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PHRM 828 Exam 2 > Knipp's 2nd Set > Flashcards

Knipp's 2nd Set Flashcards

1
Q

Sites of Drug Metabolism

A
  • First Pass Metabolism: GI, liver
  • Systemic Metabolism: blood stream
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2
Q

Classes of Metabolism

A

Phase 1: metabolism of main compound
Ex. decarboxylases, oxygenase, deamidation

Phase 2: metabolism through addition, conjugation
Ex. glucuronidation, sulfation

Phase 3: transport - multidrug resistance

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3
Q

Objectives of Drug Metabolism

A
  • eliminate the pharmacological activity of drug
  • make a compound continuously more soluble until it cannot escape excretion
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4
Q

How to get Drug Metabolism

A
  • change molecules shape to block its receptor binding
  • change molecules lipophilic character to a more hydrophilic character & increase solubility
  • increase molecules size
  • make molecule more recognizable to efflux pumps
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5
Q

Metabolic Enzymes

A
  • defense mechanism to highly lipophilic, aromatics that naturally occur in environment
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6
Q

Phase 1 Metabolism Focus

A

Cytochrome P450 –> CYP3A4

CYP3A5 actually metabolize many compounds thought to be done by CYP3A4

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7
Q

Process of Oral Absorption

A
  1. Drug molecule at surface dissolves to form saturated solution
  2. Dissolve drug pass throughout the dissolve fluid and diffuse from high to low concentration
  3. Drug molecules diffuse through bulk solution to mucosa
  4. Absorbed
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8
Q

Particle Size

A
  • surface area increases as solids are broken into smaller pieces
  • Increased SA leads to Increased Dissolution Rate
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9
Q

Dissolution

A

Rate of Dissolution
- dM/dt
- change in amount of mass of solution over time

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10
Q

Dependents of Dissolution

A

D: diffusion coefficient
S: surface area of tablet
h: thickness of layer
Cd: concentration of drug in donor
Ca: concentration of drug in bulk solution

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11
Q

Noyes Whitney Equation

A

dM/dt = DS/h (Cd-Ca)

  • dissolution rate is proportional to D
  • increase rate of diffusion –> increase dissolution
  • dissolution rate is proportional to particle surface area
  • dissolution rate is proportional to difference in concentration gradient
  • high to low
  • dissolution rate is inverse proportional to h
  • increased h = less steep concentration gradient
  • decrease h by increasing stirring rate
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12
Q

Permeability

A
  • diffusion across a cell membrane barrier
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13
Q

Factors Limiting Oral Drug Absorption

A

Solubility

Dissolution

Permeability

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14
Q

Limited Solubility

A

Dissolution is fast
Permeability is Fast
Drug doesn’t get in solution

Observations:
- gut is saturated by high dose
- absorption does not increase with increased dose

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15
Q

Limited Dissolution

A

Tdiss is greater than residence time
Permeability is fast
Cant get out of dosage form

Observations:
- dissolution can be enhanced by particle size reduction
- absorption increases with increasing dose

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16
Q

Limited Permeability

A

Dissolution is fast
Permeability is low

Observations:
- amount of drug absorbed increases with increased dose

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17
Q

Rate Limiting Factors of Permeability

A

Physiochemical properties of drug

Physiochemical properties of membrane

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18
Q

Rate Limiting Factors of Dissolution

A

Physiochemical properties of drug

Physiochemical properties of formulation

19
Q

Definition of Generic Drug

A

drug product that is comparable to brand in dosage form, strength, route of administration, quality and performance, and intended use

20
Q

Therapeutic Equivalence

A

Pharmaceutical Equivalence
Bioequivalence

21
Q

Pharmaceutical Equvalence

A

The same:
- API
- dosage form
- route of administration
- identical strength/concentration

Differ:
- shape, excipients, color

22
Q

Bioequivalence

A

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

a drug product is considered bioequivalent if 90% confidence interval of ratios of the test mean values for AUC and Cmax are within 80%-125%

23
Q

Generic vs Brand Therapeutic Equivalence

A
  • can contain the same AUC but not the same therapeutic effect
24
Q

Study on Switch to Generic

A

2885 patients examined

  • 70.5% no problems
  • 10.8% including reappearance of problem
  • 9.8% unspecified issue
  • 8.8% other issues

30% of respondents reported an issue

25
Q

IVIVC

A
  • no correlation between bioavailability of generic vs brand
  • no correlation between dissolution rate and AUC

ISSUE IN INTERCHANGEABILITY OF PRODUCTS

26
Q

Mimicking Clinical Conditions

A

Dosage form design requires consideration of patient related variables

Patient related variables are not accurately assessed during development

Absorption windows are defined more based on physical-chemical properties and not physiology

Better in vitro and in vivo testing models are required for optimizing dosage form design

27
Q

Control of Drug Performance

A

Interplay of excipients (formulation)

Physiochemical properties of drug

Physiological barriers between GI tract and site of action

28
Q

Oral Delivery Summary

A

Oral formulations can control absorption rate to yield a safe and efficacious response

Dosage form design is dynamic and unpredictable so patient habits have to be considered

Patients vary in response

Generic formulations are not the innovator

29
Q

Pharmacotherapy and Pregnancy

A
  • 60 million women at reproductive age
  • 10% are pregnant annually
  • many are on meds for pre-existing conditions
  • physiological changes alter ADME
  • toxicity is concern
30
Q

Fetal Imprinting

A
  • genetics, diet, and environment can impact fetus

Linked to:
- cardivascular disease
- neurological disorder
- obesity and diaabetes

31
Q

Pediatric Drug Development

A
  • encourage pediatric drug development in order to create a situation where substantially more children have access to safe and effective medication
32
Q

Challenges for Pediatric Testing

A
  • lack of incentives for companies to study drugs on neonates, infant, children
  • lack of technology to monitor patients and assay
  • lack of suitable pediatric clinical infrastructure
33
Q

Pediatric Pharmacology

A
  • children are therapeutic orphans
  • 20-30% of approved drugs have pediatric labeling
34
Q

Why is it hard for pediatrics?

A
  • children are not miniature adults
  • dose on weight is not predictable
  • animal studies are not predictive
  • clinical studies fraught with ethical and financial hurdles
  • administration of drug is hard
35
Q

Pediatric Biopharmaceutics Classification System

A
  • expedite generic and drug repurposing formulations
36
Q

3 Factors the Influence Bioavailability

A

Solubility

Permeation

Dissolution

37
Q

OATP1B1 SNP and Methotrexate Case Results

A

Low clearance rates are associated with higher toxicity

dose lowering and higher hydration must be required

38
Q

Difference in Animals and Children

A

Length of gestation and timing of events

relative organ function maturity at birth

39
Q

Overall Challenges in Pediatrics

A

Biological:
- ontogenic changes
- compositional changes

Clinical:
- clinical trials
- caregiver requirements

Formulation:
- dosage form selection
- flexibility in dosing
- excipient selection
- taste masking

40
Q

Paradigm Shift

A

Going to protecting children from clinical research to protecting children through clinical research

41
Q

Safety and Toxicology of Excipients for Pediatrics

A
  • collaboration of EMA and NICHD
  • draws attention to use of traditional excipients
  • encourages greater use of solid dosage forms
42
Q

Minitablet Formulation

A

Incorporation of BSC Class 1 and III
- less effect of formulation

Easy Translation to Market
- pediatric compliance
- flexible dosing

Minimal Excipients
- single filler, disintegrant, lubricant

Same Manufacturing Conditons
- size is constant

43
Q

Film Advantage vs Disadvantage

A

Advantage:
- acceptable for patients with dysphagia
- easy and accurate
- increased stability
- faster onset of action

Disadvantage:
- difficult to manufacture
- moisture sensitivity
- limited dosing capacity
- increased packaging cost

44
Q

What challenges Remain?

A
  • age based dosage form
  • children are not miniature adults
  • animal models need to be refined
  • better means of drug administration

PHRM 828 Exam 2 (3 decks)

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