Pharmacodynamics are the pharmacological principles that describe drug effects on the body, explaining both mechanism of action and dose–response relationship.
2.1 Drug–Receptor Interactions
Most drug effects are produced by interaction with specific plasma membrane or intracellular receptors, leading to molecular changes that produce a given response (Fig. 2.1). These receptors are mainly proteins or nucleic acids. Binding is usually reversible and occurs by low-energy forces (hydrogen bonds, hydrophobic bonds, and van der Waals bonds), although a few examples of drug action associated with ionic or covalent binding are known. The binding of a drug to a receptor requires structural specificity and often stereospecificity (specificity for one stereoisomer of the drug).
Drugs may also exert their effects by physical or chemical interactions that do not involve receptors. Examples include antacids that work by neutralizing gastric pH; chelators that bind to heavy metals, inactivating them; and osmotic diuretics that act by absorbing water into the lumen of the kidney to maintain osmotic balance.
Fig. 2.1 Site at which drugs act to modify cell function.
Drugs cause cellular changes, leading to their physiological effects. They may act at receptors, causing a direct effect (e.g., opening of an ion channel), or receptor binding may activate a signal transduction system, leading to the cellular response. Drugs may also act by altering the activity of a cellular transport system; or by activating or inhibiting enzymes that control intracellular processes. They may also act on DNA to damage it or to alter the transcription of proteins.
Receptors and Their Signal Transduction
Types of Receptors
– Ligand-gated ion channels are specialized membrane pores made up of multisubunit proteins. Binding of ligands, e.g., endogenous compounds or drugs, to these receptors opens or closes the pores thus changing the permeability of Na+, K+, Cl–, or other ions (Fig. 2.2).
– G protein–coupled receptors (GPCRs). Guanine-nucleotide-binding proteins (G proteins) are transducers of information between ligand–receptor binding to GPCRs and the formation of several intracellular second messengers that culminate in a cellular response. The mechanisms of G protein signal transduction are discussed below.
– Voltage-dependent ion channels normally open or close in response to changes in the membrane potential, but they can also function as receptors for drugs. For example, the calcium channel blockers bind to voltage-dependent Ca2+ channels and block Ca2+ entry into cells when stimulated. This causes decreased contractility in target tissues, such as cardiac and smooth muscle.
– Enzyme-linked membrane receptors. When a drug binds to this type of receptor, it causes an enzyme to become “switched on” intracellularly. This enzyme then catalyzes the formation of other signal proteins that ultimately lead to the cellular response (Fig. 2.3).
– Intracellular receptors. Lipid-soluble drugs diffuse through cell membranes and bind either in the cellular cytosol or in the nucleus. Gene expression is altered, and protein synthesis is either increased or decreased, which causes the cellular response (Fig. 2.4). This mechanism is the slowest, and effects can usually be measured in terms of hours rather than minutes or seconds.
Fig. 2.2 Ligand-gated ion channel.
An example of a ligand-gated ion channel is the nicotinic cholinergic receptor on the motor end plate. When two acetylcholine (Ach) molecules bind to this receptor simultaneously (at the α-subunits) and the inner pore opens, Na+ enters the cell and K+ leaves the cell. This causes membrane depolarization and action potential propagation, resulting in muscle contraction.
Fig. 2.3 Enzyme-linked membrane receptor.
Insulin binding to the tyrosine kinase receptor causes the enzyme to phosphorylate tyrosine residues in proteins. These proteins can then signal other proteins to be formed, resulting in glucose uptake into cells.
Fig. 2.4 Intracellular receptor.
Lipophilic substances, such as steroid hormones and thyroid hormones, can diffuse through the cell membrane and interact with receptors in the cytoplasm or nucleus. The hormone-receptor complex then alters gene transcription, causing the synthesis of effector proteins. The hormone-receptor complex interacts with DNA in pairs; these may be identical (homodimeric) or nonidentical (heterodimeric) pairs.
G Protein Signal Transduction
Heterotrimeric G-proteins couple to membrane receptors, e.g., α-adrenergic receptors. When the receptor binds a ligand, this causes the α-subunit of the G protein to split from the β and γ subunits (Fig. 2.5). The now free subunits then interact with other proteins in the membrane that may produce second messengers. These second messengers are cyclic AMP (cAMP), diacylglycerol (DAG), and inositol 1, 4, 5-triphosphate (IP3).
Fig. 2.5 G-protein-mediated effect of an agonist.
(1) This shows the G-protein-coupled receptor in the resting state. (2) When an agonist binds to the G-protein-coupled receptor, it causes the receptor and G-protein to change conformation. The α-subunit exchanges guanosine triphosphate (GTP) for guanosine diphosphate (GDP) and dissociates from the other subunits, where it interacts with an effector protein (adenylate cyclase or phospholipase C) (3). This effector protein can then stimulate or inhibit second messenger molecules to produce a physiological effect. The α-subunit then hydrolyses the bound GTP to GDP and reassociates with the other subunits (4).
– Gs proteins activate cAMP.
– Gi proteins inhibit cAMP.
– Gq proteins activate phospholipase C, which increases DAG and IP3.
When G proteins are activated, GTP replaces GDP on the α-subunit. Following activation of G-proteins, GTP is rapidly degraded to inactive GDP by the activity of the α-subunit GTPase.
Adenylate cyclase system. Ligands that bind to a GPCR that activates Gs stimulate adenylate cyclase to convert ATP to cyclic AMP (cAMP) (Fig. 2.6A). Cyclic AMP then activates protein kinase A which prophorylates proteins, resulting in the physiologic response. Cyclic AMP is degraded to 5’AMP by phosphodiesterases. Ligands that bind to a GPCR that activates Gi inhibit adenylate cyclase (↓cyclic AMP), therefore protein kinase A is not activated, and proteins are not phosphorylated.
DAG and IP3 system. GPCRs may also couple to Gq. Gq activates the enzyme phospholipase C, which produces the second messengers IP3 and DAG from phosphatidylinositol 4,5-bisphosphate (PIP2) (Fig. 2.6B).
Hydrophilic IP3 diffuses from the membrane to the endoplasmic reticulum and releases Ca2+. The Ca2+ released can then cause physiologic effects in the following ways:
– Activation of protein kinase C (with DAG) leading to the phosphorylation of proteins
– Binding to calmodulin with the resultant complex mediating further effects, e.g., production of nitric oxide (NO).
Lipophilic DAG has two functions:
– Activation of protein kinase C. This process is Ca2+-dependent.
– Formation of arachidonic acid (an eicosanoid precursor) following its degradation by DAG lipase.
Fig. 2.6 G proteins, second messengers, and effects.
G-proteins can stimulate or inhibit adenylate cyclase. If activated, adenylate cyclase stimulates the second messenger, cyclic adenosine monophosphate (cAMP) to cause phosphorylation of proteins, which then exert the physiological effect (A). Similarly, G-proteins can activate phospholipase C and its second messenger substances to cause the physiological effect (B). G-proteins can also cause ion channels to open. The movement of ions may then initiate an action potential, or it may normalize intracellular ion content (C). (ATP, adenosine triphosphate; DAG, diacylglycerol; IP3, inositol triphosphate)
Other effects of G proteins. G proteins may also interact directly with ion channels to alter ionic conductance and cellular excitability (Fig. 2.6C).
Table 2.1 gives examples of each of the types of receptors above and substances that bind to these receptors.
Table 2.1 Types of Receptors
Type of Receptor
Ligand-gated ion channels
Nicotinic receptors (bind ACh)
Muscarinic receptors (bind ACh)
Voltage-dependent ion channels
Ca2+ channels on cardiac or smooth muscle
Enzyme-linked membrane receptor
Tyrosine kinase receptor (binds insulin)
Thyroid hormone (thyroxine)
Abbreviations: GABAA, gamma-aminobutyric acid, type A; ACh, acetylcholine.
Drug Classification Based on Interaction with Receptors
Agonists bind to a receptor, causing a change in its conformation that leads to a cellular response. The magnitude of the response for any given concentration of drug is determined by its efficacy, which is the maximum effect a given drug can produce, and by its affinity, which is the propensity of a drug to bind to a receptor.
– Full agonists are drugs of high intrinsic efficacy.
– Partial agonists are drugs with efficacy lower than full agonists.
– Tissue factors (receptor number and/or receptor coupling to transduction mechanisms) may cause markedly different relative responses for the same partial agonist when applied to different tissues.
– Partial agonists may antagonize the effects of full agonists at sufficient concentrations and may have greater affinity than full agonists for the same receptor.
Inverse agonists are drugs that cause an effect opposite that of conventional agonists. This action is inhibited by specific antagonists for the receptor. This action implies tonic (ongoing) receptor or signal transduction activity in the tissue. An example is Ro15–4513, which is an inverse agonist of the benzodiazepine receptor. It binds to gamma-aminobutyric acid (GABA) receptors, causing anxiety rather than sedation (produced by benzodiazepines).
Antagonists bind to a receptor, usually with high affinity, but they do not produce an intrinsic cellular response (they lack efficacy). They block the effects of agonists. If given simultaneously with agonists, competitive antagonists compete for binding to the receptor (Fig. 2.7). Their respective affinities and concentration will determine which predominates. Noncompetitive antagonists either prevent the agonist from binding to the receptor or prevent the agonist from activating the receptor. This cannot be overcome by increasing the agonist concentration.
Fig. 2.7 Competitive antagonism.
Agonists and competitive antagonists compete for receptor binding. Their affinities for the receptor and their concentration will determine which one predominates; therefore, an increase in agonist concentration can overcome the blockage of the competitive antagonist and allow it to reach its maximal effect.
2.2 Dose–Response Relationship
Responses to drugs may be graded (response magnitude is proportional to dose) or quantal (response is all or none). Comparisons between drugs are usually made based on the median effective dose that produces a response in 50% of patients, the ED50 (Fig. 2.8).
Potency refers to the amount of drug required to produce an effect of a given intensity. It is convenient to set this intensity value at the EC50, which is the median effective concentration that corresponds to 50% of the maximal response. The higher the potency of a drug, the lower the concentration needed to reach EC50. Often potency and toxicity are linked because the toxic response is an extension of the therapeutic effect; therefore, a more potent drug is not necessarily a better drug.
Fig. 2.8 Safety of a drug as determined by quantal dose-response curves.
This graph illustrates the ED50 which is the dose that provides a therapeutic effect (e.g., vasodilation) in 50% of patients, the TD50, which is the dose producing a toxic effect in 50% of patients (e.g., arrhythmia), and the LD50, which is the lethal dose in 50% of patients.
The therapeutic index is a means of comparing the amount of a drug required to attain the therapeutic level in 50% of patients to the amount that is lethal to 50% of patients. It is expressed as the ratio LD50/ED50. A high therapeutic index is preferable, as the margin of safety between the dose that would be sufficient to achieve therapeutic levels and that which would produce toxic effects is high.
Certain Safety Factor
The certain safety factor is defined as the LD1:ED99, that is, the amount that would be lethal to just 1% of patients compared with the amount that would elicit a therapeutic effect in 99% of patients. It is another estimate of risk that indicates the degree of overlap of the lethal and therapeutic effect curves.