Lab 4: Routes Of Drug Administration

Question 0

What are the 3 Rs?

Answer 0

Replacement
Refinement
Reduction

Question 1

How should drugs be administered to mice via the oral route?

Answer 1

Grab the skin over the shoulders firmly with the thumb and middle finger;
stretch the head and neck with the index finger to make the oesophagus straight.
Using a ball-tip needle, feed the needle along the roof of the mouth and toward the right side of the back of the pharynx, and then gently pass down into the oesophagus.
Advance slowly into the stomach. No resistance should be felt

Question 2

What is replacement?

Answer 2

Replacement: the use of non-animal methods such as cell cultures, human volunteers and computer modelling instead of animals to achieve a scientific aim.

Question 3

What is refinement?

Answer 3

Refinement: the use of methods that alleviate or minimise potential pain, suffering or distress, and that enhance animal welfare for those animals that cannot be replaced.

Question 4

What is reduction?

Answer 4

Reduction: the use of methods that enable researchers to obtain comparable amounts of information from fewer animals, or more information from the same number of animals.

Question 5

How is an drug administered via the IV route for mice?

Answer 5

The principal function of these veins is for thermoregulation. They will dilate when the mouse’s body temperature rises in order to disseminate heat.
Applying heat to the whole animal or locally to the tail can be used to cause venodilation making vascular access easier.

The mouse should be restrained so that its tail is accessible. A 25 gauge bevelled needle is used. The vein is located, the needle inserted by directing the needle into the vein with its bevel pointing upward at an angle of approximately 20 degrees. The needle is inserted slowly visualizing the needle as it enters the vein

Question 6

What is the righting reflex?

Answer 6

Rodents will try to right themselves when placed in an abnormal position, this is termed their righting reflex.

When under the effects of anasthesia, they will lose this reflex which can be used as a marker of the onset and duration of the drug.

Question 7

What is the mechanism of action of pentobarbitone?

Answer 7

Pentobarbital binds at the GABAA receptor, increasing the duration of time for which the Cl- ionopore is open, prolonging the post-synaptic inhibitory effect of GABA in the thalamus.

Pentobarbitone is more lipophilic than phenobarbitone and will cross the blood brain barrier more easily, resulting in a faster onset and shorter duration

Question 8

What is the mechanism of phenobarbitone?

Answer 8

Phenobarbital acts on GABAA receptors, increasing synaptic inhibition.
This can therefore elevate the seizure threshold, reducing the spread of seizure activity from a seizure focus.

Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release.

The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal.

Question 9

What is the main physicochemical difference between pentobarbitone and phenobarbitone that result in their differing effects?

Answer 9

Pentobarbitone is more lipophilic than phenobarbitone. It will have a faster onset of action.

Question 10

What causes determines the duration of a drug effect?

Answer 10

Whether or not the journey of the drug encounters first pass metabolism. This is where a fraction of the drug is metabolised in the liver before it reaches the receptor.
If a drug does not undergo FPM such as a drug administered via the SC or IV route, it will have a longer duration of action

Question 11

Does the oral or intraperitoneal route have the longer duration ?

Answer 11

The intraperitoneal route will have a longer duration as while both routes of administration are subjected to first pass metabolism, some of the drug is also likely to be broken down in the stomach in oral administration, so there is less bioavailability thus exerting a shorter duration of effect

Question 12

Does the intraperitoneal or oral route have the faster onset of action?

Answer 12

The intraperitoneal route as it is closer to the receptors and does not have go through most of the GIT first

Question 13

What is the magnitude of the effect if drug in a whole animal a function of?

Answer 13

Its concentration at the receptor site.
As this concentration increases, a threshold concentration will be reached where an effect of the drug is detectable.

Further increasing this concentration at the receptor site leads to increased intensity of huge effect

Question 14

What are the factors affecting the concentration of the drug at the receptor site?

Answer 14

The pharmacokinetic properties
Abosrption
Distribution 
Metabolism
Excretion

Question 15

What must drugs do in order to move from their site of administration to the tissues or cells where they will act?

Answer 15

They must gain access to the bloodstream,

And usually will have to traverse one or more biological barriers

Question 16

What does the rate and amount of drug entering the blood stream depend on?

Answer 16

The route of administration.

Question 17

What does the choice of the route of administration depend on?

Answer 17

The physical and chemical properties of the drug

The rapidity with which the drug is required to act.

Question 18

What is the relationship between absorption and vasculature?

Answer 18

The more vascular the site, the more rapid the abosrption

Question 19

How do most drugs cross biological membranes?

Answer 19

Most drugs are weak electrolytes and their movement across biological membranes largely occurs by passive diffusion down the concentration gradient.

Question 20

What is the rate of diffusion of a drug proportional to?

Answer 20

The degree of the drugs ionisation.
The greater the un ionised fraction, the greater the rate of diffusion

It is also proportional to the lipid/water partition coefficient of the nondissociated form

Question 21

What type of drugs are phenobarbitone and pentobarbitone ?

Answer 21

Weak acid drugs.

Question 22

What are the general mechanisms of the barbituates?

Answer 22

They can produce all degrees of depression of the CNS ranging from mild sedation to general anaesthesia.
The receptors are located in the brain so the drug needs to gain access to the vascular system and pass through the bbb to reach the effector site,

Brain capillaries are particularly impermeable to the diffusion of water soluble or ionised molecules.

Question 23

Which drug had the longest mean onset time? Why?

Answer 23

Phenobarbitone had the longer mean onset time in both IP and IV routes of adminstration as it is not as lipid soluble as pentobarbitone.
Pheno has a logP of 3 while pento has a logP of 39.
This means that phenol diffuses much slower through the blood brain barrier to exert its effect, resulting in the much longer onset time

Question 24

Which route of administration has the quickest onset time?

Answer 24

IV has the fastest onset time
This is followed by oral, IP
SC has the slowest onset time

This is because the onset is somewhat influenced by the route of administration. In the IV route the drug is injected immediately into the bloodstream where it can then circulate to its target tissue to exert its effect.
In the IP and oral routes, the drug still needs to diffuse into the blood stream and move to the target site,
In the SC route, the drug needs to partition through the subcutaneous tissue which is poorly vasculated and will therefore be absorbed much slower, into the bloodstream, before moving to the target site.

Question 25

Which affects the duration of action of a drug?

Answer 25

There is an insignificant effect of the physicochemical properties of the drug on its duration of action.

The duration is heavily dependent on the route of administration

Question 26

Which route of administration results in the longest duration of action?

Answer 26

The IV route results in the longest duration of action.
This is because drugs administered by the IV route are not subjected to FPM, so there more of the drug to reach the target site and exert its effect.

The drugs administered via SC route, although not significantly subjected to FPM has a shorter duration of action as it takes so long to each the target site. However, the metabolising processes still occur at the same rate resulting in a shorter overall duration of action.

In the IP route, some of the drug is subjected to FPM and will be metabolised, leaving a lower proportion of drug to reach the target site and exert its effect. Thus its duration of action is less than that of IV.

In the PO route, some of the drug is subjected to FPM, and some of the drug is subjected to degradation in the stomach and throughout the GIT by digestive enzymes. This results in an even lower proportion of the drug available to reach the target site to exert its effect.

Question 27

What is the procedure for mouse bite treatment?

Answer 27

Disinfect the bite area with Mediwipes. Do not keep wiping with these wipes as it will keep bleeding due to the alcohol in it. Alcohol acts as anticoagulant.
Apply pressure on it using usual soft tissue paper to stop bleeding. Hold it for atleast 2-4min. (average clotting time is 2-6min)
Cover it with band-aid adhesive bandage. This is to avoid any exposure to infection till healing takes place.