Pharmacology 4: Diabetes and obesity Flashcards
tment which must be given immediately for diabetic ketoacidosis?
insulin-IV at a fixed rate for DKA
rehydration- IV replacement fluids, with K+ in fluid as insulin drives K+ into cells via Na+/H+ exchange stimulation and subsequent increased Na+ pump activity, so patient would otherwise become hypokalaemic very quickly, putting them at risk of cardiac arrythmias.
classes of oral hypoglycaemic drugs?
those which increase sensitivity to insulin (insulin sensitisers): biguanides e.g. metformin, thiazolineinediones (glitazones) e.g. pioglitazone.
those which stimulate insulin release: sulfonylureas e.g. tolbutamide and glipizide, and meglitinides e.g. nateglinide.
glucagon like peptide-1 analogues
dipeptidyl peptidase-4 (DPP4) inhibitors (gliptins)
alpha-Glucosidase inhibitors
how do thiazolineinediones (glitazones) work?
agonsitically bind to peroxisome proliferator-activated receptor-gamma (PPAR-gamma)= transcription factor- regulates AT differentiation and role in lipid met., which binds with another nuclear receptor- retinoid X receptor, complex upregulates wide set of genes- in liver, SM and AT, with products important in insulin signalling and so increase insulin sensitivity in AT and muscle.
increase glucose uptake
reduce glucose synthesis in liver, muscle and AT
suppress hepatic gluconeogenesis, and so reduce hepatic glucose output
how do sulfonylureas work?
antagonise beta cell K+/ATP channel activity, causing decrease in K+ current, which cause depolarisation, which then increases Ca2+ entry into cell, which governs fusion rate of insulin vesicles with beta cell membrane, and their release into circulation.
Meglitidines also work in this way.
Orlistat is a drug used to treat obesity, how does it work?
gastric and pancreatic lipase inhibitor, so reduces dietary fat conversion to FA and glycerol for absorption.
SEs of orlistat?
soft fatty stools, flatus, unpleasant faecal discharge or faecal incontinence
Sibutramine is used to treat obesity, how does it work?
NA and serotonin (5-HT) reuptake inhibitor. Suppresses appetite anf some additional reduction in hyperglycaemia rate of glucose met, poss. due to increased thermogenesis.
SEs of sibutramine
increase HR and BP- CVS risk factors present and being treated in obese diabetics
example of drug used to delay carbohydrate absorption by gut?
alpha-glucosidase inhibitors e.g. acarbose- inhibits bdown of carbohydrates to glucose
SEs: runny stools, flatulence- as carbs fermented by gut bacteria, abdominal pain, diarrhoea
effects of insulin in body, other than decreasing blood glucose levels?
STORAGE promotion hormone
- stimulates hepatic glycogen prod via increasing glucokinase activity, glycolysis, and inhibits glycogenolysis and gluconeogenesis
- stimulates hepatic FA synthesis-for transport as lipoproteins- increase circulating free FA, promote clearance of circulating free FA
- inhibition of fat b.down in hepatocytes (lipolysis)- lipase inhibition
- increase aa uptake by muscle
3 modes of action of metformin?
increase sensitivity of cells to insulin, and so stimulates glucose uptake by AT and skeletal muscle
inhibits hepatic gluconeogenesis
reduced absorption of glucose from gut
describe the process of insulin production
synthesised initially as preproinsulin- exported into ER where signal peptide cleaved by signal peptidase, to create proinsulin- folds via disulphide bond formation and is transported to secretory vesicles where cleavage via endopeptidase produces insulin (A and B peptides with 2 S-S bridges) and C peptide= released in endogenous amounts from secretory vesicle.
how is insulin secretion by pancreatic beta cells stimulated by increased glucose?
glucose met. increases IC ATP/ADP ratio.
glucose enters beta cells via GLUT2 transporter- facilitated diffusion, enters glycolytic pathway after conversion to glucose 6-phosphate by hexokinase. increase ATP closes K+/ATP sensitive channel, causing cell depolarisation, Ca2+ influx and fusion of insulin vesicles with cell membrane.
why is insulin secretion prevented by low blood glucose?
low ATP:ADP in pancreatic beta cells as low glucose met, which opens K+/ATP channel, maintaining cells in a hyperpolarised state that prevents Ca2+ influx.
how does insulin act on it target tissues e.g. AT, muscle and liver?
via a tyrosine-kinase linked receptor: binds to EC domain and activates TK, causing autophosphorylation of tyrosine and phosphorylation of intracellular insulin receptor substrate proteins. These protiens recruit 2nd messenger proteins important for insulin action.
how is glucose reabsorbed by the kidneys and how is the process affected in diabetes?
PCT: high-capacity, low-affinity Na+-glucose co-transporter= SGLT2 on apical membrane= secondary AT using Na+ gradient generated by Na+K+ATPase, generates conc gradient for glucose that allows facilitated diffusion across BL membrane via GLT2.
straight PT: high affinity, low-capacity 2Na+-glucose co-transporter (SGLT1), GLT1 on BL membrane.
diabetes= excess glucose filtered, renal threshold exceeded so excess glucose unable to be reabsorbed and is excreted in urine. Glucose increase osmolarity of filtrate, reducing H20 reabsorption- remains with glucose and is excreted.
renal threshold for glucose?
200mg/100ml
despite high glucose in type 1 diabetes, why do glycogenolysis and gluconeogenesis proceed unchecked?
unavailability of insulin to promote glucose uptake into tissues, coupled with unopposed actions of counter-regulatory hormones e.g. cortisol and glucagon- increase PEPCK and fructose 1,6-bisphosphatase activity, causing starvation like response.
how does obesity link to insulin resistance?
insulin receptor desensitisation
ectopic accumulation of lipid into liver and muscle
obesity-induced inflammation
how does insulin suppress appetite?
insulin and leptin stimulate the inhibitory primary neurone that releases POMC to inhibit appetite, and inhibit the stimulatory pathway where NPY and agouti-related peptide are released to stimulate appetite.
only aspect of insulin functioning which differs depending on which insulin you give to a patient?
rate of insulin absorption into blood following SC injection, which depends on insulin solubility and local circulation
this is dependent on aa sequence
formulation of drug different, can use recombinant DNA technology
why might insulin requirement in an individual need to be increasef?
stress
infection
trauma
during puberty
what insulin regimen may be suitable for a patient who has 3 meals a day at fixed times/structured lifestyle?
a twice daily insulin regimen/conventional insulin therapy: you will inject twice a day, once before breakfast and once before dinner, a mixture of a shorter acting insulin and intermediate acting insulin, and the shorter acting may be either short acting insulin or a rapid acting insulin.
what insulin regimen may be suitable for a patient who doesn’t have fixed meal times?
a basal-bolus regimen: involves taking a longer acting form of insulin once or twice daily to keep blood glucose levels stable through periods of fasting and separate injections of shorter acting insulin to prevent rises in blood glucose levels resulting from meals. so basal taken= long or intermediate acting insulin, and bolus with every meal- short or rapid acting insulin. Tries to replicate how a non-diabetic person’s body releases insulin, and involves number of insulin injection throughout day. Can eat when you want.
when are sulfonylureas e.g. gliclazide considered in type II diabetic patients?
patients who are not overweight, and in whom metformin is contra-indicated e.g. resp disease, compromised HRH function, or not tolerated. (mainly met in liver so can be used in renal failure patients.)
can be used if patient acutely unwell
why should glibenclamide be avoided in the elderly?
long acting sulfonyurea- assoc with greater risk of hypoglycaemia (elderly- more at risk of this, eat less, and reduced drug met- PKs altered?)
cautions with sulfonylurea administration?
elderly
obese patients- metformin= drug of choice
G6PDD patients- risk of excessive haemolysis
ADRs with sulfonylureas?
hypoglycaemia weight gain GI disturbances: diarrhoea and constipation hyponatraemia hypersensitivity reactions
when are glitazones used in type 2 DM?
NICE (May 2009) has recommended that, when glycaemic control is inadequate with existing treatment, pioglitazone can be added to:
a sulfonylurea, if metformin is contra-indicated or not tolerated;
metformin, if risks of hypoglycaemia with sulfonylurea are unacceptable or a sulfonylurea is contra-indicated or not tolerated;
a combination of metformin and a sulfonylurea, if insulin is unacceptable because of lifestyle or other personal issues, or because the patient is obese.
ADRs of glitazones?
weight gain
oedema- so contraindicated in HF patients
fractures in post-menopausal women, increased OP risk as inhibit bone formation
risk of bladder cancer- so must check for haematuria
increased LDLs and HDLs- rosiglitazone no longer used as led to CVD events
*drugs also high cost
3 main tissues insulin acts upon?
liver
skeletal muscle
adipose tissue
describe why insulin given to diabetics is associated with weight gain?
in type 2 diabetics, insulin resistance typically more severe in muscle and liver compared with AT, so insulin preferentially deposits calories in AT, causing weight gain.
AT: insulin causes increased glucose uptake, lipogenesis and esterification of FA, and increase lipoprotein lipase activity in capillary bed for FA uptake.
why are drugs for diabetes characterised by having low therapeutic indexes (TD50/ED50)?
to keep balance between hyper and hypo glycaemia
4 types of insulin available with recombinant DNA technology?
human short acting
human rapid acting analogues
isophane intermediate acting insulin
long acting basal analogues
aa structure modified to affect absorption
adverse effects of insulin?
hypoglycaemia
hyperglycaemia
lipodystrophy- hypertrophy or atrophy at injection site**
painful injections
insulin allergies- type IV (delayed) hypersentivity reactions may occur, can change brand of insulin as will be a different formulation in terms of preservative used
give 2 important factors as to why diabetics may not be compliant with treatment?
risk/perceived risk of hypoglycameia
weight gain/fear of weight gain
general HbA1c target in all type 2 diabetics?
6.5-7.5 %
despite insulin have the greatest potential for lowering HbA1c, what is its main limitation?
risk of hypoglycaemia
advantages of using metformin in type 2 diabetes?
little weight gain, may even be weight loss
reduces LDLs and VLDLs- reduces CVS events
cheap- £8-10 annually
doesn’t induce hypoglycaemia
can use slow release (extended absorption) to help cope with GI symptoms, but this is more expensive
1-2% HbA1c lowering potential
can be used in stage III CKD, but stopped once eGFR<30ml/min, or significant comorbidities
conditions other than type 2 diabetes in which metformin may be used?
PCOS- reduces insulin resistance, balances androgens and oestrogens
anti-cancer- breast and bowel?
advantages of using sulfonylureas?
1-2% HbA1c lowering potential
cheap
mainly metabolised via liver, so can be used in renal impairment
can be used if patients acutely unwell
ADRs of metformin?
lactic acidosis
reduced vit B12 absorption
GI disturbances: diarrhoea, abdominal pain
taste disturbance
ADRs of acarbose?
runny, loose stools abdominal pain abdominal distension flatulence diarrhoea
effects of glucagon like peptide-1 (GLP-1) in body?
released from intestinal L cells and it:
increases is insulin secretion
reduces glucagon secretion
increases insulin biosynthesis
increases satiety, so reduces food intake
reduces gastric emptying
increases glucose uptake in muscle and reduces glucose prod. by liver
mechanism of action of gliptins (DPP-4 inhibitors) e.g. sitagliptin, saxagliptin?
inhibit breakdown of glucagon like peptide-1 so increase post-prandial concentrations of GLP-1, which increases insulin release and reduces glucagon release, so there is increased glucose uptake, and reduced glucose output from the liver.
advantages of gliptin use?
weight neutral
low risk of hypoglycaemia
modest HbA1c reduction
ADRs of gliptins?
GI disturbances peripheral oedema URTIs headache possible pancreatitis
NICE guidelines on gliptins?
consider adding 2nd line to metformin or sulfonylurea with HbA1c >6.5% if:
patient at significant risk of hypoglycaemia and its consequences e.g. elderly, living alone
patient doesn’t tolerate sulfonylurea, or CI
can be used as triple therapy
continue only if HbA1c reduction > or equal to 0.5% is achieved and maintained over 6 mnths
ADRs of GLP-1 agonists e.g. exenatide?
GI symptoms- diarrhoea, nausea, loose stools
GO reflux
occasionally painful to inject
?pancreatitis
but low risk of hypoglycaemia
NICE guidelines on exenatide?
continue only if HbA1c reduction of 1% or more at 6 mnths
and weight loss of at least 3% at 6 mnths
action of glifozins e.g. dapaglifozin?
insulin-independent approach to remove excess glucose
inhibit SGLT2 in PCT- so inhibit glucose reabsorption
ADRs of glifozins?
increase risk of lower UT symptoms e.g. genital and UTIs
polyuria
hypoglycaemia
BUT weight neutral, and may promote weight loss
define hypoglycaemia and list its clinical signs
plasma glucose concentration of less than or equal to 3mmol/L
similar signs to someone intoxicated with alcohol
include slurring of speech, confusion, drowsiness, weakness, trembling, sweating, nausea, tingling around lips, palpitations, staggering walk
general dietary advice for diabetic patients?
– include high-fibre, low-glycaemic- index sources of carbohydrate
– include low-fat dairy products and oily fish – control the intake of foods containing saturated fats and trans fatty acids.
-Limited substitution of sucrose- containing foods for other carbohydrate is allowable, but care should be taken to avoid excess energy intake.
- Discourage use of foods marketed
specifically for people with diabetes
how should HbA1c be monitored in diabetics?
2-6mnthly until stable on unchanging therapy
then 6 mnthly when blood glucose levels and blood glucose lowering therapy stable
when might a sulfonylurea be considered rather than metformin for type 2 DM tment?
metformin CI e.g. heptic, renal or CVS dysfunction, or resp disease
patient not overweight
rapid therapeutic response required due to hyperglycaemic symptoms
