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Published by: saravanan1987 on Aug 29, 2009
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the transfer of the drug from the generalcirculation into the different organs of the body
the removal of the drug from the body,which may involve either excretion or metabolism.Each of these can be described in terms of chemical,biochemical and physiological processes and also inmathematical terms. The mathematical description ofpharmacokinetic processes determines many of thequantitative aspects of drug prescribing:
why oral and intravenous treatments may requiredifferent doses
the interval between doses during chronic therapy
the dosage adjustment that may be necessary inhepatic and renal disease
the calculation of dosages for the very young andthe elderly.The nature of the response of an individual to a par-ticular drug, for example a decrease in blood pressure,depends on the inherent pharmacological properties ofthe drug at its site of action. However, the time delaybetween drug adminstration and response, and the inten-sity and duration of response, usually depend on therate and extent of uptake from the site of administration,the distribution to different tissues, including the site ofaction, and the rate of elimination from the body: insummary, the response of the patient represents a com-bination of the effects of the drug at its site of action inthe body (
) and the effects of the bodyon drug delivery to its site of action (
)(Fig. 2.1). Both pharmacodynamic and pharmacokineticaspects are subject to a number of variables (Fig. 2.1),which affect the dose–response relationship. Pharmaco-dynamic aspects are determined by processes such asdrug–receptor interaction and are specific to the class ofthe drug, e.g.
-adrenoceptor antagonists. Pharmaco-kinetic aspects are determined by general processes,such as transfer across membranes, xenobiotic (foreigncompound) metabolism and renal elimination, whichapply irrespective of the pharmacodynamic properties.Pharmacokinetics may be divided into three basicprocesses:
the transfer of the drug from the site ofadministration to the general circulation
The biological basis of pharmacokinetics
17General considerations17
The mathematical basis of pharmacokinetics
31General considerations31
Chronic administration
Factors affecting pharmacokinetics
Pharmacogenomics, pharmacogenetics and drugresponses
43Fig. 2.1
Factors determining the response of a patient to a drug
PharmacodynamicsDose–response relationshipPharmacokinetics
Specific to drug ordrug classNon-specific, generalprocesses
Interaction with cellularcomponent e.g.receptoror target siteEffects at the site ofactionConcentration–effectrelationshipReduction in symptomsModification of diseaseprogressionUnwanted effectsDrug interactionsInter- and intrapatientdifferencesAbsorption from site ofadministrationDelivery to the site ofactionElimination from bodyTime to onset of effectDuration of effectAccumulation on repeatdosageDrug interactionsInter- and intrapatientdifferences
Ch02.qxd 3/12/05 10:58 AM Page 17
The biological basis of pharmacokinetics
Drug structures bear little resemblance to normal dietaryconstituents such as carbohydrates, fats and proteins,and they are handled in the body by different processes.Drugs that bind to the receptor for a specific endoge-nous neurotransmitter rarely resemble the natural ligandin chemical structure, and they do not usually share thesame carrier processes or metabolising enzymes with thenatural ligand. Consequently, the movement of drugsaround the body is mostly by simple passive diffusionrather than by specific transporters, while metabolism isusually by ‘drug-metabolising enzymes’, which have alow substrate specificity and can handle a wide varietyof drug substrates.
General considerations
Passage across membranes
With the exception of direct intravenous or intra-arterialinjections, a drug must cross at least one membrane inits movement from the site of administration into thegeneral circulation. Drugs acting at intracellular sitesmust also cross the cell membrane to exert an effect. Themain mechanisms by which drugs can cross membranes(Fig. 2.2) are:
passive diffusion
carrier-mediated processes: facilitated diffusion andactive transport
through pores or ion channels
by pinocytosis.
Passive diffusion.
Passive movement down a con-centration gradient occurs for all drugs. To cross a mem-brane, the drug must pass into the phospholipid bilayer(Fig. 2.2) and therefore has to have a degree of lipidsolubility. Eventually a state of equilibrium will bereached in which equal concentrations of the diffusibleform of the drug are present in solution on each side ofthe membrane.
Carrier-mediated processes.
 facilitated diffusion
,energy is not consumed and the drug cannot be trans-ported against a concentration gradient; by comparison,
active transport
is an energy-dependent mechanism result-ing in accumulation of the drug on one side of themembrane. In each case the drug or its metaboliteresembles the natural ligand for the carrier process suffi-ciently to bind to the carrier macromolecule. Examplesof drugs transported into cells via specific carriers thatare used for nutrients include levodopa (Ch. 24), whichcrosses the blood–brain barrier by facilitated diffusion,and base analogues such as 5-fluorouracil (Ch. 52), whichundergoes active uptake. There are a number of rela-tively non-specific carriers which can transport drugsout of cells, such as P-glycoprotein (PGP), organic aniontransporters (OAT1 to OAT4) and organic cation trans-porters (OCT1 and OCT2). PGPis of most importancein the gut, blood–brain barrier and kidneys, and alsoin cells that develop resistance to anticancer drugs(Ch. 52), while the others are most important in thebrain and kidneys (see later). Drugs that bind to carrierproteins but are released only slowly act as inhibitors ofthe carrier; for example, probenecid inhibits the secre-tion of anions, such as penicillins, by the renal tubule(Ch. 51).
Passage through membrane pores or ion channels.
Movement occurs down a concentration gradient andcan only occur for extremely small water-solublemolecules (<100 Da). This is applicable to therapeuticions such as lithium and radioactive iodide.
Principles of medical pharmacology and therapeutics18
Fig. 2.2
The passage of drugs (D) across membrane bilayers
Pore or openion-channelDiffusionthroughlipid bi-layerCarrierprotei(carrier-mediatedprocess)nClosedion-channelDDDDDD
Ch02.qxd 3/12/05 10:58 AM Page 18
This can be regarded as a form of carrier-mediated entry into the cell cytoplasm. Pinocytosis isnormally concerned with the uptake of macromolecules;however, successful attempts have been made to utiliseit for targeted drug uptake by incorporating the druginto a lipid vesicle or liposome (e.g. amphotericin anddoxorubicin – Ch. 51).Anumber of reversible and irreversible processescan influence the total concentration of drug present oneach side of the membrane (Fig. 2.3). Ionisation is afundamental property of most drugs and will occurwhenever the drug is in solution. The majority of drugsare either weak acids, such as aspirin, or weak bases,such as propranolol. The presence of an ionisablegroup(s) is essential for the mechanism of action of mostdrugs, because ionic forces represent a key part ofligand–receptor interactions. Drug receptors are formedby the three-dimensional arrangement of a protein(Ch. 1), and drug binding requires both lipid- andwater-soluble sites within the drug molecule; the latterare usually produced by an ionisable functional group.The overall polarity of the drug and its extent ofionisation determine the extent of distribution (forexample, entry into the brain), accumulation in adiposetissue, and mechanism and route of elimination fromthe body. Ionisation is a fundamental property and occurswhen drugs containing acidic or basic groups dissolvein an aqueous body fluid.[Acidic drug] [Acidic drug]
+ H
[Basic drug] + H
[Basic drug – H]
In general terms, the ionised form of the molecule can beregarded as the water-soluble form and the un-ionisedform as the lipid-soluble form. Drugs with ionisablegroups exist as an equilibrium between charged anduncharged forms. The extent of ionisation can affectboth the pharmacodynamics (for example, the affinityfor the receptor) and the pharmacokinetics (for example,the extent of uptake by adipose tissue and the route ofelimination). The ease with which a drug can enter andcross a lipid bilayer is determined by the lipid solubilityof its un-ionised form. Drugs that are fixed in theirionised form at all pH values, such as the quaternaryamines, cross membranes extremely slowly or not at all;they have limited effects on the brain (because of lack ofentry) and are given by injection (because of lack ofabsorption from the intestine).The extent of ionisation of a drug depends on thestrength of the ionisable group and the pH of thesolution. The extent of ionisation is given by the aciddissociation constant
.Conjugate acid Conjugate base + H
=[conjugate base] [H
](2.1)[conjugate acid]The term conjugate acid refers to a form of the drug ableto release a proton, such as an un-ionised acidic drug(Drug–COOH) or an ionised basic drug (Drug–NH
).The conjugate base is the corresponding equilibriumform of the drug that has lost the proton, such as anionised acidic drug (Drug–COO
) or an un-ionised basicdrug (Drug–NH
).For acidic drugs, the value of
is normally low (e.g.10
) and therefore it is easier to compare compoundsusing the negative logarithm of the
, which is calledthe p
(e.g. 5).For acidic functional groups, a strong acid will havea high tendency to dissociate to give H
; this results in ahigh value for
(e.g. 10
or 10
) and numerically a lowp
(e.g. 1 or 2). Thus, strongly acidic groups (such asDrug–SO
H) have a p
of 1–2, while weakly acidicgroups (such as a phenolic–OH) have a p
of 9–10. Incontrast, for basic functional groups, the stronger thebase, the greater will be its ability to retain the H
as aconjugate acid – resulting in a low
and a high p
.Thus, strongly basic groups (such as R–NH
where R isan alkyl group) have a p
of 10–11, while weakly basicgroups (such as R
N) have a p
of 2–3.
Fig. 2.3
Passive diffusion and the factors that affect the concentrations of drug freely available in solution (as an equilibrium between un-ionisedand ionised forms)
Extracellular fluidIntracellular fluidAdministrationIonisationRedistributionto other tissuesProteinbindingMetabolismExcretionProteinbindingDissolutionin fatIonisationDDD
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