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Pharmacokinetics and

Pharmacodynamics
Dr Hisham Alshaikhli
hishamibrahim69@gmail.com

Learning outcomes

Define and discuss pharmacokinetic factors

Discuss the factors that affect absorption, distribution, metabolism and


excretion-how they affect drug therapy

Define and discuss pharmacodynamic mechanisms of drug actions

Apply pharmacokinetic and pharmacodynamic concepts to patient scenarios.

Definitions
Pharmacokinetics is what the body does to
the drugs, for almost all drugs the magnitude
of pharmacological effect depends on its
concentration at its site of action.
Pharmacodynamics is what the drug does to
the body, ideally including
the molecular mechanism (s)
by which the drug acts
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Definitions
Pharmacokinetics:
the activity or fate of drugs in the body over a period of time,
including the processes of absorption, distribution, localization
in tissues, biotransformation and excretion.

Pharmacodynamics:
the study of the biochemical and physiological effects of drugs
and the mechanisms of their actions, including the correlation
of action and effects of drugs with their chemical structure;
also, the relationship between drug concentration and effect.

More Definitions

Exposure:

A measure for the amount of drug that an organism


has really "seen"

Bioavailability A measure for the proportion of the dose that


reaches the systemic circulation (not the same as
exposure)
Clearance

A measure of the elimination of a compound from


the blood given as volume cleared/time

Volume of Distribution
A measure of the theoretical volume that
a compound distributes to.
Unbound Fraction The fraction of drug not bound to proteins:
Cunbound = fu Ctotal
Half-Life

A measure of the time it takes for the organism to


decrease the concentration of the drug by 50%

Ideal PK Properties of a Drug

From a Marketing Perspective

Must be efficacious with once/day dosing


One or two dose levels should be safe and
efficacious in all individuals
No dosing adjustments should be required
with multiple dosing.

Ideal PK Properties of a Drug

From a Clinical Perspective


Should give consistent plasma concentrations in all
individuals (patients) from one dose.
No variability in metabolism
Excretion by both renal and hepatic mechanisms
for those with liver or kidney problems
Rapid, predictable onset of action
Clearance high enough so compound is removed
from body if any untoward side-effects are observed.
No accumulation
No interaction with co-administered drugs due to
High Protein Binding
Metabolism (induction or inhibition)
Interference with Excretion

Why drugs fail

Pharmacokinetics

Absorption
Distribution
Metabolism
Excretion

ADME - Summary

Pharmacokinetics v.
Pharmacodynamics
Pharmacokinetics
Action of the body on the
chemical
System: Absorption,
distribution,
metabolism,
elimination (ADME)
Output: Concentrationtime relationships

Pharmacodynamics
Action of the chemical on
the body
System: Biological
ligands or other targets
in the biophase.
Output: Biological
response

Arrange the phrases!!! Factors determining response of a


patient to a drug

1)

Drug interactions

2)

Duration of effect

3)

Unwanted effects

4)

Reduction in symptoms

5)

Modification of disease progression

6)

Accumulation on repeat dosage

7)

Absorption from the site of administration

8)

Elimination from the body

9)

Delivery to the site of action

10)

Effects at the site of action

11)

Interaction with cellular component


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Pharmacokinetics:considering such
terms as

Route

Absorption

Distribution

Hepatic Metabolism

Metabolic products

Protein Binding

Renal Excretion

Half-life

Toxicity
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Absorption
Distribution
Metabolism
Excretion
14

Absorption

Distribution

Route

Enteral
oral

Parenteral
IV

sublingual

Topical
transdermal

Absorption

inhalation

Absorption
Systemic circulation

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Absorption
Process of drug movement from the administration site to the
systemic circulation.
The amount and rate of absorption are
determined by several factors:
Physical nature of the dosage form
Presence or absence of food in the stomach
Composition of the GI contents
Gastric or intestinal pH
Mesenteric blood flow
Concurrent administration with other drugs
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Absorption

Taken from TNO Pharma Web

Most Drugs administered orally as


pills
Absorbed largely from small
intestine
Some Sublinqual absorption
Rectal Absorption (suppository)
Some Absorption from stomach
(rare)
Molecules need to be near the
intestinal mucosa to be absorbed
Compound should be soluble in
gut contents or in vehicle
Crystals are not well absorbed
Gummy stuff is not well absorbed

Anatomy of the intestines

Anatomy of the intestines

Absorption at brush border cells

Taken from Camitro Web Site

Passive transcellular thought to be major route


Non-charged compounds diffuse best

Bioavailability
Bioavailability

is the proportion of the administered dose

that reaches the systemic circulation.


Dale and Haylet, Pharmacology Condensed. 2004
Refers

to the amount and the rate of appearance

of the drug in the blood after administration in


its initial dose form
Orally

administered drug bioavailability is directly related

to the individual solubility in body fluids.


Poor solubility = low bioavailability

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Effect of Food

Bioavailability of some drugs is affected by the presence of food. E.g


penicillin's, erythromycin, rifampicin, thyroxine

Some drugs are taken before meals to allow time for drug to act before food
is taken

Gastric irritation can be caused by drugs taken on an empty stomach

Effect of food on the absorption of drugs

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First Pass Effect

Drugs that are absorbed via the GIT are

circulated to the liver first via


the hepatic portal vein

Liver then acts as a filter

Only part of the drug is

circulated systemically

The combination of

processes is termed
the First Pass effect

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Absorption animation

http://www.youtube.com/watch?v=xiuWdJYyIKs

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Absorption

Distribution

Metabolism

Factors affecting

Low albumin

Problems with:
Heart
Circulation
Diabetes

Bound drugs are pharmacologically inactive because the drug25


protein complex is unable to cross cell membranes.

Volume of Distribution
Total mass in body
V
Concentration in blood
Quantitatively describes the distribution of
the chemical throughout the body, and
ultimately to the biophase (site of action).
The greater the volume of distribution, the
greater the biological half life.
Scalable based on interspecies composition
relationships and physical chemical factors
(QSPR).

DISTRIBUTION

Determined by:

partitioning across various membranes

binding to tissue components

binding to blood components (RBC, plasma protein)

physiological volumes

DISTRIBUTION

All of the fluid in the body (referred to as the total body water), in which
a drug can be dissolved, can be roughly divided into three
compartments:

intravascular (blood plasma found within blood vessels)

interstitial/tissue (fluid surrounding cells)

intracellular (fluid within cells, i.e. cytosol)


The distribution of a drug into these compartments is dictated by it's
physical and chemical properties

TOTAL BODY WATER


Vascular

Extravascular

Intracellular

3L

9L

28 L

4% BW

13% BW

41% BW

Distribution

Apparent volume of distribution (Vd) =


Amt of drug in body/plasma drug conc

VOLUME OF DISTRIBUTION FOR SOME DRUGS


DRUG Vd (L)
cocaine 140
clonazepam 210
amitriptyline 1050
amiodarone ~5000

Factors affecting drugs Vd

Blood flow: rate varies widely as function of tissue

Muscle = slow
Organs = fast

Capillary structure:

Most capillaries are leaky and do not impede diffusion of drugs


Blood-brain barrier formed by high level of tight junctions between cells
BBB is impermeable to most water-soluble drugs

Blood Brain Barrier

Disruption by osmotic means


Use of endogenous transport
systems
Blocking of active efflux
transporters
Intracerebral implantation
Etc

Plasma Protein Binding


Many

drugs bind to plasma proteins in the blood


steam

Plasma
A drug

protein binding limits distribution.

that binds plasma protein diffuses less


efficiently, than a drug that doesnt.

Physiochemical propertiesPo/w

The Partition coefficient (Po/w) and can be used to


determine where a drug likes to go in the body
Any drug with a Po/w greater than 1(diffuse through cell
membranes easily) is likely be found throughout all three
fluid compartments
Drugs with low Po/w values (meaning that they are fairly
water-soluble) are often unable to cross and require more
time to distribute throughout the rest of the body

Physiochemical PropertiesSize of drug


The size of a drug also dictates where it can go in the body.
Most drugs : 250 and 450 Da MW
Tiny drugs (150-200 Da) with low Po/w values like caffeine can passively diffuse through
cell membranes
Antibodies and other drugs range into the thousands of daltons
Drugs >200 Da with low Po/w values cannot passively cross membranes- require
specialized protein-based transmembrane transport systems- slower distribution
Drugs < thousand daltons with high Po/w values-simply diffuse between the lipid
molecules that make up membranes, while anything larger requires specialized
transport.

Metabolism
Drugs are metabolised in the liver, lungs,
kidneys, blood and intestines.

In order for drugs to pass across the lipid cell membrane they must be
lipophilic

The higher the solubility in lipids compared to water, the more rapid the
tissue entry

Metabolic rate determines the duration of the action of the drugs

Which BNF appendix relates to patients ability to metabolise?

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Excretion
Drugs are primarily excreted by the kidneys

In order for drugs to be excreted

they need to become hydrophilic

Excretion of drugs can be affected

by the urinary pH

How the drug is excreted can

influence prescribing decisions

37

Which BNF appendix relates to patients ability to excrete?

Clearance (Cl)
Blood flow (Q) Extraction Ratio (ER)
Volume of blood per unit time (e.g. L/min) from
which chemical is completely extracted. The
higher the clearance, the smaller the half-life.
Blood flow is allometrically scalable across
mammalian species
Extraction can occur by diffusion mechanism (e.g.,
glomerular filtration in the kidney) or by metabolic
mechanism (e.g., liver).
Clearance can be flow-limited (high ER) or
capacity limited (low ER). Flow-limited clearance
across species is more likely to be scalable than
capacity-limited clearance

Half Life of Drugs

Drug excretion is commonly expressed in terms of half life


(t1/2)
This is the time required for the concentration of the drug
in the plasma to decrease by one-half of its initial value
Drug half life is variable and can be long or short
Subsequent doses are given to raise the concentration
levels to a peak
In theory, the optimal dosage interval between drug
administration is equal to the half-life of the drug
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Example
Drug 100mgs with a 6 hour half life

1st dose 100 mgs


2nd dose 100mgs + 50 mgs still present = 150mgs
3rd dose 100mgs + 75 mgs still present = 175mgs
4th dose 100mgs + 88mgs still present = 188mgs
5th dose 100mgs + 94mg still present

= 194mgs

6th dose 100mgs + 97mg still present = 197mg

As can be seen, accumulation becomes less at


each dose- steady state is achieved after 3 to 5 half lives.
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Loading Doses

Are used when the medical condition demands high concentrations very
quickly

This is achieved by an initial dose that is twice the maintenance dose

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Steady-State
Steady-state

occurs after a drug has been given


for approximately five elimination half-lives.

At

steady-state the rate of drug administration


equals the rate of elimination and plasma
concentration - time curves found after each
dose should be approximately superimposable.

Accumulation to Steady State


100 mg given every half-life
175

187.5

194

200

150
100
87.5
75
50

94

97

100

C
Cpav

t
Four half lives to reach steady state

What is Steady State (SS) ?


Why is it important ?

Rate in = Rate Out

Reached in 4 5 half-lives (linear kinetics)

Important when interpreting drug concentrations in TDM or assessing clinical


response

Therapeutic Index

Therapeutic index = toxic dose/effective dose

This is a measure of a drugs safety

A large number = a wide margin of safety

A small number = a small margin of safety

Pharmacodynamics
Cellular Level

Definitions

Efficacy

Degree to which a drug is able to produce the desired response

Potency

Amount of drug required to produce 50% of the maximal response the drug is
capable of inducing

Used to compare compounds within classes of drugs

Definitions

Effective Concentration 50% (ED50)

Concentration of the drug which induces a specified clinical effect in 50% of


subjects

Lethal Dose 50% (LD50)

Concentration of the drug which induces death in 50% of subjects

Definitions

Therapeutic Index

Measure of the safety of a drug

Calculation: LD50/ED50

Margin of Safety

Margin between the therapeutic and lethal doses of a drug

Dose-Response Relationship

Drug induced responses are not an all or none phenomenon

Increase in dose may:

Increase therapeutic response

Increase risk of toxicity

Drug Actions

Most drugs bind to cellular receptors


Initiate

biochemical reactions

Pharmacological

effect is due to the alteration of an


intrinsic physiologic process and not the creation of a
new process

Drug Receptors

Proteins or glycoproteins
Present

on cell surface, on an organelle within the cell,


or in the cytoplasm

Finite

number of receptors in a given cell

Receptor mediated responses plateau upon saturation of all receptors

Drug Receptors

Action occurs when drug binds to receptor and this action may be:

Ion channel is opened or closed

Second messenger is activated

cAMP, cGMP, Ca++, inositol phosphates, etc.

Initiates a series of chemical reactions

Normal cellular function is physically inhibited

Cellular function is turned on

Drug Receptor

Affinity

Refers to the strength of binding between a drug and receptor

Number of occupied receptors is a function of a balance between bound and free


drug

Drug Receptor

Dissociation constant (KD)

Measure of a drugs affinity for a given receptor

Defined as the concentration of drug required in solution to achieve 50% occupancy


of its receptors

Drug Receptors

Agonist

Drugs which alter the physiology of a cell by binding to plasma membrane or


intracellular receptors

Partial agonist

A drug which does not produce maximal effect even when all of the receptors are
occupied

Drug Receptors

Antagonists

Inhibit or block responses caused by agonists

Competitive antagonist

Competes with an agonist for receptors

High doses of an agonist can generally overcome antagonist

Drug Receptors

Noncompetitive antagonist

Binds to a site other than the agonist-binding domain

Induces a conformation change in the receptor such that the agonist no longer
recognizes the agonist binding site.

High doses of an agonist do not overcome the antagonist in this situation

Drug Receptors

Irreversible Antagonist

Bind permanently to the receptor binding site therefore they can not be overcome
with agonist

Thus making it impossible for the molecule to unbind and blocking the receptor
permanently until the receptor is recycled byendocytosis.

Drug dosing
Important factors
concentration of drug in plasma
rate of drug elimination
rate of drug absorption

Therapeutic window

Toxic level
Cp

Minimum
therapeutic level

time

Revision of pharmacokinetic terms


Plasma
Concn
(Cp)

zero
1st
time

1st order elimination


rate of elimination depends on plasma concentration
C = C0e-kt (k= rate constant of elimination)

Half life (t1/2)


time for plasma concentration to fall by 50%

Zero order elimination (pseudo zero order)


rate of elimination is constant and independent of plasma concentration

Zero order elimination


Half life varies with concentration

Plasma
Concn
(Cp)

time

Volume of distribution (Vd)


Vd = dose
C0
Volume of water in which a drug would have to be distributed to give its
plasma concentration at time zero.
Can be larger than total body volume
frusemide 7 litres
aspirin
14 litres
propranolol 273 litres
digitoxin
38 liters
4 ml min-1
digoxin
640 litres 130ml min -1

Plasma clearance (ClP)


volume of blood cleared of its drug content in unit time

CP= ClM + ClR + ClB + .

Bioavailability (F)
measure of the amount of drug absorbed into the general circulation

Area under the curve (AUC)


obtained from the plasma concentration v time plot
gives a measure of the amount of drug absorbed

Foral = AUCoral
AUCiv
Clearance = F. dose
AUC

iv
Cp
oral
time

Same drug, same dose different formulation


different amounts absorbed
different peak concentration
different AUCs

Cp

time

Therapeutic window
Same drug, same route, different doses

Toxic level
Cp

Minimum
therapeutic level

time

Different rates of absorption


(different routes of administration)
Assume the bioavailability is the same (i.e. 1 for all routes)

iv
Cp

sc

Slower the rate of absorption


time to peak longer
amplitude of peak is less
longer drug in body
oral

time

Intravenous infusion
At steady state
rate of infusion = rate of elimination
= Css.Clearance

Css (plateau)
Cp

C = Css(1- e-kt)
Time to 90 % of Css = 4 t1/2

time

Half life

hours

steady state

Lignocaine

8 hours

Valproate

24 hours

Digoxin

32

6 days

Digitoxin

161

28 days

Rising phase of the infusion


curve is governed by the
rate of elimination

Height of plateau is
governed by the rate of infusion

2X mg min-1

Cp

X mg min-1

time

Dosing interval

MTL
Cp

time

Multiple dosing
At Steady State
amount administered = amount eliminated between doses

Cavss

Cp

Rising phase of the curve is still


governed by the rate of elimination

time

Loading dose(s)
Loading dose = Cpeak . Volume of distribution

Cp

time

Tetracycline t1/2 = 8 hours


500mg loading dose followed by 250mg every 8 hours

Thanks

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