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Pharmacokinetics and
pharmacodynamics
Sara Williamson
Pharmacist
Fulbourn Hospital

Pharmacokinetics
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‘What the body does to the drug’
Pharmacodynamics

‘What the drug does to the body’
Absorption
and
distribution
Metabolism
and
excretion
Plasma
conc
Time
Total dose reaching the systemic
circulation = area under the curve
Bioavailability = proportion of total
dose administered that reaches
the systemic circulation
iv
Plasma
conc
sc
oral
Time
Absorption - factors affecting

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Route of administration (e.g. IV, IM, oral)
Formulation factors (e.g. MR tablets, depot
injections)
For oral dosage forms

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Food in stomach
GI motility
Drug interactions in GI tract
Specific transporters (may be saturable)
First-pass metabolism
(Enterohepatic recirculation)
Distribution

Approximates to ‘two-compartment’ model

Central compartment (plasma)

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Drug absorbed into this compartment
Drug eliminated from this compartment
Peripheral compartment (tissues including target
organs)
These compartments in dynamic equilibrium
Distribution between body ‘compartments’
Absorption
Brain
Plasma
proteins
Free drug
in plasma
Other tissues
(incl fat)
Elimination
Distribution - factors affecting




Lipid solubility of drug (crossing blood brain
barrier, sequestering in fat)
Binding to plasma proteins (albumin,
α1-glycoprotein)
Blood flow to tissues
Specific transport systems (e.g. levodopa
across blood-brain barrier)
Apparent volume of distribution Vd


Obtained by measuring concentration of drug in
plasma after IV injection
If high (>1 l/kg) drug has high affinity for tissues
outside body water (e.g. brain, fat)


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Chlorpromazine Vd 21 l/kg
Paroxetine Vd 12 l/kg
If low (c0.05 l/kg) drug has high affinity for plasma
proteins

Levothyroxine
Highly protein-bound drugs

>95% bound
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Diazepam
Amitriptyline
Warfarin
Levothyroxine
Furosemide

90-95% bound

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Phenytoin
Valproate
Propranolol
Protein-binding - factors affecting

Low plasma albumin levels

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Displacement from binding site by another drug
(usually a transient effect)

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e.g. aspirin displacing warfarin
Saturability of protein-binding within therapeutic
range


e.g. age, malnutrition, chronic liver disease
e.g. valproate
NB Plasma assays usually report ‘total’ rather than
‘free’ drug levels
Drug metabolism

Main site - liver (also some in GI wall,
plasma, lung, kidney)

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Phase I metabolism (oxidation/ reduction/
hydrolysis/ N-demethylation) to produce more
polar compounds
Phase II metabolism (conjugation, usually with
glucuronic acid) to produce inactive compounds
Some phase I metabolites have
pharmacological activity (e.g. norfluoxetine,
desmethyldiazepam)
Cytochrome P450 family

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Responsible for oxidative metabolism of most
psychotropics
Dominant isoenzyme CYP 3A4, also 2D6,
1A2, et al
Genetic variation in enzyme activity
(?pharmacogenetic testing)
Drugs may affect enzyme activity, or compete
as substrates
Reduced activity in older people, liver
disease
Some enzyme-inducers
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Carbamazepine (↓risperidone, OCs, + autoinduction)
Phenytoin (↓TCAs)
Phenobarbitone (↓warfarin)
Smoking (↓clozapine, olanzapine)
Alcohol – chronic (↓phenytoin)
St John’s wort (↓ciclosporin)
Rifampicin (↓methadone)
Some enzyme-inhibitors
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Erythromycin (↑carbamazepine)
Fluvoxamine (↑clozapine)
Valproate (↑lamotrigine)
Ciprofloxacin (↑warfarin)
Cimetidine (↑venlafaxine)
Grapefruit juice (↑sertraline)
Excretion

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Main site - kidneys (also bile, expired air,
breast milk, saliva, tears)
Drug may be excreted


Unchanged - e.g. lithium, amisulpride
As water-soluble metabolite
Excretion - factors affecting
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Renal impairment
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Age
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Acute
Chronic
Assume every elderly patient has at least some
renal impairment
Drugs that reduce renal blood flow

e.g. NSAIDs
First-order kinetics: elimination half-life
110
100
Concentration (m g/L)
90
80
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
9
Tim e (hours)
Half-life is the time taken for the concentration of drug in blood to fall by 50%
(in this case, 1 hour)
After 5 half-lives, concentration
has fallen by 95%
Elimination half-life

+/- variation within individuals and between
individuals

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Differences in plasma proteins, fat:lean, hepatic
function, renal function
May change on chronic dosing

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Enzyme induction/inhibition
Also consider effect of active metabolites
Non-first-order kinetics


Rate of elimination is not proportional to plasma
concentration
Zero-order

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Elimination rate is constant (e.g. alcohol); half-life is
variable
Capacity-limited clearance


Metabolic enzymes may be saturated at high
concentrations so zero-order (slower), becoming first-order
as concentrations come down (e.g. phenytoin)
Consider in overdoses
Withdrawal/discontinuation

Generally, discontinuation effects more
pronounced in drugs with faster elimination
(shorter half-life)

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Paroxetine vs fluoxetine
Lorazepam vs diazepam
Heroin vs methadone
Multiple doses
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For some drugs, it is appropriate to allow the plasma
concentration to reduce substantially before the next
dose is given (e.g. hypnotics)
More usually, repeated doses are given to achieve a
‘steady-state’ plasma concentration. Usual dosing
interval approximately 1 half-life
Time to reach steady state = 4-5 half-lives
Multiple doses - e.g. hypnotics
Effective
threshold
Plasma
conc
Time
Multiple dosing: 10mg / 12hrs
At steady state
amount administered = amount eliminated between doses
Cavss
Cp
Rising phase of the curve is
governed by the rate of
elimination (half-life = 12 hrs)
Time
Cavss
20mg / 12hrs
Cp
10mg / 12hrs
Cavss
Increasing the dose makes
Cavss higher but time to steady state
remains the same
Time
Cavss
10mg / 12hrs
20mg / 24hrs
Increasing the dose and increasing the interval Cavss remains the same but fluctuation in Cp is more
Therapeutic drug monitoring
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Useful for
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Drugs with low therapeutic index
Drugs where effect relates to plasma concentration
In psychiatric practice, mostly used for
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Lithium
Clozapine
Carbamazepine
Phenytoin
(Valproate?)
TDM - timing issues
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Sample collection!
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Is the plasma level at steady state?
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At least 5 half-lives
More for drugs that induce their own metabolism (e.g.
carbamazepine)
Is it a ‘trough’ sample?
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Sample immediately before next dose, or at least 12
hours after the previous dose
Depot antipsychotics
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First-generation antipsychotics: esters of active drug, dissolved in
oil
 Absorption slow
 Peak concentration after

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Rate-limiting half-life c14-21 days
 Time to reach steady state c8-12 weeks
Risperdal® Consta: aqueous suspension of microparticles
 Extremely delayed onset of absorption - 3 weeks each time
 Peaks 4-5 weeks after injection
 Risperidone released for up to 8 weeks after injection
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Fluphenazine decanoate 6-48 hours
Pipotiazine palmitate 9-10 days
Pharmacodynamics
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‘What the drug does to the body’
It includes both the desired action of the drug
and undesired actions such as adverse
effects and interactions
Mechanisms of drug action in
the body
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Binding to receptors
Interaction with enzymes
Interaction with ion channels
Interaction with carrier proteins
Interaction with structural proteins
Cellular membrane disruption
Chemical reaction
Drug action in the body
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Most psychoactive drugs affect neurotransmitters:
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Synthesis
Storage
Release
Reuptake
Degradation
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Direct action at receptors
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Second-messenger function
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Binding to receptors
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Drugs may be
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Agonists
Antagonists
Partial agonists
Efficacy is related to the size of effect
Potency is related to the amount required to
produce that effect
Binding may be
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Competitive or noncompetitive
Reversible or irreversible
Efficacy and potency
100%
Maximum effect
50%
Agonist concentration (log scale)
Competitive and
noncompetitive binding
100%
Maximum effect
with competitive
antagonist
50%
with noncompetitive
antagonist
Agonist concentration (log scale)
Partial agonists
100%
50%
Maximum effect
Full agonist
Full agonist activity,
adding partial agonist
Partial agonist
Full agonist activity
adding antagonist
Drug concentration (log scale)
Binding to receptors
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Drugs may mimic the shape, charge etc of
the natural neurotransmitter
May compete with a natural neurotransmitter
for binding at receptor
Example: first-generation antipsychotics

FGAs are dopamine D2 antagonists – block
dopamine transmission in mesolimbic (↓ positive
symptoms)
Side-effects

May be due to the primary action e.g. FGAs
also block D2 receptors in other pathways
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nigrostriatal (EPSEs)
tuberoinfundibular (↑prolactin)
May be due to action at other receptors e.g.

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muscarinic antagonist (dry mouth, constipation,
blurred vision, cognitive blunting)
H-1 histaminic antagonist (weight gain,
drowsiness)
α-1 adrenergic antagonist (dizziness, ↓BP)
Receptor profiles

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Balance of receptor affinities may improve
clinical effects or reduce side-effects
Example: second-generation antipsychotics
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SGAs have 5HT2A antagonist activity as well as
D2 antagonism
5HT2A antagonism in the nigrostriatal pathway
stimulates dopamine release (↓EPSEs)
5HT2A antagonism in the mesocortical pathway
stimulates dopamine release (may improve
affective, cognitive and negative symptoms)
Transport carriers


Move neurotransmitter from the synapse back into the
presynaptic terminal
 Need an energy source eg Na+/K+ ATPase
 May also involve an ion eg Na+ which increases the affinity of the
transporter for the neurotransmitter
Example: SSRIs
 Reuptake pump removes serotonin from the synapse – blocked
by SSRIs so ↑serotonin
 But initial effects at pre-synaptic 5HT1A receptors reduces postsynaptic serotonin release
 Down-regulation of pre-synaptic receptors allows increase in
serotonin (delayed response to antidepressant)
 Side-effects include nausea (5HT2A) and sexual dysfunction
(5HT3)
Enzymes
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Involved in the synthesis and degradation of
neurotransmitters
May be activated or inhibited by drugs
Example: monoamine oxidase inhibitors
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Monoamine oxidases break down serotonin/noradrenaline
(MAO-A) and dopamine (MAO-B)
MAOI antidepressants prevent this breakdown
‘Cheese’ reaction due to inhibition of MAO-A in gut
MAOIs (e.g. phenelzine) inhibit irreversibly; moclobemide is
a reversible inhibitor (RIMA)
Selegiline inhibits MAO-B - ↑dopamine (in Parkinson’s)
Ion channels

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Involved in fast-onset signals; may be voltage gated
or ligand gated
Example: Benzodiazepines
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Gamma-aminobutyric acid inhibits most neurons
Benzodiazepines bind to GABA-A receptors, enhancing the
effect of GABA
Example: Memantine
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Glutamate stimulates most neurons; in Alzheimer’s, excess
glutamate causes ‘background noise’ and cell damage
Memantine blocks NDMA receptors (one type of glutamate
receptor)
GABA and glutamate
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Some more examples:
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Valproate may increase GABA function and
reduce glutamate function
Carbamazepine may increase GABA function
Lamotrigine may inhibit the release of glutamate
G protein-linked receptors and
second messengers
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Neurotransmitter binds to receptor
Receptor is changed so G protein can bind
G protein binds and is changed so an enzyme can
bind
Enzyme binds and synthesizes a second messenger
(e.g. c-AMP)
This second messenger may act on ion channels,
other enzymes or gene transcription within the cell
Lithium

Mechanism of action?
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Lithium may prevent the G protein from binding to the
activated receptor; or
May prevent the enzyme from binding to the G protein
and therefore preventing a second messenger being
produced; or
May interfere with gene expression as modulated by
protein kinase C, regulating growth factors and
neuronal plasticity