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3153 IC13,18 Formulations > Parenteral (IC13) > Flashcards

Parenteral (IC13) Flashcards

1
Q

Parenteral delivery - types of injection

A

Intramuscular - 90dc, into muscle

Subcutaneous - 45dc, into sc layer

Intravenous - 25dc, into vein (dermis)

Intradermal - 10-15dc, into skin (epidermis) - more often for testing allergies, diagnostic tests; not really for drug delivery

Intrathecal - 5-15dc, into spinal canal (CSF, directly into brain)

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2
Q

Intrathecal injections

  • How is it administered?
A
  • Via scalp, into ommaya reservoir (implant)
  • Via lower back, into cerebrospinal fluid
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3
Q

Epidural VS intrathecal

A
  • Epidural: into epidural space, need to diffuse across epithelial layer into CSF
  • Intrathecal: directly into CSF
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4
Q

Describe the cerebrospinal fluid

  • Composition
  • Volume
A
  • Produced by choroid plexus
  • Clear solution: 99% water, 1% protein, ions, neurotransmitters, and glucose
  • 150ml volume (450-530ml produced per day, replaced every 5h)
  • Variable viscosity, flow rate, and pressure
  • Ebb and flow circulation, direction promoted by source (conc. gradient) and cilia
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5
Q

What are the barriers/disadvantages of non-intrathecal parenteral delivery to the brain?

A
  • Need to bypass BBB
  • More potential to distribute to other areas in the body via blood circulation
  • Encounters the reticuloendothelial system
  • Encounters metabolic enzymes
  • Invasive route
  • Require medical professional
  • Strict sterility
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6
Q

What are the barriers/disadvantages of intrathecal parenteral delivery to the brain?

A
  • Less potential to distribute to other areas in the body as more able to distribute directly to the brain via the CSF
  • Encounters the reticuloendothelial system
  • Encounters metabolic enzymes
  • Invasive route
  • Require medical professional
  • Strict sterility
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7
Q

What are the advantages of parenteral delivery to the brain?

A
  • Bypass hepatic first pass metabolism
  • Can control dosage (relatively low drug conc., and low toxicity)
  • Direct access to the brain for intrathecal route, reduce systemic side effects
  • Sustained release for IM depots, intrathecal reservoirs
  • Ideal for non-compliant, unconscious, or dysphagic patients
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8
Q

Blood to brain barriers:

  • Drug solution flows through circulatory system, what barriers?
A
  1. Reticuloendothelial system - include liver, spleen, lung etc.
  • Phagocytic system involve immune cells such as macrophages that may digest/phagocytosize the drug molecules
  1. Drug distribution
  • Unless there is active targeting, drug will distribute to other areas of the body including other organs
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9
Q

Blood to brain barriers:

  • Blood brain barrier (BBB)

Explain the transport across epithelial cells

A

Blocks uptake of 98% of small molecule drug candidates

Paracellular (tight junctions) and transcellular transport from blood through epithelial cells, into brain interstitial fluid

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10
Q

Blood to brain barriers:

  • Blood brain barrier (BBB)

Explain the action of active efflux transporters

A
  • Remove drugs from brain into the blood
  • P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multi-drug resistance proteins (MRP)
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11
Q

Blood to brain barriers:

  • Blood brain barrier (BBB)

Explain the action of transporters that facilitate entry into the brain

A

Carrier-mediated transporters (CMT)

  • e.g., transport amino acids (LAT1), glucose (GLUT1)

Receptor-mediated transporters (RMT)

  • involves transcytosis of receptor + drug ligand in a vesicle, vesicle fuse with membrane on the other side, exocytosis of drug into brain interstitial fluid
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12
Q

Ideal drug candidate for parenteral (non-intrathecal, need to pass BBB):

modified lipinski’s rule of 5

A

Molecular weight: <450 Da (instead of <500Da)

Hydrogen bond donors: <3 (instead of =<5)

Hydrogen bond acceptors: <7 (instead of =<10)

LogP: 1-3 (instead of <5)

Ionisation state: Unionized

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13
Q

Does intrathecal formulation need to fulfill lipinski’s rule?

A

No, intrathecal delivery can accomodate large molecules

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14
Q

Formulations for parenteral delivery can include:

A

Solutions

  • drug molecules
  • proteins/peptides

Suspensions

  • nano/microemulsions
  • liposomes and other lipid-based self-assembled structures
  • nanoparticles
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15
Q

Common excipients of solutions for injection

A
  • Diluent
  • Buffer salts
  • Tonicity adjusters
  • Preservatives (minimal for intrathecal)
  • Stabilizers/co-solvents
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16
Q

Considerations for parenteral delivery

  • pH
A

Ideally 7.4, but a wide range is tolerated

Intramuscular: 3-11
Subcutaneous: 3-6

Formulation stability is prioritized over ideal pH

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17
Q

Considerations for parenteral delivery

  • Tonicity
A

Ideally isotonic with blood (blood tonicity: 290 mOsm/L)

280-290 mOsm/L for large-volume parenteral

Tonicity can be increased with tonicity adjusters

Hypertonic solutions are preferred over hypotonic solutions

  • hypertonic: water leaves blood cell, into drug solution
  • hypotonic: water leaves drug solution and enters blood cell, causing them to burst/lyse
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18
Q

Considerations for parenteral delivery

  • Particle size
A

No visible particles (more applicable for IV, than SC or IM)

19
Q

Considerations for parenteral delivery

  • Volume
A

Volume not an issue, as infusion pumps can be used to administer large volumes overtime

20
Q

[Excipients of solutions for injection]

  • Buffer
A
  • Sodium acetate, citrate, phosphates, lactates
  • L-methionine
21
Q

[Excipients of solutions for injection]

  • Preservative (non-intrathecal formulation)
A
  • Benzyl alcohol
  • Chlorbutanol
  • Methylparaben
  • Propylparaben
  • Phenol
  • Thiomersal
22
Q

[Excipients of solutions for injection]

  • Tonicity adjusting agent
A
  • Mannitol (also a cryoprotectant for lyophilized formulations to protect it during sublimation process)
  • Sodium chloride
  • Potassium chloride (IC8)
  • Glycerine/Glycerol
  • Glycine
23
Q

[Excipients of solutions for injection]

  • Solvent
A
  • Ethanol
  • Glycerine/Glycerol
  • Glycine
  • PEG
  • Propylene glycol
24
Q

[Excipients of solutions for injection]

  • Surfactant
A
  • Polysorbate 20 & 80

(From IC8)

  • Glyceryl dioleate/monoleate
  • Lecithin
25
Q

Packaging and storage of parenteral formulations

A
  • Glass ampoules (scored for breakage)
  • Glass vials with rubber stoppers (for powders that require reconstitution; for products with sterile water included)
  • Pre-filled syringes
  • Need to withstand sterilization processes
26
Q

Syringes consist of:

A

Needle

  • larger gauge, smaller needle diameter

Barrel

  • graduated for measurement

Plunger

  • administer the drug solution
  • may be lubricated with silicone (biocompatible compound)

Syringes should be single use and sterile

27
Q

Catheters and reservoirs (for infusions) consist of:

A

Reservoir - for refilling
Catheter - to deliver
Pump to automate dosing

May use biocompatible materials such as Titanium as the reservoir pump inserted under the skin

28
Q

[Haloperidol Decanoate / Haldol]

Administration

A

Deep IM injection into gluteal region

  • 2-inch, 21 G needle
  • Max volume per injection site <3ml
  • Interval b/w doses: 4 weeks
29
Q

[Haloperidol Decanoate / Haldol]

Explain the function of its excipients:

  • Sesame oil
  • Benzyl alcohol
A

Sesame oil: diluent/solvent for IM injections (depot in muscular space)

Benzyl alcohol: preservative

Note: bc no water, no H+, no pH

30
Q

[Haloperidol Decanoate / Haldol]

  • PK/PD (FYI)
A

Sustained release from depot:

  • steady-state plasma levels reached within 2-4m
  • half-life: 3 weeks
  • plasma protein binding 88-92%
  • metabolized in the liver
31
Q

[Baclofen / Lioresal]

  • What is it?
A

Baclofen is a GABA receptor agonist

  • induces inhibitory action in the CNS, relaxes muscles
32
Q

[Baclofen / Lioresal]

Administration

A

Intrathecal injection

33
Q

[Baclofen / Lioresal]

Excipient function:

  • water
  • sodium chloride
A

Water: diluent
Sodium chloride: tonicity agent

recall intrathecal no need preservative

34
Q

[Baclofen / Lioresal]

  • pH
  • osmolality
A

pH: 5-7 (pH of intrathecal space ~7.3)

Osmolality: 270-300 mOsm/kg (0.05mg/mL)

*CSF osmolality around 290mOsm/kg

35
Q

[Baclofen / Lioresal]

Infusion VS Bolus

A

Infusion

  • antispastic effect seen 6-8h after administration
  • maximum efficacy at 24-48h

=> delayed activity due to infusion given at lower dose

Bolus

  • onset 0.5-1h after administration
  • peak antispastic effect 4h after dosing and last 4-8h
36
Q

[Baclofen / Lioresal]

Metabolism

A

Excreted through kidneys, pt with severe renal impairment should be treated with caution

No concerns with hepatic impairment

37
Q

[Ziconotide / Prialt]

  • What is it?
A

N-type voltage gated calcium channel blocker

  • analgesic, blocks pain signal transmission, management of chronic pain
38
Q

[Ziconotide / Prialt]

  • Administration
A

Microinfusion device, for intrathecal infusion with a microinfusion pump

39
Q

[Ziconotide / Prialt]

  • Molecular weight of 2639.2g/mol
  • how is it delivered?
A

Intrathecal can accomodate large molcules

Ziconotide is a peptide

40
Q

[Ziconotide / Prialt]

Excipient function:

  • Water
  • Sodium chloride
  • L-methionine
A

water: diluent

sodium chloride: tonicity agent

L-methionine: buffering agent, also antioxidant, also flavouring agent

41
Q

[Ziconotide / Prialt]

  • pH
  • tonicity
A

pH 4-5 (impt to maintain this to prevent denaturation of protein)

isotonic

42
Q

[Ziconotide / Prialt]

PK

  • Metabolism
  • Volume of distribution
A

Half-life: 4.6 +/- 1.8h

Metabolism: by peptidases/proteases

Vd: 140ml (volume of CSF ~150ml)

50% bound to human plasma proteins

43
Q

[Ziconotide / Prialt]

Advantage of intrathecal Ziconotide in terms of DDI

A
  • Low plasma ziconotide conc. and metabolism by ubiquitous peptidases make metabolic interactions with other drugs unlikely
  • Ziconotide not highly bound in plasma (~50%), low plasma exposure, hence unlikely for clinically relevant plasma protein displacement reactions to take place with other drugs
44
Q

[Ziconotide / Prialt]

Compare intrathecal vs intravenous

  • Clearance
  • Volume of distribution
  • Half life
A
  • Clearance (much higher in IV)
  • Volume of distribution (much higher in IV)
  • Half life (much shorter in IV)

3153 IC13,18 Formulations (2 decks)

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