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FACULTY OF SCIENCE
Pharmacology in nuclear medicine
Prof Geoff Currie, BPharm, MMedRadSc, MAppMngt, MBA, PhD
Faculty of Science, Charles Sturt University
Faculty of Medicine and Health Sciences, Macquarie University
Rural Clinical School, University of NSW
May 28 – 30, 2015, Montréal, Québec
FACULTY OF SCIENCE
Disclosure Statement: No Conflict of Interest
May 28 – 30, 2015, Montréal, Québec
I do not have an affiliation, financial or otherwise, with a pharmaceutical company, medical device or communications organization.
I have no conflicts of interest to disclose ( i.e. no industry funding received or other commercial relationships).
I have no financial relationship or advisory role with pharmaceutical or device-making companies, or CME provider.
I will not discuss or describe in my presentation at the meeting the investigational or unlabeled ("off-label") use of a medical device, product, or pharmaceutical that is classified by Health Canada as investigational for the intended use.
FACULTY OF SCIENCE
Pharmacology
• is the study of the action of drugs on living systems and the interactions of drugs with living systems
• Generally is divided into • Pharmacodynamics is the effects of the drug on
the body
• Pharmacokinetics is the effects of the body on drugs
FACULTY OF SCIENCE
Drug
• is a chemical substance that produces a biological effect and can be either synthetic or derived from plant, animal or mineral sources
• Generally is exogenous although endogenous sources might also exist
• for example, adenosine is an endogenous drug produced by the body while dipyridamole is an exogenous drug introduced to the body
FACULTY OF SCIENCE
Receptor Principles
• Receptors are proteins (macromolecules) that mediate drug activity
• The chemical signal (ligand) binds to a specific site (receptor) and triggers a response in the cells
• The intra-cellular changes initiated by the ligand-receptor complex can be through direct or indirect action, however, the ligand generally functions as an agonist or an antagonist
FACULTY OF SCIENCE
Receptor Principles• An agonist will mimic the endogenous ligand to
produce a similar response• An antagonist blocks the usual ligand and, thus,
inhibits the physiological response• Antagonist can be reversible, partially reversible or
irreversible
• Caffeine / adenosine• Beta blockers• CCB• Captopril (ACEI)
FACULTY OF SCIENCE
Receptor Principles
• Specificity is the measure of a receptors ability to respond to a single ligand
• Low specificity generally results in physiological responses not targeted or intended by the drug; side effects provide a good example
• Selectivity defines the ability of the receptor to distinguish between drugs and has the same implications as specificity; indeed the terms are often used interchangeably
FACULTY OF SCIENCE
Receptor Principles• Affinity defines the strength of attraction
between the drug and its receptor • A high affinity is generally associated with a lower dose
requirement (compared to low affinity for the same receptor).
• Potency describes the relationship between the drug dose and the magnitude of the effect
• High potency induces a maximum effect with a minimum of drug.
• Antagonist potency relates to dose required to inhibit 50% of biological effect of agonist
FACULTY OF SCIENCE
Receptor Principles
• Efficacy is the invivo potency • Antagonist has no efficacy
• The interaction (eg. absorption, metabolism, excretion) of the drug in the body may alter the relative bioavailability and thus, change the theoretical effect of the drug.
FACULTY OF SCIENCE
Pharmacodynamics
• Used to explain the relationship between the drug dose and response
• Drug effects
• Side effects
• The pharmacologic response depends on: • Drug binding to the target.
• Concentration of the drug at the receptor site.
• Disease states
• Age and gender
• Other drugs
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Dose-Response Relationships
• Concentration of the drug at the receptor controls the effect
• Typically non-linear
• Drug effect is a function of dose and time
FACULTY OF SCIENCE
Pharmacokinetics• The underlying principle of
pharmacokinetics is consistent with the philosophy of Paracelsus (medieval alchemist)
“only the dose makes a thing not a poison”
• Within a window, a specific drug will offer therapeutic benefit and outside that window there will either be no therapeutic benefit or toxicity.
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Pharmacokinetics
• A narrow therapeutic range (eg digoxin) means small variations in blood concentration may easily result in toxic or sub therapeutic concentrations.
• To maintain concentrations within the therapeutic range requires consistent bioavailability.
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Pharmacokinetics - ADME• Absorption
• Drug moves from site of administration to site of measurement
• Distribution • Reversible drug transfer too and from site of
measurement (eg. compartments)
• Metabolism • Conversion of one species to another (eg. metabolites)
• Excretion • Irreversible loss of drug from site of measurement (eg.
kidneys, biliary, bowel)
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Calculations
Time (hours) Plasma concentration
(micrograms / L)
2 139
4 65.6
6 31.1
8 14.6
A patient weighing 70kg is given an IV bolus injection of 25mg of MDP. Plasma concentrations after injection are tabulated.
0
20
40
60
80
100
120
140
160
0 2 4 6 8 10
Cp
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Calculations
Time (hours) Plasma concentration
(micrograms / L)
Log Cp
2 139 2.144 65.6 1.826 31.1 1.498 14.6 1.16
1.Calculate the elimination rate constant and half life.Log / linear plot to confirm a single compartment mono-exponential curve.
1
10
100
1000
0 2 4 6 8 10
Cp
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Calculations
Calculate the k and half life
C = C0 e-kt
14.6 = 139 e-k.6
14.6 / 139 = e-k.6
ln 0.1057 = -k.6
k = 0.3745
k = ln2 / T0.5
T0.5 = ln2 / k
T0.5 = ln2 / 0.3745
T0.5 = 1.85 hours
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CalculationsCalculate the AUC0-∞
AUC0-∞ = Cp0 / k
given k, C = C0 e
-kt
139 = C0 e-0.3745 x 2
139 = C0 x 0.4728
C0 = 139 / 0.4728
C0 = 294
AUC0-∞ = 294 / 0.3745 = 785ug or 0.785 mghrs / litre
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Calculations
Calculate the clearance.
CL = dose / AUCCL = 25000 / 785CL = 31.84 litres / hour
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Calculations
Time (min) Plasma concentration
(U / L)
0 0
1 31.3
2 49.3
3 58.6
4 62.5
5 62.8
7 58.1
10 50.6
16 36.1
24 25.3
The kidney concentrations of an IV DTPA are presented.
0
10
20
30
40
50
60
70
0 2 4 6 8 10 12 14 16 18 20 22 24
Cp
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Calculations
Calculate the elimination rate constant and half life.Log / linear plot to show mono-exponential clearance.
1
10
100
0 2 4 6 8 10 12 14 16 18 20 22 24
Cp
FACULTY OF SCIENCE
CalculationsTime (mins) Plasma
concentration (U / L)
Elimination curve
concentration
0 0
1 31.3
2 49.3
3 58.6
4 62.5
5 62.8
7 58.1 58.1
10 50.6 50.6
16 36.1 36.1
24 25.3 25.3
So.
C = C0 e-kt
25.3 = 58.1 e-k x 17
25.3 / 58.1 = e-k x 17
ln 0.4355 = -k x 17k = 0.0489 (mins-1)
k = ln2 / T0.5
T0.5 = ln2 / k
T0.5 = ln2 / 0.0489
T0.5 = 14.17 mins
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1
10
100
0 2 4 6 8 10 12 14 16 18 20 22 24
Cp
Log Cp
Calculations
Time (hours) Plasma concentration
(ugm / ml)
Elimination curve
concentration
R(plasma –
elim)0 0 81.8 81.81 31.3 77.9 46.62 49.3 74.0 24.73 58.6 70.7 12.14 62.5 67.1 4.65 62.8 64.1 1.37 58.1 58.1
10 50.6 50.6 16 36.1 36.1 24 25.3 25.3
Calculate the absorption dose rate constant and half life.
C = C0 e-ka x t
12.1 = 46.6 e-ka x 2
12.1 / 46.6 = e-ka x 2 ln 0.2596 = -ka x 2
ka = 0.6742 (mins-1)
ka = ln2 / T0.5
T0.5 = ln2 / ka
T0.5 = ln2 / 0.6742T0.5 = 1.03 Mins
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Calculations
Calculate the Tmax
Tmax = (1/[ka-k]) ln (ka/k)
Tmax = (1/[0.6742-0.0489]) ln (0.6742/0.0489)
Tmax = (1/[0.6742-0.0489]) ln (13.8)
Tmax = 1.6 x 2.6
Tmax = 4.2 mins
FACULTY OF SCIENCE
Pharmacologic Stress• Exercise limited by beta blockers or calcium
channel blocker
• Stop xanthine drugs for 48 hours
• Stop caffeine for 12-48 hours (varies)
• We usually stop all stress patients with the caffeine ‘in case’ they need pharmacologic stress
• Why?
• For how long?
• Lets ‘understand’ what we are doing.
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Purines• Dipyridamole and Adenosine are not β agonists• Adenosine is a purine:
• ATP breakdown
• Present in many tissues (CNS and peripheral)
• Acts on adenosine receptors (A1-4)
• Blocked by theophylline
• Vasodilator
• Block AV conduction
• Angina chest pain (stimulates nociceptive neurons)
• Broncho-constriction (contraindicated in asthma)
• Inhibits platelet aggregation
• Neuroprotection in cerebral ischaemia
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AdenosineThere are four main adenosine receptor sub-types :•A1, block atrioventricular (AV) conduction, reduce force of
cardiac contraction, decreased glomerular filtration rate, cardiac depression, renal vasoconstriction, decreased central nervous system (CNS) activity and bronchoconstriction.•A2A, anti-inflammatory response, vasodilation, decreased
blood pressure, decreased CNS activity, inhibition of platelet aggregation and bronchodilation.•A2B, stimulate phospholipase activity, release of mast cell
mediators, and actions on colon and bladder.•A3, stimulate phospholipase activity and release of mast
cell mediators (contributes to bronchoconstriction).
FACULTY OF SCIENCE
Figure 2
increased oxygen demand – induced ischaemia(exercise / dobutamine)
vasodilation – coronary flow reserve
(adenosine)
adenosine reuptake inhibition(dipyridamole)
Rest
coronary steal
Stress
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Adenosine and the Heart
• A1 receptors• Causes transient heart block• Relax arterial smooth muscle
• causes dilatation of the "normal" arteries
• but not where affected by plaque
• exaggerates blood flow difference between normal and stenosed vessels
• Does not necessarily cause ischaemia• Short half life• Adenosine is also a CNS depressant!
FACULTY OF SCIENCE
Xanthine / Methylxanthines• Xanthine is a purine found throughout the body• two of the building blocks of DNA itself are structural
analogues; adenine and guanine. • basic xanthine structure below• structural similarity with adenine part of adenosine means
potential antagonism of adenosine by xanthine based drugs. • There are a number of xanthine derivatives that offer
bronchodilation and mild CNS stimulation by virtue of antagonisms of adenosine.
• Methylation (substitution of H with CH3) of the xanthine
produces a number of variants called methylxanthines; caffeine, theobromine and theophylline.
FACULTY OF SCIENCE
Caffeine
• naturally occurring alkaloid • purine structure binds to same receptors as
adenosine• effects of adenosine blunted by
methylxanthines • caffeine, found in coffee and tea,
• theobromine, found in chocolate
• CNS stimulant• by blocking CNS depression by adenosine
• respiratory stimulant • cardiac stimulant and diuretic
FACULTY OF SCIENCE
Caffeine in MPS
• While 99% of caffeine is absorbed in the GI tract within 45 minutes of consumption, plasma concentrations following the same caffeine ingestion can vary amongst individuals by as much as a factor of 16
• The half life of caffeine is important but variable: • generally 4-6 hours biological half life
• increased a bit by oral contraceptives (x2) or pregnancy (15 hrs for last trimester)
• increased substantially (96 hours) in liver disease
• nicotine (smoking) can reduce the half life by 50%
• Alcohol consumption decreases half life
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Caffeine in MPS
• So why stop it for 48 hours? • Because that represents 8-10 half lives. • Same principle as decay by storage.
• Does it make a difference? • The marginal improvement up to 24 hours is probably very
worthwhile.• The marginal improvement out to 48 hours (24-48 hrs) is
probably negligible. • Especially if they only have small amounts of caffeine.
• So for the average person, 24 hours is more than enough and indeed 12 hours would probably cover it.
• People addicted to coffee and chocolate might need longer.
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Summary
• Adenosine and persantin act on adenosine receptors so are not antagonised by β blockers
• Exaggerates blood flow difference between normal and atherosclerotic vessels (vasodilation)
• Causes bronchoconstriction
• Persantin just increases the bioavailability of adenosine
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Summary• Caffeine is an adenosine antagonist• Need to stop for persantin or adenosine• No need to stop for exercise or dobutamine• 6-12 hours sufficient in normal use• Longer in liver disease or heavy consumption
• Shorter for smokers