TACHYPHYLAXIS AND TOLERANCE

TACHYPHYLAXIS AND TOLERANCE 

CONTENTS

Definition of tachyphylaxis

Definition of tolerance

Mechanisms that give rise to tachyphylaxis 

TACHYPHYLAXIS   

Defination

Tachyphylaxis is a medical term describing the decrease in the response to a drug after repeated doses. 

It is also called Desensitisation.

GRAPH SHOWING TACHYPHYLAXIS

TOLERANCE

Definition

Tolerance resembles tachyphylaxis in meaning, but this is a phenomenon where increasing the amount of a drug is required to gain the same effect. 

MECHANISMS OF DRUG TACHYPHYLAXIS:

change in receptors 

loss of receptors 

exhaustion of mediators 

increased metabolic degradation of the drug 

physiological adaptatation

active extrusion of drug from cells (mainly relevant in cancer chemotherapy)

CHANGE IN RECEPTORS

Receptors that are directly coupled to ion channels show desensitisation which is often rapid and pronounced

At the neuromuscular junction, the desensitised state is caused by a conformational(structural) change in the receptor, resulting in tight binding of the agonist molecule without opening of the ionic channel.

Phosphorylation of G-protein-coupled receptors interferes with its ability to activate second messenger cascades .although it can still bind   the agonist molecule, thus showing desensitization. 

TRANSLOCATION OF RECEPTORS

Prolonged exposure to agonists (drug) often results in internalisation of the receptors present on the cell surface unavailable for further agonist interaction (down regulation).

The internalised receptors are taken into the cells by endocytosis e.g.beta-adrenergic receptors in the presence of a low concentration of isoprenaline are internalised temporarily and recycled to the cell surface.

Similarly ,repeated exposure of a receptor to an antagonist may result in up-regulation of receptors ,in which receptor reserves are inserted into the membrane ,increasing the total number of receptors available, thus making the cells more sensitive to agonist and/or more resistant to the effect of the antagonist.

 

EXHAUSTION OF MEDIATORS

Sometimes ,desensitisation is associated with depletion of an essential intermediate substance(mediators).

For example ,Amphetamine acts by releasing amine from nerve terminals show marked tachyphylaxis because the amine stores become depleted.

ALTERED DRUG METABOLISM

Repeated administration of the same dose produces a progressively lower plasma concentration because of the increased metabolic degradation e.g barbiturates and ethanol.

On the other hand, sometimes the pronounced tolerance results mainly from decreased metabolism ,which reduce the release of the active mediator e.g in case of nitrovasodilators ,release of nitric oxide is reduced.

PHYSICAL ADAPTATION

Diminution of a drug's effect may occur because it is nullified by a homeostatic response. For example, the blood pressure-lowering effect of thiazide diuretics is limited because of a gradual activation of the renin-angiotensin system.

Many side effects of drugs like nausea or sleepliness, tend to subside even though drug administration is continued. This is physiological adaptation associated with altered genes expression .

ACTIVE EXTRUSION OF DRUG FROM CELLS

This type usually occur in cancer chemotherapy.

Decreased accumulation of cytotoxic drugs in cells as a result of the efflux pump, energy-dependent drug transport proteins e.g. dactinomycin.

 decrease in the amount of drug taken up by the cells e.g in the case of methotrexate.

insufficient activation of the drug e.g. fluorouracil, cytarabine and mercaptopurine