2/8 Diabetes Management - Jin Flashcards
regulation of blood glucose homeostasis
how altered in DM patients?
glucose-insulin negative feedback loop
players:
- pancreatic beta cells
- liver
- muscle
- adipose tissue
→ typically, insulin and glucose fluctuate within a narrow range together
in diabetes patients, either..
- insulin secretion compromised
- pancreatic B cells destroyed OR making less insulin
- insulin sensitivity compromised
- liver, muscle, adipose tissues showing insulin resistance
pharm for:
pancreatic B cell destruction
DM1
severe of absolute insulin deficiency
tx: insulin supplement
- want to do it in a way that mimics normal insulin profile
- low basal rate (5-15)
- much higher stimulated rate (60-90) in response to stim including glucose
insulin profile
components
clearance
two components:
- low basal rate (5-15)
- much higher stimulated rate (60-90) in resp to stimuli (ex. glucose)
half-life of pancreatic insulin = 3-5min
- liver clears 60%
- kidney clears 40% (prox tubule)
exogenous insulin? kidney60/liver40
types of insulin preps
x4 based on…
four preps based on diff PK props
- rapid-acting : v rapid onset, short duration
- short-acting : rapid onset, short duration
- intermediate-acting : intermed onset, intermed duration
- long-acting : slow onset, long duration - flat profile
regular insulin
x2 formulation
short-acting
subcutaneous
soluble crystalline Zn formulation of recombo human insulin
- hexamerizes at injection site
effects within 30min, peak at 2-3hr, duration 5-8hr
IV
dilute, PO4-buffer, no Zn formulation of recombo human insulin
- forms monomers instantly
*good for crisis situations
- managing DKA
- rapidly changing insulin reqs (infection, surgery, etc)
intermed-acting insulin
NPH (neutral protamine hagedorn) aka Isophane insulin
- combines insulin (neg charge) with protamine (pos charge) → neither is uncomplexed
- onset 2-5hr, duration 4-12hr
*NPH: highly unpredictable action!
rapid-acting insulin analogues
rapid onset (5-15min), peak at 1h, short duration 4-5h
- closely mimic normal endogenous prandial insulin secretion → can be injected right before each meal
- lowest variability of abs
- insulin lispro : B chain 28Pro 29Lys reversed
- insulin aspart : B chain 28Pro → 28Asp
- insulin glulisin : B chain 3Asn → 3Lys, 29Lyx →29Glu
basal insulin analogues (long acting)
- glargine : “peakless” long-acting analog
- A chain 21Asn → 21Gly, B chain : 2 Arg added to Cterm
- crystallization into slowly dissolving hexamers occurs on injection
- slow onset 1-1.5h, peak 4-6h, duration 11-24h
- provides background insulin activity
- detemir
- B chain 30Thr omited, C14 fa attached to Beta chain 29
- onset 1-2h, duration > 12h; take twice daily to get smooth background insulin activity
insulin profiles
in order to mimic normal insulin profile,
1 long lasting (basal) insulin + 3 inj of fast acting insulin
insulin delivery systems
- portable injectors
- continuous subcut insulin infusion devices
- inhalers
indications for insulin
- beta cell failiure
- type 1 DM
- pancreatitis
- post-pacreatectomy
- type 2 DM where dietary control, wt reduction, oral antidiabetics are insufficient
- gestational diabetes (type IV)
- any unstable DM → DKA or HNKC
adverse rxns to insulin
- hypoglycemia (more common in DM1)
- relieve w glucose
- weight gain (esp in DM2)
- lipodystrophy : subcut fatty tissue hypertrophy at inj sites
- abs against human insulin (rare if purified preps)
efficacy and effects can be altered by: glucocorticoids, OCPs, beta agonists/antagonists
type 1 DM drugs
pharm for:
tissue resistance to insulin action
type 2 diabetes
insulin resistance
- relative def in insulin secretion
- age and obesity predispose
interventions:
- diet control & weight reduction
- oral or injectible hypoglycemic agents
- insulin
goal:
- control blood glucose conc
- delay devpt of complications
glucose homeostasis
major categories of DM2 drugs
- metformin
- insulin secretogogues
- thiazolidinediones (glitazones)
- alpha glucosidase inhibitors
- GLP1 (glucagon like polypeptide1) based tx
- GLP1 receptor agonists
- DPP4 (dipeptidyl peptidase 4) inhibitors
picture +
- amylin agonists : slow gastric emtyping, inhibit glucagon prod
- kidney SGLT2 inhibitors : reduce glucose reabs
- insulin
other hypoglycemic agents
- bile acid binding resins (colesevelam)
- bromocriptine : DA receptor agonist
metformin
first line tx for DM2
- effecting in reducing A1C w/out causing hypoglycemia
- assoc with decr in microvasc/macrovasc complications
mech of action: not well understood
- targets: LIVER, decr hepatic glucose output, decr fasting glucose
- incr GLP1 secretion
- anti-hyperglycemic but not hypoglycemic
- does not incr body weight, can help obese pt lose weight
metabolism/excretion:
- half life 1.5-3h
- NOT metabolized by liver - excreted unchanged
adv effect
- GI disturbances (n/v, abd discomfort, diarrhea) in 20%
- decr vitB12 absorption
- contraindicated if eGFR < 30
insulin secretagogues
sulfonylureas
sulfonylureas, meglitinide, nateglinide
target: ATPsensitive K channel
- typically, glucose moves in, is metabolized → ATP produced → ATP-sensitive K channel closes → cell depolarized → insulin released via exocytosis
- sulfonylureas block the K channel, reducing threshold for closing → more depol, more insulin release
action is dependent on fxal pancreatic beta cell
glyburide
glipizide: short halflife
glimepiride: longest halflife
adverse effects:
- well tolerated, but weight gain and hypoglycemia can occur
- glyburide/glipizide inactivated by liver/kidney → contraind in pt with hepatic/renal insuff
- glimepiride inactivated by liver → contraind in pt with hepatic disease
drug interactions:
- decr effectiveness with barbiturates or rifampin (induction of CYP3A4), glucocorticoids, OCPs, thiazides, phenytoin, beta ag
insulin secretagogues
meglitinides
repaglinide
- same mech as sulfonylureas, diff structure
- rapid abs, short halflife
- fast, brief STIM OF INSULIN SECRETION
- good for post prand hyperglycemia
- halflife 1h, peak 30-60min
nateglinide
- quicker onset, shorter duration
- metabolized by liver
- save for pt with very reduced renal fx
SGLT2 inhibitors
canagliflozin, dapagliflozin, empagliflozin
mechanism: inhibit kidney SGLT2 → reduce glucose reabs, incr excretion
NOT INDICATED for DM1, DKA, severe renal insuff, ESRD, dialysis pts
adverse effects: can incr DKA risk, yeast inf, UTI
- also orthostatic hypotension due to diuretic effect
incretin GLP1 based tx
what is incretin?
incretin: GI hormone released after meals that stimulates insulin secretion
- stimulates glucose dep insulin secretion
- inhibits glucagon release
- delays gastric emptying
- reduces food intake
- normalizes fasting and postprandial insulin secretion
incretin is rapidly inactivated by enzyme DPP4 (dipeptidyl peptidase IV)
sooo increcint/GLP1 based tx can take two forms:
-
injectable, DPP4 resistant peptide agonists of GLP1 receptor
- exenatride, lirablutide, lixisenatide, dulaglutide, albiglutide
-
small molecule inhibitors of DPP4
- sitagliptin, saxagliptin, linagliptin, alogliptin
thiazolidinediones
“glitazones”
pioglitazone, rosiglitazone
primary target: adipose tissue → redist of fat
- reduces insulin resistance in adipose tissue, sk muscle, liver
- reduces hepatic glucose output
mechanism: agonist of PPARgamma, which incr transcription of genes encoding proteins mediating insulin action
- incr glucose uptake and utilization in resp to insulin in muscle, adipose, liver
- do not promote insulin release
- do not cause hypoglycemia alone
- decr visc fat deposits and incr FA uptake at other sites
- weeks-months req for beneficial effects
adverse effects
- modest weight gain
- risk of fatal liver damage (contraind if hepatic disease)
drug interactions: metabolized by CYP3A4
alpha glucosidase inhibitors
acarbose: complex oligosacch of microbial origin
miglitol: simple sugar analog
mechanism: competitive inhibitors of intestinal alpha glucosidases (enzymes digesting dietary complex starges, oligosacchs, disacchs →→→ absorbable monosacchs)
- upper intestinal digestion of starch/disacchs drops → digestion deferred to distal small int
lowers postprandial rise in pl glucose
side effects: GI disturbance (gas) due to carbohydrate fermentation in colon, diarrhea, abd pain
- contraind in GI disease
amylin agonists
pramlintide
mechanism:
- amylin is a hormon secreted by panc B cells → slows gastric emptying and reduces glucagon production
- THEREFORE, amylin agonists also slow gastric emptying, incr satieity, suppress postprandial pl glucagon and hepatic glucose output
indication: adjunt to type 1, 2 pt on insulin who havent been able to achieve glycemic target
adverse effects: nausea, hypoglycemia
- contraind in pt with gastroparesis or disorder of GI motility
bile acid binding resins
&
bromocriptine
anti-diabetic agents
