antidiabetics 59/60 Flashcards Preview

Pharm > antidiabetics 59/60 > Flashcards

Flashcards in antidiabetics 59/60 Deck (86):
1

Regular insulin (Humulin R and Novolin R)

Rapid-acting Insulin Preparation (cheap)

clear solution of human sequence insulin

**only insulin suitable for intravenous use**

works slower than native insulin due to regular insulins forming non-covalent hexamers in solution
breakdown into monomers requires time

2

Insulin aspart (NovoLog)

Rapid-acting Insulin Preparation

B28 proline is replaced by an aspartic acid residue

*works quicker than regular insulin due to forming monomers more quickly*

3

Insulin glulisine (Apidra)

Rapid-acting Insulin Preparation

B3 asparagine is replaced by a lysine residue and the
B29 lysine is replaced by a glutamic acid residue

("glu and lis" replace)

*works quicker than regular insulin due to forming monomers more quickly*

4

Insulin lispro (Humalog)

Rapid-acting Insulin Preparation

normal proline-lysine ("lis for pro") dipeptide at positions B28 and
B29 are reversed

*works quicker than regular insulin due to forming monomers more quickly*

5

NPH Insulin (Humulin N and Novolin N)

Intermediate-acting Insulin Preparation (cheap)

cloudy suspension of human sequence
insulin aggregated with protamine and zinc

unpredictable action due to a variable rate of absorption (still has peak)

mixture of NPH and regular insulin (or other short-acting) in a fixed proportion (70:30) often used

6

Insulin glargine (Lantus)

Long-acting Insulin Preparation: reproducible and convenient
background insulin replacement (last about 18-20 hours)

aspargine at position A21 is replaced by
glycine and two arginines are added to the C-terminus of the B-chain

soluble at pH 4 but poorly soluble at pH 7

injected subQ, forms fine precipitant in interstitial fluids

7

Insulin detemir (Levemir)

Long-acting Insulin Preparation: reproducible and convenient
background insulin replacement

threonine at B30 is omitted and a C14 fatty acid chain is attached to amino acid B29

long-acting due to self-association at subQ injection site and by binding to albumin in blood

8

Metformin (Glucophage, Glucophage XR, Glumetza)

Biguanide

first line for T2 DM
reduces of hepatic gluconeogenesis
through activation of the AMP-activated protein kinase (AMPK) in hepatocytes

euglycemic: prevents hyperglycemia, but does not induce hypoglycemia

9

Glyburide (Diaβeta, Micronase, Glynase PresTab)

Sulfonylurea
2nd generation

10

Repaglinide (Prandin)

Meglitinide
hypoglycemia w. skipped meal

11

Pioglitazone (Actos)

Thiazolidinedione

12

Rosiglitazone (Avandia)

Thiazolidinedione

13

Acarbose (Precose)

α-Glucosidase Inhibitor

14

Pramlitide (symlin)

Amylin Analogue

used for the treatment of type 1 and type 2 diabetes. It primarily acts as an insulin sparing agent, adjunct to insulin therapy

15

Exenatide (Byetta)

GLP-1 Agonist
synthetic exendin-4, a peptide found in Gila monster venom

monotherapy or as adjunctive therapy for T2 DM, 2x daily, subQ

now extended release 1x weekly

rapidly absorbed from the injection site and reaches a pk conc. in 2 hrs

little metab, excreted by kidney

16

Sitagliptin (Januvia)

DPP-4 Inhibitor

T2DM

17

Canagliflozin (Invokana)

SGLT2 inhibitor

18

Glucagon

29 aa peptide synthesized by the alpha cells in pancreatic islets of Langerhans
used in the emergency treatment of severe hypoglycemia, unconscious pt or glucose not available
also, tx of β–blocker OD

raises blood glucose by stimulating the breakdown of hepatic glycogen stores

binds to a G-protein coupled receptor present in the liver that stimulates adenylate cyclase and an increase in cAMP-->increase in glycogen phosphorylase activity and a decrease in glycogen synthase activity

stimulates gluconeogenesis and ketogenesis in the liver

no effect on glycogen stores in skeletal muscle.

metabolized by liver, kidney and within plasma

19

Glucose stimulation of insulin
secretion involves the uptake of glucose into the β cell via ??

GLUT-2
transporters

20

intracellular
metabolism of glucose increases the
ATP/ADP ratio, which inhibits K(ATP)
channels and potassium efflux
This
inhibition results in ??

Calcium influx does what??

β cell
depolarization and calcium influx

activates recruitment of insulin- containing granules to the cell surface and the release of insulin into the circulation

21

average individual produces ?? insulin/day

30 units

-half metabolized by liver
-rest by kidney and muscle

22

insulin is produced as a ??

prepropeptide, starts in RER-->folding, disulfide bonds added-->proinsulin goes to golgi-->packaged in granules (immature)-->proinsulin matured here-->cleaved to insulin and C-peptide (inactive compound)-->granules (in pancreatic B-cells) fuse with plasma membrane and release mature insulin into blood

always basal insulin in circulation
large insulin release after glucose spike in blood

23

if given bolus of glucose...normal pt would respond with ??

insulin spike from release of pre-formed insulin from B-cells, then depletes

second (more subtle) hump from release of newly created insulin

24

if given bolus of glucose...Type 2 diabetic pt would respond with ??

delayed and more subtle insulin hump (no spike)

25

if given bolus of glucose...Type 1 diabetic would respond with ??

no response, unable to produce insulin

26

insulin has 2 effects ????

that affects what tissues ??

anabolic and anticatabolic

liver, muscle, and
adipose tissue

27

insulin anticatabolic effects in liver ??

anabolic effects in liver ??

inhibits glycogenolysis, gluconeogenesis, ketogenesis

stimulates glycogen and fatty acid synthesis

28

insulin anticatabolic effects in muscle ??

anabolic effects in muscle ??

inhibits protein catabolism

stimulates glucose and amino acid uptake
stimulates protein and glycogen synthesis

29

insulin in adipose tissue:
anticatabolic effects ??

anabolic effects ??

inhibits lipolysis

stimulates glucose uptake
stimulates glycerol synthesis and triglyceride synthesis

30

"dawn phenomenon" in DM pts

glucose is fine before bed, high in morning
(insulin wore off, not enough to inhibit gluconeogenesis in liver)

31

history factoid: started using insulin in humans in ??

1922
before: 0% survival rate
Fredrick Banting "discovered" insulin and began testing injections

initially bovine/porcine
now human via recombinant DNA technology (cleaner prep and less hypersensitivity) since 1982

32

Type 1 diabetes mellitus

absolute deficiency in insulin due to the
autoimmune destruction of pancreatic β cells
untreated-->ketoacidosis-->coma-->death

insulin replacement therapy is necessary to sustain life

younger than 30 years old when diagnosed

33

Type 2 diabetes mellitus

90-95% of all diagnosed DM in US

initial development of insulin resistance, followed
by a relative impairment of insulin secretion
Insulin is still produced by β cells in these patients but is not sufficient to overcome the resistance

present in adulthood
dietary intervention is first tx, then oral antiDM drugs
30% benefit from insulin therapy

may need higher units: 40-300 units/day: metabolic syndrome

34

insulin regimen: give multiple shots combo shots of ???

intermediate-acting (or long-acting): to mimic 24-hour basal insulin secretion
AND
short-acting insulin: to mimic nutrient-stimulated insulin secretion (given preprandial)

35

The goals for glycemic control are:

Fasting and preprandial blood glucose level of ??

post-prandial blood glucose level two hours after meal of less than ??

Hemoglobin A 1C (HbA 1C ) less than ??

70-130 mg/dL

180 mg/dL

7% (associated with a decreased risk of long-term
complications) ("2 month test")


(not all patients achieve these goals (hypoglycemia, cognition, age))

36

inhaled insulin ??

Exubera: pulled from market

Afrezza: now available, same efficacy of injected insulin

37

Hemoglobin A 1C (HbA 1C ) levels normal ppl and uncontrolled DM

normal 4-5%
uncontrolled: 9-12%

38

most T1 DM need ?? doses

variable doses (vs. fixed doses)

may be adjusted: how they feel, checking finger-stick glucose

39

split-mixed regimen

regular and NPH before breakfast
regular and NPH before dinner

problem: NPH at dinner may wear off during night causing "dawn phenomenon" may help to take before bed-->3 shot regimen

40

basal bolus regimen

insulin aspart before B, L, D
-adjustable
1 injection insulin glargine at bedtime

41

insulin pump

baseline insulin given over intervals
-adjustable

42

main adverse effects of insulin therapy

hypoglycemia: not eating enough carbs, too much physical exertion, too large dose of insulin
-->unconciousness-->brain damage
-give sugar if conscious, IV glucose or glucagon if unconscious

weight gain (good for T1 diabetics: previously thin due to catabolic state)



43

other adverse effects of insulin therapy

allergic reactions

insulin resistance (neutralizing anti-insulin Abs)

atrophy of subQ fatty tissue (animal preps)

hypertrophy of subQ tissue with using same injection site

increased cancer risk

44

inhaled insulin adverse effects

throat pain, irritation

*cough*(most common reason to stop)

altered pulmonary function: dec. FEV1 (do PFTs before prescribing and 4 mos later)

45

Metformin SEs

GI disturbances in 20% pts
(transient, dose-related)

lactic acidosis (rare but fatal, adhere to contraindications: reduced drug elimination, reduce tissue oxygenation (i.e. )

46

2 factors that predispose patients to lactic
acidosis ??

contraindications ??

reduced drug elimination reduced tissue oxygenation


alcoholism
renal insufficiency
hepatic disease
hypoxic pulmonary disease

also CI with contrast formulations
or hospitalization for acute illness

47

metformin benefits


metformin typically taken ?? daily

if mild DM can use

does not cause weight gain (actually causes mild weight loss) or hypoglycemia

2x


metformin monotherapy

48

if monotherapy of metformin not sufficient, may be used with

sulfonylureas, thiazolidinediones, or insulin

49

other benefits of metformin

reduce circulating LDL and VLDL
reduce BP
decrease risk of macrovascular and microvascular disease
may reduce risk of certain cancers (via lowering insulin release)

50

sulfonylureas

only for T2 DM

insulin secretagogues; their mechanism of action requires functioning pancreatic β cells

increased insulin release from pancreatic β cells

bind to the K-ATP channel complex on β cell plasma membranes and inhibit their activity. This inhibition leads to depolarization of β cells, influx of calcium, and insulin release

metabolized by liver

51

1st gen sulfonylureas



2nd gen sulfonylureas

less potent, have longer half-lives, and are more likely to cause adverse effects (not covered)

glyburide, glipizide, and glimepiride.

52

Sulfonylureas SEs

Hypoglycemia
Weight gain (inc. appetite)
sulfur allergy
Increased cardiovascular mortality has been associated with long-term sulfonyluea tx

53

Sulfonylurea CIs

Hepatic impairment
Renal insufficiency
*Pregnant and breastfeeding women—sulfonylureas cross the placenta and enter breast milk*
caution in susceptible patients to whom hypoglycemia could be particularly dangerous (e.g. elderly patients or patients with acute CV disease)

54

Sulfonylurea uses

taken how often?

reduced efficacy when?

combo tx??

type 2 diabetes

1x or 2x daily

As β cell function declines, this class of drugs loses efficacy

can be combined with metformin or thiazolidinediones.

55

MEGLITINIDES

insulin secretagogues with a similar mechanism of action to sulfonylureas: increase insulin release from pancreatic β cells through inhibition of β cell KATP channels

repaglinide and nateglinide

1 hr half life, metabolized by liver

56

meglitinide SEs

Hypoglycemia may occur with repaglinide if taken before a meal that is subsequently
delayed or skipped. Hypoglycemia is less frequent with nateglinide.

57

meglitinide CIs

caution when prescribing repaglinide with hepatic impairment
or renal insufficiency

Nateglinide is generally safer in patients with reduced renal function, though the dose may need to be adjusted in such cases

58

Meglitinide uses

type 2 diabetes
more rapid
pharmacokinetics as compared to sulfonylureas
more frequent preprandial dosing of meglitinides is possible

*may be used in patients with sulfur allergies*

monotherapy or in conjunction with metformin.

59

THIAZOLIDINEDIONES

type 2 diabetes

“glitazones” or “Tzds” increase insulin sensitivity in target tissues.

peroxisome proliferator-activated receptor gamma (PPARγ) agonists
PPARγ receptors are nuclear hormone receptors that modulate the expression of genes involved in lipid and glucose metabolism. These receptors are highly expressed in adipose tissue, which is the primary site of action

principal effect: differentiation of adipocytes, resulting in the increased sensitivity to insulin-stimulated uptake of glucose and fatty acids, as well as altered adipokine production (e.g. leptin, adiponectin)

metabolized by liver

60

effects of thiazolidinediones

Increased insulin sensitivity in skeletal muscle and liver also occurs

Long term effects: lowering of triglyceride levels and a slight rise in HDL and LDL cholesterol levels

61

thiazolidinedione SEs

*Weight gain and edema*
Osteoporosis and bone fracture (women)
CHF
CV events (see later)
For pioglitazone, an additional risk of bladder cancer occurs with higher doses

62

Black box warning w. thiazolidinedione: rosiglitazone

black box warning for an increased risk in CV events
(MI or stroke) has been observed. This observation is controversial and additional monitoring and evaluation is ongoing. Currently, rosiglitazone carries a black box warning for such adverse effects and can only be prescribed for patients whose blood sugar cannot be controlled with other antidiabetic agents. The future availability of rosiglitazone is uncertain.

This restriction has been removed due to reevaluation of clinical trial data

63

thiazolidinedione CIs

Pregnancy
Hepatic impairment
Heart failure
Due to the hepatic toxicity of troglitazone, liver function tests are periodically required while taking other thiazolidinediones

64

thiazolidinedione uses
taken how often?
monotx or combo?
why do the effects take so long?
future use?

T2 DM
taken 1x/day
They may be used as a monotherapy, or in conjunction with metformin, sulfonylureas, or
insulin.
Since the effects of thiazolidinediones are mediated by altered gene expression and cell differentiation, maximal effect on glucose homeostasis takes 1-3 months to be seen.
While very effective in the treatment of type 2 diabetes, the adverse risks of this class will likely limit their future use.

65

α-GLUCOSIDASE INHIBITORS

competitive inhibitors of enteric α-glucosidases, enzymes that break down complex carbohydrates and oligosaccharides

only monosaccharides can be absorbed from the intestinal tract, α-glucosidase inhibitors *delay postprandial absorption of glucose*

results in *attenuation of postprandial increases in plasma glucose*, which creates an insulin-sparing effect

Acarbose is minimally absorbed.

66

a-glucosidase inhibitor SEs

GI disturbances (flatulence, diarrhea,
abdominal pain)

from bacterial metabolism of undigested carbohydrates in the colon-diminishes over time due to upregulation of α-glucosidases in the distal small intestine

67

a-glucosidase inhibitor CIs

inflammatory bowel disease
Renal impairment
Any GI conditions worsened by gas or distension

68

a-glucosidase inhibitor uses
taken when?
mono or combo?

T2 DM
immediately before each meal
monotherapy, or in conjunction with other oral antidiabetic agents
or insulin
slowly titrated upward to minimize GI disturbances
used in prediabetic patients to prevent the progression to T2 DM

69

in mild to moderate cases of hypoglycemia, patients taking an α-glucosidase
inhibitor should be given a source of ??

glucose (e.g. Dex Tabs) not sucrose, as sucrose metabolism into the monosaccharides glucose and fructose is impaired in these patients

70

Bile acid sequestrants

proposed mechanisms:
reduction in intestinal glucose absorption
signaling through nuclear receptors, such as farnesoid X receptor

lower LDL cholesterol
only Colesevelam for T2 DM tx
(not the greatest)

adverse effects: GI disturbances, inc. plasma TGs, interfere with absorption of meds

CI:
hypertriglyceridemia
hx of pancreatitis
esophogeal/GI disorders

taken 2x/day

71

AMYLIN ANALOGUES

peptide secreted with insulin from pancreatic β cells, which acts on the amylin receptor in the hindbrain

(like amylin) suppresses glucagon release, delays gastric emptying, and promotes satiety.

subQ
not plasma protein bound, met/exc by kidney

72

amylin analogue SEs

*Hypoglycemia*
GI disturbances, particularly nausea
*Weight loss*

73

amylin analogue CIs

*Gastroparesis or other GI motility disorders*

74

amylin analogue uses

T1 and T2 DM
*adjunct to insulin therapy*
administered *separately*, diff. syringes
subQ, preprandially
lowers amount of insulin needed to regulate glucose: to avoid hypoglycemia, *mealtime insulin doses should be reduced by ~50%*

75

GLP-1 AGONISTS

Incretins: class of GI hormones secreted after meals and augment insulin released from pancreatic β-cells.
Glucagon-like polypeptide-1 (GLP-1) is one type of incretin

activate GLP-1 receptor (esp. pancreatic β-cells)
increased insulin synthesis and secretion in a *glucose-dependent manner*

delayed gastric emptying and decreased appetite (GLP-1 rec in PNS, CNS, GIT)

suppress the release of postprandial glucagon (better insulin effect)

76

GLP-1 agonist SEs

GI disturbances, (esp. nausea at beginning)
Weight loss
Hypoglycemia, when combined with a sulfonylurea
Pancreatitis, rare but serious

Due to delayed gastric emptying, can alter the pharmacokinetics of drugs that require rapid GI absorption (i.e. OCTs and abx)

77

GLP-1 agonist CIs

History of pancreatitis

For liraglutide, an increase in thyroid C-cell cancer was observed in rodents. Currently,
liraglutide carries a black box warning that contraindicates its use in patients with family history of medullary cancer or multiple endocrine neoplasia type 2.

78

DPP-4 INHIBITORS

inhibit enzyme that degrades incretin hormones
-->increase circulating levels of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP)
-->resulting in increase in postprandial insulin secretion and a decrease in glucagon levels

monotherapy or as adjunctive therapy, T2DM
taken 1x day
high oral availability and achieve >95% inhibition of DPP-4 for 12
hours

remain unbound in the circulation and are excreted renally

79

DPP-4 inhibitor SEs

Increased rate of infections (DPP-4 is expressed in lymphocytes)
Headache
Hypoglycemia, when combined with a sulfonylurea
Hypersensitivity reactions
Pancreatitis

80

DPP-4 inhibitor CIs: Saxagliptin dose should be decreased when administered with ??

CYP3A4/5 inhibitors
(antiviral, antifungal, and antibacterial agents).

81

SGLT2 INHIBITORS

Sodium-glucose co-
transporter 2 (SGLT2) transports filtered glucose from the proximal renal tubule into tubular epithelial cells. Thus, inhibition of SGLT2 reduces glucose reabsorption

new drugs, monotherapy or as adjunctive therapy T2DM, 1x daily

inhibits SGLT2 activity in the kidney, resulting in decreased glucose reabsorption, increased urinary glucose excretion, and lowering of blood glucose levels

82

SGLT2 inhibitor SEs

*Genital mycotic infections (inc. glucose in urine)*
*UTIs*
Can have a diuretic effect
Canagliflozin can increase serum concentrations of digoxin
Dapagliflozin may increase the risk of bladder cancer
Long term safety unknown (i.e. ketoacidosis, fx risk under investigation)

83

SGLT2 inhibitor CIs

Severe renal impairment

84

DOPAMINE AGONISTS

not used much, Kopf doesn't want to spend time on
Bromocriptine: ergonline derivative approved for type 2DM (also hyperprolactinaemia, galactorrhea, Parkinsonism)
increases insulin sensitivity

85

Table 3

relative efficacy of drugs to lower HbA1c levels

86

glucagon SEs

Transient N/V

inotropic and chronotropic effects in the heart (similar to β–adrenergic agonists)-->transient tachycardia and HTN may also occur