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MP422 > Lecture 5 - Formulation & Delivery of CNS Treatments: Neurodevelopmental & Neurological Disorders > Flashcards

Lecture 5 - Formulation & Delivery of CNS Treatments: Neurodevelopmental & Neurological Disorders Flashcards

1
Q

Which factors should influence the choice of dosage form and route of administration?

A
  • The age of the patient (children and the elderly)
  • The type of CNS condition (i.e. psychiatric or neurological?)
  • The severity of the condition
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2
Q

What is the difference between a psychiatric disorder and a neurological disorder?

A
  • Psychiatric = disorder of the mind
  • Neurological = disorder of the brain
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3
Q

Psychiatric disorders are primarily … in origin.

A

“functional”

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4
Q

Neurological disorders are primarily … in origin.

A

“organic”

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5
Q

Give three examples of psychiatric disorders.

A
  • Anxiety
  • Depression
  • Schizophrenia
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6
Q

Give four examples of neurological disorders.

A
  • Parkinson’s disease
  • Epilepsy
  • Brain tumour
  • Migraine
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7
Q

What causes Parkinson’s disease?

A

A lack of dopaminergic signalling between the Substantia nigra and Striatum/Caudate

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8
Q

What two properties does a drug need to have to cross the BBB by diffusion?

A
  • Must be lipid-soluble
  • Must have a MW < 400 Da
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9
Q

Can dopamine cross the BBB by diffusion? Why?

A

Although it has a MW of 153 g/mol, it is hydrophilic (not lipid-soluble).

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10
Q

What is L-Dopa?

A

Levodopa is a dopamine precursor.

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11
Q

Can L-dopa cross the BBB? How?

A

It has a MW of 197 g/mol, and is hydrophilic. It crosses the BBB by carrier-mediated transport (via the large neutral amino acid transporter).

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12
Q

Why does levodopa need to be co-administered with an enzyme inhibitor (as co-beneldopa or co-careldopa)?

A
  • Levodopa is quickly metabolised to dopamine by enzymes in the bloodstream (which is then further converted to other metabolites). These metabolites cannot cross the BBB rendering the drug useless.
  • The enzyme inhibitor prevents levodopa metabolism, allowing the drug to be delivered to the brain.
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13
Q

Can levodopa be used for Parkinson’s disease?

A

Yes

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14
Q

Why might early-stage Parkinson’s be treated with different formulations than late-stage Parkinson’s?

A

Early-stage PD patients can be given medicines via oral administration, whereas late-stage patients may require transdermal or subcutaneous administration, or even a nasogastric tube, as they may be “nil by mouth” (due to dyskinesia).

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15
Q

What is the aim of Parkinson’s medications?

A

To improve quality of life (not prevent disease progression)

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16
Q

What is dyskinesia?

A

Dyskinesias are involuntary, erratic, writhing movements of the face, arms, legs or trunk.

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17
Q

What usually causes dyskinesia as Parkinson’s progresses?

A

Dyskinesia is a side-effect of long-term levodopa use (levodopa is usually used in the management of Parkinson’s).

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18
Q

What is the aim of drug therapy in epilepsy?

A

To prevent seizures or to keep seizures to a minimum compatible with acceptable adverse effects.

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19
Q

What are the three main targets of anti-epileptic drugs?

A
  • Inhibition of voltage-gated sodium channels.
  • Inhibition of voltage-gated calcium channels.
  • Promotion of inhibitory neurotransmission (i.e. GABA).
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20
Q

How do most anti-epileptic drugs cross the BBB?

A

By diffusion (via the transcellular lipophilic pathway)

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21
Q

What is the first-line treatment for generalised seizures and how does it cross the BBB?

A

Sodium valproate crosses the BBB by diffusion and carrier-mediated transport (via the monocarboxylate transporter)

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22
Q

What is the first-line treatment for focal seizures and how does it cross the BBB?

A

Lamotrigine crosses the BBB by carrier-mediated transport (via organic cation transporter 1 (OCT1))

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23
Q

What is the first-line treatment for absence seizures and how does it cross the BBB?

A

Ethosuximide crosses the BBB by diffusion

24
Q

What is the first-line treatment for status epilepticus and how does it cross the BBB?

A

Lorazepam crosses the BBB by diffusion

25
Q

Do drugs have a faster onset when they cross the BBB by diffusion or by carrier-mediated transport?

A

Diffusion

26
Q

Do most anti-epileptic drugs have a long enough half-life to allow once daily dosing?

A

Yes (except sodium valproate, carbamazepine, and gabapentin)

27
Q

How is epilepsy treated pharmacologically?

A

It is treated by preventing the occurrence of seizures by maintaining an effective dose of one or more anti-epileptic drugs

28
Q

What determines the choice of anti-epileptic treatment?

A

The seizure type

29
Q

What route of administration is used for milder seizures?

A

Oral

30
Q

Which routes of administration are used for acute seizures?

A

IV, IM, or rectal

31
Q

What are the advantages of tablets?

A
  • Accurate dosing of the drug
  • Convenient to handle
  • Easy to take
  • Controlled release of the drug
32
Q

What are the disadvantages of tablets?

A
  • Some drugs have poor bioavailability so the oral route is not ideal
  • Local irritant effects leading to harm to the GI mucosa (note that AEDs and Parkinson’s drugs are used in the long-term so are more likely to cause this)
33
Q

How do gastro-resistant / enteric-coated tablets work?

A

These tablets have a barrier coating to control the site of release of the drug. This coating is designed to resist the low pH of gastric fluids (1.5-4), but to dissolve when the tablet enters the higher pH of the duodenum (from pH 5 upwards).

34
Q

What is the enteric coat made out of?

A

Polyvinyl acetate phthalate or diethyl phthalate

35
Q

How many times a day should enteric-coated tablets be taken?

A

Twice daily

36
Q

Why should enteric-coated tablets be swallowed whole?

A

Crushing or chewing will break down the enteric coating

37
Q

What are the advantages of gastro-resistant / enteric-coated tablets?

A

Release of the drug is delayed until it reaches the small intestine. This will:

  • protect drugs that would be degraded by gastric fluid
  • protect the stomach against drugs which can produce nausea and mucosal irritation if released at this site.
38
Q

Give an example of an AED which is formulated as a gastro-resistant tablet

A

Sodium valproate (Epilim)

39
Q

What are orodispersible tablets?

A

These tablets disintegrate in the mouth within 1 min in the presence of saliva. They can also be dispersed in a liquid before administration (some patients may not produce enough saliva to dissolve the tablet without dispersion in liquid)

40
Q

What are the advantages of orodispersible tablets?

A
  • Can be used in patients with more minor swallowing difficulties (i.e. early-stage Parkinson’s)
  • More accurate dosage of drugs for young children (compared to solution/suspension)
  • Fast effect
41
Q

Give two examples of orodispersible tablets

A
  • Co-beneldopa (for Parkinson’s)
  • Lamotrigine (anti-epileptic)
42
Q

How do chewable tablets work?

A
  • Tablets are mechanically disintegrated in the mouth and the drug dissolves in the stomach or intestine.
43
Q

What are the advantages of chewable tablets?

A
  • Quick and complete disintegration of the tablet leads to a rapid drug effect
  • Easy administration (easy to swallow) (useful for Parkinson’s and young children)
  • No disintegrant is required when manufacturing the tablet
44
Q

What is a disadvantage of chewable tablets?

A

The use of flavouring (sorbitol and mannitol) is required to ensure patient compliance

45
Q

Give two examples of chewable tablets

A
  • Carbamazepine (Tegretol Chewtabs)
  • Phenytoin
46
Q

What are the two main types of controlled matrix systems used in modified-release preparations?

A
  • Erosion-controlled matrix systems
  • Diffusion-controlled matrix systems
47
Q

What are the main APIs in Sinemet?

A
  • Carbidopa
  • Levodopa
48
Q

What is Sinemet?

A

Sinemet (carbidopa and levodopa) is a modified-release tablet for Parkinson’s disease which uses an erosion-controlled matrix system.

49
Q

How does an erosion-controlled matrix system work?

A

The rate of drug release is controlled by the erosion of a matrix in which the drug is dispersed.

50
Q

What substances are used in the eroding matrix?

A
  • Lipids
  • Waxes
  • Polymers (hydroxyethylcellulose)
51
Q

How do diffusion-controlled matrix systems work?

A
  • The drug is dispersed as solid particles within a porous matrix made of a water-insoluble polymer (polyvinyl chloride).
  • There is dissolution of drug particles located close to the surface.
  • Then, there is diffusion of the drug through the pores.
52
Q

How does the formulation of ropinirole in ReQuip XL facilitate the modified release of the drug?

A
  • ReQuip XL is formulated as a three-layered tablet which uses a diffusion-controlled matrix system.
  • A central, drug-containing, slow-release layer is surrounded by 2 placebo outer layers acting as barrier layers.
  • The placebo layers prevent the drug from being released too rapidly from the central layer (by diffusion).
53
Q

What are the advantages of formulating ReQuip XL (ropinirole) as a three-layered tablet with a diffusion-controlled matrix system?

A
  • Prevention of in vitro burst effect
  • Prevention of in vivo dose dumping
54
Q

What are the disadvantages of formulating ReQuip XL (ropinirole) as a three-layered tablet with a diffusion-controlled matrix system?

A
  • A sophisticated tri-layer tablet compression machine is required (expensive)
  • It is a more labour-intensive process (it takes longer to produce and it is more difficult to produce)
55
Q

Give three examples of medicines formulated with both diffusion- and erosion-controlled matrix systems

A
  • Mirapexin (pramipexole ER)
  • Epilim Chrono (sodium valproate)
  • Epival CR (sodium valproate)
56
Q

How do modified-release tablets using both diffusion- and erosion-controlled matrix systems work?

A
  • Penetration of GI fluids in the matrix
  • Dissolution of the drug, followed by diffusion
  • Separation of the matrix surface from the core (erosion)
  • Release of the drug

MP422 (1 decks)

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