1
Q
Physical and chemical properties of the drug that are criteria for selection of a specific drug route
A
solubility
stability
susceptibility to degradation
2
Q
Onset of action
A
speed with which the drug is absorbed and/or released
a criterion for selecting a route of administration
criteris for selecting a drug route
speed drug is absorbed or released
3
Q
The action of the drug is…
A
a criterion for selecting a route of administration
4
Q
Site where the action of the drug is required is a …
A
criterion for selecting a route of administration
local, systemic or non reachable
5
Q
Inhalation time until effect
A
2-3 mins
5
Q
Patient related factors that are criteria for selecting a route of administration
A
age
disease state
unconscious
uncooperative
vomiting
ADUUV
6
Q
Route that has slowest time of onset
A
Oral: 30-90 mins
transdermal: minutes to hours
6
Q
Route that has fastest time of onset
A
IV
7
Q
IV time until effect
A
30-60 seconds
8
Q
IM time until effect
A
10-20 mins
9
Q
SC time until effect
A
15-30 mins
9
Q
Sublingual time until effect
A
3-5 mins
10
Q
Oral time until effect
A
30-90 mins
11
Q
Important disadvantages of IV route
A
inconvenient, painful
requires trained personnel
12
Q
Rectal time until effect
A
5-30 mins
12
Q
Important Advantages IV route
A
rapid onset of action
large volumes can be delivered
13
Q
Transdermal time until effect
A
varies minutes-hours
14
Q
Important Advantages of SC route
A
rapid onset of action
smooth, constant absorption
can be done by patient
14
Q
Important Advantages of IM route
A
rapid onset
easier to administer than IV
larger volumes than SC
depot injection can be given**
15
Q
Important limitations of IM route
A
inconvenient, painful
large volumes cannot be administered
requires trained personnel
absorption can be erratic for poorly soluble drugs
potential for nerve damage, abscess formation
16
Q
Important limitations of SC route
A
site of injection influences extent of absoption
limited volume of injection <2 mL
17
Q
Important Advantages of Pulmonary/Inhalation routes
A
large surface for absorption
bypass first pass metabolism
17
Q
Important Advantages of IN route
A
**non-invasive **
bypass hepatic metabolism
reduction systemic effects
18
Q
Important disadvantages of IN route
A
efficacy depends on delivery system
need for formulation enhancers
19
Important Advantages of Topical/transdermal routes
ease of admin
non-invasive
19
Important Limitations of Pulmonary/Inhalation routes
dependent on formulation factors and delivery system
20
Important Advantages of sublingual/buccal routes
avoid first pass metablism
21
Important Limitations of sublingual/buccal routes
**limited dose**
need special excipients
**not suitable for large doses**
22
Important Limitations of Topical/transdermal routes
need formulation** enhancers**
**Efficacy**: ointment
23
Important Advantages of ocular route
avoids first-pass metabolism
delivers higher drug conc. in localized ares
24
Important Limitations of ocular route
needs special excipients
25
Important limitations of rectal route
**erratic**/variable drug absorption
25
Important Advantages of rectal route
avoid first-pass metabolism
26
Saliva pH, time food spends
pH: 6.5-7.5
time: up to 1 min
27
Lower stomach pH, time food spends
pH: **1.5-4**
time: **1-3 hrs**
27
Upper stomach/fundie pH, time food spends
pH: **4-6.5**
time: 30-60 mins
28
small intestine pH, time food spends
pH: **4-7**
time: **10 hrs-several days**
29
duodenum pH, time food spends
pH: **7-8.5**
time: **30-60** mins
30
Order the following from largest to smallest surface area:
folds of kerkring
microvilli
villi
cylinder
cylinder>folds of kerking>villi>microvilli
31
Disintegration
**dosage form** to **granules**
32
Deaggregation
**granules** to fine **particles**
33
At low pH, do acids or bases get absorbed?
acid
34
At high pH, do acids or bases get absorbed?
bases
35
List the 5 mechanisms for absorption across cells
1. Transcellular passive diffusion
2. Active (influx/effluc) transcellular
3. Paracellular passive diffusion
4. Transcytosis
36
Permeability rate limited absorption
**Dissolution is much faster than absorption**
most of the drug is dissolved before an appreciable fraction is absorbed
*solution/red line has a higher peak
37
Dissolution rate limited absorption
Dissolution proceeds relatively slowly
**absorption cannot proceed any faster than the rate at which the drug dissolves**
* solution/red line has a lower peak
38
For zero-order absorption, a plot of amount remaining to be absorbed against time yields a straight line, the slope of which is the -
rate of absorption
39
first-order absorption, the amount declines linearly with time when plotted -
semilogarithmically
40
Absorption related parameters:
Rate of drug absorption (**ka**)
Extent of drug absorption = Bioavailability (**F**)
41
Disposition parameters
**Cl,Kel,V**
41
Major PK Parameters
F
ka
CL (kel)
V
41
Tmax is determined by -
**ka, kel** (CL, V)
42
Cmax is determined by -
D, F, Tmax
43
AUC is determined by -
D, F, **CL**
44
Effect of Dose on Cp vs. Time Profile
The higher Dose the higher the concentration values at each time point
increase dose:
**Cmax and AUC increase** **
**Tmax unchanged**
45
Effect of F on Cp vs. Time Profile
increase F:
**Cmax and AUC increase**
**Tmax and T0.5 is unchanged.**
46
Effect of ka on Cp vs. Time Profile
Increase Ka:
**Cmax higher and earlier**
**Tmax gets smaller **
**AUC is not affected**
47
ka>>kel
**drug’s elimination** controls the fall in Cp at later times (≈ terminal t1/2 unchanged)
48
ka < kel
Flip-flop kinetics
49
Flip-flop kinetics
**drug’s absorption** and not its elimination **controls the fall in Cp at later times **
A more prolonged absorption results and thus slower drug elimination (≈ terminal t1/2 is increased)
50
Dissolution Testing basic units
motor
stirring device
thermostated beaker
sampling method
51
De-solvation and formation of a neutral molecule is unfavourable if ...
compound forms many **H or ionic bonds with water**
52
ct and water log p: ratio is
100,000
53
A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in - water over a pH range of -
< 250 ml (8 oz)
1 to **7.5**
54
A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be- of an administered dose, based on mass-balance or in comparison to an intravenous reference dose.
> 90%
55
A drug product is considered to be RAPIDLY DISSOLVING when - of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of - buffer solutions
> 85%
<900 ml
56
Class I IVIVC expectations
IVIVC expected if **dissolution rate is slower than gastric emptying**
| dissolution rate slower than gastric emptying
57
Class II IVIVC expectations
expected if in vitro dissolution is similar to in vivo dissolution rate
| in vitro similar to in vivo
58
Class III IVIVC expectations
**absorption/permeability is rate determining and limited** or no IVIVC
59
Class IV IVIVC expectations
limited or no IVIVC
60
Mean plasma concentration
time profiles observed after placing an aqueous solution (6 mL) containing 150 mg of ranitidine hydrochloride into the stomach
| putting ranitidine HCl into stomach
61
Remifentanil
ultra short-acting opioid **narcotic analgesic**
which **slows gastric emptying**
62
Can the rate of gastric emptying be a controlling step in the speed of drug absorption?
Yes- because absorption is greater in the small intestine
63
When do absorption windows occur?
intestinal absorption of a drug is mediated by uptake transporters
location of the transporters is limited to a relatively small area of the intestinal surface
64
When absorption windows are present, when will bioavailability be poor?
when dosage form does not release the drug **before **it passes the absorption window
65
Delay gastric emptying
**Prolonged residence time of an acid labile drug in the stomach**
If drug stable in stomach and drug enters small intestine dissolved, then increased rate of absorption and increased extent
66
Increase intestinal transit time
If drug stable, then likely increase extent and could delay rate
67
Food, particularly a heavy meal, - the gastric transit time of small pellets
**increases**
68
Blank affects the small intestine transit time.
neither the food nor the physical size of the solid
| nothing
69
Double Peak Phenomenon
For a drug with high water solubility, dissolution of the drug occurs in the stomach, and partial emptying of the drug into the duodenum will result in the first absorption peak.
A **delay in stomach emptying** results in a second absorption peak as the remainder of the dose is emptied into the duodenum.
70
Enterohepatic circulation
process whereby a drug or a metastable metabolite thereof in the **liver **is secreted into the **bile,** stored in the **gall bladder**, and subsequently released into the **small intestine**, where the drug can be reabsorbed back into circulation and subsequently returned to the liver
| LBGS; recycling
70
Hepatic drug clearance (CLH)
volume of blood from which drug is **removed completely **by the liver per unit time
71
The hepatic clearance of low ER (or low CL) drugs is mainly influenced by changes in - and -
blood binding (i.e. fu)
intrinsic hepatic clearance (i.e. CLint)
71
The hepatic clearance of high ER (or high CL) drugs is - limited
blood flow
72
Low ER drugs
drugs with **“Capacity-Limited” **hepatic clearance
have **low degree of first “pass metabolism”**
73
High ER drugs
drugs with **"Flow Dependent"** hepatic clearance
will **undergo extensive “first pass” metabolism**
74
Brand v. Genetric Active ingredient
no difference
75
generic drug
medication created to be the same as an already marketed brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use.
75
Brand v. Genetric price
brand- higher in cost
76
Brand v. Genetric insurance coverage
Brand- covered if no generic form exists
generic- normally always covered
77
Brand v. Genetric Inactive Ingredients
Brand- tested and approved by** FDA**
Generic- may differ but accepted by **FDA**
78
Brand v. Genetric Strength/Dose
no difference
79
Brand v. Genetric Appearance/Look
brand: drugs are standard in size, color, packaging, etc.
Generic: packaging and look itself my be different
80
Hatch-Waxman Act 1984 Purpose
**bioequivalence**
81
The 1984 action by Congress has eliminated safety and effectiveness testing requirements for generic drugs and has thus reduced the confidence that physicians and patients can have in the safety and effectiveness of generic drugs.
mythical statement
82
FDA requires pioneer drug manufacturers to study their drugs in thousands of patients, but it requires generic firms to test their drug products in 20 or 30 healthy volunteers.
mythical statement
83
Plasma level studies (measuring the amount of a drug in the blood) do not show how a drug acts at the site of action and therefore are not indicative of how well a drug will perform.
mythical statement
84
Bioequivalence studies are performed in healthy volunteers, who are usually in their twenties. However, many of the drugs are used primarily in elderly patients. These elderly patients can be expected to absorb and metabolize the drug differently than do the healthy volunteers. Therefore, bioequivalence testing is not an indicator of how the drug will perform in patients.
mythical statement
85
The FDA applies lower standards for generic approval compared to those required for the brand name products.
mythical statement
86
The FDA has no written rules or criteria for how it determines bioequivalence.
mythical statement
87
Because the FDA allows a variation of + 20 or 30% in the blood levels between the brand name and the generic products, generics may differ by as much as 60% from each other.
mythical statement
88
Brand-name drugs are made in modern facilities, while generics are often made in substandard facilities. Thus, generics are of generally inferior quality.
mythical statement
89
In calling drugs bioequivalent, the FDA overlooks documented cases of bioinequivalence
mythical statement
90
Patients using generic products are more likely to suffer adverse reactions than those taking the brand name drug.
mythical statement
91
A drug product shall be considered to be bioequivalent to a list drug product if the
**rate and extent of absorption** of the drug product do not show a significant difference from that rate and extent of absorption of the listed drug product when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple dose.
92
order of preference for bioequivalency testing is established:
1. **In vivo** measurement of **active moiety** (or moieties) in biological fluids
2. **In vivo** **PD** measurements
3. **In vivo** **clinical comparison**
4. In vitro comparison
| MPC
93
Bioequivalence criteria
1. The antilog of the mean difference of **log AUC** from the two treatments is between 0.8 and 1.25
2. The antilog of the mean difference of **log Cmax** from the two treatments is between 0.8 and 1.25
3. The **90% confidence interval of the mean difference of log AUC ratio** is between 0.8 and 1.25
4. The 9**0% confidence interval of the mean difference of log Cmax ratio** is **between 0.8 and 1.25.**
Failure of any ONE of these four criteria would mean that the two products are NOT bioequivalent.
94
TAKE HOME POINTS: Bioequivalency decisions depend on how the trials are designed. - and - lead to a better chance of two products being declared bioequivalent.
**Larger test populations** (n)
**lower variability** in the data (lower SD)
PHM 531
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