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
2
Q
Insulin Preparations
A
- Short acting
- Rapid acting
- Intermediate acting
- Longer-acting
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
- Regular Insulin (Humulin R, Novolin R)
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
- Lispro (Humalog) – lysine + proline added
- Onset of Action: 15 min (These products predominantly exist as monomers → have a quick onset of action)
- Peak: 1 h; Duration: 4 hrs
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)
- Protamine (highly + charged) and regular insulin
- 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)
- Neutral protamine Hagedorn (NPH) insulin (Humulin N, Novolin N)
- Peak: 4-8 h; Duration: 12-18 hrs
6
Q
Longer-Acting Insulins
A
Glargine (Lantus)
Detemir (Levemir)
Degludec (Tresiba)
Ryzodeg
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
- glargine (Lantus)
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
- Detemir (Levemir)
- Onset: 2 hrs, DOA: 12-24 hrs
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)
- Degludec (Tresiba) – possible ultra-long acting (up to 42 hours)
- Onset: 1 hr
- DOA: >24hrs
10
Q
Ryzodeg
A
- Longer Acting Insulin
- Ryzodeg
- (70% degludec and 30% aspart)
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
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
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
14
Q
Q: Which of the following insulin formulations when administered forms a precipitate in the body?
A
Glargine (Lantus)
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.
- Secreted in gut from L-cells
- 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
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).
- Rationale: GLP-1 agonists or DDP-IV inhibitors are effective agents to control blood glucose levels in diabetic patients
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
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
- Synthetic version of Exendin-4 (natural product synthesized from saliva of gila monster?)
- 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
- Exenatide (Byetta)
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
- Liraglutide (Victoza)
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
- Albiglutide (Tanzeum)
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
- Lixisenatide (Adlyxin)
22
Q
Dulaglutide
A
- GLP-1 Receptor Agonist
- Dulaglutide (Trulicity)
- Newer Drug (2014)
- GLP-1 analog + Linker + Modified IgG4 Fc Domain
- Dulaglutide (Trulicity)
- 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
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
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
- Substitution with Proline (25, 28, and 29)
- Pramlintide (Symlin)
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)
- Kidney, t 1/2 elimination: 48 min
- Incompatibility with insulin products (pH 7.8) v. pramlintide (pH 4)
- Pharmacokinetics:
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
- Highly protein bound drugs → hypoglycemia
- 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)
- Repaglinide (Prandin)
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.
- Nateglinide (Starlix)
38
Q
Biguanides
A
- Metformin (Glucophage)
- MOA:
- ↓ hepatic glucose production
- ↓ gluconeogenesis
- Increase glucose utilization
- ↓ hepatic glucose production
- Advantages:
- Improved lipid profile (can lower free fatty acid concentrations)
- Do not induce weight gain
- No/rare hypoglycemia
- MOA:
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
- Metformin (Glucophage)
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
- PPARγ expression is highest in adipose tissue. With retinoid X receptor causes transcription of insulin-sensitive genes.
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
- Rosiglitazone (Avandia)
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
- Pioglitazone (Actos)
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)
- Sitagliptin (Januvia)
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
- Saxagliptin (Onglyza)
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
- Linagliptin (Tradjenta)
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)
- Alogliptin (Nesina)
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
- Acarbose (Precose)
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
- Miglitol (Glyset)
54
Q
Review: MOA of oral antidiabetic drugs
A
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
- Empagliflozin (Jardiance)
