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mp322 > L18 - > Flashcards

L18 - Flashcards

1
Q

Metformin
- Reduced HbA1c by 1-2%

  • mechanism of action
A
  • no weight gain or hyperglycaemia
  • taken with food
  1. Inhibits ATP synthesis, increasing AMP & activating AMPK (AMP Activated Kinase)
  2. Phosphorylates CRTC2, inhibiting it, which stops gluconeogenic genes
  3. reduces glucose secretion

Side Effects - diarrhoea, anorexia, B12 deficiency, lactic acidosis

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2
Q

Sulfonylureas
- antidiabetic drug

  • insulin stimulator
  • Decreases HbA1c by 1-2%
A
  • risk of hypoglycaemia
  • causes weight gain
  1. binds to sulfonylurea receptor 1 (SUR-1) sub unit of the ATP senstive K-channels in the beta-cell
  2. causing channel closure & membrane depolarisation
  3. leads to Ca2+ channel opening and insulin secretion
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3
Q

SGLT2 inhibitors

  • antidiabetic drugs
    Sodium-Glucose Co-Transport Inhibitors
A
  • Act by inhibiting glucose transporter SGLT-2 which causes glucose reabsorption in the kidneys

-HbA1c decrease 5mmol/mol
Weight loss
BP reduction
No hypos

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4
Q

GLP-1 Analogues
- Incretin Mimetics

  • antidiabetic drugs
A
  1. release of active GLP1 & GIP when glucose conc. increases in intestine
  2. these promote insulin release and decreases glucagon release
  3. DPP-4 quickly degrades incretins. GLP-1 analogues increase conc. of insulin promoters
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5
Q

DPP-4 Inhibitors (gliptins)
- allow incretin accumulation

  • antidiabetic drugs
A

DPP-4 Inhibitors: (gliptins)

  1. GLP-1 release in intestine causes DPP-4 to break down gLP-1 and other incretins
  2. DPP-4 inhibitors prevent GLP-1 and GIP breakdown allowing accumulation
  3. GLP-1 and GIP promote insulin release and decrease glucagon breakdown
  • reduces HbA1c by approx 0.7%
  • Takes time to exert effect
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6
Q

Thiazolidinediones (glitazones)

  • PPARy
  • insulin sensitisers
A
  1. bind to and activate nuclear receptor PPARy
  2. PPARy & RXR factor transcribe genes that cause insulin sensitivity

contraindications with
- heart failure, fractures + haematuria

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7
Q

Meglitinides

  • similar mechanism to sulphonylureas
A
  • rapid onset, short action
  • take before meals
  1. Weaker binding and dissociation from the SUR-1 binding site of the ATP sensitive K-channel
  • causes weight gain
  • increased risk of hypoglycaemia
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8
Q

Diabetes Treatment Options
- Insulin sensitisers
- insulin stimulators
- glucose secretion through kidneys

A

Insulin Sensitisers - metformin, thiazolidinediones

Insulin Stimulators - sulphonylureas, meglitinides, GLP-1 agonists, DPP-4 inhibitors

Glucose secretion through kidneys - SGLT-2 inhibitors

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9
Q

Pre-Insulin to Post Insulin
- Steps

A
  1. Pre-Insulin is in Endoplasmic Reticulum packaged in secretory vesicles
  2. Pro-Insulin is made when PRE signal sequence is cleaved off by protease
  3. Cysteine residue from A & B chain form disulphide bonds from sulphur groups
  4. proteases then cleave off both ends of the C chain - giving insulin (A & B chain joined by disulphide bridge) and a C peptide
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10
Q

Insulin Hexamers
- made of 3 insulin dimers or 6 insulin monomers

A
  • The insulin molecules are negative and are held together by the positive Zinc ion (Zn2+) in the middle
  • This is how the Insulin molecules are stored in vesicles in pancreatic beta-cells (inactive form)
  • upon release to the blood stream hexamer breaks down releasing active insulin
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11
Q

Insulin Preparation Types

A

Short-acting / Rapid-acting
- short duration with rapid onset. e.g. soluble insulin
- insulin analogues: insulin aspart, insulin glulisine & insulin lispro

Medium-Acting
- intermediate action e.g. isophane insulin

Long-Acting
- slower onset but longer lasting effect
- e.g. insulin detemir & insulin glargine

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12
Q

Insulin Preparation Mixing (biphasic)
-mixing insulin preparations gives response closer to true natural physiological response to insulin.

A

Natural Insulin Response - steep rise of plasma insulin after a meal and slow decline.
Insulin Injection Response - gradual rise and gradual descent

Biphasic = mix of short-acting / rapid-acting insulin analogues with intermediate-acting insulin

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13
Q

Humulin I vs Humulin S
- explain different insulin profiles

A

Humulin I
- contains a small basic protein (positive), protamine, which attracts negative insulin monomers and dimers to make them cluster
- this slows absorption through capillaries

Humulin S
- does not have protamine so allows for quicker absorption

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14
Q

Rapid Acting Insulin Analogues
- all protein changes in B chain

  • Insulin Aspart
  • Insulin Lispro
  • Insulin Glulisine
A

Insulin Aspart
- Proline substituted for aspartate on the B chain of insulin.
- this reduces its tendency to form hexamers so it has more rapid absorption once injected

Insulin Lispro
- switches proteins 28 for 29 making 2 changes in the B chain
- reduces chances of insulin self associating

Insulin Glulisine
- Asparagine replaced with Lysine. and Lysine replaced with Glutamic Acid
- reduces insulin self-association

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15
Q

Long Acting Insulin
- protein changes in A & B chain

  • glargine (Lantus)
  • detemir (Levemir)
  • 18-26hrs
A

Insulin glargine (Lantus)
- Asparagine to Glycine substitution in A chain.
- two arginine’s added to the Carboxyl terminal end on B chain.
- makes it less soluble in physiological pH to slow absorption

Insulin detemir (Levemir)
- fatty acid (myristic acid) attached to B chain making it bind to albumin in blood
- Albumin & Insulin Receptor compete for binding to insulin detemir, prolonging its action

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16
Q

Long Acting Insulin
- Insulin degludec (Tresiba)

A

hydrophobic fatty-acid-like group added, making more multi-hexamers and causing binding to albumin

  • multi-hexamers slowly release active monomers, prolonging duration of action beyond 40hrs
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17
Q

Injection of Insulin for Type 1
- insulin stored under 25 degrees ideally in fridge

A

Injection Sites: stomach, thighs, behind
- injection sites are rotated to avoid lipohypertrophy

  • multiple daily injections of short or rapid-acting insulin analogues mixed with an intermediate-acting insulin

Insulin Pump Therapy - continuous dose of short or rapid acting

18
Q

Chemical Structures of Anti-Diabetics
- Biguanides (metformin)

A

LogP : -1.2 Hydrophilic
pKa: 12.4 Basic

has Guanide group
- carbon double bonded to NH and bonded to amide

  • basic pKa because amide group stabilises the positive charge when the molecule becomes ionised
  • orally available because of active uptake
19
Q

Chemistry of Oral Anti-Diabetics
- Sulphonylureas

A

pKa - 5.9 weakly acidic

  • sulphur is bonded to amide, C=O, amide
  • nitrogen gives away protons but it is not readily taken back like in equilibrium. negative charge is stabilised in aromatic ring.
20
Q

Thyroid Gland

  • develops in 1st trimester

5-iodinases make T4 to T3

A

Thyroid Follicle
- epithelial cells arranged in spheres.
- thyroglobulin synthesised here
- T3 and T4 released from here

Thyroid Colloid
- where thyroid precursors are found
- tyrosine residue on thyroglobulin is iodised here

21
Q

T3 and T4 secretion

  • maintain homeostasis
  • basal temp, growth/development, symp. output
A
  1. Hypothalamus releases Thyrotropin-Releasing Hormone (TRH)
  2. goes to anterior pituitary and stimulates secretion of Thyroid Stimulating Hormone (TSH)
  3. goes to thyroid gland to secrete T3 and T4

T3 & t4 are plasma protein bound to thyroxine-binding globulin (TBG) and Transthyretin (TTR)

22
Q

TSH uses

A
  • increases protein synthesis in follicular epithelial cells
  • increases DNA replication and cell division
  • increases rough endoplasmic reticulum
23
Q

Synthesis of Thyroid Hormone T3 & T4

  • in thyroid gland when TSH released
A
  1. iodide from diet transported across basal membrane into Follicle by Na+/I- transporter and diffuses into colloid
  2. Thyroglobulin from follicle is secreted to colloid contains tyrosine residue which iodine reacts with
  3. Thyroid Peroxidases oxidise iodide to make iodine which attaches to tyrosine residue to make DIT & MIT
  4. iodinated rings join and endocytose back to follicle where lysosomal enzymes release T3 & T4 from TG
  5. it is then secreted into blood
24
Q

Iodine Deficiency Disease

A
  • reduces growth, mental state, impaired body function

caused by:
- inadequate dietary intake - RDA 150mcg/day
- maternal iodine deficiency - RDA 220mcg/day in pregnancy

25
Q

Thyroid Function Testing

  • TSH
  • Free T4
  • Free T3
A

TSH normal range : 0.27 - 4.2 mU/L

Free T4 normal range : 12 -22 pmol/L

Free T3 normal range : 3.1 - 6.8 pmol/L

26
Q

Primary Hypothyroidism

  • T3 & T4 low
  • TSH is high
A

caused by:

Hashimoto’s Hypothyroidism
- autoimmune disease antibodies attack thyroid peroxidases to stop T3 and T4 from being formed

  • any damage or loss to thyroid tissue
27
Q

Treatments for Primary Hypothyroidism

  • Levothyroxine (synthetic T4)
A
  • dose adjusted until TSH in mid range

LogP = 7.4 pKa = 10 (phenol)

Side Effects: hair loss at start, insomnia, pounding heart

28
Q

Treatments for Primary Hypothyroidism

  • Liothyronine (synthetic T3)
A
  • risk from T3 on bone osteoporosis & heart arrhythmia
  • 5x more biologivally potent than T4

single dose max effect in 24hrs and passes off in 1 week
- T 1/2 is 2 days if euthyroid

similar side effects

29
Q

Secondary Hypothyroidism & Myxoedema Coma
- very rare
- T3, T4 & TSH all below normal

A

Same symptoms and Treatments as Primary

untreated leads to Myxoedema Coma
- requires urgent treatment

  • loss of consciousness, hypothermia, seizures
  • leads to death
30
Q

Drugs Affecting Thyroid Function

A

Corticosteroids
- can decrease basal production of TSH & TRH, decreasing thyroid hormone levels

Lithium (manic depression)
- inhibits release of thyroid hormones and interferes with their peripheral de-iodination

Amiodarone (antiarrhythmic)
- contains iodine and can cause hypo & hyperthyroidism

Cholestyramine (reduces blood cholesterol)
- reduces absorption of thyroxine

31
Q

Hyperthyroidism & its symptoms

A

thyroid produces excess T4
- reduces TSH due to negative feedback
- T3 usually elevated too

Symptoms:
- heat intolerance, palpitations, weight loss, fatigue

32
Q

Grave’s Disease
- autoimmune condition

A
  • caused by antibody thyroid-stimulating immunoglobulin (TSI)
  • activates TSH receptors on thyroid follicular cells increasing secretion of thyroid hormones

Treatment:
- surgery
- radioactive iodine (oral or solution) radiation kills epithelial cells in thyroid

33
Q

Antithyroid Drugs

  • carbimazole
  • propylthiouracil
A

Carbimazole - prodrug becomes methimazole
- accumulates in thyroid and inhibits thyroid peroxidases, stopping iodination of tyrosine residues

Propylthiouracil
- also inhibits peripheral de-iodination by 5-iodinase

slow onset of effect 4-6weeks

34
Q

Adrenal Gland

  • produces adrenocorticoids and hormones
A

Mineralocorticoids - primarily aldosterone
- Na+ resorption and K+ excretion in kidneys

Glucocorticoids - primarily cortisol
- regulates bodys response to stress
- is antinflammatory
- raises/controls blood glucose levels

Sex Hormones - androgens
- control reproduction

35
Q

Cortisol Release by Adrenal Gland

A
  1. stress causes hypothalamus to secrete Corticotrophin-releasing hormone (CRH)
  2. this goes to the anterior pituitary which produces Adrenocorticotrophic Hormone (ACTH)
  3. this goes to the adrenal glands and promotes secretion of cortisol
36
Q

Cortisol Functions & Targets

  • trauma, burns, injury, illness release cortisol
A

Functions (main glucocorticoid)
- anti-inflammatory and immunosuppressant

Targets
many tissues - lowers glucose & amino acid uptake
Adipose Tissue - increases fat breakdown (lipolysis)
Muscle - more protein breakdown & lower synthesis
Liver - increases gluconeogenisis

37
Q

Cortisol Action Pathway

A
  1. cortisol free roaming in blood and diffuses into cytoplasm. plasma-protein bound cortisol wont diffuse
  2. cortisol binds to glucocorticoid receptor in cytoplasm allowing it into the nucleus
  3. in the nucleus it can A) bind to another cortisol (dimer) for transactivation, promoting gene expression

or B) binds to Kappa-B for transpression to inhibit gene expression

38
Q

Addison’s Disease

  • due to destruction of adrenal cortex
A
  • lowers glucocorticoid, mineralocorticoid & sex hormone production
  • only becomes symptomatic when 90% of Adrenal Cortices are destroyed

Symptoms: darkening of skin due to ACTH build up from no cortisol negative feedback

  • extreme fatigue
  • low blood pressure
  • GI nausea, diarrhoea, vomiting
39
Q

Secondary Adrenal Insufficiency

  • ACTH insufficiency
A
  • lack of ACTH from pituitary
  • no hyperpigmentation

can be due to glucocorticoid drug therapy
- or if you come off treatment too abruptly

  • only treat with glucocorticoid
40
Q

Causes and Treatments for Addison’s Disease

  • lifelong treatment required
A

Causes:
- autoimmune destruction of gland
- infections (TB, HIV, Cryptococci)
- Invasion or Haemorrhage

Treatment:

Hydrocortisone (glucocorticoid), can be prednisolone
- 15-30mg (10 morning, 5 noon, 5 night) mimics natural cortisol levels

  • Fludrocortisone (mineralocorticoid)
41
Q

Cushing’s Syndrome & its Treatment

  • hypersecretion of cortisol
A
  • excessive bone resorption
  • metabolic complications (T2 Diabetes)
  • bruise very easily

Treatment: surgery to remove tumour

42
Q

Cushing’s Syndrome Causes

A

Pituitary Tumour
- increased secretion of ACTH (65-70% cases)
- Cushing’s disease, ACTH independant

External Tumours e.g. ectopic
- tumour secretes ACTH, ACTH dependant

Adrenocortical Tumours
- or bilateral adrenal hyperplasia (15-20% cases)
- ACTH independent
- adrenal gland makes excess cortisol

mp322 (4 decks)

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