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48 Cards in this Set
- Front
- Back
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Are sulfonylureas weak acids or bases?
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weak acids due to extensive electron delocalization
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Sulfonylurease or strongly / weakly bout to proteins?
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strongly bound like other weak acids
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What are sulfonylureas MOA?
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interact with various pancreatic beta cell receptors to block ATP-gated K channels
this depolarizes due to Ca influx and causes the beta cell to release insulin |
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What are a few first class sulfonylureas?
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Tolbutamide
Tolazamide Chlorpropamide Acetohexamide |
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What was the first clinically significant sulfonylurea, what is its drawback?
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Tolbutamide
hepatic metabolism forms hydroxyl group which is rapidly converted to an inactivaed carboxcylic acid short duration of action ~6-8h tolazamide undergoes the same two stage oxidation to a carboxcylic acid; also hydroxylation on azapine ring |
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Why is tolzalamides duration of action longer than tolbutamide?
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the hydroxylated tolzalamides have a longer t1/2 and are more potent
Duration of action - 10-14 hrs |
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What is special about chlorpropamide?
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the substitution of a methyl with a chlorine haults hydroxylation and extends half life
also the n-propyl chain undergoes slow hydroxylations duration is ~60hrs |
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How is Acetohexamide unique?
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Its metabolite is 2.5X as strong as toldbutamide and this helps it have a longer duration of action
12-24 hours |
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What is the difference between 1st and 2nd generation sulfonylureas?
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2nd generation have larger non-poplar substituents on the benzene ring
still feature the cyclohexyurea of acetohexamide |
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How much more potent are 2nd generation sulfonylureas than first generations?
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2-5mg doses rather then 100mg doses (chlorpropamide and tolbutamide)
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Do 2nd generation sulfonylureas have active metabolites?
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NO!
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Name two 2nd generation sulfonylureas.
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Glipizid (Glucatrol)
Gylburide (Diabeta) duration for both 10-24 hrs |
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SAR for 1st and 2nd generation sulfonylureas:
1. What must be present on the urea nitrogen? 2. Does there need to be substitution on Aromatic sulfonyl? 3. Whats one aspect of 2nd generation sulfonylureas that may account for increased potency? |
1. a bulky substituent (methyl and ethyl not active)
2. YES 3. spatial relationship between the sulfonamide and substituent amide nitrogen |
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Why might 3rd generation sulfonylureas work differentely?
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Binding site on the beta receptor may be different then 1st and 2nd generation.
glimperide and other 3rd generations may have extra pancreatic effects such as increasing GLUT 4 transolcation |
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What is the 3rd generation discussed in the notes and why is its duration of action longer?
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Glimperide (Amaryl)
the first metabolite is active urea methyl -->hydroxyl --> carboxcylic acid |
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What are some problems associated with sulfonylureas?
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sulfonamide hpersensitivity
excessive hypoglycemia hyperinsulinemia (1st & 2nd gen) CV risks (controversial) |
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What are Meglitinides MOA?
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bind to unique sites as well as sites bound by sulfonylureas
closes ATP-dependent K channels and inturn Ca channels open depolarizing cell and causing eflux of insulin |
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how are meglitinides metabolized?
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glucuronidation
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What meglitinides were covered in the notes?
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Repaglinide (Prandin)
Nateglinide (Starlix) free of prolonged hyperinsulinemia |
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What was used in medieval Europe as a treatment for diabetes?
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Goat's rue (Galega officinalis)
Galegine is active comonent but also toxic |
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What are the Biguanides discussed in the notes?
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Metformin (Glucophage)
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What is the MOA of Metformin?
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MOA is unclear
does not depend on functioning of beta cells or insulin secretion no effect on glucagon, cortisol, or somatostatin |
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What are important effects of metformin?
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inhibits gluconeogenesis
increases anaerobic glucose use in small intestine increases aerobic glucose use in other tissue OVERAL GLUCOSE UTILIZATION |
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How is metformin metabolized?
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Its not metabolized; however, it is renally excreted quickely
Duration of action is 10 -12 hrs |
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Metformin induces hypoglycemia? y/n?
Metformin is inactive in patients unresponsive to sulfonylureas? y/n? |
metformin does not induce hypoglycemia
drug is active in patients who are unresponsive to sulfonylureas? |
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What enzyme degrades complex carbohydrates to oligosaccharides, trisaccharides & disaccharides?
What enzyme takes alpha sugars (maltose and sucrose) to monosaccharides? What en |
a-amylases
a-Glucosidease |
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What is the mechanism of alpha Glucosidase inhibitors?
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since Type II diabetics have slow insulin response a-Glucosidase inhibitors slow the absorbtion of sugars into the blood stream
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a-Glucosidase inhibitors:
cause hypoglycemia? y/n? stop disaccharide hydrolysis is blocked? y/n What is the main side effect? |
a-Glucosidase inhibitors do NOT cause hypoglycemia
disaccharide hydrolysis is not blocked but delayed GI upset: flatulence, bloating, diarrhea) |
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What are the three a-Glucosidase inhibitors discussed in the notes?
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Acarbose (Precose)
Miglitol (Diastabol) Voglibose (Basen) |
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What is the MOA of Acarbose?
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competitive inhibitor or a-glucosidase.
the carvosine unit is important for activity the basicity and position of secondary amine blocks the active site of a-Glucosidase carboxcylic acid that protonates the oxygen of glycosidic bonds of a-sugar substrates |
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What are the Biguanides discussed in the notes?
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Metformin (Glucophage)
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What is the MOA of Metformin?
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MOA is unclear
does not depend on functioning of beta cells or insulin secretion no effect on glucagon, cortisol, or somatostatin |
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What are important effects of metformin?
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inhibits gluconeogenesis
increases anaerobic glucose use in small intestine increases aerobic glucose use in other tissue OVERAL GLUCOSE UTILIZATION |
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How is metformin metabolized?
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Its not metabolized; however, it is renally excreted quickely
Duration of action is 10 -12 hrs |
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Metformin induces hypoglycemia? y/n?
Metformin is inactive in patients unresponsive to sulfonylureas? y/n? |
metformin does not induce hypoglycemia
drug is active in patients who are unresponsive to sulfonylureas? |
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What enzyme degrades complex carbohydrates to oligosaccharides, trisaccharides & disaccharides?
What enzyme takes alpha sugars (maltose and sucrose) to monosaccharides? What en |
a-amylases
a-Glucosidease |
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What is the mechanism of alpha Glucosidase inhibitors?
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since Type II diabetics have slow insulin response a-Glucosidase inhibitors slow the absorbtion of sugars into the blood stream
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a-Glucosidase inhibitors:
cause hypoglycemia? y/n? stop disaccharide hydrolysis is blocked? y/n What is the main side effect? |
a-Glucosidase inhibitors do NOT cause hypoglycemia
disaccharide hydrolysis is not blocked but delayed GI upset: flatulence, bloating, diarrhea) |
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What are the three a-Glucosidase inhibitors discussed in the notes?
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Acarbose (Precose)
Miglitol (Diastabol) Voglibose (Basen) |
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What is the MOA of Acarbose?
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competitive inhibitor or a-glucosidase.
the carvosine unit is important for activity the basicity and position of secondary amine blocks the active site of a-Glucosidase carboxcylic acid that protonates the oxygen of glycosidic bonds of a-sugar substrates |
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What are two thiazolidinediones?
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Pioglitazone (Actos)
Rosiglitazone (Avandia) |
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What are the thiazolidinediones?
MOA |
Lower blood glucose levels by inproving target tissue (adipose, skeletal, and liver) sensitivity to insulin.
INSULIN ENHANCERS kind of like benzos to GABAreceptor |
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What receptor to thiazolidinediones bind to?
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PPARgama (peroxisome proliferator activated receptor gamma)
when this is activated there is increased transcription of a wide variety of metabolic regulators |
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What do the inceased concentration metabolic regulators produced by thiazolidinediones accomplish?
What is MAIN goal use? |
increase expression of genes involved in:
glucose and lipid metabolism MAIN GOAL IS: increase glucose uptake and metabolism in muscle and adipose tissues; hepatic gluconeogenesis also restrained THIAZOLIDINEDIONES DEPEND ON INSULIN FOR ACTIVITY |
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What hypoglycemics work on the liver (increased hepatic glucose output)?
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Metformin
thiazolidinediones |
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What works on skeletal muscle?
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thiazolidinediones
metformin |
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What works on the Pancreas?
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Insulin
Meglitinides Sulfonlyureas |
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What works on the GI tract?
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a-Glycosidase inhibitors
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