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Ischaemic heart disease > Delivery of nitrates > Flashcards

Delivery of nitrates Flashcards

1
Q

what is systemic drug delivery

A

still largely tend to fill all of the body with drug even though only a specific region needs to be treated
- assume if drug is present in plasma, then also at site of action

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2
Q

what is absolute bioavailability

A

the amount of drug that can be absorbed into the bloodstream that is available to have an effect

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3
Q

what is the IV bioavailability

A

always 100%

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4
Q

how can bioavailability be measured

A

area under curve on a plasma conc time graph is an indication of bioavailability

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5
Q

what is the one compartment open model for the GIT

A
  1. drug in formulation
  2. drug in gastrointestinal fluid
  3. drug in body compartment (input)
  4. drug eliminated (output)
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6
Q

what are the assumptions of the open model for the GIT

A
  1. Once released from the formulation and absorbed, drug is distributed instantly throughout body
  2. changes in drug in plasma directly affects change in drug at the site of action
  3. drug input and output is described by first order kinetics
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7
Q

what is the rate of drug input

A
  1. rate of drug input is proportional to the concentration
    rate of drug input (at time t)= -KaC
    - C= Conc of drug available for absorption
    - t= time
    - Ka= apparent absorption rate constant in time^-1
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8
Q

what is the rate of drug elimination

A

rate of drug elimination (at time t) = -KeCt

  • Ct= conc of drug in body compartment at time t
  • Ke= apparent elimination rate constant
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9
Q

what is the biological/elimination half life of a drug in the body

A

t1/2= 0.693/Ke

  • the time required for the body to eliminate 50% of the drug it contains
  • inversely related to elimination rate
  • first order elimination
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10
Q

what are multiple dosing regimes

A

when a drug is given repeatedly

  • only a few drugs are given as one dose only, typically several doses given in a treatment
  • the dose size, frequency and regularity can significantly affect therapy
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11
Q

describe the effect of multiple dosing on plasma concentration

A

steady state:

  • attained after approximately four half times
  • time to reach steady state depends on t1/2 and is independent of the dose size and dosing interval
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12
Q

what is the average steady state concentration of drug in the plasma

A

C^ss~Ave= FDt1/2 x 1.44/ TV~d

  • F= fraction absorbed (bioavailability)
  • D= dose
  • t1/2= biological half life
  • T= fixed time (dosing) interval
  • Vd= volume of distribution
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13
Q

what is the volume of distribution

A

relates to the amount of drug in the body to the concentration of drug that is measured

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14
Q

describe the effect of changing dose size at constant dosing intervals

A
  1. the larger the administered drug dose, the higher the maximum, minimum and average plasma concentrations of the drug are achieved at steady state
    - larger fluctuations in drug plasma concentrations
    - can be dangerous for drugs with narrow therapeutic window
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15
Q

describe the effect of changing dosing intervals at constant dose size

A
  1. the dose of the administered drug is kept constant but dosing interval is varied
  2. if the dosing interval is shorter than the t1/2 of the drug, higher steady state plasma concentration is obtained
  3. of dosing interval is longer than the t1/2 of the drug, lower steady state plasma concentration obtained
    - fluctuations between minimum and maximum drug concentrations stay the same
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16
Q

how is the loading dose calculated

A

4 variables used to calculate
Loading dose= C~pV~d/FS
- Cp= desired peak concentration of drug
- Vd= volume of distribution of drug in body
- F= bioavailability
- S= fraction of drug salt from which drug is active drug

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17
Q

define dose dumping

A

drug is released straight into the body- conventional tablets and capsules

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18
Q

what are modified release tablets

A

drug release is modified- usually extended

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19
Q

what are delayed release tablets

A

drug release is delayed d

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20
Q

what are prolonged/extended release tablets

A

allows extended therapeutic blood levels of the drug

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21
Q

what is zero order (controlled) release

A

drug is released at constant rate, independent of remaining drug within the formulation

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22
Q

what is variable release tablets

A

release is timed to optimise therapy

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23
Q

what is a bioresponsive release

A

drug is released in response to an external stimuli

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24
Q

why are modified/prologed released systems used

A
  1. improve patient compliance
  2. improve control of maintenance of therapeutic plasma levels of drug, leading to:
    - improved therapy chronic conditions
    - improved night time therapy
    - reduce side effects
    - reduced amount of drug administered
  3. reduction in localised side effects
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25
Q

what are the factors in controlling drug release

A

usually require a rapid release priming (loading) dose and extended release component, to achieve rapid and then prolonged drug delivery

26
Q

what are the mechanisms of controlling the rate of drug release from a formulation

A
  1. diffusion controlled
  2. dissolution controlled
  3. osmosis controlled
  4. mechanical controlled
  5. bioresponsive controlled
    - 2 designs: matrix and barrier coating
27
Q

describe the typical constituents of a modified release oral dosage form matrix tablet

A
  1. active drug
  2. release controlling agent
  3. release rate modifying agent
  4. aid to drug solubility
  5. lubricant/glidant
  6. coating
  7. can also have matrix pellets or granules
28
Q

describe the components of a barrier/membrane controlled system in barrier coating design

A
  1. single unit systems
  2. coating- film coat
    - polymer
    - plasticiser
    - other additives (colour, release modifiers)
  3. core- usually a compressed tablet containing
    - active drug
    - filler
    - lubricant/glidant
  4. can also have pellets or granules with barrier coatings
29
Q

how can diffusion be controlled in the rate of drug release from a formulation

A
  1. barrier coatings
  2. multiple unit system
  3. plastic matrices
  4. transdermal patch
30
Q

what does a multiple unit system consist of

A
  1. core:
    - spheroid pellets containing drug
    - diluent
    - binder
  2. film coating (as for single unit dosage form)
  3. hard gelatine capsule
  4. loading dose in coat, or incorporated separately as uncoated particles
31
Q

what are the constituents of a plastic matrix

A
  1. insoluble polymer- eg. polyethylene
  2. formulation additives- lubricant, fillers, aid to solubility
  3. coating
  4. can be made by compressing plastic particles with drug particles in a tablet machine, then coating
    - eg. Gradumet
32
Q

what is the gradumet system

A

M~t= Kt^0.5

  • Mt= drug release at time t
  • K= constant
33
Q

what does a transdermal patch consist of

A
  1. backing layer- polyester film
  2. a drug reservoir alcohol USP gelled with hydroxyethyl cellulose or silicone oil
  3. an ethylene vinyl acetate copolymer membrane containing silicone adhesive
  4. protective liner covering the adhesive layer before application to skin
34
Q

how can dissolution be controlled in rate of drug release from a formulation

A
  1. simplest (eg testosterone implants)- pellets/tablets/particles of sparingly soluble drug
  2. hydrophobic systems
  3. release by erosion/dissolution of fat to expose the drug
  4. multiple release products
  5. ion exchange resins
35
Q

what does a dissolution controlled hydrophobic system contain

A
  1. drug
  2. sparingly soluble waxes (solid at body temperature)
  3. release modifiers
  4. aids to solubility
  5. lubricant/glidants
  6. binding agents
  7. coating
  8. manufacture- typically granulation and compression
36
Q

what does multiple release products contain

A
  1. loading dose in uncoated granules

2. contains same waxes as matrices, but sprayed onto granules as a coating

37
Q

what do ion exchange resins contain

A
  1. dissociation of drug resin complex
  2. formulation:
    - resins (amberlite, dowex)
    - obtained as spheres, loaded with drug
    - diffusion alors helps regulate release
38
Q

what is a suscard buccal/Buccastem

A
  1. release by hydration, gelation, dissolution of polymer then drug dissolution and diffusion
  2. controls dissolution and distribution in rate of drug release
39
Q

what are the components of a hydrophilic matrix system

A
  1. active drug
  2. gelling agent/hydrophilic colloid
  3. aid to solubility
  4. binder/compression aid
  5. lubricant/glidant
  6. film coating
    eg. suscard buccal
40
Q

what is a continuous system

A

eg. Phyllocontin
1. controls dissolution and diffusion in rate of drug release
2. drug granulated with hydroxyalkyl cellulose, mixed with melted higher aliphatic alcohol (wax), granulated and compressed into tablets
3. on exposure to gastrointestinal fluid, wax erodes, cellulose swells and gels, drug release controlled by rate of wax erosion and diffusion through gel

41
Q

how is osmosis controlled in rate of drug release

A
  1. principle

2. constituents osmotic pump

42
Q

what does a constituent osmotic pump consist of

A
  1. core:
    - active drug
    - osmotically active agent
    - filler
    - lubricant/glidant
    - aid to solubility
    - viscosity modifier
  2. coat
    - polymer (with semi permeable membrane properties)
    - plasticiser
    - other (colour etc)
  3. can get very close to zero order drug release from this formulation
43
Q

describe the reasons for use of buccal/sublingual route

A
  1. local- treatment conditions of the oral cavity
  2. systemic- avoid first pass effects, veins don’t drain to the liver via the hepatic portal system
    - rapid onset of action (sublingual)
    - controlled drug release possible (buccal)
    - avoid acid/digestive enzymes in lower GIT
44
Q

Describe the structure of oral cavity

A
  1. beginning of alimentary tract

2. bound by cheeks, lips, hard palate sublingual mucosa

45
Q

describe the functions of the oral cavity

A
  1. process food
  2. mastication
  3. lubrication
  4. digestion
  5. sampling and evaluation foodstuffs (taste)
46
Q

what is teeth enamel made from

A

hydroxyapatite

47
Q

what does the oral mucosa consist of

A
  1. squamous stratified epithelia
  2. keratinised- gingiva (gums), hard palate (areas abrasion)
  3. non keratinised- buccal mucosa, sublingual mucosa
  4. specialised mucosa- upper tongue
48
Q

what is the role of saliva

A

lubrication, digestion, remineralisation of teeth, antimicrobial effects

49
Q

describe the flow rates of saliva

A
  1. background- mainly mucous secretions, circa 0.5ml min-1- varies with time of day (greatest afternoon, least at night)
  2. stimulated- mainly serous secretions, up to circa 7ml min-1
50
Q

what is the salivary pellicle

A

a salivary coating of all internal surfaces of the oral cavity, protective or lubricating

51
Q

describe the microbiology of the oral cavity

A

bacteria: including Streptococcus, enterococcus, staphylococcus
- also some fungi, viruses, mycoplasmas and protazoa

52
Q

what is dental plaque

A
  1. teeth- a hard, non shedding surface for microbial colonisation
  2. microorganisms exist in a biofilm, a complex matrix composed of microbial extracellular products and salivary compounds
  3. multiple habitats are associated with the tooth surface, each supporting different populations of oral bacteria
53
Q

describe the absorption across the oral mucosa

A
  1. not designed for absorption
  2. small surface area for absorption
  3. best absorption in thinnest areas (sublingual), worst through keratinised epithelia (gingiva)
  4. so variable but generally low permeability
  5. smaller, stable, potent, lipophilic molecules absorbed best
    - therapeutic proteins poorly absorbed
54
Q

describe the route for drug permeability through the oral mucosa

A
  • mucosal barrier formidable
  • major barrier is stratified epithelia
  • possible routes: transcellular, paracellular
55
Q

what are the main problems of drug delivery via the oral cavity

A
  1. patient acceptability- taste, mouthfeel, odour
  2. ease of absorption- normally only small amounts of drug absorbed from mouth, needs to have correct properties
  3. retention- duration of application (mouthwashes less than a minute) and salivary washout
  4. distribution within oral cavity and salivary route- drugs follow saliva when released, pool in lower part oral cavity and swallowed, not distributed throughout cavity
56
Q

what are formulations and mechanisms of drug release relevant to nitrate drug delivery

A
  1. aerosol sprays
  2. orally disintegrating/orodispersible tablets
  3. sublingual tablets
  4. bioadhesive tablets
  5. injection
  6. transdermal patches
57
Q

what aerosol sprays could be used in nitrate drug delivery

A

eg. nitrolingual, core nitro spray

- delivers unit dose of GTN under the tongue for rapid absorption

58
Q

what orodispersable tablets could be used in nitrate drug delivery

A
  1. lightly compressed, porous tablets
    - rapidly disintegrate, normally to allow drug to be swallowed, by those with difficulty
    - similar to tablets but with less binder and a very effective disintegrant
    - eg. calpol fast melts, nurofen meltlets, zydis ODT
59
Q

what sublingual tablets could be used in nitrate drug delivery

A
  1. drug to be mainly absorbed in the sublingual region, under tongue
  2. eg. glyceryl trinitate tablets
60
Q

what bioadhesive tablets could be used in nitrate drug delivery

A
  1. adhere to the oral mucosa, usually the upper buccal pouch and deliver drugs slowly either systemically into the mucosa or into the oral cavity
  2. no need for disintegrant since want to achieve slow release
  3. eg. suscard buccal, GTN
  4. small compressed tablets with flat face for adhesion, contains a bioadhesive polymer that adheres on moistening
61
Q

what injections could be used in nitrate drug delivery

A
  1. glyceryl trinitate for injection contains 1-5mg/mL of glyceryl trinitate, absolute ethanol and propylene glycol in water for injections
  2. must be diluted and often given in infusion
    - glycerol trinitate is compatable with following infusion solutions: 0.9% NaCl solution, 5% dextrose/glucose
62
Q

what transdermal patches could be used in nitrate drug delivery

A
  1. 5-10mg in a patch, slowly released over day

2. patch applied during the day and removed at night

Ischaemic heart disease (8 decks)

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