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2016 Endocrine > Test 2 Diabetes MedChem > Flashcards

Test 2 Diabetes MedChem Flashcards

1
Q

Insulin:

A
  • Hormone
    • Secreted by β cells of islet of Langerhans
  • In the liver and muscle tissues, insulin promotes the storage of excess glucose as glycogen.
  • Composition (51 amino acid peptide):
    • A chain (21-amino-acid)
    • B chain (30-amino-acid)
    • Linked by disulfide bond between the 2 cysteines
  • Exists as dimers and hexamers (can form an interaction with zinc – concentration dependent)
  • To be biologically active, insulin must be in monomeric form
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2
Q

Insulin Preparations

A
  • Short acting
  • Rapid acting
  • Intermediate acting
  • Longer-acting
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3
Q

Short-acting Insulin

A
  • Short-acting:
    • Regular Insulin (Humulin R, Novolin R)
      • Onset of Action: 0.5-1 h; Peak: 2-4 h;
      • Duration: 6-8 hrs
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4
Q

Rapid-Acting Insulin

A
  • Rapid-Acting - Products: B28 and B29 are changed in most of these agents à may alter the secondary structure (fewer beta sheets)
    • Lispro (Humalog) – lysine + proline added
      • Change: B28 Pro → Lys; B29 Lys → Pro
      • (Lysine and proline are switched around)
    • Aspart (NovoLog) – asparagine added
      • Change: B28 Pro → Asp
    • Glulisine (Apidra)
      • Change: B3 Asn → Lys; B29 Lys → Glu
  • Onset of Action: 15 min (These products predominantly exist as monomers → have a quick onset of action)
  • Peak: 1 h; Duration: 4 hrs
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5
Q

Intermediate-acting Insulin

A
  • Intermediate-acting:
    • Neutral protamine Hagedorn (NPH) insulin (Humulin N, Novolin N)
      • Protamine (highly + charged) and regular insulin
        • Protamine contains arginine – used in heparin overdose (forms an ionic interaction)
    • Cloudy appearance – has poor solubility (Not completely soluble)
    • Onset of Action: 2 hrs (Onset takes longer than regular insulin because it must dissociate from the protamine)
  • Peak: 4-8 h; Duration: 12-18 hrs
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6
Q

Longer-Acting Insulins

A

Glargine (Lantus)

Detemir (Levemir)

Degludec (Tresiba)

Ryzodeg

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7
Q

Glargine

A
  • Longer Acting Insulin
    • glargine (Lantus)
      • Change: A21 Asn → Gly
      • Add: B31 Arg and B32 Arg
      • Clear solution in bottle (pH 4).
        • When injected, at body pH (7.4) it precipitates
        • (isoelectric point is ~6.8, which is lower than physiologic pH → leads to longer DOA )
        • DONT mix with formulations that have a different pH
    • Onset: 2 hrs, DOA: 20-24 hrs
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8
Q

Detemir

A
  • Longer Acting Insulin
    • Detemir (Levemir)
      • Remove: B30 Thr
      • Add: C14 fatty acid (myristic acid=increased lipophilicity) to B29 Lys.
        • Increases lipophilicity
    • Fatty acid side chain binds to non-covalently plasma albumin to produce a longer action
  • Onset: 2 hrs, DOA: 12-24 hrs
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9
Q

Degludec

A
  • Longer Acting Insulin
    • Degludec (Tresiba) – possible ultra-long acting (up to 42 hours)
      • Remove: B30 Thr
      • Add: glutamic acid and a hexadecanedioic fatty acid (increases lipophilicity causing it to be bound to proteins which gives long duration)
  • Onset: 1 hr
  • DOA: >24hrs
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10
Q

Ryzodeg

A
  • Longer Acting Insulin
    • Ryzodeg
    • (70% degludec and 30% aspart)
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11
Q

Inhaled insulin

A
  • Inhaled insulin (Afrezza)
    • Dry powder formulation of regular insulin
    • Approved in adults
    • Peak level is reached in 12 – 15 min; quicker onset of action
    • Adverse effects: cough
    • Contraindicated in smokers and COPD
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12
Q

· Medications That May Affect Glycemic Control: hyperglycemic activity

A
  • Medications with hyperglycemic activity (give higher dose of insulin)
    • Glucocorticoids
    • Niacin
    • Diuretics (thiazides)
    • Hydantoins (phenytoin)
    • Atypical antipsychotics
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13
Q

· Medications That May Affect Glycemic Control: hypoglycemic activity

A
  • Medications with hypoglycemic activity (give lower dose of insulin)
    • Oral antidiabetic agents
    • Angiotensin-converting enzyme inhibitors
    • Salicylates
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14
Q

Q: Which of the following insulin formulations when administered forms a precipitate in the body?

A

Glargine (Lantus)

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15
Q

What is GLP-1?

A
  • An incretin hormone; 37–amino acid peptide
    • Secreted in gut from L-cells
      • ↑ insulin secretion, ↓ glucagon release, delays gastric emptying (not direct action), ↓ food intake, and normalizes fasting and postprandial insulin secretion.
  • Limited/ No clinical applicability: Rapidly hydrolyzed by dipetidyl peptidase IV (DPP-IV): t½= 1 to 2 min
  • Not available as a drug because it can be rapidly hydrolyzed by DPP-IV
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16
Q

Ways to increase GLP-1

A
  • GLP-1 agonist, DPP-IV inhibitor
    • Rationale: GLP-1 agonists or DDP-IV inhibitors are effective agents to control blood glucose levels in diabetic patients
      • GLP-1 is hydrolyzed by the DiPeptidyl Peptidase IV (DPP-IV) enzyme
      • GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP-4
        • Both GLP-1 and glucagon are products derived from preproglucagon, a 180–amino acid precursor with five separately processed domains (Figure 43–9) (Drucker, 2006). An amino-terminal signal peptide is followed by glicentin-related pancreatic peptide, glucagon, and glucagon-like peptide 2 (GLP-2).
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17
Q

GLP-1 Receptor Agonists

A
  • GLP-1 agonists or DDP-IV inhibitors are effective agents to control blood glucose levels in diabetic patients
  • Exenatide (Byetta)
  • Liraglutide (Victoza)
  • Albiglutide (Tanzeum)
  • Dulaglutide (Trulicity)
  • Lixisenatide (Adlyxin)
    • DDI: May delay the absorption of other medications
    • Boxed Warning: increased risk of thyroid tumors
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18
Q

Exenatide

A
  • GLP-1 Receptor Agonist
    • Exenatide (Byetta)
      • Synthetic version of Exendin-4 (natural product synthesized from saliva of gila monster?)
        • 53% homology to human GLP-1
    • t½ elimination
      • IR (twice daily) formulation: 3 -4 hours
      • ER (weekly) formulation (Bydureon)[Microspheres]: ~2 weeks
        • Longer half-life → less frequent dosing
        • Contains microspheres
    • Metabolism and elimination: glomerular filtration and proteolytic degradation
    • Severe renal impairment: should not be used
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19
Q

liraglutide

A
  • GLP-1 Receptor Agonist
    • Liraglutide (Victoza)
      • 96% homology to human GLP-1
      • Arg34®Lys; C16 fatty acid chain attached to Lys26
    • BA: SubQ: ~55%
    • PB: >98% - fatty acid chain can interact w/ proteins
    • Metabolism: proteolytic degradation
    • t ½ elimination: 13 h; Once-daily administration
      • Fatty acid chain binds to albumin and is slowly released
    • Renal Impairment. No dose adjustment, but use with caution
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20
Q

Albiglutide

A
  • GLP-1 Receptor Agonist
    • Albiglutide (Tanzeum)
      • Newer Drug (2014)
      • GLP-1 dimer(2 GLP-1) fused to albumin (fusion protein)
        • Covalent interaction
      • Amino acid substitution Ala (GLP1) to Glu (Albiglutide)
      • Dimer improves receptor interaction in the presence of albumin
    • t ½= 5 days (much longer)
    • Administered once-weekly
    • Metabolism: proteolytic degradation
    • Decreased renal clearance due to bigger size
    • Renal impairment: No dose adjustment
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21
Q

Lixisenatide

A
  • GLP-1 Receptor Agonist
    • Lixisenatide (Adlyxin)
      • Newer Drug (2016)
      • Exendin-4 AA 38 proline is deleted and six lysine residues are added
    • t ½ elimination: about 3 hours
    • Once-daily administration
    • Metabolism: proteolytic degradation
    • Mild to moderate renal impairment: No dose adjustment
    • Severe renal impairment: Don’t give or adjust
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22
Q

Dulaglutide

A
  • GLP-1 Receptor Agonist
    • Dulaglutide (Trulicity)
      • Newer Drug (2014)
      • GLP-1 analog + Linker + Modified IgG4 Fc Domain
  • Absolute bioavailability: 47% - 65 %
  • t ½ elimination: 5 days
  • Once-weekly administration
  • Metabolism: Possible proteolytic degradation
  • Renal impairment: No dose adjustment
    • Peptide fused to IgG → higher MW → longer t 1/2
    • T 1/2 of native GLP-1 = minutes
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23
Q

What is Amylin?

A
  • 37–amino acid peptide
  • Released from pancreatic beta cells
  • Cosecreted with insulin
  • Role:
    • Delayed gastric emptying and suppression of glucagon secretion
    • Also regulates food intake (appetite center in brain)
  • Amylin itself is unsuitable as a drug because
    • Aggregates
    • Insoluble in solution
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24
Q

pramlintide

A
  • Amylin Agonist
    • Pramlintide (Symlin)
      • Substitution with Proline (25, 28, and 29)
        • ­­increased water solubility
        • decreased self aggregation
      • MOA:
        • Reduction of postprandial rise in glucagon
        • Prolongation of gastric emptying
        • Reduction of caloric intake
      • Drug Interactions:
        • May delay the absorption of other medications. E.g., oral pain medications and antibiotics
25
Q

pramlintide pharmacokinetics

A
  • Pramlintide (Symlin)
  • Amylin Agonist
    • Pharmacokinetics:
      • Bioavailability: 30-40% SC inj
      • Metabolism: proteolysis
        • Des-lys1 pramlintide (active)
    • Elimination:
      • Kidney, t 1/2 elimination: 48 min
        • Not used as frequently as GLP-1 agonists (due to frequency of administration)
    • Incompatibility with insulin products (pH 7.8) v. pramlintide (pH 4)
26
Q

Non-Peptide Drugs

A
  • Sulfonylureas
    • 1st Gen: Chlorpropamide, Tolbutamide, Tolazamide
    • 2nd Gen: Glyburide, Glipizide, Glimepiride (DOA is 12-24h)
  • Meglitinides
  • Biguanides
  • Thiazolidinediones
  • Dipeptidyl Peptidase IV (DPP-IV) inhibitors
  • a-glucosidase inhibitors
  • Sodium-glucose Cotransporter 2 inhibitor
27
Q

Sulfonylureas

A
  • MOA:
    • Stimulate insulin release → may lead to hypoglycemia and weight gain
    • Binding to the sulfonylurea receptor (SUR) of the ATP-sensitive K+ channel on the pancreatic beta-cells
      • Also binds to SUR on cardiac and smooth muscles
  • Potency:
    • 1st Gen: Less potent
    • 2nd Gen: More potent
  • DOA: Long for chlorpropamide (> 48 h)
  • DDI: more w/ 1st Gen
    • Highly protein bound drugs → hypoglycemia
      • Warfarin, salicylates, sulfonamides, etc.
      • Sulfonylureas are protein bound → displaced from proteins by other drugs → increased plasma levels
  • ADR: Hypoglycemia; Hemolytic anemia (G6PD); allergic skin reaction
  • Warnings: May increased risk of CV mortality
    • Sulfonylurea receptors are present on cardiac muscle (contraindicated in patient’s with sulfa allergy)
28
Q

1st generation vs 2nd generation sulfonylureas

A
  • First Gen:
    • Small substitution (R1)
    • cyclic and non-cyclic aliphatic groups (R2)
  • Second Gen:
    • Bulky Substitution (R1)
    • cyclic aliphatic groups (R2)
29
Q

Chlorpropamide

A
  • Chlorpropamide (Diabinese) – 1st Gen sulfonylurea
    • Metabolism: Slow ω and ω-1 hydroxylation of the propyl group.
    • Significant amount (~20%) is removed unchanged.
    • t 1/2 elimination: 32 hrs
    • DOA: > 48 hrs
30
Q

Tolbutamide

A
  • Tolbutamide (Orinase) - 1st Gen sulfonylurea
    • t 1/2 elimination: 4-5 hrs
    • DOA: 6-12 hrs
    • Metabolism:
      • Benzylic oxidation
31
Q

Tolazaamide

A
  • Tolazaamide (Tolinase)- 1st Gen sulfonylurea
    • t 1/2 elimination: ~ 7 hrs
    • DOA: 12-24 hrs
    • Metabolism:
    • Benzylic oxidation
      • Aliphatic ring hydroxylation
32
Q

Glyburide

A
  • Glyburide (DiaBeta) – 2nd Gen sulfonylurea
    • t 1/2 elimination: 10 hrs
    • DOA: 12-24 hrs
33
Q

Glipizide

A
  • Glipizide (Glucotrol) – 2nd Gen sulfonylurea
    • t 1/2 elimination: 2-4 hrs
    • DOA: 12-18 hrs
    • DOA (ER): 24 hrs
34
Q

Glimepiride

A
  • Glimepiride (Amaryl) – 2nd Gen sulfonylurea
    • t 1/2 elimination : 5-9 hrs
    • DOA: up to 24 hrs
35
Q

Meglitinides

A
  • Meglitinides – discovered from sulfonylurea
    • Repaglinide
    • Nateglinide
  • MOA: stimulates insulin release (similar to sulfonylureas –insulin secretagogue)
    • Advantage over sulfonylureas:
    • Some are more selective to beta cells of pancreas
    • Do not contain sulfonylurea group → replaced with carboxylic acid
36
Q

Repaglinide

A
  • Meglitinide
    • Repaglinide (Prandin)
      • Absorption: Rapid and complete
      • Bioavailability: ~56%
        • Protein binding, plasma: >98% to albumin
      • Metabolism: Hepatic via CYP3A4 and CYP2C8 and glucuronidation
      • Various DDIs
      • Elimination t1/2: 1.5 hours
      • DOA: 4-6 hrs (shorter than 2nd gen sulfonylureas)
37
Q

Nateglinide

A
  • Meglitinide
    • Nateglinide (Starlix)
      • Bioavailability: 73%
      • 98% protein bound (primarily to albumin)
      • Metabolism: Hepatic via CYP 2C9 and CYP 3A4 and glucuronide derivatives
      • Elimination t 1/2: 1.5 hours
      • DOA: 4 hrs
      • Selectively binds to SUR1 on the beta-cells of pancreas. Much lower affinity for cardiac and skeletal muscle tissue.
38
Q

Biguanides

A
  • Metformin (Glucophage)
    • MOA:
      • ↓ hepatic glucose production
        • ↓ gluconeogenesis
      • ­Increase glucose utilization
    • Advantages:
      • Improved lipid profile (can lower free fatty acid concentrations)
      • Do not induce weight gain
      • No/rare hypoglycemia
39
Q

Metformin

A
  • Biguanide
    • Metformin (Glucophage)
      • Absorption: Rapid; Bioavailability: 50-60%.
      • Distribution: Not protein bound. Accumulates in the wall of small intestine
      • Metabolism: Little/none
      • Plasma t 1/2: ~ 6 hours
      • DOA: Up to 24 hrs
      • Elimination: Renal (Contraindication: renal disease)
        • By active tubular secretion (OCT)
      • Lactic Acidosis (rare but serious) – glucose broken down into lactic acid
        • ↑ risk: Renal or hepatic impairment, alcohol abuse, acute CHF
      • DDI:
        • Cimetidine (↑ metformin serum conc.) – competes with the same OCT transporter
        • Iodinated contrast Agents: May enhance metformin adverse effects
          • Can acquire a + charge at physiological pH
          • Organic cation transporter (located in kidney) → helps with elimination
40
Q

Thiazolidinediones

A
  • Drugs: Rosiglitazone (Avandia) and Pioglitazone (Actos)
    • Referred as glitazones
  • MOA: Stimulate peroxisome proliferator-activated receptor (PPAR)-γ stimulation
    • PPARγ expression is highest in adipose tissue. With retinoid X receptor causes transcription of insulin-sensitive genes.
      • ↑ insulin sensitivity in adipose, liver, muscle
      • ↑ glucose uptake, fatty acid uptake, glycolysis and glucose oxidation
      • ↓Gluconeogenesis and Glycogenolysis
41
Q

rosiglitazone

A
  • Thiazolidinediones
    • Rosiglitazone (Avandia)
      • BA: 99%
      • Protein binding: 99.8%; primarily albumin
      • Metabolism: CYP 2C8 - hydroxylation, N-demethylation, sulfate and glucuronic acid conjugates
      • Inactive metabolites
      • t 1/2 elimination: 3-4 hours
      • DOA: 24 hrs
      • DDI w/ 2C8 inhibitor (gemfibrozil) or 2C8 inducer (rifampin)
      • Side effects: Congestive heart failure (rapid weight gain, edema), ↑ bone fractures in females
42
Q

Pioglitazone

A
  • Thiazolidinediones
    • Pioglitazone (Actos)
      • Protein binding: >99%
      • Metabolism: oxidation, sulfate and glucuronic acid conjugates
      • Some metabolites are active
      • t1/2 elimination: Parent drug: 3-7 hours; total: 16-24 hours
      • DOA: 24 hrs
      • DDI w/ 2C8 inhibitor (gemfibrozil) or 2C8 inducer (rifampin)
      • Side effects: Congestive heart failure (rapid weight gain, edema), ↑ bone fractures in females
43
Q

Q: Which of the following drugs may lead to a rare side effect that may be characterized by decreased blood pH (lactic acidosis)?

44
Q

Q: Which medication should you temporarily hold in patients undergoing administration of a iodinated contrast agent?

45
Q

DPP-IV Inhibitors

A
  • DPP-IV Inhibitors (DiPeptidyl Peptidase IV inhibitors)
    • Incretin hormones:
      • Glucagon-like peptide-1 (GLP-1)
      • Glucose-dependent insulinotropic polypeptide (GIP)
  • MOA: Block breakdown of GLP-1 → Enhanced GLP-1 activity
    • Increases β-cell sensitivity to glucose (­↑ insulin secretion)
    • Suppresses glucagon secretion
    • Many Serine protease dipeptidyl peptidases → selectivity for DPP-IV to avoid unwanted toxicity
      • DPP-8; DPP-9
  • Drugs: Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin (Tradjenta), Alogliptin (Nesina)
46
Q

sitagliptin

A
  • DPP-IV Inhibitors
    • Sitagliptin (Januvia)
      • OB: ~ 87%
      • t 1/2: ~ 12 hrs
      • Metabolism: Not extensively metabolized
      • Excretion: 87 % in urine
      • Janumet (Sitagliptan w/ Metformin)
47
Q

Saxagliptin

A
  • DPP-IV Inhibitors
    • Saxagliptin (Onglyza)
      • Nitrile group: forms a covalent bond with Ser630 of DPP-IV (irreversibly inactivation)
      • t 1/2: 2.5 hrs; 5-hydroxy saxagliptin: 3.1 hours
      • CYP3A4 metabolized: 5-hydroxy-saxagliptin
      • Excretion: Urine 75% (36% as 5-hydroxy saxagliptin)
      • 10 x more potent as DPP-IV inhibitor than sitagliptin
      • Higher specificity for DPP-IV compared to DPP-VIII and DPP-IX
48
Q

Linagliptin

A
  • DPP-IV Inhibitors
    • Linagliptin (Tradjenta)
      • Xanthine derivative
      • Oral BA: 30%
      • Binds extensively to plasma proteins (70% to 80%)
      • Metabolism: Mostly unchanged
      • Excretion: ~ 80% unchanged in feces; 5% urine unchanged
      • t ½=12 h
49
Q

Alogliptin

A
  • DPP-IV Inhibitors
    • Alogliptin (Nesina)
      • Absorption: Extensive (~100%)
      • Bioavailability: ~100%
      • Metabolism: Not extensively metabolized
      • t ½= ~21 hrs
      • Excretion: Urine 76% (60% to 71% as unchanged drug)
50
Q

Q: A patient with renal impairment is on a DPP-IV inhibitor. Which of the following agents can be administered with no dose adjustment?

A

Linagliptin (mostly eliminated in feces)

51
Q

α-Glucosidase Inhibitors

A
  • Drugs: Acarbose (Precose) and Miglitol (Glyset)
  • Rationale: α-glucosidase inhibitors prevent the hydrolysis of carbohydrates → their rate of absorption could be reduced
    • α-glucosidases act on disaccharides (i.e., maltose, isomaltose, and sucrose)
    • Clinical studies on α-glucosidase inhibitors reveal that disaccharide hydrolysis is not completely blocked but, rather, is delayed.
      • To be absorbed from the GI tract into the bloodstream, the complex carbohydrates that we ingest (i.e., starch) as part of our diet must first be hydrolyzed to monosaccharides
      • Starch → maltose in the presence of a-amylase → monosaccharides in the presence of a-glucosidase
      • Complex carbs are broken down into monosaccharides for absorption
52
Q

Acarbose

A
  • α-Glucosidase Inhibitors
    • Acarbose (Precose)
      • Oligosaccharide from Actinomyces
      • Contains glycosidic bonds
      • Impacts end-stage hydrolysis of both complex carbohydrates and disaccharides. It also affects all primary dietary sources of glucose.
      • Only minimally absorbed(<2%) as intact drug into the bloodstream (larger molecule – difficult to absorb)
      • Extensive metabolism in GI Þ GI distress (not readily absorbed)
      • DOA: 1-3 hrs
53
Q

Miglitol

A
  • α-Glucosidase Inhibitors
    • Miglitol (Glyset)
      • Produce similar results as acarbose
      • Rapidly absorbed (25 mg dose: Completely absorbed) into the bloodstream following oral administration. Saturated at high dose (100 mg dose: 50 – 70 % absorbed).
      • Decreased absorption at higher doses
      • It is distributed primarily to the extracellular space, and it is rapidly cleared through the kidney
      • DOA: 1-3 hrs
54
Q

Review: MOA of oral antidiabetic drugs

55
Q

Sodium-glucose Cotransporter 2

A
  • Na+ and glucose are reabsorbed together (cotransport via SGLT-2)
    • Blocking this transporter may cause electrolyte disorder (hyponatremia) and UTI; hypotension (due to decreased Na+)
    • May lead to ketoacidosis (common across the class)
56
Q

Canagliflozin

A
  • SGLT-2 Inhibitor
    • Canagliflozin (Invokana)
    • BA: ~65%
    • Protein binding: 99%
    • Metabolism: O-glucuronidation
      • Addition of glucuronic acid
    • t 1/2 elimination: ~10-13 hours
      • ↓ Weight – eliminating glucose→ eliminating calories
    • Excretion: Feces and urine (unchanged drug and O-glucuronide metabolites)
    • Adverse effects: UTI, Polyuria, genitourinary infection, hyperkalemia
      • Spironolactone and eplerenone also cause hyperkalemia
    • Renal Impairment: Monitor renal function (drug action is in the renal PCT)
    • May lead to ketoacidosis
57
Q

Dapagliflozin

A
  • SGLT-2 Inhibitor
    • Dapagliflozin (Farxiga)
    • BA: ~78%
    • Protein binding: 91%
    • ↓ Weight
    • Metabolism: O-glucuronide metabolite
    • t1/2 elimination: ~12.9 hours
    • Excretion: Feces and urine (unchanged drug and O-glucuronide metabolites)
    • Adverse effects: UTI, Polyuria, genitourinary infection
      • Should not be used : Active bladder cancer and prior history of bladder cancer
    • Renal Impairment: Monitor renal function
    • May lead to ketoacidosis
58
Q

Empagliflozin

A
  • SGLT-2 Inhibitor
    • Empagliflozin (Jardiance)
      • BA: ~86%
      • Protein binding: 86%
      • ↓ Weight
      • Metabolism: O-glucuronide metabolite
      • t1/2 elimination: ~12.4 hours
      • Excretion: Feces and urine (unchanged drug and O-glucuronide metabolites)
      • Adverse effects: UTI, Polyuria, genitourinary infection
      • Renal Impairment: Monitor renal function
      • May lead to ketoacidosis
59
Q

Q: Which of the following agent will prolong the half-life of endogenously produced GLP-1?

Nateglinide

Alogliptin

Acarbose

Metformin

Pioglitazone

A

o Alogliptin (DDP-IV inhibitor)

2016 Endocrine (19 decks)

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