ROUTES OF DRUG ADMINISTRATION
Syllabus: Routes
of drug administration and introduction
to important pharmacological terms.
Questions:
1) Write short notes on - route of drug administration. [92, 93, 96] [4]
2) Classify the different routes
of drug administration mentioning the advantages and disadvantages of each such
route. [94] [13]
3) Name the route in which maximum volume of fluid can be injected.
[93] [2]
4) Name the route in which maximum volume of fluid can be injected.
[93] [2]
5) Name the route having slowest onset of action. (93) [2]
Route of drug
administration:
A drug will produce its action only
when it enters the body, tissue or cells (i.e. site of action). So the entrance
through which a drug is delivered is called the route of drug administration.
CLASSIFICATION OF ROUTES OF DRUG OF ADMINISTRATION
Route of drug
administration
 |
LOCAL
ROUTES SYSTEMIC
ROUTES
1.
Topical routes
Skin
Mucous
membranes
Deeper
tissues
Arterial
supply
|
1.
Oral
2.
Sublingual or buccal
3.
Rectal
4.
Cutaneous
5.
Inhalation
6.
Nasal
7.
Parenteral
Subcutaneous
(s.c.)
Intramuscular
(i.m)
Intravenous
(i.v)
Intradermal
|
LOCAL ROUTES
These routes can
only be used for localized lesions at accessible sites. Systemic absorption of
the drug from these routes is minimal or absent. Thus high concentrations are
attained at the desired site without exposing the rest of the body.
1. TOPICAL
This refers to external
application of the drug to the surface for localized action.
(a) Skin: Drug is applied as ointment, cream, lotion, paste, powder,
dressing etc.
(b) Mucous membrane: The dosageform depends on the site :
(i) Mouth
and pharynx: Paints, lozenges, mouth washes, gargles.
(ii) Eyes,
ears and nose: As drops, ointments, irrigation, nasal spray.
(iii)Gastrointestinal
tract: As nonabsorbable drugs given orally e.g. aluminum hydroxide, kaolin,
neomycin.
(iv)Bronchi
and lungs: As inhalations, aerosols (nebulized solution or fine powder)-
e.g. salbutamol, cromolyn sodium.
(v) Urethra:
As jellies e.g. lidocaine, irrigating solutions.
(vi)Vagina:
As pessaries, vaginal tablets, inserts, cream, powders, douches.
(vii)Anal
canal: As ointment, suppositories.
2. DEEPER TISSUES
Certain deep
areas can be approached by using a syringe and needle, but the drug should be
such that systemic absorption is slow;
e.g. intra-articular
injection (hydrocortisone acetate)
intra-thecal
injection (lidocaine, amphotericin B)
retrobulbar
injection (xylocaine)
3. ARTERIAL SUPPLY
Close
intra-arterial injection is used for contrast media in femoral or bronchial
artery for limb malignancies. In these cases the drug is injected into the
artery that is supplying the blood to the desired site (i.e., site for
diagnosis or the cancerous tissues); the drug is conveyed by the blood flow
towards the tissue it is perfusing and not towards the heart, thus systemic
action is avoided and localized action is achieved.
N.B.
In case of vein the drug will be carried to the heart and from there to the
system (i.e. to the whole body).
SYSTEMIC ROUTES
The drug
administered through systemic routes is intended to be absorbed into blood and
distributed all over, including the site of action, through circulation.
1. Oral
The drug is taken through the
mouth and it is absorbed from the gastro-intestinal tract.
e.g. Both solid
dosage forms (e.g. tablets, capsules, powders) and liquid dosage forms (e.g
elixirs, syrups, emulsions, mixtures) can be given orally.
Advantages:
(i) It
is more safer, more convenient.
(ii) No
assistance is required for administration.
(iii)It is painless.
(iv)The medicament need not be sterile and so is
cheaper.
Disadvantages:
(i) Action
is slower and thus not suitable for emergencies.
(ii) Unpalatable
drugs (e.g. paraldehyde) are difficult to administer.
(iii)May cause nausea and vomiting (e.g. emetine).
(iv)Cannot be used for uncooperative / unconscious /
vomiting patients.
(v) Certain
drugs are not absorbed (e.g. streptomycin).
(vi)Some drugs are destroyed by digestive juices (e.g.
penicillin G, insulin) or in liver (e.g., nitroglycerin, testosterone,
lidocaine).
2. Sublingual or Buccal
The tablet or
pellet containing the drug is placed under the tongue (sublingual) or crushed
in the mouth and spread over the buccal mucosa. The drug is absorbed through
the buccal mucosa. e.g. nitroglycerine, isoprenaline, clonidine, nifedipine.
Advantages:
(i) Absorption
is relatively rapid - action can be produced in a minute.
(ii) One
can spit the drug after the desired effect has been obtained.
(iii)The liver is bypassed and drugs with high
first-pass metabolism can be absorbed directly into the systemic circulation.
Disadvantages:
(i) Only
lipid soluble and non-irritating drugs can be administered in this way.
(ii) Drugs
with bad taste or objectionable odour are not possible to administer on the
tongue.
3 Rectal
The drug containing dosage form
is either inserted or put into the rectum as suppositories or retention enema.
One part of the absorbed drug passes to the liver, another part to the systemic
circulation.
Advantages:
(i)
Drugs having bad taste or odour can be given through
this route.
(ii)
Drug that degrades in acidic pH of the gastric juice
can be given through this route.
(iii)
This route can also be used when the patient is having
recurrent vomiting.
Disadvantages:
(i)
Administration of drug through this route is rather
inconvenient and embarrassing.
(ii)
Absorption is slower, irregular and often
unpredictable.
(iii)
Drug absorbed into external haemorrhoidal veins (about
50%) bypasses liver, but not that absorbed into internal haemorrhoidal veins.
(iv)
Rectal inflammation ca result from highly irritant
drugs.
e.g. Aminophylline, indomethacin,
paraldehyde, diazepam, ergotamine and few other drugs are sometimes given
rectally.
4.Cutaneous
The dosage form is applied or
placed on the skin and the drug penetrates the skin to reach the blood i.e.
cutaneous route is meant for systemic absorption.
Advantages:
(i)
Highly lipid soluble drugs can be applied over the skin
for slow and prolonged absorption.
(ii)
The liver is bypassed through this route.
(iii)
The drug can be incorporated in an ointment and applied
over specified area of skin.
(iv)
Transdermal drug delivery systems deliver the drug in a
controlled manner and for a prolonged period. They provide smooth plasma
concentration of drug.
Disadvantages:
(i)
Absorption is very slow. So it cannot be used in
emergency situation.
(ii)
Water soluble drugs are minimally absorbed through the
skin.
e.g. Transdermal patches of nitroglycerin,
hyoscine, clonidine and estradiol are available in many countries. Other drugs
developed as transdermal drug delivery system are timolol, testosterone,
nicotine and isosorbide dinitrite.
5. Inhalation
The drug is
administered through nose or mouth, carried by the air to reach the lung. The
alveoli are rich with capillary vessels. The drug is diffused into the blood
stream. Thus systemic action is obtained.
Advantages:
(i)
Absorption takes place from the vast surface of alveoli
- hence action is very rapid.
(ii)
When administration is discontinued the drug diffuses
back and is rapidly eliminated in expired air. Thus controlled administration
is possible with time to time adjustment.
(iii)
Bypasses the liver.
Disadvantages:
(i)
Irritant vapors (ether) cause inflammation of
respiratory tract and increase secretion.
e.g. Volatile liquids and gases
are given by inhalation- such as general anaesthetics, amylnitrite.
6. Nasal
The drug is
administered as snuff or spray or nebulized solution in the nose; where the
drug penetrates the nasal mucous membrane to reach the blood.
Advantages:
(i)
The drug can avoid digestive juices and liver.
(ii)
Drugs are readily absorbed from this route.
Disadvantages:
(i)
Irritant drugs cannot be administered through this
route.
e.g. Posterior pituitary powder
and desmopressin are applied as snuff.
7. Parenteral
(Par- beyond, enteral- intestinal) Routes of drug administration other than oral
route are known as parenteral route. This refers to administration by injection
which takes the drug directly into the tissue fluid or blood without having to
cross the intestinal mucosa and subsequently liver.
Advantages:
(i)
Absorption is faster and surer, hence drug can be
administered rapidly and in accurate dose in time of emergencies.
(ii)
Gastric irritation and vomiting are not provoked.
(iii)
It can be employed in unconscious, uncooperative or
vomiting patients.
(iv)
There are no chances of interference by food or
digestive juices.
(v)
Liver is bypassed.
Disadvantages:
(i)
The preparation has to be sterilized and is costlier.
(ii)
The injection may be painful.
(iii)
Self medication is difficult - another trained person
is required to give the injection.
(iv)
Abcess and inflammation at the site of injection may
take place.
Intradermal injection
The
drug is injected into the dermis of skin raising a bleb (e.g. BCG vaccine,
sensitivity testing of drugs) or scarring / multiple puncture of the epidermis
through a drop of the drug (small pox vaccine) is done. This route is employed
for specific purpose only.
Subcutaneous injection
The
drug is injected under the skin. The drug is deposited in the loose
subcutaneous tissue which is richly supplied by nerves (irritant drugs cannot
be injected but is less vascular (absorption is slower).
Advantages:
(i)
Self injection is possible because deep penetration is
not required.
(ii)
oily solutions or aqueous suspensions can form a depot
which will release drug slowly for a prolonged period.
Disadvantages:
(i)
Since skin is richly supplied by nerve-endings hence
irritant drugs cannot be injected.
(ii)
This route should be avoided in shock patients.
e.g. Insulin injection.
Intramuscular injection
The
drug is injected in one of the large skeletal muscles- deltoid, triceps,
gluteus maximus, rectus femoris etc.
Advantages:
(i)
Muscle is less richly supplied with sensory nerves,
hence mild irritants can be injected.
(ii)
Muscle is more vascular hence absorption is faster than
subcutaneous route.
(iii)
It is less painful.
(iv)
Depot preparations can be injected by this route and
the action of the drug may be prolonged.
Disadvantages:
(i)
Since deep penetration is needed hence self-medication
is not possible.
(ii)
Large volume cannot be given.
e.g. Low volume injections -
Vitamin A, hydrocortisone acetate, tetanus toxoid, antibiotic etc.
Intravenous
The
drug is injected as a bolus or infused slowly over hours in one of the
superficial veins (generally brachial vein).
Advantages:
(i)
The drug directly reaches the blood stream and effect
is produced immediately, hence, this route can be used in emergencies.
(ii)
The inside of the veins is insensitive and drug gets
diluted with blood quickly, therefore, even highly irritant drugs can be
injected intravenously.
(iii)
Large volumes can be infused (e.g. normal saline).
(iv)
It is useful in unconscious patients.
(v)
Desired blood concentration can be achieved.
Disadvantages:
(i)
Drugs that precipitate in the blood cannot be
administered. Only aqueous solution can be administered.
(ii)
If the needle puncture the vessel (i.e. extra vasation)
then thrombophlebitis of the injected vein and necrosis of the adjoining tissues
may occur.
(iii)
No drug can be given in depot form - so the action is
not prolonged compared to other parenteral administrations.
(iv)
Untoward reactions if occur are immediate.
(v)
Once administered, withdrawal of the drug is not
possible.
Intra-arterial
A
drug is injected into an artery. The effect of a drug can be localized in a
particular organ or tissue by choosing the appropriate artery. Anticancer drugs
are sometimes administered by this route.
Intra-peritoneal
In
this route a drug is injected into the peritoneal cavity. By this route fluids
like glucose and saline can be given to children.
PHARMACEUTICAL TERMS
DOSE AND DOSAGE
Dose is the quantity of a drug to be administered at one time to
achieve a therapeutic response.
e.g. Oral adult dose of paracetamol
is 300 mg.
Dosage is the determination and regulation of the size (dose),
frequency, and number of doses.
e.g. Oral adult dosage of
paracetamol is 300 mg 4 times daily.
PHARMACOKINETICS AND
PHARMACODYNAMICS
Pharmacokinetics is the subject that deals with ‘what body does to
the drug’.
This subject includes absorption,
distribution, metabolism and excretion of the drugs. It determine the routes of
administration, dose, onset of action, time of peak action, duration of action
and frequency of administration.
Pharamcodynamics is the subject that deals with ‘what drug does to
the body’.
It is the study of the effect of
drug on the body, its mechanism of action, dose-effect relationship, drug-drug
interaction, and factors modifying drug action.
TERATOGENICITY
It
refers to the capacity of a drug to produce gross structural malformations
during foetal development when administered to pregnant mother.
During
organogenesis stage of foetal
development (17 to 60 days, i.e. first trimester of pregnancy) drugs may cause
gross malformation of the foetus. Drugs reported to have adverse effects on
human foetal development are Thallidomide (produce phocomelia or seal-like limbs), Penicillamine, Warfarin,
Corticosteriods, Androgens, Oestrogens, Stilbosterol, Phenytoin etc.
ED50, LD50 and THERAPEUTIC INDEX
ED50
There are two type of ED50 with
which normally the dose effect relationship of a drug is related.
(A) 50% Effective dose or Individual ED50 and (B) Median effective dose
(A) 50% Effective dose
In
order to have dose-effect relationship the intensity
of biological effect of a drug is plotted against the dose [or log(dose)]of the drug. Individual ED50 is the dose
required to elicit 50% of the maximum intensity of the biological effect.
Individual ED50 is required to compare the effect between two drugs
in an individual.
The relative potency of any drug may be obtained by dividing the ED50
of the standard, or prototype drug by that of the drug in question.
Since
dose-intensity curve varies from individual to individual hence individual
ED50 is not accurate enough.
(B) Median effective dose
In
this case % of animals showing a desired level of effect is plotted against log
(dose) (i.e. dose-frequency relationship).
The curves generally produced are sigmoidal in nature.
ED50 is the dose at which 50% of
the animal shows the desired level of effect.
Therapeutic index
By
this term the therapeutic effect and untoward effect of a drug is compared. The
untoward effect is expressed by TD50 i.e toxic dose for 50% animals and the
therapeutic effect by ED50 i.e. effective dose for 50% of animals.
And therapeutic index expressed as the ratio of TD50 / ED50.
Therapeutic index is also
expressed as the ratio of LD50 / ED50.
When
the therapeutic index is small the drug should be administered under careful
observation because the probability of precipitation of toxic effect is higher.
When the therapeutic effect is large it is more safer to administer the drug
than with smaller therapeutic index.
50% effective dose or
Individual ED50
Fig:- The relationship of the intensity of
the blood-pressure response of the cat to the log(dose) of nor-epinephrine
(drug)
|
Median effective dose
Fig:- The relationship of the number of
mice convulse to the dose of pentylene tertrazole (drug)
|
e.g. benzodiazepines have greater
therapeutic index than barbiturates, hence, are less likely to kill when taken
in accidental overdose.
LD50
Before
any new drug molecule is approved for testing in man, extensive toxicity
testing is done in various animal species.
100
  % 50
Mortality
log (LD50)
0
log
(dose)
|
The crudest type of toxicity test
is the LD50.
LD50 is defined as the lethal
dose for 50% of a group of animals.
Methods of determination
Various doses of drugs are
administered to groups of 10 animals. The mortality (death) in each group
within a fixed period of time (say 2 days) is determined and used to construct
a curve relating fraction mortality to log (dose).
Significance
It
is a parameter which defines (though not adequately) the chemical toxicity of a
drug molecule.