PCEUT 532 > Midterm #3 > Flashcards

Midterm #3 Flashcards

(59 cards)

Study These Flashcards
1
Q

Definition of Bioavailability

A
  • Amount of unchanged drug reaching systemic circulation
  • F=bioavailable dose/administered dose
  • describes extent to which drug is absorbed
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2
Q

How to Measure Oral Bioavailability

A

F=(AUCoral/AUCiv)*(Div/Doral)

AUCoral=(F*Doral)/CL

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3
Q

Absolute vs Relative Bioavailability

A
  • Absolute: oral AUC vs. IV AUC
  • Relative: two oral formulation AUC
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4
Q

Measuring BA using Urinary Excretion Data

A
  • Ae, iv=feDiv
  • Ae,o=feDoF
  • F=(Ae,o/Ae, iv)=(Ae,o/fe*D)
  • Only applies to drugs with 30% or greater fe
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5
Q

Absorption Extent vs. Absorption Rate

A
  • Extent: how much reaches systemic circulation
    • absolute bioavailability (F)
    • measured by (AUC/D), Aetotal, Cmax
  • Rate: how fast
    • ​ka or t1/2 absorption
    • change in these affects Tmax and Cmax, may not affect extent (F, AUC)
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6
Q

Effect of Doubling Dose on Cmax and AUC

A

Double dose, double AUC and Cmax

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7
Q

Effect of decreasing F on Cmax and AUC

A

Decrease F, decrease Cmax and AUC proportionally

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8
Q

Effect of decreasing Ka of Tmax and Cmax

A

increases Tmax and decreases Cmax

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9
Q

Factors Affecting Oral Drug Absorption

A
  • Dissolution
  • Membrane Permeability
  • First Pass metabolism
  • Intestinal efflux and influx transporters
  • Drug stability in GI tract
  • GI physiology
  • Food and other medications
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10
Q

Dissolution Effect on Oral Absorption

A
  • depend on solubility, exciptient, formulation
  • affects dissolution
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11
Q

Membrane Permeability Effect of Oral Absorption

A
  • affects intestinal absorption
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12
Q

First Pass Metabolism Effect of Oral Absorption

A
  • Affects intestinal absorption and liver first pass
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13
Q

Follow Pathway of Drug

A
  • green=dissolution
  • yellow=membrane permeability
  • blue=efflux/influx transporters
  • purple=drug stabilty
  • pink=GI physiology
  • gray=food and other meds
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14
Q

Effect of Formualtion

A
  • Rate Tablet Dissintegration
    • Tablet compression, excipients
  • Rate of Dissolution
    • particle size
    • drug solubility
  • Modified Release
    • reduce frequency of admin
    • deliver drug to site of action
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15
Q

Food and Oral Drug Absorption

A
  • Delays gastric emptying
  • Gastric secretion
  • Bile salt secretion
  • Bind Ca2+, reduces absorption
  • Can interact with enzymes or transporter
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16
Q

Food and Acid Sensitive Drugs

A
  • decreases Abs
  • decreases Cmax
  • decreases F
  • Take 30-60 min before food
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17
Q

Brand Name Drugs

A
  • A new drug (new chemical entity)
  • Approved by FDA under New Drug Applications (NDAs)
  • Marketed by the pharmaceutical company under a branded name
  • Protected by patents for certain years
  • Expensive
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18
Q

Generic Drugs

A
  • Same active drug (chemical entity) as the brand name drug but sold under a different name (often the chemical name of the active drug)
  • Approved by FDA under Abbreviated New Drug Applications (ANDAs)
  • Cost-saving
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19
Q

1906 Pure Food and Drug Act

A

established regulation of Food and Drugs.

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20
Q

1938 Federal Food, Drug and Cosmetic (FFD&C) Act

A

introduced safety standards.

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21
Q

1962 Kefauver-Harris Amendment to the FFD&C Act

A

tightened safety standards and introduced requirement that drugs must be effective.

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22
Q

1984 Hatch-Waxman Act

A
  • created an abbreviated mechanism (ANDA) for approval of generic versions of brand-name drugs without conducting costly and duplicative pre-clinical and clinical testing.
  • increased availability of generics, greatly reduced the cost of prescription drugs
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23
Q

Bioequivalence replaces these 3 things in ANDA

A

clinical studies, animal studies, bioavailabilty

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24
Q

generic drug definition

Study These Flashcards
A
  • drug product that is comparable to brand/reference listed drug product in:
    • dosage form
    • strength
    • route of administration
    • quality and performance characteristics
    • intended use
25
Pharmaceutical Equivalence
* Same active ingredients * Same route of admin * Same dosage form * Same strength
26
Labeling
Same conditions of use
27
Therapeutic Equivalence
* Same performance characteristices * efficacy and saftey
28
Pharmaceutical Alternative
different salts, esters, dosage form or strength, also ER vs. IR
29
Therapeutic Interchange
drugs in the same therapeutic class (Atorvastatin vs. Simvistatin)
30
Does PE=TE
* NO! * TE=BE+PE
31
Two products are bioequivalent if
* They are pharmaceutically equivalent * Systemic absorption (both **rate and extent**) after administration are not significantly different
32
BE Testing, Key PK parameters
* Compare Cmax and total exposure
33
* e.g. drug with very long half-life (e.g. amiodarone) * e.g. drugs with highly variable PK * e.g. pt trials and ER/IR * e.g. topicals, nasal drugs
* Single-dose parallel design * Single-dose, replicate design * Multiple-dose, two-way crossover * Clinical endpoint study
34
Absorption, Distribution and Elimination barriers
* Absorption: * Oral: Small intestine mucosal layer * Topical: Skin: Stratum Corneum * Intranasal: Nasal Membrane * Distribution: * BBB * placenta * Elimination: * Kidney Secretion: proximal tubule epithelium * Hepatobiliary Secretion: hepatocyte membrane
35
Paracellular Transport
* indepent of size, charge, lipophilicity * not for protein bound * pore transport/filtration
36
Fick's First Law of Diffusion
* Jc=P\*SA\*(Cu1-Cu2) * Jc=rate of diffusion (mg/min) * P=permeability (cm/sec)
37
Permeability Coefficient
* P=(K\*D)/delta x * K=**partition coefficient** depending on **hydrophobiticity **and **charge** * D=**diffusion coefficient** depending on **size** and **membrane viscosity** * delta x: membrane thickness
38
too lipophilic and too polar
* too lipophilic: * insoluable, bind plasma protein * too polar * not get though gut wall or BBB
39
Lipinski Rule of 5
* Poor Abs/Permeability when: * MW\>500 * LogP\>5 * 5 H-bond donors * 10 H-bond acceptors * Exceptions: substrates relying on drug transporters
40
Ionization
41
pH Partition Hypothesis
* only unionized get into equilibrium at membrane * total concentration on each side depends on ionization degree * greater iniozation, greater total C
42
Characteristics of Carrier-Mediated Transport
* specific, inhibitable, saturable
43
MM equation
* V=(Vmax\*S)/(Km+S)
44
SLC Transporters
* OATPs, OAT, OCT * Gene: SLC(family #) A (member #) * Protein: related to function * Exception: SLCO family (OATP)
45
ABC Transporters
* P-gp, MDR * Gene: ABC (family letter)(member #) * Protein: Reflects function
46
Importance of Drug Transporters
* determinant of drug disposition and response * DDI * Inter-individual intervariability * Source for non-linear kinetics
47
P-gp
* efflux transporter * part of ABC family * lipophilic, cationic, nuetral, bulky rings * substrates are ampipathic, MW \>400kDa. positive charge at pH 7.4 * inhibited by clarithromycin * induction of P-gp by rifampin decreases oral absorption * Pumps drugs back into intestine lumen, decrease oral absorption * facilitate bilary secretion * faciitatie renal recretion * prevent drug into brain * preven drug into placenta
48
Drug Elimination in Liver and Drug Transporters
49
OATPs
* 1b1, 1b3, 2b in liver * sinusidol side of liver * drug uptake into liver * Eliminate statins * cyclosporin inhibit 1b1 * create 10 fold increase in AUC of statin...myopathies
50
First Approach to Determining Renal Clearance
* blood and urine collection over several t1/2 * CLr=(Ae/D)\*CL=feCL
51
Second Approach to Determining Renal Clearance
* urine collection over short period and blood collection at midpoint * CLr=(dA/dt)/Cmid
52
Renal Clearance from these 3 process
1. Glomerular Filtration 2. Tubular Secretion 3. Tubular Reabsorption * Rate Exrection=(1-FR)(Rate of Filtration + Rate Secretion) * FR=fraction reabsorbed from lumen
53
Glomerular Filtration
* 120 mL/min * urine flow 1-2 mL/min * Rate Filtration=GFR\*Cu=GFR\*fu\*C * Renal Extraction Ratio (E)=CLr/Qr=(120 mL/min)/1200=0.1 * glomerular filtration is a low efficiency process
54
CLr
* CLr=(fu\*GFR)+CLsecretion-CLreabsorption * CLfiltration=fu\*GFR * if CLr\>CLfiltration, net secretion * if CLrfiltration, net reabsorption
55
Organic Kidney Anion Secretion
OAT1/3, MRP, OATP
56
Organic Kidney Cation Secretin
OCT2 and MATE-1
57
OCT2, OATP1/3, and P-gp in renal tubular cells
* OCT2 and OATP1/3: from blood to cell * P-gp: from cell to urine
58
OAT1/3 inhibitor, interactions
* probenecid * interacts with beta-lactams, NSAID, diuretics, antiviral, etc. * transport anionic drugs
59
OCT2 inhibitor and interactions
* interact wtih cations * metformin, H2 blockers, endogenous calcium * ​​inhibited by cimetidine
PCEUT 532
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