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SCHOOL OF PHARMACEUTICAL SCIENCES

FAR 142/3
BASIC PHARMACOLOGY AND BIOCHEMISTRY

EXPERIMENT 4:
ROUTES OF DRUG ADMINISTRATION

COORDINATOR: PROF. MADYA DR. AMIN MALIK SHAH

NAMES : FATIN NASUHA BINTI MAHYUDDIN
MATRIC NO : 123877
DATE OF EXPERIMENT : 10 APRIL 2015

AIMS

To compare the influence of the routes of administration on the onset and duration of action in response to a hypnotic drug, sodium pentobarbitone (60mg/kg), in mice.

INTRODUCTION

Drugs need to reach the sites of action in order to produce an effect. A suitable route of administration is important to ensure the drug entering the blood circulation to finally reach their site of action. The selection of the best route of administration of the drug depends on its physical and chemical properties. Drugs are introduced into the body by several routes. They may be taken by mouth (orally); given by injection into a vein (intravenously), into a muscle (intramuscularly), into the space around the spinal cord (intrathecally), or beneath the skin (subcutaneously); placed under the tongue (sublingually); inserted in the rectum (rectally) or vagina (vaginally); instilled in the eye (by the ocular route); sprayed into the nose and absorbed through the nasal membranes (nasally); breathed into the lungs, usually through the mouth (by inhalation); applied to the skin (cutaneously) for a local (topical) or bodywide (systemic) effect; or delivered through the skin by a patch (transdermally) for a systemic effect. Each route has specific purposes, advantages, and disadvantages. This will determine the effectiveness of the drug to cause the site of action to produce a response. Identical drugs can produce different results depending on the route of administration.

In this practical, we will observe the onset and duration of action in response to the drug that are administrated in five different routes, which is by orally (p.o.), subcutaneous (s.c.) where drug is injected at the skin of neck, intramuscular (i.m.) where drug is injected at skeletal muscle of thigh, intraperitoneal (i.p.) where the drug is injected at centre of abdomen and intravenous (i.v.). The mice will be injected with the hypnotic drug, sodium pentobarbitone and time taken for the mice to loss of righting reflexes and the time taken to stand on fours again are recorded. Righting reflexes is a reflex that corrects the orientation of the body when it is taken out of its normal upright position and in this experimet is the ability of the mice to stand on fours again. The time when the mice lose their righting reflexes is called onset of action of drug sodium pentobarbitone whereas the duration taken for the mice to gain ability to stand on allfours again after hypnosis is called as duration of action. Hypnotic drug is the drug that produces sleep by depressing brain function and is used for the short-term treatment of insomnia and sleep disturbances, which act directly towards the central nervous system (CNS). Most of such drugs exert a quieting or calming effect at low doses and a sleep-inducing effect in larger doses.

METHODS
As in the pharmacology practical manual on page 29-31.

RESULTS

THE INFLUENCE OF ROUTE OF SODIUM PENTOBARBITONE ADMINISTRATION ON THE TIME OF ONSET AND DURATION OF HYPNOSIS IN MICE.

| |Route of administration of sodium pentobarbitone |
| |p.o |s.c |i.m |i.p |i.v |
|Body weight (gram) |35.5 |26.0 |25.0 |28.0 |36.3 |
|Volume of drug solution (ml) |0.355 |0.26 |0.25 |0.28 |0.363 |
|Time of drug administration (hour,min) |10.22 |10.13 |10.45 |10.52 |10.34 |
|Time of loss of righting reflexes (hour,min) |10.30 |10.19 |10.47 |10.55 |10.34 |
|Duration taken for onset of drug action (min) |8 |6 |2 |3 |0 |
|Time able to stand on four legs again |10.44 |10.50 |11.10 |11.38 |11.36 |
|(hour,min) | | | | | |
|Duration of drug action (min) |14 |28 |28 |43 |62 |

p.o = parenteral oral i.p = intraperitoneal
s.c = subcutaneous i.v = intravenous
i.m = intramuscular

DISCUSSION

The route of administration is defined as the path by which a drug or other substance enters the body. The aim of therapeutic administration is to compare the influence of the route of administration on the onset and duration of action in response to a hypnotic drug, sodium pentobarbitone. The routes of drug entry into the body may be divided into two classes which are enteral and parenteral. The examples of enteral route are the oral, sublingual and rectum. While, the examples of parenteral route are intravenous, intramuscular, subcutaneous, intraperitoneal and inhalation.

According to the results, the administration route that has the shortest time for onset of drug action is intravenous, followed by intramuscular, intraperietoneal, subcutaneous and lastly the longest oral. Oral is the safest and most convenient route but it take the longest duration for onset of drug action. This is because it is subject to first-pass effect where the drug need to pass the digestive system and transported to liver to be metabolized and hence, cause reduction in amount of drug that reaches the systemic circulation and ultimately to the site of action. That is why the site of action take time before producing a response. Oral administration route takes 8 minutes for drug action onset.

The subcutaneous takes shorter time than oral which is 6 minutes because it bypass the first-pass effect but the rate of absorption is slow and constant which makes duration taken for onset of drug action is longer too. The subcutaneous injection of drug is given to beneath the skin where the drug will moves into the scapillaries and is carried away by the bloodstream or reaches the bloodstream through the lymphatic vessels.

The intraperitoneal injection is the injection of a substance into the peritoneum (body cavity) i.e the central of abdomen. Administering drug through this route will give a relatively short duration of onset that is 3 minutes. The intramuscular injection is the injection of the drug deep into skeletal muscle of the thigh or arm as they are rich in blood vessels and lacking in nerves and this route is used to produce systemic effect of the drugs. The intramuscular route take shorter time for onset of drug action which is 2 minutes compared to intraperitoneal because it has rich blood supply.

The intravenous has the shortest duration taken for onset of drug action which is 0 minute because it guarantees drug delivery right into the systemic circulation since the drug is injected directly into the vein of the mouse’s tail. It also bypassed the first-pass effect. Once the drug injected, there is no recall. It produces effect once the drug is injected. Intravenous administration is the best way to deliver a precise dose quickly and in a well-controlled manner throughout the body.

In contrast, for duration of drug action, the intravenous administration took the longest which is 62 minutes followed by intraperitoneal at 43 minutes, intramuscular and subcutaneous at 28 minutesand the shortest is the oral administration which is for only 14 miutes. The duration of action of a drug is the length of time that particular drug is effective. Duration of action is a function of several parameters including plasma half-life, the time to equilibrate between plasma and target compartments, and the off rate of the drug from its biological target. The duration of drug action depend on the rates of absorption, distribution and elimination of the drugs and is dependent on the dose administered. In contrast of duration of onset drug action, the duration of drug action of intravenous injection took some time because a large percentage of doses reach the site of action while the other else is still distributed throughout the whole body in the blood circulation. Longer time of action shows that the drugs are still effective and can still give response after quite a time. The intraperitoneal administration took 43 minutes for the drug to be effective. It seems that large percentage of amount of the drug given act directly and continuously to the site of action which causes the mice to still be in hypnotic situation. The duration taken for drug action of subcutaneously administrated drug should be longer than the duration taken for drug action of other parenteral route of drug administration. However, the result obtained in our experiment show that the duration taken for drug action through subcutaneous route which is 28 minutes is shorter than the duration taken for drug action through intraperitoneal and intravenous route. This may be due to the wrong drug administrated technique such as the drug is directly injected into the blood capillaries beneath the skin that caused the local drug concentration increases rapidly. So, the rate of drug metabolism and excretion will be increased. Thus, the duration of drug half-life and duration taken for drug action will be decreased. In contrast, the duration of action of oral is the fastest which is 14 minutes. The first-pass effect causes the drug that reach at the site of action is smaller than what is administered since it is metabolised by gastrointestinal tract and liver enzymes. The bioavailability decreases and causes the effectivity of the drug to decrease. It can also give response for a short time since the concentration of the drug at the site of action is small.

There were several errors occurred through out this experiment. The onset and duration periodwas not well observed as the experimenters could not assume the exact situation of immobility of the mouse for oral administration. Besides, the dose of the drug was reduced as sodium pentobarbitone was not fully injected into the mouse. Nervous situation of the mice might also affected theabsorption and metabolism of the drug.

QUESTIONS

1) Discuss the basis of differences in the duration taken for the onset of drug action and the duration of action for the various routes of drug administration in this experiment.

The difference in the duration taken for the onset of drug action is because of the differences route of administration drugs. It will cause difference rate of substance or drugs must be transported from the site of entry to the part of the body where its action is desired to take place. The onset of drug action depend on the rates of absorption of the routes of administration. The higher the rates of absorption, the shorter time it takes for the drug to give a re sponse. It is found that intravenous injection has the highest rate of absorption since the drug is injected directly to blood vessels. Meanwhile, oral has the slowest rate of absorption and it need s time before the drug is absorbed since it need to pass the digestive system before reaching the site of action.
The duration of action for various routes of drug administration is differ because the difference of rate of absorption of drug, amount of drug which been absorbed into the blood plasma and difference rate of metabolism and elimination of drug through the various of drug administration. For any given rate of absorption, the faster the onset of action, the higher the peak concentration and the longer the duration of action.

2) Explain why pentobarbitone and drugs of its kind are no more used as anxiolytics and hypnotics
Pentobarbitones and drugs of its kind may be habit forming. Tolerance, psychological dependence, and physical dependence may occur especially following prolonged use of high dose of these kinds of drugs. Barbiturates are no longer prescribed due to their high likelihood of abuse, damaging effects on the body, and complicated withdrawal syndromes. Much more efficient and safer drugs now exist to treat anxiety and sleep disorders. The symptoms of barbiturate withdrawal can be severe and may cause death.

3) List routes of drug administration other than those stated in this experiment. Give one example of drug administrated via each route given and the rationale for choosing the example route.

i) Sublingual administration
Sublingual administration is route of administration in which certain drugs are entered directly into the bloodstream via absorption under the tongue. One of the examples of the drug via this administration is nitroglycerin which is used to relieve angina (chest pain). It is placed under the tongue so that they can be absorbed directly into the small blood vessels that lie beneath the tongue. The absorption is rapid and the drug immediately enters the bloodstream without first passing through the intestinal wall and liver.

ii) Rectal
Example of drug that uses rectal as route of administration is paracetamol, which function to relieve pain or hedache. In this form, a drug is mixed with a waxy substance that dissolves or liquefies after it is inserted into the rectum. Because the rectum's wall is thin and its blood supply rich, the drug is readily absorbed. A suppository is prescribed for people who cannot take a drug orally because they have nausea, cannot swallow, or have restrictions on eating, as is required after many surgical operations.

iii) Inhalation
Inhalation is the movement of air from the external environment, through the airways, into the alveoli during breathing. The example of drug via this administration is salbutamol.
Salbutamol is used for the asthma patient. Inhalation make the salbutamol arrived at the lungs and then provide the higher concentration of salbutamol at the lungs compare at the other part of the body. Inhalation also make the salbutamol to react at the local effect only and does not give any side effect.

4) Discuss the possibilities of administering sodium pentobarbitone via intrarectal, inhalation and topical routes.

i) Intrarectal
If sodium pentobarbitone is administrated via intrarectal, the amount of drug that absorb into the blood circulation is unknown. The dose that we assume safe may be initiate the dangerous overdose effect. So, intrarectal administration is not suitable and less effective for the sodium pentobarbitone.

ii) Inhalation
Sodium pentobarbitone is not necessary needed in the respiratory tract while the purpose of inhalation is the movement of air from the external environment, through the airways, into the alveoli during breathing. Thus, sodium pentobarbitone’s effect is not effective to be absorbed at the other part of body.

iii) Topical routes
Sodium pentobarbitone is salt, and its solubility is better than lipid solubility, If sodium pentobarbitone is administrated via topical routes, which is administration to a particular spot on the outer surface of the body. So, the drug will find difficult to be absorbed into the skin, because of the hindrance by dead cells at the skin.The low absorption is impossible in production of any action of drugs. It will also cause rash, urticaria, and exfoliative dermatitis to the topical site. At the same time, it may take a long duration of onset because it has to diffuse across a lot of physical barrier, such as the skin.

PRECAUTIONS

1. The mice are hold carefully and gently but firmly to ensure that the sodium pentobarbitone can be easily injected into the mice through the various routes.

2. Make sure that a sharp needle is used for injection.

3. Make sure that there are no air bubbles in the drug solution before injection.

4. An antiseptic is used to clean the wound area immediately caused by the biting of the mice.

CONCLUSION

The duration taken for onset of drug action should decreased from oral route, subcutaneous route, intramuscular route, intraperitoneal route, to the intravenous route. Generally, the duration taken for onset of drug action is shorter in parenteral routes compared to other routes. The intravenous administration has the shortest duration for onset of drug action while the oral administration route takes the longest time.

Meanwhile, the duration taken for drug action should be longer in the drug administrated through subcutaneous route compared to the drug administrated through parenteral routes. The intravenous administration took the longest duration of the drug action while oral route takes the shortest time.

REFERENCES

1. http://www.paincommunitycentre.org/article/route-administration-0 2. https://books.google.com.my/books?id=WKLn6zGorDQC&pg=PA253&lpg=PA253&dq=duration+of+drug+action+for+different+administration+routes&source=bl&ots=PxdkLx8HsW&sig=DbuwOFPvQPeYp83gQnE3htvRMXg&hl=ms&sa=X&ei=eygxVbedHOW0mwWatoCgDg&redir_esc=y#v=onepage&q=duration%20of%20drug%20action%20for%20different%20administration%20routes&f=false 3. Practical Manual Basic Pharmacology and Biochemistry