Intro Pharmacology &

Pharmacokinetics
Dr. dr. Nicolaski Lumbuun, SpFK
 Learning Objectives

To explain the physicochemical factors in

drug transport
To explain the route of drug administration
To explain the drug absorption, and its
application in therapy
To explain the drug distribution, and its
application in therapy
 Learning Objectives

To explain the drug metabolism, and its

application in therapy
To explain the drug excretion, and its
application in therapy
To explain the bioavailability,
bioequivalence & those applications in
therapy
To explain the applications of the concept
of pharmacokinetics in clinical practice
 MEDICATION

What is drug?
All substance which can produce biologically effect in
the body, in a small or limited amount
Just a modifier/optimizer effect in human body
Cant give a new thing/feature

How drug can cure a disease ?

Need an adequate level in the serum/target organ
Need an interaction with body substance
 Potential Therapeutic Outcomes
Efficacy with toxicity : Treatment, potentially curative
Efficacy without toxicity : Palliation/supportive
therapy
Toxicity without efficacy : Poison
Neither toxicity nor efficacy : Alternative medicine

The goal of therapeutics is to

achieve a desired beneficial effect w/ minimal adverse
effects
 PK / PD
Pharmacokinetic (PK) processes of absorption,
distribution, metabolism and elimination. Determine how
rapidly (onset) and for how long (duration) the drug will
appear at the target organ

Pharmacodynamic concepts of maximum response and

sensitivity determine the magnitude of the effect at a
particular concentration

In other words
Pharmacokinetics (PK) deals with the dose-
concentration part
Pharmacodynamics (PD) governs the concentration-
effect part of the interaction
PK / PD
 Terminology of
Pharmacokinetic
The science of the rate of movement of
drugs within biological systems, as affected
by the absorption, distribution, metabolism,
and elimination of medications
ADME - overview
 LOCUS OF ACTION TISSUE
RECEPTORS RESERVOIRS
Boun Free Free Bound
d

ABSORPTION Free Drug EXCRETION

SYSTEMIC
Bound Drug CIRCULATION

BIOTRANSFORMATION
 Pharmacokinetics

Drug concentration at sites of action

influenced by several factors, such as:
Route of administration

Dose

Characteristics of drug molecules (e.g.,

passage through lipid membranes, lipid
solubility)
 Passage through membranes

Diffusion through gaps between cells

(glomerulus; capillary; brain capillary - tight
junction)
Passage through the cell membrane
diffuse through pore (very small molecul weight)
carrier mediated transport (specific, saturable;
Fe in gut; L-DOPA at blood-brain barrier)
pinocytosis (insulin in CNS; botulinum toxin in
Transpo
gut)Pore rt active

Ion Pinocytosis Diffusion

Carrier
channel
Passage through lipid membranes

Passive diffusion through lipid of cell

membrane (depends on AREA, DIFFUSION
GRADIENT, DIFFUSION COEFFICIENT, LIPID
SOLUBILITY)
Important things : Physicochemical profile of a
drug
Molecular weight
Ionized vs Unionized
Lipophilic vs Hydrophilic
 Diffusion : weak acids and weak
bases
HA <==> H+ + A- B + HCl <==> BH+ + Cl-
[ UI ] [I] [ UI ] [I]

pKa=pH+log(HA/A-) pKa=pH+log(BH+/B)

ASPIRIN pKa = 4.5 (weak acid) STRYCHNINE pKa = 9.5 (weak base)
100mg orally 100mg orally

0.1 = [ I ] 99.9 = [ I ] Blood

Blood
Stomach pH = Stomach pH =
pH = 2 7.4 pH = 2 7.4

99.9 = [ UI ] [ UI ] 0.1 = [ UI ] [ UI ]

Aspirin is reasonably absorbed Strychnine not absorbed until

from stomach (fast action) enters duodenum
 Routes of administration

Enteral; oral, sub-lingual (buccal), rectal. Note

soluble, enteric coated or slow release
formulations
Parenteral; iv, im, sc, id, etc. Different rates of
absorption, different plasma peaks. Note iv
infusors
Skin; for local or systemic effect - note patches
Lungs; inhalation; local or systemic effect?
Vaginal; (usually local)
Eye; (usually local)
 Factors affecting oral
absorption
Formulation
Disintegration of dosage form
Dissolution of particles
Chemical stability of drug
Motility and mixing in GI tract
Presence and type of food
Passage across GI tract wall
Blood flow to GI tract
Gastric emptying time
 Bioavailability
The fraction of unchanged drug
reaching the systemic
circulation following administration
by any route
i.v injection gives 100%
bioavailability.
Calculated from comparison of
the area under the curve (AUC)
relating plasma concentration
to time for iv dosage compared
with other route.
Bioavailability (f) =
(AUC)oral / (AUC)iv
Says nothing about effectiveness.
 Bioavailability

Destroyed Not Destroyed Destroyed

in gut absorbed by gut wall by liver

to
systemic
circulation
Dose
Dose
Dose

Dose
Dose
Bioavailability
A
C
 Bioavailability
Extent of Absorption After oral administration, a
drug may be incompletely absorbed, mainly due to lack
of absorption from the gut (too hydrophilic or too
lipophilic)
First-Pass Elimination Following absorption across the
gut wall, the portal blood delivers the drug to the liver
prior to entry into the systemic circulation.
Rate of Absorption gastric emptying rate
(peristalsis)
Alternative Routes of Administration & the First-Pass
Effect topical, transdermal, sublingual, rectal
suppositories
 Modified preparations
Depot injections (oily, viscous, particle
size)
Multilayer tablets (pellet)
Sustained release capsules (resins)
Infusors (with or without sensors)
Skin patches (nicotine, Nitroglycerine)
Pro-drugs
Liposomes Targeted drugs , antibody-
directed
 DISTRIBUTION - overview
The body is a container in which a drug is
distributed by blood (different flow to different
organs) - but the body is not homogeneous.
Volume of distribution = Vd = D/Co

Membrane permeability
cross membranes to site of action
Plasma protein binding
bound drugs do not cross membranes
malnutrition = albumin = free drug
Lipophilicity of drug
lipophilic drugs accumulate in adipose tissue
Volume of distribution
 LOCUS OF ACTION TISSUE
RECEPTORS RESERVOIRS
Boun Free Free Bound
d

ABSORPTION Free Drug EXCRETION

SYSTEMIC
Bound Drug CIRCULATION

BIOTRANSFORMATION
 Distribution into body
compartments
Plasma 3.5 litres, (heparin, plasma expanders)
Extracellular fluid 14 litres, (tubocurarine)
Total body water 30-40 litres, (ethanol, theophillin)
Chloroquine 15000L Shows highly lipophilic
molecules which sequester into total body fat.
Transcellular small, CSF, eye, foetus

VD influenced by : Membrane permeability

Lipophilicity of drug
Plasma protein binding
Alter plasma binding of drugs (10%
dissociation)

1000 molecules

99.9 % bound 90.0

1 molecules free 100

100-fold increase in free pharmacologically
active concentration at site of action.

Effective TOXIC
Alter plasma binding of drugs (50%
dissociation)

1000 molecules

10 % bound 5

900 molecules free 950

50-fold increase in free pharmacologically
active concentration at site of action.

Not too significantly different

METABOLISM/BIOTRANSFORMATION
overview
Drug molecules are processed by enzymes
evolved to cope with natural compounds
Drug actions may increased or decreased or
changed
Individual variation genetically determined
May be several routes of metabolism
May not be what terminates drug action
May take place anywhere BUT liver is prime
site
Not constant - can be changed by other drugs;
basic of many drug-drug interactions
 Sites of biotransformation
where ever appropriate enzymes occur;
plasma, kidney, lung, gut wall and Liver

the liver is ideally placed to intercept natural

ingested toxins and has a major role in
biotransformation
 The liver

Hepatocytes
smooth
portal bile
venous endoplasmic
blood reticulum
microsomes
contain cytochrome
systemic P450
arterial dependent
blood mixed function oxidases
venous blood
 Types of biotransformation
reaction
Any structural change in a drug molecule may
change its activity
Phase I - changes drugs and creates site for phase
II
oxidation (adds O) eg. Microsomes (P450);
reduction; hydrolysis (eg. by plasma esterases),
others
OH O-SO
Phase II - couples group to existing (or phase I3
formed) conjugation site glucuronide (with
glucuronic acid), sulphate, others
Phase
Phase
I
II
 Genetic polymorphism in
cytochrome P450 dependent
mixed function oxidases
CYP 450 Cytochrome P450
FOUR families 1-4
SIX sub-families A-F
up to TWENTY isoenzymes 1-20
CYP3A4 : CYP2D6 : CYP2C9 : CYP2C19 :CYP2A6

Known Polymorphysm:
CYP2D6*17: Caucasian 0%, African 6%, Asian 51%
- reduced affinity for substrates
 Plasma conc in 267 pts after 9.8 mg/kg isoniazid orally
No. of patients

0 1 2 3 Isoniazid conc. ug/ml 9 10 11 12

 Other (non-microsomal)
reactions
Hydrolysis in plasma by esterases
(suxamethonium by cholinesterase)
Alcohol and aldehyde dehydrogenase in
cytosolic fraction of liver (ethanol)
Monoamine oxidase in mitochondria
(tyramine, noradrenaline, dopamine, amines)
Xanthine oxidase (6-mercaptopurine, uric
acid production)
Enzymes for particular drugs (tyrosine
hydroxylase, dopa-decarboxylase, etc)
 Factors affecting
biotransformation
race (CYP2C9; warfarin (bleeding) phenytoin (ataxia)
Losartan (less cleared but less activated as well); also
fast and slow isoniazid acetylators, fast = 95% Inuit,
50% Brits, 13% Finns, 13% Egyptians).
age (reduced in aged patients & children)
sex (women slower ethanol metabilizers)
species (phenylbutazone 3h rabbit, 6h horse, 8h
monkey, 18h mouse, 36h man)
clinical or physiological condition
other drug administration (induction or inhibition)
food (charcoal grill ++CYP1A)(grapefruit juice
--CYP3A)
first-pass (pre-systemic) metabolism
 Inhibitors & inducers of
microsomal enz
INHIBITORS : cimetidine ; prolongs action
of drugs or inhibits action of those
biotransformed to active agents (pro-
drugs)
INDUCERS barbiturates, carbamazepine
shorten action of drugs or increase effects
of those biotransformed to active agents
BLOCKERS acting on non-microsomal
enzymes (MAOI, anticholinesterase drugs)
 EXCRETION - overview
Urine is the main but NOT the only route.
Glomerular filtration allows drugs <25D MW to pass
into urine; reduced by plasma protein binding; only
a portion of plasma is filtered.
Tubular secretion active carrier process for cations
and for anions; inhibited by probenicid.
Passive re-absorption of lipid soluble drugs back
into the body across the tubule cells.
Note : effect of pH to make more of weak acid drug
present in ionised form in alkaline pH therefore re-
absorbed less and excreted faster; vica-versa for
weak bases.
 Effect of lipid solubility and
pH

Glomerular blood
flow; filtrate
ionised drug is less lipid soluble
99% of GF is not re-absorbed;
concentration of drug rises in tubule

If lipid soluble drug moves

down concentration gradient
back into blood

Re-absorption