diabetic drugs

Question 1

what are types of diabetes

Answer 1

insulin dependent/ juvenille onset/type 1: usually severe, insulin therapy is necessary otherwise rapid progression to ketosis and coma may occur

non insulin dependent/mature onset/ type 2: may respond to dietetic control alone or together with oral hypoglycaemic drugs

Question 2

what is the structure of insulin

Answer 2

peptide hormone; 2 polypeptide chains containing 30 and 21AAs, joined by 2 disulphide bridges

formed from biologically less active single chain precursor (proinsulin) by cleavage of a C-peptide

amino acid differences between different species are small in chains, larger difference in C-peptide

Question 3

what are different therapeutic preparations of insulin

Answer 3

therapeutic preparations of insulin are bovine, porcine or human

non human insulins are antigenic but rarely cause reactions of clinical significance

use of these reduces likelihood of immune response:

highly purified porcine insulin,

semi synthetic human insulin (porcine insulin which has had terminal alanine in B chaine removed)

human insulin produced by recombinant tech

Question 4

what is insulin action on its receptors

Answer 4

receptors identified in membranes of various tissues, particularly liver, adipose tissue and muscle

receptor is a glycoprotein complex consisting of 2 extracellular alpha subunits and 2 transmembrane beta subunits

binding of insulin to alpha subunits causes tyrosine kinase domaine of beta subunits to be activated, causing autophosphorylation at several sites

Question 5

how does insulin receptor mediate its activity

Answer 5

after tyrosine kinase domain has been autophosphorylated

autophosphorylation enhances action of kinase on other protein targets including insulin receptor substrate (IRS-1)

IRS-1 is phosphorylated by at least 5 tyrosine residues and forms link between receptor and signalling proteins which cause protein kinase activity

receptor also causes activation of phospholipase C, producing second messenger IP3 which activates serine-threonine phosphatases

activation of insulin receptor also causes GLUT-4 transporters to move to membrane

Question 6

what are general metabolic effects of insulin

Answer 6

causes anabolic effects on carbohydrates, proteins, fats and nucleic acids

increases glucose metabolism: increased glucose uptake, glycogen synthesis, decreased gluconeogensis, decreased glycogen breakdown

decrease in lipolysis, proteolysism ureogenesis, ketogenesis

Question 7

what are non metabolic effects of insulin

Answer 7

increase in plasma membrane transfer of glucose and other monosaccharides, some amino acids, some fatty acids, potassium and magnesium

Question 8

how does insulin resistance develop

Answer 8

high requirement of insulin exceeding 200 units/day may occur acutely in infections and ketoacidosis

chronic resistance may be caused by a large amount of antibodies against injected foreign insulin or by antagonists to insulin

insulin requirement is increased in obese people

Question 9

what are unwanted effects of insulin treatment

Answer 9

insulin treatment only in type 1 diabetes

hypoglycaemia, treated with glucose given orally or via iv

allergic reactions, rebound hyperglycaemia due to excess production of counter regulatory hormones

Question 10

what are different preparations of insulin and how does it effect their pharmacokinetic properties

Answer 10

different preparations have different pharmacokinetics:

all insulin preparations given via subcutaneous injection (peptide hormone)

soluble insulin: onset of 30 mins, duration of action is 5-8 hours

isophane insulin: has onset of 1 hour, total duration is 20-24 hours

lente insulin: is insulin zinc suspension, has amorphous crystalline structure, has onset of 2 hours, duration is 12-24 hours

ultralente insulin: insulin zinc suspension with crystalline structure, has onset of 2-4 hours and duration of 24-36 hours

Question 11

what is simplest insulin dosing regime

Answer 11

use of soluble insulin 30-40 mins prior to each meal

dose is adjusted by self testing of blood glucose

disadvantage is number of injections but modern injector pens make this convenient

Question 12

what are groups of hypoglaemic agents other than insulin

Answer 12

2 main groups:

sulphonylureas and sulphapyrimidines

biguanides

Question 13

what are sulphonylureas, give examples of drugs

Answer 13

consists of arylsulphonylurea with substitutions on benzene and urea groups

basic structure for hypoglycaemic activity is sulphonylurea radical

different derivatives differ in action and pharmacokinetic properties

first gen: tolbutamide (short acting), chlorpropamide (long acting)

2nd gen: glibenclamide; very potent and fast acting

gliclazide (1st gen) shows greater specificity than glibenclamide (2nd get)

Question 14

when are sulphonylureas and sulphapyrimidines used

Answer 14

primary action is an increase in insulin release (not synthesis, which glucose promotes) from beta cells of pancreatic islets of langerhans

no effect in pancreatectomised patients, also no effect in type 1 diabetics since no functioning beta cells which drugs are dependent on

effective in type 2 diabetics when beta cells can still secrete insulin

used in type 2 diabetics when diet alone is ineffective and in diagnosis of insulin secreting tumours

Question 15

what is mechanism of action for sulphonylureas and sulphapyrimidines

Answer 15

block potassium efflux from cells through ATP sensitive potassium channel which is controlled by glucose

stimulation of insulin secretion appears to be mediated by a reduced potassium movement through ATP sensitive potassium channels and increased calcium entry caused by depolarisation

these drugs may have minor actions outside pancreas

Question 16

what are disadvantages of sulphonylureas

Answer 16

hypoglycaemia which may be severe and prolonged

toxic/allergic reactions

variety of drug interactions:

diuretics reduce sulphonylurea action, drugs which displace plasma albumin increase action

chlorpropamide has antidiuretic activity

no protection against CV complications of diabetes which is provided by insulin

travels cross placenta in pregnant women

Question 17

give an example of a biguanide

Answer 17

phenformin: half life is 3 hours, slow release preparations are available

Question 18

what is mechanism of action of biguanides

Answer 18

in vivo actions uncertain

main hypothesis is increase in peripheral glucose utilisation, decrease in hepatic gluconeogenesis and decreased glucose absorption from GIT

Question 19

when are biguanides used

Answer 19

type 2 diabetes which is not controled by diet or by sulphonylurea derivatives

may also help reduce insulin dosage in insulin treated patients (type 1)

Question 20

what are disadvantages of biguanides

Answer 20

side effects are common, mostly gastrointestinal

lactic acidosis represents serious risk

minimised by avoiding predisposing factors

lack ability to protect against CV complications

Question 21

give an example of other types of drugs used to treat diabetes (not insulin or sulphonylureas or biguanides)

Answer 21

thiazolidinediones:

derivatives potentiate action of insulin in target tissues, potential use in type 2 diabetes

act on skeletal muscle and adipose tissue to increase insulin stimulated glucose uptake

they are agonists for PPARgamma: upregulates target genes including IRS1, IRS2 and GLUT4

gliptins/DPP-4 inhibitors:

compounds inhibit enzyme that inactivates GLP-1 thereby enhancing glucose lowering incretin effect of postprandially released GLP-1

alpha glucosidase inhibitors: such as acarbose, reduces post prandial glucose peaks, useful in obese type 2 patients who are irresponsive to other agents

Question 22

what are adjuncts given in diabetes treatment

Answer 22

alpha glucosidase inhibitors can be used as monotherapy or as adjuncts

guar gum: delays gastric emptying, reducing post prandial glucose levels

both adjuncts cause flatulence due to fermentation of unabsorbed sugar

Question 23

what are counter regulatory hormone effects

Answer 23

are caused by fasting or exercise, important regulator maintain glucose supply to brain and kidneys which cannot use free fatty acids as energy source

glucagon, secreted by pancreatic alpha cells: increases glyconeolysis and gluconeogenesis

catecholamines secreted in adrenal medulla cause increased glycogenolysis and decreased glucose uptake

glucocorticoids secreted in adrenal medulla cause increased gluconeogenesis and decrease in glucose uptake and utilisation

growth hormone also has counter regulatory effects

Question 24

what are effects of insulin

Answer 24

causes increased uptake of glucose in all cells

increased utilisation of glucose, amino acids and fat in all cells

increased uptake of potassium and calcium in all cells

in liver:
causes increased glycogen synthesis, reducing glucose concentration

reduced glycogen breakdown
increased glucose utilisation
reduced gluconeogenesis

in muscle:
increased glucose uptake, glycolysis and glycogen synthesis, increased amino acid uptake and protein synthesis

adipose tissue:
reduced lipolysis
increased lipogenesis

Question 25

what types of pancreatic cells are there, what are their functions

Answer 25

endocrine parts of pancreas are composed of islets of langerhans

beta cells secrete insulin
alpha cells secrete glucagon
delta cells secrete somatostatin
F cells secrete pancreatic polypeptide