Pharmacokinetics

Nur Permatasari
 Dosage Plasma Site of
Effects
Concen. Action

Pharmacokinetics Pharmacodynamics
PHARMACOKINETICS 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 TISSUE
“RECEPTORS” RESERVOIRS
Bound Free Free Bound

ABSORPTION Free Drug EXCRETION

SYSTEMIC
Bound Drug CIRCULATION

BIOTRANSFORMATION
In order to reach their site of action, drugs
have to pass through several membranes 
transmembrane transport
 Structure of the plasma membrane
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
pKa, and the local biophase pH...
Henderson-Hasselbach equation

pH - pKa = log base

acid

For an acidic drug: acid = HA; base = A-

For 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.
 AUC = area under the curve

plasma concentration of drug AUC oral

Bioavailability = X 100
AUC injected i.v.

AUC
injected I.v.

AUC
oral

time
 Important Properties Affecting
Drug Absorption

 Chemical properties  Physiologic variables

 acid or base
 degree of ionization
 polarity
 molecular weight
 lipid solubility or...
 partition coefficient
 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 don’t
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 Disadvantage
• Fast • Painful
• Bypasses first pass • Too fast to respond if
• Bypasses digestion bad reaction or overdose
• More accurate dose • Potential for infection
• Can be done by • Unless planning IV, must
person with training be careful to avoid veins
• No recall of drug
 LUNG
 Inhalation: passive diffusion, rapid
absorption, dependent on particle size (6
µm cutoff)

Advantage Disadvantage
• Painless and quick • Potential harm to lungs
• Easy and discreet – Short term = pneumonia
• Very rapid; – Long term = cancer
• 5 - 8 sec to brain • Exacerbation of abuse
• Intense effects liability
• Smoke Examples: • Only viable for volatile
metapmphetamine forms of drugs or that can
• Vapor examples: be in very tiny particles
anasthetics • Drug is sometimes
destroyed in process
 MUCOUS MEMBRANE
 sublingual, buccal, nasal, vaginal or rectal
mucosa: passive diffusion

Advantage Disadvantage
• Quick absorption • Can taste bad or
• Easy and discreet irritate membranes
• Little chance of • Not all drugs
infection or tissue absorbed readily
harm (except with • Ease and speed
vasoconstrictors) exacerbate abuseliable
drugs’ potential
for abuse
 SKIN
Transdermal
Advantage Disadvantage
• Easy • Can fall off
• Not painful • Potential toxicity to
• Slow, sustained children and pets
release • Very few drugs
• Bypasses GI tract absorbed sufficiently,
& first pass low permeability of
• Only have to change skin
every few days / • Local irritation possible
weeks • 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
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.
Redistribution of thiopental after
intravenous injection

100
blood
(as percent of initial dose)
Thiopental concentration

brain
muscle adipose
50

0
1 10 100 1000
minutes
 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 (don’t 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