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Intro Pharmacology &

Pharmacokinetics
Dr. dr. Nicolaski Lumbuun, SpFK

This teaching material is copyrighted.


No part of this work may be reproduced, including photocopied, without written permission of Universitas Pelita Harapan .
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
– Can’t 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
Bound Free Free Bound

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 gut)

Transport
Pore
active

Ion Pinocytosis Diffusion


Carrier
channel
Passage through lipid membranes

– 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.
• Says nothing about effectiveness.
Bioavailability
Bioavailability

Destroyed Not Destroyed Destroyed


in gut absorbed by gut wall by liver

to
systemic
circulation
Dose
Dose
Dose

Dose
Dose
Bioavailability = (AUC)oral / (AUC)intravein

70
P
L
60
A
S 50
M
A 40 intravein route
C 30
O oral route
N
C
20
E
N 10
T
R. 0
0 2 4 6 8 10

Time (hours)
Time to Peak Concentration

100
90
80
concentration

70
60 IV
50 Oral
40 Rectal
30
20
10
0
0 5 10 20 30 60 120 180
minutes
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
Sustained release 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
Bound Free Free Bound

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 (must pass tight junctions)

Factors affecting drugs distribution :


Plasma protein binding; Tissue sequestration; pH partition
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 - 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
portal smooth 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
• Phase II - couples group to existing (or phase I formed)
conjugation site glucuronide (with glucuronic acid), sulphate,
others
OH O-SO3

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
25

20
No. of patients

15

10

0
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)
• Xanthene 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 (not CYP2D6 ) 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 <25K 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 ionised drug is less lipid soluble


flow; filtrate
99% of GF is re-absorbed;
concentration of drug rises in tubule

If lipid soluble drug moves


down concentration gradient
back into blood

Re-absorption