L18 - Flashcards
Metformin
- Reduced HbA1c by 1-2%
- mechanism of action
- no weight gain or hyperglycaemia
- taken with food
- Inhibits ATP synthesis, increasing AMP & activating AMPK (AMP Activated Kinase)
- Phosphorylates CRTC2, inhibiting it, which stops gluconeogenic genes
- reduces glucose secretion
Side Effects - diarrhoea, anorexia, B12 deficiency, lactic acidosis
Sulfonylureas
- antidiabetic drug
- insulin stimulator
- Decreases HbA1c by 1-2%
- risk of hypoglycaemia
- causes weight gain
- binds to sulfonylurea receptor 1 (SUR-1) sub unit of the ATP senstive K-channels in the beta-cell
- causing channel closure & membrane depolarisation
- leads to Ca2+ channel opening and insulin secretion
SGLT2 inhibitors
- antidiabetic drugs
Sodium-Glucose Co-Transport Inhibitors
- Act by inhibiting glucose transporter SGLT-2 which causes glucose reabsorption in the kidneys
-HbA1c decrease 5mmol/mol
Weight loss
BP reduction
No hypos
GLP-1 Analogues
- Incretin Mimetics
- antidiabetic drugs
- release of active GLP1 & GIP when glucose conc. increases in intestine
- these promote insulin release and decreases glucagon release
- DPP-4 quickly degrades incretins. GLP-1 analogues increase conc. of insulin promoters
DPP-4 Inhibitors (gliptins)
- allow incretin accumulation
- antidiabetic drugs
DPP-4 Inhibitors: (gliptins)
- GLP-1 release in intestine causes DPP-4 to break down gLP-1 and other incretins
- DPP-4 inhibitors prevent GLP-1 and GIP breakdown allowing accumulation
- GLP-1 and GIP promote insulin release and decrease glucagon breakdown
- reduces HbA1c by approx 0.7%
- Takes time to exert effect
Thiazolidinediones (glitazones)
- PPARy
- insulin sensitisers
- bind to and activate nuclear receptor PPARy
- PPARy & RXR factor transcribe genes that cause insulin sensitivity
contraindications with
- heart failure, fractures + haematuria
Meglitinides
- similar mechanism to sulphonylureas
- rapid onset, short action
- take before meals
- Weaker binding and dissociation from the SUR-1 binding site of the ATP sensitive K-channel
- causes weight gain
- increased risk of hypoglycaemia
Diabetes Treatment Options
- Insulin sensitisers
- insulin stimulators
- glucose secretion through kidneys
Insulin Sensitisers - metformin, thiazolidinediones
Insulin Stimulators - sulphonylureas, meglitinides, GLP-1 agonists, DPP-4 inhibitors
Glucose secretion through kidneys - SGLT-2 inhibitors
Pre-Insulin to Post Insulin
- Steps
- Pre-Insulin is in Endoplasmic Reticulum packaged in secretory vesicles
- Pro-Insulin is made when PRE signal sequence is cleaved off by protease
- Cysteine residue from A & B chain form disulphide bonds from sulphur groups
- proteases then cleave off both ends of the C chain - giving insulin (A & B chain joined by disulphide bridge) and a C peptide
Insulin Hexamers
- made of 3 insulin dimers or 6 insulin monomers
- 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
Insulin Preparation Types
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
Insulin Preparation Mixing (biphasic)
-mixing insulin preparations gives response closer to true natural physiological response to insulin.
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
Humulin I vs Humulin S
- explain different insulin profiles
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
Rapid Acting Insulin Analogues
- all protein changes in B chain
- Insulin Aspart
- Insulin Lispro
- Insulin Glulisine
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
Long Acting Insulin
- protein changes in A & B chain
- glargine (Lantus)
- detemir (Levemir)
- 18-26hrs
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
Long Acting Insulin
- Insulin degludec (Tresiba)
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
Injection of Insulin for Type 1
- insulin stored under 25 degrees ideally in fridge
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
Chemical Structures of Anti-Diabetics
- Biguanides (metformin)
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
Chemistry of Oral Anti-Diabetics
- Sulphonylureas
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.
Thyroid Gland
- develops in 1st trimester
5-iodinases make T4 to T3
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
T3 and T4 secretion
- maintain homeostasis
- basal temp, growth/development, symp. output
- Hypothalamus releases Thyrotropin-Releasing Hormone (TRH)
- goes to anterior pituitary and stimulates secretion of Thyroid Stimulating Hormone (TSH)
- goes to thyroid gland to secrete T3 and T4
T3 & t4 are plasma protein bound to thyroxine-binding globulin (TBG) and Transthyretin (TTR)
TSH uses
- increases protein synthesis in follicular epithelial cells
- increases DNA replication and cell division
- increases rough endoplasmic reticulum
Synthesis of Thyroid Hormone T3 & T4
- in thyroid gland when TSH released
- iodide from diet transported across basal membrane into Follicle by Na+/I- transporter and diffuses into colloid
- Thyroglobulin from follicle is secreted to colloid contains tyrosine residue which iodine reacts with
- Thyroid Peroxidases oxidise iodide to make iodine which attaches to tyrosine residue to make DIT & MIT
- iodinated rings join and endocytose back to follicle where lysosomal enzymes release T3 & T4 from TG
- it is then secreted into blood
Iodine Deficiency Disease
- reduces growth, mental state, impaired body function
caused by:
- inadequate dietary intake - RDA 150mcg/day
- maternal iodine deficiency - RDA 220mcg/day in pregnancy
Thyroid Function Testing
- TSH
- Free T4
- Free T3
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
Primary Hypothyroidism
- T3 & T4 low
- TSH is high
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
Treatments for Primary Hypothyroidism
- Levothyroxine (synthetic T4)
- dose adjusted until TSH in mid range
LogP = 7.4 pKa = 10 (phenol)
Side Effects: hair loss at start, insomnia, pounding heart
Treatments for Primary Hypothyroidism
- Liothyronine (synthetic T3)
- 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
Secondary Hypothyroidism & Myxoedema Coma
- very rare
- T3, T4 & TSH all below normal
Same symptoms and Treatments as Primary
untreated leads to Myxoedema Coma
- requires urgent treatment
- loss of consciousness, hypothermia, seizures
- leads to death
Drugs Affecting Thyroid Function
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
Hyperthyroidism & its symptoms
thyroid produces excess T4
- reduces TSH due to negative feedback
- T3 usually elevated too
Symptoms:
- heat intolerance, palpitations, weight loss, fatigue
Grave’s Disease
- autoimmune condition
- 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
Antithyroid Drugs
- carbimazole
- propylthiouracil
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
Adrenal Gland
- produces adrenocorticoids and hormones
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
Cortisol Release by Adrenal Gland
- stress causes hypothalamus to secrete Corticotrophin-releasing hormone (CRH)
- this goes to the anterior pituitary which produces Adrenocorticotrophic Hormone (ACTH)
- this goes to the adrenal glands and promotes secretion of cortisol
Cortisol Functions & Targets
- trauma, burns, injury, illness release cortisol
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
Cortisol Action Pathway
- cortisol free roaming in blood and diffuses into cytoplasm. plasma-protein bound cortisol wont diffuse
- cortisol binds to glucocorticoid receptor in cytoplasm allowing it into the nucleus
- 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
Addison’s Disease
- due to destruction of adrenal cortex
- 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
Secondary Adrenal Insufficiency
- ACTH insufficiency
- 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
Causes and Treatments for Addison’s Disease
- lifelong treatment required
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)
Cushing’s Syndrome & its Treatment
- hypersecretion of cortisol
- excessive bone resorption
- metabolic complications (T2 Diabetes)
- bruise very easily
Treatment: surgery to remove tumour
Cushing’s Syndrome Causes
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
