antidiabetics 59/60

Question 1

Regular insulin (Humulin R and Novolin R)

Answer 1

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

Question 2

Insulin aspart (NovoLog)

Answer 2

Rapid-acting Insulin Preparation

B28 proline is replaced by an aspartic acid residue

works quicker than regular insulin due to forming monomers more quickly

Question 3

Insulin glulisine (Apidra)

Answer 3

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

Question 4

Insulin lispro (Humalog)

Answer 4

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

Question 5

NPH Insulin (Humulin N and Novolin N)

Answer 5

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

Question 6

Insulin glargine (Lantus)

Answer 6

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

Question 7

Insulin detemir (Levemir)

Answer 7

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

Question 8

Metformin (Glucophage, Glucophage XR, Glumetza)

Answer 8

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

Question 9

Glyburide (Diaβeta, Micronase, Glynase PresTab)

Answer 9

Sulfonylurea

2nd generation

Question 10

Repaglinide (Prandin)

Answer 10

Meglitinide

hypoglycemia w. skipped meal

Question 11

Pioglitazone (Actos)

Answer 11

Thiazolidinedione

Question 12

Rosiglitazone (Avandia)

Answer 12

Thiazolidinedione

Question 13

Acarbose (Precose)

Answer 13

α-Glucosidase Inhibitor

Question 14

Pramlitide (symlin)

Answer 14

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

Question 15

Exenatide (Byetta)

Answer 15

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

Question 16

Sitagliptin (Januvia)

Answer 16

DPP-4 Inhibitor

T2DM

Question 17

Canagliflozin (Invokana)

Answer 17

SGLT2 inhibitor

Question 18

Glucagon

Answer 18

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

Question 19

Glucose stimulation of insulin

secretion involves the uptake of glucose into the β cell via ??

Answer 19

GLUT-2

transporters

Question 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??

Answer 20

β cell
depolarization and calcium influx

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

Question 21

average individual produces ?? insulin/day

Answer 21

30 units

• half metabolized by liver
• rest by kidney and muscle

Question 22

insulin is produced as a ??

Answer 22

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

Question 23

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

Answer 23

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

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

Question 24

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

Answer 24

delayed and more subtle insulin hump (no spike)

Question 25

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

Answer 25

no response, unable to produce insulin

Question 26

insulin has 2 effects ???? that affects what tissues ??

Answer 26

anabolic and anticatabolic liver, muscle, and adipose tissue

Question 27

insulin anticatabolic effects in liver ?? anabolic effects in liver ??

Answer 27

inhibits glycogenolysis, gluconeogenesis, ketogenesis stimulates glycogen and fatty acid synthesis

Question 28

insulin anticatabolic effects in muscle ?? anabolic effects in muscle ??

Answer 28

inhibits protein catabolism stimulates glucose and amino acid uptake stimulates protein and glycogen synthesis

Question 29

insulin in adipose tissue: anticatabolic effects ?? anabolic effects ??

Answer 29

inhibits lipolysis stimulates glucose uptake stimulates glycerol synthesis and triglyceride synthesis

Question 30

"dawn phenomenon" in DM pts

Answer 30

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

Question 31

history factoid: started using insulin in humans in ??

Answer 31

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

Question 32

Type 1 diabetes mellitus

Answer 32

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

Question 33

Type 2 diabetes mellitus

Answer 33

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

Question 34

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

Answer 34

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

Question 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 ??

Answer 35

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))

Question 36

inhaled insulin ??

Answer 36

Exubera: pulled from market Afrezza: now available, same efficacy of injected insulin

Question 37

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

Answer 37

normal 4-5% | uncontrolled: 9-12%

Question 38

most T1 DM need ?? doses

Answer 38

variable doses (vs. fixed doses) may be adjusted: how they feel, checking finger-stick glucose

Question 39

split-mixed regimen

Answer 39

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

Question 40

basal bolus regimen

Answer 40

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

Question 41

insulin pump

Answer 41

baseline insulin given over intervals | -adjustable

Question 42

main adverse effects of insulin therapy

Answer 42

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)

Question 43

other adverse effects of insulin therapy

Answer 43

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

Question 44

inhaled insulin adverse effects

Answer 44

throat pain, irritation *cough*(most common reason to stop) altered pulmonary function: dec. FEV1 (do PFTs before prescribing and 4 mos later)

Question 45

Metformin SEs

Answer 45

GI disturbances in 20% pts (transient, dose-related) lactic acidosis (rare but fatal, adhere to contraindications: reduced drug elimination, reduce tissue oxygenation (i.e. )

Question 46

2 factors that predispose patients to lactic acidosis ?? contraindications ??

Answer 46

reduced drug elimination reduced tissue oxygenation alcoholism renal insufficiency hepatic disease hypoxic pulmonary disease also CI with contrast formulations or hospitalization for acute illness

Question 47

metformin benefits metformin typically taken ?? daily if mild DM can use

Answer 47

does not cause weight gain (actually causes mild weight loss) or hypoglycemia 2x metformin monotherapy

Question 48

if monotherapy of metformin not sufficient, may be used with

Answer 48

sulfonylureas, thiazolidinediones, or insulin

Question 49

other benefits of metformin

Answer 49

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

Question 50

sulfonylureas

Answer 50

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

Question 51

1st gen sulfonylureas 2nd gen sulfonylureas

Answer 51

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

Question 52

Sulfonylureas SEs

Answer 52

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

Question 53

Sulfonylurea CIs

Answer 53

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)

Question 54

Sulfonylurea uses taken how often? reduced efficacy when? combo tx??

Answer 54

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.

Question 55

MEGLITINIDES

Answer 55

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

Question 56

meglitinide SEs

Answer 56

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

Question 57

meglitinide CIs

Answer 57

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

Question 58

Meglitinide uses

Answer 58

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.

Question 59

THIAZOLIDINEDIONES

Answer 59

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

Question 60

effects of thiazolidinediones

Answer 60

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

Question 61

thiazolidinedione SEs

Answer 61

``` *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 ```

Question 62

Black box warning w. thiazolidinedione: rosiglitazone

Answer 62

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

Question 63

thiazolidinedione CIs

Answer 63

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

Question 64

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

Answer 64

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.

Question 65

α-GLUCOSIDASE INHIBITORS

Answer 65

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.

Question 66

a-glucosidase inhibitor SEs

Answer 66

``` 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

Question 67

a-glucosidase inhibitor CIs

Answer 67

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

Question 68

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

Answer 68

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

Question 69

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

Answer 69

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

Question 70

Bile acid sequestrants

Answer 70

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

Question 71

AMYLIN ANALOGUES

Answer 71

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

Question 72

amylin analogue SEs

Answer 72

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

Question 73

amylin analogue CIs

Answer 73

*Gastroparesis or other GI motility disorders*

Question 74

amylin analogue uses

Answer 74

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%*

Question 75

GLP-1 AGONISTS

Answer 75

``` 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)

Question 76

GLP-1 agonist SEs

Answer 76

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)

Question 77

GLP-1 agonist CIs

Answer 77

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.

Question 78

DPP-4 INHIBITORS

Answer 78

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

Question 79

DPP-4 inhibitor SEs

Answer 79

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

Question 80

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

Answer 80

CYP3A4/5 inhibitors | antiviral, antifungal, and antibacterial agents

Question 81

SGLT2 INHIBITORS

Answer 81

``` 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

Question 82

SGLT2 inhibitor SEs

Answer 82

*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)

Question 83

SGLT2 inhibitor CIs

Answer 83

Severe renal impairment

Question 84

DOPAMINE AGONISTS

Answer 84

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

Question 85

Table 3

Answer 85

relative efficacy of drugs to lower HbA1c levels

Question 86

glucagon SEs

Answer 86

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