Week 1 - Brain Physiology Flashcards
What is tha anatomy of the meninges (CNS)
Meninges = 3 protective layers that cover the brain + spinal cord (CNS)
CNS is the brain (found in cranium) and the spinal cord (found in vertebral column)
Meninges (3 layers):
is layers of connective tissue
1. Dura mater = outer layer
- is durable + tough
2. Arachnoid mater = middle layer
- web like structure
3. Pia mater = inner layer
What are the 2 types of meningitis
Meningitis is a CNS disease
Meningitis - inflammation of meninges
Bacterial meningitis = inflammation caused by meningococcal infection
- test for this using glass test
- roll glass over rash firmly + if colour doesnt fade = sign of sepsis
- sepsis is associated with meningits
What are the treatments for bacterial meningitis
Meningitis is a CNS disease
- Benzylpenicillin
- Cefotaxime (if have penicillin allergy)
Usually requires immediate hospitilisation
How is epidural pain relief administered
Into epidural space of the lower spinal cord
- have individual neurons in lower 1/3 of spinal cord
- done in lower region to avoid potential damage to spinal cord
What is the function of the BBB
BBB separates CNS from the rest of body
- BBB MAINTAINS CNS homeostasis
- restricts moveemnt of H2O. ions, hormones etc. from blood to brain
- Controls what molecules can cross to enter brain
- ONLY SMALL, HYDROPHILLIC ions / molecules can PASS through tight junctions
- other molecules must cross BBB e.g. SMALL LIPOPHILIC molecules via passive DIFFUSION
- Drug diffusion across BBB is aidied by lipinski rule of 5
- Controls what molecules can cross to enter brain
- restricts moveemnt of H2O. ions, hormones etc. from blood to brain
- BBB limits brain exposure to toxic circulating compounds
- Ensures brain interstial fluid is optimal e.g. conc. of ions (affects function)
What is the structure of the BBB
BBB = Blood-Brain Barrier
Brain capillaries form BBB
Disruption to blood supply = inadequate supply = leads to tissue damage (e.g. stroke) as brain function can’t be maintained
- brain has vast capillary network (supplying O2 + nutirents) maintains brain function, disruption to blood supply leads to tissue damage (e.g. stroke)
Brain Capillary Structure:
- capilaries have specialised endothelial cells
- have space between cells (tight junctions) allowing compounds to pass out of blood
- MITOCHONDRIA found in endothelial cells = provide energy
- ASTROCYTES (around endothelial cells) = maintain BBB integrity
- NOT leaky (like most capillaries) = protective nature
- does NOT have intraceullar space allowing compounds to leak out
What are the 2 types of movement across BBB
- Passive Diffusion
- have to be small, lipophillic molecules to cross BBB
- Transcellular Diffusion
- route for other molecules e.g large, ionised etc.
- require transporters to cross BBB
- Paraceullar
- is movemnt between the cell
- small, hydrophillic molecules can pass through tigh junctions (in capillary endothelial cells)
List some BBB transporters and their substrates
Transporters transport molecules like glucose, a.acids between blood + brain
Embedded in membrane
Transporters:
- LAT1 (large amino acid transporter 1)
- trannsports substance from blood - endothelial cell - brain
Efflux Transporters:
(pump out drug from brain to cell, then out of cell back into blood ~ needs ATP)
- P-glycoprotin (P-gp)
- BCRP (breast cancer resistance protein)
- MRPs (multidrug resistance-associated proteins)
Substrate for LAT1:
- L-dopa
- converted into dopamine by decarboxylase (dopamine itself is NOT adminsitered as it can’t cross BBB effectively)
- Gabapentin
- Melphalan
- Paraquat (banned in UK, toxic weed killer)
Substrate for P-gp:
- SSRIs e.g. sertraline, paroxetine
- Antipsyschotics risperidone, paliperidone, sulpiride
- Antihistamines (newer ones e.g. fexofenadine)
= non-sedating effects as does NOT enter brain
Substrate for BCRP:
- Sulpride
Brain Tumours and Chemotherapy
Drugs admisntered orally or IV must cross BBB
- some admisnteretd intrathecally (IT) bypass BBB
Commonly sued chemo. therapuetics are efflux transporters = wouldnt use to traet brain tumor
- drug would be pumped out of brain immediately
NOTE:
- methotrexate = IT drug
- vincristine = IV drug
- if give vincristine IT = medicale emergency
- need to remove drug from CNS ASAP, via irrigating CNS with plasma
- plasma binds to vincristine removing it from CNS
What characteristics aid drug diffusion across the BBB
Drug diffusion across BBB is aidied by lipinski rule of 5:
- Low molecular weight (<400-500 Da)
- Optimal lipophilicity - ideal logP is 1.5-2.5
- can partition into membrane, across epithelial cell
- Low polar surface area (60-90 Å2)
- Up to 5 H-bond donors and 10 H-bond acceptors
How are Hydrogen bonds formed
When an hydrogen bond donor donates a H atom to a hydrogen acceptor
Formed when a H atom is bound to 2 small highly electronegative atoms
- both atoms have unshared electron pair (shown via :)
What functional groups are involved in Hydrogen bonding
Donor / Acceptor can be:
- H20, OH (alcohol) , NH3 (ammonoia)
- the :O (in OH) and :N (in NH3) = acceptors
