Endocrine Pharmacology - Laulima...A Beale PHRM 203 - Endocrine 3 Pancreas is a combination of...

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)


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


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


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


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)


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


Very high blood glucose treated with insulin


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


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



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


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


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)!


1st generation sulfonylureas are water soluble and less potent than 2nd

generation sulfonylureas which are lipid soluble.


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


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


¨  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


¨  Congestive HF

PO, SID


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.


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


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


¨  Thyroid cancer seen in rodents

SC, SID


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


PO, up to TID with meals


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.


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)


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.


SC, IV, IM


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

Endocrine Pharmacology - Laulima...A Beale PHRM 203 - Endocrine 3 Pancreas is a combination of...

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