diabetic drugs Flashcards
what are types of diabetes
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
what is the structure of insulin
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
what are different therapeutic preparations of insulin
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
what is insulin action on its receptors
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
how does insulin receptor mediate its activity
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
what are general metabolic effects of insulin
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
what are non metabolic effects of insulin
increase in plasma membrane transfer of glucose and other monosaccharides, some amino acids, some fatty acids, potassium and magnesium
how does insulin resistance develop
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
what are unwanted effects of insulin treatment
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
what are different preparations of insulin and how does it effect their pharmacokinetic properties
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
what is simplest insulin dosing regime
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
what are groups of hypoglaemic agents other than insulin
2 main groups:
sulphonylureas and sulphapyrimidines
biguanides
what are sulphonylureas, give examples of drugs
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)
when are sulphonylureas and sulphapyrimidines used
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
what is mechanism of action for sulphonylureas and sulphapyrimidines
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
what are disadvantages of sulphonylureas
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
give an example of a biguanide
phenformin: half life is 3 hours, slow release preparations are available
what is mechanism of action of biguanides
in vivo actions uncertain
main hypothesis is increase in peripheral glucose utilisation, decrease in hepatic gluconeogenesis and decreased glucose absorption from GIT
when are biguanides used
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)
what are disadvantages of biguanides
side effects are common, mostly gastrointestinal
lactic acidosis represents serious risk
minimised by avoiding predisposing factors
lack ability to protect against CV complications
give an example of other types of drugs used to treat diabetes (not insulin or sulphonylureas or biguanides)
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
what are adjuncts given in diabetes treatment
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
what are counter regulatory hormone effects
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
what are effects of insulin
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
what types of pancreatic cells are there, what are their functions
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
