Flashcards in Ph- Antidiabetic drugs Deck (54):
What are the rapid-acting bolus insulins?
What is the short-acting bolus insulin?
What is the intermediate-acting basal insulin?
What are the long-acting basal insulins?
[for a LONG time i am going to have GLARing DEbT]
What are the 5 classes of oral agents for diabetes?
4. DPP-IV Inhibitors
5. SGLT2 inhibitors
What are the 3 sulfonylurea oral antidiabetic agents?
What is the mechanism of action of sulfonylureas?
What patients use these drugs?
How are they delivered?
MOA: stimulate insulin secretion from B-cells by binding to and inhibiting ATP-sensitive K channel.
These drugs are only useful in type 2 diabetics with functioning B-cells. Delivered orally 1-2x /day
What drug is the thiozolidinedione [TZDs] oral antidiabetic agent?
What is the mechanism of action?
pioglitazone [Thio, pio]
MOA: improves insulin sensitivity in peripheral fat, muscle by binding to and activating PPARs [TFs that regulate FA metabolism].
1. TZDs differentiate pre-adipocytes to adipocytes with increased storage for fast subcutaneously.
2. redistribute fat storage from muscle, liver, heart and pancreas to subcutaneous sites
3. direct effect to improve liver insulin sensitivity
What drug is the biguanide oral antidiabetic agent?
What oral antidiabetic drug is the DPP-IV inhibitor?
What oral antidiabetic drug is the SGLT2 inhibitor?
What is the glucagon-like peptide modulator?
GLP analog = liraglutide
How is insulin synthesized and secreted?
1. Synthesis: as a single chain preprohormone within the B-cells of the islet of langerhans
2. Processing: into a a molecule with disulfide linked alpha and beta chains by carboxypeptidase. C-protein is released.
3. Storage: in secretory vesicles in B cells until stimulus provokes it to release into hepatic circulation
How does the concentration of insulin differ from portal circulation and systemic circulation?
Insulin is 50-100microns/ml in portal circulation compared to 12 microns/ml systemically.
This concentration differential is NOT achieved with insulin replacement therapy
How much insulin is secreted per day for a normal pancreas?
What are the 2 phases by which it is released?
What is each phase required for?
The loss of which phase is one of the earliest defects in type 2 DM?
Pancreas normally secretes 25-30 units a day
Phase 1 = priming phase. Burst of secretion with food that occurs within the first 10 minutes.
This is required for:
1. normal hepatic sensitivity to insulin
2. normal body glucose homeostasis
Phase 2 = slower, delayed phase. Insulin is secreted over several hours after the first phase.
This is required for:
1. long term glucose control
Loss of phase 1 is one of the first defects in DM2
What is the difference between bolus dosing and basal dosing for insulin therapy?
What insulins are used for each type?
Bolus dosing is used to imitate the first phase of glucose secretion. It is given coinciding with meals to limit post-prandial hyperglycemia.
-rapid acting [lispro, aspart, glulisine] OR short-acting [normal insulin]
Basal dosing is used to maintain steady state insulin levels by suppressing glucose between meals and overnight.
-longer-acting = [glargine, detemir]
- intermediate = NPH
What is the goal of basal-bolus treatment?
It attempts to mimic normal kinetics of insulin secretion by combining a long/intermediate insuling with a rapid/short acting insulin.
For basal-bolus treatments, which can come premixed?
Which must be given as 2 separate injections?
1. NPH and regular insulin
2. NPH and [lispro, aspart, glulisine]
Theses are fixed ratios and are NOT flexible
Glargine cannot be combined physically with any other insulin prep and must be given as a separate injection
What about the structure allows rapid-acting insulins to be rapid-acting?
What are they given to treat?
What is the most commonly used preparation?
They have a mutation that makes them like normal insulin with a less stable hexamer. This makes them:
1. readily soluble
2. rapidly absorbed
They are given to treat post-prandial hyperglycemia and should be administered 5-10min before the meal.
The most common preparation is insulin pump
When should normal insulin be given?
30 minutes before the meal. You need to be careful that you actually eat the meal though, and eat as much as you had expected or else it can lead to hypoglycemia
When is NPH used to treat hyperglycemia? What are the two ways it can be delivered?
It is an intermediate-acting insulin and is used basally. Give it 2x daily.
The two ways it can be delivered are:
1. premixed with rapid or short acting insulin in a fixed ratio
2. mixed with rapid/short acting insulin just prior to administration in a flexible ratio
A patient comes in to refill a perscription of insulin. You ask which one they are on and they reply "I don't know. The cloudy one."
What insulin are they on? Why is it cloudy?
NPH and it is cloudy because it is mixed with protamine to reduce solubility.
How and when are long-acting insulins given?
They are usually given once daily at bedtime
What chemical factors allow glargine to be released slowly?
What chemical factors allow detemir to be released slowly?
Glargine = has AA changes that make it soluble at pH 4, but form microprecipitates at physiological pH. This results in slow dissolution and release after injection.
Detemir = has change at lysine29 which increases self-association and binding to albumin slowing the release of free insulin into blood.
Which long-acting insulin can be mixed with other insulins in preparation?
Which long-acting insulin is approved for pregnant women and children?
[glargine is NOT approved]
What is the peak action and duration of action of:
1. peak-1hr, duration- 3-4
2. peak- 2-4hr, duration 6-8
3. peak 6-8, duration 12-16
4. peak 3-9, duration up to 24hr
How do you calculate the total daily dose of insulin?
Once you calculate TDD, how must you further break it down?
Naive = body wt in kg x 0.5
On insulin = current daily amount
TDD needs to be 50% basal, 50% bolus.
Bolus = 450/TDD + 1800/TDD
What is the difference between intensive insulin therapy and traditional insulin therapy?
Intensive = flexible insulin dose that you can adjust to compensate for diet and exercise
Tradition = fixed dose. You need to cater what you eat and how much you exercise to the dose
How do continuous subcutaneous insulin infusion devices work?
Insulin pumps use mainly rapid acting insulin.
1. set basal rate to cover insulin requirements in absence of food. You can adjust it to be different "basal rate" at different times of the day [ex. raise basal in the morning bc people get "dawn phenomenon", lower it for times of exercise]
2. calculate mealtime boluses to cover calories and carbs consumed
3. correction dose to cover unexpected escursions of blood glucose. Given premeal with the bolus.
What are the 5 most adverse effects of insulin?
2. allergic reaction
3. local reaction
4. weight gain
5. aggravation of retinopathy
How is hypoglycemia treated in a diabetic that has taken too much insulin?
What if the hypoglycemia is SEVERE?
Rule of 15:
1. ingest 15g of glucose [4oz soda, 5 lifesavers]
2. wait 15 minutes
3. repeat until normal glucose levels are restored
If the hypoglycemia is severe, give patients a glucagon kit to acutely raise blood sugar
What has reduced the incidence of allergic rxn in people using insulin?
We used to use cow, pig insulin. Now we use human recombinant so usually there is no allergic rxn.
Occasionally, patients will make anti-insulin antibodies which leads to allergic rxn AND insulin resistance
What adverse effect can insulin have on injection site?
What limits the problem?
lipoatrophy - immune response
lipohypertrophy- lipogenic action of insulin
Rotating injection sites limits the problem
What are 3 causes for weight gain in patients on insulin?
1. no more glucosuria
2. insulin increases hunger
3. fear of hypoglycemia makes patients eat more
What are the 4 major disadvantages of using sulfonylureas [glyburide, glipizide, glimerpiride] ?
1. hypoglycemia in elderly and renal failure due to decreased drug clearance
2. weight gain ***
3. can't be used if patient has sulfa allergy
4. can have secondary failure as B-cells wane, poor durability
What are the 3 advantages of sulfonylureas?
1. low cost
2. early response
3. physiological source of insulin so no allergic rxns
How do TZDs work?
What are the 5 major advantages?
They bind PPARs in adipocytes to redistribute fat from liver, muscle, heart, pancreas to subcutaneous sites by improving insulin sensitivity.
1. address the main concern of type2 DM [peripheral insulin resistance]
2. 1x a day dose
3. lower serum TGs and raise HDL
4. NO hypoglycemia
5. improve NAFLD
What are the disadvantages of pioglitazone?
1. variable monotherapy response, potential drug interactions
2. black box warning that it may precipitate heart failure
3. takes wks-months for max response
4. weight gain [edema/fat]
6. LDL increase
7. bladder cancer
What is the mechanism of action of metformin?
What are the advantages?
It improves liver insulin sensitivity which:
1. decreases gluconeogenesis and hepatic glucose output and increases glucose uptake
2. slow glucose absorption from the gut
1. rapid onset of action
2. no weight gain, maybe weight loss
3. no associated hypoglycemia
4. improved lipid profile
What are the disadvantages of metformin?
1. lactic acidosis in patients with renal or liver impairment
2. GI effects [pain, diarrhea] so start low dose and titrate up
3. B12 deficiency
What is dosing for metformin?
take with meals 3x a day.
Can be combined with:
1. glipizide, glyburide [sulfonylurea]
2. pioglitazone [TZD]
3. sitagliptin [DPP-IV inhibitor]
What is the mechanism of action for GLP-1 analogs [Liraglutide]?
Mimic GLP1 but with a longer half life.
1. Stimulates insulin release and b-cell growth
2. decreases gastric emptying
3. suppresses glucagon
4. suppresses appetite
What are the advantages of liraglutide?
What are the disadvantages?
1. stimulates insulin release ONLY when glucose is hight
2. lower overall insulin secretion, lowers weight
3. increased b-cell mass [useful for type 1?]
1. only injectable
2. nausea/vomiting for weeks after initiation
3. acute pancreatitis exacerbation
4. *** cannot use for MEN mutation or family history of medullary carcinoma of the thyroid because it can cause parafollicular C cell hyperplasia
What is the mechanism of action of DPP-IV inhibitors?
DPP-IV degrades endogenous GLP1 and GIP. Inhibition of this enzyme leads to elevated GLP1 and GIP
In terms of total GLP1 levels, how do liraglutide and sitagliptin differ?
Liraglutide is a GLP1 mimic and raises it by a lot [pharmacological range]
Sitagliptin blocks degradation of endogenous GLP1 by blocking DPP-IV so it will raise GLP1 but only within the physiological range
What are advantages and disadvantages to sitagliptin [DPP-IV inhibitor]?
1. oral administration
2. hypoglycemia is rare when taken alone
3. less nausea, vomiting than liraglutide
1. no weight loss
2. not as potent as liraglutide
What is the mechanism of action of SGLT2 inhibitors? [canagliflozin]
Reduces blood glucose by lowering the renal threshold for glucose and increasing urinary glucose excretion [MILD osmotic diuresis, net calorie loss]
What are advantages and disadvantages of canagliflozin?
1. oral agent
2. hypoglycemia is RARE unless combined with insulin
3. method to lower glucose is independent of islet status so can be used at any stage of type 2
4. modest weight loss, BP improvement
1. ineffective if patient has renal insufficiency [GFR<45]
2. increased risk for genital infection in females and males
3. risk of hypotension in elderly esp if they are on diuretic/antihypertension meds
4. high LDL
What is the mainstay of therapy for type 1 diabetics?
Insulin in its various forms
What is the mainstay of therapy for type 2 diabetics?
Patient centered approach to design a good double or triple therapy using oral agents with or without insulin.
What factors should you consider when deciding what therapy choice to use with type 2 diabetes?
1. degree of HBA1c lowering desired
2. risk for hypoglycemia
3. concern of weight gain
5. compliance/patient attitude
6. duration of diabetes
7. comorbid conditions
8. risks of side effects
9. vascular complications
For MOST patients, starting with what drug is a safe, low cost, efficacious option?
When would you NOT use it?
Metformin - biguanide that improves insulin sensitivity in the liver
[Can't use it if the patient has renal/liver disease because it puts them at risk for lactic acidosis ]
After initial drug therapy for type 2 diabetes, when do you check HBA1c levels again? If HBA1c doesn't go down, what do you do?
2-3 months if HBA1c doesn't go down prescribe a second oral drug.
You can add a third drug 2-3 months after that.
If all orals fail--> insulin