pancreatic hormones (pharma 1+2) Flashcards by Haya Alameeri

out of the following which ones are chronic complications of diabetes.
Organ damage
muscle wasting
nephropathy, retinopahty, neuropathy
polyphagia, polypsia, polyuria.
ketonuria (common in type 1)
coronary artery/peripheral vascular disease
-impaired wound healing
Hyperglycemia, glucosuria
foot ulcer
-neurochemical imbalance (CNS)

organ damage
- nephropathy, retinopathy, neuropathy
-coronary artery/peripheral vascular disease
-impaired wound healing -foot ulcer
-neurochemical imbalance (CNS)

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out of the following which ones are acute complications of diabetes.
Organ damage
muscle wasting
nephropathy, retinopahty, neuropathy
polyphagia, polypsia, polyuria.
ketonuria (common in type 1)
coronary artery/peripheral vascular disease
-impaired wound healing
Hyperglycemia, glucosuria
foot ulcer
-neurochemical imbalance (CNS)

Hyperglycemia, glucosuria
- ketonuria (common in type 1)
- polyphagia, polypsia, polyuria.
- muscle wasting

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what is the insulin content in the body?

8 mg / 200 units

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what is the insulin content in the body?

8 mg / 200 units

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what’s the half life of insulin?

5 -7 mins

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what is insulin?

acidic protein secreted by pancreatic beta cells

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what are the subunits insulin is made of?

alpha and beta

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insulin is connected by ?

c peptide and disulfide bonds

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where is preproinsulin synthesized?

rER

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Preproinsulin is cleaved into …?

proinsulin

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Proinsulin is transported where?

to golgi

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in Golgi proinsulin is cleaved into C peptide and insulin by what?

membrane proteases

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When a stimulus attaches to its receptor for insulin release, Beta granules will be exocytosed secreting what?

mostly insulin and C-peptide (90-97%) and proinsulin (3-4%).

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what stimulates insulin secretion?

glucose
gh hormones
autonomic nts
pancreatic hormones

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glucose mediated insulin secretion
st 1 ???????
st 2 glucose → G6P by hexokinase and enters TCA to generate ATP
st 3 ↑↑ ATP in cell will close K+ channels → depolarization
st 4 Ca+ influx through Ca+ channels → binds to calmodulin and activates PKA
5th: PKA activates myosin filaments→ promotes Beta granules migration and fusion on plasma membrane → exocytosis

glucose is taken up by GLUT2

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glucose mediated insulin secretion
st 1 glucose is taken up by GLUT2
st 2 ???????????
st 3 ↑↑ ATP in cell will close K+ channels → depolarization
st 4 Ca+ influx through Ca+ channels → binds to calmodulin and activates PKA
5th: PKA activates myosin filaments→ promotes Beta granules migration and fusion on plasma membrane → exocytosis

glucose → G6P by hexokinase and enters TCA to generate ATP

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glucose mediated insulin secretion
st 1 glucose is taken up by GLUT2
st 2 glucose → G6P by hexokinase and enters TCA to generate ATP
st 3 ??????????
st 4 Ca+ influx through Ca+ channels → binds to calmodulin and activates PKA
5th: PKA activates myosin filaments→ promotes Beta granules migration and fusion on plasma membrane → exocytosis

↑↑ ATP in cell will close K+ channels → depolarization

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glucose mediated insulin secretion
st 1 glucose is taken up by GLUT2
st 2 glucose → G6P by hexokinase and enters TCA to generate ATP
st 3 ↑↑ ATP in cell will close K+ channels → depolarization
st 4 ???????????
5th: PKA activates myosin filaments→ promotes Beta granules migration and fusion on plasma membrane → exocytosis

Ca+ influx through Ca+ channels → binds to calmodulin and activates PKA

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glucose mediated insulin secretion
st 1 glucose is taken up by GLUT2
st 2 glucose → G6P by hexokinase and enters TCA to generate ATP
st 3 ↑↑ ATP in cell will close K+ channels → depolarization
st 4 Ca+ influx through Ca+ channels → binds to calmodulin and activates PKA
5th: PKA activates myosin filaments→ promotes Beta granules migration and fusion on plasma membrane → exocytosis

PKA activates myosin filaments→ promotes Beta granules migration and fusion on plasma membrane → exocytosis

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what are the GI hormones that play a role in insulin secretion?

gastrin
secretin
VIP
GLP

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what are the autonomic its involved in insulin secretion?

Ach
Epi
NE

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………….→activation of PLC→Cleavage of Phosphatidyl inositol to IP3 (promotes Ca2+ from SR) and DAG (activates protein kinases)→stimulates insulin secretion

Ach binds to muscarinic receptors

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Ach binds to muscarinic receptors→…………→Cleavage of Phosphatidyl inositol to IP3 (promotes Ca2+ from SR) and DAG (activates protein kinases)→stimulates insulin secretion

activation of PLC

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Ach binds to muscarinic receptors→activation of PLC→……………→stimulates insulin secretion

Cleavage of Phosphatidyl inositol to IP3 (promotes Ca2+ from SR) and DAG (activates protein kinases)

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Ach binds to muscarinic receptors→activation of PLC→Cleavage of Phosphatidyl inositol to IP3 (promotes Ca2+ from SR) and DAG (activates protein kinases)→.........

stimulates insulin secretion

..................→activation of Adenylyl cyclase→ generating cAMP from ATP→activation of protein kinases→promoting insulin secretion

Epinephrine binds to B2 adrenoceptors

Epinephrine binds to B2 adrenoceptors→................→ generating cAMP from ATP→activation of protein kinases→promoting insulin secretion

activation of Adenylyl cyclase

Epinephrine binds to B2 adrenoceptors→activation of Adenylyl cyclase→ ............→activation of protein kinases→promoting insulin secretion

generating cAMP from ATP

Epinephrine binds to B2 adrenoceptors→activation of Adenylyl cyclase→ generating cAMP from ATP→..................→promoting insulin secretion

activation of protein kinases

Epinephrine binds to B2 adrenoceptors→activation of Adenylyl cyclase→ generating cAMP from ATP→activation of protein kinases→..........

promoting insulin secretion

.............→promotes insulin secretion but activation of a2 adrenoceptors→inhibits insulin secretion

activation of B2 adrenoceptors

activation of B2 adrenoceptors→.....................→inhibits insulin secretion

promotes insulin secretion but activation of a2 adrenoceptors

activation of B2 adrenoceptors→promotes insulin secretion but activation of a2 adrenoceptors→.....................

inhibits insulin secretion

what are the pancreatic hormones involved in insulin secretion?

insulin glucagon somatostatin

role of insulin in insulin secretion

inhibit glucagon

role of glucagon in insulin secretion

activates insulin + somatostatin

role of somatostatin in insulin secretion

inhibit insulin and glucagon

where is insulin metabolized?

kidneys + liver

insulinase aka glutathione insulin transhydrogenase function

inactivates insulin by hydrolysis of insulin disulfide bonds →make insulin susceptible for degradation by cytosolic proteases into peptides and AAs

where is the insulin receptor found?

cell membrane

insulin binds to what SU on the receptor?

alpha

what happens when insulin binds to alpha subunit on receptor?

activate TK → phosphorylate beta SU and IRS1 → IRS1 receipt P13K → biological response

what is a key mediator in insulin pathway?

P13 kinase

Therapy / Glycemic goal of insulin: - To maintain FPG of 90 – 130 mg/dL = 5 mmol/L and ...

increasing energy expenditure increasing energy availability increasing metabolic insulin action = insulin pharmacodynamics by: 1. increasing # of insulin receptors and the affinity of insulin to its receptors increasing amount of intracellular mediators following the activation of insulin receptors - Primarily acts on liver, muscles, and heart.

what happens to carbs in the liver?

increase glycolysis + glycogenesis inhibit gluconeogenesis + glycogenolysis

what happens to fat in the liver?

increase lipogenesis inhibit lipolysis

what happens to proteins in the liver?

inhibit protein breakdown

what happens to carbs in muscle?

increase glucose uptake, glycolysis, glycogenesis

what happens to protein in muscle?

increase aa uptake and protein synthesis

what happens to carbs in adipose tissue?

increase glucose uptake and glycerol synthesis

what happens to fat in adipose tissue?

synthesis of TAG, FA Inhibit lipolysis

what does diabetic therapy depend on?

diet exercise pharmacotherapy

what are ROA of insulin?

subcutaneous injection ultrarapid / rapid can be even via IV useful against DKA insulin pump = continuous subcutaneous (regular or ultra rapid)

what pharmacotherapy is used in T1D?

insulin

what pharmacotherapy is used in T2D?

oral anti diabetics /insulin

what are the 7 insulin synthetics?

lisopro regular insulin = crystalline zinc insulin lente isophane (NPH) ultralente glargine

what is an ultra rapid insulin synthetic?

lisopro

what is a rapid insulin synthetic?

regular insulin aka crystalline insulin

what are the two intermediate insulin synthetics?

lente + NPH

what are the two intermediate insulin synthetics?

lente + NPH

what are the two long insulin synthetics?

ultralente + Glargine

when is lisopro taken?

few mins before meals

onset of lisopro

5 - 15 mins

when does lisopro peak?

45-75 mins

ROA of lisopro

uses of lisopro

meals + acute hyperglycemia (DKA)

DOA of regular insulin

5-7 hrs

when is regular insulin taken?

30 mins before meals to control prandial blood glucose

onset of regular insulin

30 min to 1 hour

when does regular insulin peak?

2 - 4 hrs

how many times is regular insulin given?

3 times a day

what's the drug of choice in case of DKA?

regular insulin

lente onset

1 - 2 hours

lente peaks when

8-12 hours

uses of lente

basal insulin for overnight coverage

lente recommendation is to take it....

twice a day morning and night

isophane (NPH) insulin onset

1 - 2 hours

isophane peaks

8-12 hours

uses of isophane

basal insulin and for overnight coverage

isophane reccomendations

given twice a day morning and night

ultralente onset

4 - 8 hours

when does ultralente peak?

16-18 hours

ultralente usage

basal insulin + overnight coverage

ultralente should be taken...

1 dose per day

onset of glargine

2 hours

peak of glargine

it has no peak :P

uses of glargine

basal insulin + overnight coverage

glargine should be taken

once a day

what drug is less likely to cause hypoglycemia?

glargine

Lisopro peak coincides with postprandial hyperglycemia = best to control postprandial hyperglycemia § Ultralente has a wide peak and covers the whole day § Glargine rises at the beginning and then stays @ baseline level = less likely to develop hypoglycemia § Best combination to prevent hypoglycemia = Lisopro after each meal and Glargine once/day.

what decrease insulin?

alcohol and beta blockers

what physiological states affect daily insulin requirements?

pregnancy (increase) diabetogenic lifestyle (increase) chronic exercise (decrease)

what pathophysiological states affect daily insulin requirements?

surgery insulin resistance acute illness/infection (all increase)

what drug drug interactions affect daily insulin requirements?

glucocorticoids thiazide diuretics oral contraceptives (all increase)

what are the side effects of insulin?

hypoglycemia (major) lipodystrophy/lipohypertrophy insulin resistance = hyperinsulinemia urticaria + angioedema (less common now)

what are the main oral anti diabetic agents?

sulfonylureas meglitinides biguanides alpha glucosidase inhibitors thiaizolindinediones dipeptidyl peptidase IV inhibitors incretin mimetics SGLT2 inhibitors

what are the sulfonylureas?

tolbutamide chloropropamide glyburide glipizide glimipiride

what are the first generation sulfonylureas?

tolbutamide chloropropamide

what are the second generation sulfonylureas?

glyburide glipizide

what is a third generation sulfonylurea?

glimipiride

Chlorpropamide DOA

60 hours (longest of all sulfonylureas)

- Causes disulfiram effect due to accumulation of acetaldehyde by blocking aldehyde - Dilutional hyponatremia mostly seen w/ it. dehydrogenase

Chlorpropamide

Second generation sulfonylureas - Has 16 to 24 hrs. duration of action - High potency - 50% excreted in feces (all other agents excreted in urine) - Less likely to cross the placenta → recommended during pregnancy

Glyburide

Second generation sulfonylureas - Has 12 to 24 hrs. duration of action - High potency

Glipizide:

Third generation sulfonylureas - Has >24 hrs. duration of action - High potency - Recommended for patients with cardiovascular diseases because it is the only drug that does NOT bind to the 140 subunit of the receptor, which is found on Beta cells and heart.

Glimipiride

Major MOA: acts on pancreas to improved glucose-mediated insulin secretion - glucagon secretion - Enhanced insulin secretion - Reduced hepatic insulin extraction Reduced

Sulfonylureas mechanism of action:

- - - Main SE = hypoglycemia * Increased hypoglycemia action of sulfonylureas if combined w/ other drugs that: o urinary excretion of sulfonylureas à its t1/2 o Displaces sulfonylureas from plasma proteins à activity o Inhibits CYP450 à sulfonylureas metabolism Dilutional hyponatremia = mostly seen in chlorpropamide due to ADH-like effect Hemolytic anemia and weight gain Disulfiram syndrome associated w/ tachycardia and hyperventilation due to inhibition of

Sulfonylureas side effects:

Acts like sulfonylureas - Has 4 to 6 hrs. duration of action = very short, peak=1 hr - MOA= block A TP sensitive K channels - Used to control postprandial hyperglycemia (less effect on FBG) - Mostly metabolized by liver - Minor renal excretion = good choice for patients w/ kidney disease - Useful replacement for patients w/ sulfa allergies

Meglitinides --> Repaglinide

Major MOA: * acts on liveràinhibit hepatic glucose output by inhibiting gluconeogenesis * Activity of insulin receptor (FBG by 20% and HbA1c by 1.5%) * Metabolic responses Decreases TG and FFA, small decrease in LDL, increase in HDL Duration= 6hrs, peak =2hrs Main excretion route is kidneys (unchanged) Excreted unchanged in the urine Rapidly absorbed in small intestine

Metformin

Side effects: * Major SEàNausea and vomiting * Interferes w/ Vit.B12 absorption * Lactic acidosisàdue to blockage of flow of acidic molecules through gluconeogenesis Contraindications: Any condition that predisposes the patient for metabolic acidosis = lactic acidosis * Hepatic diseases * Respiratory diseases * Renal diseases * CHF * Hypoxemia * Alcohol abuse

Metformin

Mainly acts on the GIT - Starch blockersàinhibits conversion of starch into glucoseàno absorption of glucose into systemic circulation - Does NOT cause hypoglycemiaàcan be taken w/out having diabetes

alpha glucosidase inhibitors - acarbose

Inhibits pancreatic alpha-amylase - Uses: control postprandial blood glucose - SEs: Diarrhea and abdominal discomfort because it stays in the GIT for long period of time Contraindications: inflammatory bowel disease and intestinal obstruction

alpha glucosidase inhibitors - acarbose

Mainly acts on muscles (max effect is 6-14 weeks) ↑↑Insulin sensitivity by activating: Peroxisome proliferator – activated receptor – gamma (PPyR)→ glucose utilization genes→ insulin sensitivity in muscles mainly, adipose tissue, and liver→ TGs, FFA, insulin, and glucose (i.e. as insulin sensitivity increases, insulin need decreases) FBG w/ moderate effect on postprandial glucose ↑↑CYP450 metabolism Contraindicated in liver and CHF disease SEs: mild anemia,sinusitis, bone loss, weight gain (subcutaneous not visceral), fluid retention

Thiazolindinediones 1. Rosiglitazone

MOA:inhibits dipeptidyl peptidase→ ↑ GLP→ ↑glucose-mediated insulin secretion - rapid absorption in GIT, duration= 24hrs, peak= 1-4 hrs -Excreted unchanged in the urine -SEs: → Nasopharyngitis → headache → acute pancreatitis → Rash (Stevens Johnson Syndrome)

Dipeptidyl Peptidase – IV inhibitors 1. Sitagliptin:

Has similar structure to GLP→stimulates GLP peptide → glucose-mediated insulin secretion - Route of administration: SC ( not effective orally) - Can slow gastric emptying time - May Postprandial glucagon secretion - ↑Beta cell proliferation

Incretin mimetics 1. Exenatide:

Reduce hyperglycemia by promoting glucose excretion in urine by blocking sodium- glucose linked co trasportor 2 (SGLT2) at the proximal tubules ® reduction in reabsorption of filtered glucose and increase in its excretion - Reduces sodium reabsorption and increases delivery to distal tubule ® excretion - Downregulate sympathetic activity - Lower pre- and afterload of heart - Decreases intraglomerular pressure SE: mainly UTI, hyperkalemia, hypotension

SGLT2 inhibitors Canagliflozin & dapagliflozin