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Endocrinology I -
Exam #4 info
93
Pharmacology
Graduate
06/07/2010

Additional Pharmacology Flashcards

 


 

Cards

Term
Insulin
Definition

 

  • synthesized in pancreatic β cells as proinsulin
  • proinsulin is processed to form C-Peptide and  insulin
  • all commercially available insulin contains only active insulin peptide
  • controls storage and metabolism of carbohydrates, proteins, and fats (activity occurs 1º in liver, muscle, & fat tissue)

 

Term
Release of insulin
Definition

release from pancreas is stimulated by increased blood glucose, incretins, vagal nerve stimulation, ...etc.

 

(incretins = local hormones produced in GI tract)

Term
Physiologic effects of insulin
Definition

  1. Facilitates entry of glucose into muscle, adipose and several other tissues 
  2. stimulates liver to store glucose as glycogen
    • both 1 & 2↓ [glucose] in blood
  3. Stimulates lipogenesis (liver)
  4. Inhibits lipolysis (release of FFA from adipose)
  5. Stimulates protein synthesis
  6. Promotes an intracellular shift of K+ and Mg+, thus appears to temp. ↓ elevated blood [ ] s of theses ions

Term
What happens in diabetes
Definition

  • Impaired insulin secretion (Type I)
  • Abnormal muscle and fat metabolism → insulin resistance (Type II)
  • Increased hepatic lipid production

Term
Insulin resistance
Definition

less glucose utilization at muscle, liver, fat →  

 ↑ hepatic glucose output → hyperglycemia

Term
effects of increased lipid production seen with diabetes
Definition
FFA flux from adipocytes is increased, leading to increased lipid (VLDL and triglycerides) synthesis in hepatocytes
Term
Manufactured Insulin
Definition

  • Recombinant DNA tech now exclusively used
  • consist of the aa sequence of human insulin or variations thereof
  • animal source insulin no longer used

Term
Insulin classifications
Definition

  • Rapid acting (e.g. insulin analogs aspart, lispro)
  • Short acting (e.g regular insulin)
  • Intermediate acting (e.g. NPH)
  • Long-acting (e.g. insulin analogs glarginie and detemir)

Term
Prandial insulin
Definition

given around meals

(rapid and short acting insulin)

Term
differences among insulin preparations 
Definition

  • differ mainly in onset, peak and duration of action following SC administration
  • by adding either protamine or zinc to pure insulin, its action can be prolonged
  • inter-individual and intra-individual variation in above values may occur based on site of injection, injection tech., tissue blood supply, temp., presence of insulin Abs., exercise, excipients in insulin formulations, and individual response

Term
Basal insuin
Definition

  • given regardless of meals, at constant longer acting levels 
  • no peak
  • provide insulin required to maintain body functions
  • long acting and intermediate (mostly considered basilar, but gives a peak: does not last all day)

Term
Rapid acting insulin
Definition

  • Insulin Analogs
  • Better for paitents than regular insulin b/c:
    • Onset is quicker, peak is closer to hyperglycemic effect due to meals, and duration is shorter so hypoglycemic effect is not prolonged past meals
  • Examples: Aspart, lispro, inhalation 

Term
Short acting 
Definition
Regular insulin 
Term
Intermediate acting insulin
Definition

mostly considered basilar, but gives a peak and does not last all day (duration = 10-16 hrs)

  • example: NPH

Term
 Long acting insulin
Definition

insulin analogs glargine, detemir

 

provide constant low levels of insulin for entire day

Term
Premixed formulations of insulin
Definition

 

  • usually contain intermediate with short acting insulins
  • provide short onset with prolonged duration 
  • must be given with meals (or will cause hypoglycemia)
  • not good choice for newly diagnosed patients

 

Term
Insulin analogs
Definition
synthetically derived preparations from human insulin with slightly modified aa sequence resulting in altered PKs
Term
Lispro, aspart, glulisine
Definition

  • Rapid acting (prandial) insulin preparations
  • equal or better efficacy than regular insulin
  • less hypoglycemia than regular insulin

 

 

Term
Inhaled insulin
Definition

  • Rapid acting insulin prep
  • significant respiratory side effects (↓ FEV, infections, cough)

 

 

Term
regular insulin
Definition

  • inject SC 30-45 min before meal
  • can be used IV: immediate action, shorter duration

Term
NPH (nerual protamine hagedorn)
Definition

  • addition of protamine results in longer duration and more delayed peak compared with regular insulin
  • given 1 or 2x per day
  • considered basal insulin
  • evening admin can cause nocturnal hypoglycemia

Term
Glargine
Definition

 

  • peak-less basal insulin
  • pH = 4: precipitates upon injection (in neutral body pH) and acts as depot providing slow continuous release

 

Term
Detemir
Definition

  • exhibits intermediate and long acting action
  • dose-dependent onset and duration of action
  • considered a basal insulin

Term
Complications of insulin
Definition

  • hypoglycemia
  • insulin allergy
  • immune insulin resistance
  • lipodystrophy at injection sites

Term
Management of hypoglycemia
Definition

Conscious patient:

Dextrose tablets (1st choice)

orange juice or glucose gel

 

Unconscious patient:

IV dextros 50% (if IV access available)

Glucagon IM

Term
Insulin secretagogues
Definition

2 classes:

Sulfonylureas (2nd generation agents)

Meglitinides

 

- Both classes have same mech of action:

promote insulin secretion from β cells of pancreas

- Classes have different PKs

Term
Sulfonylureas
Definition
  • a class of insulin secretagogues
  • used as monotherapy or in combo 
  • average ↓ in HgA1C = 1.5%
  • Main adverse effects:
    • weight gain
    • Hypoglycemia
  • frequent loss of efficacy over long period of time (due to depletion of insulin from β cells) (add another agent if this occurs)
Term
dosing of sulfonylureas
Definition

 

  • due to gradual loss of β cell function, glucose lowering effect plateaus at ≈ 1/2 max recommended dose
  • therefore, do not give patient more than 1/2 max recommended dose. Will achieve better results if a 2nd agent is added instead
  • start slow an ↑ q2-4 weeks (especially in elderly with renal insufficiency)

 

 

 

Term
names of sulfonylurea drugs
Definition

Glyburide

Gliqizide

Glimepiride

Term
Sulfonylureas PKs
Definition

t1/2: 5-10 hrs

duration: glyburide and glimepride 24 hrs; glipizide 12-24 hrs

Metabolism: Mainly Hepatic, also renal component

Term
Meglitinides
Definition
  • class of insulin secretagogues
  • oral agents that act like insulin
  • controls post-prandial hyperglycemia
  • ↓ dose in elderly or pts not previously treated with hypoglycemic agents
  • Adverse effects: Weight gain, Hypoglycemis

 

Term
meglitinides PKs
Definition

 

  • rapid and complete oral absorption
  • Hepatic metabolism, with some renal excretion
  • shorter duration, onset, and t1/2 than sulfonylureas

 

Term
Example of Biguanides
Definition

Metformin / glucophage

  • average ↓ in HbA1C = 1.5%
  • used as monotherapy or in combination with other agents

Term
Mechanism of action of biguanides (metformin)
Definition

 

  • Main mechanism: ↓ hepatic glucose production by ↑ hepatic sensitivity to insulin
    • requires insulin therefore, only used for type II
  • 2º mechanisms: ↑ peripheral glucose uptake & utilization
    • insulin sensitizer (counters insulin resis.)
  • Other metabolic effects:
  • ↓ triglycerides and LDL, ↑ HDL (?)
  • weight reduction or stabilization
  • impairs hepatic metabolism of lactic acid

 

 

Term
PKs of metformin
Definition

 

  • Onset: within days
  • negligible protein binding
  • Not metabolize by liver
  • excreted in urine (90% unchanged)

 

Term
Contraindications of Metformin
Definition
  • Renal disease
    • serum creatinine > 1.5 mg/dl in males, or 1.4 in females
  • alcoholism
  • hepatic disease
  • conditions predisposing to tissue anoxia (due to risk of lactic acidosis)
  • Hold for 48 hrs after radiologic tests using iodinated contrast (can be renally toxic)
Term
Adverse effects of Metformin
Definition

 

  • GI (20%) - titrate dose slowly, give with food, or use extended release form)
  • <1% lactic acidosis (dose related)
  • ↓ B12 absorption (with long term therapy)

 

Term
Ideal candidates for metformin therapy
Definition

  • obese patient with type II diabetes mellitus
  • normal kidney function
  • no contraindications or other conditions predisposing to development of lactic acidosis

Term
Thiazolidinediones (TZD) mechanism of action
Definition

  • improve insulin sensitivity via multiple actions on gene regulation (requires insulin)
  • Stimulate a nuclear receptor peroxisome proliferator-activated receptor (PPARγ) 1º in adipose, and less so in muscle and liver
  • Promotes glucose uptake by adipose, spare skeletal muscle, and liver from harmful metabolic effects of high FFFA (keeps fat where it belongs) 

Term
TZD agents
Definition

Piglotazone 

Rosiglitazone

combination products: Avandemet, avandaryl, ActoPlusMet

Term
PKs and PDs of TZD
Definition

  • onset of action takes weeks to months
  • extensive liver metabolism by CYP450, excretion not renal dependent
  • High protein binding >99%

Term
Effects of TZD use
Definition

  • used as mono or combo therapy
  • do not contribute to hypoglycemia
    • combo of TZD and metformin has advantage of not causing hypoglycemia
  • Average ↓ HgA1C = 1%
  • long term: ↓ triglycerides, slight ↑ HDL and LDL (minor effects)

Term
Adverse effects of TZDs
Definition

 

  • Weight gain (dose related)
  • Fluid retention
    • presents as anemia (↓ Hgb adn Hct) and peripheral edema
    • occurs more frequently when used in combo with insulin
    • may precipitate heart failure (not recommended for class III or IV HF)
  • Hepatotoxicity: hepatic failure, hepatitis

 

Term
α-Glucosidase inhibitors (AGI)
Definition

 

  • "Starch blockers"
  • produces modest drop in HgA1c 0.5-1%
  • Not absorbed systemically, therefore lack hypoglycemia and weight gain
  • hypoglycemia may occur with concurrent sulfonylurea treatment
  • Rarely used as monotherapy due to mild efficacy

 

Term
AGI agents
Definition

Acarbose

Miglitol

Term
AGI mechanism of action
Definition

 

  • work locally in GI
  • competitively inhibit intestinal a-glucosidases at brush border and ↓ postprandial digestion and absorption of starch and disaccharides

 

Term
Adverse effects of AGIs
Definition

  • GI: flatulence, diarrhea, and discomfort (due to undigested carbs reaching lower bowel where gas is produced by bacterial flora)
    • products containing alpha glucosidase (i.e. beano) interfere with therapeutic action and are contraindicated in combo
    • use antacids and bismuth for relief of GI side effects

Term
Contraindications of AGIs
Definition

 

  • patients with inflammatory bowel disease or any intestinal condition that could be worsened by gas and distention
  • Miglitol should not be used in renal failure

 

Term
AGI excretion
Definition

Miglitol: urine (95% unchanged drug)

- do not use in renal failure

 

Acarbose: mostly fecal; urine (2%)

Term
AGI dosing
Definition
Start at half recommended dose and gradually increase over 4-6 weeks
Term
Incretin effect
Definition
  • insulin response to an oral glucose load exceeds that measured after IV administration of equivalent amount of glucose
Term
Incretins
Definition

 

  • Hormones that produce gut-derived signals in response to oral nutrient intake 
  • stimulate glucose dependent insulin secretion
  • inhibit glucagon release
    • both these actions lower blood glucose 

 

Term
Examples of incretin hormones
Definition

  • Gastric inhibitory polypeptide (GIP)
  • Glucagon like peptide-1 (GLP-1)

Term
incretin effects in diabetes
Definition

  • GIP: effects on insulin secretion are weak or absence in type 2
  • GLP-1: insulin secretion in response to GLP-1 are mostly preserved
    • can use GLP-1 as mediator to insulin secretion

 

Term
Physiologic actions of GLP-1
Definition

  • short t1/2 of 2 minutes
  • many options now available to ↑ t1/2:
    • Incretin mimetics
    • DPP-4 inhibition

Term
Incretin mimetic agents
Definition

Exenatide

Liraglutide

 

analogues of GLP-1, prolong t1/2 of GLP-1

Term
mech of action of incretin mimetics 
Definition

 

  • GLP-1 analogues (stimulate glucose dependent insulin secretion)
  • ↓ HgA1c by additional 1%, when adjunct to sulfonylureas or metformin
  • Weight loss has been demonstrated
  • slows gastric emptying, ↓ post-prandial glucagon secretion (lowers hyperglycemia after meals)

 

Term
Incretin mimetics contraindications
Definition

  • Exenatide: not recommended in ClCr < ml/min
  • no dose adjustment of Liraglutide is reccommemded with kidney impairment
  • administer other meds at least 1 hr prior to incretin mimetics to avoid ↓ rate of absorption (due to slowing of gastric emptying)

Term
Adverse effects of incretin mimetics
Definition

  • nausea and vomiting (up to 44% with higher doses) generally subsides with continued use
  • Hypoglycemia (only if given with sulfonylurea)

Term
Dipeptidyl-Peptidase 4 inhibitors (DPP-4 Inhibitors)
Definition

  • Prevent breakdown of GLP-1 and enhance GLP-1 function
  • referred to as "gliptins"

 

Term
DPP-4 inhibitor mechanism of action
Definition

 

  • GLP-1 is rapidly degraded by DPP-4 enzyme. 
  • DPP-4 found throughout body, but highest [ ]s found in intestines, kidneys, lymphocytes, and bone marrow
  • DPP-4 inhibitors prevent degradation of incretin hormones by DPP-4, thereby enhancing their fxn to ↑ insulin release and ↓ glucagon levels in circulation

 

Term
DPP-4 inhibitor products
Definition

Sitagliptin

Saxagliptin

Term
indications for use of DPP-4 use
Definition

  • adjunct to diet and exercise to improve glycemic control in type 2 diabetes
  • monotherapy or combo with metformin or TZD, when single agent with diet and exercised does not provide adequate glycemic control

Term
Pharmacological effects of DPP-4 inhibitors
Definition

  • stimulation of insulin secretion
  • inhibition of glucagon secretion
  • do not slow gastric emptying or cause weight loss (in contrast to GLP-1 agonists)

Term
PKs of DPP-4 inhibitors
Definition

  • reduce dose of sitagliptin and saxagliptin in renal failure

Term
adverse effects of DPP-4 inhibitors
Definition

  • generally mild
  • upper respiratory tract infection, headache, nasopharyngitis, pancreatitis (sitagliptin)
  • do not cause severe hypoglycemia or weight gain

Term
GLP-1 analogues vs DPP-4 inhibitors
Definition

         GLP-1 analogues DPP-4 inhibitors

Incretin:   Mimetic ;enhancer

Nausea: More; Less

GI effects: significant; fewer

weight: loss; neutral

renal dys: not reccommended; adjust dose

HgA1c ↓: .8-1%; 0.6-0.8%

form: injectable; tablet

Term
Amylin mimetic products
Definition
Pramlintide
Term
Amylin
Definition

  • Hormone, co-secreted with insulin by β cells
  • Type 1 diabetes: absolute deficiency of amylin and insulin
  • Type 2: relative deficiency of amylin and insulin
  • amylin replacement may provide benefits when combined with insulin, and can be used with type 1 & 2 DM

Term
Physiologic actions of amylin
Definition

  • delays gastric emptying
  • suppressed glucagon secretion
  • ↓ appetite and produces weight loss (central mechanism)

Term
Pramlintide side effects
Definition

  • ↑ risk of insulin-induced hypoglycemia
    • most common in 1st 3 months of therapy
    • in both type 1 & 2 DM
    • occurs with in 3 hrs of injection
    • ↓ prandial insulin dose by 50% when pramlintide is started
  • GI: Nausea, anorexia, vomiting
  • slight weight loss

Term
Pramlintide dosing
Definition

  • give immediately before meal by injection
  • ↓ prandial insulin dose by 50% when pramlintide is started

Term
Pramlintide place in therapy
Definition

 

  • only as adjunctive therapy with mealtime insulin in patients with type 1 or 2 diabetes who have failed to achieve desired glucose control despite optimal insulin therapy.
    • in type 2: may be used with or without sulfonylureas or metformin
  • ↓ in HgA1c is minimal (0.3-0.4%)

 

Term
Adrenal cortex hormones
Definition

Adrenocorticoids = steroid hormones secreted by the adrenal cortes. (aka adrenal steroids)

 

2 classes:

  1. Glucocorticoids 
  2. Mineralocorticoids

Term
Glucocorticoids
Definition

  • class of steroid hormones, released by adrenal cortex
  • affect carbohydrate metabolism
  • eg. cortisol, hydorcortisone

 

Term
Mineralocorticoids
Definition

  • class of steroid hormones, released by adrenal cortex
  • affect electrolyte and water balance in body tissues
  • e.g. aldosterone

Term
Zones of the adrenal cortex
Definition

3 layers:

  1. outer = zona glomerulosa: produces mineralocorticoids
  2. Middle = zona fasciculata: produces glucocorticoids
  3. inner = zona retucularis: produces adrenal androgens

Term
adrenocorticoid mechanism of action
Definition

  • bind specific cytoplasmic receptor targets in tissue
  • receptor-hormone complexes translocated into nucleus and attaches to gene promotor elements to turn genes on or off (depending on tissue)

Term
adrenocorticoid receptor locations
Definition

Glucocorticoid receptors: widely distributed throughout the body

 

Mineralocorticoid receptors: confined to excretory organs (kidney, colon, salivary and sweat glands)

Term
biological activity of adrenocorticoids
Definition

structure determines biological activity (glucocorticoid vs. mineralocorticoid)

  • hydrocortisone has equal activity at both receptor types
  • others have strong preference 

Term
Metabolic effects of Corticosteroids
Definition

  • ↑ gluconeogenesis, antagonize actions of insulin
  • ↑ serum glucose (hyperglycemia)
  • Glycogen synthesis
  • inhibit peripheral glucose uptake

Term
Catabolic effects of Corticosteroids
Definition

  • Protein (negative nitrogen balance), except liver
  • Stimulate lipolysis
  • lymphoid tissue (produce lymphocytopenia)
  • Muscly, C.T., bone, skin atrophy
  • Peripheral fat (↑ fat redistribution from peripheral to central areas of body)

Term
GI tract effects of Corticosteroids
Definition

  • ↓ Calcium and iron absorption
  • ↑ acid, pepsin (can ↑ chance of ulcer)
  • ↓ local immune response against H. pylori 
  • antiemetic activity

Term
 effects of Corticosteroids on fetal lung
Definition
accelerate lung maturation
Term
effects of Corticosteroids on CNS
Definition

  • Euphoria and behavioral changes
  • ↑ alpha rhythm of EEG and induce depression

Term
effects of Corticosteroids on hematopoietic system
Definition

  • ↑ in neutrophil count and platelets (WBC will ↑ after few days of use)
  • ↓ in lymphocytes (T and B cells), monocytes, eosinophils, and basophils
  • inhibit function of tissue macrophages  and T cells (↓ phagocyte competence)

Term
effects of Corticosteroids on kidneys
Definition

  • ↑ reabsorption of water, sodium, chloride
  • ↑ excretion of potassium, calcium

Term
effects of Corticosteroids on cardiovascular system
Definition
↑ BP (↑ blood volume, adrenergic stimulation on small vessels) - minor effect
Term
effects of Corticosteroids on endocrine system
Definition
  1. during long term use, HPA axis suppression develops (atrophy of adrenal cortex)
  2. inhibit Vitamin D mediated absorption of Ca+
    • may lead to hyperparathyroidism, therefore to an increase in bone resorption
    • long term use may lead to osteoporosis

 

Term
HPA axis suppression due to  corticosteroid use
Definition

(Hypothalamic-pituitary-adrenal)

  • this depends on dose, frequency, time of administration & duration of glucocorticoid use
  • patients develop cushingoid (hypercorticism) features
  • chronic use should be tapered slowly with gradually decreasing doses

Term
Discontinuance of corticosteroid use
Definition

  • withdrawal following long term use (> 2 wks) with pharmacologic dosages of systemic glucocorticoids should be very gradual until recovery of HPA axis function occurs
  • many methods for this described

Term
When to avoid corticosteroids 
Definition

  •  
    • peptic ulcer
    • heart failure
    • certain infectious illnesses (varicella and TB - immune suppressed pts)
    • psychoses
    • diabetes 
    • osteoporosis

Term
Inhibitors of adrenocorticoid biosynthesis
Definition

Mitotane

Aminogluethimide

Ketoconazole

Metyrapone

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