Diabetic Drugs Flashcards
What are the actions of biguanides?
Increase insulin receptor sensitivity
- > Reduce insulin resistance
- > Reduce hepatic gluconeogenesis
- > Increase uptake of glucose in muscle & adipose
- > Reduce absorption of glucose from gut
NO ACTION ON BETA-CELLS:
- effective when the beta cells are non-functional
- reduce risk of hypoglycaemia
- weight neutral
note: reduced risk of CVS events
Describe the pharmacokinetics of biguanides. When are they indicated?
t1/2 = ~2-3hrs (given 2-3/day prior to meals)
Dose range = 500mg-2.5g
Indications: first choice in overweight patients where diet has failed to control diabetes or sulfonylureas are inadequate at controlling
(beta cells do not need to be functional)
What are the ADRs associated with biguanides?
- GI disturbance (~1/3)
- lactic acidosis (rare) = contraindicated in renal/cardiac/liver/resp. failure
- increased bowel activity may affect vit. B12 absorption
What are the action of sulfonylureas? Give some examples of sulfonylureas.
Gliclazide, glimepiride, glipizide, tolbutamide
Stimulate beta-cells to release insulin by antagonising K+/ATP channel —> increased [K+]cell —> depolarisation —> increased Ca2+ entry —> insulin release
THEREFORE FUNCTIONAL BETA-CELLS ARE REQUIRED!
note: reduced risk of microvascular events (UKPDS study)
Describe the pharmacokinetics of sulfonylureas. When are they indicated?
Highly bound to plasma proteins
Given 1/day
Different types have different half lives:
- short-acting (give 30min before meal) e.g. tolbutamide: t1/2 = ~4hrs (action 6-12hrs)
- long-acting e.g. glibencamide, glipizide: t1/2 = ~7-10hrs (action 16-24hrs)
Metabolised in liver (therefore can be used in renal impairment)
Indications:
- patients who are not overweight
- when metformin is contra-indicated (e.g. renal failure)/not tolerated
- add to metformin to improve glycaemic control
Beta-cells need to be functional
What are the ADRs associated with sulfonylureas?
- GI disturbances
- weight gain (increased muscle mass)
- risk of hypoglycaemia (esp. in elderly, missed meals, excess alcohol)
- hyponatraemia (glimepiride, glipizide)
What are the actions of pioglitazone?
Increase insulin sensitivity in muscle and adipose (via peroxisome proliferator-activated receptors = PPAR-gamma)
- > reduced gluconeogenesis in adipose, muscle, and liver
- > increased glucose utilisation
Describe the pharmacokinetics of pioglitazone. When is it indicated?
Heavily bound to plasma proteins
t1/2 = ~7hrs (but metabolites are also pharmacologically active - given 1/day)
PPAR-gamma receptors present in high amounts in adipose
Effects on muscle and liver caused by reduced fatty acid release into blood
Indications:
- add to sulfonylurea if metformin is contra-indicated/not tolerated
- add to metformin if sulfonylureas are contra-indicated/not tolerate or if risk of hypoglycaemia is too high
- add to metformin and sulfonylureas if insulin is unacceptable or if patient is obese
What are the ADRs associated with pioglitazone? Give some examples of similar drugs withdrawn for their ADRs.
- weight gain
- fluid retention (contraindicated in heart failure)
- increased LDLs & HDLs
- fractures in post-menopausal women
- bladder cancers
note: does not induce hypoglycaemia
Troglitazone = withdrawn for causing aggressive hepatitis Rosiglitazone = withdrawn for causing heart failure
What are meglitinides?
e.g. repaglinide, nateglinide
Similar action to sulfonylureas (K+/ATP channel) but more rapid
t1/2 = ~1-3hrs (short-acting; taken before meals)
- weight neutral
- low risk of hypoglycaemia
What is ascarbose?
Inhibits alpah-glucosidase —> reduced breakdown of carbohydrates to glucose —> reduced glucose absorption rate
- flatulence
- loose stools
- diarrhoea
What are gliptins?
Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors)
e.g. sitagliptin, vildagliptin, saxagliptin, linagliptin
Protects native GLP-1 from inactivation by DPP-4 —> increased active incretin levels (post-prandial)
- > increased insulin secretion —> increased peripheral glucose uptake
- > reduced postprandial glucagon secretion —> reduced hepatic glucose output
- GI disturbance
- possible increased risk of pancreatitis
- weight neutral
- low risk of hypoglycaemia
What are GLP-1 receptor agonists?
e.g. exenatide
Increase active incretin levels
- > increased insulin secretion —> increased peripheral glucose uptake
- > reduced glucagon secretion —> reduced hepatic glucose output
- painful to inject
- GI disturbances
- GORD
- low risk of hypoglycaemia
What is GLP-1?
Glucagon-like peptide
Released from intestinal L cells
- > increased satiety in the brain —> reduced food intake
- > reduced gastric emptying
Activates incretin
- > increased insulin secretion
- > reduced glucagon secretion
What are SGLT2 inhibitors?
Sodium-glucose co-transport inhibitors
e.g. dapaglifozin, canaglifozin, empagliflozin
Inhibits SGLT2 in PCT —> reduced glucose reabsorption —> increased urinary excretion of glucose
- lower urinary tract symptoms e.g. thrush, UTIs
- polyuria
- thirst
- low risk of hypoglycaemia
What is the mechanism of action of insulins?
Molecular:
- insulin receptor (tyrosine kinase)
- alpha-subunits are binding site
- beta-subunits autophosphorylate (catalytic activity)
- disulfide bonds
Activating hexokinase, glycogen synthase, and phosphofructokinase and inhibition of G-6-phosphatase —> Increased glycogenesis in liver
Increased GLUT-4 transporter insertion —> increased uptake of glucose into liver, muscle, and adipose
- > reduced hepatic glucose output via inhibition of gluconeogenesis
- > inhibits glycogenolysis
Glycogen saturation —> Increased fatty acid synthesis and inhibition of lipolysis —> increased uptake of fats (weight gain)
note: ideally insulin drugs should mimic the normal characteristics of insulin i.e. increased secretion after meals, amount matches the spike in blood glucose
Describe the pharmacokinetics of rapid-acting insulins. When are they indicated? Give some examples.
e.g. aspart (Novorapid), lispro
Onset of action = 5-15min
Duration of action = 4-6hrs
Indications:
- inject just before/after meal in children (less need to snack in between meals)
- acute hyperglycaemia
Describe the pharmacokinetics of short-acting insulins. When are they indicated? Give some examples.
e.g. soluble insulin
Onset of action = 30-60min
Peaks at 2-3hrs
Duration of action = 8-10hrs
Indications:
- inject 15-30min before meals
- acute hyperglycaemia
Increased risk of hypoglycaemia, therefore take snacks between meals
Describe the pharmacokinetics of intermediate-acting insulins. When are they indicated? Give some examples.
e.g. NPH (Humulin N/Novolin N/ isophane insulin)
Onset of action = 2-4hrs
Peaks at 4-8hrs
Duration of action = 12-20hrs
Indications:
- basal insulin
- overnight control
Increased risk of nocturnal hypoglycaemia, therefore snack before bed
Describe the pharmacokinetics of long-acting and very long-acting insulins. When are they indicated? Give some examples.
e.g. ultralente, glargine, degludec
Onset of action = 2-6hrs
Duration of action = up to 24hrs
Indications:
- basal insulin
- overnight control
Reduced peaks, therefore less need to snack between meals/before bed
Can adapt use according to lifestyle by supplementing with short-acting insulins
What are some ADRs associated with insulins?
- hypoglycaemia
- hyperglycaemia
- lipodystrophy = lipohypertrophy (same injection site —> lumps of fat/scar tissue —> affects insulin absorption) & lipoatrophy (hollows)
- painful injection (acidic solution)
- insulin allergies = usually allergic to added preservatives (switch insulin formulation/type)
What are some important points to remember when prescribing insulins?
Take care to identify the correct type and dose of insulin
e.g. Humalog mixtures with varying amounts of active ingredient
NEVER put “u” after insulin dose (can be mistaken for a zero)
What system is responsible for the warning symptoms of hypoglycaemia? When may this be affected?
ANS
Therefore ANS neuropathy can hide the symptoms of hypoglycaemia (hypoglycaemia unawareness)
Outline the insulin regimen for Type 1 diabetics.
Pre-mixed insulin 2/day (morning and evening meals)
Basal bolus insulin = intermediate-acting insulin + short-acting insulin (3-5/day to cover meals)
Outline the insulin regimen for Type 2 diabetics.
- Diet, exercise, lifestyle changes
- Metformin
- If HbA1c > 7%, add sulfonylurea
- If HbA1c > 7.5%, add pioglitazone OR insulin
- If HbA1c > 7.5% still, titrate doses up
Give some examples of anti-obesity drugs and how they work.
Orlistat = gastric & pancreatic lipase inhibitor
-> reduced conversion of dietary fat to fatty acids and glycerol
ADRs:
- soft, fatty stools
- increased flatus
- unpleasant faecal discharge
- faecal discharge
Silbutramine = NA & serotonin re-uptake inhibitor
- > reduced appetite
- > reduced blood glucose
- > reduced rate of glucose metabolism
- > ?increased thermogenesis
ADRs:
- tachycardia
- hypertension
What are the NICE targets for the HbA1c values in Type 2 diabetes?
Managed by lifestyle and diet or by single drug not associated with hypoglycaemia = HbA1c of 6.5%
Not controlled by single drug = HbA1c of 7%
What are the NICE guidelines regarding the management of Type 1 diabetes?
Blood glucose:
Aim for fasting blood glucose of 5-7mmol/l on waking and plasma glucose level of 4-7mmol/l before meals
Insulin:
Multiple daily injection basal-bolus (BD detemir)
Rapid-acting insulin analogues injected before meals
Consider adding metformin if:
- BMI > 25
- improve blood glucose whilst minimising insulin dose required
Hypoglycaemia causing decreased level of consciousness:
- family member give IM glucagon
- wait 10min, give IV glucose if no improvement
- give oral carbohydrate when safe and then monitor
Prevent hypertension
Eye screenings, foot clinics
Annual urine screenings (albumin:creatinine) and TSH
Ask about erectile dysfunction
What are the NICE guidelines regarding the management of Type 2 diabetes?
BP monitoring (at least annually)
Anti-hypertensives indicated if BP > 130/80mmHg despite lifestyle advice
Oral hypoglycaemics:
- Metformin (or if contraindicated/not tolerated use DPP-4 inhibitor, pioglitazone, or sulfonylurea)
- Add DPP-4 inhibitor, pioglitazone, or sulfonylurea (or if metformin is contraindicated/not tolerated use two of DPP-4 inhibitor, pioglitazone, and sulfonylurea)
- Triple therapy (metformin + DPP-4 inhibitor + sulfonylurea OR metformin + pioglitazone + sulfonylurea) OR insulin
- Add GLP-1 agonist
Insulin:
- NPH insulin OD or BD
- Add short-acting insulin (can use biphasic preparation)
- Alternative to NPH insulin is insulin detemir or glargine
Foot clinics
Ask about erectile dysfunction
Eye screening
Compare the advantages of basal bolus insulin regimes and pre-mixed insulin regimes.
BASAL BOLUS = long-acting insulin (background) + fast-acting insulin with meals (5/day)
- greater glycaemic control
- flexible
PRE-MIXED = slow-acting + fast-acting (2/day)
- fewer SC injections
What is the emergency management for diabetic ketoacidosis?
Insulin + NaCL IV (reverse DKA and maintain BP)
Calcium gluconate + ECG (pre-emptive management for hyperkalaemia)
Monitor [ketones]blood and [glucose]blood (adjust rate of insulin infusion)
Monitor U&Es
+ KCl IV (if hypokalaemia later occurs)
How may NSAIDs affect the efficacy of sulfonylureas?
Displace sulfonylureas from plasma proteins
Increases [free sulfonylurea]blood
Increases effect of sulfonylureas
Reduced blood glucose
