DISTRIBUTION OF DRUGS

After a drug is absorbed, there is a process called Distribution takes place and the drug is distributed to various body tissues and fluids.

The extent of distribution of a drug depends on its-

> lipid solubility

> ionization at physiological pH

> extent of binding to plasma and tissue proteins

> presence of tissue-specific transporters

> differences in regional blood flow

Drugs which easily pass through cell membrane achieve wide distribution and drugs which do not pass through cell membrane are limited in their distribution.

Distribution of drug proceeds until an equilibrium of unbound drug in plasma and tissue fluids is established.

Factors that affects the volume of drug distribution are,

-Lipid : water portion coefficient of the drug

-pKa value of drug

-Degree of plasma protein binding

-Affinity for different tissues

-Fat : lean body mass ratio, which can vary with age, sex, obesity etc.

-Diseases like CHF, uremia, cirrhosis

Penetration or entry into brain and CSF(Cerebrospinal fluid) or central nervous system :-

   Entry of drug into central nervous system is controlled by blood brain barrier.

   It is a hypothetical barrier which exists between plasma and extracellular surface of brain.

   This barrier is constituted by glial cells and capillary endothelium in the brain.

   Only lipid soluble, non ionized drugs readily passed through this barrier.

Passage across placenta or fetal circulation :-

   Entry of drugs into fetal circulation is controlled by blood placental barrier.

   It is also a hypothetical barrier which exists between maternal and fetal circulation.

   It permits the entry of only lipid soluble and non ionized forms of drugs.

Accumulation :-

   A drug can accumulate at different areas of the body. Slow release of the drug from these areas can produce prolonged effects. The drugs can be mostly accumulate in following storage sites,

> Cells like liver cells E.g. Quinacrine an antimalarial drug.

> Plasma proteins like albumin E.g. Phenylbutazone and sulfonamides.

> Connective tissues like bone E.g. Heavy metals and tetracyclines.

> Fat, if the drug is highly lipid soluble E.g. Thiopental, a lipid soluble barbiturate. 

ROUTE OF DRUG ADMINISTRATION

Route of drug administration-Pharmacy concepts

Most drugs can be administered by a variety of routes.Route of administration is an important factor which affects the absorption of a drug. The interval between administration and onset of action is determined by the route of administration.

The interval between administration of a drug and development of response is called Biological lag.

The choice of appropriate route in a given situation depends both on drug as well as patient related factors. The most common factors are as follows,

> Physical and chemical properties of drug

> Site of desired action (local or general action)

> Rate and extent of absorption of drug

> Effect of digestive enzymes and first pass metabolism

> Rapidity of response desired

> Accuracy of dosage required

> Patient's condition

Route of drug administration-Pharmacy concepts

The routes of administration can be classified as :

(1) ORAL OR ENTERAL ROUTE

(2) PARENTERAL ROUTE :- (a) Injection

                                                   (b) Inhalation

                                                   (c) Transcutaneous

                                                   (d) Transmucosal

                                                   (e) Drug delivery systems

(3) LOCAL APPLICATION

*ORAL OR ENTERAL ROUTE :

It is the oldest and most commonly used route of administration.

Advantages :

1. It is a safe, convenient and economical route.

2. Self medication is possible.

3. Withdrawal of the drug is possible.

Disadvantages :

1. Onset of drug action is slow.

2. Drugs which are bitter in taste are hard to administer.

3. Drugs producing nausea and vomiting cannot be administered.

4. The drug may be inactivated by gastric enzymes.

5. This route is not possible in an unconscious patient.

*PARENTERAL ROUTE :

Routes of administration other than oral route are referred as parenteral.

Advantages:

1. Absorption is quick and rapid.

2. Accurate dose of drug can be administered.

3. The drug enters into systemic circulation in an active form.

4. It is greatly useful in case of emergency.

5. It is also useful in an unconscious patient.

Disadvantages :

1. Pain may be produced at the site of administration.

2. There is a chance for abscess and inflammation.

3. Sterile procedures are required for this route.

4. It is an expensive route.

5. Self medication is not possible.

(a) Injection :-

Route of drug administration-Pharmacy concepts

> Intradermal : The drug is injected in the layers of skin.

                          E.g. B.C.G. vaccine

> Subcutaneous : Non-irritant substances alone can be injected by this route. Only small volume can be administered subcutaneously.

> Intramuscular : The drug is injected deep into muscle tissue. Depot preparations (oily solutions, aqueous suspensions) can be injected by this route.

> Intravenous: A drug is directly injected into a vein. The drug reaches directly into the blood stream and effects are produced immediately.

Advantages of this route:

-The drug enters into circulation in an active form.

-Desired blood concentration can be obtained.

-Irritant drugs can be administered by this route.

-Quick and immediate effects can be produced.

-It is useful in case of emergency.

-It is useful in an unconscious patient.

Disadvantages :

-Only solution can be administered by this route.

-Drugs which precipitate blood constituents cannot be administered.

-Untoward effects, if occur are immediate.

-Withdrawal of drug is not possible.

> Intra-arterial : A drug is injected into an artery in this route. The effect of drug can be localized in a particular organ or tissue by choosing the appropriate artery. Anticancer drugs are sometimes administered by this route.

> Intraperitoneal : In this route, a drug is injected into the peritoneal cavity. By this route, fluids like glucose and saline can be given to children.

> Bone-Marrow : It is very similar to intravenous injection. This route is useful when veins are not available due to circulatory collapse or thrombosis. In adults, the sternum and in children, tibia or femur is chosen for injection.

(b) Inhalation :-
Gases, volatile liquids, aerosols or vapors can be administered by this route. E.g. General anesthetics.

Advantages:-
-Rapid onset of action.
-Immediate absorption of drug.
-Localization of the effect in diseases of the respiratory tract.

Disadvantages:-
-Administration process is difficult.
-Poor ability to regulate the dose.
-Local irritation of the respiratory tract may occur.

(c) Transcutaneous Route :-
Highly lipid soluble drugs can be applied over the skin for slow and prolonged absorption. In this route, absorption of the drug can be increased by rubbing the preparation, by using an oily base and by an occlusive dressing.
This route is further classified as Iontophoresis, Inunction, Jet injection, Adhesive units.

(d) Trans mucosal route :- This route is classified as Sublingual, Trans nasal and Trans rectal.

Sublingual route :-
In this route, the tablet of medicament is to be placed below the tongue and is allowed to dissolve in the mouth cavity. Thus, the active medicament gets absorbed through the buccal mucous membrane. The absorbed material is then directly passed into systemic circulation. E.g. Ephedrine Hydrochloride tablet is administered by this route for the treatment of asthma. Also, for the treatment of angina pectoris, the tablet of Nitroglycerine is administered sublingually.

Advantages :-
-Rapid onset of action.
-Termination of the effect by spitting the tablet.
-Inactivation of the drug in the stomach is avoided.
-The drug enters directly into systemic circulation without inactivation in the liver.
-It is useful in medicinal emergency cases such as angina pectoris.

Disadvantages :-
-The only disadvantage of this route is that the drugs having direct or toxic effects on heart should be cautiously administered by taking at most care to avoid any such effect.

Trans-nasal route :-
In this route, the drug is rapidly absorbed through the mucous membrane of nose. E.g. posterior pituitary powder. It is useful for drugs in the form of snuff or nasal spray.  However, only certain drugs like GnRH agonists and desmopressin applied as a spray or nebulized solution have been used by this route. 

Trans rectal route :-
Certain irritant or unpleasant drugs can be put into rectum as suppositories or retention enema for systemic effect. E.g. Aminophylline for bronchospasm, Diazepam for status epilepticus. This route can be used when the patient is having vomiting or is unconscious.

Advantages :-
-Gastric irritation is avoided.
-Useful route in old and terminally ill patients.

(e) New drug delivery system :- It contains,

-Occusert :- In this system, the drug is placed directly under the eyelid. E.g. Pilocarpine fro prolonged effect.

-Progestasert :- It is an intrauterine contraceptive device. It produces controlled release of progesterone within the uterus for a year.

-Prodrug :- It is an inactive drug which after administration is metabolized into an active drug. E.g. L-Dopa is an inactive compound but after administration, it is metabolized to the active drug Dopamine which is effective in parkinsonism.

* LOCAL APPIACATION :-
Drugs in the form of powder, paste, lotion, drops and ointment can be administered locally for action at the site of application. Drugs can be applied on mucous membrane of nose, conjunctiva, vagina, urethra and rectum.
E.g. Bougie for urethra, Pessary for vagina, Suppository for vagina and rectum, Enema for rectum are the preparations used for local application.

BIOAVAILABILITY

                               BIOAVAILABILITY

It is defined as the quantity and the rate of the drug that is absorbed and reaches the systemic circulation after non-vascular administration.

It is a measure of the fraction(F) of administered dose of a drug that reaches the systemic circulation in the unchanged form.

The bioavailability is 100% after intravenous injection.

But it is less after oral administration because----
(1) the drug may be incompletely absorbed.
(2) the absorbed drug may undergo first pass metabolism.

Bioavailability is affected by factors like,
(1) Physical properties of drug
(2) Dosage form
(3) Physiological factors

Differences in bioavailability are seen mostly with poorly soluble and slowly absorbed drugs. 

FACTORS AFFECTING OR MODIFYING DRUG ABSORPTION

The absorption of a drug can be affected or modified by the following factors :

(1) PHYSICAL STATE : Drugs in the form of liquid or a drug given as watery solution is absorbed faster than when the same is given in solid form or as oily solution. Gases are quickly absorbed through lungs.

(2) PARTICLE SIZE : The rate of absorption is faster when a particle size of drug is smaller. If the particle size is large, the drug is slowly absorbed and hence the action is delayed.

(3) SOLUBILITY : An easily soluble drug is quickly absorbed. Also drug in the form of solutions are quickly absorbed then solids.

(4) CONCENTRATION : Drug given as concentrated solution is absorbed faster than dilute solution.

(5) AREA OF ABSORBING SURFACE : Larger the area of absorbing surface, faster is the absorption of drug. For example, lungs and peritoneal cavity are large surface areas from where drugs can be quickly absorbed.

(6) CIRCULATION TO THE SITE OF ABSORPTION : Increased blood flow to the site of absorption can increase the absorption of a drug. This can be achieved by massage or local application of heat. Vasoconstrictors decrease blood flow and so decrease the absorption of a drug.

(7) ROUTE OF ADMINISTRATION : This affects drug absorption because each route has its own mechanism or pattern of absorption. This is a very important factor which determines drug absorption. Some drugs are absorbed only on parenteral administration and they fail to get absorbed on oral administration. For example, Insulin. So it is necessary to carefully choose the route of administration of drug.  

ABSORPTION OF DRUGS

ABSORPTION is the process that makes the movement of the drug from its site of administration into the circulation.

Absorption - pharmacyconcepts

The absorption of a drug involves its passage across cell membrane. Not only the fraction of administered dose that gets absorbed, but also the rate of absorption is important.

As a rule, lipid insoluble and water insoluble drugs are not absorbed from the gut.

Passage of drugs across cell or biological membrane : Drugs are transported across the membranes by......

(A) PASSIVE TRANSFER :

       1-Simple Diffusion

       2-Filtration

(B) SPECIALISED TRANSPORT :

       1-Active Transport

       2-Facilitated Diffusion

       3-Pinocytosis

(A-1) SIMPLE DIFFUSION : It is a bidirectional process. The membrane plays no active role when the drug diffuses across the membrane. Polar water soluble and non polar lipid soluble substances can be transported by this process. This is the most important mechanism for majority of the drugs.

(A-2) FILTRATION : It involves passage through pores present in the cell membrane (aqueous pores or paracellular spaces). Only water soluble substances can be transported by this process.

(B-1) ACTIVE TRANSPORT : It is selective process which requires energy. It also requires a carrier so it is called Carrier mediated transport.

(B-2) FACILITATED DIFFUSION : It is very similar to Carrier mediated transport, but it does not require energy.

(B-3) PINOCYTOSIS : It is the process of transport across the cell in particulate form by formation of vesicles. Proteins and macromolecules are transported by this process. It is similar to Phagocytosis where cells engulf fluids or macromolecules from the surroundings.