Drug Absorption And Routes Of Administration

Question 1

what are the different physical states of a drug

Answer 1

liquid : solution, suspensions, emulsion

gas : sprays, aerosols

semisolid : creams, ointments, gels, pastes

solid : powders, tablets, suppositories.

Question 2

what are the different routes of administration

Answer 2

1) parental:

IV— aqueous solution

IM,SC,ID,IP— Can be aqueous, oily or even
solid (e.g., implants)

2)through the skin

dermal (topical)
transdermal(systemic)

3) through the mucosal membranes
– Oral: the most important and the most popular
route of administration
– Buccal: adhesives tablets
– Sublingual: tablets
– Nasal: sprays and inhalers
– Rectal: suppositories
– Vaginal: suppositories, rings

Question 3

Transdermal delivery is difficult to achieve due to
the presence of the stratum corneum barrier.
• For the ideal transdermal controlled drug
delivery system: the drug release and uptake is
controlled by the dosage forms and not by the
stratum corneum.

Question 4

what are the factors that affect the oral route

Answer 4

1. Transit time in the GIT: may vary considerably (with the
   gastric residence time being the most variable)
   • Between patients and within the same patient
   • The physical state of the dosage form (liquid versus
   solid)
   • Fasted and fed state of the patient.
2. pH condition: variation in pH may affect
   • Stability
   • Ionization state
   » Solubility
   » Partition coefficient (permeability)
3. First-pass metabolism

Question 5

what are the routes of administration according to the FDA

Answer 5

1. Topical: local effect, substance is applied directly
   where its action is desired.
2. Enteral: desired effect is systemic (non-local),
   substance is given via the digestive tract.
3. Parenteral: desired effect is systemic; substance is
   given by routes other than the digestive tract.

Question 6

what are the different topical drugs

Answer 6

– Epicutaneous (application onto the skin): e.g. allergy
testing, typical local anesthesia
– Inhalational: e.g. asthma medications
– Enema: e.g. contrast media for imaging of the bowel
– Eye drops (onto the conjunctiva): e.g. antibiotics for
conjunctivitis
– Ear drops: such as antibiotics and corticosteroids for
otitis externa
– Intranasal route (into the nose): e.g. decongestant
nasal sprays
– Vaginal: e.g. topical estrogens, antibacterials

Question 7

what are the different parental drugs

Answer 7

– Intravenous (into a vein)
– Intraarterial (into an artery): e.g. vasodilator drugs in the
treatment of vasospasm and thrombolytic drugs for
treatment of embolism
– Intramuscular (into a muscle)
– Intracardiac (into the heart), e.g. adrenaline during
cardiopulmonary resuscitation
– Subcutaneous (under the skin)
– Intradermal, (into the skin itself) is used for skin testing
some allergens, and also for tattoos
– Intrathecal (into the spinal canal) is most commonly
used for spinal anesthesia and chemotherapy
– Intraperitoneal, (infusion or injection into the peritoneum)
e.g. peritoneal dialysis
– Intravesical infusion is infusion into the urinary bladder.
– Transdermal (diffusion through the intact skin)
– Transmucosal (diffusion through a mucous
membrane), e.g. insufflation (snorting) of cocaine,
sublingual nitroglycerine, buccal (absorbed through
cheek near gumline),
– Inhalational, e.g. inhalational anesthetics

Question 8

what is enteral administration

Answer 8

any form of administration that involves any
part of the gastrointestinal tract:
– By mouth (orally): many drugs as tablets, capsules, or
drops
– By gastric feeding tube: duodenal feeding tube
– Rectally: various drugs in suppository or enema form

Question 9

what are the drugs depending on their mechanism of relase

Answer 9

immediate—- fast onset

modified—- extended or delayed

Question 10

why do we modify a drug release

Answer 10

■ Increase stability of the drug
■ Increase safety of the drug
■Increase efficacy of the drug
■ improve therapeutic outcome of the drug treatment
■ Increase patient compliance and convenience of administration

Question 11

what is the order of dosage forms depending on their onset time

Answer 11

1– IV injection and infusions (why?)
2– IM and SQ
3– Oral solutions
4– Granules
5– Tablets and capsules

Question 12

what order does immediate release follows

Answer 12

first order

Question 13

how do we solve the drug has a short biological half life (fast elimination)  it will require frequent dosing  low
patient compliance

Answer 13

increasing the dosing or modifying the release

Question 14

what is a delayed release

Answer 14

Systems that are formulated to release the active
ingredient at a time other than immediately after
administration.
– They control where the drug is released
• When the dosage forms reaches the small intestine
(enteric coated)
• When the dosage forms reaches the colon (colon-
specific)

Question 15

when should we develop a modified release

Answer 15

• When the drug is degraded in the low pH environment
of the stomach.
• When there is a need to protect the stomach from
irritation by the drug

Question 16

what is an extended release

Answer 16

Allow for the drug to be released over prolonged time
periods
– By extending the release profile of the drug  the
frequency of dosing can be reduced.
– Very useful for treating chronic diseases when the
patient needs to take the medication for prolonged
periods of time.
– Can be achieved using
• Sustained release dosage forms
• Controlled release dosage forms

Question 17

what is sustained release (only in oral)

Answer 17

Maintain the release of the drug over a sustained
period, e.g., the release takes place throughout the
entire GIT
– This will reduce the Cmax and prolong the time
interval of drug concentration in the therapeutic range

Question 18

how can we achieve sustained release

Answer 18

By the use of suitable
polymers:
• To coat granules or tablets (reservoir system)
• To form a matrix in which the drug is dissolved or
dispersed (matrix system)

Question 19

What is the difference between sustained release and
controlled release dosage forms?

Answer 19

1-Controlled release dosage forms Also
offer a sustained release profile but they are designed
to lead to predictably constant plasma concentrations,
independently of the biological environment of the
application site.
 They are not just sustaining the release of the
drug, but they are actually controlling its
concentration in the body

(2) These systems are used in a variety of
administration routes: oral, transdermal, vaginal.

Question 20

what kinetics does controlled release follow

Answer 20

The release kinetics are usually zero order

– In the ideal controlled release dosage forms, the
release rate is of utmost importance as it should be
the rate-determining step for absorption of the drug
and thus, for the drug concentration in the plasma
and target site.

Question 21

remember the flatter the curve the better

Answer 21

flat is justice

Question 22

its better to have varying releases for the same drug , give some examples on the disease

Answer 22

– Insulin is needed in higher concentration after meals
– Blood pressure has been found to be higher in the
morning and after noon and drops off during the night
– Patients with rheumatoid arthritis suffer from pain
more strongly in the morning than at night
– Patients with osteoarthritis suffer from pain more
strongly at night than in the morning

Question 23

what is the targeted release form

Answer 23

• When less drug binds to its therapeutic target 
↓efficacy &↑toxicity
• Drug targeting aims to control the distribution of a drug within the body such that the majority of the dose
selectively interacts with the target tissue.

Question 24

what are the different types of targeting

Answer 24

1. Passive targeting: the drug delivery system
   utilizes the natural distribution mechanism
   within the body
2. Active targeting: the drug delivery system
   has targeting groups such as antibodies and
   ligands that bind a specific receptor on cells
   in order to direct the delivery system to the
   appropriate target tissue.

Question 25

the absorption is dependent on?

Answer 25

– The site of absorption
– The nature of the drug

Question 26

What is the epithelia

Answer 26

are tissues composed of one or more layers
of cells. The layers are supported by a basement
membrane which lies on top of the supporting
connective tissue.
•
They can be classified by their:
1. Shape:
– Squamous
- Columnar - cuboidal
2. Stratification (number of cell layers)
– Simple
- stratified
3. Specialization (some epithelia will have a
specialized function)
– Keratinized
- ciliated

Question 27

Give some examples on epithelia

Answer 27

Blood vessels: single layer squamous cells

Oral : single layer of columnar, with villi and microvilli to increase their surface area

Buccal: keratinized stratified squamous cells

Question 28

What is the mucus?

Answer 28

• Mucus is synthesized and secreted by goblet cells
• Mucus is viscous in nature and is composed of highly
glycosylated peptides known as mucins and inorganic
salts in water.
• Its main rule is to protect and lubricate the epithelial
lining.
• In drug delivery: mucus serves a physical barrier to
absorption.
Viscosity and thickness of the mucus layer and any
interaction that the drug or the delivery system may
have with the mucus must be considered.

Question 29

What are the drug absorption mechanisms in the transcellular route

Answer 29

1. Passive diffusion:
   •
   Involves diffusion of drug across the lipid bilayer
   of the cell
   •
   Driven by concentration gradient
   •
   The rate is governed by Fick’s law
   •
   Factors controlling the rate of diffusion include:
    Drug concentration
    Partition coefficient of the drug
    Area of absorptive tissue
   •
   The lipophilicity of the drug is of a particular
   importance as the drug must diffuse across the
   cell membrane
    An optimum logP is usually observed for
   passive diffusion.
2. Carrier-mediated transport:
   –
   Involves specific carrier proteins in the cell
   membrane
   –
   Can be classified into
    Facilitated diffusion: with the concentration
   gradient
    Active absorption: against the concentration
   gradient
3. Endocytosis:
   –
   Involves internalization of substances by engulfment
   of the cell membrane  forms a membrane-based
   vesicle with the cell called endosomes.
   –
   It allows for large molecules or particulates to enter
   the cell.

Question 30

What is the paracellular route

Answer 30

– Through the gaps between the cells
– Governed by passive diffusion
– Only for small molecules
– Can be enhanced by penetration enhancers which
damages the tight junctions  possible toxicity.

Question 31

What is the efflux

Answer 31

– Substances can be pushed back out of the cells by an
energy-dependent efflux system.
– There are various apical transmembrane proteins
which can transport drug out of the cell.

Question 32

How does the biological membrane work?

Answer 32

The main function of biological membranes is to contain
the aqueous contents of cells and separate them from an
aqueous exterior phase.
– To achieve this, membranes are lipoidal in nature.

Question 33

How do different compounds move through the membrane

Answer 33

nutrients to pass into the cell and waste
products to move out  biological membranes are
selectively permeable.

Question 34

How do water soluble compounds move through the membrane and how do the lipid soluble do

Answer 34

Membranes have specialized transport systems to assist
the passage of water-soluble materials and ions through
their lipid interior.

• Lipid-soluble agents can pass by passive diffusion
through the membrane from a region of high
concentration to one of low concentration.

Question 35

What is the biological membrane made of?

Answer 35

Biological membranes differ from polymer
membranes in that they are composed not of
polymers but of small amphipathic molecules:
– Phospholipids with two hydrophobic chains
– Cholesterol
– Sphingolipids
• All these components associate into lipoidal bilayers
in aqueous media.
• Embodied in the matrix of lipid molecules are
proteins which are generally hydrophobic in nature
 they are embedded in the matrix of lipid
molecules.
• Thus, the membrane has a hydrophilic exterior and
a hydrophobic interior.

Question 36

What is cholesterol

Answer 36

Cholesterol is a major component of most
mammalian biological membranes
– Its removal causes the membrane to lose its
structural integrity and to become highly
permeable.
• Cholesterol complexes with phospholipids and its
presence reduces the permeability of phospholipid
membranes to water, cations, glycerol and glucose.
• The shape of the cholesterol molecule allows it to fit
closely in bilayers with the hydrocarbon chains of
unsaturated fatty acids.
• The present consensus of opinion is that cholesterol
condenses and rigidifies membranes without
solidifying them

Question 37

What does the Flexibility of the membrane do?

Answer 37

giving them their ability
to re-form and to adapt to changed
environments.
• Biological membranes behaves as a
continuous hydrophobic phase through which
nonelectrolytes permeate.
• However, a fraction of the membrane may be
composed of aqueous channels which are
continuous across the membrane.
– That is, there are pores which offer a
pathway parallel to the diffusion pathway
through the lipid.

Question 38

What are pores

Answer 38

pores play a minor part in the transfer of
drugs
• Nevertheless, in the case of ions and charged
drugs such as the quaternary ammonium
compounds the pore pathway must be
important.
• These pores may be provided by the conjunction
of hydrophilic faces of proteins or the polar
heads of fatty acids and phospholipids
orientated in the appropriate direction.
• The fluid mosaic model, in particular, allows the
protein–lipid complexes to form either
hydrophilic or hydrophobic ‘gates’ to allow
transport of materials with different
characteristics

Question 39

Overall, membrane permeability is controlled by ?

Answer 39

– The nature of the membrane.
– Its degree of internal bonding and rigidity
– Its surface charge
– The nature of the solute being transported: Drugs
with little affinity for the membrane are unlikely to
permeate

Question 40

It has been also suggested that the permeability of the
lipid bilayer (hydrophobic in nature) is regulated by the
density of hydrogen bonding in the outer polar layers
of the membranes.
• These layers contain the phosphate, ammonium and
carboxyl head groups of phospholipids and the
hydroxyl groups of cholesterol.

Question 41

How does the membrane charge effects the distribution

Answer 41

egative
charge this might influence permeation.
• Studies has shown that membranes with unionized
surfaces (such as cellophane) or positively charged
surfaces such as collagen have different permeability
characteristics for ionic drugs.
– For example, the order of permeation in collagen
membranes is: unionised > anionic > cationic form. ..
– Collagen is rich with basic amino acids lysine,
arginine and histidine.
– The pKa of lysine and of arginine is about 10.
– At pH 7.4 (physiological pH) the basic groups in these
amino acids are positively charged.
– Therefore, cationic drugs will be repelled from the
surface

Question 42

How Does the basic structure affect absorption

Answer 42

• Tissues derived from the ectoderm (the epidermis, the
epithelium of nose and mouth, and the tissues of the
nervous system) have protective and sensory
functions.
• Tissues evolved from the endoderm, such as the
epithelium of the gastrointestinal tract, have evolved
mainly to allow absorption

Question 43

How does the lipophilicity effect the absorption

Answer 43

a plot of percentage absorption
versus log P would be parabolic with the
optimum value designated as log Po.
• By noting the values of optimal partition
coefficient for different absorbing membranes
and surfaces, one can deduce something about
their nature (how lipophilic it is)

Question 44

Why activity–log P plots has a parabolic
nature?

Answer 44

– Initially, increasing the lipophilicity tends to
improve the absorption via biological
membranes.
– However, when log P value becomes too high
 protein binding, low solubility and binding
to extraneous sites cause a lower measured
activity.

Question 45

How does the molecular weight effect drug absorption

Answer 45

The larger drug molecules are  the poorer
will be their ability to traverse biological
membranes.

Question 46

What is the Permeability and the pH–
partition hypothesis

Answer 46

• As most drugs are weak electrolytes  it is to be
expected that the unionised form (U) of either acids or
bases is the more lipid-soluble species and thus, it will
diffuse across the membrane
• On the other hand, the ionised forms (I) will be rejected.
• And since ionization is pH-dependent  drug absorption
and solute transport across membranes is considered as
well pH-dependent

Question 47

– In very broad terms, one would expect acids
to be absorbed from the stomach and bases
from the intestine

Question 48

Explain why it will be seen that
salicylic acid is absorbed from the rat
intestine at pH 8 (10% absorption),
although with a pKa of 3.0 it is virtually
completely ionized at this pH?

Answer 48

– Absorption and ionizations are both dynamic
processes and that the small amount of
unionized drug absorbed is replenished
– The bulk pH is not the actual pH at the
membrane

Question 49

Why the bulk pH is not the actual pH at the
membrane?

Answer 49

– The local pH at the membrane is lower due to the
attraction of hydrogen ions by the negative groups
of membrane components so that in the intestine:
• The bulk pH is around 7
• The surface pH is near 6

Question 50

it should be remembered that absorption and
ionization processes are dynamic processes.
– As the unionized species is absorbed  so the
level of [U] in the bulk falls  shift in equilibrium 
more of the unionized species appears in the bulk.

Question 51

What are the Problems in the quantitative application
of the pH–partition hypothesis

Answer 51

– Variability in pH conditions
– pH at membrane surfaces
– Convective water flow
– Unstirred water layers
– Effect of the drug
– Ion pairing
– Other complicating factors

Question 52

What does the variability in pH conditions effect

Answer 52

The variation in the stomach pH in human subjects is
remarkable.
– Keep in mind that each pH unit represents a ten-fold
difference in hydrogen ion concentration.
– While the normally quoted range of stomach pH is 1–
3  studies using pH-sensitive radiotelemetric
capsules have shown a greater spread of values,
ranging up to pH 7.
– This means that the dissolution rate of many drugs
will vary markedly in individuals  this is indeed one
of the reasons for individual-to-individual variation in
drug availability.
– The scope for variation in the small intestine is less 
although in some pathological states the pH of the
duodenum may be quite low owing to hypersecretion
of acid in the stomach

Question 53

pH at membrane surfaces how does it work

Answer 53

– This is expected because the hydrogen ion
concentration at the surface would be greater (and
hence pH lower) at the membrane surface as
hydrogen ions would accumulate near anionic
groups.
– The secretion of acidic and basic substances in
many parts of the gut wall is also a complicating
factor  the local pH in the region of the microvilli
of the small intestine will undoubtedly influence the
absorption of weak electrolytes.
• A drug molecule in the bulk will diffuse towards the
membrane surface and so meet different pH conditions
from those in the bulk phase.
• Whether or not this influences the extent of absorption
will depend on the pH changes and the pKa of the drug
in question.
• The negative charge on the membrane will attract small
cations towards the surface and small anions will be
repelled  one might thus expect some selectivity in the
absorption process.
• The use of microelectrodes revealed the existence of a
layer on the (rat) jejunum with a pH of 5.5 when the pH
of the bathing buffer was 7.2.
• The existence of this more acid layer has also been
demonstrated on the surface of the human intestine

Question 54

What does the convective water flow affect

Answer 54

– The movement of water molecules into and out of the
alimentary canal (GIT) will affect the rate of passage
of small molecules across the membrane.
– The reasons for water flow are the differences in
osmotic pressure between blood and the contents of
the lumen
– It can be appreciated that the absorption of water soluble drugs will be increased if water flows from the
lumen to the blood side across the mucosa (provided
that drug and water are using the same route).
– Water movement is greatest within the jejunum.
• Absorption of benzoic acid, salicylic acid, benzyl
alcohol and digitoxin has been shown to be
increased by efflux of water from the lumen and
decreased by flow into the lumen.
• One likely explanation is that when water flows
from the lumen the drug becomes concentrated
and drug absorption is increased because of the
more advantageous concentration gradient.
• Suggestions that water flow affects the
‘unstirred’ layers close to the membrane may
also be valid in interpreting these data.

Question 55

What is the unstirred water layer effect

Answer 55

– A layer of relatively unstirred water lies adjacent to
all biological membranes.
– The boundary between the bulk water and this
unstirred layer is indistinct but, nevertheless, it
has a real thickness.
– During absorption, drug molecules must diffuse
across this layer and then on through the lipid
layer.
• Compounds with a large permeability
coefficient (lipophilic compounds) may be
able to penetrate across cell membranes
much faster than they can be transported
through the unstirred layer.
• Under these circumstances diffusion
through the water layer becomes the ratelimiting step in the absorption process.

Question 56

What is the effect of the drug

Answer 56

– Drugs must be in their molecular form (dissolved)
before diffusional absorption processes take place.
– Bases are expected to be more soluble than acids in
the stomach, but it is impossible to generalize in this
way.
– Although the basic form of a drug as its hydrochloride
salt should be soluble to some extent in this medium
 this is not always so.
– Indeed, the free bases of (for example
chlortetracycline, dimethylchlortetracycline and
Methacycline) are more soluble than their
corresponding hydrochlorides in the pH range of the
stomach
• It has been shown that mean plasma levels
following administration of the free base and the
hydrochloride of these tetracyclines reflect the
differences in solubility  the bases giving
higher levels.
• The reason is most likely the influence of high
ionic strength on the solubility of the drug
substance (the common ion effect).
• As absorption of the tetracyclines takes place
mainly from the duodenum  it is vital that they
reach the intestine in a dissolved or readily
soluble form, as their solubility is low at the pH
conditions prevailing in the duodenum.
• The presence of buffer components in the
formulation also creates a pH
microenvironment around dissolving
particles which may aid drug dissolution.
• If dissolution is the rate-limiting step in the
absorption process  this will be
significant in determining absorption.
• Bulk pH will then give little help in
calculating the solution rate on the basis of
a knowledge of saturation solubilities in
bulk conditions.

Question 57

What is the ion pairing

Answer 57

– Phenomenon: quaternary ammonium compounds that
are ionized under all pH conditions, still show some
absorption.
– Explanation: The interaction of such drugs in the
charged form with other ions to form absorbable
species with a sufficient lipid solubility
– These ions which pair with drug are organic and their
origin is not clear.
– The significance of the phenomenon is that ion pairs
have the property of being almost neutral species 
so that the ion pair can partition into an oily phase
when its parent ionic species cannot.
• This property is important in drug absorption and
drug extraction procedures

Question 58

What are some other complicating factors

Answer 58

– The very high surface-area of the small
intestine also upsets the calculation of
absorption based on considerations of
theoretical absorption across identical areas
of absorbing surface.
– Changes in bulk pH: for example, on ingestion
of antacids or drugs such as cimetidine which
reduce gastric acid secretion.
• Cimetidine administration would show a
rise in resting pH from below 2 to near
neutrality.

– In the following cases, drugs might not be
absorbed in the way they are expected:
• Drugs that are unstable in the gastrointestinal
tract (for example, erythromycin).
• Drugs that are metabolized on their passage
through the gut wall
• Drugs that are hydrolysed in the stomach to
active forms (prodrugs)
• Drugs that bind to mucin or form complexes
with bile salts
• Drugs that are substrates for efflux system
• Drugs that are absorbed in micellar form

Question 59

 Why can’t the pH partition hypothesis be applicable to all
medicinal molecules? Why there are outliers to this
hypothesis?

Answer 59

• This hypothesis is not valid because it focus on the
ionization state of the molecule (dissociated versus
undissociated).
• However, the ionization state of the molecule is not
everything. It is only one aspect of the big picture, which
is the polarity of the molecule and the drug partitioning
from GIT fluid to intestinal mucosa and then from
intestinal mucosa to plasma.
• A balance in the polarity and thus, the partition
coefficient is required for faster penetration and transport
through the intestinal wall