pancreatic hormones (pharma 1+2) Flashcards
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)
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
what is the insulin content in the body?
8 mg / 200 units
what is the insulin content in the body?
8 mg / 200 units
what’s the half life of insulin?
5 -7 mins
what is insulin?
acidic protein secreted by pancreatic beta cells
what are the subunits insulin is made of?
alpha and beta
insulin is connected by ?
c peptide and disulfide bonds
where is preproinsulin synthesized?
rER
Preproinsulin is cleaved into …?
proinsulin
Proinsulin is transported where?
to golgi
in Golgi proinsulin is cleaved into C peptide and insulin by what?
membrane proteases
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%).
what stimulates insulin secretion?
glucose
gh hormones
autonomic nts
pancreatic hormones
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
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
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
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
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
what are the GI hormones that play a role in insulin secretion?
gastrin
secretin
VIP
GLP
what are the autonomic its involved in insulin secretion?
Ach
Epi
NE
………….→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
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
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)
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
IV
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 aldehydeDilutional hyponatremia mostly seen w/ it. dehydrogenase
Chlorpropamide
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:
-
- -
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
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
