Absorption of drugs

ABSORPTION OF DRUGS
DR NIKITA INGALE
JR1,
DEPARTMENT OF PHARMACOLOGY
GMC NAGPUR
23/08/17 ABSORPTION OF DRUGS 1

Definition
Mechanism of action
Factors affecting it
Bioavailiability and
Bioequivalence
23/08/17ABSORPTION OF DRUGS
OVERVIEW-

Study of time course of drug
absorption, distribution ,
metabolism & excretion and their
relationship with its therapeutic
and toxic effects of drug
Pharmacokinetics

PHARMACOKINETICS
DISPOSITIONABSORPTION
ELIMINATIONDISTRIBUTION
METABOLISM
EXCRETION

Pharmacokinetic Process
Administration
Absorption
Distribution
Metabolism
Excretion
Removal
oral
Unchanged
reabsorbe
d
I V
I V

DEFINITION-
Process of movement of unchanged
drug from site of administration to
systemic circulation
ABSORPTION-

Cell membrane structure-
A) ABSORPTION THROUGH GIT-

Mechanism of drug
absorption
•Passive transport
•Passive diffusion
•Pore transport
•Ion-pair transport
•Facilitated diffusion
•Active transport
•Primary
•Secondary
(A)Transcellular
/ intracellular

•Through tight junction
•Persorption
(B)Paracellular
/ Intercellular
•Pinocytosis
•Phagocytosis
(C)Vescicular /
Corpuscular

Mechanism of drug absorption

 Non – energy dependant
 Major process for absorption of
90% of drugs
 Driving force- Concentration or
electrochemical gradient
 It follows Fick’s first law of
diffusion
Passive diffusion

 Responsible for transport of molecules into cells
through the protein channels in cell membrane
 Driving force- hydrostatic force or osmotic
differences across membrane
 Important in absorption of low molecular weight
compounds up to 400 daltons
 Eg- removal of drug from CSF
Pore transport/ convective
transport/ bulk transport/
filtration

 Penetration of membrane by forming reversible
neutral complexes with endogenous ions of GIT (
mucin )
 Example propranolol with oleic acid
Ion-pair transport

 Carrier (component of membrane) binds reversibly
or non covalently with solute molecules and
complex traverses to other side of membrane
1. Carriers – no directionality
2. Structure specific
3. Capacity limited
Carrier mediated
transport

 Carrier mediated
transport operates
down the
concentration
gradient (downhill
transport)
 Driving force –
Concentration
gradient
 No energy
expenditure 23/08/17ABSORPTION OF DRUGS
Facilitated diffusion

 Requires energy in form of ATP
Primary active transport
direct energy required
1} Ion transporters
Transporting ion in/out cell
Example - Organic anion – provastatin, atorvastatin
Organic cation – diphenhydramin
2} ABC [ATP binding cassette] transporters
small foreign molecules out of cells ( exsorption )
Example – P – glycoprotien in pumping anticancer
drugs out of the cell.
Active transport

Secondary active transport
No direct energy requirement
1] Symport ( co – transport)
Transport of both molecules in same
direction
Example - H+ coupled peptide transporter
(PEPT1) implicated in intestinal
transport of beta lactam antibiotics
2] Antiport (counter – transport)
Movement in opposite direction
Example - expulsion H+ using Na+
gradient in kidneys

CHARACTE
RISTICS
SIMPLE
DIFFUSION
FACILITATE
D
DIFFUSION
ACTIVE
TRANSPOR
T
1] incidence Commonest Less common Least common
2] process Slow Quick Very quick
3]movement Along gradient Along gradient Against
gradient
4] direction Bidirectional Bidirectional Unidirectional
5]carrier No No Needed
6]energy No No Required
7]selectivity Absent Present Present
8]metabolic
inhibition
Cannot block it Cannot block it Can block it

Paracellular / Intercellular
Through the junction between G I epithelium
Minor importance in drug absorption

Vesicular / corpuscular transport
Energy dependant
Only mechanism where drug does not have to be
in aqueous form
Responsible for uptake of
Fats and starch
Oil soluble vit like A,D,E,K
Vit B12
insulin

Pinocytosis :
(cell drinking)
uptake in fluid state
e.g. oral polio,
botulism toxin
Phagocytosis
cell eating

Combined absorption mechanism
•passive as well as
•activeCardiac
glycosides
•passive diffusion,
•facilitated diffusion
and
•endocytosis
Vit B12

Chain of events of absorption :
Disintegration
Deaggregation and
subsequent release
Dissolution of drug
Absorption

Absorption from common routes of drug
administration-
• Buccal / sublingual
• Oral
• RectalEnteral
•Intravenous
•Intramuscular
•Subcutaneous
Parenteral
•intranasal, inhalational,
intravaginal, intradermalTopical

Buccal/Sublingual Administration
Bucc
al
Sublingua
l

In buccal route the medicament is placed between
the cheek and the gum.
In sublingual the drug is placed under the tongue.
Barrier to drug absorption from these route is
epithelium of oral mucosa.
Absorption of drug is by passive diffusion.
23/08/17
Examples—
Antianginals – nitrates
Antihypertensive - nifidipine
Analgesics – morphine
Estradiol and oxytocin

RECTAL ABSORPTION-

1]Important route for children & geriatric patients
2]Drugs administered as solution [micro enemas]
and suppositories
3]Highly vascularised but slower absorption due
to limited surface area
RECTAL ABSORPTION-

Advantages Disadvantages
Useful in patients having nausea &
vomiting
Chances of rectal inflammation
50 % of drug bypasses 1st pass
effect
Irritating suppositories promote
defecation & drug loss
Useful for gastric irritant drugs Limited surface area – slower
absorption
Cyp 3A4 is present in lesser
amount in lower intestine
Faecal matter retards absorption
Inconvenient & embarrassing to
patient
RECTAL ABSORPTION-

Examples – Bisacodyl & glycerine
suppositories

RATE OF ABSORPTION FROM FASTEST TO
LOWEST-
SUBLINGUAL > RECTAL > ORAL

B) ABSORPTION THROUGH OTHER NON-ORAL
ROUTES:
INTRAMUSCULAR
SUBCUTANEOUS
INTRAVENOUS
INTRA-
ARTERIAL
INTRA-
THECAL
PULMON
ARY
OCCUSER
TS
INTRA-
OCULAR
INTRA-
NASAL

sites-
- Deltoid, gluteal mass and
vastus muscle
Example-depot injection of
testesterone, haloperidol depot
injections
23/08/17 ABSORPTION OF DRUGS
INTRAMUSCULAR
ROUTE-
LIMITATIONS-
1. Irritant drugs can’t be given
2. Large volume can’t be given
(max 5 ml can be given)
3. Chances of abscess formation
4. Chances of nerve damage

Absorption - Slower than IM sites
due to poor perfusion
Used – 1. When slow response is desired
2. Drug degrade when taken orally
Limitations – 1. Irritant drugs can’t be given as
necrosis occurs
2. Large volume can’t be given(max -1ml)
Example - Insulin & low molecular weight heparin
SUBCUTANEOUS
ROUTE-

Site- in lumen of the artery
-large amount of drug delivered at desired site
-Diagnostic purpose- coronary angiography &
cerebral angiography ( radiopaque contrast media)
,many anticancer drugs.
INTRA-ARTERIAL
ROUTE-

Site- subarachnoid space
Local rapid effects of drugs on meninges and spinal
cord
Limitation – strict aseptic condition & great
expertise is required
Examples – xylocaine in Spinal anesthesia, acute
CNS infections (amphotericin –B)
INTRATHECAL ROUTE-

Site- inspiration by nose or mouth
Extremely rapid absorption due to-
Large surface area of alveoli
High permeability of alveoli
Rich perfusion
Limitation- bronchial irritation
Example – Oxygen, general anesthetics, salbutamol,
beclomethasone, cromolyn sodium
PULMONARY ROUTE-

-For local effects as mydriasis, miosis, anesthesia
and glaucoma
-Sterile aqueous solution of drug
-Cornea – Major barrier - both hydrophilic and
lipophilic characters.
-Drug should posses biphasic solubility
INTRAOCULAR ROUTE-

-Elliptical micro units (drug reservoir)
-Drug -delivered slowly at steady rate
-Example – pilocarpine occuserts
OCCUSERTS-

Intended to act locally e.g.
infection, contraception
Used for systemic delivery of
contraceptive and other steroids.
Factors effecting—
-vaginal secretions.
-microbes at vaginal lumen.
Examples-ointments, foams , pessaries
of metronidazole 23/08/17ABSORPTION OF DRUGS
Vaginal Administration

TOPICAL ABSORPTION-

-Largest organ of body
-Weight 2kg & area 2 m2
-Skin is made up 3 distinct layers
1]Epidermis- Non vascular
2]Dermis- Highly vascular
3]Subcutaneous fat tissue
SKIN-

Factors that influence passive
percutaneous absorption of drugs
are-
1]Skin conditions
2]Composition of topical vehicle
3]Application procedures or application condition
Principal barrier is stratum corneum

1]Thickness : Very slow from foot & palm (thickened
stratum corneum)
2]Hair follicles : Rapid from Scalp (numerous hair follicles)
3]Trauma : Destruction of stratum corneum promote
absorption e.g. Cuts, rashses ,inflammation, mild burns
4]Hydration of skin : Soaking of skin in water (using
emollients, plastic film or dressing )promote hydration of
skin and ↑drug absorption
5]Age : elderly more prone for allergy
SKIN CONDITIONS--

Vehicle or base :
In which drug is dissolved than dispersed
promotes absorption
Permeation enhancers :
Incorporation of chemicals like propylene glycol ,
azone promote absorption
COMPOSITION OF TOPICAL
VEHICLES --

1]Rubbing : ↑ blood circulation to area of
application and thus ↑ drug permeation
2]Occlusion : Trapped moisture endogenous or
exogenous → hydrates stratum corneum →
promotes drug permeation
3]Loss of vehicle : Loss of vehicle ↓ transdermal
permeation
APPLICATION CONDITIONS--

Remain superficial - Sunscreen , insect repellants
, cosmetics
Delivery to appendages – Anti- infective , antiacne
, antiperspirants /hair removers
Delivery to local tissues – Antimitotics , anti-
inflammatories , antihistamines , anaesthetics
Systemic delivery – Clonidine , scopolamine,
nicotine , fentanyl , oestradiol
EXAMPLES--

TRANSDERMAL DRUG
DELIVERY-
When topically applied drugs are meant to
produce systemic effects, the mode of
administration is called Transdermal or
percutaneous drug delivery.
Useful for drugs with short oral availability and
short action
Example- Nitroglycerine
Estradiol, Betamethasone

Factors influencing GI absorption of drugs
Physicochemical
properties of
drug
Pharmaceutical
/
Pharmaco-
technical factors
Patient
related
factors

Particle size
↓ particle size  Surface area ↑ Drug dissolves
rapidly
Eg-Micronisation of poorly
soluble drugs like griseofulvin,
chloramphenicol

Crystal form
-Absorption rate depends on its crystalline
form
Amorphous chloramphenicol
palmitate > crystalline
chloramphenicol palmitate

Solid
dosage
form
Solid
drug
particals
Drug in sol at
the absorption
site
Drug
in the
body
Disintegration
/deaggregatio
n
Dissolution
Permeation
across the
biomembrane
Rate limiting
step for
lipophilic drugs
Eg.
Griseofulvin,
spironolactone
Rate limiting
step for
hydrophilic
drugs
Eg. Cromolyn
sodium,
neomycine
ABSORPTION OF DRUGS 23/08/17
DRUG SOLUBILITY AND DISSOLUTION RATE-

Formulation of drug
1) Excipient is a pharmacological inert
substance but can modify absorption &
bioavailiability
2) Ca/Mg never to be combined with
tetracyclines  forms insoluble cholates
3) Calcium lactate used as adjuvant in
calciferol can cause hypocalcemia
4)Use of calcium lactate/ lactose with
phenytoin decreases bioavailability

Vehicle- major component of liquid, oral and
parenteral dosage form
Diluents – commonly added to tablet and capsule
formulations to produce the necessary bulk
Commonly used excipients
Binders and granulating agents – used to hold
powders together to form granules or promote
cohesive compact for directly compressible materials
and to ensure that tablet remains intact after
compression

Disintegrants – agent overcome cohesive strength of tablet
and break them up on contact with water(mostly hydrophillic)
Lubricants – added to tablet formulation to aid flow of granules,
to reduce interparticle friction and sticking or adhesion of
particles
Coatings – Deleterious effects of various coatings on drug
dissolution
Enteric coat> sugar coat> non enteric coat

The more complex a dosage form,
greater the number of rate
limiting steps and greater the
potential for bioavailability
problems
Nature & type of dosage form

ABSORPTIONRATE
Tablet
Capsule
Powders
Suspension
Emulsion
Solution
Granules
Fine
partials
Dissolution
Drug in sol
In blood
Slowest
Fastest
deaggregation
Dissolution
Disintegration
absorptio
n

1 • Age
2 • Gastric Empting
3 • Intestinal Transit
4 • GI pH
5 • Blood Flow to GIT
6 • Diseased State
7 • GI Content
8 • First pass effect

Gastric emptying and git motility
-Factors that accelerate gastric emptying ↑
bioavailability of drugs
Gastric emptying
promoted by
1) Fasting
2) Anxiety
3) Lying on right side
4) Hyperthyroidism
5) Gastro kinetic
drugs
Gastric emptying
retarded by
1) Fatty diet
2) Endogenous
depression
3) Lying on left side
4) Pyloric stenosis
5) Hypothyroidism
6) Drugs - Atropine

Intestinal transit
the residence time of drug in small intestine.
Small intestine is major site for drug absorption
:long intestinal transit time is desired for complete
drug absorption.
Residence time depends upon intestinal motility
or contraction.
Peristaltic contraction promote drug absorption by
increasing the drug intestinal membrane contact,
by enhancing drug dissolution.
Metaclopropamide, laxative, promote intestinal
transit time & enhance absorption of rapidly
soluble drugs. 23/08/17ABSORPTION OF DRUGS

Delayed intestinal transit is desirable for:
Drugs that release slowly (sustained release)
Drugs that dissolve only in intestine (enteric coated)
Drugs which are absorbed from specific site in the
intestine (Lithium carbonate, Vitamin B)
When drug penetrate the intestinal mucosa very slowly
(e.g. acyclovir)
When absorption of drug from colon is minimal.

1st pass effect
↓ - bioavailability and
therapeutic response
Examples
23/08/17 ABSORPTION OF DRUGS
1] L dopa
2] Morphine
3] Nitroglycerine
4] Isosorbide
nitrate
5] Propranalol

BIOAVAILABILITY

--Rate and extent of absorption of
unchanged drug from its dosage
form
Bioavailability of drugs

Determined by concentration-time curve in blood or
by its excretion in urine
Measurement Of Bioavailability

-- Peak plasma concentration (C max)
--Time to attain peak plasma concentration
(T max)
--Area under the curve (AUC) : Reflects extent of absorption
--Drug bioavailability % =AUC (oral)/ AUC (i.v.) × 100
CHARACTERISTICS OF GRAPH

Bioequivalence
Chemical equivalence
Clinical equivalence
Therapeutic equivalence
EQUIVALENCE TYPES-

--Bioavailability after IV administration is 100%
--Close to 100% with subcutaneous or
intramuscular injection due to precipitation at site
of administration
--Difference in bioavailability less than 25% no
significant effect on clinical outcome
BIOEQUIVALENCE-

-2 or more dosage forms of same drug contain
same labelled quantities of drugs as specified in
pharmacopaie
-2 brands may be chemically equivalent but may
not be bioequivalent
CHEMICAL EQUIVALENCE-

--If they provide identical
in vivo pharmacological
response ( control of
symptoms or disease)
THERAPEUTIC
EQUIVALENCE-
CLINICAL
EQUIVALENCE-
--Structurally different drugs
provide same therapeutic or
clinical response as another
drug
--Example - trifluperazine
(phenothiazine group) &
Haloperidol (butyrophenone
group) may be therapeutic
equivalent in schizophrenia

 Absorption is very important aspect of
pharmacokinetic study of drug
 Knowledge of absorption helps us to decide route
of administration
 Knowledge of absorption gives us idea about
bioavailability of drug which in turn helps us in
deciding dose
 Pharmaceutical industry utilises knowledge of
absorption to prepare different formulation
Summary

1)HL Sharma & KK Sharma.pharmacokinetics.sharma and
sharma’s principles of pharmacology.3rd
edition.hyderabad,Paras Medical Publisher;2017.p
2]D.M Brahmankar & Sunil B. Jaiswal.Absorption of
drugs.Biopharmaceutics & pharmacokinetics a treatise.1st
edition.Delhi,Vallabh prakashan;2008.p5-75
REFERENCES-

Absorption of drugs

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