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Pharmacology & Therapeutics > Diabetic Drugs > Flashcards

Diabetic Drugs Flashcards

1
Q

What are the actions of biguanides?

A

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

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2
Q

Describe the pharmacokinetics of biguanides. When are they indicated?

A

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)

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3
Q

What are the ADRs associated with biguanides?

A
  • GI disturbance (~1/3)
  • lactic acidosis (rare) = contraindicated in renal/cardiac/liver/resp. failure
  • increased bowel activity may affect vit. B12 absorption
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4
Q

What are the action of sulfonylureas? Give some examples of sulfonylureas.

A

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)

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5
Q

Describe the pharmacokinetics of sulfonylureas. When are they indicated?

A

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

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6
Q

What are the ADRs associated with sulfonylureas?

A
  • GI disturbances
  • weight gain (increased muscle mass)
  • risk of hypoglycaemia (esp. in elderly, missed meals, excess alcohol)
  • hyponatraemia (glimepiride, glipizide)
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7
Q

What are the actions of pioglitazone?

A

Increase insulin sensitivity in muscle and adipose (via peroxisome proliferator-activated receptors = PPAR-gamma)

  • > reduced gluconeogenesis in adipose, muscle, and liver
  • > increased glucose utilisation
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8
Q

Describe the pharmacokinetics of pioglitazone. When is it indicated?

A

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
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9
Q

What are the ADRs associated with pioglitazone? Give some examples of similar drugs withdrawn for their ADRs.

A
  • 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
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10
Q

What are meglitinides?

A

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
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11
Q

What is ascarbose?

A

Inhibits alpah-glucosidase —> reduced breakdown of carbohydrates to glucose —> reduced glucose absorption rate

  • flatulence
  • loose stools
  • diarrhoea
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12
Q

What are gliptins?

A

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
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13
Q

What are GLP-1 receptor agonists?

A

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
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14
Q

What is GLP-1?

A

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
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15
Q

What are SGLT2 inhibitors?

A

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
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16
Q

What is the mechanism of action of insulins?

A

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

17
Q

Describe the pharmacokinetics of rapid-acting insulins. When are they indicated? Give some examples.

A

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
18
Q

Describe the pharmacokinetics of short-acting insulins. When are they indicated? Give some examples.

A

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

19
Q

Describe the pharmacokinetics of intermediate-acting insulins. When are they indicated? Give some examples.

A

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

20
Q

Describe the pharmacokinetics of long-acting and very long-acting insulins. When are they indicated? Give some examples.

A

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

21
Q

What are some ADRs associated with insulins?

A
  • 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)
22
Q

What are some important points to remember when prescribing insulins?

A

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)

23
Q

What system is responsible for the warning symptoms of hypoglycaemia? When may this be affected?

A

ANS

Therefore ANS neuropathy can hide the symptoms of hypoglycaemia (hypoglycaemia unawareness)

24
Q

Outline the insulin regimen for Type 1 diabetics.

A

Pre-mixed insulin 2/day (morning and evening meals)

Basal bolus insulin = intermediate-acting insulin + short-acting insulin (3-5/day to cover meals)

25
Q

Outline the insulin regimen for Type 2 diabetics.

A
  1. Diet, exercise, lifestyle changes
  2. Metformin
  3. If HbA1c > 7%, add sulfonylurea
  4. If HbA1c > 7.5%, add pioglitazone OR insulin
  5. If HbA1c > 7.5% still, titrate doses up
26
Q

Give some examples of anti-obesity drugs and how they work.

A

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
27
Q

What are the NICE targets for the HbA1c values in Type 2 diabetes?

A

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%

28
Q

What are the NICE guidelines regarding the management of Type 1 diabetes?

A

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

29
Q

What are the NICE guidelines regarding the management of Type 2 diabetes?

A

BP monitoring (at least annually)

Anti-hypertensives indicated if BP > 130/80mmHg despite lifestyle advice

Oral hypoglycaemics:

  1. Metformin (or if contraindicated/not tolerated use DPP-4 inhibitor, pioglitazone, or sulfonylurea)
  2. Add DPP-4 inhibitor, pioglitazone, or sulfonylurea (or if metformin is contraindicated/not tolerated use two of DPP-4 inhibitor, pioglitazone, and sulfonylurea)
  3. Triple therapy (metformin + DPP-4 inhibitor + sulfonylurea OR metformin + pioglitazone + sulfonylurea) OR insulin
  4. 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

30
Q

Compare the advantages of basal bolus insulin regimes and pre-mixed insulin regimes.

A

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
31
Q

What is the emergency management for diabetic ketoacidosis?

A

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)

32
Q

How may NSAIDs affect the efficacy of sulfonylureas?

A

Displace sulfonylureas from plasma proteins

Increases [free sulfonylurea]blood

Increases effect of sulfonylureas

Reduced blood glucose

Pharmacology & Therapeutics (18 decks)

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