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PHRM 828 > Knipp 3 > Flashcards

Knipp 3 Flashcards

1
Q

Drug metabolism purpose

A

to eliminate pharmacological activity of a drug
to make a compound continuously more soluble until it cannot escape excretion
TO DO SO:
change molecule’s shape to block binding
change molecule lipophillic character to more hydrophillic to increase solubility
increase molecule size so it is more cleared by bile/urine
make moleucle more recognizable by efflux pumps to increase elimination

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2
Q

sites of drug metabolism

A

first pass: GI epithelium and liver
systemic: occurs in all organs and in blood stream

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3
Q

classes of metabolidm

A

phase 1: metabolism of the main compound. decarboxylases, oxygenases, deamindation.
phase 2: metabolism through addition, conjugation, glucuronidation, sulfation
phase 3: transport-multidrug resistance

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4
Q

metabolism of tamoxifen

A

TAM w/ CYP3A4 -> NDM w/ CYP2D6 -> 4OH-NDM
TAM w/ CYP2B6 -> 4OHT w/ 3A4 -> 4OH NDM(endoxifen)

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5
Q

drug metabolism CYPs & enzymes

A

enzymes evolved as defense for highly lipophilic aromatics like phyoestrogens in plants + polycyclic hydrocarbs from fire
phase 1: main focus is CYP450
CYPs are grouped into families where two CYPs have ~40% AA homology

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6
Q

nonlinear PK lead to nonlinear TK

A

accumulation/ saturation lead to side effects
induction leads to less therapeutic response

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7
Q

Processes required for oral absorption of monolithic dosage forms

A

drug molecules at surface dissolve to form saturated solution
dissolved drug molecules pass through dissolving fluid from high to low conc.
drug molecules diffuse through bulk solution to absorbing mocosa are absorbed
replenishment of drug molecules in diffusion layer is acheived by further dissolution

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8
Q

effect of particle size

A

surface area increases when solids are broken to smaller peices which increases absorption
effect continues as you move from tablet to granules to particles
increase SA is increase dissolution rate

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9
Q

dissolution

A

rate of dissolution: change in amount of mass that appears in solution over time
dependent on:
D - diffusion coefficient
S - SA
Cd - concentration of drug in donor
Ca - concentration of drug in bulk solution

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10
Q

Noyes-Whitney

A

dissolution rate is proportional to D and tab/particle SA
dissolution rate is proportional to difference in concentration gradient
dissolution rate is inversely proportional to h:
increasing h means a less steep concentration gradient

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11
Q

permeability

A

similar but different than dissolution
diffusion across barrier instead of across unstirred layer
needs partition coefficient K
D - diffusivity
S - SA of boundary (GI SA)
K - partition coefficient
Cd - donor (GI) concentration
h - Thickness of barrier (GI thickness)
P - DK/h = permeability

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12
Q

factors limiting oral drug absorption

A

3 factors:
solubility - cant get enough drug into solution
dissolution - cant get drug out of tablet
permeability - cant get drug across GI cell membrane

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13
Q

solubility limited

A

drugs w/ poor solubility are often limited as dug candidates
represented as a small Cd value in previous equations
dosage form dissolves fast and drug permeates readily
increasing dose doesnt increase blood levels as GI fluids are already saturated
bigger molecules - decrease solubility

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14
Q

dissolution limited

A

drug is unable to dissolve into solution from dosage form in sub-saturated fluid
dissolution time is greater than time for absorption in intestines
due to poor manufacturing/formulation
need to have tab that can dissolve but withstand shipping and delivery

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15
Q

permeability limited

A

characteristic of API
now barrier is getting through intestinal wall
dissolution is fast w/ sub-saturated fluids
increasing amount of drug increases absorption
increase Cd by increasing amount of drug
increase dM/dt which is absorption

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16
Q

solubility/dissolution

A

permeability rate limited: drug in solution is high, solid drug is low. rate limiting factors - physiochemical properties (drug) and physiological prop (membrane)
dissolution rate limited: solid drug high, drug insolution low. rate lim factors - physicochemical(drug + formulation)

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17
Q

generic drug definition

A

a drug product that is comparable to a brand/reference listed drug product on dosage form
generic drug product: therapeutic equivalence- pharmaceutical and bioequivalence
generic product judged therapeutically equivalent to reference drug

18
Q

pharmaeceutical equivalence

A

same active ingredients; dosage form; route of administration; strength/concentration.
may differ in looks

19
Q

bioequivalence

A

pharmaceutical equivalents whose rate and extent of absorption are not statistic different when administered to humans at the same dose

20
Q

generics and therapeutic equivalence

A

two graphs have same AUC, but one does not reach therapeutic window

21
Q

assessing switch to generic

A

70.5 % no problems after switch
30% respondents reported an issue with a switch to generic

22
Q

meyer study

A

a drug is considered bioequivalent id it is in 90% confidence interval,
so AUC and Cmax within 80-125%
differences in Cmax and Tmax were due to faster disolution of generic compared to RLD

23
Q

IVIVC

A

generics were a lot steeper slope than the RLD so they were not interchangeable products

24
Q

***Mimicking clinical condition

A

dosage form design requires consideration of patient related variables
patient related variables are not accurately assessed during development and scale up
absorption windows are more defined based on physical and chem properties
better in vitro and in vivo testing models are required for optimizing dosage form

25
***Oral delivery summary
drug performance (PK/PD) is controlled by the interplay of excipients, physicochemical properties of the drug, and barriers between GI and site of action oral formulations can control the absorption rate (Kabs) which needs to be optimized dosage form design is dynamic and unpredictable so patient habits are considered patients will vary in response generic formulations are not the innovator, so they can cause performance problems
26
pharmacotherapy and pregnancy
60 mil women at reproductive age 10% become pregnant annually and are on meds for chronic illness PK of drugs during pregnancy is complex --> changes in ADMET of drugs and toxcity placenta can be male
27
fetal imprinting
developing fetus has rapid changes in 9 months genetics diet environment is important fetal imprinting linked to cardiovascular disease, neurological disorders, obesity
28
other PED pharmacology issues
thalidomide in caused in utero malfunctions exposure to xenobiotics caused in utero programming of cancer xenobiotic exposure can lead to PK/PD changes
29
PED drug development
early USA regulation 1962 - amendments required efficacy and safety for FDA approval legislative incentrives to promote pediatric development
30
best pharmaceuticals in children act
testing drugs in children have lots of challenges which discourages it act incentives for companies to study drugs in neonates, children, infants tech to monitor patients and assay very small amounts of blood pediatric clinical infrastructure
31
pediatric pharmacology approved drugs
children are theapeutic orphans 20-30% of approved drugs have pediatric labeling FDA encourage pediatric studies
32
pediatric pharmacy
descriptive pharmacology is lacking in pediatric patients: children are not mini adults animal studies arent always predictive clinical studies in children fraught w/ ethical and financial hurdles administering drugs can be a problem
33
PED biopharmaceutics classification system (PBCS)
BCS has been used to expedite generic and drug repurposing formulations classification is based on 3 factors: solubility, intestinal permeation, dissolution rate urgent need to expedite PED formulation disposition drives safety and efficacy
34
PBCS class system
Class 1: rapid dissolution for immediate release Class 2: dissolution criteria are critically needed Class 3: very rapid dissolution Class 4: same as BCS class 2
35
extrapolation between species
the relevance of animal models can limit extrapolation to humans length of gestation and timing of events + relative organ function maturity significant species differences exist in transport protein and machinery
36
pediatric drug transporter research
what impacts growth and development? - nuclear receptor regulation + endocrine changes do gene variation add to age variation
37
PED challenges
CYP3A4 not in children bio: ontogenic + compositional challenges clinical: clinical trials + caregiver requirements formulation: dosage form selection, flexibility in dosing ,excipeint selection, taste masking
38
PED drug development initiatives
protect children through clinical research children are not mini adults PED patients need to be age classified and age appropriate formulations
39
PED formulation
safety and toxicology of excipients for PED database encourages solid dosage form draws attention to use of traditional excipients
40
mini tablet
ability to incorporate BCS class 1 + 3 more beneficial for testing meds on market pediatric compliance, flexible dosing, protect from degradation minimal excipients, size is constant
41
pharmaceutical film considerations
advantages: acceptable for patients w/ dysphagia, ease and accuracy of dosing, stability, faster onset, life cycle management disadvantages: difficult to manufacture, moisture sensitive, limited dosing capacity, increased packaging costs
42
***PED pharmacology, challenges remain
age based dosage form selection need for descriptive pharmacology children are not mini adults animal models need to be refined enable clinical studies by looking at ethical + financial hurdles better means of drug administration are needed

PHRM 828 (7 decks)

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