PHARMACOKINETICS

Pharmacokinetic can be define as the profile of absorption,

distribution, metabolism and excretion of drugs and their
metabolites. The four important pharmacokinetic parameters are
bioavailability, clearance, volume of distribution and half-life.
Pharmacokinetic – pharmacodynamic principles – helps to relate
dose of a drug and its effect (dose – effect relationship).
Pharmacokinetic deals with the dose-concentration relationship
while pharmacodynamic deals with the concentration-effect
relationship.
ABSORPTION
Absorption is the process of transporting a drug form its site of
administration into systemic circulation. The rate of absorption
depend largely on the route of administration, solubility and other
physico-chemical properties of the drug, and some disease conditions
affecting absorption mechanism.
Bioavailability is a pharmacokinetic parameter (of clinical important)
that measures the extent of absorption. Bioavailability can be defined
as the fraction of unchanged drug that reaches systemic circulation
following administration by any route.
ROUTES OF ADMINISTRATION
i) Oral
ii) bucal
iii) Sublingual
iv) Transdermal
v) Rectal
vi) Parenteral (IV, IM & SC, & ID)
vii) Intra-arterial
viii) Intrathecal
ix) Pulmonary
x) Topical
ORAL ADMINISTRATION
It is the most common route of drug administration. It is the safest,
most convenient and the most economical.
Disadvantages of oral route include; limited absorption of some
drugs because of their physical properties (e.g. poor water solubility
or poor lipid solubility), emesis as a result of irritation of the GI
mucosa, destruction of some drugs by digestive enzymes or acidic
gastric pH, irregularities in absorption of some drugs in the presence
of food etc.
Additionally drugs administered through the GI may be metabolized
by the enzymes of the intestinal mucosa or liver before entering
systemic circulation. This process of elimination is called “first-pass
elimination”.
N.B: All these factors mentioned above could affect oral
bioavailability
Oral absorption depends on factors like surface area for absorption,
blood flow to the site of absorption, physical state of the drug
(solution, suspension, or solid dosage form), its water solubility and
the drug’s concentration at the site of absorption. Drug given in solid
form, the rate of dissolution may limit its absorption especially drug
of low aqueous solubility. Since most drugs absorption from the GI
occurs by passive diffusion across the lipid membrane, absorption is
favored when the drug is in the non-ionized lipophilic form.
Weak acids would be better absorbed from the stomach (pH 1-2) than
the intestine (pH – 3 – 6). And vice – versa for weak bases.
AH  A-- + H+ (Weak acid)
BH+  B + H+ (Weak base)
However, the surface area of the stomach is smaller relative to
extremely large surface area of the intestinal villi. Hence, the rate of
absorption form the intestine will be greater than that from the
stomach even if the drug is predominantly ionized in the intestinal
and largely un-ionized in the stomach. Thus any factor that
accelerates gastric emptying will likely increase the rate of absorption
and vice – versa.
The Henderson – Hesselbatch equation relates the ratio of protonated
to unprotonated weak acid or weak base on the drug’s pka and the
pH of the medium as shown below.
Pka – PH = log (protonated)
(unprotonated)
The lower the pH relative to the pka, the greater the fraction of the
drug in the protonated form, hence more of the weak acid will be in
the lipid soluble form (unionized) at acid pH. Likewise more of the
weak base will be in the lipid soluble form (unionized) at alkaline
pH.
Application of this principle is important in the manipulation of drug
excretion by the kidney. If a lipid soluble (unionized) drug is filtered
in the glomerulus, a significant fraction will be reabsorbed by simple
passive diffusion in the renal tubule. Urinary pH can be adjusted to
convert the lipid soluble drug to water soluble ionized form. The
drug will then be “trapped” in the urine. Weak acids are usually
excreted faster in alkaline urine, weak bases are usually excreted
faster in acidic urine.
TRANSPORT OF DRUGS ACROSS CELL MEMBRANE
Drugs cross membrane either by passive or active transport.
Passive Diffusion: It is the main transport mechanism. In passive
diffusion the drug molecule diffuses across a concentration gradient
by virtue of its solubility to the lipid bi-layer. Passive diffusion is
directly proportion to the concentration gradient across cell
membranes, membrane surface area and the lipid-water partition
coefficient of the drug (as stated by Fick’s)
Fick’s law stated that,
Passive flux (of molecule per unit tone)
= (C1 – C2) x Surface area x Partition coefficient
Thickness
Active Transport: In active transport energy in form of ATP or a
carrier protein or both is/are required.
Active transport include carrier mediated membrane transport;
facilitated diffusion and endocytosis/exocytosis
FACTORS AFFECTING ORAL BIOAVAILABILITY
The factors already listed that influence the rate of absorption could
affect oral bioavailability. The most important of the factors is the
first pass elimination.
FIRST PASS ELIMINATION/METABOLISM
This compromise of Hepatic and intestinal first pass. Hepatic First
pass is the metabolism of the drug by the liver (while in portal
system & after absorption) before the drug reaches systemic
circulation. The liver can also excrete the drug into the bile. Intestinal
first pas is the metabolism by the intestinal enzyme (CYP3A4) before
absorption.
So, bioavailability of morphine after oral administration is 33%

Drugs that are highly extracted by liver (or that undergoes extensive
first pass elimination) include verapamil, lidocaine, nitroglycerin
propranolol, morphine, isoniazid and tricyclic anti-depressants like
impramine, amitryptyline e.t.c

Drugs on the other hand that are poorly extracted by the liver are
diazepam, phenytoin, theophylline, warfarin e.t.c.

Sublinqual Administration

Venous drainage from the mouth is to the superior vena cava, hence
bye passing the portal circulation and thereby protecting the drugs
from rapid intestinal and hepatic first pass metabolism eg Sublinqual
nitroglycerin is very effective treatment of Angina. Additionally the
sublingual area is highly perfused, this also enhance absorption even
though the surface area compare to oral route is small.
RECTAL ADMINISTRATION

Approximately 50%of the drug that is absorbed from the rectum will
by-pass the liver hence hepatic first pass metabolism is less than that
of the oral route. Furthermore the major intestinal enzyme CYP3A4
is present in the upper intestine but not in the lower intestine.

Rectal route can cause irritation of the rectal mucosa. E g Diazepam,

Misoprostol, Artesunate e.t.c.

TRANSDERMAL ADMINISTRATION

Absorption of drugs through the skin depends on the surface area

and lipid solubility of the drugs, since the epidermis is a lipid
barrier. The dermis however is freely permeable to many solutes.
The rate of absorption increase with burned, abraded or denuded
skin. Inflammatory condition of the skin increase cutaneous blood
flow and enhance absorption. e.g. of transdermal administration is
nitroglycerin patch for erectile dysfunction/angina, fentanyl patch
for pain relieve and Oestrogen transdermal patch, Testosterone
patch e.t.c.

PULMONARY ADMINISTRATION \INTRANASAL\

INHALATIONAL
The rate of absorption from this route is fast because of the lungs
large surface area and the high pulmonary blood flow. Avoidance of
hepatic and intestinal first pass in another advantage. Inhalational
anesthetic agents like halothane and nitrous oxide are administered
inhalationally. In asthmatic attack nebulized salbutamol can be
administered inhalationally using face mask connected to the
nebulizer. Toxic substances like cocaine, organophosphorus
compound can be absorbed from this route.
PARENTERAL INJECTION:
This include intravenous, intramuscular, subcutaneous route and
intradermal. Bioavailability is more rapid, extensive and predictable
following parenteral injection. The bioavailability for intravenous
injection is 100%. In emergency conditions and when the patient is
unconscious, uncooperative, or vomiting, parenteral injection may be
necessary. Disadvantages of parenteral injection include sepsis, pain
at the site and the self-medications is difficult (it require skills).The
rate of absorption from intramuscular injection is slightly greater
than from the subcutaneous route. The rate of absorption from SC &
IM general depends on blood flow and the solubility of the
preparation.
E.g. of drugs given subcutaneously; SC insulin in the treatment of
type 1 DM, DKA or gestational DM.
SC Lidocaine with epinephrine (a vasoconstrictor) as local anesthetic
agents.
N.B: Substance too irritating to be given SCLY could be given
intramuscularly. Site of intramuscular & subcutaneous injection
include, thigh, arm, abdominal wall and the buttocks.
INTRATHECAL ADMINISTRATION:
Drugs are injected into the subarachnoid space of the spinal cord,
hence bye passing the blood brain barrier. Intrathecal route delivers
drugs that poorly penetrate the BBB directly into the CSF. It also
reduces the dosage require to achieve optimal effects thereby
reducing side effects. The disadvantages of the route include; pains,
sepsis, seizure, neurological deficit, injury to nerves and surrounding
tissues and technicality associated with the procedure.
e.g.:
a) In spinal anesthesia, propofol can be administered intrathecally
b) Intrathecal administration of opiods analgesics like morphine.
c) Intrathecal administration of Methotrexate
INTRA ARTERIAL:
Rarely drug is administrated directly into an artery to localize its
effect in a particular tissue or organ, like in the treatment of liver
tumor & head\neck tumours. Intra-arterial route require great care
and should be reserve for experts.
NB: Drugs administered by any route, excluding intra-arterial route
are subject to first pass elimination in the lung.
TOPICAL APPLICATION
Drugs can be applied to the mucous membrane of conjunctiva,
vagina, oropharynx, nasopharynx, urethral, rectum, skin etc primary
for their local effects.
DISTRIBUTION OF DRUGS
Following absorption, drugs moves from systemic circulation to
various body tissues and fluids. This process is known as
Distribution.
Volume of distribution (Vd) is the pharmacokinetic parameter that
measures the extent of distribution.
Volume of distribution relate the amount of drug in the body to the
blood concentration of the drug (c)
Vd = Amount of drug in the body
C
Volume of distribution is the volume apparently necessary to contain
the amount of drug homogenously as the concentration found in the
blood. Drugs with high volume of distribution have higher
concentration in the extravascular tissue. On the other hand, drugs
with minimum volume of distribution equal to the blood volume are
completely retained in the vascular compartment.
e.g. Vd for chloroquine is 13,000L\70kg, this is even greater than the
TBW (0.6L\Kg). Chloroquire is highly distributed in extra vascular
tissue than in the vascular compartment.
Vd of Digoxin is 500L/70kg.
Volume of distribution is important in calculation the loading dose of
a drug.
Loading dose = Amount in the body
Amount in the body = Vd x Tc
Tc =Target concentration
Loading dose= Vd x Tc
Working example:
A target plasma theophylline concentration of 10mg\L is desired to
relieve acute bronchial asthma in a patient. Calculate the loading
dose. Vd of theophylline = 35L\70kg.
Solution:
Loading dose =35 x 10
35L\70kg x 10mg\L =350mg
350mg/70kg
Loading dose: A Loading dose is the initial higher dose given to
promptly raise the plasma concentration of the drug to the target
concentration. It is usually useful for drugs with longer half-life (four
half-lives have to elapse to attain steady state concentration).
FACTORS THAT MIGHT AFFECT Vd
Lipid solubilty is directly proportional to Vd
Volume of distribution reflects binding of drugs to tissues which
decrease the drug plasma concentration ( ses Vd) and binding of
drug to plasma proteins which increases the drug plasma
concentration ( ses Vd). Changes in tissue mass and plasma proteins
level could affect the volume of distribution e g older people have
decreases skeletal muscle mass and hence have smaller volume of
distribution Ascites and pleural effusion can increase the volume of
distribution of drugs like gentamicin that are hydrophilic and have
small volume of distribution.
DRUG ELIMINATION BY METABOLISM & EXCRETION
Drug Elimination: This occurs by metabolism and /or excretion.
Drug metabolism/biotransformation is the process by which a drug
is chemically modified (biotransformed) to another compound called
metabolite. In most cases the metabolite are inactive or less active.
However in some cases the metabolites are as active as or more active
than the parent drug. E g Diazepam is metabolized to nor-diazepam
and oxazepam, both of which are active. 4-hydrotamoxifen is more
active than tamoxofen. Some drugs are administered as pro-drugs,
in-active or less active form to promote pharmacokinetic profiles E g
Levodopa, an antiparkinsonian drug is metabolized to active
dopamine, α-methyldopa is metabolized to active α-
methylnoradranalin. Fosphenytoin is a phosphate ester of phenytoin.
fosphenytoin is water soluble unlike phenytoin, hence can be given
intravenously.
N.B: Drug metabolism occurs predominantly in the liver.
Drug metabolism is usually divided into two phases, phase I and
phase II.
Phase I (functionalization reaction) and
Phase II (Conjugation reactions)
Phase I:
This involves biotransformation of a drug to more polar metabolite
by introducing or unmasking a functional group. Phase I reactions
are classified as microsomal oxidations, non-microsomal oxidations,
reductions, hydrolysis and hydration.
Oxidation reaction are the commonest reactions and are catalyzed by
mixed function oxidase (MFO).
Microsomal Oxidation: This is catalyzed by microsomal mixed
function oxidase (cytochrome P450) found in the endoplasmic
reticulum of the liver, kidney, lung and intestinal mucosa. All the
reactions involve the initial insertion of a single oxygen atom.
 PHASE II METABOLISM

This usually occur in the liver. It involve conjugation of a drug or its

phase I metabolite with an endogenous substance.

The resulting conjugate is less active and more polar that can be
readily excreted by kidneys. The commonest conjugation reaction
are;

(i) Glucuronidation: Morphine is a good example. Morphine – 3 –

Glucuronide is the major metabolite of morphine.
(ii) Glycine Conjugation: Drugs conjugated with glycine include
salicylic acid and isonicotinic acid.
(iii) Sulfate Conjugation: This is a major conjugation for phenols.
Paracetamol is a good example.
(iv) Acetylation: This involves conjugation with acetylCOA. Sulfon
amide, procainamide and isoniazid are transformed by this
mechanism.

N.B: It is important to note that a drug may be metabolized through

more than one pathway e.g. paracetamol.

Others: Glutathione conjugation, methylation & water conjugation.

EXCRETION OF DRUGS

Renal excretion is majorly responsible for the elimination of most

drugs and/or their metabolites. The main route of excretion of drug
and/or metabolite is the urine, followed by feaces. Some gaseous
substances are excreted through the lungs.
Others include sweat and milk.
However some drugs excreted into the bile are reabsorbed from the
intestine, a process known as entero-hepatic circulation thus
prolonging the effects of the drugs.
The pharmacokinetic parameter that measure the rate of elimination
in relation to the concentration of the drug is known as clearance.
CLEARANCE
Clearance is equivalent to the volume of body fluid from which the
drug is removed per unit time e.g. plasma clearance of 100mls/min
means that, in 1 minute, all of the drug will be removed from 100ml
of plasma.
Clearance is mathematically represented as
CL = Rate of Elimination
Plasma concentration
Since, Cl = Rate of eliminate
C
Rate of elimination = Cl x C
For most drugs clearance is constant over range of therapeutic
concentration. Hence, the rate of elimination is directly proportional
to the plasma concentration of the drug. This is called first-order
elimination. Here the elimination is not saturable.
On the other hand, some drugs like phenytoin, alcohol and aspirin
exhibit a pseudo-zero order, saturable, non-linear – michaelis –
menten elimination. At the concentration greater than km (conc. at
which rate of elimination is 50% of the maximum elimination) the
elimination rate is independent on the concentration.
HALF-LIFE (t1/2):
This is the time required for one-half (50%) of the drug to be removed
from the body. Half-life is useful in determining the time required for
a dosing regimen to achieve steady-state concentration, usually it
takes four (4) half-lives to achieve steady state concentration. It also
takes four (4) half-lives for a drug to be completely eliminated
following direct IV infusion.
Half-life = 0.7 x Vd
Cl

SOURCES OF DRUGS

(i) Natural : From plants, Animals or microorganism

Plant source: Artemisinins – Artemisia annua

Quinine -- Bark of a Cinchona tree

Atropine and Scopolamine --- Mushrooms

Morphine --- Poppy juice (Opium)

D- Tubocurarine ---- Curare Plant

Nicotine ----- Tobacco

 Animal source: Porcine and bovine insulin obtained from the pancreas of

slaughter pigs and cattle’s.

Microorganism: Most of the Antibiotics

Penicillin Mold (fungus) penicillium

Oxytetracycline Steptomyces rimosus

Steptomycin Steptomyces griseus

Chloramphenicol Steptomyces venezulae

Erythromycin Steptomyces erythreus

(ii) Chemical modification of known drug

Some drugs are synthesized in the laboratory by structural modification of the natural

existing compound. e. g. Cholinomimetic agents; natural agents are nicotine, muscarine

and pilocarpine while synthetics are methacholine, Bethanechol and carbachol.

This is the function of a synthetic chemist.

(iii) Denovo Laboratory Synthesis of Drug

This is the ability to predict the appropriate chemical structure of a drug with a prior

knowledge of the structure of its biological receptor. This is called also rational drug

design.

In the past drugs were discovered through random testing of laboratory synthesized

chemicals against a particular disease.

(iv) Highthroughput Sceening (HTS) OR Computer aided drug design: This

is a computer based screening process. A combinatorial chemist creates a

large chemical library (containing hundreds of thousands of structurally

similar chemical compounds). These are now tested against a single drug

target. The chemical compound with the best affinity for the target is the lead

compound.

(v) Biotechnology: Scientist can genetically engineer living system to produce

human insulin, human antibodies and human growth hormone.

(vi) Combination of known drugs to obtain additive or synergistic effects or

Repositioning of a known drug for a new therapeutic use. E. g Coartem is

combination of Artemether with Lumefantrine (Synergism), Fansidar is

combination of Sulfadoxine and Pyrimethamine (Synergism), Lorsatrust-H is

combination of Lorsartan and hydrochlorothiazide (Additive effect) and

repositioning of Artesunate as anti schistosomal agent.

SCOPE OF PHARMACOLOGY