Drug Absorption and Oral Route I and II Flashcards
1
Q
Process of absorption for Intramuscular and Subcutaneous injection
A
Tissues -> Circulatory system -> Metabolic sites -> Excretion
2
Q
Biopharmaceutics
A
is the study of the physicochemical properties of the drug and the drug product on the absorption of the drug to produce a desired therapeutic effect
3
Q
Physicochemical properties
A
- Molecular weight
- hydrogen bond donors and receptors
- salt form and polymorphs
- pKa
- partitioning coefficient
- solubility
- permeability
4
Q
Biopharmaceutics links
A
the in-vivo performance of the drug and the drug product to their in-vitro performance
5
Q
In-vivo performance
A
- PK studies
- Bioavailability
6
Q
In-vitro performance
A
- Dissolution rate
- Drug release rate
7
Q
Passage of orally administered drugs through the digestive system
A
Oral cavity -> Esophagus -> Stomach -> Small intestines -> Large intestine -> Rectum
8
Q
Dosage forms for oral administrationg
A
Oral solution : Absorption
Oral suspension or powder: Dissolution -> Absorption
Capsules and Tablets: Disintegration -> dissolution -> Absorption
9
Q
How can we evaluate the in-vivo performance of an orally administered drug>
A
- PK profile
- Onset (lag time and Tmax)
- Cmax
- AUC ( area under plasma conc. vs. time curve or exposure
10
Q
Bioavailability
A
a measure of the amount of drug that can reach systemic circulation
- can be portrayed by a plasma conc. vs time curve
11
Q
Looking at the curve the duration of action is when
A
the concentration is greater than the MEC ( minimum effective conc.)
12
Q
Bioavailability depends on
A
Hepatic extraction ratio (E)
F = 1-E or F=(1-E)Fabs
When F= bioavailable
properties of the drug and its route of administration
13
Q
The hepatic extraction ratio (E) is
A
a fraction of absorbed drugs (Fabs) which accounts for
- Not available for absorption
- Degraded function
- Metabolized and effluxed fractions
the fraction of the drug entering the liver in the blood
14
Q
Absolute bioavailability
A
in reference to the same drug administered by a single IV dosing
F= ( [AUC] po )/ Dpo
[AUC] iv / D iv
Oral tablet/ IV solution
15
Q
Relative bioavailability
A
in reference to the same drug administered by an oral solution
F= ( [AUC] solid / Dsolid )
[AUC] solution / D solution
Oral tablet / Oral solution
16
Q
Factors affecting oral drug absorption
A
Physicochemical factors
- Drug properties
Physiological factors of the GI tract
- Anatomic features
- Food factors
- Disease states and drugs
Dosage form factors
17
Q
Physiochemical Factors (solubility)
A
Solubility in the GI tract
- Drug ionization
pH changes along the GI tarct
Stomach pH 1-4
Duodenum pH 5-7
Ileum pH 7-8
Henderson-Hasselbach equation
18
Q
Ionized forms (less lipophilic) is
A
more soluble that the non-ionized form (more lipophilic)
19
Q
Physiochemical Factors (pH0
A
Acids
% ionization= 1
1+10^ (pKa -pH) *100
Bases
% ionization= 1
1+10^ (pH -pKa) *100
20
Q
Physiochemical Factors ( Acids and Bases chart
A
Acidic Drug. Basic Drug
Acidic Environment Unionized Ionized
Basic Environment Ionized Unionized
21
Q
Physiochemical Factors ( Dissolution)
A
Dissolution Rate : Noyes-Whitney equation
- Dependent on drug solubility
Smaller particle size -? Increased total surface area (S)
22
Q
Drug Transport
A
Drug must cross the mucous membrane of the epithelial cells of the GI tract
23
Q
Mechanisms of drug transport
A
- Paracellular transport
- Passive diffusion
- Carrier-mediated transport
- Efflux
24
Q
Paracellular Transport
A
passage of molecules between adjacent epithelial cells
- passes through the intercellular spaces between the cells
25
Passive diffusion
Also called simple diffusion
- passage or transport of molecules across a cell membrane from higher conc. to a lower conc. without using energy
- most common method for drugs to cross cell membrane
26
Carrier-mediated transport
- energy dependent pathway used by small hydrophilic molecules
- Uniport, Symport and Antiport
27
Efflux
flowing out of a particular substance or particle
28
Biological membranes
Biomolecule lipoid (fat containing) layer attached on both sides to a protein layer
29
Fick's first law of diffusion
describes the diffusion process under the condition of "steady state"
30
Steady state
when the concentration gradient does not change with time ( not time dependent)
31
Flux (J)
is the amount of material (M) flowing through a unit cross section (S) of a barrier in unit time (t). J is flux, g/ (cm^2 *s)
J = 1 dM
S dt
32
Ficks first law states that
flux (J) is proportional to the concentration gradient (dC/dx)
J = -D dC
dx
33
dM/dt is
the rate of diffusion (g/s)
34
P is the
permeability coefficient (cm/s)
35
S is the
cross section of the barrier (cm^2)
36
Cd is the
the concentration of the donor compartment
37
D is the
Diffusion coefficient ( cm^2 /s)
38
K is the
Partitio coefficient
39
h is the
thickness of the membrane
40
Cr is the
concentration of the receptor compartment
41
C1 is the
concentration within the membrane on the donor compartment side (g/mL)
42
C2 is the
concentration within the membrane on the receptor compartment side (g/mL)
43
Permeability coefficient (P)
P = DK/ h
related to lipophilicity and pH
44
Low permeability means
High solubility
45
High permeability means
Low solubility
46
When Diffusion coefficient (D) increases
permeability increases
47
When partition coefficient increases
permeability increases
48
When the thickness of the membrane (h) decreases
permeability increases
49
When permeability increases
diffusion rate increases
50
When cross section of the barrier S increases
diffusion rate increases
51
When Cd increases
diffusion rate increases
52
Facilitated diffusion
movement of a solute across the membrane from a region of higher to lower concentration assisted by transmembrane carriers, does not use energy
53
Active transport
a movement of solute across the membrane against a concentration gradient assisted by transmembrane carriers (enzymes/other agents)
- requires energy
54
Anatomic and Physiologic considerations
Features of the GI tract
- Stomach
- Small intestines
- Large intestines
Gastric pH
Gastric emptying time
Intestinal transit time
55
Gastric pH
Fasted -> 1.4 -2.1
Fed -> 4.3 -5.4
56
Low gastric pH means
- Slower dissolution for acids
| - Degradation of some drugs (penicillin)
57
Increases(High) in gastric pH
- Achlorhydria (pH is larger than 5.1 in mean and larger than 6.8 in women
- Intake of antacids, H2 receptor inhibitors or Proton Pump Inhibitor
-
58
Stomach gastric emptying time
Half life: 8-15 mins (liquid-fasted)
Half life: 30 min (liquid-small meal)
Half life: 70-130 min (solid meal)
Liquids empties faster than solids
59
Lying on left side will
decrease gastric emptying rate
60
Anxiety will
increase gastric emptying rate
61
Eating meals with fatty acids, fats, carbs and amino acids will
decrease gastric emptying time
Fats and high energy meals dramatically inhibit emptying
62
GI physiology - Small intestines
Duodenum, jejunum and ileum
Length: 6.25 m
Diameter: 4-5 cm
pH: 6.8
63
Bile acids are secreted into the_____ and re-absorbed into the _____
1. Duodenum
| 2. Ileum
64
Food Effect on Absorption
- presence in the GI tract can affect absorption of drugs
- is not always predictable
- is more pronounced when the the drug is taken:
20 mins before a meal, with a meal and within 2 hours after a meal
- high in calories and fat content are more likely to affect GI physiology
65
Examples of medications that increase absorption
Nitrofurantoin, Vitamin A derivatives, Riboflavin, Diazepam
66
Examples of medications that decrease absorption
```
Warfarin
Ethanol
Penicillins
Atenolol
Erythromycin
```
67
Examples of medications that have a delayed absorption
Aspirin
| Acetaminophen
68
The effect of delayed gastric emptying is less for
- solution formulations
| - suspension, powders and multiparticulate formulations
69
The effect of delayed gastric emptying is more for
- Tablets that has long disintegration time
- enteric coated tablets
- non-disintegrating tablets
70
Effect of disease states on drug absorption
- Intestinal blood flow
• congestive heart failure (CHF)- reduced
- Changes in stomach emptying time
• Long-standing diabetes - decrease
• HIV-Aids: increase
• Celiac disease: increase
```
- Changes in intestinal motility
• Parkinsons disease: slow
• Depression: slow
• HIV-Aids: fast (diarrhea)
• Celiac disease : fast
```
- Changes in gastric pH
- Changes in permeability of the gut wall and normal GI flora
• Inflammatory bowel disease (Crohn's)
71
Effects of drugs on absorption
- Decrease acid secretion in stomach
• Anticholinergic drugs (atropine, scopolamine)
•Proton pump inhibitors (Omeprazole, Lansoprazole)
- Reduce GI mobility
• Tricyclic antidepressant and antipsychotics (Phenothiazines)
• Anticholinergic (Propantheline bromide)
- Increase GI motility
• Metochlopramide
• Cisapride
72
Dosage forms can have effects on
disintegration, dissolution and absorbtion
73
Disintegration
- Immediate release (IR) tablets need to disintegrate in a short period ( <30 min) in stomach
- Delayed disintegration can result in a delay in onset of drug action (longer lag time)
- Non-disintegrating tablets
• Sustained release formulation
74
Special formulations with fast disintegration
```
Effervescent tablets (Alka Seltzer)
• Fast disintegration
• Release of CO2
```
Fast disintegrating tablets
• Suitable for pediatric and geriatric patients
75
Effect of dosage forms
Difference among oral solutions, suspensions and solid dosage forms in PK parameters
76
Noyes-Whitney equation
- describes rate of dissolution as a function of time
77
Diffusion layer
As a drug particle undergoes dissolution, the drug molecules on the surface are the first to enter into the solution, creating a saturated layer of drug solution that envelops the surface of the solid drug particle -> diffusion layer.
78
dc/dt
rate of dissolution
79
k
dissolution rate constant
80
S
Surface area of the dissolving solid
81
Cs
Saturation concentration of the drug in the diffusion layer
- Max solubility of the drug in the solvent
- Independent of time
82
Ct
Concentration of the drug in bulk solution at time t
- Bulk solution is a homogenous solution
- Dependent of time
83
The Noyes-Whitney equation cannot
describe the condition when the drug particle first encounters the solvent or when the particle is completely dissolved into the solve
84
Strategies to increase dissolution
1. increase the total surface area (S)
2. increase the solubility of the drug in the diffusion layer (cs)
3. increase the dissolution rate constant (k)
85
Surface area must be
solvent-accessible
86
Increasing surface area may be bad such as:
- Powders may entrap and absorb air; for tablet into which very minute holes are drilled, surface tension may prevent solvent penetration.
- Fine particles can float on solvent due to surface tension
87
Crystalline
definite identifiable shape, ordered and low energy state
88
Amorphous
no definite structure, not order, metastable state
89
How does physical forms of the drug affect solubility?
Some drugs are essentially inactive when administered in crystalline form, but when they are administered in the amorphous form, absorption from the G.I. tract proceeds rapidly, producing therapeutic response.
90
Polymorphism
substance that exist in more than one crystalline form
91
Salt form is
generally more soluble
92
State of hydration
the anhydrous form of an organic molecule is usually more soluble than the hydrated form
93
You can increase dissolution rate constant k by
Increasing the intensity of agitation of the solvent
•Increasing diffusion coefficient: For a given drug, the diffusion coefficient and usually Cs will increase with increasing temperature
•Reducing the viscosity of the solvent (by drinking water)
94
If the dissolution of a given drug particle is rapid or if the drug is administered as a solution,
the absorption rate depends mainly on its ability to traverse the membrane barrier
95
If the rate of dissolution for a drug particle is slow,
dissolution itself is the rate-limiting step
96
Absorption and BCS classes
```
class I - no special formulation strategy needed
class II - formulation strategy is very important
class III - formulation effect is limited
```
97
Class I
High solubility
| High permeability
98
Class II
Low solubility
| High permeability
99
Class III
High solubility
| Low permeability
100
Class IV
Low solubility
| Low permeability
101
Formulation Strategies that can improve absorption
1. for BCS class II - improve solubility
2. lipid-based systems - lipid solutions
3. solid lipid nanoparticles
4. self emulsifying or self micro emulsifying drug delivery systems (SEDDS or SMEDDS), 5. two cyclosporin formulations: Sandimmune and Neoral
102
Pharmaceutical equivalents
drug products that contain identical amounts of the identical active ingredient that is the same salt or ester of the same therapeutic moiety, in same dosage form
103
Pharmaceutical alternatives
drug products that contain the identical therapeutic moiety or its precursors but not necessarily in the same amount or dosage form
104
Bioequivalent drug products
pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the therapeutic moiety, can be single or multiple dosage forms
105
Therapeutic equivalents
pharmaceutical equivalents that provide essentially the same therapeutic effect when administered to the same individuals in the same dosage regimen
106
Counterfeit drug
drugs as those sold under a product name without authorization
- can apply to both brand and generic products where the identity of the source is mislabeled
107
Counterfeit products
may include products without the active ingredient, with an insufficient or excessive quantity of the active ingredient, with the wrong active ingredient or fake packaging
108
Health Risks of counterfeit drugs
- if no active ingredients: no treatment benefit
- if improper or incorrect ingredients:
- unexpected side effects
- allergic reactions
- worsening of medical condition
109
Gray market
aka parallel market
| - supply channel that is unofficial, unauthorized or unintended by the original manufacturer
