Pharm Diabetics- Melissa** Flashcards by Leah Stalnaker

Describe briefly the 2 steps of insulin biosynthesis.

What is REQUIRED for insulin release by B cells?
What is released in granules containing insulin?

-Preproinsulin–> Proinsulin (RER)
-Proinsulin + Ca-dep endopeptidase make sec. granules
(golgi)

CALCIUM is required for release of insulin by B cells!!

Granules release: Insulin/C-peptide/Amylin

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What are the three forms of insulin and how is it stored?

Which form is biologically active?

Insulin is chelated to ZINC + stored in secretory granules:

monomer (biologically active– short acting insulin)
dimer
hexameter (storage from– long acting insulin; larger complex, longer to diffuse)

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What is the strongest stimulus of insulin release?

What are the 6 steps to insulin release + what is released along with insulin?

GLUCOSE = strongest stimulus for insulin release by B cells

Glucose uptake–> G6P–> ^ ATP/ADP ratio–>
CLOSE ATP-dep K+ channels–> OPEN VGCa++ channels–>
^ INTRACELLULAR Ca++–> release insulin, amylin, and C-peptide

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Why is an oral glucose tolerance test superior to IV?

Oral glucose stimulates GASTRIN, SECRETIN, and other GI hormones that promote insulin release

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How does glucagon influence insulin production?

Glucagon ^ insulin production as compensatory mechanism

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What are 4 digestive hormones/ products that ^ insulin production?

What are four things that block insulin release

Gastrin and secretin (hormones )
AAs and FAs (products)

Blocked by: B2 ANTagonists, a2 agonist, diazoxide, somatostatin

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What is different between human insulin and insulin analogs?
What are three rapidly acting insulin analogs?

**When is insulin used? When are the other drugs in this lecture used?

Analogs = insulin MONOMERS w rapid onset, short t1/2
Created by changing 1 or 2 amino acids

aspart
glulisine
lyspro

Insulin mainly for DM1, also for DM2 later in disease.
–>The other drugs are largely for DM2 NOT NOT DM1
(THANK YOU!❤️🙌)

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Two therapeutic advantages to rapid insulin?
ROA?
compatible with NPH?

Give diabetics flexibility (less postprandial hyperglycemia)
MORE EFFECTIVE than insulin at lowering glucose
ROA: SQ, IV, pump (with a needle, NOT ORAL)
can be given with NPH

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Which rapid acting insulin is fastest?

Which insulin is “short” acting?

Aspart; can take it 5 mins before eating

Short: regular human insulin

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Which insulin is intermediate acting?

What is one potential problem with this form of insulin?

NPH insulin

Contains PROTAMINE, heparin antidote
Not good for fish allergy and must watch in patient with heparin OD

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What are the two long acting insulins?

How are they given?

-Insulin Determir & Glargine=24hrs (degludec=42hrs)
(the “others”– the ones that aren’t made up of amino acid words like aspart)
-ROA: subQ

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What are 4 factors influencing insulin action/ absorption?

blood flow (skin temp)
insulin prep (mixture short + long etc)
^ physical activity = ^ absorption
site of injection

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Rank injection sites in order of FASTEST to SLOWEST absorption:

abdomen–> arm–> thigh–> bum

** patients may get hypoglycemic from rotating to injection site with ^ absorbance

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What are some circumstances that INCREASE insulin requirements?

Things that rev up the sympathetic nervous system like:

stress (physical or psychological) + HYPERTHYROID

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What are some circumstances that DECREASE insulin requirements (3)?

N/V due to decreased caloric intake
HYPOthyroidism
liver or renal impairment

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What is the primary ADR associated with insulin use?

+ special consideration when also using BBers

HYPOGLYCEMIA due to poor timing/ skipping meals or increased exercise
Remember that B-blockers will inhibit physiological response (sweats, tremors, dizziness, etc.)

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Describe the symptoms of HYPERglycemia.

How can this occur when patient is on insulin regimen (3)?

Insulin prevents HYPERglycemia (loss of appetite, thirst, lethargy, fruity breath)

Can occur with the following:

too little insulin at last dose
^ stress
overeating

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What are the two ADRs that can occur at insulin injection sites?

Lypohypertrophy: ^ fat at injection site (insulin ^ FA synth)
Lipoatrophy: depression at injection site (immune rxn)

**patients must rotate injection sites

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Describe two situations when patients might temporarily go on insulin regimen:

DM2 patients undergoing surgery or in ICU

- Gestational diabetes

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Pramlintide: Drug class?
MOA (2)
ROA, with insulin?

Amylin Analogue

MOA:

Inhibit glucagon –> DECREASE hepatic GLUCOSE output
SLOW gastric emptying –> decrease appetite

ROA: SubQ, not in the same vial as insulin.

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Pramlintide: ADRs (1) and CIs (2)?

ADR: HYPOGLYCEMIA
CI: noncompliant patients + gastroparesis (slows gastric empyting)

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What are the two drug classes that INCREASE insulin release from pancreas?
List the drugs within these classes.

What type of DM should these NOT be used in?

Sulfonylureas:
Gen1: Tolbutamide, Chloropropamide (AMIDE)
Gen2: Glyburide, Glimepiride (IDE)

Metaglinides:
RepaGLINIDE + NateGLINIDE

*THESE (and any others that ^^ insulin) SHOULDN’T BE USED IN SEVERE DM2 PRONE TO KETOACIDOSIS

(usually DM2 doesn’t have this but it can in uncontrolled/ bad cases!!)

Sulfonylureas:
What are the drugs in this class?
MOA–where do they bind ?
Extra pancreatic effects (2)?

Sulfonylureas:
Gen1: Tolbutamide, Chloropropamide
Gen2: Glyburide, Glimepiride

MOA: Act on PANCREAS
BIND +INHIBIT receptor near K+ channels–>^ INSULIN RELEASE

Extra pancreatic effects:

DECREASE hepatic gluconeogenesis
^ # Glu transporters + peripheral insulin receptors

Which sulfonylurea can be used to treat central DI?

Is this first or second line therapy?

Chloropropamide

^^^s ADH
second line therapy for patients intolerant to desmopressin

What are the 2 ADRs associated with Sulphonylureas only? (mainly 1st gen) What ADR is assc with sulphonylureas AND metaglinides?

- Water retention due to ^ ADH - cholestatic jaundice Both sulfonyls and metaglinides ^^ insulin and therefore can cause hypoglycemia

What are the differences between Gen1 and Gen2 Sulfonylureas? Which have more ADRs and which are more potent?

Sulfonylureas: Gen1: Tolbutamide, Chloropropamide - LESS POTENT with MORE ADRS - ^ binding displacement and DD interactions - ^ ADH activity--> H2O retention-->wt gain Gen2: Glyburide, Glimepiride - MORE POTENT with LESS ADRs (better choice unless treating DI)

Drugs that induce hypoglycemia and DECREASE sulfonylurea +metaglinide clearance?

Azole antifungals (P450 INHIBITORS)

Describe how ASN and NSAIDS interact with sulpholyulureas:

Interact with *first generation drugs* to displace protein binding--> ^ amount of drug

``` Metaglinides: List the two drugs in this class and their MOA. Can they be adminstered in combo w other drugs? ```

Repaglinide + Nateglinide MOA: similar to sulfonylureas (act at diff. site) Can be given WITH metformin

Which drug is in the Biguanide class? What is its MOA (3) Biggest Benefit?

Metformin (Is the "Big-UAN" 'cause it's most commonly used) MOA: **ALL EXTRAPANCREATIC EFFECTS** - DECREASE hepatic glucose production - DECREASE GI glucose absorption - INCREASE peripheral insulin sensitivity (mm uptake, etc) -Extrapancreatic so NO HYPOGLYCEMIA!!

What are some advantages to treatment of DM2 with metformin (3)?

- No hypoglycemia - Decreases hyperlipidimia + weight gain (they give this in OBGYN for the sole purpose of weight loss?... not sure that its appropriate but they do.😱)

List 3 ADRs assocated with metfromin. | When is it CI?

- GI n/v/d - DECREASE B12 absorption - Lactic acidosis w/ ETOH CI: **Hx of keto/lactic ACIDOSIS**, liver or renal disease, CHF (will decrease renal perfusion --> ^ risk lactic acidosis)

What other condition is metformin used to treat other than DM2? Describe the logic:

PCOS with insulin resistance: | Decrease insulin resistance--> ^ synth sex hormone binding globulin--> DECREASE circulating androgens

Acarbose + Miglitol: MOA and site of action? When is it taken?

MOA: - Competitive inhibition of amylase + a-glucosidase - small intestine--> DECREASE starch absorption - taken immediately before meal

List some ADRs (2) assocated with Acarbose and Miglitol. | With which drug are they worse?

- GI pain, diarrhea, flatulance (worse with acarabose) | - hepatotocicity-- must monitor liver fxn

ThiaZOlinediones: List the two drugs in this class. What is the MOA (2)?

PioglitaZOne, RosiglitaZOne (pio/rosi-GLITAZONE) MOA: - Nuclear PPAR-Y Agonist--> ^ insulin response gene transcription--> ^ glucose uptake in skeletal mm - DECREASE hepatic glucose production

Pioglitazone, Rosiglitazone: Advantage to use? ADRs (2 + black box)?

Advantage: no hypoglycemia ADRs: hepatotoxic, edema/ weight gain, BLACK BOX FOR CHF EXACERBATION (esp. with Rosi)

GLP-1 Agonists: What are the two drugs in this class? What is their MOA? ADRs (3)? Which is the black box?

ExenaTIDE + LaragluTIDE MOA: - ^^ GLP-1(=incretin hormone) secretion from intestinal cells w/ a meal--> ^^ insulin release - ^ glucose dependent insulin release ADRs: - hypoglycemia - pancreatitis * *BLACK BOX: THYROID CANCER

AloGLIPTIN, SaxaGLIPTIN, SitaGLIPTIN: What is the drug class and their MOA? ADRs?

MOA: DDP4 INHIBITORS - inhibit DDP4 which degrades GLP-1 - ^ endogenous GLP-1 ADRs: -Hypoglycemia (lower than sulphonylureas and meglatides) - Pancreatic, Renal and hepatotoxicity

``` CanaGLIFLOZIN + DapaGLIFLOZIN: Drug class and MOA? ```

Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors MOA: Inhibit SGLT2--> DECREASE proximal tubule reabsorption of glucose--> INCREASE renal excretion of glucose **Requires good renal funciton** *If drug has "flo"=act on kidney, bc kidneys make the pee 'flo' . Canagli'flo'zin + Dapagli'flo'zin

Canagliflozin: | List the ADRs (3) and CI (1):

ADRs: - ^ UTI, especially in females - Hyperkalemia - HypoTN due to osmotic diuresis **CI in patients with renal impairment!!

Drugs classes that induce hypoglycemia (4)

- Sulphonylureas + megalinides - Insulins - DDP4 Inhibitors - GLP-1 Agonists (anything that ^^ insulin, and anything that DOES NOT ^^ insulin does NOT cause hypoglycemia, therefore benefit of all other drugs is less hypoglycemia.)

Drugs classes that require Hepatic monitoring (3)

- Acarbose - Thiazolinediones (have --glitazone in name) - DPP-4 inhibotors (have --gliptin in name)

Drug classes that cause weight gain and water retention (2)

- Thiazolinediones (-glitazone 's) + Chlorpropamide

Diazoxide: | MOA/ Theapeutic use?

MOA: maintains ATP sensitive K+ channels OPEN--> DECREASE insulin release--> ^ Blood sugar --patients with insulin secreting tumors

Glucagon (Drug): | ROA, Therapeutic use:

ROA/Tx: IV, IM, SQ for hypoglycemia (admin prior to giving glucose IV)

Drugs that stimulate insulin release:

Sulphonylureas and meglitinides

Drugs that decrease hepatic glucose (4)

Biguanides (metformin) possibly pramlintide, sulphonylureas + metaglinides, thiazolinediones

Drugs that dercrease carb absorption:

a-glucosidase inhibitors | acarbose, miglitol

Drugs that are peripheral cell insulin sensitizers

Thiazolinediones (Pio*glitazone*, Rosi*glitazone*) Mary: I also think Metformin, Sulphonylureas/Metaglinides

What is the #1 drug used to treat DM2?

METFORMIN

Drugs that are black box for thyroid cancer? | What else can they cause?

``` GLP analogs (exenatide, laraglutide) Also cause pancreatitis ```

Two groups of drugs that can cause pancreatitis?

GLPs/DPP4i

Drug contraindicated in CHF, liver, renal disease?

Metformin --> odd because it's most commonly used in DM2 and these patients usually have several diseases!!