anabolic steroids
Isoniazid Nicotine Aspirin (high doses)
Octreotide Phenothiazines Disopyramide (Norpace)
Phenytoin Rifampin Ganciclovir, saquinavir
Management of Hospitalized Patients with Type 2 diabetes Mellitus, SH Lilley and GI Levine, AAFP, 1 March 1998
Quinine (high doses)
Sulfonamides
Patients on SSRIs often report hypoglycemia
Ketoacidosis • If cells can’t take up
glucose (DMT1), or if glucose is unavailable, respiration shifts to fatty acid oxidation
• Fatty acids produce acidic lactones when burned
VERY HIGH or VERY LOW blood sugar
• Thirst • Fruity breath • Vomiting • Dehydration • Deep, gasping breath • Confusion • Dry, flushed skin • Coma and death
A Beale PHRM 203 - Endocrine 8
Very high blood glucose treated with insulin
A Beale PHRM 203 - Endocrine 9
Parenteral Antihyperglycemic Drug Indication
Insulin (human – Humulin R or Novolin R) !
Diabetes mellitus (all types), treatment of severe ketoacidosis, hyperkalemia, gestational diabetes.
Expect nighttime hypoglycemia, especially in DMT2 patients when using insulin and/or insulin analogs.
Short acting, used if eating 30-60 minutes after
injection
R = Regular
Which means, Human
SC, IV, IM
Top 4 drugs associated with medication errors: 1. Insulin 2. Morphine 3. Fentanyl 4. Tie: Metoprolol, Albuterol &
Potassium chloride
What about other routes?
• Insulin is a protein – Subject to extensive
and rapid metabolism
• Afrezza (human insulin of rDNA origin) – Previously called
Afresa – Nasal inhalation
powder – Approved 2014
A Beale PHRM 203 - Endocrine 10
Image: Huffington Post
Types of insulin
Aspart
Detem
ir
Glargine
Glulisine
Lispro
Isophane (NPH) – intermediate form produced by chemically combining insulin with protamine and zinc
Regular - recombinant
Zinc – intermediate form. Zinc polymerizes the insulin making it last longer.
Analogs – produced by making slight changes to amino acid sequence. Some like Glargine are also complexed with zinc. These changes alter the kinetics.
Analog, Beef or Pork – analog = recombinant, beef/pork isolated at slaughter (rarely used now)
Human - recombinant
Analog or Pork
Novolog
Levemir
Lantus
Apidra
Hum
alog
Humulin N Novolin N Relion Novolin N Iletin NPH Insulin Purified NPH Pork
Humulin R Novolin R Iletin II Regular (Ultralente)
Iletin Lente Iletin Lente Pork Lente Iletin II Novolin L
A Beale PHRM 203 - Endocrine 11
A Beale PHRM 203 - Endocrine 12
Onset of action for Insulin types Rapid-Acting - for meals eaten at time of injection, typically used with longer-acting form
Drug Onset (minutes) Peak (hours) Duration (hours)
Lispro (Humalog) ! 15-30 0.5-1.5 3-5
Novolog or Aspart 10-20 40-50
Short-Acting - for meals eaten within 30-60 minutes of injection
Regular (R ) (Humulin R) ! 30-60 2-5 5-8
Intermediate-Acting - for overnight, or about 1/2 the day. Usually combined with above forms.
Neutral Protamine Hagedorn - NPH (N) ! (Humulin N)
1-2 hours 4-12 18-24
Lente (Humulin L) ! 1 - 2.5 hours 3-10
Long-Acting - covers insulin needs for an entire day. May be combined with rapid/short form.
Glargine (Lantus) ! 1-3 hours 10-20 20-36
A Beale PHRM 203 - Endocrine 13
1st Generation Sulfonylureas Oral sulfonylureas stimulate the pancreas to secrete insulin
“Secretagogues”
Drug Indication
Chlorpropamide (Diabinese) !
Adjunct to diet and exercise for type 2 DM
Tolazamide
Tolbutamide
Table adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins. 2008
If taking a sulfonylurea, patient must have a functional pancreas and be able to
recognize and respond to symptoms of hypoglycemia
A Beale PHRM 203 - Endocrine 14
2nd Generation Sulfonylureas Oral sulfonylureas can cause severe hypoglycemia &
↑ risk of CV death
Drug Indication
Glimepiride Adjunct to diet and exercise for type 2 DM
Glipizide
Glyburide (Micronase)!
Table adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins. 2008
1st generation sulfonylureas are water soluble and less potent than 2nd
generation sulfonylureas which are lipid soluble.
A Beale PHRM 203 - Endocrine 15
Sulfonylureas
• ADRs – SIADH – ↑ Risk of CV death – Hypoglycemia risk – Blood dyscrasias – Disulfiram-like rxns – GI upset – Dizziness, headache
• Drugs that ⇑ hypoglycemic risk w/sulfonylureas – NSAIDs & other highly PPB
drugs – Salicylates – Sulfonamides – Chloramphenicol – Probenecid – Coumarins – MAOIs – β blockers – Other antidiabetes drugs
• Including the Sodium-Glucose Co-transporter 2 (SGLT2) inhibitors
– Canaglifozin (Invokana) – Empagliflozin (Jardiance)
G6PD
A Beale PHRM 203 - Endocrine 16
Nonsulfonylureas
Drug Indication
Metformin (Glucophage)!
• “Biguanide” • Adjunct to diet & exercise for DMT2, also treats
polycystic ovary syndrome • Does not cause hypoglycemia and protects against CV
effects of diabetes. Works mainly by ⊗ hepatic gluconeogenesis.
Pioglitazone (Actos) !
• “PPARγ agonist” • Adjunct to diet & exercise for DMT2 in combo with
insulin or sulfonylureas to control blood sugar when one drug alone won’t work
• NEW FDA WARNING: RISK OF BLADDER CANCER
Metformin (Glucophage) !
• ↑ Hypoglycemic action – Ketoconazole – Erythromycin – Chloramphenicol – NSAIDs, salicylates – Probenecid – Warfarin
• ↓ action – Corticosteroids – Estrogens – INH – Phenytoin – Thiazides
• Glucose control destabilized by
• β blockers • Quinolones • Thyroid hormone
A Beale PHRM 203 - Endocrine 17
¨ Lactic acidosis
PO, SID/BID with meals
Need functional kidneys
Pioglitazone (Actos) ! • Insulin must be
present – It ↓ insulin resistance
• Activation of PPARγ nuclear receptors modulates transcription of several insulin responsive genes involved in the control of glucose and lipid metabolism.
• Indicated as an adjunct to diet & exercise to improve glycemic control in adults with type 2 DM
• ADRs – Hypoglycemia risk – Edema – Weight gain – May trigger ovulation
A Beale PHRM 203 - Endocrine 18
¨ Congestive HF
PO, SID
A Beale PHRM 203 - Endocrine 19
Nonsulfonylureas
Drug Indication
Sitagliptin (Januvia) !
“DPP4 inhibitor” - Adjunct to diet & exercise for type 2 diabetes. Acts by inhibiting the enzyme, dipeptidyl peptidase 4, that breaks down incretins (glucagon-like peptide and glucose-dependant insulinotropic polypeptide)
Exenatide (Byetta) Liraglutide (Victoza) !
Think: Lizard spit “Incretin mimics” - Adjunct to diet & exercise for type 2 diabetes. Increase insulin secretion, decrease glucagon secretion and gastric emptying time. Boxed warning (Victoza) for thyroid cancer risk.
Table adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins. 2008
Sitagliptin (Januvia) !
• ADRs – Risk of hypoglycemia – Pancreatitis – Serious allergic rxns – Upper RTI – Nasopharyngitis – Headache
• Blocks the breakdown of incretins
– Dipeptidyl peptidase-4 (DPP4) inhibitor
• Incretins function to: – ↓ glucagon secretion – ↓ gastric emptying
time – ↓ appetite – ↑ insulin secretion
A Beale PHRM 203 - Endocrine 20
PO, SID
Janumet = sitagliptin + metformin
Liraglutide (Victoza) ! • Glucagon-like Peptide-1
(GLP-1) receptor agonist
• ADRs – Severe hypoglycemia
risk with sulfonylureas – Headache – Nausea – Diarrhea – Anti-liraglutide Ab
– Regardless of meals – Causes slow weight
loss • Hypothalmus
interaction
– Glucose-dependent • Only ↑insulin in the
presence of glucose
A Beale PHRM 203 - Endocrine 21
¨ Thyroid cancer seen in rodents
SC, SID
A Beale PHRM 203 - Endocrine 22
Nonsulfonylureas
Drug Indication
Bromocriptine (Cycloset)!
• Ergot alkaloid, Dopamine agonist • Adjunct to diet & exercise for DMT2 • Must be given within 2 hours of waking
• May cause nausea, hypotension, somnolence, and worsening of psychotic conditions
Canaglifozin (Invokana) !
• “SGLT2 inhibitor” • Adjunct to diet & exercise for DMT2 • Also given 1st thing in the morning, before eating
• May cause bacterial/fungal UTIs, hypotension, hyperkalemia, hypoglycemia, increased LDL-C…
PO, SID
PO, SID
Other Diabetes medications Acarbose (Precose) !
• α-Glucosidase inhibitor (inhibits carbohydrate digestion and absorption) - Helps prevent rapid glucose rise after eating.
• Indication: adjunct to diet and exercise to improve glycemic control in adults with DMT2
• Should be taken with first bite of each meal.
• ↓wt. gain and insulinotropic effects of sulfonylureas, but since CBH remain in GIT, microbes ferment the CBHs producing GAS
A Beale PHRM 203 - Endocrine 23
PO, up to TID with meals
A Beale PHRM 203 - Endocrine 24
Other Diabetes medications
Drug Indication T2DM /comments
Pramlintide (Symlin)
“Amylin analog” - Adjunct to type 1 or 2 diabetes using meal-time insulin but without glycemic control
Repaglinide (Prandon)
“Insulin secretagogue” (stimulates the pancreas to secrete more insulin, similar to sulfonylureas) - Increases circulating insulin. Take tablet(s) with meals.
A Beale PHRM 203 - Endocrine 25
Glucose elevating agents
Drug Indication
Diazoxide Oral management of hypoglycemia, IV for severe hypertension
Glucagon (Glucagen) !
Injectable to control severe hypoglycemic reactions (increases blood glucose and relax GIT smooth muscle)
Table adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins. 2008
Glucose elevating agents Glucagon (Glucagen) !
• rDNA Polypeptide
hormone • Exogenous glucagon
stimulates catecholamine release
• Must have sufficient liver glycogen. It won’t work in states of: – Starvation – Adrenal insufficiency – Chronic hypoglycemia
• Indications 1. Treatment of severe
hypoglycemia 2. As a diagnostic aid in
the radiologic exam of GIT when reduced GIT motility is needed.
A Beale PHRM 203 - Endocrine 26
SC, IV, IM
A Beale PHRM 203 - Endocrine 27
Other Endocrine Glands
Gland Hormone
Stomach Gastrin → Stimulates gastric acid & digestive enzyme release
Small intestine
Secretin → Stimulates pancreas to release bicarb Cholecystokinin → Stimulates gall bladder contractions
Heart Atrial natriuretic hormone → ⊗ ADH release
Placenta Chorionic gonadotropin → Stimulates ovaries to maintain pregnancy