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A STUDY OF MECHANISM FOR NICOTINE TACHYPHLAIXS ON GUINEA PIG ILEUM.

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A STUDY OF MECHANISM FOR NICOTINE TACHYPHLAIXS ON GUINEA PIG ILEUM.

 

TABLE OF CONTENTS

1          TITLE

2          DECLARATION

3          DEDICATION

4          ACKNOWLEDGEMENT

5          ABSTRACT

6          INTRODUCTION

7          MATERIALS

8          METHOD

9          RESULTS, TABLES, GRAPHS AND TRACINGS

10       DISCUSSION

11       CONCLUSION

12       REFERENCES

 

ABSTRACT

Effect of varying time (drug contact time/cycle time), calcium concentration on Nicotine Tachylaxis was studied. Mechanisms for tachyphylaxis has been suggested by D. palaic and P. Lemorvan (1971) as being due to:

  • Change in specific receptors (desensitization, saturation of receptors as change in the number of receptors).
  • Exhaustion of certain endogenous mediators of agonist and finally inactivation of the agonist by storage mechanism located in the effector organ. Decrease in drug cycle time (drug contact/cycle time ratio) increased Nicotine tacchyphylaixs. Increase in calcium ion concentration seemed to improve Nicotine tachyphylaxis.

 

  • INTRODUCTION:

Tachyphylaxis can be defined as a decrease in the response of an excitable tissue after repeated administration of the same dose of a drug. Various mechanisms have been suggested for tachyphylaxis (D. palaic and P. Lemorvan, 1971).

  1. A change in specific receptors, (desentization of the receptors, saturation of receptors, a change in the number of receptors).
  2. Exhaustion of a certain endogenous meditor of agonist action.
  3. Increased enzyme-destroying activity for the agonist.
  4. Inactivation of the agonist by a storage mechanism located in the effector organ or other ill-defined factors.

Tachyphylaxis to a particular drug develops very rapidly within a short time duration and many drugs have been known to exhibit the phenomenon of tachyphylaxis, example include; Nicotine, tyramine and Amphetamine.

The phenomenon is quite similar to tolerance. Drug tolerance is a state of decreased responsiveness to the pharmacological effect of a drug resulting from a prior exposure to that drug or to a related drug so that increased dose of the drug are needed to produce the same effect. In contrast, tachyphylaxis to a drug does not need a prior exposure to that drug for days or weeks for it to develop. It develops within a short time duration of minutes or even seconds. In most cases when a tissue become tachyphylatic to a drug, the responses cannot be obtained by increasing the drug dose, what is needed is time for the tissue to get over the tachyphylactic effect.

Various workers have actually looked into different aspects of thephenomenon of tachyphylaxis, palaic, D. and Lemorvan, P. (1971) studied angiotensin tachyphylacxis in guinea pig aortic strip.

ICOTINE:

 

 

 

CH3

Nicotine was first isolated from the leaves of tobacco plant Nicotiana tabaccum by posset and Reiman (1828) while dorfila (1843) was the first to carry out the pharmacological studies of the alkaloid. Largely and Dickinson (1889) painted the superior ganglion of rabbits with nicotine and demonstrated that its site of action was the ganglion.

Nicotine has no therapeutic application, however, its high toxicity and presence in tabocco give it a considerable measure of medicinal importance.

Nicotine is an extremely toxic substance. Two or three drops of the pure alkaloid on the tongue will rapidly kill an adult. The lowest reported fatal dose is about 30mg/kg body wt.

Nicotine is one of the few natural liquid alkaloids. It is a colourless volatile base of pka 8.5 that turns brown and acquires the soluble in water and forms water soluble salts.

PHARMACOLOGY OF NICOTINE:

Nicotine is classified with other drugs as a ganglionic stimulant. It owes of its pharmacological activity to its actions at the autonomic ganglion.

Nicotine acts by binding to specific receptors referred to as nicotinic receptors. Peripheral cotinic receptors are located on the post syneptic membrane of the neuromuscular junction and autonomic ganglion cells and to aminor extend in the central nervous system. These receptors are differentiated from muscarinic receptors which are found in intestinal smooth muscle, the heart, blood vessels, salivary glands or central nervous system. Themuscarinic actions of acctylecholine are blocked by atropine whereas the nicotinic actions are not blocked by atropine.

DRUGS WITH NICOTINIC ACTIONS:

Drugs with this type of action depolarise the membranes of the post sympathetic nerve fibres and cell bodies of both sympathetic and parasympathetic ganglion causing them to discharge impulses along the post ganglionic axons which in turn release their transmitters on the effector cells.

Chromaffin cells in the adrenal medulla and elsewhere in the body are also stimulated andadrenaline adnnoradrenaline are released into the blood stream.

Like acetylcholine, nicotine depolarizes the neuromuscular junction end-plate but it is not destroyed by cholinesterase.

KINETICS OF DRUG RECEPTOR COMBINATION:

Effect of drugs in biological system must be regarded as ultimate consequences of physic-chemical interactions between that drug and functionally important molecules in the living organism.

In the great majority of cases however, drugs are presumed to interact with macro-molecular components of tissues to elicit a pharmacological response. These elements with which drugs combine to produce their effects are referred to as the receptors.

Drug + Receptor                                         drugs/receptors complex            response

 

D + R                                             DR Complex

Where           D =      Drug concentration

R =      free receptors concentration

DR = Drug/receptor complex

Ka =    the association rate constant

Kd =    the dissociation rate constant

Drugs are classified as agonist, antagonist, depending on their ka and kd values.

THEORY BASED ON THE RATE OF DRUG

RECEPTORS COMBINATION (RATE THEORY)

The general concept is that instead of attributing excitation to the occupation of receptors by drug molecules, it is attributed to the process of occupation, each association between a drug molecule and a receptor providing one quantium of excitation. The magnitude of a response is proportional to therate at which drug molecules associate with receptors sites.

This rate depends upon the concentration of free drug, the contration fo free receptors sites and ka (the rate content for association of drug molecules with receptors).

According to this theory the distinction between an agonist and antagonist is determined solely by the value of kd (the rate constant for dissociation of drug from drug/receptor complex). If kd is large then the rate of dissociation for the drug – receptors complex behind, making free receptor sites available at a high fate for new effective collisions with drug molecules. Thus drugs with high kd are agonist.

In contrast, if kd is small the drug receptor complex once formed will be stable, the rate of dissociation will be slow, free receptors will become available for new association events only infrequently and consequently there will be little or no excitation.

Therefore drugs with low kd will only display weak agonist action or none at all. The persistent occupancy of receptor sties by such a drug will reduce the number of receptive sites available for combination with an agonist, so that the drug will behave as an antagonist.

Due to the bulkiness of antagonists, they interact very slowly with the receptors with a consequent slow onset of action. A partial agonist is that which occupies an intermediate position between an agonist and antagonist. Nicotine is a partial agonist, this is supported by its stimulant and depressant activities on the autonomic ganglia.

They are often referred to as dualists. Agonists. Agonists have affinity as well as efficacy however antagonists have affinity but no efficacy.

For agonist

Ka                                                                                                                                           Rapid

Kd                                                                                                                                           Rapid

Partial Antagonist

Ka                                                                                                                                           Rapid

Kd                                                                                                                                           slow

 

Antagonist

Ka                                                                                                                                           slow

Ka                                                                                                                                           slow

Rate theory explanations as to why some drugs are agonists, some partial agonist and some antagonist, depending upon the value of kd, this was greatly elaborated by paton and Rang in their kinetic Approach to the mechanism of drug action. They suggested that excitation (Agonist action) may actually depend upon an ion displacement mechanism wherein the magnitude of response is determined by the rate of displacement of ions (example k+) from receptors sites in a membrane. It is claimed that the theory explains why agonist that are very potent have slow onset of action, since the more potent they are, the lower the dose (or concentration) at which they must be used consequently the slower will they equilibrate.

Rate theory offers explanation for the finding that some antagonists stimulate first then block as the stimulation fades. A good example is nicotine which initially excites the autonomic ganglion cells, then blocks it so that it no longer responds to various agonist including nicotine itself. The stimulation is a consequence of initial association between drug molecules and receptors which proceeds at a high rate (much as is assumed for antagonist) because at the outset all receptors are vacant. However this kind of initial stimulatory behaviour which is predicted by the theory is not observed with all antagonists.

This projects involves a study of mechanism for tachyphylaxis using such parameters as effect of time course and Ca++ ions on nicotine tachyphylaxis.

 

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