The Endocrine System

Advanced Pharmacology: Endocrine Pharmacology Part I Thomas W. Barkley, Jr., PhD, ACNP‐BC, FAANP President, Barkley & Associates www.NPCourses.com and...
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Advanced Pharmacology: Endocrine Pharmacology Part I Thomas W. Barkley, Jr., PhD, ACNP‐BC, FAANP President, Barkley & Associates www.NPCourses.com and Professor of Nursing Director of Nurse Practitioner Programs California State University, Los Angeles Robert Fellin, Pharm.D., BCPS Lecturer, Barkley & Associates Clinical Pharmacist  Cedars‐Sinai Medical Center Los Angeles, CA ©2014 Barkley & Associates

Unit 6

The Endocrine System • Comprised of various glands that secrete hormones (chemical messengers released in response to a change in the body’s internal homeostasis)

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Hypothalamus and Pituitary: Physiology Review • Hypothalamus: secretes releasing hormones  pituitary • Releasing hormones trigger the pituitary to know which hormones are to be released • Hypothalamus secretes thyrotropin-releasing hormone (TRH)  pituitary  secrete TSH  thyroid hormones • Pituitary • Anterior (adenohypophysis): consists of glandular tissue and secretes ACTH, TSH, growth hormone, prolactin, FSH and LH • Posterior (neurohypophysis): contains nervous tissue rather than glandular, and neurons in the posterior pituitary store ADH and oxytocin (released in response from nerve stimulation in the hypothalamus) ©2014 Barkley & Associates

Unit 6

Hypothalamic & Pituitary Hormones

Pharmacology for Nurses: A Pathophysiologic Approach (4th Edition)

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Hypothalamic & Pituitary Hormones Hypothalamic Hormone

Anterior Pituitary Hormone

Growth hormonereleasing hormone

Growth hormone (GH, somatotropin)

(GHRH) (+) Somatostatin (−) Thyrotropinreleasing hormone (TRH) (+)

Thyroid-stimulating hormone (TSH)

Target Organ

Primary Target Organ Hormone/Mediator

Liver, bone, muscle, Insulin-like growth kidney, and factor-I (IGF-I) others

Thyroid

Thyroxine, tri-iodothyronine

(+), stimulant; (–), inhibitor ©2014 Barkley & Associates

Unit 6

Hypothalamic & Pituitary Hormones Hypothalamic Hormone

Anterior Pituitary Hormone

Target Organ

Primary Target Organ Hormone/Mediator

Corticotropinreleasing hormone (CRH) (+)

Adrenocorticotropin (ACTH)

Adrenal cortex

Cortisol

Gonads

Estrogen, progesterone, testosterone

Gonadotropinreleasing hormone (GnRH) (+)

Dopamine (−) Unit 6

Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Prolactin (PRL)

(+), stimulant; (–), inhibitor

Breast ©2014 Barkley & Associates

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Clinical Uses of Hypothalamic Hormones Hypothalamic Hormone Growth hormone-releasing hormone (GHRH)

Clinical Uses Used rarely as a diagnostic test for GH and GHRH sufficiency

Thyrotropin-releasing hormone (TRH, protirelin)

May be used to diagnose TRH or TSH deficiencies

Corticotropin-releasing hormone (CRH)

Used rarely to distinguish Cushing's disease from ectopic ACTH secretion

Gonadotropin-releasing hormone (GnRH)

May be used in pulses to treat infertility caused by GnRH deficiency

Dopamine

Dopamine agonists (bromocriptine, cabergoline) used for treatment of hyperprolactinemia ©2014 Barkley & Associates

Unit 6

Anterior Pituitary Agents GROWTH HORMONE (GH) somatropin MOA: Recombinant form of human GH; acts through GH receptors to increase production of IGF-I Effects: Restores normal growth and metabolic GH effects in GH-deficient individuals Increases final adult height in some children with short stature not due to GH deficiency Clinical Replacement in GH deficiency Applications: Increased final adult height in children with certain conditions associated with short stature Wasting in HIV infection Short bowel syndrome Unit 6

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Anterior Pituitary Agents SOMATOSTATIN ANALOGS octreotide, lanreotide MOA:

Agonist at somatostatin receptors

Effects:

Inhibits production of GH and, to a lesser extent, of TSH, glucagon, insulin and gastrin

Clinical Applications:

Acromegaly and several other hormone-secreting tumors Octreotide: Acute control of bleeding from esophageal varices Lanreotide: similar to octreotide; available as a longacting formulation for acromegaly ©2014 Barkley & Associates

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Anterior Pituitary Agents IGF-I AGONIST mecasermin MOA:

Recombinant form of IGF-I that stimulates IGF-I receptors

Effects:

Improves growth and metabolic IGF-I effects in individuals with IGF-I deficiency due to severe GH resistance

Clinical Applications:

Replacement in IGF-I deficiency that is not responsive to exogenous GH

GH RECEPTOR ANTAGONIST pegvisomant MOA: Blocks GH receptors Effects: Ameliorates effects of excess GH production Clinical Applications: Acromegaly Unit 6

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Anterior Pituitary Agents Hormone

Diagnostic Use

Thyroid-stimulating hormone (TSH; thyrotropin)

In patients who have been treated surgically for thyroid carcinoma, to test for recurrence by assessing TSH-stimulated whole-body 131I scans and serum thyroglobulin determinations Adrenocorticotropin In patients suspected of adrenal (ACTH, Cosyntropin) insufficiency, either central (CRH/ACTH deficiency) or peripheral (cortisol deficiency), in particular in suspected cases of congenital adrenal hyperplasia ©2014 Barkley & Associates

Unit 6

Posterior Pituitary Agents OXYTOCIN MOA: Effects: Clinical Applications:

Activates oxytocin receptors Increased uterine contractions Induction and augmentation of labor Control of uterine hemorrhage after delivery

OXYTOCIN RECEPTOR ANTAGONIST Atosiban MOA: Blocks oxytocin receptors Effects: Decreased uterine contractions Clinical Tocolysis for preterm labor Applications: Unit 6

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Posterior Pituitary Agents VASOPRESSIN RECEPTOR AGONISTS desmopressin, vasopressin MOA: relatively selective vasopressin V2 receptor agonist Effects: Acts in the kidney collecting duct cells to decrease the excretion of water; acts on extrarenal V2 receptors to increase factor VIII and von Willebrand factor Clinical Pituitary diabetes insipidus; pediatric primary nocturnal Applications: Enuresis; Hemophilia A and von Willebrand disease VASOPRESSIN RECEPTOR ANTAGONIST conivaptan, tolvaptan MOA: Antagonist of vasopressin V1a and V2 receptors Effects: Increase in water excretion, decrease in urine osmolality, increased serum sodium concentration Clinical Reduced renal excretion of water in conditions associated with Applications: increased vasopressin; hyponatremia in hospitalized patients ©2014 Barkley & Associates

Unit 6

Thyroid Physiology • Thyroid gland secretes hormones to normalize growth and development, body temperature and energy levels Pharmacology for Nurses: A Pathophysiologic Approach (4th Edition)

• Follicular cells in the gland secrete thyroid hormone, which actually consists of two different hormones: • thyroxine (T4) • tri-iodothyronine (T3) • Parafollicular cells secrete calcitonin, a hormone that is involved with calcium homeostasis Unit 6

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Thyroid Physiology • Secretes sufficient amounts of the thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) to maintain the basal metabolic rate which ensures normal growth and development • Hormones contain iodine as an essential part of the molecule • Hashimoto’s thyroiditis: autoimmune destruction of thyroid; most common presentation of HYPOthyroidism • Graves' disease: autoimmune disorder in which helper T lymphocytes stimulate B lymphocytes to synthesize antibodies to thyroidal antigens; most common form of HYPERthyroidism • Adjunct therapy for hyperthyroidism: beta-adrenoceptorblocking agents ©2014 Barkley & Associates

Unit 6

Values for Thyroid Function Tests Test Total thyroxine (T4) Total triiodothyronine (T3) Free T4 (FT4) Free T3 (FT3) Thyrotropic hormone (TSH) Unit 6

Normal Value 4.8-10.4 mcg/dL (62-134 nmol/L) 60-181 ng/dL (0.92-2.79 nmol/L) 0.8-2.7 ng/dL (10.3-34.7 pmol/L) 230-420 pg/dL (3.5-6.47 pmol/L) 0.4-4 μIU/mL (0.4-4 mIU/L)

Results in Hypothyroidism Low

Results in Hyperthyroidism High

Normal or low

High

Low

High

Low

High

High

Low ©2014 Barkley & Associates

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Thyroid Agents levothyroxine (T4) (Levothroid, Synthroid), liothyronine (T3) (Cytomel, Triostat), liotrix (Thyrolar), thyroid (Armour Thyroid, Thyroid USP) MOA: Activation of nuclear receptors results in gene expression with RNA formation and protein synthesis Indication: Hypothyroidism Comments: Maximum effect seen after 6–8 weeks of therapy Toxicity: symptoms of thyroid excess ©2014 Barkley & Associates

Unit 6

Anti-Thyroid Agents THIOAMIDES: methimazole (Tapazole), propylthiouracil (PTU) MOA:

Inhibit thyroid peroxidase reactions block iodine organification inhibit peripheral deiodination of T4 and T3 (primarily PTU)

Indication: Comments:

Hyperthyroidism Oral Delayed onset of action Methimazole duration of action: 24 hours PTU duration of action: 6–8 hours

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Anti-Thyroid Agents IODIDES: Lugol's solution, potassium iodide MOA: Indication:

Inhibit organification and hormone release reduce the size and vascularity of the gland Preparation for surgical thyroidectomy

Comments:

Oral; acute onset within 2–7 days

RADIOACTIVE IODINE131I (RAI) MOA: Radiation destruction of thyroid parenchyma Indication:

Hyperthyroidism

Comments:

Oral; half-life 5 days; onset of 6–12 weeks, maximum effect in 3–6 months; patients should be euthyroid or on betablockers before RAI; avoid in pregnancy/nursing mothers

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Adrenal Glands: Physiology Review Secrete 3 essential classes of steroids: 1. Gonadocorticoids:  Androgens > estrogens (less than testes or ovaries) 2. Mineralocorticoids:  Aldosterone accounts for 95%  Primary function is to regulate plasma volume (promote Na reabsorption and K excretion by the renal tubules)  Decreased plasma volume  kidneys secrete renin  production of angiotensin II  aldosterone secretion  promotes Na and water retention  Hyperaldosteronism: excessive aldosterone secretion usually a result of adrenal tumors, characterized by HTN and hypokalemia 3. Glucocorticoids:  More than 30 glucocorticoids are secreted  Cortisol (hydrocortisone) secreted in highest amount  Influence the function of most cells in the body Unit 6

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Glucocorticoids • Wide range of physiologic effects, including regulation of intermediary metabolism, cardiovascular function as well as growth and immunity • Hydrocortisone (cortisol): most important pharmacologically; prepares the body for long-term stress • Glucocorticoids & mineralocorticoids also called corticosteroids or adrenocortical hormones • Glucocorticoid & corticosteroid often used interchangeably, however “corticosteroid” implies both glucocorticoid and mineralocorticoid activity • Corticosteroids: primarily used as replacement therapy for adrenal insufficiency (lack of corticosteroid) and reduce inflammation & immune response ©2014 Barkley & Associates

Unit 6

Glucocorticoid Secretion Hypothalamus: Secretes corticotropin-releasing factor (CRF; CRF= CRH) travels to Pituitary: Causes release of ACTH travels to Adrenal cortex: Releases glucocorticoids Increased level of cortisol in the blood provides negative feedback to the hypothalamus & pituitary to shut off further release of corticosteroids Pharmacology for Nurses: A Pathophysiologic Approach (4th Edition)

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Effects of Glucocorticoids Physiologic Effects

Permissive effects: without glucocorticoids many normal functions become deficient: response of vascular and bronchial smooth muscle to catecholamines is diminished in the absence of cortisol and restored by physiologic amounts Effects are dose-related: become magnified when large amounts are administered

Metabolic Effects

Influence carbohydrate, protein and fat metabolism; stimulate gluconeogenesis

Catabolic and Antianabolic Effects

Involved in lymphoid and connective tissue, muscle, peripheral fat, bone and skin

Anti-Inflammatory & Immunosuppressive Effects

Reduce inflammation through suppression of inflammatory cytokines; inhibit macrophage function; reduce prostaglandin synthesis

Other Effects

Influence the nervous system; produce behavioral disturbances, suppress pituitary release of ACTH, GH, TSH ©2014 Barkley & Associates

Unit 6

Select Indications for Glucocorticoids Indication Comments Adrenocortical Insufficiency Acute: Initiate treatment immediately hydrocortisone (usually large doses initially) supplementation with mineralcorticoid (fludrocortisone) is delayed until hydrocortisone is reduced to 50 mg/day Chronic (Addison's Disease): Unit 6

Hydrocortisone supplemented with a mineralocorticoid (fludrocortisone) ©2014 Barkley & Associates

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Select Indications for Glucocorticoids Indication Comments Use of Glucocorticoids for Diagnostic Purposes Dexamethasone Diagnosis of Cushing's syndrome suppression test Cosyntropin Diagnose or exclude primary and stimulation test secondary adrenal insufficiency; Measurement of cortisol in serum for evaluation of adrenal dysfunction Cosyntropin 250 mcg IV x1 then check cortisol level at 30 minutes and 60 minutes ©2014 Barkley & Associates

Unit 6

Select Indications for Glucocorticoids Indication

Comments

Hyperaldosteronism Primary:

usually results from excessive production of aldosterone by an adrenal adenoma

Secondary:

spironolactone, an aldosterone receptorblocking agent can be used

Miscellaneous Corticosteroids and stimulation of lung maturation in the fetus

Unit 6

When delivery is anticipated before 34 weeks of gestation, intramuscular betamethasone 12 mg, followed by an additional dose of 12 mg 18-24 hours later, is commonly used ©2014 Barkley & Associates

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Select Indications for Glucocorticoids Nonadrenal Disorders         

Allergies (seasonal rhinitis) Chronic inflammatory bowel disease Asthma and COPD Edematous states caused by hepatic, neurological and renal disorders Neoplastic disease Post-transplant surgery Rheumatic diseases Shock Skin disorders (rashes, contact dermatitis, etc.) ©2014 Barkley & Associates

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Glucocorticoids 



 Unit 6

Many drug-drug interactions • Hyperglycemic effects may reduce effectiveness of the anti-diabetic agents • Combining with NSAIDs increase risk for PUD • Administering with non-potassium-sparing diuretics  hypokalemia and hypocalcemia Glucocorticoid prescribing strategies: • Use lowest possible dose to achieve therapeutic effect • Administer every other day to limit adrenal atrophy • Acute conditions: large amounts for a few days, then gradually decrease the dose until discontinued • Use inhalation, topical or intra-arterial routes to reduce the possibility of systemic effects Long-term administration  Cushing’s syndrome ©2014 Barkley & Associates

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Select Glucocorticoids Agent

AntiInflammatory* Short- to medium-acting glucocorticoids Hydrocortisone (cortisol) 1

Topical*

Salt-Retaining*

Forms Available

1

1

Oral, injectable, topical

Cortisone 0.8 Prednisone 4 Prednisolone 5 Methylprednisolone 5 Intermediate-acting glucocorticoids Triamcinolone 5

0 0 4 5

0.8 0.3 0.3 0.25

53

0

Oral, injectable, topical

Long-acting glucocorticoids Betamethasone

25-40

10

0

Oral, injectable, topical

Dexamethasone

30

10

0

Oral, injectable, topical

Mineralocorticoids Fludrocortisone

10

0

250

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* Potency relative to hydrocortisone

Oral Oral Oral, injectable Oral, injectable

Oral ©2014 Barkley & Associates

Diabetes

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Common Early Morning Hyperglycemia Problems 

Dawn Phenomenon: results when tissue becomes desensitized to insulin nocturnally – blood glucose becomes progressively elevated throughout the night 



Tx: Add or increase the bedtime dose of insulin

Somogyi Effect: nocturnal hypoglycemia develops, stimulating a surge of counter regulatory hormones which raises blood sugar 

Tx: Reduce or omit bedtime dose of insulin ©2014 Barkley & Associates

Unit 6

Biguanides Indications: Agents: MOA: Adverse Effects: Comments:

Unit 6

DOC; first line therapy for Type 2 DM metformin (Glucophage) decreases hepatic gluconeogenesis, improves insulin sensitivity, increases glucose utilization by muscle nausea, vomiting, diarrhea, decreased appetite, lactic acidosis Liver disease: avoid metformin Contraindicated: renal dysfunction (serum creatinine > 1.5 mg/dL (males) or 1.4 mg/dL (females)); monitor serum creatinine Promotes weight loss Special instructions for patients who require contrast ©2014 Barkley & Associates

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Insulin Secretagogues Indications: Agents: MOA: Adverse Effects: Comments:

Monotherapy or combination therapy for Type 2 DM nateglinide (Starlix), repaglinide (Prandin) stimulates insulin release from pancreas hypoglycemia, diarrhea, arthralgia, headache, sinusitis, upper respiratory infection Liver disease: use with caution May require dose adjustment for renal dysfunction Several drug-drug interactions Rapid onset (given with meals) Short duration of action (requires TID dosing) Nonsulfonylureas (Glinides) ©2014 Barkley & Associates

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Insulin Secretagogues Indications: Agents: MOA: Adverse Effects: Comments:

Unit 6

Monotherapy or combination therapy for Type 2 DM chlorpropamide (Diabinese), tolazamide (Tolinase), tolbutamide (Tol-Tab), glyburide (Diabeta, Micronase), glipizide (Glucotrol), glimepiride (Amaryl) stimulates insulin release from pancreas, enhances beta cell sensitivity to glucose hypoglycemia, nausea, bloating, weight gain, photosensitivity, disulfiram reaction (chlorpropamide) Use with caution in liver dysfunction Dose adjustment required for renal dysfunction Several drug-drug interactions Over time response to therapy may diminish Sulfonylureas ©2014 Barkley & Associates

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Thiazolidinediones Indications: Agents: MOA:

Monotherapy or combination therapy for Type 2 DM pioglitazone (Actos), rosiglitazone (Avandia) increases receptor sensitivity to insulin, decreases both insulin resistance and hepatic gluconeogenesis hepatotoxicity, weight gain, peripheral edema, rash, macular edema, heart failure exacerbation, increased risk of MI (rosiglitazone) Use with caution (if at all) in liver dysfunction Baseline LFT’s then periodically thereafter Several drug-drug interactions Contraindicated in NYHA class III or IV May increase risk of osteoporosis May increase risk of bladder cancer (pioglitazone) REMS program (rosiglitazone)

Adverse Effects: Comments:

©2014 Barkley & Associates

Unit 6

Alpha-glucosidase Inhibitors Indications: Agents: MOA: Adverse Effects: Comments:

Unit 6

Adjunct therapy only for Type 2 DM acarbose (Precose), miglitol (Glyset) reduces rate and extent of CHO digestion and absorption flatulence, diarrhea, abdominal pain, decrease absorption of iron (anemia) Do not use in renal dysfunction (creatinine > 2.0) Baseline LFT’s then periodically thereafter (acarbose) May influence the absorption of other drugs Contraindicated in malabsorption, IBD or intestinal obstruction Glucose (dextrose) is recommended for treating hypoglycemia as sucrose metabolism is inhibited ©2014 Barkley & Associates

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Glucagon-Like Peptide-1 Agonists Indications: Agents: MOA: Adverse Effects: Comments:

Monotherapy (exenatide) or combination therapy for Type 2 DM; generally considered as adjunct exenatide (Byetta), liraglutide (Victoza) increase insulin release in the presence of elevated glucose concentrations, decrease glucagon secretion in a glucosedependent manner and delay gastric emptying nausea, vomiting, diarrhea, headache, hypoglycemia, pancreatitis, teratogenic, injection site reactions, renal failure, thyroid tumors Several drug-drug interactions Contraindicated in severe renal dysfunction (both), h/o pancreatitis (both) or h/o thyroid cancer (liraglutide) Does NOT replace insulin REMS program ©2014 Barkley & Associates

Unit 6

Dipeptidyl Peptidase-4 Inhibitors Indications: Agents: MOA: Adverse Effects: Comments:

Unit 6

Monotherapy or combination therapy for Type 2 DM; generally considered as adjunct therapy sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta) Inhibit the degradation of GIP and GLP-1 increased risk of infection, headache, hypoglycemia, pancreatitis, hypersensitivity reactions, peripheral edema (saxagliptin) Several drug-drug interactions (saxagliptin) Contraindicated in ESRD (sitagliptin, saxagliptin) Dose adjustment in renal impairment (sitagliptin, saxagliptin) ©2014 Barkley & Associates

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GLP-1 and DPP-4 MOA:

http://casesblog.blogspot.com/2006/11/dpp-4-inhibitors-for-treatment-of.html ©2014 Barkley & Associates

Unit 6

Amylin Receptor Agonists Indications:

Adjunct therapy for Type 1 and Type 2 DM

Agents: MOA: Adverse Effects: Comments:

pramlintide (Symlin) Inhibit the degradation of GIP and GLP-1 abdominal pain, loss of appetite, nausea, vomiting, hypoglycemia, dizziness, headache, cough, fatigue Contraindicated in patients with hypoglycemic unawareness or gastroparesis Black box warning for individuals while driving Severe hypoglycemia with concurrent insulin or oral hypoglycemic agent When initiating pramlintide: reduce dose of any secretagogues; reduce insulin dose by at least 50%

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Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor Indications: Agents: MOA: Adverse Effects: Comments:

Type 2 DM; place in therapy currently unclear canagliflozin (Invokana) increases the excretion of urinary glucose polyuria, UTI, genital mycotic infections, hypovolemia, hyperkalemia, pancreatitis, renal impairment Adjust dose in renal impairment Avoid use in severe liver impairment Can cause severe hypoglycemia Safety/effectiveness not established in patients younger than 18 years Long-term safety issues (cardiovascular, cancer risk) Role not addressed in recent ADA guidelines More clinical trials will better establish their role ©2014 Barkley & Associates

Unit 6

Insulin Preparations Insulin Preparation

Onset of Action (hours)

Peak Action (hours)

Duration of Action (hours)

5-15 minutes

30-90 minutes