Ion channel receptor pharmacology & local anaesthesia W13 Flashcards
What does the phosholipid bilayer do?
Semi permeable barrier seperating cytosol and interstial fluid (intracellular and extracelluar compartments)
What is the main component of the cell membrane and how does this effect movement across the membrane?
Composed of mainly lipids.
= electrically charged particles cant pass
Pores in the membrane (transmembrane proteins) are selectivly permeable, allowing some ions to pass but not others. What determines what can pass through?
Only ions of appropriate size and charge can pass through the pore. The amino acids lining the pore lumen determine selectivity.
Pores that are open all the time are called ____, (give example), others that open when stimulated are called _____.
Leak channels Ex. Na leak channel
Gated ion channels
What are the main types of ion channels
Voltage-gated ion channels
Ligand-gated ion channels
Mechanically-gated channels
What is a gap junction - give an example
Pores that allow direct communication between adjacent cells. Connexon proteins form the pore
Ex. Cardiac myocytes connected via Gap junction (= electical coupling)
What is the difference between leak channels and gap junctions?
Leak channels are selective for specific ions, Gap junctions are pores that are mostly non-selective and allow the movement of many small things.
How might one get better control over ion movement across membranes?
Introduce a gate (or valve), More selective pumps, Selectivity filter in the pores, Change the ion concentrations on either side of the membrane.
What are aqaua porins
Pores allowing H2O to pass through- e.g. ADH inserts them for water reabsorption.
What types of stimuli operate the gates?
Mechanical, voltage, chemical, ligand
Name the following channels
Which of the following is an example of a ligand-gated channel?
Nicotinic channel
voltage-gate K+channel
Na+/ K+ATPase
Leak channel
Gap junction
Nicotinic channel (Ach = ligand)
Which of the following is an example of a voltage-gated channel?
Nicotinic channel
voltage-gate K+channel
Na+/ K+ATPase
Leak channel
Gap junction
voltage-gate K+channel
How do intra-oral lasers cause analgesia? Where do they act?
Na+/K+ ATPase pump
Prevent the return to resting membrane potential
Describe the chemical structure of L.A
3 components
Aromatic ring linked by ester or amide bond to tertiary amine
Where do local anaesthetics act?
voltage-gate Na+channel
Where on the channel do LA act?
Block pore from the inside - cytosolic side = prevent voltage dependent initiation/propagation of AP
The terminal amine can exist in 2 states…?
Tertiary= 3 bond, lipid soluble
Quaternary = 4 bond, water soluble
Which state has a weak vs strong channel blocking activity and why?
Tertiary - lipid soluble, unionised = can cross membrane easily but weak blocking effect.
Quaternary - water soluble, ionised = block more strongly.
Describe the steps from injection to onset of L.A
- Quaternary (ionised) form injected
- Changes to Tertiary form at certain pH (7.4)
- Tertiary form (unionised) crosses the membrane
- Tertiary -> quaternary in the cytosol = blocks Na+ channels = Onset
How can inflammation disrupt the onset of L.A?
inflammation/infection -> acidic environment
= favours quaternary (ionised form)
= can’t cross membrane = no onset
L.A is most effective on ____ nerve fibres.
Non-myelinated
- Mostly post-ganglionic
Voltage gates Na+ channels can exist in 3 states…
- Open
- Closed
- Inactive
Explain the two componets of the use-dependent block of L.A’s
- L.A’s binds mostly to inactivate state Na+ channels = reduced number of channels avaiable for opening = prolonged refractory period
- Following noxious (pain) stimulus, nerve fires an AP = Na+ channels to cycle between open and inactivated state (both bond more L.A than in the closed state) = pain transmission effectively blocked > sensory stimuli
Which part of the L.A chemical structure provides resistance to metabolic hydolysis in the plasma or tissues?
Amide/Ester bond
