(PM3B) CNS Drug Delivery Flashcards

1
Q

What are the compartments of the brain?

A

(1) Blood
(2) Cerebrospinal fluid
(3) Brain

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2
Q

Where is cerebrospinal fluid held?

A

(1) Ventricles

(2) Subarachnoid + intrathecal spaces

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3
Q

What is the volume of the cerebrospinal fluid?

A

140mL

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4
Q

What is the rate of production of cerebrospinal fluid?

A

35 mL/hr

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5
Q

At what rate does blood flow through the brain?

A

60 L/hr

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6
Q

What barrier is between the brain and the blood?

A

Blood brain barrier

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7
Q

What barrier is between the blood and the cerebrospinal fluid?

A

(1) Arachnoid villi

(2) Chloroid plexus

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8
Q

What barrier is between the cerebrospinal fluid and the brain?

A

Ependyma

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9
Q

What is the blood brain barrier?

A

Tight junctions between cells

Blocks diffusion of polar solutes

Limited paracellular pathways

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10
Q

How is the blood brain barrier selective?

A

Brain capillaries have restricted permeability compared to peripheral capillaries

Permeability restricted to <600Da (small molecules) + lipophilic substances

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11
Q

How do cells in the brain get solutes?

A

(1) Small lipophilic drugs diffuse freely

(2) Carrier-mediates transport of glucose/ amino acids/ proteins from high to low concentration

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12
Q

What are efflux pumps?

A

Transporters

Responsible for extruding drugs from brain

ATP-binding cassette transporter P-gp + multidrug resistant protein are key principles of efflux mechanism

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13
Q

What are some strategies for CNS drug delivery?

A

(1) Between tight junctions of BBB
(2) Through BBB –enhancement of transport across the endothelium
(3) Around the BBB – direct intracranial drug delivery

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14
Q

What is intracarotid drug delivery?

A

Injection directly into carotid artery

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15
Q

What is the role of osmotic agents in CNS drug delivery?

A

Strategy to cross BBB

Usually hypertonic mannitol

(1) 25% solution infused into carotid artery over 30 seconds
(2) Injection of drug through same cannula it can freely diffuse into the CNS

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16
Q

How does mannitol increase blood brain barrier permeability (mechanism of action)?

A

(1) Hypertonic solution thought to osmotically pull water out of endothelial cells – causes cell shrinkage
(2) Cause disengagement of extracellular domains of proteins forming the tight BBB junctions

17
Q

What is the purpose of disruption of blood brain barrier via penetration enhancers?

A

Strategy to cross BBB

(1) Surfactant molecules disrupt BBB by acting with phosphatidylcholine head groups
e. g. ethanol surfactants: SDS/ glycerol/ polysorbate-80

18
Q

What are some potential issues with disruption of blood brain barrier via penetration enhancers?

A

Toxicity issues

(1) Neuronal damage
(2) Infarction
(3) Learning impairment
(4) Gliosis – scars in CNS

19
Q

What is the purpose of the use of prodrugs at the blood brain barrier?

A

Strategy to cross the BBB

(1) DP-VPA is designed to penetrate CNS intact
(2) Release VPA through hydrolytic activity of phospholipase A2

In testing – phase 2 trials have begun

20
Q

What are some potential benefits of combining drugs and pumps for brain/ CNS delivery?

A

(1) Significantly lower dose – fewer side effects
(2) Target effectiveness – avoiding 1st pass metabolism
(3) Improved adherence – overcomes inability to take medication
(4) Additional drug options –targeted nature of delivery allows for more drug candidates

21
Q

What is intracerebral (intraparenchymal) delivery?

A

Drug delivery directly into parenchymal space in brain

(1) Can be injected directly by intrathecal catheters
(2) via controlled-release matrices
(3) via microencapsulated chemicals
(4) via recombinant cells

22
Q

Why is a high local dose required for intracerebral (intraparenchymal) delivery?

A

To drive convection enhanced diffusion (CED)

Drives drugs to larger tissue regions

23
Q

What are intracerebral devices?

A

Implants made of either biodegradable/ non-biodegradable polymeric materials

Encapsulate drugs within them

e.g. Ommaya reservoir

Used to deliver chemotherapy

24
Q

What are Ommaya reservoirs?

A

Intracerebal devices

Used to deliver chemotherapy

Contain etoposide (anti tumour agent)

Treatment of metastatic brain tumour

25
Give an example of an osmotic implant.
DUROS
26
What is DUROS?
Osmotic implant Delivers drug for 3-12 months Precise zero order delivery kinetics
27
What is a GLIADEL wafer?
Polymer depot Approved for brain-tumour therapy Contains carmustine
28
What is inrtaventricular delivery?
Transcranial drug delivery Bypasses BBB Injection directly into cerebral ventricle Best suited for meningioma treatment + metastatic cells of cerebrospinal fluid Distributes drugs mainly into ventricles + subarachnoidal area of the brain
29
Give an advantage of intraventricular delivery.
Lack of interconnection with interstitial fluid of brain – unlike intracerebal delivery Achieves higher concentration in the brain
30
Give a disadvantage of intraventricular delivery.
Chance of causing subependymal astrogliatic reaction | - Due to high drug exposure at ependymal surface of brain
31
What is DepoCyt?
Liposomal sustained-release formulation Contains cytarabine Direct administration into cerebrospinal fluid
32
Give an advantage of using DepoCyt.
(1) Half-life of 5.9-82.4hrs compared to just 10 minutes | (2) Systemic exposure is low following intrathecal administration
33
What is intrathecal drug delivery?
Direct administration of drugs through intrathecal route into cisterna magna of brain
34
What is ITB?
Intrathecal baclofen Treatment of spasticity
35
Give an advantage of intrathecal delivery.
Less invasive than intraventricular
36
Give a disadvantage of intrathecal delivery.
Chance of drug spreading along distal space of spinal canal
37
What are some types of non-opioid drugs used for treatment of chronic pain via the spinal route?
(1) Local anaesthetics (2) Adrenergic agonists (3) NMDA antagonists (4) Others – e.g. aspirin/ baclofen/ gabapentin