DRUG DISPOSITION
Syllabus: Distribution in blood,
cellular distribution drug penetration to CNS. Drug excretion. salivary
excretion. Drug metabolism, plasma-protein binding and its effect on drug
disposition.
Questions:
1. Illustrate the different
routes of drug degradation. Suggest the means for protection of drugs. (99) 12+4
2. Write short notes on (a)
Renal excretion, (b) Plasma protein binding. (98) 8+8
3. Why is distribution of a
drug not uniform throughout the body? Discuss the factors affecting drug
distribution. (97) 16
4. Write the distribution of
drugs in different body tissues. (96) 8
5. Describe the plasma-protein
binding and its effect on drug disposition. (96) 10
6. Write briefly renal
excretion process. (96) 6
Definition of
drug disposition
After entry into the systemic circulation, either by
i.v. injection or by absorption from any of the various extravascular sites,
the drug is subjected to a number of processes (e.g. distribution, elimination)
called as disposition process that
tend to lower its plasma concentration.
Two major processes are:
1. Distribution
which involves reversible transfer of drug between compartments and
2. Elimination
which causes irreversible loss of drug from the body.
Drug Disposition
 |
Distribution Elimination |
Biotransformation Excretion
(Metabolism)
DISTRIBUTION
Distribution Distribution is the
reversible transfer of a drug between one compartment and other.
Since
the process is carried out by the circulation of blood, one compartment is
always the blood or the plasma and the other represents extravascular fluids
and other body tissues.
Distribution
of a drug is not uniform through out the body because different tissues receive
the drug form plasma at different rates
and to different extents. Differences
in drug distribution among the tissues arise as a result of a number of factors
as follows:
1. Tissue permeability of the drug
(a)
Physicochemical properties like molecular size, pKa and o/w partition coefficient.
(b)
Physiological barriers to diffusion of drugs.
2. Organ / tissue size and perfusion rate.
3. Binding of drugs to tissue components
(a)
Binding of drugs to blood components
(b)
Binding of drugs to extravascular tissue proteins.
4. Miscellaneous factors
(a)
Age (b) Pregnancy (c) Obesity
(d)
Diet (e) Disease states (f) Drug interactions
TISSUE
PERMEABILITY OF DRUGS
Two major rate-determining steps in the distribution
of drugs are:
1. Rate of blood perfusion
2. Rate of tissue permeability
If the
blood perfusion to the tissues are high then the tissue permeability will be
the rate determining step in the process of distribution.
The
tissue permeability of a drug depends upon the physicochemical properties of
the drug as well as the physiological barriers.
(i)Physicochemical properties of the drugs
(a) Molecular
size
MW < 500 daltons MW <50
daltons
Blood Extracellular Cells
Capillary fluids Cell
membrane
membrane Water
channels
Almost
all drugs having molecular weight less than 500 to 600 daltons easily cross the
capillary membrane to diffuse into the extracellular fluid (ECF).
Only
small, water-soluble molecules and ions of size below 50 daltons enter the cell
through water channels. Larger molecules are transported through specialised
transport system existing on the cell membrane.
(b) Degree of
ionisation
Blood
and ECF pH normally remains constant at 7.4, they do not have much of an
influence on drug diffusion unless altered in conditions such as systemic
acidosis or alkalosis.
Most
drugs are either weak acids or weak bases and their degree of ionization at
plasma or ECF pH (i.e. 7.4) depends upon their pKa. All the drugs that ionize
ar plasma pH (i.e. polar hydrophilic drugs) cannot penetrate the lipoidal cell
membrane and tissue permeability is the rate determining step.
Only
unionized drugs which are generally lipophilic, rapidly cross the cell
membrane.
Species
which has greater Ko/w (partition coefficient) penetrates well.
e.g. pentobarbital
and salicylic acid
have
same Ko/w but
pentobarbital
is more unionized at blood pH than salicylic acid and hence distributes
rapidly.
e.g. thiopental,
a nonpolar, lipophilic drug, largely unionise at plasma pH readily diffuses
into the brain.
e.g. penicillins
are polar, and ionized at plasma pH, hence does not cross the
blood-brain-barrier.
(ii) Physiological barriers to distribution of drugs
Some of the important simple and specialised
physiologic barriers are:
1. Simple capillary endothelial
barrier
2. Simple cell membrane barrier
3. Blood-Brain-Barrier (BBB)
4. Cerebro Spinal Fluid Barrier
(CSF Barrier)
5. Placental Barrier
6. Blood-Testis Barrier
1. The simple capillary endothelial barrier:
The
membrane of capillary are unicellular in thickness; are practically no barrier
for drugs having molecular weight under 600 daltons. Only drugs bound to blood
components e.g. plasma protein, blood corpuscles are restricted due to large
molecular size of the complex.
2. The simple cell membrane barrier
Once
a drug diffuses from the capillaruy wall into the extracellular fluid, its
further entry into cells of most tissues is limited by its permeability through
the cell membrane that lines such cells.
The
physicochemical properties that influence permeation of drug across such a
barrier are summarised in the figure above.
3. Blood Brain Barrier
Unlike
the capillaries found in other parts of the body, the capillaries in the brain
are highly specialized and much less permeable to hydrophilic molecules.
The
brain capillaries consist of endothelial cells which are joined to one another
by continuous, tightly intercellular junctions comprising what is called as the
blood-brain-barrier.
More
over the glial cells and basement membrane forms a solid envelope around the
brain capillaries. As a result, the intercellular passage is blocked and for a
drug to gain access from the capillaries circulation into the brain, it has to
pass through cells rather than between
them.
[N.B. However, there are specific sites where BBB
does not exist, namely, in the chemo-receptor trigger zone, and the median
hypothalamic eminence.
Drugs administered intransally may diffuse directly
into the CNS because of the continuity between submucosal area of the nose and
the submucosal area of the nose and the
subarachnoid space of the olfactory lobe.]
·
Since the BBB is a lipoidal barrier, it allows only the drugs having
high Ko/w to diffuse passively.
·
Moderately lipid soluble and partially ionized molecules penetrate at a
slow rate.
e.g.
thiopental is 50 times more lipid
soluble than pentobarbital and
crosses BBB much more rapidly.
·
Polar, natural substances such as sugar,
amino acids are tansported to brain actively.
e.g. For CNS disorders
specialized drug molecules are administered Parkinsonism is a disease caused by
depletion of dopamine in the brain, but it cannot be treated by administration
of dopamine as it does not cross the BBB. Hence, levodopa is given. It diffuses into the brain, metabolized there to
produce dopamine.
4. Blood-cerebrospinal
barrier
The cerebro-spinal fluid (CSF) is formed mainly by the
choroidal plexus of the lateral, third and fourth ventricles and is similar in
composition to the ECF of brain. The capillary endothelium that lines the
choroid plexus have open junctions or gaps and drugs can flow freely into the
extracellular space between the capillary wall and the choroidal cells.
However, the choroidal cells are joined to each other by tight junctions
forming the blood-CSF barrier which has permeability characteristics similar to
that of the BBB.
·
Only highly lipid soluble drugs can cross the blood-CSF barrier with
relative ease.
·
Moderately lipid soluble and partially ionized drugs permeate slowly. A
drug that enters the CSF slowly cannot achieve a high concentration as the bulk
flow of CSF continuously removes the drug.
5. Placental barrier
The
maternal and fetal blood vessels are separated by a number of tissue layers
made of fetal trophoblast basement membrane and the endothelium which
constitute the placental barrier.
The
human placental barrier has a mean thickness of 25 mm in early pregnancy that reduces to 2 mm at full term. Many drugs having molecular
weight less than 1000 daltons and moderate to high lipid solubility e.g.
ethanol, sulfonamides, barbiturates, gaseous anaesthetics, steroids, narcotic
analgesic, anticonvulsants and some antibiotics, cross the barrier by simple
diffusion quite rapidly. Hence, the placental barrier is not as effective as a
barrier as that of BBB.
Nutirents
essential for fetal growth are transported by carrier-mediated processes.
Immunoglobulins transported by endocytosis.
Drugs are particularly dangerous to the fetus.
6. Blood
Testis Barrier
This
barrier is located at the capillary endothelium level but at sertoli-sertoli
cell junction. It is the tight junction between the neighbouring sertoli cells
the act as blood-testis barrier. This barrier restricts the passage of drugs to
spermatocytes.
ORGAN/TISSUE
SIZE AND PERFUSION RATE
Perfusion rate is defined as the volume of
blood that flows per unit time per unit volume of the tissue. It is expressed
in ml (of blood)/min/ml (of the tissue).
Relative
volume of different organs and tissues and their perfusion rates
(Assumption: Normally total body volume is 70
liters)
Organ/Tissue
|
% of Body volume
|
Perfusion rate
(ml/min/ml)
|
I. Highly
perfused tissue
1.
Lungs
2.
Kidneys
3.
Adrenals
4.
Liver
5.
Heart
6.
Brain
II. Moderately
perfused tissue
7.
Muscles
8.
Skin
III. Poorly
perfused
9.
Fat (adipose tissue)
10.Bone
(skeleton)
|
0.7
0.4
0.03
2.3
0.5
2.0
42.0
15.0
10.0
16.0
|
10.2
4.5
1.2
0.8
0.6
0.5
0.034
0.033
0.03
0.02
|
kt is the first-order distribution rate
constant.
Now kt is given by the following equation:L
where Kt/b is the tissue/blood partition
coefficient of a drug.
Extent of
distribution:
The extent to which a drug is distributed in a
particular tissue of organ depends upon the size of the tissue (i.e tissue
volume) and the tissue/blood partition coefficient Kt/b .
Example:
Properties of thiopental:
1. Thiopental is a short acting
anaesthetic. It is injected intravenously.
2. It
is lipophilic drug and has affinity for both brain tissue and adipose tissue
(fat). Blood-adipose partition
coefficient is higher than the blood-brain partition coefficient.
3. Brain
is the site of action of thiopental.
Events
|
Cause
|
1.
When an i.v injection is given it shows rapid onset of action
2.
Short duration of action and rapid termination of action
|
1.
Thiopental diffuses rapidly into the brain.
Adipose tissue being
poorly perfused, takes longer to get distributed with thiopental
2. As the concentration of
thiopental in the adipose proceeds towards equilibrium, the drug rapidly
diffuses out of the brain and localizes in the adipose tissue whose volume is
more than 5 times that of brain and has greater affinity for the drug. The
result is rapid termination of action of thiopental due to such tissue
redistribution.
|
FACTORS
AFFECTING DRUG DISTRIBUTION
Age
Differences in distribution pattern
of a drug in different age groups are mainly due to differences in –
(a)
Total body water (both intracellular
and extracellular) – is much greater in infants.
(b)
Fat content – is also higher in
infants and elderly.
(c)
Skeletal muscles – are lesser in
infants and in elderly.
(d)
Organ composition – the blood brain
barrier is poorly developed in infants, the myelin content is low and cerebral
blood flow is high, hence greater penetration of drugs in the brain.
(e)
Plasma protein content – low albumin
content in both infants and in elderly.
Pregnancy
During pregnancy, the growth of
uterus, placenta and fetus increases the volume available for distribution of
drugs. The fetus represents a separate compartment in which a drug can
distribute. The plasma and the extracellular fluid volume also increase but
their is a fall in albumin content.
Obesity
In obese persons, the high adipose
tissue content can take up a large fraction of lipophilic drugs despite the
fact that perfusion through it is low. The high fatty acid levels in obese
persons alter the binding characteristics of acidic drugs.
Diet
A diet high in fats will increase
drugs such as NSAIDs to albumin.
Disease states
A number of mechanisms may be involved in the alteration of drug
distribution characteristics in disease states:
a. Altered albumin and other drug-binding protein
concentration
b. Altered or reduced perfusion to organs or tissues
c. Altered tissue pH.
Example: An
interesting example of altered permeability of the physiologic barrier is that
of blood brain barrier (BBB). In meningitis and encephalitis, the BBB becomes
more permeable and thus polar antibiotics such as penicillin G and ampicillin
which do not normally cross it, gain access to the brain.
Drug interactions
Drug interactions that affect
distribution are mainly due to differences in plasma protein or tissue binding
of drugs.
PROTEIN BINDING OF DRUGS
A drug in the body can interact with
several tissue components of which the two major categories are blood and
extravascular tissues. The interacting molecules are generally the
macromolecules such as proteins, DNS and adipose tissue.
The
phenomenon of complex formation with proteins is called protein binding of drugs.
Protein-drug
binding: Binding of drugs to various tissue components and its influence on
deposition and clinical response. Only the unbound drug moves reversibly
between the compartments.
BONDS
INVOLVED IN PROTEIN BINDING
Binding
of drugs generally involves weak chemical bonds such as
1. hydrogen bonds,
2. hydrophobic bonds,
3. ionic bonds, or
4. vander Waal’s forces
and,
therefore is a reversible process.
Irreversible
drug binding, though rare, arises as a result of covalent binding and is often
a reason for the carcinogenicity or tissue toxicity of the drug; for example
chloroform (CHCl3) and the metabolite of paracetamol binds
irreversible with liver and thus results in hepatoxicity.
Binding
of drugs falls into two classes:
1. Binding of drugs to blood components like -
(a) Plasma proteins
(b) Blood cells
2. Binding of drugs to extravascular tissue
proteins, fats, bones, etc.
Of
all type of binding, the plasma protein-drug binding is the most significant
and most widely studied.
BINDING
OF DRUGS TO BLOOD COMPONENTS
Plasma Protein Binding
The extent or order of binding of
drugs to various plasma proteins is:
albumin > a1Acid Glycoprotein >
lipoproteins > globulins
Blood
proteins to which drugs binds
Protein
|
Molecular weight
|
Concentration (g %)
|
Drugs that bind
|
Human
serum albumin
a1 - Acid glycoprotein
Lipoproteins
a1- Globulin
a2- Globulin
Hemoglobin
|
65,000
44,000
200,000
to 3,400,000
59,000
134,000
64,000
|
3.5
- 5.0
0.04
- 0.1
variable
0.003-0.007
0.015-0.060
11-16
|
large
variety of all types of drugs
basic
drugs such as imipramine, lidocaine, quinidine, etc.
basic,
lipophilic drugs like chlorpromazine
steroids
like corticosterone, and thyroxine and cyanocobolamine (Vit. B12)
vitamins
A, D, E and K and cupric ions
Phenytoin,
pentobarbital and phenothiazines
|
Binding of drugs to blood
cells
More than 40% of the blood comprises
of blood cells of which 95% is RBC. Thus significant RBC binding of drug is
possible. The RBC comprises of 3 components:
1. Haemoglobin:
Phenytoin, pentobarbital and
phenothiazines bind to haemoglobin.
2. Carbonic
anhydrase : Acetazolamide and
chlorthalidone (carbonic anhydrase inhibitors)
3. Cell
membranes : Imipramine and
chlorpromazine are reported to bind to RBC membrane.
Tissue binding of drugs
Drug can bind to various tissues.
Tissue-drug binding is important from two point of views:
(i) It increase the volume of distribution (by reducing the
concentration of free drug in the plasma) and
(ii) drug bound to tissue acts as
a reservoir and hence biological half
life increases.
For
majority of drugs that bind to extravascular tissues, the order of binding is :
liver > kidney > lung > muscle.
1. Liver:
Oxidation products of carbon tetrachloride and paracetamol bind irreversibly
with liver tissues resulting in hepatotoxicity.
2. Kidneys: Metallothionin, a protein present in the kidneys, binds to heavy
metals such as lead, mercury and cadmium.
3. Lungs
: Basic drugs like imipramine, chlorpromazine and antihistamines accumulate in
the lungs.
4. Skin
: Chloroquine ad phenothiazines accumulate in the skin by interacting with
melanin pigment.
5. Hairs
: Arsenicals are deposited in hair shafts.
6. Bones
: Tetracycline bind to bones and teeth. [N.B. Administration of
tetracycline to infants or children during odontogenesis results in permanent
brown-yellow coloration of teeth .]
7. Adipose tissues : Lipophilic drugs such as thiopental and pesticide like DDT
accumulate in adipose tissues (fat tissues).
8. Nucleic acid : DNA interacts with drugs like chloroquine and quinacrine resulting
in distortion its double helical structure.
Drug-protein binding is influenced
by a number of important factors, including the following:
1.
The drug
Physicochemical properties of the
drug
Total concentration of the drug in
the body
2.
The protein
Quantity of protein available for
drug-protein binding.
quality or physicochemical nature of
the protein synthesized.
3.
The affinity between drug and protein
4.
Drug interactions
Competition for the drug by other
substances at a protein-binding site.
Alteration of the protein by a substance that modifies the affinity of the drug for
the protein
5.
The pathophysiologic condition of the patient
e.g. drug-protein binding may be
reduced in hepatic diseases.
Kinetics of protein binding
Assumptions: The drug-protein binding is reversible.
On the protein molecule
one binding site is present
Under
this condition the protein binding of drug may be described as follows:
From the law of mass action
eqn
(i)
where
Ka is the association constant. Drugs strongly bound to protein have a very
large Ka.
[ ] this symbol denotes molar concentration
To
study the binding behavior of drugs, a ratio
‘r’ is defined as follows:
hence,
eqn. (ii)
eqn. (ii)
Substituting [PD] = Ka [P] [D] from eqn (i) into eqn (ii) we get:
eq.
(iii)
Eqn.
(iii) describes the situation where 1 mole of drug binds to one mole of protein
in a 1 : 1 complex.
If
drug molecules can bind independently to ‘n’ number of identical sites per
protein molecule then the following equation may be used:
Significance of protein
binding
1. Absorption
From the absorption site the drug is
absorbed to the blood. This absorption process will stop when free drug
concentration at both sides become equal. If the drug is bound significantly to
plasma protein then free drug in the plasma becomes less and hence the
absorption process goes on. Thus much more amount of drug is absorbed.
2. Systemic solubility of drugs
Water insoluble drugs, neutral
endogenous macromolecules (such as heparin, steroids and oil soluble vitamins)
are circulated and distributed to tissues by binding to lipoproteins.
3. Distribution
Some drug may bind to a specific
tissue and may produce toxic reaction to the tissue. Plasma protein binding
restricts the entry of the drug into a tissue, thus saves the tissue. A protein
bound drug does not cross the blood brain barrier, the placental barrier and
the glomerulus.
4. Tissue binding, apparent volume of
distribution and drug storage
A drug that is extensively bound to
blood components remains confined to blood and very little amount of drug will
be available for distribution in the tissues. In this case the apparent volume
of distribution (Vd) will be decreased.
If the drug is bound to some tissue
then the concentration of drug in the blood compartment will be less hence the
Vd will be high.
In both the cases the drug-protein
complex will act as drug reservoir.
5. Elimination
Only the unbound or free drug can be
eliminated because the drug-protein complex cannot penetrate into the
metabolising organ (e.g. liver). The large molecular size of the complex
prevents it from filtration through glomerulus. Thus drugs which are more than
95% bound to protein eliminates slowly and the elimination half life will be prolonged.
6. Displacement interaction and toxicity
If two drugs A and B, both have the
same binding sites to plasma protein then one drug will displace the other.
Thus the free drug concentration of both the drug in the plasma will rise and
may precipitate toxic reaction. e.g. warfarin and phenylbutazone.
7. Diagnosis
Thyroid gland (tissue) has great
affinity for iodine. So any disorder of thyroid gland can be detected by
administering compounds with radioactive iodine (I131)
8. Therapy and drug targeting
The
binding of drugs to lipoproteins can be used for site specific delivery of
hydrophilic moieties. e.g. in cancer therapy tumour cells have great affinity
for LDL (low density lipoprotein) than normal tissues. Hence binding of
suitable neoplastic agent to LDL can be used as a therapeutic tool.
DRUG
ELIMINATION
Drug elimination refers
to the irreversible removal of drug from the body by all routes of elimination.
Drug elimination
 |
Excretion Biotransformation
(Metabolism)
Drug excretion is the removal of the
intact drug. Non-volatile drugs are mainly excreted by renal excretion (i.e. drugs passes through kidneys). Other routes
of excretion are bile, sweat, saliva, milk or other body fluids. Volatile drugs
are excreted through the lungs
Biotransformation or drug
metabolism is the process by which the drug is chemically converted in the
body to a metabolite. Biootransformation is usually enzymatic but some of the
drugs may be chemically changed by nonenzymatic process.
RENAL
DRUG EXCRETION
Drug candidates for renal
excretion:
Drugs that are non-volatile, water soluble, have a low molecular weight, or are
slowly biotransformed by the liver will be eliminated by renal excretion.
Drug
may be excreted via the kidneys by any combination of the following processes:
·
Glomerular filtration
·
Active tubular secretion
·
Tubular reabsorption
Glomerular filtration
·
Most small molecules (MW< 500), including undissociated
(non-ionized) and dissociated (ionized) drugs passes through the wall of the
capillaries in the glomerulus. Large protein-bound drugs do not get filtered at
the glomerulus.
·
The driving force of this filtration is the hydrostatic pressure within
the glomerular capillaries.
·
GFR (glomerular filtration rate) is measured by using a drug that is
excreted by filtration only and that is neither reabsorbed nor actively
secreted. e.g. inulin and creatinine.
The clearance value for
inulin (or creatinine) is equal to 125 to 130 ml/min.
Active tubular secretion
It is an active transport process.
In the renal tubule drug molecules are transported from plasma to the renal
tubule by a carrier mediated system that
·
requires energy
·
it is capacity limited i.e. when the carrier molecules are saturated no
further increase in the transport rate is observed.
·
drugs with similar structures may compete for the site in the carrier
molecule. e.g. Probeneacid will compete with penicillin for the same carrier
system.
·
Two active tubular secretions are found : (1) weak acids and (2) weak
bases.
·
Drug commonly used for measuring active tubular secretion is p-amino hippuric acid (PAH) and
iodopyracet (Diodrast). These drugs are filtered by glomeruli and secreted by
tubular cells. Practically all the drug that enters the kindeys is eliminated
in a single pass (i.e. no reabsorption), hence the clearance for these drugs
reflects the effective renal plasma flow (EPRF)
which varies form 425 to 650 ml/min.
·
Even reversible protein-bound drug can be excreted by active secretion.
The free drug is actively excreted and the bound drugs is then released which
is again excreted.
Tubular reabsorption
After the drug is filtered through
the glomerulus. It may be reabsorbed by the distal convoluted tubules by an
active or passive process.
·
If a drug is completely reabsorbed (e.g. glucose), then the value for
clearance of the drug is approximately zero. For drugs that are partially
reabsorbed, clearance values will be less than the GFR (125 to 130 ml/min).
·
The reabsorption of drugs (weakly acidic or basic) are influenced by
the urine pH and the pKa of the drug. Because undissociated molecules have
greater membrane permeability than the ionized ones. In case of weak acids such
as salicylic acid, acidification of the urine causes greater reabsorption of
the drug and alkalinization of the urine causes more rapid excretion of the
drug.
Drug
|
Glomerular
Filtration Rate (GFR) (ml/min)
|
Active
Secretion Rate
|
Reabsorption
Rate
|
Clearance
(ml/min)
|
Inulin
|
125 – 130
|
0
|
0
|
125 ml/min
|
Clearance
= GFR + Active Secretion Rate – Reabsorption Rate
If
[CL]drug > GFR Þ The
drug is actively secreted
If
[CL]drug = GFR Þ The
drug is filtered only and
No
active secretion of reabsorption is taking place
If
[CL]drug < GFR Þ The
drug is partially reabsorbed.
If
[CL]drug = 0 Þ The
drug is totally reabsorbed.
Since
inulin or creatinine are filtered and through glomerulus and are not reabsorbed
at all hence, the clearance value of inulin or creatiinine is equal to the GFR.
BIO-TRANSFORMATION / DRUG
METABOLISM
Biotransformation
of drugs is defined as the conversion of the drug molecule to another
form by bio-chemical reactions. The reaction is called metabolism and the
altered molecule is called the metabolite.
Metabolism
Drug Metabolite
After
metabolism the metabolites may have the following activities to the original
drug.
Drugs |
Metabolites |
1. Pharmacological
inactivation
Active
Amphetamine
Phenobarbital
Phenytoin
Salicylic acid
|
Inactive
Phenylbutazone
Hydroxyphenobarbital
p-Hydroxyphenytoin
Salicyluric acid
|
2. No change in pharmacological
activity
Active
Amytryptyline
Imipramine
Codeine
Phenylbutazone
Diazepam
Digoxin
|
Active
Nortryptyline
Desipramine
Morphine
Oxyphenbutazone
Temazepam
Digoxin
|
3. Toxicologic activity
Active
Isoniazid
Paracetamol
|
Toxic
Tissue
acetylating intermediate
Imidoquinone
of N-hydroxylated metabolite
|
4. Pharmacologic
activation
Inactive (Prodrugs)
Aspirin
Phenacetin
Sulfasalazine
Pivampicillin
Enalapril
Chloramphenicol palmitate
|
Active
Salicylic acid
Paracetamol
Mesalamine and sulfapyridine
Ampicillin
Enalaprilat
Chloramphenicol
|
5. Change in
Pharmacological Activity
Iproniazid (antidepressant)
Diazepam (tranquilizer)
|
Isoniazid (antitubercular)
Oxazepam (anticonvulsant)
|
Drug metabolizing organs
Liver is the primary site of
metabolism of almost all drugs because it contains a large variety of enzymes
in large amounts.
The
decreasing order of drug metabolizing ability of various is:
Liver
> Lungs > Kidneys > Intestine > Placenta > Adrenals > Skin.
Brain,
testes, muscles, spleen etc. also metabolize drugs to a small extent.
Drug metabolizing enzymes
The enzymes are broadly divided into
two categories:
(i)
microsomal
(ii)
non-microsomal
Microsomal enzymes
These enzymes catalyze the following
reactions
(i) oxidative, (ii) reductive, (iii) hydrolytic, (iv) glucuronidation
The
microsomal enzymes have affinity towards lipid-soluble molecules. They convert
these lipid soluble drugs or molecules into more water-soluble molecules.
Non-microsomal enzymes
These enzymes are present in the
cytoplasm and those attached to the mitochondria but not to endoplasmic
reticulum. The non-microsomal enzymes catalyses :
(i)
few oxidative reactions
(ii)
some reductive reactions
(iii)
some hydrolytic reactions
(iv)
some conjugation reactions other than glucuronidation.
Non-microsomal
enzymes act on relatively water-soluble drugs. Examples of enzymes are
oxidases,
peroxidases, dehydrogenases, esterases etc.
Chemical pathways of drug biotransformation
R.T.Williams
divided the pathways of drug metabolism reactions into two general categories: Phase-I
and Phase-II reactions.
Phase-I reactions
By these reactions a functional
group (e.g. –OH, –COOH, –NH2 and – SH) is introduced or exposed on
the drug molecule.
Phase-I
reactions are also called functionalisation reactions or asynthetic reactions.
|
Phase-I
reactions:
Oxidative reactions
Aromatic hydroxylation
Side chain hydroxylation
N–, O– and S–
dealkylation
Deamination
Sulfoxidation,
N-oxidation
N-hydroxylation
Reduction
Azoreduction
Nitro reduction
Alcohol dehydrogenation
Hydrolysis
Ester hydrolysis
Amide hydrolysis
Phase-II Reaction
|
Once polar functional groups are placed into the molecule by
the Phase-I reactions, phase-II reaction occurs. In phase-II reactions the
drugs or metabolites (from phase-I reactions) are conjugated with suitable
moiety such as glucuronic acid, sulfate, glycine, etc. in presence of enzyme
transferase. Phase-II reactions forms highly polar, readily excretable and
pharmacologically inert products.
Phase-II
reactions are as follows:
Glucuronide conjugation
Ether glucuronide
Ester glucuronide
Amide glucuronide
Peptide conjugation
Glycine conjugation
(hippurate)]
Methylation
N-methylation
O-methylation
Acetylation
Sulphate conjugation
Mercapturic acid synthesis
FACTORS
AFFECTING METABOLISM OF DRUGS
The
therapeutic efficacy, toxicity and biological half-life of a drug greatly
depends upon its metabolic rate. A number of factors may influence the rate of
drug metabolism, they are:
1. Physiological properties of
the drugs
2. Chemical factors
- Induction of drug
metabolizing enzyme
- Inhibition of drug
metabolizing enzymes
- Environmental chemicals
3. Biological factors
- Species difference
- Strain differences
- Sex difference
- Age
- Diet
4. Altered physiologic factors
- Pregnancy
- Hormonal imbalance
- Disease states
5. Temporal factors
- Circadian rhythym
- Circannual rhythm
