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PM3B: Spring > CNS drug delivery > Flashcards

CNS drug delivery Flashcards

1
Q

What is the CNS comprised of

A
  1. Extracellular fluid compartments make up BRAIN and SPINAL CORD PARENCHYMAL INTERSTITIAL FLUID (ISF) and the CEREBROSPINAL FLUID (CSF)
  2. ISF and CSF are contained within ventricles of brain and cerebral + spinal subarachnoid spaces
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2
Q

What are the three compartments of the brain and describe each one in relation to the other

A

Blood CSF Brain

Blood to brain: BBB

CSF to brain: diffusion

Brain to CSF: Ependyma bulk flow

CSF to blood: Choroid plexus

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3
Q

Describe the blood brain barrier, what its made up of and how it works

A
  1. Endothelial cells at their adjacent margins form TIGHT JUNCTIONS- made by several transmembrane proteins that project and seal the PARACELLULAR PATHWAY
  2. Interaction of these junctional proteins: OCCLUDIN and CLAUDIN diffusion for polar solutes from blood
  3. Denies these solutes free assess to brain interstitial (extracellular fluid)
  4. Any molecule entry into brain parenchyma via parenteral administration is controlled by BBB and the blood cerebrospinal fluid barrier
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4
Q

What does a high turnover rate of CSF lead to

A

Continuous flushing of injected drug back to blood

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5
Q

What does the blood brain vessel have compared to a normal cell

A

Glial brain cells support barrier

Tight junction (no pores) create barrier

Operates by carrier mediated transport

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6
Q

Give an example of a small drug molecule

A

GABAPENTIN

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7
Q

What do the peripheral capillary and brain capillary allow

A
  1. Protein and glucose

2. Small molecules and lipophilic substances

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8
Q

What are the various transmembrane transporters

A

GLUT1 glucose carrier
LAT1 Amino acid carrier
Transferring receptors and insulin receptors
Lipoprotein receptors
ATP family of efflux transporters like P-gp

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9
Q

What is carrier mediated transport

A
  1. Binding of a solute such as glucose or amino acids to a protein transporter on one side of the membrane
  2. Triggers conformational change in protein resulting in transport of substance to the other side of membrane (HIGH TO LOW
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10
Q

What are efflux pumps responsible for

A

Forcing drugs out of brain

Mechanism: accumulation of a wide range of biological active molecules

Principle mechanism:
ATP binding cassette ABC transporter

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11
Q

Give examples of drugs that goes through carrier mediated transport and explain it

A
  1. LEVODOPA (L-DOPA): Small, water soluble, does cross BBB via LAT1

Dopamine: Small, water soluble, does NOT cross BBB

  1. GABApentin: small, water soluble, does cross BBB via LAT1
    Conformation puts carboxyl and amine in positions to mimic alpha amino acid
    Similar to baclofen
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12
Q

What are the strategies for CNS drug delivery

A
  1. Between: permeabilise TIGHT Junctions
  2. Through: enhance transport across endothelium
  3. Around: direct intracranial drug delivery
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13
Q

Describe intracerebral (intraparenchymal) delivery

A
  1. Direct delivery of drug into parenchymal space of brain- cerebrum
  2. Drugs injected directly (bolus or infusion) via intrathecal catheters, controlled release matrices, micro encapsulated chemicals or recombinant cells
  3. High dose: required for appropriate drug concentration in parenchymal due to closely packed arrangement of cells in both gray and white matter- restricts diffusion
  4. Convection enhanced diffusion (CED) drive drugs in larger tissue region
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14
Q

What is an intracerebral implant

A
  1. Devices that control release of drug at target site of brain
  2. Made up of biodegradable/non biodegradable polymeric materials encapsulating drugs in it
  3. CSF: fluid that surrounds brain and spinal cord made in ventricle
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15
Q

Give examples of intracerebral implants (3)

A
  1. Ommaya reservar pump: dome shaped device with a catheter attached to the underside (delivers chemo such as etoposide for brain tumour)
  2. DUROS: osmotic phenomena, delivers drugs from 3 months to 1 year with precise zero order delivery
  3. Polymer depots: delivers drug into cerebral environment in tumour cavity of brain
    Present in polymer matrix as core material, offers sustained release of drug by biodegradation of polymer
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16
Q

Give an example of a polymer depot

A

Gliadel Water
Treats brain tumour therapy by containing carmustine
Releases over a period of 5 days when placed in tumour resection cavity

17
Q

What is intraventricular delivery (transcranial drug delivery)

A
  1. Approach to bypass BBB: therapeutic agents instilled directly into cerebral ventricles
  2. Route best suited for meningioma treatment and metastatic cells of CSF
  3. Distributes drugs mainly into ventricles and subarachnoidal area of brain (bone area)
18
Q

What are the advatanges of intraventricular delivery

A
  1. Lack of interconnection with interstitial fluid of brain unlike intracerebral delivery
  2. Drug achieves higher concentration in brain compared to extravascular distribution
19
Q

What are the disadvantages of intraventricular delivery

A
  1. Chance of causing subependymal astrogliatic reaction

2. High drug exposure of ependymal brain surface

20
Q

What is a depocyt

A

Sustained release formulation of API cytarabine that is designed for direct administration into cerebrospinal fluid (CSF) intrathecally

21
Q

What are the benefits of delivering drugs directly to brain fluid

A
  1. Significant lower dose: less side effect risk and organ toxicity, improved tolerability
  2. Target effectiveness: consistent drug levels, lessen difficulty finding therapeutic ratio for each patient
  3. Last pass metabolism: drugs do not go firs through GI tract then liver
  4. Adherence: overcoming patients inability to take medicine
  5. Allows assess to additional drug candidates
22
Q

Give an example of a drug given by intracerebroventricular drug delivery and describe it

A

Drug: ICVrx001

Indication: refractory epilepsy

Duration: life long

Effect: reduce seizure frequency and severity, reduce adverse effects

23
Q

What is intrathecal delivery and its disadvantages

A

Delivery of neurotherapeutic agents to brain by cisterna magna of brain (back of brain)

Low drug accumulation in parenchymal structures of the deep brain: essential for sustained release of drug

Disadvantage: chance of drugs spreading across the distal space of spinal canal: lead to loss of co-ordination and ataxia

24
Q

Give examples of intrathecal devices that have been made

A

Infumorph: intrathecal morphine device

Gablofen: intrathecal baclofen device- treatment of dystonia

25
Q

Give examples of local anaesthetics used in the spinal route

A

Bupivicaine
Ropivicaine
Tetracaine

26
Q

Give examples of adrenergic agonists used in the spinal route

A

Clonidine

Tizanidine

27
Q

Give examples of NMDA antagonists used in the spinal route

A

KETAMINE

28
Q

What is intracarotid drug delivery, how can it disrupt the BBB, the agent used and the mechanism of it

A
  1. Infusion via internal/external/common carotid artery
  2. Hyperosmotic agent: administered via intracarotid arterial infusion along with drug via cannula
  3. Osmotic agent = mannitol
  4. Mechanism: hypertonic solution osmotically pulls water out of endothelial cells (cell shrinkage), disengagement of extracellular domains of proteins forming + regulating tight junctions
29
Q

What are penetration enhancers and give examples of these agents

A
  1. Surfactant molecules able to disrupt BB via interaction with phosphatidylcholine head groups
  2. Examples: Ethanol, glycerol, surfactants, polysorbate 80, polyethylene glycol, hydroxy stearate

PM3B: Spring (21 decks)

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