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PM3B > CNS drug delivery (spring) > Flashcards

CNS drug delivery (spring) Flashcards

1
Q

how many compartments does the brain have?

A

Three compartments

Blood ↔ CSF ↔ Brain

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2
Q

where is the CSF?

A

CSF is held within a defined set of compartments

> yellow – ventricles

> light blue – subarachnoid & intrathecal

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3
Q

Volume of CSF?

Rate of CSF production?

CSF turnover?

Blood flows through the brain at a rate of?

A

Volume of CSF: 140ml

Rate of CSF production: 35ml/hr

CSF turnover: 4-6x/day

Blood flows through the brain at a rate of 60 l/hr

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4
Q

fill in the diagram

A
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5
Q

describe the characteristics of the Blood brain barrier

A

Tight junctions between cells

Blocks diffusion for polar solutes from blood along these potential

Limited paracellular pathways and thus denies solutes access to brain interstitial fluid

CSF continuously flushing the injected drug (i.e. those injected into the ventricle) back to the blood

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6
Q

compare the permeability of the Peripheral Capillary and Brain Capillary

A

permeability of the Brain Capillary is restricted to small molecules (<600D) and lipophilic substances.

proteins can pass through the Peripheral Capillary but not the Brain Capillary

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7
Q

How do cells in the brain get solutes?

A

Carrier-mediated transport, glucose or amino acids to a protein from high to low concentration.

Free diffusion is limited to small lipophilic drugs

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8
Q

do the following drugs cross the BBB?

Levodopa (L-dopa)

Dopamine

Gabapentin

A

Levodopa (L-dopa) - Small, water soluble. Does cross BBB

Dopamine - Small, water soluble. Does not cross BBB

Gabapentin - Small, water soluble. Does cross BBB

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9
Q

what are efflux pumps and what do they do?

A

Efflux pumps or transporters are responsible for extruding drugs from the brain

ATP binding cassette (ABC) transporter P-gp and multidrug resistant protein (MRP) being the principle efflux mechanism of these agents

Different strategies been developed to reduce impact

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10
Q

give an example of an Anti-epileptic CNS drug

A

Phenytoin

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11
Q

give an example of an Anxiolytic CNS drug

A

Diazepam

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12
Q

give an example of an Anti-depressant CNS drug

A

Paroxetine

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13
Q

Strategies for CNS drug delivery?

A
  1. between - permeabilize tight junction
  2. through - enhance transport across the endothelium
  3. around - direct intracranial drug delivery
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14
Q

list Strategies to cross the BBB

A
  1. Use of osmotic agents
  2. Disruption of BBB via penetration enhancers
  3. Use of prodrugs
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15
Q

The use of osmotic agents is a strategy used to cross the BBB

how does this work?

any issues?

A

The osmotic agent usually employed is hypertonic mannitol

A 25% solution is infused into a carotid artery (in the human at a rate of 4–8 mL/sec) over a period of 30 sec.

This treatment opens the barrier rapidly and it remains open for up to 30 min.

If a drug is then administered through the same cannula while the barrier is open, it can freely diffuse into the CNS.

issue:

  • The hypertonic solution is thought to osmotically pull water out of the endothelial cells, causing cell shrinkage.
  • This may cause disengagement of the extracellular domains of the proteins forming and regulating the tight junctions.
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16
Q

Disruption of the BBB via penetration enhancers is a strategy used to cross the BBB

how does this work?

any issues?

A

Surfactant molecules are able to disrupt the BBB via interacting with the phosphatidylcholine head groups

The various examples of these agents are ethanol, surfactants like sodium dodecyl sulfate (SDS), glycerol and polysorbate-80 (Tween-80), polyethylene glycol hydroxy stearate

Toxicity issues (neuronal damage, infarction, learning impairment, gliosis)

17
Q

The use of prodrugs is a strategy used to cross the BBB

how does this work?

any issues?

A

DP-VPA phospholipid prodrug of valproic acid

Designed to penetrate the CNS intact and release VPA through hydrolytic activity of phopholipase A2

Phase 2 trials underway

18
Q

what are the benefits of combining drugs & pumps
for brain delivery?

A

Significantly Lower dose

  • Less risk of side effects and organ toxicity
  • Improved Tolerability

Target effectiveness

  • Consistent drug levels
  • Avoiding first pass metabolism

Adherence - Overcome patients inability to take medication

Additional drug options for refractory disease - targeted nature of the delivery platform allows additional drug candidates

19
Q

what is Intracerebral (intraparenchymal) delivery?

A

Intracerebral delivery involves delivery of drug directly into parenchymal space of the brain

Drugs can be injected directly via intrathecal catheters, by controlled release matrices, microencapsulated chemicals or recombinant cells.

High local dose is needed to drive convection enhanced diffusion (CED) to drive the drugs to larger tissue regions

20
Q

Intracerebral devices

A

Implants are made up of biodegradable/non-biodegradable polymeric materials encapsulating drugs inside it.

Devices like Ommaya® reservoir pump (a dome-shaped device, with a catheter attached to the underside used to deliver chemotherapy)

Containing etoposide, an antitumor agent used for treating metastatic brain tumor showed 100-fold more effective concentration

21
Q

what are Osmotic implant DUROS™?

benefits?

A

DUROS™ have been developed as osmotic implant that delivers drug for 3 months to 1 year with precise zero-order delivery kinetics.

Formulation maximizes drug payload, stabilizes drugs chemically and physically at body temperature, and involves the use of aqueous and non-aqueous vehicles

22
Q

what is a Gliadel® wafer?

A

A polymer depot that has been approved by FDA for brain tumor therapy (high-grade malignant gliomas) containing carmustine showed its release over a period of 5 days when placed in the tumor resection cavity

It consists of a copolymer matrix of 1,3-bis(p-carboxyphenoxy)propane and sebacic acid in a 20 to 80 molar ratio

23
Q

what is Intraventricular delivery (transcranial drug delivery)?

what treatment is this route best suited for?

A

Like other approaches intraventricular route also act as an approach to bypass BBB where therapeutic agents are instilled directly into cerebral ventricle

This route is best suited for meningioma treatment and metastatic cells of CSF as it distributes drugs mainly into ventricles and subarachnoidal area of the brain

24
Q

advantage and disadvantage of Intraventricular delivery (transcranial drug delivery)

A

Major advantage is its lack of interconnection with interstitial fluid of brain unlike intracerebral delivery. Hence the drug achieves higher concentration in brain

The major disadvantage is the chance of causing subependymal astrogliatic reaction due to high drug exposure at the ependymal surface of brain

25
Q

what is DepoCyt?

half-life?

A

DepoCyt is a sustained-release formulation of the active ingredient cytarabine designed for direct administration into the cerebrospinal fluid (CSF)

The half-life for the free CSF cytarabine ranged from of 5.9 to 82.4 hours (Compared to10min!).

Systemic exposure to cytarabine was negligible following IT

26
Q

which drugs are used for DepoCyt formulations?

A

Dioleoylphosphatidylcholine (DOPC)

Cholesterol

Dipalmitoylphosphatidylglycerol (DPPG)

27
Q

what is Intrathecal delivery (intra-csf drug delivery)?

advantage and disadvantage?

A

Direct administration of drugs through intrathecal route into cisterna magna of brain-e.g. Intrathecal baclofen (ITB) has been used to treat spasticity since 1988

Substantially less invasive than intraventricular

The major disadvantage of this route is the chance of drug spreading along the distal space of spinal canal

28
Q

Non-Opioid Drugs used for Treatment of Chronic Pain by the Spinal Route

Local Anesthetics:

Adrenergic Agonists

NMDA Antagonists

A

Local Anesthetics:

  • Bupivicaine
  • Ropivicaine
  • Tetracaine

Adrenergic Agonists

  • Clonidine
  • Tizanidine

NMDA Antagonists

  • Ketamine

PM3B (14 decks)

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