Pharmacokinetics

Nur Permatasari

Dosage

Plasma Site of
Concen. Action

Pharmacokinetics
PHARMACOKINETICS

Effects

Pharmacodynamics
PHARMACODYNAMICS

Systemic Availability

Therapeutics
index

Pharmacokinetics refers to the dynamics of

the movement of drugs through the biological
system, includes

Absorption
Distribution
Metabolism
Excretion

LOCUS OF ACTION
RECEPTORS

Bound

ABSORPTION

Free

TISSUE
RESERVOIRS

Free

Bound

Free Drug
Bound Drug

SYSTEMIC
CIRCULATION

BIOTRANSFORMATION

EXCRETION

In order to reach their site of action, drugs

have to pass through several membranes
transmembrane transport

Structureoftheplasmamembrane

Mechanismsoftransport

Passive diffusion: passage of drugs

through the lipid surface (major
mechanism of drug absorption)
Lipid-soluble

drugs
Small water-soluble drugs
Noncharged form of weak electrolytes

Membrane permeability versus lipid (olive

oil):water partition coefficient solubility
The greater the partition coefficient,
the higher the lipid-solubility of the
drug, and the greater its diffusion
across membranes.

Weak electrolytes and membrane permeability

Most drugs are small (MW < 1000) weak
electrolytes (acids/bases). This influences
passive diffusion since cell membranes are
hydrophobic lipid bilayers that are much
more permeable to the non-ionized forms
of drugs.
The fraction of drug that is non-ionized
depends on its chemical nature, its
pKa, and the local biophase pH...

Henderson-Hasselbach equation

pH - pKa = log base

acid
For an acidic drug: acid = HA; base = AFor a basic drug: acid = BH+; base = B

% Ionized vs. pH

For HA acids:
% ionization = 100/(1 + 10(pKa pH))

For BH+ acids:

% ionization = 100/(1 + 10(pH pKa))

Example: Percentage ionized pseudoephedrine HCl

(pKa 9.9) in the small intestine at pH 8.0?
% ionization = 100/(1 + 10(8.0 9.9))
% ionization = 100/(1 + 0.0126)
% ionization = 100/1.0126
% ionization = 98.76%

Acids are increasingly ionized with

increasing pH (basic environment),
whereas
Bases are increasingly ionized with
decreasing pH (acidic environment).

Other transmembrane transport

Filtration: bulk flow of water-soluble drugs

through pores (glomerular, capillary)

Facilitated diffusion: carrier-mediated,

ATP not required (e.g., glucose)

Active transport: carrier-mediated, ATP

required (e.g., Na+, K+, Ca++)

Endocytosis and exocytosis: (e.g., for very

large compounds)

Routes of Administration

ORAL INGESTION , governed by:

surface

area for absorption, blood flow,

physical state of drug, concentration.

occurs

via passive process.

In

theory: weak acids optimally absorbed in

stomach, weak bases in intestine.

In

reality: the overall rate of absorption of

drugs is always greater in the intestine
(surface area, organ function).

Unique characteristics of the oral route

Influences of gastric emptying (accelerates gastric

emptying increase the rate of absorption)

Small intestine usually most important because of

large surface area (folds of Kerckring, villi,
microvilli)

The motility of the small intestine

Drug inactivation important for oral route stomach

(acid), small intestine (ester/other enzyme), distal
small intestine/colon (gut bact)

Ingestion of a solid dosage form with a

glass of cold water, fasting, lying on the
right side, hyperthyroidism accelerate
gastric emptying

Ingestion with a fatty meal, acidic drink, or

with another drug with anticholinergic
properties, lying on the left side,
hypothyroidism, sympathetic output (as in
stress) retard gastric emptying.

First-Pass Metabolism

Extent of metabolism occurring before

drug enters systemic circulation
Main site: Liver
Decrease in drug efficacy (orally) can be
overcome by using a greater dose
Example: Propranolol (5 mg vs. 100 mg)
Extensive metabolism may render oral
admin. impossible
Example: Lidocaine

The fraction of drug eliminated from

portal blood during absorption hepatic
extraction ratio (ERH)
ERH = ClH/ QH

Bioavaibilty (F) F = 1- ERH

Drug Absorption & Route of

administration
Absorption describes the rate and extent
at which a drug leaves its site of
administration.
Bioavailability (F) is the extent to which a
drug reaches its site of action, or to a
biological fluid (such as plasma) from which
the drug has access to its site of action.

plasma concentration of drug

AUC = area under the curve

AUC oral
Bioavailability =

AUC
injected I.v.

AUC
oral

time

AUC injected i.v.

X 100

Important Properties Affecting

Drug Absorption

Chemical properties
acid or base
degree of ionization
polarity
molecular weight
lipid solubility or...
partition coefficient

Physiologic variables
gastric motility
pH at the absorption site
area of absorbing surface
blood flow
pre absorptive hydrolysis
ingestion w/wo food

Advantage

Relatively Fast
Painless (usually)
Easy
Safe
No need for equipment
or help
Most drugs can be
given orally
E.g., medications in pill
form, barbiturates, LSD,
caffeine, alcohol

Disadvantage

Not very fast

Some drugs dont
withstand stomach/GI
conditions (insulin,
cocaine)
Drug absorption more
variable
May cause GI distress
Not suitable for
uncooperative, vomiting,
unconscious
FIRST PASS through
liver

INJECTION

subcutaneous, intramuscular absorbed by

diffusion and affected by blood flow

intravenous, intraarterial injection avoids

absorption
Other

Injection types

Intraperitoneal = (I.P.) into stomach cavity (between

organs). Faster than P.O.

Intrathecal = into subdural spaces of the spinal

cord; bypasses blood- brain barrier but invasive
Intracerebroventricular = into the ventricles (where
cerebrospinal fluid is produced) in the brain;
bypasses blood- brain barrier but extremely invasive
Intracerebral = into the brain itself

Injection, in general
Advantage

Fast
Bypasses first pass
Bypasses digestion
More accurate dose
Can be done by
person with training

Disadvantage

Painful
Too fast to respond if
bad reaction or overdose
Potential for infection
Unless planning IV, must
be careful to avoid veins
No recall of drug

LUNG

Inhalation: passive diffusion, rapid absorption,

dependent on particle size (6 m cutoff)

Advantage
Painless and quick
Easy and discreet
Very rapid;
5 - 8 sec to brain
Intense effects
Smoke Examples:
metapmphetamine
Vapor examples:
anasthetics

Disadvantage
Potential harm to lungs
Short term = pneumonia
Long term = cancer
Exacerbation of abuse
liability
Only viable for volatile
forms of drugs or that can
be in very tiny particles
Drug is sometimes
destroyed in process

MUCOUS MEMBRANE
sublingual, buccal, nasal, vaginal or rectal
mucosa: passive diffusion
Advantage
Quick absorption
Easy and discreet
Little chance of
infection or tissue
harm (except with
vasoconstrictors)

Disadvantage
Can taste bad or
irritate membranes
Not all drugs
absorbed readily
Ease and speed
exacerbate abuseliable
drugs potential
for abuse

SKIN
Transdermal
Advantage
Easy
Not painful
Slow, sustained
release
Bypasses GI tract
& first pass
Only have to change
every few days /
weeks

Disadvantage
Can fall off
Potential toxicity to
children and pets
Very few drugs
absorbed sufficiently,
low permeability of
skin
Local irritation possible
Toxicity if additional
drug consumed

Distribution
Only that fraction of drug which is non-

protein-bound can bind to cellular

receptors and pass across tissue
membranes, thus being distributed to
other body tissues, metabolized, and
excreted.

The actual pattern of drug distribution

reflects various physiological factors and

physicochemical properties of the drug.

Plasma protein

albumin
- binds many acidic drugs

a1-acid glycoprotein for basic drugs

The fraction of total drug in plasma that
is bound is determined by its
concentration, its binding affinity, and
the number of binding sites.

Phases of Distribution

first phase
reflects cardiac output and regional
blood flow. Thus, heart, liver,
kidney & brain receive most of the
drug during the first few minutes
after absorption.
next phase
delivery to muscle, most viscera,
skin and adipose is slower, and
involves a far larger fraction of the
body mass.

Drugs Binding Primarily to

Albumin
barbiturate
benzodiazepines
bilirubin
digotoxin
fatty acids
penicillins
phenytoin
phenylbutazone

probenecid
streptomycin
sulfonamides
tetracycline
tolbutamide
valproic acid
warfarin

Drugs Binding Primarily to

1-Acid Glycoprotein
alprenolol
bupivicaine
desmethylperazine
dipyridamole
disopyramide
etidocaine
imipramine

lidocaine
methadone
prazosin
propranolol
quinidine
verapamil

Drugs Binding Primarily to

Lipoproteins
amitriptyline
nortriptyline

Drug Reservoirs
Body compartments where a drug can
accumulate are reservoirs. They have
dynamic effects on drug availability.

GIT
plasma proteins as reservoirs (bind
drug)
cellular reservoirs
Adipose (lipophilic drugs)
Bone (crystal lattice)
Transcellular (ion trapping)

Bone Reservoir

Tetracycline antibiotics (and other

divalent metal ion-chelating agents) and
heavy metals may accumulate in bone.
They are adsorbed onto the bone-crystal
surface and eventually become
incorporated into the crystal lattice.

Bone then can become a reservoir for

slow release of toxic agents (e.g., lead,
radium) into the blood.

Adipose Reservoir

Many lipid-soluble drugs are stored in

fat. In obesity, fat content may be as
high as 50%, and in starvation it may
still be only as low as 10% of body
weight.

70% of a thiopental dose may be

found in fat 3 hr after administration.

GI Tract as Reservoir

Weak bases are passively concentrated in

the stomach from the blood because of
the large pH differential.

Some drugs are excreted in the bile in

active form or as a conjugate that can be
hydrolyzed in the intestine and
reabsorbed.

In these cases, and when orally

administered drugs are slowly absorbed,
the GI tract serves as a reservoir.

Redistribution
Termination of drug action is normally
by biotransformation/excretion, but
may also occur as a result of
redistribution between various
compartments.
Particularly true for lipid-soluble
drugs that affect brain and heart.

Thiopental concentration
(as percent of initial dose)

Redistribution of thiopental after

intravenous injection

100

blood

brain

muscle

50

adipose

0
1

100

10

minutes

1000

Central nervous system: permeable to lipidsoluble drugs only; limited permeability to

water-soluble drugs when inflamed

Placental transfer: limited by blood flow,

not by a "barrier"

Penetrating into the Brain

Drugs that are small molecules

Lipid-soluble

Active transport systems (require energy:

mitochondria)

Carrier-mediated transport systems (dont need

energy), Pinocytotic vesicles

Other factors that affect absorption into the CNS

Drugs that are highly bound to plasma proteins are
less likely to penetrate the BBB
Drugs that are weak acids (are highly ionized at the
pH of blood, 7.4) are less likely to penetrate (have
low lipid-solubility)

Volume of distribution (Vd) relates the

amount of drug in the body to the plasma
concentration of drug (C).
total drug in body (mg)
Vd =----------------------------plasma conc. (mg/ml)

Tissue Distribution - Factors

Plasma protein binding
Specific receptor sites in tissues
Regional blood flow
Lipid solubility
Active transport
Disease
Effects of other drugs