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Pharmacodynamics for the prescriber
CLINICAL PHARMACOLOGY
Pharmacodynamics for the prescriber
Key points C
Most drugs exert their effects by binding to receptor proteins (e.g. channel-linked, G-protein-coupled, kinase-linked, DNAlinked) located in cell membranes or nuclei, although there are many other drug targets (e.g. enzymes, voltage-gated channels, transport proteins)
C
Drugs that activate receptors to produce a biological response are known as agonists, whereas those that bind the same receptors but do not cause biological responses are known as antagonists
C
The relationship between drug dose and biological response is called the doseeresponse curve and is normally plotted on a logarithmic dose scale, appearing as a sigmoid curve
C
Agonists and antagonists compete for receptor binding, and the presence of antagonists shifts the doseeresponse curve of the agonist to the right. The presence of increasing antagonist concentration moves the curve further to the right
C
The efficacy of a drug is a measure of its capacity to produce a biological effect (the maximum effect being known as Emax), and the potency of a drug is an expression of the amount of a drug required to produce biological effects (normally expressed as the ED50, the dose required to produce 50% of Emax)
C
The therapeutic index is the ratio between the dose of a drug that causes adverse effects and the dose that achieves therapeutic benefits
C
Desensitization to drugs is a common phenomenon; when it occurs rapidly it is known as tachyphylaxis, and when it occurs more slowly it is known as tolerance
Simon RJ Maxwell
Abstract Pharmacodynamics is the study of how drugs have effects on the body. The most common mechanism is by the interaction of the drug with tissue receptors located either in cell membranes or in the intracellular fluid. The extent of receptor activation, and the subsequent biological response, is related to the concentration of the activating drug (the agonist). This relationship is described by the dose eresponse curve, which plots the drug dose (or concentration) against its effect. This important pharmacodynamic relationship can be influenced by patient factors (e.g. age, disease) and by the presence of other drugs that compete for binding at the same receptor (e.g. receptor antagonists). Some drugs acting at the same receptor (or tissue) differ in the magnitude of the biological responses that they can achieve (i.e. their efficacy) and the amount of the drug required to achieve a response (i.e. their potency). Drug receptors can be classified on the basis of their selective response to different drugs. Constant exposure of receptors or body systems to drugs sometimes leads to a reduced response (i.e. desensitization).
Keywords Affinity; agonist; antagonist; desensitization; dose eresponse curve; pharmacodynamics; receptors; selectivity; therapeutic index
What is meant by the term ‘pharmacodynamics’? Pharmacodynamics is the study of: the biochemical and physiological effects of drugs on the body the mechanisms of drug action the relationship between drug concentration and drug effect.1,2 Pharmacodynamics can be simply described as the study of ‘what a drug does to the body’. Basic pharmacodynamic studies involve exposing cells or tissues to constant concentrations of a drug and observing their effect. For prescribers, the situation is more complex, because drug exposure depends on how effectively drug molecules are taken into the body and reach their site of action (absorption, distribution) and how quickly they are removed from the body (metabolism, excretion). These
processes are collectively known as pharmacokinetics (the study of ‘what the body does to a drug’).
What are the ways in which drugs produce effects in body systems? The pathophysiology underlying the progression of most diseases involves the disordered structure and function of cells and tissues, which are composed of complex molecules and biochemical processes. Drugs are intended to restore normal function by acting on ‘target molecules’ in the affected tissue or organ. Binding exerts a biological effect, either by initiating new events or by blocking the actions of endogenous substances (e.g. neurotransmitters, hormones). Resulting effects include changing the ion content of cells, promoting the secretion of hormones, reducing electrical signalling by excitable cells, reducing contractile activity, stimulating the synthesis of new proteins, and many others. Many of these responses result from interactions between drugs and endogenous ‘receptors’.
Simon RJ Maxwell MB ChB MD PhD FRCP FRCPE FHEA is Professor of Student Learning (Clinical Pharmacology and Prescribing) at the University of Edinburgh and Honorary Consultant Physician at the Western General Hospital, Edinburgh, UK. His main research interests relate to the causes and prevention of prescribing errors with particular emphasis on the importance of training and assessment of junior prescribers. He is Medical Director of the UK Prescribing Safety Assessment. Competing interests: none declared.
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high, but the agonist is then cleared rapidly by active transport. In contrast, growth factors are typically peptides with very high affinity for their receptors, and achieve their effects at concentrations that are difficult to detect in vivo.
What are receptors? Receptors are typically glycoproteins located in cell membranes that specifically recognize smaller molecules (including drugs) that are capable of binding (‘ligating’) themselves to the receptor protein. This binding initiates a conformational change in the receptor protein leading to a series of biochemical reactions inside the cell (signal transduction), often involving the generation of ‘secondary messengers’, that is eventually translated into a biological response (e.g. muscle contraction, hormone secretion) (Figure 1). Although the ligands of interest to prescribers are exogenous compounds (i.e. drugs), receptors in human tissues have evolved to bind endogenous ligands such as neurotransmitters, hormones and growth factors. Formation of the drug ereceptor complex is usually reversible, and the proportion of receptors occupied (and thus the response) is directly related to the concentration of the drug. Reversibility enables biological responses to be modulated and means that similar ligands can compete for access to the receptor. The term ‘receptor’ is usually restricted to describing proteins whose only function is to bind a ligand; however, it is sometimes used more widely in pharmacology to include other kinds of drug target such as voltagesensitive ion channels, enzymes and transporter proteins (Figure 1).1,2
What do the terms agonist, antagonist and partial agonist mean? Receptor ligands can be distinguished on the basis of their potential to initiate a biological response following receptor binding: Agonists bind to a receptor protein to produce a conformational change, which initiates a signal that is coupled to a biological response. As the free ligand concentration increases, so does the proportion of receptors occupied, and hence the biological effect. When all the receptors are occupied, the maximum response is achieved. Antagonists bind to a receptor but do not produce the conformational change that initiates an intracellular signal. Occupation of the receptor by a competitive antagonist prevents binding of other ligands and so ‘antagonizes’ the biological response to the agonist. The inhibition that antagonists produce can be overcome by increasing the dose of the agonist. Some antagonists interfere with the response to the agonist in ways other than receptor competition and are known as non-competitive antagonists. Simply increasing the dose of the agonist cannot overcome their effects, so the maximum response to the agonist (its efficacy) is reduced. Partial agonists are able to activate a receptor but cannot produce a maximal signalling effect equivalent to that of a full agonist even when all the available receptors are occupied.
How do receptors mediate pharmacological responses? The main types of drug targets and their mechanisms of action are described in Table 1.
What is meant by ‘receptor affinity’? Affinity of ligands is a function of both the rate of association and the rate of dissociation of the ligandereceptor complex;3 the former depends on the ‘goodness of fit’ at a molecular level, whereas the latter depends on how tightly the ligand is bound (the strength of the chemical bond). Systems requiring rapid fine modulation (e.g. nerve synapses) must have agonists with a low receptor affinity because those with high receptor affinity would produce unnecessarily prolonged responses. During stimulation, the agonist concentration near the receptor must be relatively
What is the relationship between drug dose and response? 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 doseeresponse curve (Figure 2a). Clinical responses that might be plotted in this way include change in heart rate,
Receptors and other drug targets b. A channel-linked receptor
a. A G-protein-coupled receptor (GPCR) Drug
Na+
c. An enzyme drug target
d. A transport protein drug target Drug
Drug
Drug Substrate molecules
Products
G-protein complex G-protein activates a target protein
Conformational Na+ change in the channel increases ion conductance
Enzyme Na+
K+
Target protein initiates further events leading to a biological response
Figure 1
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Receptors and other drug targets (see Figure 1) Drug target Receptors Channel-linked receptors
G-protein-coupled receptors
Kinase-linked receptors
DNA-linked receptors
Other targets Voltage-sensitive ion channels
Enzymes
Transporter proteins
Description
Example
Coupled directly to an ion channel. Activation opens the channel, making a cell membrane permeable to specific ions. These channels are known as ligand-gated because it is receptor binding that operates them (in contrast to voltage-gated channels that respond to changes in membrane potential) Coupled to intracellular effector mechanisms via a family of closely related G-proteins that participate in signal transduction by coupling receptor binding to intracellular enzyme activation or the opening of an ion channel. Secondary messenger systems include the enzymes adenylate cyclase and guanylate cyclase, which generate cyclic adenosine monophosphate and cyclic guanosine monophosphate, respectively Linked directly to an intracellular protein kinase that triggers a cascade of phosphorylation reactions Intracellular and also known as nuclear receptors. Binding of a ligand promotes or inhibits synthesis of new proteins, which may take hours or days to promote a biological effect
Nicotinic acetylcholine receptor g-Aminobutyric acid (GABA) receptor
Found in excitable tissues and a potential target for drugs that can block the channel or interfere with conductance in other ways Catalyse biochemical reactions, some of which involve the production of key mediators of physiological processes in body systems. Drugs interfere with the active site of the enzyme or affect co-factors required by the enzyme for activity. In most cases, inhibition of the active site is competitive, although in some cases it can be long-lasting and effectively irreversible (e.g. aspirin) Specialized proteins that carry ions or molecules across cell membranes. Movement can be in either direction and can involve exchange of one substance for another, cotransport of two or more substances in the same direction, or ‘pumping’ of a single substance into or out of a cell or organelle. Drugs can act on transporters to inhibit their activity or can also act as ‘false substrates’, preventing the transport of the normal biological substrate
Muscarinic acetylcholine receptor b-Adrenoceptors Dopamine receptors Serotonin receptors Opioid receptors
Insulin receptor
Corticosteroid receptors Thyroid receptors Vitamin D receptors
Naþ channels that are blocked by local anaesthetics such as lidocaine Cyclo-oxygenase e inhibited by aspirin Angiotensin-converting enzyme e inhibited by enalapril Xanthine oxidase e inhibited by allopurinol
The serotonin reuptake transporter, which is inhibited by fluoxetine
Table 1
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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
100
Emax
30 20 10 ED50
80 60
Agonist + competitive agonist
Agonist alone
40 20 0
0 0.01
0.1
1
10
Drug dose (µg)
100
Drug response (% maximum )
40
Agonist alone
80
50
Drug response (% maximum )
Drug response (increase in heart rate)
100
60 40
Agonist + non-competitive agonist
20 0
0.001 0.01 0.1
1
10
100 1000
Agonist and competitive
0.001 0.01
0.1
1
10
100
1000
Agonist and non-competitive
µg, micrograms
Figure 2
bind irreversibly to the target molecule and require synthesis of new receptors or enzyme before normal function is restored.
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 the 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 called the ED50 (or EC50).
What is meant by efficacy and potency? Efficacy is the term used to describe the extent to which a drug can produce a response when all available receptors or binding sites are occupied (i.e. Emax on the doseeresponse curve) (Figure 2a). When comparing drugs acting at the same receptor, a full agonist has the greatest efficacy and can produce the maximum response of which the receptor is capable. A partial agonist at the same receptor has, by definition, a lower efficacy, even when all the receptor sites are occupied. The concept of efficacy is not restricted to comparing the effects of drugs that act at the same receptor. The term therapeutic efficacy is used to describe the comparison of drugs that produce the same therapeutic effects on a biological system but do so via different pharmacological mechanisms (e.g. loop and thiazide diuretics, proton pump inhibitors and H2-receptor antagonists). Potency is a term used to describe the amount of a drug required for a given response. More potent drugs produce biological effects at lower doses (or concentrations), which means that they have a lower ED50 (Figure 3). The potency of a drug is related to its affinity for the receptor. More potent drugs occupy a given proportion of receptors at lower concentration. This is reflected in the varying dose recommendations for drugs in the same class acting at the same receptors (e.g. H2-receptor antagonists, angiotensin-converting enzyme inhibitors).
What is the effect of antagonists on the doseeresponse curve of an agonist? The presence of a competitive antagonist displaces the agonist doseeresponse curve to the right because higher agonist concentrations are now required to achieve a given percentage receptor occupancy (and therefore effect) (Figure 2b). Dose eresponse curves of the agonist constructed in the presence of increasing doses of a competitive antagonist are progressively displaced 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 (e.g. atenolol, naloxone, atropine, cimetidine) are competitive antagonists. 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 the maximum response even at very high agonist concentrations. The presence of a non-competitive antagonist not only displaces the agonist doseeresponse curve to the right, but also decreases the Emax (Figure 2c). Some drugs that appear to be non-competitive antagonists are, in fact, irreversible antagonists (e.g. aspirin, omeprazole). They
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What is receptor selectivity? Receptors are named on the basis of their major endogenous agonist (e.g. adrenergic, serotoninergic, opioid). They are then usually ‘subtyped’ on the basis of their selectivity for agonists or antagonists. Agonist selectivity is determined by the ratio of EC50 of the doseeresponse curve at the two different receptor subtypes. For example, b-adrenoceptors can be subtyped into b1 and b2 on the basis of their responsiveness to the endogenous agonist noradrenaline (norepinephrine). The concentration required to
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Dose–response curves for drugs with high, medium and low potency acting on the same target
Dose–response curves for the beneficial and adverse effects of a drug Prescribers will aim to prescribe doses that maximize benefits and minimize harms. That is easier for drugs where the ratio between the dose causing harm and that causing benefit (the ‘therapeutic index’) is high
250
Low potency
200
Drug response (% maximum)
Drug response (arbitrary units)
Note that the drug with the highest potency has the lowest efficacy and vice versa
Medium potency
150
100
High potency
50
100
80
60
Beneficial effect ED50 = 0.1
Therapeutic index = 100
Adverse effect ED50 = 10
40
20
0
Minimum effective (threshold) dose
Maximum tolerated dose
0 0.001
0.01
0.1
1
10
100
1000
0.001
Drug dose (mg/kg)
0.01
0.1
1
10
100
1000
Drug dose (µg) µg, micrograms
Figure 3 Figure 4
cause bronchodilation (via b2-adrenoceptors) is 10 times higher than that required to cause tachycardia (via b1-adrenoceptors). Receptor subtypes can also be distinguished by the relative effectiveness of drugs that antagonize the effects of their full agonist, measured as the relative shift of the agonist dose eresponse curves achieved by a single dose of antagonist affecting responses mediated through the two receptors. It is important for prescribers to remember that selectivity for a receptor subtype is only a relative concept (i.e. selectivity does not equate with specificity). Agonist or antagonist drugs that are considered to be ‘selective’ for one receptor subtype can still produce significant effects at other subtypes if a high enough dose is given (e.g. ‘cardioselective’ b-adrenoceptor-blocking drugs can cause bronchospasm in the lung in patients with asthma).
carefully for individual patients to maximize benefits but avoid adverse effects. This is done by monitoring drug effects, either clinically or using regular blood tests (often known as therapeutic drug monitoring).
Why do patients differ in their response to drugs? Prescribers never know the actual doseeresponse relationships for the particular patients they treat. They have to make dose selections based on average doseeresponse data derived from observations from many individuals. Pharmacodynamic variation arises 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 clinical practice, it is this pharmacokinetic variation that explains most of inter-individual variation in drug response.
What is the ‘therapeutic index’? The adverse effects of drugs are often dose-related in a similar way to the beneficial effects. It is possible to construct a dose eresponse curve for these adverse effects in the same way as shown for the beneficial effects, with higher doses usually required to cause the adverse effect. The ED50 points for each curve in Figure 4 indicate that the ratio between the doses that have similar proportionate effects on the two outcomes is 10/0.1 ¼ 100. This ratio is known as the ‘therapeutic index’. In reality, drugs have multiple potential adverse effects, but the concept of therapeutic index is usually reserved for those requiring dose reduction or discontinuation. For most drugs, the therapeutic index is >100, but there are some notable exceptions with therapeutic indices <10 that are in common use (e.g. digoxin, warfarin, insulin, phenytoin, opioids).4 Drugs with low therapeutic indices are more difficult to prescribe and hazardous for patients, but they are still preferred if there are no alternative drugs with similar efficacy (e.g. anticancer drugs). The doses of such drugs have to be titrated
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Why do the effects of some drugs diminish over time? Desensitization refers to the common situation in which the biological response to a drug diminishes when it is given continuously or repeatedly. It may be possible to restore the response by increasing the dose (or concentration) of the drug, but in some cases the target organ can become completely refractory to its effect. The term tachyphylaxis is used to describe desensitization that occurs very rapidly, sometimes with the initial dose. The term tolerance is conventionally used to describe a more gradual loss of response to a drug that occurs over days or weeks. There is no clear distinction, but the different scales imply
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that different mechanisms may be involved. Rapid desensitization implies the depletion of chemicals that may be necessary for the pharmacological actions of the drug (e.g. a stored neurotransmitter released from a nerve terminal) or receptor phosphorylation. Slower development implies changes in receptor number or the development of counter-regulatory physiological changes that offset the actions of the drug (e.g. accumulation of salt and water in response to vasodilator therapy) or reduction of target receptor numbers. Where desensitization to a drug arises because of established chemical, hormonal and physiological changes that offset the actions of the drug, discontinuation may mean that these changes cause ‘rebound’ withdrawal effects (e.g. nitrates, opioids, benzodiazepines).5 A
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KEY REFERENCES 1 Rang HP, Ritter JM, Flower R, Henderson G. How drugs act: general principles. In: Pharmacology. 8th edn. New York: Churchill Livingstone, 2015; 6e21. 2 Brunton LL, JG, Chabner BA, Knollman JC. Pharmacodynamics: molecular mechanisms of drug action. In: Goodman & Gilman’s the pharmacological basis of therapeutics. 12th edn. New York: McGraw Hill, 2011; 41e72. 3 Colquhoun D. Binding, gating, affinity and efficacy. Br J Pharmacol 1998; 125: 923e47. 4 Levy G. What are narrow therapeutic index drugs? Clin Pharmacol Ther 1998; 63: 501e5. 5 Christie MJ. Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. Br J Pharmacol 2008; 154: 384e96.
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Pharmacodynamics for the prescriber
Key points C
Most drugs exert their effects by binding to receptor proteins (e.g. channel-linked, G-protein-coupled, kinase-linked, DNAlinked) located in cell membranes or nuclei, although there are many other drug targets (e.g. enzymes, voltage-gated channels, transport proteins)
C
Drugs that activate receptors to produce a biological response are known as agonists, whereas those that bind the same receptors but do not cause biological responses are known as antagonists
C
The relationship between drug dose and biological response is called the doseeresponse curve and is normally plotted on a logarithmic dose scale, appearing as a sigmoid curve
C
Agonists and antagonists compete for receptor binding, and the presence of antagonists shifts the doseeresponse curve of the agonist to the right. The presence of increasing antagonist concentration moves the curve further to the right
C
The efficacy of a drug is a measure of its capacity to produce a biological effect (the maximum effect being known as Emax), and the potency of a drug is an expression of the amount of a drug required to produce biological effects (normally expressed as the ED50, the dose required to produce 50% of Emax)
C
The therapeutic index is the ratio between the dose of a drug that causes adverse effects and the dose that achieves therapeutic benefits
C
Desensitization to drugs is a common phenomenon; when it occurs rapidly it is known as tachyphylaxis, and when it occurs more slowly it is known as tolerance
Simon RJ Maxwell
Abstract Pharmacodynamics is the study of how drugs have effects on the body. The most common mechanism is by the interaction of the drug with tissue receptors located either in cell membranes or in the intracellular fluid. The extent of receptor activation, and the subsequent biological response, is related to the concentration of the activating drug (the agonist). This relationship is described by the dose eresponse curve, which plots the drug dose (or concentration) against its effect. This important pharmacodynamic relationship can be influenced by patient factors (e.g. age, disease) and by the presence of other drugs that compete for binding at the same receptor (e.g. receptor antagonists). Some drugs acting at the same receptor (or tissue) differ in the magnitude of the biological responses that they can achieve (i.e. their efficacy) and the amount of the drug required to achieve a response (i.e. their potency). Drug receptors can be classified on the basis of their selective response to different drugs. Constant exposure of receptors or body systems to drugs sometimes leads to a reduced response (i.e. desensitization).
Keywords Affinity; agonist; antagonist; desensitization; dose eresponse curve; pharmacodynamics; receptors; selectivity; therapeutic index
What is meant by the term ‘pharmacodynamics’? Pharmacodynamics is the study of: the biochemical and physiological effects of drugs on the body the mechanisms of drug action the relationship between drug concentration and drug effect.1,2 Pharmacodynamics can be simply described as the study of ‘what a drug does to the body’. Basic pharmacodynamic studies involve exposing cells or tissues to constant concentrations of a drug and observing their effect. For prescribers, the situation is more complex, because drug exposure depends on how effectively drug molecules are taken into the body and reach their site of action (absorption, distribution) and how quickly they are removed from the body (metabolism, excretion). These
processes are collectively known as pharmacokinetics (the study of ‘what the body does to a drug’).
What are the ways in which drugs produce effects in body systems? The pathophysiology underlying the progression of most diseases involves the disordered structure and function of cells and tissues, which are composed of complex molecules and biochemical processes. Drugs are intended to restore normal function by acting on ‘target molecules’ in the affected tissue or organ. Binding exerts a biological effect, either by initiating new events or by blocking the actions of endogenous substances (e.g. neurotransmitters, hormones). Resulting effects include changing the ion content of cells, promoting the secretion of hormones, reducing electrical signalling by excitable cells, reducing contractile activity, stimulating the synthesis of new proteins, and many others. Many of these responses result from interactions between drugs and endogenous ‘receptors’.
Simon RJ Maxwell MB ChB MD PhD FRCP FRCPE FHEA is Professor of Student Learning (Clinical Pharmacology and Prescribing) at the University of Edinburgh and Honorary Consultant Physician at the Western General Hospital, Edinburgh, UK. His main research interests relate to the causes and prevention of prescribing errors with particular emphasis on the importance of training and assessment of junior prescribers. He is Medical Director of the UK Prescribing Safety Assessment. Competing interests: none declared.
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high, but the agonist is then cleared rapidly by active transport. In contrast, growth factors are typically peptides with very high affinity for their receptors, and achieve their effects at concentrations that are difficult to detect in vivo.
What are receptors? Receptors are typically glycoproteins located in cell membranes that specifically recognize smaller molecules (including drugs) that are capable of binding (‘ligating’) themselves to the receptor protein. This binding initiates a conformational change in the receptor protein leading to a series of biochemical reactions inside the cell (signal transduction), often involving the generation of ‘secondary messengers’, that is eventually translated into a biological response (e.g. muscle contraction, hormone secretion) (Figure 1). Although the ligands of interest to prescribers are exogenous compounds (i.e. drugs), receptors in human tissues have evolved to bind endogenous ligands such as neurotransmitters, hormones and growth factors. Formation of the drug ereceptor complex is usually reversible, and the proportion of receptors occupied (and thus the response) is directly related to the concentration of the drug. Reversibility enables biological responses to be modulated and means that similar ligands can compete for access to the receptor. The term ‘receptor’ is usually restricted to describing proteins whose only function is to bind a ligand; however, it is sometimes used more widely in pharmacology to include other kinds of drug target such as voltagesensitive ion channels, enzymes and transporter proteins (Figure 1).1,2
What do the terms agonist, antagonist and partial agonist mean? Receptor ligands can be distinguished on the basis of their potential to initiate a biological response following receptor binding: Agonists bind to a receptor protein to produce a conformational change, which initiates a signal that is coupled to a biological response. As the free ligand concentration increases, so does the proportion of receptors occupied, and hence the biological effect. When all the receptors are occupied, the maximum response is achieved. Antagonists bind to a receptor but do not produce the conformational change that initiates an intracellular signal. Occupation of the receptor by a competitive antagonist prevents binding of other ligands and so ‘antagonizes’ the biological response to the agonist. The inhibition that antagonists produce can be overcome by increasing the dose of the agonist. Some antagonists interfere with the response to the agonist in ways other than receptor competition and are known as non-competitive antagonists. Simply increasing the dose of the agonist cannot overcome their effects, so the maximum response to the agonist (its efficacy) is reduced. Partial agonists are able to activate a receptor but cannot produce a maximal signalling effect equivalent to that of a full agonist even when all the available receptors are occupied.
How do receptors mediate pharmacological responses? The main types of drug targets and their mechanisms of action are described in Table 1.
What is meant by ‘receptor affinity’? Affinity of ligands is a function of both the rate of association and the rate of dissociation of the ligandereceptor complex;3 the former depends on the ‘goodness of fit’ at a molecular level, whereas the latter depends on how tightly the ligand is bound (the strength of the chemical bond). Systems requiring rapid fine modulation (e.g. nerve synapses) must have agonists with a low receptor affinity because those with high receptor affinity would produce unnecessarily prolonged responses. During stimulation, the agonist concentration near the receptor must be relatively
What is the relationship between drug dose and response? 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 doseeresponse curve (Figure 2a). Clinical responses that might be plotted in this way include change in heart rate,
Receptors and other drug targets b. A channel-linked receptor
a. A G-protein-coupled receptor (GPCR) Drug
Na+
c. An enzyme drug target
d. A transport protein drug target Drug
Drug
Drug Substrate molecules
Products
G-protein complex G-protein activates a target protein
Conformational Na+ change in the channel increases ion conductance
Enzyme Na+
K+
Target protein initiates further events leading to a biological response
Figure 1
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Receptors and other drug targets (see Figure 1) Drug target Receptors Channel-linked receptors
G-protein-coupled receptors
Kinase-linked receptors
DNA-linked receptors
Other targets Voltage-sensitive ion channels
Enzymes
Transporter proteins
Description
Example
Coupled directly to an ion channel. Activation opens the channel, making a cell membrane permeable to specific ions. These channels are known as ligand-gated because it is receptor binding that operates them (in contrast to voltage-gated channels that respond to changes in membrane potential) Coupled to intracellular effector mechanisms via a family of closely related G-proteins that participate in signal transduction by coupling receptor binding to intracellular enzyme activation or the opening of an ion channel. Secondary messenger systems include the enzymes adenylate cyclase and guanylate cyclase, which generate cyclic adenosine monophosphate and cyclic guanosine monophosphate, respectively Linked directly to an intracellular protein kinase that triggers a cascade of phosphorylation reactions Intracellular and also known as nuclear receptors. Binding of a ligand promotes or inhibits synthesis of new proteins, which may take hours or days to promote a biological effect
Nicotinic acetylcholine receptor g-Aminobutyric acid (GABA) receptor
Found in excitable tissues and a potential target for drugs that can block the channel or interfere with conductance in other ways Catalyse biochemical reactions, some of which involve the production of key mediators of physiological processes in body systems. Drugs interfere with the active site of the enzyme or affect co-factors required by the enzyme for activity. In most cases, inhibition of the active site is competitive, although in some cases it can be long-lasting and effectively irreversible (e.g. aspirin) Specialized proteins that carry ions or molecules across cell membranes. Movement can be in either direction and can involve exchange of one substance for another, cotransport of two or more substances in the same direction, or ‘pumping’ of a single substance into or out of a cell or organelle. Drugs can act on transporters to inhibit their activity or can also act as ‘false substrates’, preventing the transport of the normal biological substrate
Muscarinic acetylcholine receptor b-Adrenoceptors Dopamine receptors Serotonin receptors Opioid receptors
Insulin receptor
Corticosteroid receptors Thyroid receptors Vitamin D receptors
Naþ channels that are blocked by local anaesthetics such as lidocaine Cyclo-oxygenase e inhibited by aspirin Angiotensin-converting enzyme e inhibited by enalapril Xanthine oxidase e inhibited by allopurinol
The serotonin reuptake transporter, which is inhibited by fluoxetine
Table 1
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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
100
Emax
30 20 10 ED50
80 60
Agonist + competitive agonist
Agonist alone
40 20 0
0 0.01
0.1
1
10
Drug dose (µg)
100
Drug response (% maximum )
40
Agonist alone
80
50
Drug response (% maximum )
Drug response (increase in heart rate)
100
60 40
Agonist + non-competitive agonist
20 0
0.001 0.01 0.1
1
10
100 1000
Agonist and competitive
0.001 0.01
0.1
1
10
100
1000
Agonist and non-competitive
µg, micrograms
Figure 2
bind irreversibly to the target molecule and require synthesis of new receptors or enzyme before normal function is restored.
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 the 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 called the ED50 (or EC50).
What is meant by efficacy and potency? Efficacy is the term used to describe the extent to which a drug can produce a response when all available receptors or binding sites are occupied (i.e. Emax on the doseeresponse curve) (Figure 2a). When comparing drugs acting at the same receptor, a full agonist has the greatest efficacy and can produce the maximum response of which the receptor is capable. A partial agonist at the same receptor has, by definition, a lower efficacy, even when all the receptor sites are occupied. The concept of efficacy is not restricted to comparing the effects of drugs that act at the same receptor. The term therapeutic efficacy is used to describe the comparison of drugs that produce the same therapeutic effects on a biological system but do so via different pharmacological mechanisms (e.g. loop and thiazide diuretics, proton pump inhibitors and H2-receptor antagonists). Potency is a term used to describe the amount of a drug required for a given response. More potent drugs produce biological effects at lower doses (or concentrations), which means that they have a lower ED50 (Figure 3). The potency of a drug is related to its affinity for the receptor. More potent drugs occupy a given proportion of receptors at lower concentration. This is reflected in the varying dose recommendations for drugs in the same class acting at the same receptors (e.g. H2-receptor antagonists, angiotensin-converting enzyme inhibitors).
What is the effect of antagonists on the doseeresponse curve of an agonist? The presence of a competitive antagonist displaces the agonist doseeresponse curve to the right because higher agonist concentrations are now required to achieve a given percentage receptor occupancy (and therefore effect) (Figure 2b). Dose eresponse curves of the agonist constructed in the presence of increasing doses of a competitive antagonist are progressively displaced 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 (e.g. atenolol, naloxone, atropine, cimetidine) are competitive antagonists. 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 the maximum response even at very high agonist concentrations. The presence of a non-competitive antagonist not only displaces the agonist doseeresponse curve to the right, but also decreases the Emax (Figure 2c). Some drugs that appear to be non-competitive antagonists are, in fact, irreversible antagonists (e.g. aspirin, omeprazole). They
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What is receptor selectivity? Receptors are named on the basis of their major endogenous agonist (e.g. adrenergic, serotoninergic, opioid). They are then usually ‘subtyped’ on the basis of their selectivity for agonists or antagonists. Agonist selectivity is determined by the ratio of EC50 of the doseeresponse curve at the two different receptor subtypes. For example, b-adrenoceptors can be subtyped into b1 and b2 on the basis of their responsiveness to the endogenous agonist noradrenaline (norepinephrine). The concentration required to
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Dose–response curves for drugs with high, medium and low potency acting on the same target
Dose–response curves for the beneficial and adverse effects of a drug Prescribers will aim to prescribe doses that maximize benefits and minimize harms. That is easier for drugs where the ratio between the dose causing harm and that causing benefit (the ‘therapeutic index’) is high
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Note that the drug with the highest potency has the lowest efficacy and vice versa
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Therapeutic index = 100
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Figure 3 Figure 4
cause bronchodilation (via b2-adrenoceptors) is 10 times higher than that required to cause tachycardia (via b1-adrenoceptors). Receptor subtypes can also be distinguished by the relative effectiveness of drugs that antagonize the effects of their full agonist, measured as the relative shift of the agonist dose eresponse curves achieved by a single dose of antagonist affecting responses mediated through the two receptors. It is important for prescribers to remember that selectivity for a receptor subtype is only a relative concept (i.e. selectivity does not equate with specificity). Agonist or antagonist drugs that are considered to be ‘selective’ for one receptor subtype can still produce significant effects at other subtypes if a high enough dose is given (e.g. ‘cardioselective’ b-adrenoceptor-blocking drugs can cause bronchospasm in the lung in patients with asthma).
carefully for individual patients to maximize benefits but avoid adverse effects. This is done by monitoring drug effects, either clinically or using regular blood tests (often known as therapeutic drug monitoring).
Why do patients differ in their response to drugs? Prescribers never know the actual doseeresponse relationships for the particular patients they treat. They have to make dose selections based on average doseeresponse data derived from observations from many individuals. Pharmacodynamic variation arises 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 clinical practice, it is this pharmacokinetic variation that explains most of inter-individual variation in drug response.
What is the ‘therapeutic index’? The adverse effects of drugs are often dose-related in a similar way to the beneficial effects. It is possible to construct a dose eresponse curve for these adverse effects in the same way as shown for the beneficial effects, with higher doses usually required to cause the adverse effect. The ED50 points for each curve in Figure 4 indicate that the ratio between the doses that have similar proportionate effects on the two outcomes is 10/0.1 ¼ 100. This ratio is known as the ‘therapeutic index’. In reality, drugs have multiple potential adverse effects, but the concept of therapeutic index is usually reserved for those requiring dose reduction or discontinuation. For most drugs, the therapeutic index is >100, but there are some notable exceptions with therapeutic indices <10 that are in common use (e.g. digoxin, warfarin, insulin, phenytoin, opioids).4 Drugs with low therapeutic indices are more difficult to prescribe and hazardous for patients, but they are still preferred if there are no alternative drugs with similar efficacy (e.g. anticancer drugs). The doses of such drugs have to be titrated
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Why do the effects of some drugs diminish over time? Desensitization refers to the common situation in which the biological response to a drug diminishes when it is given continuously or repeatedly. It may be possible to restore the response by increasing the dose (or concentration) of the drug, but in some cases the target organ can become completely refractory to its effect. The term tachyphylaxis is used to describe desensitization that occurs very rapidly, sometimes with the initial dose. The term tolerance is conventionally used to describe a more gradual loss of response to a drug that occurs over days or weeks. There is no clear distinction, but the different scales imply
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that different mechanisms may be involved. Rapid desensitization implies the depletion of chemicals that may be necessary for the pharmacological actions of the drug (e.g. a stored neurotransmitter released from a nerve terminal) or receptor phosphorylation. Slower development implies changes in receptor number or the development of counter-regulatory physiological changes that offset the actions of the drug (e.g. accumulation of salt and water in response to vasodilator therapy) or reduction of target receptor numbers. Where desensitization to a drug arises because of established chemical, hormonal and physiological changes that offset the actions of the drug, discontinuation may mean that these changes cause ‘rebound’ withdrawal effects (e.g. nitrates, opioids, benzodiazepines).5 A
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KEY REFERENCES 1 Rang HP, Ritter JM, Flower R, Henderson G. How drugs act: general principles. In: Pharmacology. 8th edn. New York: Churchill Livingstone, 2015; 6e21. 2 Brunton LL, JG, Chabner BA, Knollman JC. Pharmacodynamics: molecular mechanisms of drug action. In: Goodman & Gilman’s the pharmacological basis of therapeutics. 12th edn. New York: McGraw Hill, 2011; 41e72. 3 Colquhoun D. Binding, gating, affinity and efficacy. Br J Pharmacol 1998; 125: 923e47. 4 Levy G. What are narrow therapeutic index drugs? Clin Pharmacol Ther 1998; 63: 501e5. 5 Christie MJ. Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction. Br J Pharmacol 2008; 154: 384e96.
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