This article throws light upon the three main things you need to know about drug action. They are: 1. Potency 2. Efficacy 3. Dose Response Curve.
1. Potency:
It refers to the dose of a drug that must be administered to produce a particular effect of given intensity. In simple words, it is the amount of drug in relation to its effect, e.g., if drug A has a greater effect than drug B, then drug A is more potent than drug B (fig. 3.5). The diuretic effect of bumetanide 1 mg is equivalent to furosemide 50 mg, thus bumetanide is more potent than frusemide.
Potency is influenced by the affinity of a drug for its receptor sites. Potency is a relative term rather than an absolute expression, so for potency determination a standard must be defined. Low potency and extremely high potency, both can be dangerous.
Potency is useful in therapeutics for calculating rational drug combination, e.g, salicylates are potent somatic analgesic and morphine is a potent visceral analgesic, a combination of both will give a potent analgesic for mixed type of pains.
2. Efficacy:
Efficacy is the capacity of a drug to produce an effect and it refers to the magnitude of maximal response that drug can produce. Efficacy is influenced by intrinsic activity of a drug and unlike potency, it is an absolute expression, (fig. 3.5)
e.g., If drug A can produce a therapeutic effect that can not be obtained with drug B, however, much of drug B is given, then A has the higher therapeutic efficacy. The dose required to produce a same degree of response is lower with drug B compared to drug A denoting that drug B is more potent than drug A.
Whereas the maximal response exerted by drug B is only 75%, while drug A exerts a maximal response of 100%, hence drug A has a higher therapeutic efficacy than drug B.
3. Dose Response Curve:
It is the mathematical description of relationship between dose administered and response obtained by quantitative analysis of drug action. It is assumed that the effect of a drug is proportional to the fraction of receptors occupied by drugs and that maximal effect results when all receptors are occupied.
It is frequently convenient to plot the magnitude of effect versus log [Dose], because a wide range of drug concentrations is easily displayed and the potency of different drugs can be easily compared since the dose-response curve becomes linear particularly at the middle part, (fig 3.6)
The demonstration of a dose response relationship is the first step in the investigation of a compounds pharmacological activity. There are two types of DR-relationship; viz graded DR-relationship seen in individual organism and quantal DR- relationship seen in the population.
A dose-response relationship is characterized by following parameters:
(i) Maximal or ceiling effect commonly referred to as Emax or efficacy:
It is the maximal response a drug can produce.
(ii) ED5q or Median Effective dose:
It is the effective dose of a drug to elicit 50% of maximal response.
(iii) Therapeutic index (TI):
When the dose of a drug is increased progressively; the desired response in the patient usually rises accordingly up to maximum, beyond which a further increase in dose elicits unwanted or toxic effects. Thus, every drug has two different dose-response curves; one for therapeutic or beneficial effects and another for toxic effects (as shown in fig 3.6 I and II).
The dose response curve for toxic effects of a drug is characterised by LD50 which is the dose that kills half of the test population.
The therapeutic index of a drug is a measure of a drug’s safety and is obtained by dividing LD50 by ED50. The higher the value, the safer is the drug.
TI = LD50/ED50 = 20/2 = 10
A TI value of 10 or more on a log scale for a drug is considered to be safe. The TI value of a drug also gives a rough idea of drug’s selectivity. A higher value indicates that the drug is highly selective in its action while a lower value indicates that the drug is non-selective in its action.
It seems logical that drug safety could be better assessed by using a ratio derived from extremes of the respective quantal curve, such as LD1/ ED99. This ratio is known as the certain safety factor A value of 4 or more is considered to be adequate as regards drug’s safety.
Generally values of minimum toxic (LD1) and maximum therapeutic (ED99) doses are less precise than the medium (LD50, ED50) and hence therapeutic index values are preferred over certain safety factors.
(iv) Position and Slope of the Curve:
The position of the curve in relation to the dose axis gives an idea about the affinity or potency of the drug. For example, when the curve is more towards the left, it is more potent and vice versa.
The steepness, or slope of the linear part of the curve indicates the extent by which dosage must be increased to secure an increase in response, i.e., the steeper the curve the smaller the dose increment to secure the same response increment.
(v) Selectivity and Specificity:
No drug produces only a single effect. Most drugs produce multiple effects and thus have several dose-response relationships, e.g morphine is a narcotic analgesic, but it also causes sedation, respiratory depression, release of ADH, constipation, etc.
A drug is said to be relatively selective; if it produces a particular effect preferentially than other and that characteristic effect of the drug is produced at a lower doses than those required to elicit other responses. A truly selective drug would produce only a single effect.
The anticoagulant heparin is a good example of a drug that has selective action. The distribution pattern of a drug, lipid solubility, route of administration, etc. can influence selectively.
When all effects produced by a drug are due to a single mechanism of action, the drug is said to be specific. A specific drug acts at only one type of receptor but may produce multiple pharmacological effects because of location of receptors in various organs.
Atropine is a best example of a specific drug while phenothiazine derivative acepromazine is an example of a non-specific drug. For therapeutic applications, the more specific the nature and the greater the selectivity of drug action, the less the likelihood of undesirable effects and the wider the margin of safety.
Chemical specificity refers to the fact that changes in chemical structure of a drug molecule may have a large or small effect on its pharmacological activity.
(vi) Structure-Activity Relationship (S.A.R.):
Both the affinity of a drug for its receptor and its intrinsic activity are intimately related to its chemical structure. The relationship is frequently quite stringent. Relatively minor modifications in the drug molecule, including such subtle changes as stereoisomerism, may result in major changes in pharmacological properties. Exploitation of S.A.R. has on many occasions led to the synthesis of valuable therapeutic agents.
It has been possible to develop a congener with a more favourable ratio of therapeutic to toxic effects, enhanced selectivity among different cells or tissues, or more acceptable secondary characteristics than those of the parent drug. Therapeutically useful antagonists of hormones or neurotransmitters have been developed by chemical modification of the structure of the physiological agonist.
Minor modifications of structure can also have profound effects on the pharmacokinetic properties of drugs.
Given adequate information about both the molecular structures and pharmacological activities of a relatively large group of congeners, it should be possible to identify those properties that are required for optimal action at the receptor-size, shape, the position and orientation of charged groups or hydrogen bond donors, and so on.