Clinical Pharmacology - The Basics 3

8/2/2019 Clinical Pharmacology - The Basics 3

1/5

Deinitions

MeDiCine 36:7 339 2008 elvr Ld. All rgh rrvd.

Cliical parmacoloy: tebasicsD nchla Bama

Mchal eddl

Abstract

Clcal pharmaclgy cmpa a udradg hw drug

wrk ad hr apprpra u huma. th chapr gv a vr-

vw h gral prcpl, ad ubqu crbu wll xplr

h ara mr dal. sm rc rrc ar cludd gud

radg arud h pc dcud.

Keywords bavalably; dlvry ym; drug mrg; lma;

hal-l; pharmacdyamc; pharmacgc; pharmackc;hrapuc dxParmacodyamics

The measurement o the eects o drugs on humans (or, in basic

pharmacology, an organ system) is termed pharmacodynamics.

This term encompasses both the mechanism o action and the

end-point (e.g. heart rate, blood pressure).

Receptors

The actions o most drugs are mediated by the binding and inter-

action o drug molecules with specic molecular substances ormacromolecules located on the cell surace, termed receptors.

A ew receptor sites are intracellular (e.g. steroid receptors). The

drugreceptor interaction leads to a molecular change in the

receptor, which triggers a chain o events leading to a response.

This may be because o a secondary intracellular change medi-

ated by second messenger systems such as G proteins, or

because o the change in permeability o an ion channel in the

D Nicholas Bateman MD FRCP FRCPE FBPharmacolS FBTS is Proessor in Clinical

Toxicology and Consultant Physician at the Royal Infrmary, Edinburgh,

UK, and Director o the National Poisons Inormation Service,

Edinburgh. He qualifed rom Guys Hospital, London, and trained at

the Royal Postgraduate Medical School, London, and in Newcastle

upon Tyne, UK. His research interests are pharmaco-epidemiology,

clinical toxicology, and poisons inormation systems. Competing

interests: none declared.

Michael Eddleston MRCP is a Wellcome Trust Career Development Fellow

in the Department o Clinical Pharmacology, Edinburgh University,

UK, and Specialist Registrar at the Royal Infrmary o Edinburgh.

His research interests include the natural history, management, and

prevention o organophosphorus pesticide sel-poisoning and the

clinical pharmacology o antidotes or poisoning. Competing interests:

none declared.

cell membrane.13 Receptors tend to be highly specic, inter-

acting with a limited number o structurally related molecules.

There are subgroups o many receptor types, e.g. dopamine 1

and 2, and opioid mu, kappa and delta. For some drugs, the

receptor is nonspecic (e.g. an alkylating agent that cross-binds

molecules within DNA).

Aoists ad ataoistsAgonists are drugs that activate a receptor response. Antagonists

are drugs that block receptor response. Examples o such recep-

tor systems include:

adrenergic (agonist: salbutamol, antagonist: atenolol)

dopaminergic (agonist: dopamine, antagonist: haloperidol)

cholinergic (agonist: bethanecol, antagonist: atropine).

Potecy

The magnitude o the eect ollowing a drugreceptor interaction

usually depends on the dose o drug given; this relationship is com-

monly expressed in the orm o a doseresponse curve. Onset o

response occurs at a threshold dose. For dierent drugs with simi-

lar actions, use o a doseresponse curve allows comparison o: potency (the amount o drug necessary to achieve a certain

eect)

ED50 (the dose that produces a 50% response)

ecacy (the overall eect o a drug).

Potency has little clinical relevance, however, because a drug

that is more potent than another may also produce more dose-

related adverse eects. It is oten possible to use a higher dose o

a less potent drug to get the same eect as a more potent drug,

sometimes with ewer adverse eects.

Terapetic idex

The therapeutic index (therapeutic ratio) is the ratio between the

toxic dose and the therapeutic dose o a drug. The closer this ratiois to 1, the more dicult the drug is to use in clinical practice. The

therapeutic index or digoxin, or example, is very low, whereas

that or amoxicillin is extremely high. Clinical use o drugs with a

narrow therapeutic index has led to the monitoring o drug con-

centrations in patients therapeutic drug monitoring in which

the plasma concentration o a drug is measured and the dose

adjusted to achieve a desired therapeutic drug concentration (see

below).

LD50In the past, toxicology studies in animals involved measure-

ment o the dose o drug required to kill acutely. The single dose

required to kill 50% o a population is called the LD50. This is nota helpul measure in clinical practice, however, and other mea-

sures o toxicity are now generally applied, particularly because

o animal welare concerns.

ED50When a drug is given to an animal or human, it has an eect

and elicits a measurable response such as increased intracellular

calcium level, reduced blood pressure, or reduced heart rate. A

doseresponse curve is created by plotting the response on the

y axis and the dose o drug on the x axis (usually in log units).

The dose at which the response is 50% o the maximal eect is

termed the ED50.


2/5

Deinitions


Parmacokietics ad dr metabolism

The term pharmacokinetics reers to the rate and manner in

which drugs are absorbed, distributed, metabolized, and elimi-

nated (termed ADME) within and rom the body. Knowledge o

drug pharmacokinetics claries the relationships between dose,

dose requency, intensity o pharmacological eects, disease,

and adverse events.4,5

Absorptio ad bioavailability

Orally administered drugs must be absorbed rom the gut

(usually in the upper small bowel, where the surace area is

greatest). Not all o an orally administered dose may enter the

systemic circulation, however, because o inecient absorption,

or because o metabolism in the gut wall or liver beore the drug

enters the systemic circulation. This metabolism beore a drug

reaches the systemic circulation is termed rst-pass metabo-

lism. The amount o drug entering the systemic circulation as

a proportion o that administered is termed the bioavailability.

Bioavailability can be calculated by comparing areas under the

plasma concentrationtime curves or the same dose given orallyand intravenously (intravenous doses are completely absorbed

and undergo no rst-pass eect). Bioavailability is expressed as

a percentage.

It is possible to avoid rst-pass metabolism by giving drugs by

other routes; or example, sublingual or dermal administration

may occasionally be appropriate or nitrates. Alternatively, the

oral dose can be increased appropriately.

Some drugs have been pharmaceutically designed to alter

their absorption properties. Some are released slowly rom

tablets so-called slow-release products. This is oten done to

lengthen the dosing interval, but may make dose titration more

dicult. Others are designed to pass through the small bowel

and be released in the large bowel, where they have their eect.This has been done or some ulcerative colitis treatments by syn-

thesizing esters that are broken down by colonic bacterial fora.

Alternatively, pH-sensitive coatings can be applied which release

the drug as gut pH rises in the colon.

Distribtio

To allow simple mathematical modelling o the uptake and dis-

tribution o drugs in humans, the body is regarded as a single

fuid-lled compartment.

The simplest situation is a drug given intravenously that is

distributed throughout the body via the bloodstream.

Following intravenous injection, the drug passes through the

lungs and heart, and then to dependent organs. Organs and tissues with the greatest blood supply (e.g. brain,

kidneys, liver) are exposed to a greater amount o drug than

those with a low blood supply.

The drug equilibrates with these tissues according to blood

supply and its relative water (hydrophilic) or lipid (lipophilic)

solubility. As a rule o thumb, the more lipophilic the drug, the

more o it enters lipid-rich tissues; the less lipophilic the drug, the

more remains in the plasma.

The period during which a drug is distributed through body

tissues is termed the distribution phase.

Some drugs are bound to plasma proteins. In this state, they

are inactive as they cannot interact with receptors. Only ree

drug is active. This is important i measurement o the drugs

total plasma concentration is assumed to give the concentration

o active drug. In conditions such as renal ailure, drugprotein

binding alters. During dialysis, highly protein-bound drugs are

less easily removed. However, protein binding is rarely clinically

important, except or some drug interactions.

Apparet volme o distribtio (Vd)Vd is a theoretical volume into which a dose o drug appears to

have been dissolved on administration to a patient. It is deter-

mined by measuring the plasma concentration during the distri-

bution phase beore elimination has occurred (Vd = D/C, where

D is the total amount o drug in the body and C is the concentra-

tion o drug in the plasma). In practice, Vd is determined rom a

plot o plasma concentration versus time. Knowledge o the Vd is

important clinically since it determines how large a loading dose

is required o a particular drug to ll up the body and get the drug

working optimally.

Drugs that are highly at soluble, or taken up rapidly by

certain tissues, are removed rom the circulation quickly and

thereore have a low plasma concentration. As a result, Vd ishigh possibly greater than the volume o the patient (e.g. the

volume o distribution o tricyclic antidepressants and phenothi-

azine antipsychotics is several thousand litres).

For drugs that are water soluble, Vd is low, and more closely

similar to plasma volume (e.g. that o ethanol is about two-thirds

o body weight).

Elimiatio

Drugs are eliminated rom the body by various processes, o

which the most important are renal, biliary, and (or volatile

compounds such as anaesthetics) respiratory.

Phase I and phase II metabolism: beore elimination can occur,lipid-soluble drugs must be converted into more water-soluble

compounds by processes known as phase I and phase II enzymatic

metabolism. The most important drug-metabolizing enzymes or

phase I metabolism are members o the cytochrome P450 super-

amily o haem protein enzymes (e.g. CYP1A2, CYP2D6 and

CYP3A4). These enzymes are responsible or the metabolism o

a wide variety o drugs. Sulphate, glucuronide and glutathione

transerase enzymes are important phase II enzymes. Dierences

in enzyme activities may have clinical implications.6

In phase I metabolism, reactive groups are introduced into

the drug molecule by oxidation, reduction or hydrolysis. Poly-

morphisms (genetic variations) o these enzymes are common

and have important eects on drug metabolism see pages355 359.

In phase II metabolism, these groups undergo conjugation,

usually in the liver with glucuronide or sulphate.

Elimination in liver disease: drug-metabolizing enzymes are

present in many body tissues, including plasma, but are most

active in the liver. Drug metabolism may thereore be impaired in

patients with liver disease.

Elimination in renal disease: drug excretion is oten reduced in

patients with renal impairment; this is particularly important or

drugs that are excreted unchanged or have active metabolites.


3/5

Deinitions


An example is codeine; this is metabolized to orm morphine,

which is urther metabolized to an active 6-glucuronide com-

pound. Accumulation o this compound can occur in renal ail-

ure, leading to excess sedation and respiratory depression.

Effects of other drugs: the activity o drug-metabolizing enzymes

in the liver may be increased (induced) or reduced (inhibited) by

external actors. Changes in metabolism are particularly impor-tant or drugs with a low therapeutic index (e.g. wararin, the-

ophylline, phenytoin). Common examples o compounds that

inhibit and induce drug metabolism are shown in Table 1.

First-order kinetics: in general, the rate at which drugs are

metabolized and eliminated rom the body is proportional to the

blood concentration, and hence to the dose o drug administered.

Such drugs are said to obey rst-order kinetics. An eective

measure o the rate o elimination o such drugs is the plasma

hal-lie (t, see below); drugs are considered to be completely

eliminated ater our to ve hal-lives.

Zero-order kinetics: occasionally, enzyme metabolism is satu-rable, i.e. the body is unable to eliminate more than a certain

amount o drug over a xed period o time due to a limiting

amount o metabolizing enzyme. Drugs such as phenytoin and

alcohol are said to obey zero-order (saturation) kinetics. Unlike

drugs obeying rst-order kinetics (or which doubling the dose

eectively doubles the plasma concentration), even a small

increase in the dose o these drugs produces a disproportion-

ately large increase in plasma concentration that may precipitate

toxicity.

Elimination rate constant: drug elimination may be quantied

by determining the rate o elimination, described by the elimina-

tion rate constant (K). The simplest method to calculate K is romthe slope o a natural logarithm plot o the plasma concentra-

tiontime curve, which is a straight line. Drug elimination can

also be measured in terms o clearance (in a manner analogous

to creatinine clearance) as the volume o plasma cleared o drug

per unit time.

Half-life: a simpler means o understanding and using these elim-

ination parameters, and o acilitating patient care, is to express

the inormation in terms o t. This is dened as the time taken

or the plasma concentration o a drug to decrease to 50% o

the original value. Thus, i the plasma concentration o a drug

decreases rom 8 mmol/L to 4 mmol/L in 4 hours, the elimina-

tion t o that drug is 4 hours. The t can also be calculated romthe equation t = 0.693/K. t is clinically important because it

enables determination o:

dosing requency as drugs with short hal-lives need to be

given more oten. As an approximation, most drugs need to

be given at around one to two hal-lie intervals. (A drug such

as digoxin with a t o 36 hours can be given once per day.

Theophylline has a short t and is thereore dicult to use

in conventional tablets, since as many as 10 doses would be

needed each day. The pharmacokinetics o short t drugs may

be altered by pharmaceutical means, usually by administering

the drug in a slow-release ormulation.)

the time elapsed beore a steady-state plasma concentration is

reached ollowing repeat dosing (our to ve hal-lives) whether use o a loading dose is appropriate (appropriate

when drug action is required beore our to ve hal-lives has

elapsed).

However, many drugs exhibit a pharmacological action (pharma-

codynamic) that is longer than the elimination t, because they

produce secondary cellular changes that persist ater the drug

has gone. There may also be a delay in the onset o eect ater

the peak blood level, e.g. wararin, where eect is determined by

alterations in clotting actor synthesis.

Parmacoeetics

Several drug-metabolizing enzymes are subject to genetic varia-tion in activity, and this can lead to large dierences in the rate

o drug clearance rom the plasma, unexpected prolongation o

t and increased adverse eects. Pharmacogenetic variations are

relatively common and may vary signicantly between races.7,8

Slow metabolizers are more likely to develop adverse eects

such as peripheral neuropathy with isoniazid, while ast metab-

olizers may never be able to attain a therapeutic concentration

o the drug. Amongst Caucasians, slow metabolizers o a drug

such as metoprolol, by the cytochrome p450 isoorm CYP2D6,

comprise about 8% o the population. These polymorphisms are

clinically important; or example, codeine is converted to mor-

phine by CYP2D6 and 8% o the UK population may not get

Commoly sed drs ad evirometal actorstat idce or iibit dr metabolism

Ezyme-idci aets

Carbamazp

Phbarb

Phy

Rampc

Chrc hal cump

smkg

Barbcud ma

s Jh wr

Ezyme-iibiti aets

Cmd

Cprfxac

C-rmxazl

eryhrmyc ad clarhrmyc

Kcazl ad hr mdazl augal Grapru juc

Drs wit wic tese aets commoly iteract

Warar

Carbamazp

Cclpr

Phy

thphyll

Lw-d ral cracpv

All h drug hav rlavly arrw hrapuc rag.

Table 1


4/5

Deinitions


adequate analgesia. Increasing numbers o drugs are recognized

to be subject to such variable metabolism, and testing or com-

mon genetic polymorphisms is now a routine part o new drug

development. This knowledge is also now aecting how some

drugs are used. For example mercaptopurine toxicity is linked to

its detoxication genotype.9

The routine use o pharmacogenetics in clinical practice still

seems some way o.10

Terapetic dr moitori

Therapeutic drug monitoring may be required or some drugs with

a low therapeutic index in which the relationship between dose

and plasma concentration is not easily calculated but or which

the plasma level/biological eect is well documented. Usually,

this process involves measuring the plasma drug concentration

at steady-state (e.g. digoxin, phenytoin). In some circumstances,

the trough plasma concentration o the drug (i.e. the concentra-

tion immediately beore the next dose is administered; e.g. van-

comycin) or the peak plasma concentration (e.g. gentamicin) may

need to be measured. Dosing interval and t aect the amount odrug in the body at any one time, and knowledge o these actors

enables implementation o logical dosing regimens.

Dr iteractios

Interactions between drugs may result in changes in their pharma-

cokinetics (pharmacokinetic interaction) or an increase or decrease

in their biological eect (pharmacodynamic interaction).

Parmacokietic iteractios

Pharmacokinetic interactions most commonly involve changes in

metabolism in the liver (enzyme inhibition see above) or excre-

tion by the kidneys. Rarely, protein-binding displacement causes achange in distribution.

Parmacodyamic iteractios

In pharmacodynamic interactions, dierent drugs act at dierent

receptor systems to produce, most commonly, an increased bio-

logical eect. A useul pharmacodynamic interaction is the anti-

hypertensive eect o concurrent ACE inhibitor and calcium

channel antagonist therapy in hypertensive patients. This inter-

action may be detrimental, however, when the same drugs cause

hypotensive blackouts in patients treated or angina.

Adverse dr reactiosAdverse drug reactions are common and give rise to considerable

morbidity and mortality. On an average general medical take o 30

patients it is likely that two patients will have presented as a direct

result o adverse drug eects.11 Adverse drug reactions can be clas-

sied in a number o ways, but in essence, harm results rom:

toxic eects when the concentration o drug is too high, e.g.

respiratory depression occurring in a patient receiving mor-

phine in whom renal ailure has resulted in accumulation o

morphine and its active metabolites

collateral eects when the drug is present at the desired con-

centration but unintended side eects arise, e.g. dicloenac

causing gastrointestinal bleeding

hypersusceptibility to a drug, e.g. an allergic reaction to

penicillin.

See pages 364368 or urther inormation.

Parmacoviilace

Pharmacovigilance is the branch o pharmaco-epidemiology that

concentrates on the detection o adverse drug reactions. Adverse

drug reactions oten mimic common disease states, and uncom-mon adverse drug reactions may be dicult to detect unless they

are severe or are clearly temporally related to a specic medication.

In the UK, there are three types o pharmacovigilance study.12,13

The Yellow Card reporting system is a spontaneous-reporting

alerting system that may be used as a hypothesis-generating proc-

ess. It relies on healthcare proessionals reporting any adverse

event that they suspect may be caused by a medication. There is

no requirement or proo.

Prescription Event Monitoring is a systematic cohort approach

that may also act as a hypothesis-generating and testing process.

It is typied by the Green Form in the UK, and is based on the

monitoring o dispensed prescriptions or new drugs via a central

agency. The third technique involves hypothesis testing, when pre-

vious data have suggested that a drug may be responsible or

a particular adverse event. Hypothesis testing usually involves

case-control studies. Randomized clinical studies and cohort

studies are usually less ecient, because large numbers o

patients are required to detect rare events.

Delivery systems

For most drugs, there is a direct relationship between pharma-

cological response and concentration at the receptor; thus, to be

biologically active, the drug must gain access to the systemic

circulation and then come into contact with the receptor. Plasmadrug concentration depends on both drug kinetics and the design

o the drug delivery system.

Oral admiistratio

The most commonly used delivery systems involve absorption o

drug rom the gastrointestinal tract ollowing buccal, sublingual,

rectal or, most oten, oral administration. Commonly encoun-

tered oral orms include:

solutions

suspensions

capsules

tablets

coated tablets modied-release tablets.

The time taken or the drug to appear in the systemic circula-

tion ollowing oral administration increases in approximately the

same order.

Tablets are the most common delivery system. They have the

advantages o convenience and accuracy o dose. Tablets con-

tain many chemicals apart rom the active drug these are the

excipients, which include taste, colour and other ormulation

materials.

Coated tablets it is possible to alter the delivery and appar-

ent kinetics o drugs by changing the dissolution characteristics o


5/5

Deinitions


tablets. Thus, a tablet may be enteric-coated to prevent breakdown

in the stomach, ensuring that it remains intact until it reaches the

small bowel. This approach is commonly used to protect drugs

that are destroyed by gastric acid (e.g. omeprazole).

Modifed-release tablets the excipients o tablets may

be modied to improve drug delivery by controlling the rate,

amount, and duration o drug release over a 24-hour period.

This approach is used or drugs with a short t, which requirerequent dosing to maintain therapeutic levels (e.g. theophylline,

verapamil).

Pro-drugs are inactive compounds that are activated by bio-

logical fuids or metabolizing enzymes ollowing administration

(e.g. enalapril is converted to its active orm enalaprilat). Their

eect is usually similar to other drugs in the same class.

Sblial ad bccal admiistratio

These routes are increasingly used as tools to deliver drugs more

rapidly than orally but without the need or injection. Passage

across the mucosa is rapid or some compounds (e.g. nitrates)

and avoids rst-pass metabolism.

Ialatio

Inhaled drugs generally have less systemic availability so allow

smaller doses to be given or a direct eect on the lung. Some

absorption does occur, and may be clinically important in caus-

ing adverse eects in the case o high-potency steroids, or nebu-

lized -agonists.

Itraveos admiistratio

Intravenous administration is most commonly used when rapid

onset o action and careul control o plasma levels are required.

Drugs may be given as a:

bolus injection

slow inusion continuous inusion.

Slow inusion is used when excessively high transient plasma

levels are undesirable (e.g. phenytoin).

Continuous inusion is used when the drug has a short t or

when its therapeutic index is narrow and sustained controlled

blood levels are required.

Cliical trials

Clinical trials are discussed on pages 369376 and 377381.

Cocordace ad compliaceI a drug is to achieve the desired therapeutic eect, it is neces-

sary or the patient to take their medical therapy. Concordance,

ormerly called compliance, is the term that is used to describe

the extent to which patients ollow the course o treatment. Fac-

tors believed to be important in ensuring patient concordance

include the complexity o the therapeutic regimen, patients

understanding o their disease, and the need or and benets

o treatment. Careul studies have shown that 33% o patients

on long-term therapy show complete concordance while 66%

are at least reasonably concordant (i.e. missing occasional doses

at worst). About one third o patients take their treatment in a

completely haphazard way, i at all. Surprisingly, studies have

shown that concordance with lie-saving therapy, such as immu-

nosuppression or cancer chemotherapy, is no better. This should

be born in mind when extrapolating clinical trial data, in which

concordance is careully monitored.

REfEREnCES

1 Brur-obr H, Wlldrph P, J AA. srucur,

pharmaclgy ad hrapuc prpc amly C G-pr

cupld rcpr. Curr Drug Targets 2007; 8: 16984.

2 sadr RD, Bra D, Maz M. G-pr-cupld rcpr. Handb

Exp Pharmacol 2008; 182: 93117.

3 Hllma MW, srumpr D, Hrrdr s, Durux Me. Rcpr,

G pr, ad hr rac.Anesthesiology2005; 103:

106678.

4 Rbr DM, Buckly nA. Pharmackc cdra clcal

xclgy: clcal applca. Clin Pharmacokinet2007; 46:

897939.5 Dgma J, Appl-Dgma s. igrad pharmackc

ad pharmacdyamc drug dvlpm. Clin Pharmacokinet

2007; 46: 71337.

6 Brl L. Mablm adpra ad urlpc drug by

cychrm p450: clcal ad rhc apc. Clin Pharmacol

Ther2007; 82: 6069.

7 Laar De, McLd HL. Pharmacgc: ug DnA pmz

drug hrapy.Am Fam Physician 2007; 76: 117982.

8 Baudhu LM, Lagma LJ, oKa DJ. trala

pharmacgc cl cally rlva g mdal. Clin

Pharmacol Ther2007; 82: 37376.

9 R CJ, Kazv H, Carl B, Hayd MR. Pharmacgmc ad

mplca r aummu da.J Autoimmun 2007; 28:12228.

10 Luh Je, Prmhamd M, Gurwz D. Pralzd mdc:

dcad away? Pharmacogenomics 2006; 7: 23741.

11 Prmhamd M, Brckrdg AM, Krgham nR, Park BK.

Advr drug rac. BMJ1998; 316: 129598.

12 Prmhamd M, Park BK. Advr drug rac: back h uur.

Br J Clin Pharmacol 2003; 55: 48692.

13 Mybm RH, egbr AC, edward iR, Hkr YA, d Kg H,

Grbau W. Prcpl gal dc pharmacvglac.

Drug Sa1997; 16: 35565.

fuRThER READIng

eurpa Agcy r h evalua Mdcal Prduc (eMeA)

wb. Avalabl a: www.ma.u.

MHRA. Drug ay upda ad Yllw card dal. Avalabl a: www.

mhra.gv.uk/dx.hm

Mucklw JC, Wallr DG. Gradua hrapuc. A prmr r MRCP ad

pcal rag. oxrd: Burwrh-Hma, 2001.

Pag C, Cur M, sur M, al. igrad pharmaclgy, 2d d.

s Lu: Mby, 2002.

Rd JL, Rub PC, Walr MR. Clcal pharmaclgy ad hrapuc,

7h d. oxrd: Blackwll, 2006.
http://www.emea.eu.int/http://www.mhra.gov.uk/index.htmhttp://www.mhra.gov.uk/index.htmhttp://www.mhra.gov.uk/index.htmhttp://www.mhra.gov.uk/index.htmhttp://www.emea.eu.int/

Documents

Clinical Pharmacology - The Basics 3