Pharmacokinetics

INTRODUCTION TO
PHARMACOLOGY
CONCEPTS
Dr Sufyan Akram

WHAT ARE DRUGS?
Pharmacology studies the effects of chemical
substances on the function of living organisms.
Initially, tissue and animal experiments enabled
observation of the qualitative effects and
measurement of quantitative effects of these
chemicals.
Therapeutic uses were discovered for human
beings, and later, drugs were developed and even
designed to exert specific effects.

WHAT ARE DRUGS?
More recently, advances in the study of cell and
molecular biology have moved the theoretical basis
of pharmacology rapidly forward. Newer concepts
have replaced the historical theories, and
biotechnology now underpins the development of
drugs.
The typing and cloning of the human genome has
given further, exciting prospects for therapeutic
development. The genetic makeup of individuals
determines their response to drugs, and genetic
variation is complex. Pharmacogenetics is an
evolving subject, and although still theoretical, the
future of pharmacogenomics could be very
promising.

The route of
administration
determines the degree
of absorption, and thus
the dose required for
sufficient drug to enter
plasma in the systemic
circulation. The drug
leaves the plasma to be
distributed to its site of
action and to storage
sites (fat deposits).
Finally, the majority of
drugs are metabolised
before excretion.

PHARMACOKINETICS
Absorption, into the body and into cells
Distribution, around the different compartments of
the body
Metabolism, when the drug is broken down and
inactivated, or sometimes transformed into an active
form
Elimination or excretion from the body

ABSORPTION
Absorption is important for all routes of drug
administration except intravenous injection.
A drug must cross at least one cell membrane to be
absorbed, reach its site of action and eventually be
eliminated.
The ways that drugs, nutrients and other substances
(solutes) in aqueous solution cross a membrane barrier
are by:
 Passive diffusion through cell membranes
 Carrier-mediated transport
 Endocytosis and exocytosis
 Diffusion through aqueous pores and intracellular pores
Absorption Distribution Metabolism Elimination

PASSIVE
(No Energy
Required)
ACTIVE
(Requires Energy)
Kinds of
Transport
No
Help
Membrane
Proteins
Vesicle
s
Diffusi
on
Facilitate
d
Diffusion
Pumps Endocyto
sis
Exocyto
sis
e.g. O2 and
CO2
Carrie
r
Protei
ns
Chann
els
e.g.
Glucos
e
Aquapori
ns
Ion
Chann
els
e.g.
H2O e.g.
Na+
and K+
e.g. Na+- K+
pump
Used by
Glogi for
export
e.g.
Phagocyto
sis and
Pinocytosi
s

A. PASSIVE DIFFUSION
The majority of drugs pass through cell membranes by
the passive diffusion of molecules down a concentration
gradient, which does not involve energy expenditure.
The rate of diffusion across the membrane depends on:
 The lipid solubility of the drug
 The area over which absorption occurs
 The concentration gradient across the membrane
A drug must be water soluble to be distributed
throughout the body. However, cell membranes are
mostly composed of lipids !

Ionised and non-ionised forms of a drug
 Most drug molecules exist in solution as a mixture of ionised
and non-ionised forms
 The ionised form carries an electrical charge, has very low
lipid solubility and cannot easily permeate lipid membranes.
The non-ionised form carries no charge, is lipid soluble and
easily diffuses across cell membranes
If the pH on either side of a cell membrane is different,
the degree of ionisation of a drug on either side will also
be different
The effect of pH partitioning results in the accumulation
of weak acids in compartments with relatively high pH
(basic), and weak bases accumulate in compartments
with a relatively low pH (acidic). This is the concept of ion
trapping

Changes in plasma pH due to acidosis or alkalosis can
have a significant effect on the pH partitioning or ‘ion
trapping’ of drugs:
 In acidosis, blood pH falls so that the pH difference, or
gradient, between the extracellular and intracellular fluids
rises. An acidic drug would be retained in the cells.
 In alkalosis, blood pH rises so that indirectly, the difference
between interstitial pH and intracellular pH decreases. Acidic
drugs would tend to accumulate in the extracellular fluid.
The effects of metabolic or respiratory acidosis or
alkalosis on drug absorption and distribution are of
importance when treating patients with conditions such
as respiratory failure and diabetic ketoacidosis.

B. CARRIER-MEDIATED
TRANSPORT
Drugs that are ionised in plasma and will not diffuse into
the cells, require specialist transmembrane proteins to
carry them across cell membranes.
Cells have two major classes of transmembrane proteins:
 Transporters (carrier proteins)
 Ion channel proteins
Transporters (Carrier Proteins):
A given transporter is specific for a small group of
related substrate molecules, which compete for the
transporter. Protein transporters can be the sites of drug
action, when the drug is similar to the substrate and
competitively binds to the transporter.

B. CARRIER-MEDIATED
TRANSPORT
There are three classes of transporters:
 Uniporters
 Symporters
 Antiporters

B. CARRIER-MEDIATED
TRANSPORT
Ion Channel Proteins:
Ion channel proteins are large proteins forming water-
filled pores that span the lipid bilayer of cell membranes.
These channels allow ions of appropriate size and charge
to be transferred across.
All ion channel proteins allow solutes to cross
membranes by facilitated diffusion without energy
expenditure. The channel, or pore structure, is either
open or closed and the conformational change is called
gating, as in opening and closing a gate

C. ENDOCYTOSIS &
EXOCYTOSIS
Very large molecules (macromolecules), such as proteins,
cannot be transported across the cell membrane by
transporters, and have to be taken into or out of the cells
through the processes of endocytosis and exocytosis.
Drugs can facilitate or inhibit these processes.

D. AQUEOUS &
INTRACELLULAR PORES
Most biological membranes are relatively permeable to
water that passes across the cell membrane via aqueous
pores that results from osmotic differences across the
membrane, carrying extremely small, water-soluble
molecules of less than 100 daltons in diameter with it
(e.g. lithium, urea, ethanol).
Gap Junctions:
Gap Junctions between cells may allow the transfer of
free, not protein bound, drug molecules in solution.
Other junctions prevent the transfer of molecules, and
are known as tight junctions.

D. INTRACELLULAR PORES
The ability of drugs to penetrate the endothelial
membrane varies from one tissue to another.
Gap junctions in vascular endothelium allow bulk
transfer of drug molecules free in solution but not those
bound to plasma proteins.
In contrast, in the blood–brain barrier and the placenta,
the capillary membranes are tightly joined together with
only a few tight junctions, so that drugs can only pass
through the membrane either by passive diffusion (lipid
soluble molecules) or carrier-mediated transport.

DISTRIBUTION
Depending on pH, ionisation and lipid solubility, drugs
can be moved for short distances by diffusion and
membrane transport.
Rapid transport over long distances around the body has
to be done in the bloodstream, partly in solution as free
(unbound) drug and partly bound to blood components
(plasma proteins, blood cells).
The bound and unbound forms are in equilibrium, and
only the unbound drug is available for passive diffusion
from the bloodstream to tissue sites where the
pharmacological effects occur.

DISTRIBUTION
Drug distribution is the process by which a drug is
transferred from the bloodstream (plasma) to tissues
(interstitial fluid and cells). The rate and degree of drug
distribution throughout the body depends on:
 Blood flow
 Capillary permeability
 Protein binding
 Accumulation in and redistribution to other sites
Once a drug enters the body, it can be distributed
between four major aqueous compartments:
 Plasma
 Interstitial
 Intracellular
 Transcellular

BODY FLUID COMPARTMENTS
Total body water, as a percentage of body weight, varies
from approximately 50% to 75%, depending on age and
sex. Women tend to have lower body water due to
increased body fat
The pattern, or extent of drug distribution into the fluid
compartments depends on:
 Permeability between cell membranes
 Protein binding within compartments
 pH partitioning
 Accumulation in adipose tissue
The estimated amount of drug that is distributed from
plasma to other aqueous compartments is important,
because the pharmacological effects of drugs are exerted
in those compartments

Some drugs remain in the plasma because their
molecules are too big to cross capillary membranes into
tissues (e.g. heparin).
Highly protein-bound drugs tend to remain in the
plasma.
The amount of drug needed to reach a plasma
concentration that enables adequate distribution to
effector tissues depends on the extent of distribution
from plasma. This will determine the therapeutic dosage
that needs to be administered
While it is possible to measure drug concentration in
total body water in animal experiments, only plasma
concentration is measurable in humans

The apparent volume of distribution measures the
concentration of free and protein-bound drug remaining
in the plasma after distribution is completed, and is used
to predict distribution of the drug in the various
compartments of the body.
However, it does not indicate where and how much drug
has been taken up by effector tissues.
Apparent volume of distribution:
 Gives an estimate of total drug in the body in relation to
plasma concentration, and the concept is useful for
monitoring progress when treating drug toxicity and
overdose.
 Is related to drug clearance from the body and indicates the
overall rate of drug elimination
 Can predict tissue drug concentration from the above two

OTHER FACTORS…
Protein-binding of Drugs:
At therapeutic plasma concentrations, many drugs bind
extensively to plasma and intracellular proteins. This
limits the amount of drug available for distribution
outside the bloodstream. The protein-bound drug
molecules cannot permeate cell membranes, be
metabolised, excreted or produce their effect.
Drug Distribution to Special Organs:
Many drugs cannot gain access to the brain because of
the blood–brain barrier by virtue of tight junctions.
Lipid-soluble drugs given to the pregnant mother can
cross the placental barrier to the fetus by passive
diffusion.

METABOLISM
Drug metabolism is the process by which the body
produces a change to the chemical structure of a drug
molecule by enzyme activity.
The outcomes of drug metabolism may be:
 The inactivation of drug so that it no longer has any
biological activity
 To produce metabolites with less biological activity
 To produce active metabolites that may be more potent and
persist longer than the parent compound
 To convert an inactive pro-drug to the active form
 To produce toxic metabolites
 To produce inactive metabolites that are water soluble for
excretion

METABOLISM
The liver is the major organ for drug metabolism. After
absorption from the gastrointestinal tract, orally
administered drugs pass through the liver via the portal
vein before distribution to other organs. The liver may
extensively metabolise and inactivate some drugs. This is
the concept of first pass metabolism.
Metabolic reactions for drugs are classified as:
 Phase I reactions, or pre-conjugation reactions followed by
 Phase II reactions, consisting mainly of conjugation
The enzymes involved in both phases are located in:
 Smooth endoplasmic reticulum (Microsomal Enzymes)
 Cytoplasm
 Mitochondria

‘PHASE I’ REACTIONS
Phase I reactions, or pre-conjugation consisting of
oxidation, reduction and hydrolysis reactions
Mainly take place in the liver and are mediated by
microsomal enzymes. The collective term, the mixed
function oxidase (MFO) system, is used to describe the
hepatic microsomal enzymes
Oxidation is the most important of phase I reactions
Cytochrome P-450 is the most important enzyme system
in the diverse group of enzymes that catalyse oxidation
in humans
The cytochrome P-450 system is a superfamily of related
but distinct microsomal liver enzymes, subject to genetic
variation

‘PHASE I’ REACTIONS
Some drugs cause enzyme induction or inhibition,
thereby reducing or enhancing the therapeutic effect of
another, co-administered drug
 Some anticonvulsants (e.g. phenytoin) and rifampicin induce
cytochrome P-450 enzymes, which increase the rate of
metabolism and thus reduce the therapeutic effect of warfarin
if administered at the same time. Patients on anticoagulant
therapy being prescribed rifampicin or phenytoin will need a
higher dose of warfarin
 Grapefruit Juice ?!

‘PHASE II’ REACTIONS
Phase II reactions, consisting of conjugation and
acetylation reactions
Synthesis of a covalent bond between a highly polar,
normal substance in the body (endogenous) with a phase
I metabolite or sometimes with the parent drug
Energy is needed for synthesising the bond. The
conjugate is a less lipid-soluble, more water-soluble
compound that is readily excreted in urine and/or bile
and usually pharmacologically inactive
The most important phase II reaction is glucuronidation,
when a molecule of glucuronic acid is transferred to the
drug molecule
Conjugation with glutathione represents a major
detoxification pathway for a number of drugs

FACTORS AFFECTING DRUG
METABOLISM
Genetic factors
 When known, differences in the expression of metabolic
enzymes in different groups of people need to be taken into
account when prescribing. There is genetic variation in the
ability of unrelated individuals to metabolise drugs
Environmental contaminants and drugs
 The activity of drug metabolising enzymes can be induced
(increased) or inhibited (decreased) by chemicals contained in
environmental contaminants and drugs (e.g;
Organophosphate pesticides, Polycyclic aromatic
hydrocarbons (contained in cigarette smoke), Alcohol in
chronic alcohol consumption)

EXCRETION
Water-soluble drugs may be excreted unchanged,
whereas metabolic inactivation makes drugs more
soluble for excretion. The main routes of excretion for
drugs and their metabolites are via:
 The renal system
 The hepatic/biliary system
 The lungs: this route is important in the excretion of gaseous
anaesthetics

A. THE RENAL SYSTEM
Glomerular filtration
Drugs and metabolites are excreted via renal glomeruli
by filtration. The kidneys are highly perfused organs and
receive about 25% of cardiac output of which 20% is
filtered (180 L/day) to produce the initial urine.
Glomerular capillaries allow the filtration of molecules
with a molecular weight of below 20 000, irrespective of
whether they are anions or cations, ionised or non-
ionised.
Plasma proteins, which have a molecular weight of 68
000 or more, and protein-bound drugs are not normally
filtered. Therefore protein binding of drugs significantly
affects their elimination via glomerular filtration.

A. THE RENAL SYSTEM
Tubular secretion
Tubular secretion takes place in the proximal renal
tubules. Here the tubule removes a wide variety of
substances from plasma into the lumen of the tubule
through active transport.
In the proximal tubule there are two non-specific
carrier-mediated transport processes:
 A cation transporter for weak bases (e.g. quinine, morphine)
 An anion transporter for weak acids (e.g. penicillin,
furosemide)
These two processes are rapid and saturable. In contrast
to glomerular filtration, protein binding of the drug has
no effect on drug clearance via tubular secretion.

A. THE RENAL SYSTEM
Tubular reabsorption
Tubular reabsorption of drugs takes place in the distal
convoluted tubules of the kidney.
There are specific transporters in the nephron for the
reabsorption of essential constituents of tubular filtrate
(e.g. amino acids, glucose, vitamins, water), but only very
rarely are drugs reabsorbed in this way.
The majority of drugs that are reabsorbed are lipid
soluble and pass through the distal convoluted tubule
membranes by passive diffusion.

A. THE RENAL SYSTEM
As the degree of ionisation of a drug depends upon the
pH of the urine and pKa of the drug, altering the pH of
urine can promote drug excretion !

B. HEPATOBILIARY
EXCRETION
Drugs, and glucuronide conjugates formed in the liver,
can be secreted into the bile by active transport
processes similar to those found in the renal tubules for
anions and cations.
Basic drugs (e.g. atropine) and non-ionised molecules
(e.g. digoxin) can also be secreted into bile. Biliary
secretion becomes more important as the molecular
weight exceeds 300.
Drugs and their metabolites with molecular weight
exceeding 300 are released into the alimentary tract
where:
 Either the drug or conjugate can be excreted via the faeces
 Or the bacterial flora of the lower intestine may hydrolyse the
conjugated drug back to the original drug, which is then
reabsorbed by the intestine (e.g. oestrogens, morphine). This

ROUTES OF DRUG
ADMINISTRATION
Choosing how any particular drug is administered
depends on how quickly effective plasma concentrations
must be achieved, and how the drug is absorbed into the
systemic circulation, metabolised and excreted.
The main routes of administration of a drug are:
 Oral (PO)
 Parenteral: intravenous (IV), intramuscular (IM), subcutaneous
(SC)
 Buccal/sublingual
 Rectal (PR)
 Transdermal and topical (vaginal, nasal, ocular)
 Inhalation

SOME BASIC MATHEMATICS

The mathematical basis of pharmacokinetics seeks to
analyse the drug concentration in different parts of the
body, over time from administration to arrival at the site
of action.
The mathematics is complicated, attempting to
synthesise the four basic processes of drug absorption,
distribution, metabolism and excretion. These processes
affect:
 The amount of drug that arrives at the site of action
 The intensity of action
 The duration of action

SOME BASIC MATHEMATICS

First-order Kinetics
Zero-order Kinetics
Multiple Dosing and Steady State

Drug
Accumulation
and Steady
State
Concentration

REFERENCES
Naish et al. Medical Sciences (2011)
 Chapter 4
Lippincott Illustrated Reviews: Pharmacology 5th ed
(2011)
 Chapter 1

Pharmacokinetics

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Pharmacokinetics