CNS Flashcards
(30 cards)
What are Ionotropic receptors - excitatory synapses
Transmitter depolarizes and excites
* Inward positive current
* Excitatory postsynaptic potential (EPSP)
* Glutamate
* Aspartate
* Acetylcholine (nicotinic)
What are ionotropic receptors - inhibitory synapses
Transmitter hyperpolarizes and inhibits
* Inward negative current
* Inhibitory postsynaptic potential (IPSP)
* GABA (-amino butyric acid)
* Glycine
What are G-protein coupled receptors to
Linked to ion channels
*K+
*Ca++
Linked to enzymes
* adenylyl cyclase
* phospholipase C
BBB - Blood brain barrier
network of vessels that form a
structural and chemical barrier between the
brain and systemic circulation
* Nerve cells in brain: require stable environment
* Protects brain but also a barrier to neuroactive
pharmaceuticals
* Cells
* Astrocyte
* Pericyte
* Capillary endothelial cell
Difference between brain capillaries and normal capillaries
General capillary
* Fenestrated or continuous
* small solutes can diffuse through intercellular
clefts
* pinocytosis independent of molecular size
(pass large molecules)
Brain capillary
* Continuous
* no fenestra
* tight junctions
* reduced pinocytosis
* astrocyte foot processes
What is a neurone? and give types
Neurones are a particular type of cell that carry information
messages or signals to and from the brain and the rest of the body.
Types: sensory, inter-neurone and motor neurone
Describe resting state of a neurone
resting state is polarised
Neurones stay at rest with their sodium ions on the
outside of the cell body (soma) and potassium ion
on the inside
Describe excited state of neurons
Depolarised
Neurons get excited when the sodium ions rush inside (from
outside), and potassium ions rush out (from inside) the cell body.
This rushing in and out causes depolarisation and generates action
potential (electrical impulse) racing down the axon.
How does sodium/potassium move in/out in the neurone?
Active transport: Sodium/Potassium ATPase pumps
Ion Channels (ionotropic/voltage-sensing & ligan-gated)
what is the most widely used way of bypassing the BBB to deliver to the brain?
Intraspinal injections
How does the drug get to the brain via Intraspinal injection?
- The brain and spinal cord is
surrounded by the
cerebrospinal fluid (CSF) - CSF provides cushioning to the
brain and spinal cord and also
facilitates waste product
removal - Drug administration to the
CSF via the intraspinal route is
a potential way of delivering a
drug to the brain
what are the two types of intraspinal drug delivery?
- Epidural route is most
commonly used to administer
anaesthetics for a regional
affect (often during labour and
some surgeries)- 1-2 litres of drug solution
may be administered via a
catheter
- 1-2 litres of drug solution
- Intrathecal route is also largely
used for pain relief, but can
also be a route for delivery to
the brain- Wider variety of drugs
delivered including
antibiotics and cytotoxics - Also used for CSF removal
and testing, i.e. a “lumbar
puncture”
- Wider variety of drugs
What specific formulation does Intrathecal injections require?
- Sterile, pyrogen-free,
isosmotic with CSF - Preservative free
- 10 mL is the max formulation
volume delivered intrathecally
What is the only site in the body where the CNS is in direct contact with the external environment?
Nasal cavity
What are the two routes for intranasal delivery?
- Olfactory nerve cells (neurons) route
- Trigeminal nerve route
What drug is used for polymer implants for brain drug delivery and how is it delivered?
Carmustine is the drug used and the copolymer P(CPP-SA) is used for its delivery
how does the BBB protect the brain from entering of drugs and other exogenous compounds?
- Tight Junctions
- Absence of fenestrations
- Active transport mechanisms
(influx and efflux) - Drug metabolising enzymes in
brain endothelial cells
What molecular properties are needed to pass through the BBB by passive diffusion?
- Lipid-soluble molecules (logD)
- Low polar surface area
- Low molecular weight
- Small molecules do not
necessarily cross the BBB (98%
of all small molecules do not
cross, only 5% of the >7000
drugs in CMC database treat
the CNS)
What properties are needed to pass through the BBB by active efflux?
- Active = ATP required
- Xenobiotics, metabolites,
toxins, drugs - Many transport from
endothelium to blood - Some are bi-directional
What properties are needed to pass through the BBB by carrier-mediated transport?
There are many essential polar molecules
Glucose, amino acids
CMTs are encoded genes within the Solute Carrier Transporter Gene Family
Preferential distribution across both sides of BBB confers polarised behaviour of BBB
What are the two types of transcyptosis?
- RMT (Receptor-mediated transcryptosis)
- AMT (Adsorptive-mediated transcryptosis)
When to use RMT
When to use AMT
When is cell diapedesis used for drug brain delivery?
- Most common example is
Neutrophils (WBC) that
provide defense against
invading microorganisms and
so must be able to cross the
endothelial BBB. - Also used for tissue repair but
if not controlled can lead to
inflammation (e.g. arthritis,
vascular inflammation etc) - Can be manipulated to
transport drugs across the
BBB
