Endocrine- DM Flashcards
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
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
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
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
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
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
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
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
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
Onset, peak, duration, and Use for: (table)
Rapid acting (lispro)
short acting (regular)
intermed (NPH)
Long acting (glargine)
ultralong ancting (dugludec)
What are some of the convenient ways to administer insulin?
insulin pens
jet injectors
insulin pumps (be sure to disable/remove)
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
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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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!
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:
PB
metab
What should you use with renal impairment?
SE
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
-
Improves insulin sensitivity/decreases resistance
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)
