Absorption & Distribution
Content
General Pharmacology
• Absorption
and bioavailability
• Mechanisms
of drug transport
• Factors
affecting absorption and bioavailability of drugs
• Process
of drug distribution
• Protein
binding
• Volume
of distribution
• Barriers
to drug passage
Intended Learning Outcomes
At the
end of this lecture, student will be able to
• Explain
absorption and bioavailability
• Describe
mechanisms of drug transport
• Explain
the factors affecting absorption and bioavailability of drugs
• Explain
the process of drug distribution
• Describe
protein binding
• Explain
volume of distribution
• Outline
the barriers to drug passage
Absorption and Bioavailability
• Drugs
– systemic circulation
• Drugs
divided into 3 groups:
– Non
ionised, non-polar, lipid soluble
– Ionised
polar, water soluble
– Partly
ionised and non ionised
Absorption Process
Molecules cross biological membrane by:
• Simple
or passive diffusion
– Lipid
diffusion
– Aqueous
diffusion
• Transport
using transmembrane transporters
– Uptake
transpoters
– Efflux
transporters
Transport using transmembrane transporters
• Facilitated
diffusion
– SLC
moves down the chemical or electrical gradient
• By
active transport
– Carrier
protein against electrical or chemical gradient
– Via
ion channels
– By
endocytosis
Bioavailability
• Amount
or % of drug absorbed from given dosage
• Following
non vascular administration
• Available
at the desired site of action
• IV
bioavailability – 100%
• Valid
test for F: level of drug in biological fluid
• Measurable
parameter of therapeutic efficacy
AUC after oral
dose
• F =
—————————- X 100
AUC after IV dose
AUC
Drug
• Pharmaceutically
equivalent:
– Same
active ingredients
– Identical
in strength, conc., dosage forms
·
Bioequivalent:
– Rate
and extent of F
– Active
ingredients in 2 formulations
– Do
not differ significantly
– Likely
to be therapeutically equivalent
Factors affecting drug absorption and bioavailability
Drug related
• Physical
properties of the drug
• Nature
of the dosage form
Patient related
• Physiological
factors
• Pharmacogenetic
factors
• Disease
states
Physical properties
• Physical
state
• Lipid/
water soubility
Nature of Dosage forms
• Particle
size: Reduction – dosage can be reduced
• Disintegration
time: Break up into drug granules
• Dissolution
rate: Drug goes to solution
• Formulation:
Diluents, fillers
Physiological Factors
• Ionisation
• pH
of the GI fluid and blood
• GI
transit time
• Enterohepatic
cycling
• Area
of the absorbing surface and local circulation
• First
pass elimination
• Presence
of other agents
Distribution
• Drug
enters/ passes through several body fluid compartments:
– Plasma
– Intertitial
fluid compartment
– Transcellular
fluid compartment: GI, Bronchi, CSF
– Intracellular
fluid compartment
• Apparent
volume of distribution: volume into which the total amount of drug in the body
appears to be uniformly distributed
• Vd
(L) = Total amount administered / Plasma Conc
• Drugs
penetrate into & exist in more than one compartment
• Rate
of passage depends on pH & pK of body compartment
• pK
( Dissociation constant)
• Non
– ionised: readily cross membrane, larger Vd
• Highly
protein bound: low Vd
• Vd=
16 L – distributed in ECF includes plasma
Volume of distribution
• If
Vd= 42 L
• Exceeds
total body volume
• Possibility
of drug accumulation in tissue
• Digoxin
(420 L) : Accumulation in skeletal muscle
• Chloroquine
(13000 L) : Conc in liver
Distribution of drugs
• Total
body water – small water soluble (Alcohol)
• E.C
space – large water soluble (Mannitol)
• I.V
space –
Very large, strongly protein bound (Heparin)
• Body
fat – Highly lipid soluble (Thiopentone)
• Bones
– Fluoride, lead
Protein
binding of acidic and basic drugs
|
Acidic drugs to albumin |
Basic to α1 acid glycoprotein |
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Protein
binding
• Restricted
to vascular compartment
• Temporary
storage of drug
• Makes
drug longer acting
• Plasma
concentration refers to bound and free form
• Displacement
interactions
– Salicylates
displace sulfonyl urea, methotrexate
– Indomethacin,
phenytoin displaces warfarin
To tissue proteins
• Digoxin
• Emetine
Miscellaneous
• Steroids
– Transcortin
• Thyroxine
– α Globulin
Drug
storage
• Skeletal muscle, heart: Digoxin,
emetine
• Kidney: Digoxin, chloroquine
• Brain: Chlorpromazine, isoniazid
• Bone, teeth: Tetracycline, heavymetals
• Thyroid: Iodine
• Retina: Chloroquine
• Iris: Ephedrine, atropine
• Liver: Chloroquine, tetracycline
• Adipose tissue: Thipentone, DDT
Termination
of drug effects
• By
biotransformation and excretion
• By
redistribution
• Greater
lipid solubility – faster the redistribution
• Eg.
Thiopental redirtribution
Barriers to
drug passage
• Placental
barrier – incomplete
• Blood
brain barrier
• Blood
CSF barrier
Summary
• Absorption: Process by which the drugs
enter the systemic circulation
• Bioavailability: Amount or % of drug
absorbed from given dosage
• Drug transport: Passive diffusion,
facilitated transport
• Factors affecting absorption and
bioavailability: Physical properties of the drug, nature of the dosage
form, physiological factors, pharmacogenetic factors and disease states
• Drug transport: Passive diffusion,
facilitated transport
• Acidic
drugs bind to albumin
• Basic
drugs bind to alpha 1 acid glycoprotein
• Apparent volume of distribution: volume
into which the total amount of drug in the body appears to be uniformly
distributed
• Greater
lipid solubility – faster the redistribution (Eg. Thiopental redistribution)
