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Pharmacodynamics
Dr Hisham Alshaikhli
hishamibrahim69@gmail.com
Learning outcomes
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
3
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:
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
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
1)
Drug interactions
2)
Duration of effect
3)
Unwanted effects
4)
Reduction in symptoms
5)
6)
7)
8)
9)
10)
11)
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
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Absorption
Distribution
Route
Enteral
oral
Parenteral
IV
sublingual
Topical
transdermal
Absorption
inhalation
Absorption
Systemic circulation
15
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
Bioavailability
Bioavailability
21
Effect of Food
Some drugs are taken before meals to allow time for drug to act before food
is taken
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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
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:
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:
Extravascular
Intracellular
3L
9L
28 L
4% BW
13% BW
41% BW
Distribution
Muscle = slow
Organs = fast
Capillary structure:
Plasma
A drug
Physiochemical propertiesPo/w
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
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Excretion
Drugs are primarily excreted by the kidneys
by the urinary pH
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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
Example
Drug 100mgs with a 6 hour half life
= 194mgs
Loading Doses
Are used when the medical condition demands high concentrations very
quickly
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Steady-State
Steady-state
At
187.5
194
200
150
100
87.5
75
50
94
97
100
C
Cpav
t
Four half lives to reach steady state
Therapeutic Index
Pharmacodynamics
Cellular Level
Definitions
Efficacy
Potency
Amount of drug required to produce 50% of the maximal response the drug is
capable of inducing
Definitions
Definitions
Therapeutic Index
Calculation: LD50/ED50
Margin of Safety
Dose-Response Relationship
Drug Actions
biochemical reactions
Pharmacological
Drug Receptors
Proteins or glycoproteins
Present
Finite
Drug Receptors
Action occurs when drug binds to receptor and this action may be:
Drug Receptor
Affinity
Drug Receptor
Drug Receptors
Agonist
Partial agonist
A drug which does not produce maximal effect even when all of the receptors are
occupied
Drug Receptors
Antagonists
Competitive antagonist
Drug Receptors
Noncompetitive antagonist
Induces a conformation change in the receptor such that the agonist no longer
recognizes the agonist binding site.
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
zero
1st
time
Plasma
Concn
(Cp)
time
Bioavailability (F)
measure of the amount of drug absorbed into the general circulation
Foral = AUCoral
AUCiv
Clearance = F. dose
AUC
iv
Cp
oral
time
Cp
time
Therapeutic window
Same drug, same route, different doses
Toxic level
Cp
Minimum
therapeutic level
time
iv
Cp
sc
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
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
time
Loading dose(s)
Loading dose = Cpeak . Volume of distribution
Cp
time
Thanks