Endocrine- DM Flashcards by Maggie McDonell

How is Insulin released?

What is the structure of insulin?

Insulin is released as proinsulin, a precursor molecule
Insulin is a small protein consisting of a chain of 21 amino acids linked by two disulfide (s-s) bridges to a Beta chain of 30 amino acids

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What is the MOA of insulin?

Insulin binds to plasma membrane receptors initiating an intracellular cascade of enzymatic events
- glucose diffusion into cell
- glucose storage mode (glycogen synthetase)
- uptake of amino acids, phosphate, K, and Mg
- protein syntheisis and inhibition of proteolysis
- increased fatty acid and triglyceride synthesis; decreased lipolysis
- regulate DNA/gene expression via insulin regulatory elements

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What is normal endogenous insulin physiology?

Portal circulation receives basal rate of 1 U per hour
With meals this rate of insulin secretion increases 5-10x
40U is average daily requirement
“units” is a term used to quantify potency
- i.e. ability to decrease serum BS
ANS does influence insulin secretion
- alpha decreases insulin secretion
- beta and PSNS increase insulin secretion

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Who needs insulin therapy?

Type 1 diabetics
- insulin dependent b/c their body produces NO insulin
Type 2 diabetics
- do not always produce enough insulin

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What are the three different ways insulin has been made over time?

Stage 1: insulin was extracted from the glands of cows and pigs
Stage 2: Pig insulin was converted into human insulin by removing the one amino acid that was different and replacing it with human kind
Stage 3: Insert human insulin into E.coli and culture the recombinant E.coli to produce insulin. (Humulin)
- Yeast can also be used (Novolin)
- recombinant method has also made it possible to have insulins that work faster or slower than regular

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What are the different types of insulin?

Ultrarapid acting
- Lispro (humalog)
- Aspart (Novolog)
- Glulisine (apidra)
Short acting
- Regular (humulin R, novolin R)
Intermediate acting
- NPH (humulin N, Novolin N)
Long acting
- Glargine (lantus)- has no peak
- Detemir (levemir)
- ultralente

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How do the peak effects of the different SQ insulins vary?

(graph)

short duration, fast acting (lispro)- 1-2 hours
short duration , slow acting (regular)- 3-4 hours
intermediate duration, slow acting (NPH)- 6-7 hours
long duration, slowest acting (glargine)- no peak

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Random insulin considerations:

HOw can insulin be administered?

What are the benefits of all the different options?

Which insulin can you not mix with any others?

Insulin can be administered parenterally and nasally
- SQ is most common
Benefits of different onsets/durations:
- rapid- convenient, can inject minutes before a meal
- mixtures (rapid/NPH)- R covers breakfast, NPH covers lunch; R covers dinner, NPH covers o/n
- Long acting- mimics basal insulin
Do not mix Glargine with any other insulins

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What are the pharmacokinetics of IV regular insulin?

E1/2t

DOA

metabolism

formulation?

E1/2t- 5-10 minutes
DOA- 30-60 minuts
- longer than you would expect with short 1/2t b/c insulin tightly binds to receptors
Metabolized in liver and kidney by proteolytic enzymes
Only the U100 formulation should be used
- there is a U500 formulation that should never be administered IV

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Onset, peak, duration, and Use for: (table)

Rapid acting (lispro)

short acting (regular)

intermed (NPH)

Long acting (glargine)

ultralong ancting (dugludec)

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What are some of the convenient ways to administer insulin?

insulin pens

jet injectors

insulin pumps (be sure to disable/remove)

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What are the adverse effects of insulin?

Injection site rxns
lipodystrophy at injection site
protamine allergy
weight gain
HYPOGLYCEMIA
- diaphoresis, tachycardia, HTN, CNS agitation, sz, coma

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What drugs interact with insulin?

Appose the hypoglycemic effects of insulin:
- ACTH, glucagon, estrogens
Decrease release of insulin and stimulates mobilization of glucose:
- epinephrine
prolongs DOA:
- tetracycline, chloramphenicol, salicylates
Increase hypoglycemic effects
- MAOIs

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Pacito a pacito,

suave suavecito…

…..Des-pa-cito!!

¡Vamos a una playa en Puerto Rico!!

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How much does 1U insulin decrease BS in a pt with type 1 DM?

Type 2 DM?

Type 1- 1U decreases BS by 40-50 mg/dl
Type 2- 1U decreases BS by 30-40 mg/dl
**individual sensitivity is highly variable!

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What are the benefits of tight control of BS?

tight control reduces the risk of chronic complications in type 1 diabetics
may affect surgical morbidity and mortality
- increased wound healing
- decreased infection
- decreased osmotic diuresis
- decreased incidence of diabetic ketoacidosis

What are the drawbacks of tight control of BS?

risk of hypoglycemia
- can cause permanent neurological damage
- signs and symptoms are masked by anesthesia
tight control is labor intensive
requires BS monitoring q30 min

How do you treat hyperkalemia with insulin?

10 U RegularIV and 25 g of glucose (1 amp of 50% dextrose solution over 5 minutes)

How do you treat hypoglycemia?

Critical to avoid brain damage and death!
If conscious, give fast acting oral sugar
If under anesthesia/impaired, 25-50 ml of 50% dextrose

What are the different types of oral antidiabetic medications?

How do they work?

*bolded answers are the ones that have risk of hypoglycemia

Sulfonylureas- increase insulin secretion from Beta cells
Biguanides- increase insulin sensitivity at target tissue
Thiazolidinediones- increase insulin sensitivity at target tissues
Alpha-glucosidase inhibitors- slows absorption from the gut
Meglitinides- increase insulin secretion from B cells
GLP-1 Mimetics/Gliptins (DPP-4 inhibitors)- increase insulin from B cells

Sulfonylureas

MOA

MOA- stimulate release of insulin from pancreatic beta cells
- binds to ATP sensitive K channels in the cell membrane resulting in depolarization, Ca influc and insulin release

What are the Sulfonylureas that we use?

What are each of their DOA?

second generation- 100x more potent with less SE than first generation
- glipizide- DOA 12-24 hours
- Glyburide (Micronase, Diabeta)- DOA 18-24 hours
- Glimepiride (Amaryl)
first generation (don’t use)
- Tolbutamide (Orinase)- DOA 6-12 hours
- Chlorpropamide (Diabinese)- DOA 36-72 hours

Pharmacokinetics of Sulfonylureas:

metab

What should you use with renal impairment?

How long should it be held pre-op?

90-98% PB (albumin)
All metabolized hepatically, some have active metabolites; avoid in hepatic disease
If renally impaired, use glipizide or tolbutamide- completely metabolized to inactive or weakly active states
SE
- GI- nauesea, fullness, heartburn, cholestasis, appetite stimulant
- GU- ADH like effect, Na and H2O retention
- Derm- pruritis, rash
- Hypoglycemia
Hold 24-48 hours pre-op

Biguanides

only drug

MOA

excretion

clinical effects

Metformin (Glucophage)
MOA
- decreases hepatic and renal glucose producition (gluconeogenesis and glycogenolysis)
- enhances insulin receptor binding
- increases glucose utilization and decreases insulin resistance
Excreted by kidneys
Clinical effects:
- decreases FPG 60 mg/dl
- additive effect with sulfonylureas

Biguanides (Metformin) benefits adverse effects contraindications

* Benefits * no wt gain, even modest wt loss * may increase HDL, decrease LDL and TG * Hypoglycemia rare when used alone * Adverse effects * GI distress- diarrhea/nausea * lactic acidosis * rash * Contraindications * ESRD (CR\>1.4) * hepatic dysfunction * CHF, shock, hypoxic pulmonary disease

What are the Thiazolidinediones (TZDs) MOA

* Pioglitazone (Actos) * Rosiglitazone (Avandia) * MOA * **Improves insulin sensitivity/decreases resistance** * especially in skeletal muscle and adipose tissue * Reduces hepatic glucose production * requires the presence of insulin for effect

Thiazolidinediones Clinical effect pharmacokinetics other effects

* Clinical effects: * decreases FPG up to 50 mg/dl * decreases Hgb A1c 1-2% * Pharmacokinetics * PO * hepatic metabolism * Other effects- resumption of ovulation in premenopausal women who were experiencing anovulation from insulin resistance

Thiazolidinediones Major adverse effects

* Adverse effects: * edema * weight gain * hepatoxicity- monitor LFTs, counsel pts about symptoms of jaundice * BLACK BOX * CHF- can cause or exacerbate * MI

What are the Alpha-glucosidase inhibitors? MOA?

* Acarbose (Precose) * Miglitol (Glyset) * MOA * Competitively and reversibly antagonizes enzymes in the intestinal brush border responsible for digesting complex carbs * delays glucose absorption * lowers post-prandial hyperglycemia

Alpha-glucosidase inhibitors clinical effect pharmacokinetics adverse effects

* clinical effect * Only decreases FBG 25-30 mg/dl * decreases PPG 60-70 mg/dl (post prandial) * decreases HghA1c 0.7-0.9% * Pharmacokinetics * Taken with first bit of food * not absorbed after oral administaration * excreted in stool * Adverse effects * GI- distension, pain, diarrhea, flatulence * Caution in pts with IBD, UC, obstruction

What are the Meglitinides? MOA?

* Repaglinide (prandin) * Nateglinide (Starlix) * MOA * stimulates insulin secretion from the B cells * quick onset and peak effect (1 hour) * short DOA (4 hours) * reduces PPG

How are Meglitinides administered? SE?

* Dosing PO * 15-30 minutes before a meal * skip a meal, skip a dose * SE * similar to sulfonylureas * hypoglycemia * GI- N/V/C/D, heartburn * HA

How do the GLP-1 Agonists and Mimetics "Gliptins" work?

* Inhibit DPP-4 (dipeptidyl peptidase), an enzyme that inactivates incretin hormones (GLP-1) * Enhances glucose-dependent insulin secretion * reduces glucagon secretion * exhibits other anti-hypoglycemic actions once released from the gut including decreased appetite and slowing gastric emptying

What GLP-1 agonist do you especially have to worry about risk of aspiration with?

* Sitagliptan (Januvia) * E1/2t 12 hours * modestly reduces PPG and FPG * SE comparable to placebo

What type of drug is Exenatide (Byetta)?

* Injectable (SQ) Synthetic GLP-1 analog that mimics GLP-1 * nearly identical affects as gliptins * adjuct to metformin or sulfonylureas * no wt gain * Adverse effects: * N/V * some pts develop antibody agains the drug * pancreatitis- potentially fatal * renal failure- 1:13,000 (transplant required) * hypersensitivity * delayed gastric emptying

What are the Amylin Mimetics?

* Pramlintide SQ- synthetic analog of amylin, a pancreatic hormone released with insulin, that decreases gastric emptying, decreases glucagon secretion, and increases sensation of satiety * Reduces PPG * peakse 20 min after injection, 49 min 1/2 life * metabolized in kidneys * enhances insulin effects * SE- **hypoglycemia**, decreased absorption of drugs (ABX, oral contraceptives 1 hr before or 2 hr after injection)