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828 Dosage > Physiological barriers to drug discovery > Flashcards

Physiological barriers to drug discovery Flashcards

1
Q

Coatings

A

-control diffusion rates
-modify release properties

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2
Q

disintegrants

A

control regions of release

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3
Q

Lubricants

A

slow dissolution

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4
Q

Internal excipients

A

-swellable and nonswellable matrices
-inert plastics

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5
Q

Coating goals

A

-protection
-mask taste
-release
-aesthetics
-prevent inadvertent contact with drug

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6
Q

Aqueous film coatings contain

A

-film-forming polymer
-plasticizer (flexibility/elasticity)
-colorant and opafier
-vehicle

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7
Q

Non-aqueous film coatings contain

A

-film-forming polymer
-alloying substance (for solubility)
-plasticizer
-surfactants (film coat spreading)
-colorant and opafier (aesthetic)
-flavors
-glossant (luster)
-volatile solvent (spreading/evap)

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8
Q

Enteric coatings

A

-added to prevent early release of API in a region where it may undergo chemical breakdown

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9
Q

Reasons for enteric coating

A

-protect API from gastric fluids
-prevent gastric distress from API
-target delivery to an intestinal site
-delayed release
-deliver in higher local concentration

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10
Q

sustained release

A

-slow release
-delay onset of action but effect is sustained

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11
Q

Controlled release

A

-sustained but with reproducibility/predictability in drug release kinetics
-allows us to maintain a narrow drug plasma concentration-steady state

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12
Q

Controlled release fromulations

A

-coated beads, granules, microspheres
-multitablet system
-microencapsulated
-drug embedding in slowly eroding matrix

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13
Q

coated beads, granules, microspheres

A

-release by programmed erosion
-contacts

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14
Q

multitablet system

A

small tablets in a gelatin capsule

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15
Q

microencapsulated

A

-into walled material that allows spreading of particles across absorbing surface

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16
Q

Drug embedding in a slowly eroding or hydrophilic matrix

A

-drug homogenously dispersed in the eroding matrix
-release controlled by erosion rate

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17
Q

Steady state

A

rate going into body must equal the disposition

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18
Q

Drugs best suited for oral controlled release form

A

-exhibit neither slow nor fast rates of absorption/excretion
-uniformly absorbed from gas tract
-relatively small doses
-good therapeutic window
-chronic therapies better suited than acute

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19
Q

Factors of absorption: Permeability

A

functional and molecular characteristics of transporters and metabolism

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20
Q

epithelia

A

-line most external surfaces but does include endothelial cells
-sit on layer of extracellular matrix proteins (basal lamina)

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21
Q

simple squamous epithelia

A

-thin, flat layer
-pretty permeable
-lines most blood vessels, placenta

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22
Q

simple columnar epithelia

A

usually in GI tract

23
Q

translational epithelia

A

-several layers with dif shapes
-usually need to stretch

24
Q

Stratified squamous epithelia

A

-multiple layers of squamous cells that cover wear and tear areas like skin

25
Q

Endothelial cells

A

line inside surfaces of body cavities, blood vessels, lymph
-simple squamous

26
Q

Cell membrane

A

-semi-permeable
-lipid composition is POLARIZED, and intracellular membrane lipids different from extracellular

27
Q

Cholesterol in membranes

A

-provides fluidity at low levels
-too much can cause phase transition

28
Q

atherosclerosis

A

hardening of membrane from liquid to crystalline state because of cholesterol in the vascular system

29
Q

Permeability coefficient: used in membrane and cell-based assays

A

Papp = (dQ/dt) / ACo60 cmsec^(-1)

dQ/dt= amt of compund appearing on receiver side as function of time

A=surface area of filter support

Co=initial concentratioin of compound apllied to donor side

1/Papp = (1/PM)+(1/PABLFC)

30
Q

PAMPA sandwich system for permeability assays

A

-donor and acceptor plates (sandwich)
-acceptor wells (pH buffer + surfactant)
-donor wells (pH buffer + sample)
-membrane sandwiched between acceptor and donor well (plates)

31
Q

Lipid composition

A

-vary according to organ
-high in blood brain barrier
-changes influence absorption and function of cells

32
Q

Transport mechanisms

A

-passive (non-saturable)
-carrier-mediated (saturable)

33
Q

Passive (non-saturable) transport

A

-paracellular
-transcellular
=through and between cells
-Fick’s first Law idk prob doesnt matter

34
Q

carrier-mediated (saturable)

A

-active (energy dependent)
-facilitated diffusion (energy independent)

35
Q

paracellular transport

A

-hydrophobicity
-size and shape
-pKa

36
Q

transcellular transport

A

-lipophilicity (hydrophobicity)(H bond potential)
-size and shape
-pKa

37
Q

Typical Permeability Assays

A

-PAMPA: passive, during exploratory
-Caco-2: passive, active, paracellular, during development
-both: mech info, during discovery and pre development

38
Q

Caco-2 vs PAMPA permeability graph

A

y=x
-slope=passive diffusion
-top left half is ABSORPTIVE influx/uptake and/or paracellular transport
-bottom right half is SECRETORY and efflux transport, metabolism

39
Q

Permeability deviations

A

-some hindered due to drug resistance/secretory transporters (efflux)
-some enhanced by absorptive influx permeability

40
Q

Drug Transporters

A

-membrane bound proteins
-move molecules across membranes
-determinant of tissue and cellular distribution of drugs
-variations in transporter activity can affect drug response

41
Q

Nutrient and Xenobiotic transporter types

A

-SLC
-ABC

42
Q

Nutrient and Xenobiotic transporters nomenclature

A

transporter type; family number; species variant
ex: PepT1 –> SLC 15 A1
*no spaces just wanted to show breakdown

43
Q

Solute carrier (SLC)

A

-43 subfamilies
->300 identified
-generally infux or secretory efflux transporters
-PepT1, OATs, OATPs

44
Q

ATP-binding Cassette (ABC)

A

-7 subfamilies
-50 members
-generally efflux-multidrug resistant transporters
-P-glycoprotein, MRPs

45
Q

Absorption routes of permeability

A

A. Influx transporter mediated (through)
B. passive transcellular (through)
C. passive transcellular and efflux (through then out)
D. Passive paracellular (between)
E. metabolism (inside)
F. Efflux of metabolites (out)

46
Q

Influx transporters

A

substrates INTO cells

47
Q

Efflux transporters

A

substrates OUT of cells

48
Q

Absorptive transporters

A

substrates into blood circulation

49
Q

Secretory transporters

A

substrates from blood into bile, urine, GI lumen

50
Q

Permeability barrier

A

Pbarrier = Ppara + Ppassive transport + P active1transport + P activeNtransport
-efflux and metabolism give negative values

51
Q

Passive Paracellular Permeation (Ppara)

A

-linear increase in permebility with increasing concentration
-adjuvants can open tight junctions and increase transport

52
Q

Passive transcellular permeation

A

-permeability increase with concentration increase
-dissolution/solubility limited with high lipophilicity

53
Q

Facilitated/Active transcellular permeation

A

-affinity (KM), capacity (Vmax)
-concentration dependent saturation
-expression level (constitutive, induced)
-function (interactions, inhibition)
-excipients can limit effects of efflux by Pgp or BCRP

828 Dosage (27 decks)

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