Introduction to the dose-response relationship

Introduction to the dose-response relationship

When the relation between drug dose (X-axis) and drug response (Y-axis) is plotted on a base 10 logarithmic scale, this produces a sigmoidal dose–response curve (Fig A). This representation is more useful than a linear plot because it expands the dose scale in the region where drug response is changing rapidly and compresses the scale at higher doses where large changes have little effect on response. Clinical responses that might be plotted in this way include change in heart rate, blood pressure, gastric pH or blood glucose, as well as more subtle phenomena such as enzyme activity, accumulation of an intracellular second messenger, membrane potential, secretion of a hormone, or contraction of a muscle.

Progressive increases in drug dose produce increasing drug effects, but these occur over a relatively narrow part of the overall concentration range; further increases in drug dose (or concentration) beyond this range produce little extra effect. The clinical implication of this relationship is that simply increasing drug dose may not result in any further beneficial effects for patients and may cause adverse effects. The maximum response on the curve is referred to as the Emax and the dose (or concentration) producing half this value (Emax/2) is the ED50 (or EC50). The effective dose range can be considered as spanning the straight-line segment of the log dose–response curve (corresponding to 20–80% of Emax). The maximum tolerated dose is the highest dose of a drug that can be administered without the development of dose-related adverse effects.

The addition of a competitive antagonist to an agonist will lead to a shift in the agonist dose–response curve to the right because higher agonist concentrations are now required to achieve a given percentage receptor occupancy (and therefore effect) (Fig B). Dose–response curves of the agonist constructed in the presence of increasing doses of a competitive antagonist are progressively shifted to the right. Nevertheless, the effect of a reversible competitive antagonist can always be overcome by giving the agonist at a sufficiently high concentration (i.e. it is surmountable). Many clinically useful drugs are competitive antagonists (e.g. atenolol, naloxone, atropine, cimetidine). Non-competitive antagonists inhibit the effect of an agonist in ways other than direct competition for receptor binding with the agonist (e.g. by affecting the secondary messenger system). This makes it impossible to achieve maximum response even at very high agonist concentration. At a given concentration, non-competitive antagonists not only shift the agonist dose–response curve to the right but also decrease the Emax (Fig C). Irreversible antagonists can be considered as a particular form of non-competitive antagonist characterized by antagonism that persists, even after the antagonist has been removed. Common examples are aspirin and omeprazole. This form of antagonism disappears only when new proteins or enzyme are synthesized. This explains why aspirin is effective, even when taken intermittently, as prophylaxis against cardiovascular events.

The dose-response relationship to the same drug varies between individuals because of various factors, such as differences in receptor number and structure, receptor-coupling mechanisms and physiological changes resulting from differences in genetics, age and health. For example, the effect of the loop diuretic, furosemide, is often significantly reduced at a given dose in patients with renal impairment. A further source of variability is that the same dose of drug does not achieve the same tissue drug concentrations in all individuals because of differences in handling (e.g. metabolism, excretion). In reality, it is this pharmacokinetic variation that explains most of inter-individual variation in drug response seen in clinical practice.

Figure. Dose–response curves. A. Basic features. B. The effect of co-administering an agonist with a competitive antagonist. C. The effect of administering an agonist with a non-competitive antagonist. (Note that, in reality, it is ligand concentration (and resulting receptor occupation) that affects response. When discussing 'the dose– response curve' it is often assumed that the drug dose and ligand concentration are closely linked. This is likely to be the case during an in vitro pharmacological experiment but the relation between an ingested drug dose and relevant tissue concentration in a human can be more complex.)

The Merck Manual-Dose-Response Relationships

This 350-word essay briefly describes the characteristics of a log dose-response curve and information that can be discerned when comparing dose-response curves. Each is accompanied by a figure. This is an easy to understand description of dose-response curves.

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Overview of the general principles of pharmacology

This is an almost 60 minute lecture on the general principles of pharmacology. The first half deals with drugs, pH and pKa including the Henderson-Hasselbalch equation. The latter portion of the presentation (about the last 15 minutes) focuses on dose-response relationships including graded and quantal with a discussion of potency and efficacy. This is appropriate for a beginning student in pharmacology.

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