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.
























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