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GATE:General Principles of Drug Action

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General Principles of Drug Action

1. The guiding principles of homeopathy are “like cures like” and “activity can be enhanced by dilution”.
2. Paul Ehrlich postulated that drug action should be understood in terms of conventional chemical interactions between drugs and tissues and not by any magical vital forces.
3. Some bacterial toxins (eg. diphtheria toxin) act with such precision that a single molecule taken up by a target cell is sufficient to kill it.
4. Drug molecules must be “bound” to particular constituents of cells and tissues in order to produce an effect. Ehrlich summed it up as “A drug will not work unless it is bound”.
5. Most drugs produce their effects by binding, in the first instance, to protein molecules.
6. General anaesthetics were earlier thought to produce their effect by an interaction with membrane lipid, but now it appears they mainly interact with membrane proteins.
7. The only exception to proteins as target sites is DNA. A number of antitumour, antimicrobial, mutagenic and carcinogenic agents act on DNA.
8. Four kinds of regulatory proteins are commonly involved as primary drug targets. They are
   1. receptors
   2. ion channels
   3. carrier molecules and
   4. enzymes.
9. Tubulin specifically binds colchicine.
10. Many drugs hind to (in addition to their primary targets) plasma proteins as well as to cellular constituents without producing any obvious physiological effect.
11. The voltage sensitive sodium channel of excitable membranes is the receptor for local anaesthetics.
12. The enzyme dihydrofolate reductase is the receptor for methotrexate. In the case of local anaesthetics and dihydrofloate reductase, the drug molecule combines with and incapacitates the protein molecule, thus producing its effect.
13. In the case of adrenaline – the primary function of a receptor molecule is to serve as a recognition site for catecholamines. When adrenaline binds to the receptor – action starts – leads to increase in force and rate of the heartbeat. This receptor produces an effect only when adrenaline is bound, otherwise it is functionally silent.
14. Endogenous mediators’ examples: hormones, neurotransmitters, cytokines.
15. Agonists activate the receptors.
16. Antagonists may combine at the same site without any activation.
17. Drugs should be selective and should show a high degree of binding site specificity.
18. Proteins that function as drug targets also generally show a high degree of ligand specificity. [They will recognize only ligands of a certain precise type and ignore even closely related molecules].
19. The mediator angiotensin [a peptide] acts strongly on vascular smooth muscle and on the kidney tubule but has very little effect on other kinds of smooth muscle or on the intestinal epithelium.
20. The ability of proteins to interact in a highly selective way with other molecules – including other proteins – is the basis of living machines.
21. No drug acts with complete specificity. Histamine antagonists, although they can be shown to have a higher affinity for histamine receptors than for other sites, produce many effects, such as sedation and prevention of vomiting, which do not depend on histamine antagonism.
22. In general, the lower the potency of a drug and the higher the dose needed, the more likely it is that sites of action other than the primary one will become significant. This is associated with unwanted side effects.
23. The result known as Hill – Langmuir equation is given by pA= or PA= when XA = concentration of drug or ligand, and KA = equilibrium constant for the binding reaction.
24. This equilibrium constant Ka is a characteristic of the drug and of the receptor. It has the dimensions of the concentration and is numerically equal to the concentration of drug required to occupy 50% of the sites at equilibrium.
25. When XA = KA, PA = 0.5.
26. The higher the affinity of the drug for the receptors, the lower will be KA.
27. The higher the affinity of the drug for the receptors, the lower the concentration at which it produces a given level of occupancy.
28. The same principles apply when two or more drugs compete for the same receptors; each has the effect of reducing the apparent affinity for the other.
29. In the case of acetylcholine, which is hydrolysed by cholinesterase present in most tissues, the concentration reaching the receptors can be less than 1% of that in the organ bath, and an ever bigger difference has been found with noradrenaline.
30. Schild equation, which has to do with competitive antagonism is where XB is the concentration of drug B, which is the competitive antagonist, KB is the equilibrium constant of drug B and r = where XA1 is the concentration to which a drug A may be increased so as to restore PA (the proportion of receptors occupied or occupancy, ) value reached in the absence of the antagonist.
31. If it is assumed that the response of the test system depends only on the agonist occupancy, PA1, then it is predicted that the effect of the competitive antagonist on the response can also be overcome by increasing the agonist concentration r-fold.
32. There are two characteristic features of competitive antagonism:
    1. The dose ratio “r” depends only on the concentration and equilibrium constant of the antagonist, and not on the size of response that is chosen as a reference point for the measurements, nor on the equilibrium constant for the agonist. On a semi-log plot of effect against concentration, the effect of the competitive antagonist will be to shift the curve to the right without changing its slope or maximum.
    2. The dose ratio achieved should increase linearly with XB and the slope of a plot of (r-1) against XB is equal to 1/KB. This relationship, being independent of the characteristics of the agonist, should be the same for all agonists that act on the same population of receptors.
33. The ability of a drug molecule to activate the receptors is actually a graded rather than an all or none property.
34. The difference between full and partial agonists lies in the relationship between occupancy and response.
35. In reversible competitive antagonism, the dose ratio increases linearly with antagonist concentration; the slope of this line is a measure of the affinity of the antagonist for the receptor.
36. Antagonist affinity, measured in this way, is widely used as a basis for receptor classification.
37. Stephenson, described efficacy, to describe the “strength” of a single drug-receptor complex in evoking a response of the tissue.
38. Now it is known that characteristics of the tissue (eg: the number of the coupling between the receptor and the response) as well as of the drug itself, are important and the concept of intrinsic efficacy was developed.
39. The relationship between occupancy and response can thus be represented as: Response = f In this equation: f represents the transducer function which describes the characteristics of the responding system or tissue and is the intrinsic efficacy, which is a characteristic of the drug – receptor complex.
40. Receptor mutations sometimes occur, which result in appreciable activation in the absence of any ligand, which is known as constitutive activation.
41. A ligand which binds preferentially to the inactivated state (i.e. k*>k) can shift the equilibrium towards this state. Such compounds are known as inverse agonists. They reduce the level of constitutive activation.
42. Drugs acting on receptors may be agonists or antagonists.
43. Agonists initiate changes in cell function, producing effects of various types; antagonists bind to receptors without such changes.
44. Agonist potency depends on their affinity (tendency to bind to receptors) and their efficacy (once bound, to initiate changes which lead to effects).
45. For antagonists efficacy is zero.
46. Full agonists which can produce maximal effects have high efficacy; partial agonists (which can produce only sub maximal effects) have intermediate efficacy.
47. According to the two – state model efficacy reflects the relative affinity of the compound for the resting and activated compound for the resting and activated states of the receptor. Agonists show selectivity for the activated state; and antagonists show no selectivity.
48. Inverse agonists show selectivity for the resting state of the receptor.
49. The existence of spare receptors means that the pool is larger than the number needed to evoke a full response.
50. The above arrangement means that economy of hormone or transmitter secretion is achieved at the expense of providing more receptors.
51. The binding of drugs to receptors can be measured directly by the use of radioactive drug molecules such as 3H, 14C or 125I.
52. The main requirements for this radio – active ligand are (1) it must bind with high affinity and specificity (2) it must be capable of being labeled to a sufficiently specific radioactivity to enable minute amounts of binding to be measured.
53. Method to estimate non-specific bidning (1) Find the total binding (2) Measure the radioactivity taken up in the presence of a saturating concentration of a (non-radioactive) ligand that inhibits completely the binding of the radioactive drug to the receptor (3) 2 is subtracted from 1
54. Auto radiography is used to investigate the distribution of receptors in structures such as the brain and direct labeling with ligands containing positron – emitting isotopes is now used to obtain images by positron – emission tomography (PET) by receptor distribution in humans.
55. Receptors tend to increase in number, usually over the course of a few days, if the relevant hormone or transmitter is absent or scarce and to decrease in number if it is in excess, a process of adaptation which produces gradual changes in responsiveness to drugs or hormones with continued administration.
56. Receptors can exist either unattached or coupled within the membrane to another macromolecule, the G-protein which constitutes part of the transduction system through which the receptor exerts its regulatory effect.
57. Antagonist binding does not show this complexity, because antagonists do not lead to the secondary event of G-protein coupling.
58. Five varieties of antagonism are there (a) chemical antagonism (b) pharmacokenetic antagonism (c) antagonism by receptor block (d) non-competitive antagonism, i.e., block of receptor – effector linkage (e) physiological antagonism.
59. Chemical antagonism means two substances combine in solution, so that the effect of the active drug is lost. Examples (1) Use of chelating agents (ex : dimercaprol) which bind to heavy metals and thus reduce their toxicity. (2) Use of neutralizing antibodies against protein mediators, such as cytokines and growth factors.
60. Pharmackinetic antagonism : This results in a situation in which the “antagonist” effectively reduces the concentration of the active drug at its site of action. This may happen by altering ADM or E. ex: warfarin’s hepatic metabolism is accelerated by phenobarbitone.
61. Antagonism by receptor block : Occurs by one of two mechanisms : ##reversible competitive antagonism
    1. 1. surmountability and the linear Schild plot. The rate of dissociation of the antagonist molecules is sufficiently high. The agonist is able to displace the antagonist molecules from the receptors.
    2. irreversible or non-equilibrium, comptetive antagonism.
       1. antagonist dissociates very slowly or not at all from the receptors. No change in the antagonist occupancy takes place when the agonist is applied; non-surmountable. If the fraction of receptors blocked by the antagonist is PB, the fraction accessible to the agonist is reduced to (1-PB). The antagonism is non-surmountable because no matter how high the agonist concentration, the agonist occupancy cannot exceed (1-PB)
62. Irreversible competitive antagonism occurs with drugs that posses reactive groups which form covalent bonds with the receptor.
63. Irreversible enzyme inhibitors include drugs such as aspirin, omeprazole and monoamine oxidase inhibitors.
64. Non-competitive antagonism: This describes a situation where the antagonist blocks at some point the chain of events that leads to the production of a response by the agonist. Ex: verapamil and nifedipine prevent the influx of calcium ions through the cell membrane and thus block non-specifically the contraction of smooth muscle produced by other drugs.
65. Physiological antagonism : Physiological antagonism is a term used to describe the interaction of two drugs whose opposing actions in the body tend to cancel each other.For example histamine acts on the receptors of the parietal cells of the gastric mucosa to stimulate acid secretion; omeprazole blocks this effect by inhibiting the proton pump; so the two drugs are physiological antagonists.
66. Desensitisation and Tachyphylaxis are synonymous terms used to describe the phenomenon of a gradual reduction in the efficacy of a drug when it is given continuously or repeatedly.
67. Sometimes desensitisation can develop in a few minutes.
68. The term tolerance is used to describe a more gradual decrease in responsiveness to a drug, taking days or weeks to develop.
69. Refractoriness is a term used to describe loss of therapeutic efficacy.
70. Drug resistance is a term used to describe the loss of effectiveness of antimicrobial or antitumour drugs.
71. Mechanisms responsible for Desensitization are ##change in receptors
    1. loss of receptors
    2. exhaustion of mediators
    3. increased metabolic degradation ##physiological adaptation ##active extrusion of drug from cells (mainly relevant in chemotherapy)
72. Change in receptors : At the neuromuscular junction, the desensitized state is caused by a conformational change in the receptor, resulting in tight binding of the agonist molecule without the opening of the ionic channel. For example B – adrenoceptor, on desensitization becomes unable to activate adenylate cyclase.
73. Phosphorylation of specific residues in the receptor protein is responsible for many types of desensitization.
74. Loss of receptors: Prolonged exposure to agonists results in a gradual decrease in the number of receptors. For example Ex: - adrenoreceptors.In studies on cell cultures, the number of – adrenoreceptors can fall to about 10% of normal in 8 hours in the presence of a low concentration of isoprenaline. Recovery to normal takes several days.
75. Good use of this Phenomenon : Gonadotrophin – releasing hormone is used to treat endometriosis or prostatic cancer; given continuously, this hormone paradoxically inhibits gonadotrophin release (in contrast to the normal stimulatory effect of the physiological secretion, which is pulsatile).
76. Exhaustion of mediators : In some cases, desensitization is associated with depletion of an essential intermediate substance. Drugs such as amphetamine, which act by releasing noradrenalin, and other amines from nerve terminals show marked tachyphylaxis because the releasable stores of noradrenalin become depleted.
77. Increased metabolic degradation : Tolerance to some drugs, for example barbiturates and ethanol occurs partly because repeated administration, of the same dose produces a progressively lower plasma concentration. The degree of tolerance that results is generally modest.
78. Physiological adaptation : Diminution of a drug’s effect may occur because it is nullified by a homeostatic response ex: The B.P. lowering effect of thiazide diuretics is limited because of a gradual activation of the renin-angiotensin system.

How Drugs Act : Molecular Aspects

1. Targets for drug Action : RICE The protein targets for drug action on mammalian cells are broadly divided into receptors, ion channels, carrier molecules and enzymes.
2. Receptors : Chemical messengers are hormones, transmitter substances or cytokins and growth factors.
3. Ion Channels : The simplest type of interaction involves a physical blocking of the channel by the drug molecule exemplified by the blocking action of local anaesthetics on the voltage – gated sodium channel or the blocking of sodium entry into renal tubular cells by the diuretic amiloride.
4. Channel function can also be modulated by drugs which bind to accessory sites on the channel protein, ex: the action of vasodilator drugs of the dihydropyridine type on calcium channels.

Author

This article is contributed by Smt. Prof. Jayanti Vijaya Ratna .

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