Flashcards in Pharmacology Deck (94):
What sort of glands are in the endocrine system?
How is signal specificity achieved?
Chemically distinct hormones
Specific hormone receptors
Distinct receptor distribution
What are the features of amine hormones? (Synthesis, storage, release and transport)
- Formed by enzymes
Stored in vesicles
Released in response to calcium
Transported free in plasma (hydrophilic)
What are the features of peptide + protein hormones? (Synthesis, storage, release and transport)
- From longer precursor via proteolysis
Stored in vesicles
Calcium causes release
Transported free in plasma
What are the features of steroids hormones? (Synthesis, storage, release and transport)
Synthesised and secreted on demand
- Cholesterol uptake
- Rate of conversion to pregnenolone (rate limiting)
- 90% bound to plasma proteins (lipophilic)
- Free if biologically active
What hormones are insoluble?
What are the functions of carrier proteins?
Increase hormone transport in blood
Prevent renal filtration
Prevent rapid excretion
What does cortisol-binding globulin bind?
What does thyroxine-binding globulin bind?
(+ some T3)
What does SHBG bind?
What do albumin and transthryretin bind?
- Some steroids
What do carrier proteins act as?
Buffers and reservoirs:
- Main constant [Free hormone] in blood
- Keep bound and free hormones in equilibirum
What hormones can cross capillary walls?
What happens when free hormone is removed from the plasma?
Replaced by dissociation of bound protein
What is the primary determinant of hormone plasma concentration?
Rate of secretion
What does neuroendocrine release cause?
A sudden burst in secretion to meet a stimulus:
- eg. Stress -> Hypothalamus -> CRH -> ACTH -> Cortisol
How does diurnal rhythm release work?
Secretion fluctuates with time
Entrained to external cues (Night/Day)
What organs are the most important locations for elimination of hormones?
What are the half lives of:
- Amine hormones
- Protein/Peptide hormones
- Steroids/T3 +T4
Amines -> Seconds
Proteins/Peptides -> Minutes
Steroids/T3+T4 -> Hours to days
What affects the half lives of hormones?
Where are G-protein coupled receptors found and what hormones activate them?
On cell surface
- Some proteins/peptides
What do G-protein coupled receptors couple with?
Where are receptor kinases found and what hormones activate them?
On cell surface
Activated by some proteins and peptides
Where are nuclear receptors found and why are they found here?
- Ligands are lipophilic
> Can diffuse across cell membrane
What activates Class 1 Nuclear receptors? What happens when they are activated?
- Migrate to nucleus on binding
What happens when Class 1 Nuclear Receptors are inactive?
Bound to inhibitory heat shock proteins in the cytoplasma
What activates Class 2 Nuclear receptors? Where are they found?
Mostly by lipids
In the nucelus
What activates the hybrid class nuclear receptors? What are they similar to?
Similar to Class 1
What happens when adrenaline, CRH or glucagon binds to a GPCR?
1. Gs subunit uncouples
2. Binds to adenylyl cyclase
3. Promotes ATP -> cAMP
4. cAMP activates Protein Kinase A
5. Target protein phosphorylation -> Effects
What happens when melatonin binds to a GPCR?
1. Gi subunit uncouples
2. Binds to adenylyl cyclase
3. Inhibits ATP -> cAMP
4. Less Protein Kinase A activation
5. Less target protein phosphorylation -> Inhibits effects
What happens when angiotensin ii, GRH or TRH binds to a GPCR?
1. Gq subunit uncouples
2. Binds to phospholipase C
3. Promotes PIP2 -> IP3
4. IP3 binds to IP3 receptor on endoplasmic reticulum
5. Calcium released
6. Cellular effects
What other effects does the hydrolysis of PIP2 to IP3 have?
1. Produces DAG
2. DAG activates Protein Kinase C (in membrane)
3. Target proteins are phosphorylated -> Effects
What happens when insulin binds to a receptor kinase?
1. Autophosphorylation of intracellular tryosine residues
2. Insulin receptor substrate proteins are phosphorylated
3. Cellular effects
How does signalling via Class 1 Nuclear Receptors work?
1. Steroid diffuses into cell
2. Binds to intracellular receptor + HSP dissociates
3. Moves to nucleus
4.Forms a dimer + binds to hormone response elements in DNA
5. Transactivation or Transrepression occurs
6. mRNA levels altered
7. Rate of protein synthesis changes
8. Protein levels altered
What drugs increase insulin secretion?
DPP-4 inhibitors (Gliptins)
What drugs reduce insulin resistance and reduce hepatic glucose output?
What drugs slow glucose absorption from the GI tract?
What drugs increase glucose excretion in the kidneys?
Which drugs are insulin dependent and which are insulin independent?
- Incretin mimetics
- DPP-4 inhibitors
- α-glucosidase inhibitors
- SGLT2 inhibitors
What is the physiology of insulin secretion?
1. Increased blood glucose
2. Increased glutamate diffusion into B-cell via GLUT2
3. Phosphorylation of glucose by glucokinase
4. Glycolysis of glucose-6-phosphate in mitochondria
5. Increased ATP/ADP ratio
6. ATP sensitive K+ channels close
8. Voltage-gated calcium channels open
9. Increased intracellular [Calcium]
10. Insulin secretion
What is the structure of the Katp channel?
4 inward K+ rectifier 6.2 subunits (Kir6.2)
4 sulphonylurea receptor 1 subunits (SUR1)
What is the function of the Kir6.2 tetramer?
Selective K+ channel
What is the function of the SUR1 tetramer?
Regulates K+ channel activity
When does ATP bind to Kir6.2?
When [Glucose]e is high
When does ADP-Mg2+ bind to SUR1?
When [Glucose]e is low
What are some examples of SUs?
1st generation - Tolbutamide
How do SUs work?
Displace ADP-Mg2+ from SUR1:
- Closes channel
What benefits do the 2nd generation SUs have over 1st generation?
Who are at the greatest risk of hypos with SU use?
People using 2nd generation SUs
Patients with reduced hepatic/renal function
What can SUs be used with?
What effect do SUs have on weight?
They cause weight gain
How do glinides/meglitinides work?
Bind to SUR1 at benzamido site (close channel -> depolarization -> Insulin release)
What are some examples of glinides?
When are glinides taken? Why?
- Reduce post-prandial rise in blood glucose
What can glinides be used with?
When are GLP-1 and GIP released? From what cells are they released?
When food is ingested
- L cells
- K cells
Where do GLP-1 and GIP enter?
What effects does GLP-1 have?
Increase insulin release from β-cells
Decrease gastric emptying
What effects does GIP have?
Reduce glucagon release from α-cells
Whet are the downstream effects of GLP-1 and GIP?
Enhanced glucose uptake + utilisation
Reduced glucose production
How do incretin analogues work?
Mimic GLP-1 action but are longer lasting
What is exenatide?
- A GLP-1 agonist
- Peptide in saliva of Gila monster
How does exenatide work?
Binds to GPCR GLP-1 receptors -> Increased [cAMP]i:
- Increased insulin secretion
- Reduced glucagon secretion
- Reduced gastric emptying
- Reduced appetite
What other effects do incretin mimetics have?
Modest weight loss
Reduced hepatic fat accumulation
How is exenatide administered?
S/C injection twice daily
How is liraglutide administered?
S/C injection once daily
What side effects can incretin mimetics have?
What does dipeptidyl peptidase-4 do?
Terminates GLP-1 and GIP action (in minutes)
What do DPP-4 inhibitors (gliptins) do?
Competitively inhibit DPP-4:
- Prolong GIP and GLP-1 actions
What are DPP-4 inhibitors usually used with?
What are some examples of DPP-4 inhibitors?
How often must DPP-4 inhibitors be administered?
Once daily PO
If used as monotherapy, can DPP-4 inhibitors cause hypos?
What effect do DPP-4 inhibitors have on weight?
They are weight neutral
What is α-glucosidase? What does it do?
A brush border enzyme:
- Starch and disaccharides -> Glucose
What does acarbose to?
Inhibits α-glucosidase and delays glucose absorption:
- Reduces post-prandial rise in blood glucose
When is acarbose used?
In T2DM is other drugs don't work
What are some side effects of acarbose?
Does acarbose have any risk of hypos?
What is the only therapeutic biguanide?
When is metformin the 1st line for T2DM?
In obese patients:
- With normal hepatic + renal function
What other effects does metformin have?
Reduces hepatic gluconeogenesis -> Stimulates AMPK
Increased glucose uptake and utilisation
Reduces carbohydrate absorption
Increased fatty acid oxidation
What effect does metformin have on weight?
What can metformin be combined with?
What are some side effects of metformin?
Lactic acidosis -> Avoid in hepatic/renal impairment
What do thiazolidinediones (glitazones) do?
Enhance action of insulin at target sites
How do TZDs work?
Exogenous agonists of peroxyisome proliferator-activated receptor-γ (PPARγ):
- Associated with retinoid receptor X (RXR)
- Largely confined to adipocytes
What does activated PPARγ-RXR act as?
- Binds to DNA
- Increases gene expression
- Increased protein encoding
> Insulin signalling
> Lipoprotein lipase, FFA transport + GLUT4
What are some desirable effects of TZDs?
Fatty acid uptake and storage in adipocytes
Reduce hepatic glucose output
What are some adverse effects of TZDs?
Increased weight due to adipocyte differentiation
Fluid retention due to increased Na+ reabsorption
Increased bone fractures
What TZD can be used with metformin and SUs?
How do SGLT2 inhibitors work?
Block reabsorption of glucose in PCT:
- Causes deliberate glycosuria
What effect do SGLT2 inhibitors have on weight?
- Calorific loss -> Glucose voided
- Water loss -> Osmotic diuresis