W20 CNS Drugs: Crossing the BBB (MM) Flashcards
What is the Blood-Brain Barrier? (definition)
2 other barriers?
A biological barrier at the blood-to-brain interface, effectively separating the brain from the rest of the body
blood-CSF barrier (BCB) and the arachnoid barrier
BBB info:
Features of the BBB:
Components of the BBB? (4)
- Microvascular endothelial cells lining the cerebral capillaries penetrating the brain and spinal cord of humans (and most mammals)
- Largest blood-brain exchange (12-18 m2 surface area)
- Protects the brain against blood-borne agents including drugs and other exogenous compounds
- Tight Junctions
- Absence of fenestrations
- Active transport mechanisms (influx and efflux)
- Drug metabolising enzymes in brain endothelial cells
What are the ways molecules can cross the BBB? (5)
- Passive diffusion
- Active efflux
- CMT- carrier mediated transport
- Transcytosis
- Cells diapedesis
What is Passive diffusion?
The molecules transported have what features?
- Passive = Energy not required
- 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)
e.g. gases- o2, co2, ethanol, nicotine,caffeine (lipid-soluble)
What is Active efflux (and influx)?
What molecules are transported?
- Active = ATP required (via specific transport proteins)
- Xenobiotics, metabolites, toxins, drugs
- Many transport from endothelium to blood
- Some are bi-directional transporters
Efflux- brain into blood e.g .P-gp that pumps xenobiotics out and back into bloodstream
Influx- blood into brain
What is Carrier-Mediated Transport?
What molecules are transported?
Which family of transporters is CMT part of?
- There are many essential polar molecules
- Glucose, amino acids (non-lipid soluble)
- 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 2 types of Transcytosis?
What molecules are transported?
-
RMT (Receptor-mediated transcytosis)
* Molecules are too large to use CMT (peptide bonds)
* Regulatory proteins, hormones, growth factors
* Specific receptors on the cell surface are responsible -
AMT (Adsorptive-mediated transcytosis)
* Positively charged, large molecules
* Histone, protamine, cationic proteins
* Cell surface binding sites (+ve proteins, -ve cell surface electrostatic interactions)
What is Cell Diapedesis?
What molecules are transported?
- 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
=the passage of cells through the intact vessel wall, the movement of leukocytes out of the circulatory system and towards the site of tissue damage or infection
To make a drug favourable in crossing the BBB:
What is Lipinski’s Rule of 5?
- 5 or fewer Hydrogen Bond Donors (HBD)
- 10 or fewer Hydrogen Bond Acceptors (HBA)
- Molecular weight under 500 g/mol or daltons
- LogP less than 5 (Actually: 0-3 for CNS)
Note: Use LogD - 10 or fewer rotatable bonds*
*A single non-ring bond, attached to a non-terminal, non-hydrogen atom. Amide C-N not included due to their high barrier of rotation
What is Polar Surface Area?
Measured in?
Amount of oral biovailability
Amount to cross CNS?
- The surface area of the molecule taken up by polar atoms
- Sometimes will see TPSA – Topological Polar
Surface Area - Measured in squared Angstroms ( Å2)
- Oral Bioavailability<140 Å2
- To cross into CNS <90 Å2
What are the Ideal Characteristics for CNS Drugs?
- HBD: 5 or fewer
- HBA: 10 or fewer
- MW: 450 g/mol or less
- RB: 10 or fewer
- LogD: 0-3
- PSA: <90 Å
What are some Chemical Methods for Drug Delivery to the CNS (4)
- Lipophilic Analogues
- Prodrugs
- Chemical Delivery Systems
- Molecular Packaging
These involve the transformation of the chemical structure of drugs to improve their unsatisfactory physiochemical properties (solubility, membrane penetration etc.) These
changes will change their functionalities.
What are Lipophilic Analogues?
- Lipid solubility is a key factor in passive diffusion across BBB
- Making drug molecules more lipophilic is logical
- Involves adding lipid groups to polar ends of drug molecules
- Can lead to poor tissue distribution
- Can be detrimental to oxidative metabolism by CYP-450 and other enzymes
- Also lowers PSA so can change bioavailability (especially oral drugs)
What are Prodrugs?
Usually used to make a drug..?
- Compounds that, on administration, must undergo chemical conversion by a metabolic process before becoming an active pharmacological agent
- Used to make the drug more lipophilic (usually)
- Some prodrugs alter the original tissue distribution, efficacy and/or toxicity of the parent drug
Chemical delivery system:
What are they?
3 main classes?
- Inactive chemical derivatives of a drug obtained by one or more chemical modifications.
- Provide site-specific or site-enhanced delivery of the drug through multistep transformations
- There are three main classes of CDS:
1. Enzymatic Physiochemical CDS
2. Site-specific Enzyme-activated CDS
3. Receptor-based CDS
Chemical Delivery Systems (CDS)
2 types of bioremovable moieties?
- Two types of bioremovable moieties are introduced to convert the drug into an inactive precursor:
1. Targetor: Responsible for targeting,
site-specificity and lock-in
2. Modifier: Lipophilizers, protect
certain functions, prevent unwanted or premature metabolic conversions - Sequential metabolic conversions disengage the modifier and then the target once they have completed their roles
What is Molecular Packaging?
What are its 3 benefits?
- Primarily used for peptides
- The peptide unit forms part of a bulky molecule, dominated by groups that prevent recognition by peptidases and allow for direct passage through BBB
- Can achieve 3 goals simultaneously:
1. Increased lipophilicity (enhance passive transport)
2.Prevention of premature degradation (by enzymes especially)
3. Exploits lock-in mechanism to make targeting possible
Features of Levodopa?
- Used for the treatment of Parkinson’s Disease
- Precursor for dopamine
- Converted into dopamine by DOPA decarboxylase in the brain
- Given with carbidopa or benserazide
-These inhibit DOPA decarboxylase - They do not cross the BBB so minimises peripheral degradation (and also side effects such as nausea, vomiting and hypertension
Features of Donepezil?
- Used for the treatment of Alzheimer’s Disease
(over 400 drugs being investigated currently) - Selectively and reversibly inhibits the
acetylcholinesterase enzyme (cholinesterase
inhibitor) - Thus enhances cholinergic transmission
- Transported across the BBB by an organic cation transporter – Carrier Mediated Transport
It is a competitive inhibitor of acetylcholinesterase
Features of Methylphenidate?
- First-line stimulant used to treat ADHD (previously chronic fatigue, depression, psychosis)
- Dopamine and norepinephrine transporter
stimulants - Enters the brain (and tissue) via passive diffusion
- There are 4 isomers with slightly different rates of diffusion and metabolism
- Metabolism can happen by a number of different pathways
What is a diastereomer vs enantiomer?
Enantiomers are a pair of molecules that exist in two forms that are mirror images of one another but cannot be superimposed one upon the other( chiral) . Diastereomers are defined as compounds with the same molecular formula and sequence of bonded elements but are non-superimposable non-mirror images
Explain why?
a) Levodopa can pass the BBB but Carbidopa cannot
b) Levodopa can pass the BBB but Benserazide cannot
c) Levodopa can pass the BBB but dopamine cannot
Too hydrophilic and Levodopa uses L-amino acid transporters.
What is passive diffusion?
- Passive = Energy not required
- 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)
Escitalopram is the pure S-enantiomer of
Citalopram.
(a) What effect does this have on the drug’s
ability to cross the BBB?
(b) Is escitalopram or citalopram more potent?
Why?
a) No impact- exact same characteristics
b) Escitalopram is 150x more potent as it does not contain R-enantiomers which has a dampening effect on the activity of the S-enantiomer
