Download Pharmacokinetics

BS2560 Pharmacology and Toxicology
Introduction to Pharmacokinetics
Literally means the movement of drugs inside the body. In order to determine whether
or not a drug is effective we must study its pharmacokinetic properties.
For a drug to be effective it has to:
 reach the site of action,
 in an active form and at a
 sufficiently high concentration to be effective
Pharmacokinetics involves the following aspects of drug function:
Absorbtion
Distribution
Metabolism
Excretion
Drug formulation and Administration
Pills, tablets, capsules or liquid preparations taken orally
Topical preparations – drops, creams and ointments, gels and lotions
Sub-lingual administration
Intranasal administration
Transdermal administration
Rectal administration
Vaginal administration
Parenteral (any method which avoids gastro-intestinal tract) but mainly reserved for
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Sub-cutaneous.
Intramuscular.
Intravenous injections
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More rarely Epidural (into CNS at 5th lumbar vertebra)
Or intra-articular, directly into joints
Absorbtion and Distribution
When a drug is administered by most routes, absorbtion has to take place before the
drug gains access to its site of action. In most cases drugs have to cross membrane(s).
On oral administration there are layers of protective mucus in the gastrointestinal tract
and the membranes of the lining epithelial cells which have to be crossed before the
drug reaches the bloodstream.
The chemical nature of the drug determines how this process takes place but most
drugs are absorbed by simple diffusion relying on a concentration gradient.
But the drug must be sufficiently hydrophobic (lipophilic) to cross membranes easily.
Also smaller molecules can cross membranes more easily than larger ones but if a
small molecule is ionised this will also prevent efficient absorbtion. Many drugs are
amphipathic (have both hydrophobic and hydrophilic properties) which can makes
absorbtion easier
Effect of pH in the gut
The pH of the gut varies from slightly alkaline in the saliva to about pH 3 in the
stomach and pH 8 in the duodenum. Therefore weak acids ( -COOH) become more
lipophilic and more easily absorbed in the stomach. On the other hand drugs
containing basic groups such as –NH2 will become charged (-NH3+) in the stomach
and less easily absorbed. Having said that there are two other important factors- the
time a drug spends in the stomach is relatively short compared with the time in the
small intestine and the surface area for absorbtion in the small intestine is much
greater. Hence whether a drug is taken with, before, or after a meal can have a
significant effect.
Protein Binding
When a hydrophobic drug enters the bloodstream it usually has limited solubility in
the aqueous plasma but the high concentrations of blood proteins such as albumin aid
the transport of drugs because of the amphipathic nature of proteins ((i.e. have
hydrophobic and hydrophilic regions). There is an equilibrium between the bound and
free form of the drug
P + D  [PD]  P + D
When the drug is released it can leave the bloodstream and more free drug will be
released.
Effective Drug Concentration
The stronger the protein binding the less free drug will be present in the plasma. It is
the free drug which is effective drug.
In some cases drugs taken in combination can compete for the same binding site (e.g.
warfarin and aspirin). Aspirin can increase the free form of warfarin with potentially
disastrous results. Warfarin is used as an anticoagulant but is poisonous in high
doses). Also when a patient is suffering hypoproteinaemia (kwaskiorkor or some other
cause) this can lead to abnormal levels of free drug
Role of Liver
Most drugs absorbed by the gastrointestinaltract are taken to the liver via the hepatic
portal vein. The liver is a major site of drug metabolism (and inactivation). If a drug is
metabolised before it reaches the general circulation it is going to be ineffective.
Hence for some drugs other routes of administration are preferable. Glyceryl trinitrate
(used to treat angina) is 96% eliminated via the hepatic route and is administered sublingually and absorbed via oral mucosa.
Blood-brain Barrier
The blood capillary system in the brain has a somewhat different structure which
prevents absorbtion of most drugs unless they are very lipophilic or are actively
transported. This prevents drugs circulating in the bloodstream from entering the brain
tissue with harmful consequences. The blood brain barrier is not always totally
effective for example some anti-histamines cause drowsiness because they are
sufficiently lipophilic to cross the barrier.
Volume of Distribution
The total plasma volume for a 70Kg adult is 5 litres.
Total volume of water in all compartments within the body is 40 litres
Vd = Drug Dose/concentration in plasma
If the drug is totally contained in the bloodstream (e.g. heparin) Vd = 5 litres
If the drug enters all cellular compartments Vd = 40 litres
If the drug is sequestered by binding to proteins e.g. receptors or concentrated in a
particular tissue (e.g. adipose the apparent Vd can be thousands of litres. e.g.
chloroquine used in the treatment of malaria has a Kd of~13,000 ! clearly much more
than the total volume of water
Drug metabolism
The human body takes in a lot of organic compounds for which it has no use and has
developed methods to metabolise these to a form which is less harmful and more
easily excreted
Phase 1 metabolism: Introduction of reactive groups (e.g. –OH, -NH2, -SH) or
removal of lipophilic groups (-CH3, -C2H5) to make a more polar molecule.
Oxidation: involves CytP450 or alcohol dehydrogenase
Reduction
Hydrolysis
Isomerisation
Often the drug induces enzymes responsible for the breakdown of itself and/or other
e.g alcohol induces several enzymes also responsible for drug metabolism.
Barbiturates are also potent inducers of enzymes so after a while you need higher and
higher doses of the drug to be effective
Phase II metabolism
Conjugating the drug or a metabolite from Phase I with a polar molecule (such as
glucuronicacid) to make it more water-soluble and easily excreted:
Typically UDP-Gla + Drug- OH  Drug- O-Gla +UDP
Essentially an irreversible reaction
Drug Excretion
Drugs are excreted either unchanged or as metabolites normally via the kidney in the
urine or via the liver, in the bile and eventually appear in the faeces.
There are other routes of excretion via saliva, breath, sweat and tears (Alcohol and
gaseous anaesthetics are excreted via the lungs)
Drug dosage and blood levels
The level of a drug in the bloodstream is therefore a combination of different factors
namely dose, rate of absorbtion, distribution metabolism and excretion.
Plasma clearance
The Clearance (Cl) of a drug is the volume of plasma from which the drug is
completely removed per unit time (units ml/min). The amount eliminated is
proportional to the concentration of the drug in the blood.
You can calculate this constant characteristic of a particular drug from the rate of
clearance of the drug and the volume of distribution (make sure that the units
correspond)
Cl = Kel*Vd
Kel = Cl/ Vd (Kel = slope of graph of Log plasma concentration/time)
Half –Life (t1/2)
An important kinetic parameter when discussing drug efficacy is its half-life
circulating in the plasma. This is the time required for the plasma concentration to
drop by 50% as the result of metabolism and excretion. Clearly drugs with short half
lives need to be administered more often than those with longer half-lives..
100%  50%  25%  12.5%  6.25% so after 4 half lives 93,75 of the drug has
been eliminated!
Kel and t1/2 are related
Kel = 0.693/ t1/2
and (t1/2) =0.693* Vd/Cl
This is fine but it refers to a single compartment model in which we assume that the
blood plasma is the only compartment but as we know the human body contains may
compartments which complicates matters.
Bioavailability
Fraction of the administered dose that is available in the blood. For non-protein bound
drugs injected intravenously availability is 100%. For any other route it is going to be
less than 100% because inefficient absorbtion, liver metabolism and a number of
other factors. It is calculated by comparing the graphs of concentration against time
for the drug administered orally and by intravenous injection and measuring the area
under the curve in each case. If a drug is bound to a plasma protein then only a
fraction of the drug will be available.
D R Davies 2006