Pharmacokinetics refers to the dynamics of the movement of drugs through the

biological
system, includes
Absorption
Distribution
Metabolism
Excretion
In order to reach their site of action, drugs have to pass through several
membranes transmembrane transport
Mechanisms of transport
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

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/Passive transport: 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)
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.
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 trai
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

probenecid

benzodiazepines

streptomycin

bilirubin

sulfonamides

digotoxin

tetracycline

fatty acids

tolbutamide

penicillins

valproic acid

phenytoin

warfarin

phenylbutazone
Drugs Binding Primarily to
a1-Acid Glycoprotein
alprenolol

lidocaine

 bupivicaine

methadone

desmethylperazine

prazosin

dipyridamole

propranolol

disopyramide

quinidine

etidocaine

verapamil

imipramine
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 bonecrystal 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.
Central nervous system: permeable to lipid-soluble 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