FACULTY OF SCIENCE Pharmacology in nuclear medicine Prof Geoff Currie, BPharm, MMedRadSc, MAppMngt, MBA, PhD Faculty of Science, Charles Sturt University.

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

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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.

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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

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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

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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

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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)

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Receptor Concept - Agonist

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Receptor Concept - Antagonist

No response

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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

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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

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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.

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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

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Increased efficacy

Increased potency

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Antagonist (eg caffeine on adenosine)

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Therapeutic Window

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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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2 compartment

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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

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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

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Nuclear Cardiology Case Study

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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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Adenosine

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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).

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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!

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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.

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Caffeine Theobromine Theophylline

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Caffeine

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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

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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

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Questions?