Drug Receptor Interactions
A. Drug–receptor binding
At a fundamental level, drug molecules interact with specific receptors in order to produce the ultimate pharmacological effect. This interaction may be governed by the formation of hydrogen, ionic, or van der Waals bonds between given drug–receptor pairs. In general, these types of bonds are relatively weak and allow for the dissociation of the drug from the receptor, and the eventual pharmacological effect is reversed as the drug concentration at the receptor decreases.
The tendency of drugs to bind to receptors is determined by its affinity for the receptor site as well as its concentration at that site, according to the law of mass action.
B. Drugs as agonists
Drugs that possess affinity for a specific receptor as well as intrinsic activity at that receptor are termed agonists. Agonists mimic the actions of the endogenous ligand (e.g., epinephrine for the b-adrenergic receptor) by modifying the conformation of the receptor in a manner that results in the initiation of intracellular signaling events and a biological response.
- Full agonists are able to produce increasing biological response with increasing dose until a maximal effect or efficacy (Emax) is achieved.
- Partial agonists possess reduced intrinsic activity or efficacy, which results in reduced Emax relative to a full agonist. However, a partial agonist may have greater affinity for the receptor, resulting in greater potency than a full agonist.
C. Drugs as antagonists
Drugs with affinity for a receptor but lacking intrinsic activity are called antagonists. These drugs are unable to alter receptor conformation in a way that leads to initiation of intracellular signal transduction processes and have their predominant pharmacological action by preventing the binding and actions of an endogenous ligand. Thus, atropine binds to the muscarinic receptor with high affinity but is unable to initiate a biological response; on the other hand, by occupying the binding site, it prevents the ability of acetylcholine to bind and produce an effect.
- Equilibrium-competitive antagonists reversibly interact with the same binding site on the receptor as the agonist to prevent agonist binding and activation of the receptor.
- Nonequilibrium-competitive antagonists interact with their receptors in an irreversible or pseudo- irreversible manner. This irreversibility (usually due to covalent bonding) would reduce the number of receptors available to produce a biological response, which results in an agonist dose–response curve with reduced Emax and variable effect on potency.
- Inverse agonists/antagonists reduce the basal coupling of the receptor to the intracellular signal transduction processes, producing a negative pharmacological effect even in the absence of receptor agonists.
- Noncompetitive antagonists interact with a distinct site to that occupied by the agonist to prevent the biological response initiated by the agonist.
D. Enzymes as drug receptors
In many instances, cellular enzymes behave similarly to classical receptors in their interaction with drug molecules via ionic, hydrogen, van der Waal’s, or covalent bonding. However, important differences in the behavior of enzymes warrant separate treatment.
- Competitive enzyme inhibitors are drugs that bind to the active site of an enzyme in a manner that prevents substrate binding and conversion to a product. Analogous to classical drug–receptor interactions, these inhibitors would be considered competitive regardless of whether drug binding was reversible or irreversible. The inhibition of HMG-CoA reductase by simvastatin (Zocor®) would be considered competitive with respect to the substrate HMG-CoA.
- Allosteric modulators bind to a distinct site from that of the substrate and thereby alter enzyme activity. Theoretically, this type of modulation can increase or decrease enzyme activity and not automatically be classified as inhibition. Allosteric modulators that inhibit enzyme activity may be considered noncompetitive inhibitors; for example, efavirenz (Sustiva®) inhibits the polymerase function of HIV reverse transcriptase.
E. Modulation of receptor sensitivity
- Desensitization of seven transmembrane-spanning receptors generally occurs with sustained stimulation of the receptor and occurs due to reduced coupling to G proteins. Uncoupling of the receptor is due to phosphorylation of the receptor, which prevents its interaction with the G-protein and also reduces the affinity of the agonist for the receptor. Myocardial b-receptors in patients with heart failure are thought to be desensitized due to sustained sympathetic nervous system stimulation.
- Downregulation of the receptor is the result of prolonged receptor stimulation that leads to incorporation of the receptor into clathrin-coated pits and removal of the receptor from the plasma membrane. This process reduces agonist signaling to the intracellular compartment. Ultimately, the receptor may be transported to the lysosomal compartment for destruction or recycled back to the plasma membrane to restore cell signaling. The sustained use of b-agonists like albuterol (Ventolin®) causes the downregulation of b2-receptors in asthmatic patients.
- Receptor hypersensitivity/supersensitivity is exhibited by increased response to agonist stimulation and is most likely due to increased receptor number or enhanced coupling of the receptor to intracellular signaling processes. This phenomenon usually occurs with chronic reduction in receptor stimulation due to diminished endogenous agonists (e.g., after autonomic or motor nerve destruction). Reversal of prolonged antagonist therapy has also been associated with receptor supersensitivity (e.g., abrupt withdrawal of b-blocker therapy).
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