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Spring 2 > CNS Drug Delivery > Flashcards

CNS Drug Delivery Flashcards

1
Q

What has happened that has caused a significant unmet medical need for neurological disorders and disease?

A

Large # of indications
Growing patient populations
Few effective therapies
Enormous cost of care

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2
Q

What makes the extracellular fluid compartments of the CNS?

A

CNS comprise the brain and spinal cord parenchymal interstitial fluid (ISF) and the cerebrospinal fluid (CSF),

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3
Q

At what rate does blood flow through the brain?

A

rate of 60 l/hr

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4
Q

What is the volume of CSF? and at what rate is it produced?

A

140ml

produced at 35ml/hr

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5
Q

Describe the blood brain barrier

A

The endothelial cells at their adjacent margins form tight junctions produced by the interaction of several transmembrane proteins that project into and seal the paracellular pathway

The interaction of these junctional proteins, particularly occludin and claudin, is complex and effectively blocks an aqueous route of free diffusion for polar solutes from blood along these potential paracellular pathways and thus denies these solutes free access to brain interstitial (extracellular) fluid

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6
Q

Factors that are making CNS drug therapy harder?

A

BBB excludes most drugs from brain and spinal cord

Drugs keep getting bigger

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7
Q

What is selectivity criteria of the brain capillary in regards to permeability?

A 
permeability restricted to:
small molecules (<600D)
lipophilic substances
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8
Q

What is the role of trans-membrane transporters and give exaples

A

Some of these aid the transport into the brain while others prevent the entry of many molecules

the expression of various transporters including GLUT1 glucose carrier, amino acid carrier LAT1, transferring receptors, insulin receptors, lipoprotein receptors and ATP family of efflux transporters such as p-glycoprotein (P-gp) and multidrug resistance-related proteins MRPs

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9
Q

What is the role of efflux pumps? and give examples

A

Efflux pumps or transporters are responsible for extruding drugs from the brain and this mechanism is a major obstacle for the accumulation of a wide range of biologically active molecules in the brain, with the ATP binding cassette (ABC) transporter P-gp and multidrug resistant protein (MRP) being the principle efflux mechanism of these agents

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10
Q

What is levodopa transported across the BBB by?

A

LAT1

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11
Q

What are the 3 strategies/routes for CNS drug delivery?

A 
1.  between
permeabilize tight junctions
2.  through
enhance transport across
the endothelium
3.  around
direct intracranial drug delivery
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12
Q

What is Intracerebral (intraparenchymal) delivery?

A

involves delivery of drug directly into parenchymal space of the brain

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13
Q

How are drugs administered via intracerebal delivery?

A

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

Continuous infusion method can be used which uses convection enhanced diffusion (CED) to drive the drugs to a larger tissue region

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14
Q

Why is a high dose required to result in an appropriate drug conc in the parenchyma?

A

due to the to the closely packed arrangement of cells in both gray as well as white matter microenvironment which restricts diffusion

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15
Q

Describe what an Ommaya reservoir pump is? Give an example of what drug it delivers

A

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

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16
Q

Describe what the DUROS is?

A

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

17
Q

Explain how polymer depots have been used

A

Polymer depots have been used for the delivery of drug into cerebral environment in the tumor cavity of the brain having drug being present inside the polymer matrix as a core material. It offers sustained release of drugs by the biodegradation of polymer

18
Q

An example of a polymer depost is Gliadel wafer.

What does it do?

A

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

19
Q

What is Intraventricular delivery (transcranial drug delivery)?

A

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

20
Q

What is Intraventricular delivery (transcranial drug delivery) route best for?

A

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

21
Q

What is an advantage and disadvantage of the Intraventricular delivery (transcranial drug delivery) route?

A

Major advantage of this route is its lack of interconnection with interstitial fluid of brain unlike intracerebral delivery. Hence the drug achieves higher concentration in brain in comparison to that of its extravascular distribution

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

22
Q

What is DepoCyt?

A

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

23
Q

What are the benefits of delivering drugs directly to the brain?

A

Significantly Lower dose:
Less risk of side effects and organ toxicity
Improved Tolerability

Target effectiveness:
Consistent drug levels lessens difficulty finding therapeutic ratio for an each patient
“Last pass metabolism”: Drugs do not go first through GI tract, then liver, etc…

Adherence:
Overcome patients inability to take medication

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

24
Q

What is Intrathecal delivery (intra-CSF drug delivery)?

A

Intrathecal route involves delivery of neurotherapeutic agents to brain by direct administration of drugs through intrathecal route into cisterna magna of brain

Substantially less invasive than intraventricular

25
Q

What is a major disadvantage of the intrathecal route?

A

chance of drug spreading along the distal space of spinal canal which was understood when etoposide administered through this route into the dogs led to ataxia and loss of muscle coordination

26
Q

Give some examples of infusion systems/pumps available for targeted drug delivery

A

MEDSTREAM™ Programmable Infusion Pump and Control Unit

SynchroMed II Infusion Pump & N’vision Clinical Programmer

Prometra Pump and Programmer

27
Q

Describe the Common Features of ImplantableDrug Infusion Systems?

A

Catheter Access Port – bypasses drug reservoir, used to check for catheter patency

Reservoir Refill Port – septum through which drug enters the pump upon refill

Titanium Housing – typically rigid outer housing that protects pump from mechanical damage

Drug Catheter – flexible tubing that runs from the pump with special tip for drug delivery

Programmer – used with ‘smart’ pumps, controls drug infusion rate, records drug history

28
Q

What is the Flowonix Prometra used to treat?

A

Pain

29
Q

What is the Codman MedStream used to treat?

A

Spasticity

30
Q

What examples of non-opioid drugs used for Treatment

of Chronic Pain by the Spinal Route?

A

Local Anesthetics:
Bupivicaine
Ropivicaine
Tetracaine

Adrenergic Agonists:
Clonidine
Tizanidine

NMDA Antagonists:
Ketamine

31
Q

What is intracarotid drug delivery?

A

Hyperosmotic agent is administered by intracarotid arterial infusion along with drug via cannula.

32
Q

What is the osmotic agent usually used in intracarotid drug delivery?

A

The osmotic agent usually employed is hypertonic mannitol

33
Q

How does intracarotid work?

A

Disrupts the BBB

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

34
Q

How does intracarotid disrupt the BBB?

A 
Penetration enhancers
Surfactant molecules 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)
35
Q

Give an example of a prodrug that is designed to penetrate the CNS intact

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

Spring 2 (23 decks)

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