Pharmacology Chapter 41 - Pancreatic Hormones and Antidiabetic Drugs
what OGTT 2 hr blood glucose indicates impaired glucose tolerance
140-199 mg/dL
what are the subtypes of type 1 diabetes
1a - immune mediated, most common 1b - idiopathic
what is the duration of action for the most commonly used dosages
4 hrs
what is the cutoff for HbA1C for diabetes
6.5% or greater
dapagliflozin is not recommended for pts with GFR less than
60 mL/min
How is saxagliptin metabolized?
CYP3A4/5
what are the SGLT2 inhibitors
Canagliflozin Dapagliflozin Empagliflozin
what is nateglinide
D-phenylalanine derivative, stimulates insulin release by inhibiting the K ATP channel metabolized by CYP2C9 and CYP3A4 can be used in renal impaired and elderly
how is GLP1 degraded
DPP4 and endopeptidase 24.11
what are the common autoantibodies in type 1 diabetes
GAD 65 ICA 512 ZnT8
canagliflozin and empagliflozin are CI in pts with _ and cause a modest increase in
GFR less than 45 mL/min increase in LDL
what are the toxicities of metformin
GI upset, inferferes with calcium-dependent absorption of B12 in the terminal ileum, and lactic acidosis most likely in conditions of tissue hypoxia AKI can occur in pts receiving radiocontrast agents
what is the modification of exenatide
GLP1 receptor agonist glycine substitution to reduce degradation of DPP4
pts with diabetes concerned with weight gain may benefit from
GLP1 receptor agonist, DPP4 inhibitor, or an SGLT2 inhibitor
pramlintide is not very useful in pts taking
GLP1 receptor agonists
what do the first 6 amino acids of glucagon bind to
Gs receptor
what is the ADA criteria for acceptable control of diabetes
HbA1C less than 7% pre meal glucose 90-130 mg/dL, less than 180 mg/dL after 1 hr, 150 mg/dL after 2 hrs
what are the adverse effects of thiazolidinediones
Hepatotoxicity, CHF, and weight gain
what is pramlintide
IAPP analog with substitutions of proline at positions 25, 28 and 29. soluble and doesn't aggregate
what are the first proteins to be phosphorylated by the insulin receptor
IRS
what happens in immune insulin resistance
IgG neutralizes the action of insulin to a non working extent, may be associated with other systemic AI processes
how do thiazolidinodiones decrease insulin resistance
PPAR gamma ligands, found on fat, muscle, and liver increased GLUT1 and GLUT4 expression, decreased FFA levels, decreased hepatic glucose output, increase adiponectin and decreased release of resistin from adipocytes, and increased differentiation of adipocytes
what are the meglitinide analogs
Repaglinide - fast OOA, controls postprandial glucose, used in elderly and in renal impaired, may be used in T2Ds with sulfur allergy have two binding sites in common with sulfonylureas and one unique binding site
how is glucose reabsorbed in the PCT
SLGTs
where is the favored site for subQ insulin infusions
abdomen
what is gestational diabetes
abnormality in glucose levels noted for the first time during pregnancy most pronounced in the last semester
how is glulisine different from R insulin
asparagine at B13 is replaced by lysine lysine in B29 is replaced by glutamic acid
which insulins are approved for insulin pump use
aspart, lispro, and glulisine
what is metformin
biguanide activates AMPK and reduce hepatic glucose production, may inhibit hepatic metabolism of lactic acid and increase risk of acidosis excreted by the kidneys safely used with GFR 60-45 mL/min; cautiously 45-30 mL/min; CI less than 30 mL/min
what is the first line therapy for type 2 diabetes
biguanides indicated for use in combo with insulin secretagogues or thiazolidinediones in type 2's in which monotherapy is inadequate
linagliptin is primarily excreted in the
bile
what is colesevelam hydrochloride
bile acid sequestrant and cholesterol lowering rug, used as antihyperglycemic interrupts enterohepatic circulation and decrease in FXR activation bile acids are natural ligands of FXR SE include GI complaints and can exacerbate hyperTGemia
how do alpha glucosidase inhibitors work
competitively inhibit the enzymes and reduce post meal glucose excursions by delaying the digestion and absorption of starch and disaccharides
how do you treat severe hypoglycemia
dextrose if conscious and can swallow if unconscious, 1mg glucagon injected subQ or IM
drugs that inhibit insulin release include
diazoxide, phenytoin, vinblastine, and colchicinewhat are the main organs that remove insulin from circulation
when should alogliptin be discontinued
during liver failure
why does GLP1 have a lower risk for hypoglycemia than the sulfonylureas
effect is glucose dependent, so insulin release is more pronounced when glucose is elevated but less when glucose is normal
which GLP1 receptor agonists are available for use
exenatide liraglutide albiglutide dulaglutide
what happens to short acting insulins
exist as dimers, assemble into hexamers in the presence of two zinc ions stabilized by phenolic compounds
how does powder insulin compare to subQ insulin
faster in onset, shorter in duration
what are the side effects of alpha-glucosidase inhibitors
flatulence, diarrhea, and abdominal pain hypoglycemia with sulfonylureas, which is treated with dextrose
how is DKA treated
fluids generally begins with normal saline regular insulin used for IV therapy watch sodium and potassium levels
what are the main adverse effects of SGLT2 inhibitors
genital infections and UTIs
which insulin analogs are long acting
glargine, detemir, and degludec
what is one of the precursors of glucagon
glicentin
acarbose and miglitol are inhibitors of
glucoamylase, alpha amylase, and sucrase
what is the serious side effect of vildagliptin
hepatitis
what is HHS
hyperosmolar hyperglycemic state in pts with T2D with inadequate oral hydration not acidotic unless DKA is present tx includes aggressive rehydration and restoration of glucose/electrolyte homeostasis
what are the adverse effects of pramlintide
hypoglycemia and GI symptoms
what is the major clinical use of glucagon
hypoglycemic emergencies, reverse beta blocker overdoses, aid in x-ray visualization in the bowel
what is insulin allerlgy
immediate hypersensitivity, local or systemic urticaria from IgE
SE of saxagliptin
increased rate of UTIs and URIs increase the risk of HF
nonobese patients with type 2 diabetes frequently have
increased visceral adiposity
how does rosiglitazone affect lipids
increases total cholesterol, HDL cholesterol, and LDL cholesterol doesn't affect TG
DKA occurs more frequently in pts on
insulin pumps
what are the pancreatic hormones and their functions
insulin, storage and anabolic hormone amylin, modulates gastric emptying, glucagon and insulin secretion, and appetite glucagon, mobilizes glycogen somatostatin, inhibits secretory cells PP, facilitates digestion ghrelin, increases pituitary growth hormone release
NPH is an example of which type of insulin?
intermediate acting
which insulin analogs are rapid acting
lispro, aspart, and glulisine
How are sulfonylureas metabolized?
liver excreted by the kidney, for second gens they are also partly excreted in the bile
liver and kid what are the main organs that remove insulin from circulation
liver and kidney
where is glucagon degraded
liver and kidney, as well as in plasma and at its tissue receptor sites
how does pioglitazone affect lipids
lowers TG increases HDL cholesterol without affecting TC and LDL cholesterol
Which *alpha-glucosidase inhibitors* are highly absorbed?
miglitol
pioglitazone + insulin is associated with
more weight gain and peripheral and macular edema
how is sitagliptin metabolized and what kind of pts should have low doses
mostly CYP3A4 those with impaired renal function
adverse effects of linagliptin
nasopharyngitis and hypersensitivity, as well as increased risk of pancreatitis
what are the SE of sitaliptin
nasopharyngitis, URI, headaches acute pancreatitis hypersensitivity reactions
what is the major side effect of exenatide
nausea
Qualitative detection of ketone bodies can be accomplished with the use of what tests?
nitroprusside tests
what is the common amt of insulin units pts inject
no more than 30 units
what is indicated when DKA is recurrent
noncompliance
what kind of pts are CI in exenatide use
not approved for use in pts with GFR less than 30 mL/min since it undergoes glomerular filtration
the combo of a thiazolidinedione and metformine has the advantage of
not causing hypoglycemia
increased insulin requirements typically occur with
obesity, adolescence, and during the latter trimesters of pregnancy
all GLP1 receptor agonists may increase the risk of
pancreatitis
GLP1 receptor agonists should not be used in persons with
past medical/family history of medullary thyroid cancer or MEN2
insulin glargine is described as
peakless
what is hypoglyemic unawareness
person is exposed to frequent hypoglycemic episodes, so the warning signals are less common or absent
in what kind of pts should glucagon not be used
pheochromocytoma
pts with severe insulin resistance may be candidates for pioglitazone
pioglitazone
what is diagnostic of DM
plasma glucose >126 mg/dL on more than 1 occasion or after at least 8 hrs of fasting
how is lispro different from R insulin
proline at position B28 is switched with the lysine at B29
at what times should someone administer a long acting and short acting insulin
rapid acting is 15 mins before a meal long acting is 45 mins before a meal
what are the features of rosiglitazone
rapidly absorbed and highly protein bound thiazolidinedione class metabolized by CYP2C8 mainly and to a lesser extent CYP2C9
what is the ratio of clearance for a regular person's insulin vs insulin-treated diabetics
regular - 60 liver/40 kidney diabetic - 60 kidney/40 liver
human insulin is dispensed as
regular R and neutral protamine hagedorn NPH formulas
how are insulins mixed
regular or rapid acting is drawn first, then the NPH withdraw, then injected immediately
what does glucagon do to the intesine
relaxes the intestine
what is one thing to note about insulin glargine
should not be mixed with other insulins to maintain solubility
what does glucagon do to the heart
similar effect to beta adrenoreceptor agonists without requiring a functioning beta receptor
how is aspart different from R insulin
single sub of proline for aspartic acid at B28
which DPP4 inhibitor has the best bioavailability
sitagliptin
which DPP4 inhibitors are available
sitagliptin saxagliptin alogliptin
powder insulin is CI in
smokers and patients with chronic lung disease, such as asthma or COPD
liraglutide is a _ with major side effects of
soluble fatty acid-acylated GLP1 analog nausea and vomiting
what is the features of pioglitazone
some PPAR-a as well as PPAR-y activity absorption decreased with resins metabolized by CYP2C8 and CYP3A4 affected by estrogen-containing oral contraceptives
stimulatory drugs for insulin secretion include
sulfonylureas, meglitinide and nateglinide, isoproterenol, and ACh
how is detemir different from R insulin
terminal threonine is dropped from the B30 position and myristic acid (C14 FA chain) is attached to the B29 lysine, which prolong the availability
what is the advantage of premixed insulins
they can be given within 15 mins of starting a meal and they are superior in controlling the postprandial glucose rise after a carb rich meal
dose adjustment for saxagliptin is recommended for
those with renal impairment and use of strong CYP3A4/5 inhibitors such as antiviral, antifungal, and certain antibacterial drugs
what is the modifications on insulin degludec
threonine at B30 removed and the lysine at B29 is conjugated to hexadecanoic acid via gamma-L-glutamyl spacer in the presence of phenol and zinc and self associates into large multihexameric chains
why is rotation of insulin injection sites recommended
to avoid problems with absorption due to lipohypertrophy from overuse of injection sites
what are the first gen sulfonylureas
tolbutamide - rapidly metabolized, safe in elderly and in renal impaired; hypoglycemia in pts with antibacterial sulfa drugs, phenylbutazone for arthralgias, and oral azoles chloropropamide - hypoglycemia in elderly, hyperemic flush, hyponatremia tolazamide - more slowly absored
what is the modification of dulaglutide
two GLP1 analog molecules covalently linked to an Fc fragment of human IgG4
what is the modification on insulin glargine
two arginine molecules to the B chain carboxyl terminal and substitution of a glycine for asparagine at the A21 position
what does each beta cell granule contain
two atoms of zinc and six molecules of insulin
what does the insulin receptor look like
two heterodimers that are covalently linked alpha subunit is EC beta subunit is a transmembrane protein which contains a tyrosine kinase
what are the second gen sulfonylureas
used carefully in pts with cardio disease, elderly glyburide - should not go higher than 20 mg/D; flushing, enhances free water clearance, CI in presence of hepatic/renal insufficiency glipizide - shortest half life, recommended starting dose is 5 mg/d; CI in pt with hepatic impairment; preferable to glyburide in elderly and renal impaired glimepiride - achieves target with lowest dose, completely metabolized by liver