Pharmacodynamics



Pharmacodynamics




Nature of Drug Receptors


Drugs produce their effects by interacting with specific cell molecules called receptors. By far, most ligands (drugs or neurotransmitters) bind to protein molecules, although some agents act directly on DNA or membrane lipids (Table 3-1).




Types of Drug Receptors


The largest family of receptors for pharmaceutical agents is G protein–coupled receptors (GPCRs). These membrane-spanning proteins consist of four extracellular, seven transmembrane, and four intracellular domains (Fig. 3-1). Extracellular domains and, to some extent, transmembrane regions determine ligand binding and selectivity. Intracellular loops, especially the third one, mediate the receptor interaction with its effector molecule, a guanine nucleotide binding protein (G protein).


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FIGURE 3-1 Structure of a typical G protein–coupled receptor (GPCR). All GPCRs consist of a long polypeptide chain of amino acids threaded through the cell membrane with seven transmembrane (TM) domains. These TM domains are arranged in α–helices composed of hydrophobic residues. The N-terminal of the receptor protein is outside the cell and the C-terminal is on the inside. Three extracellular loops (EL) and three intracellular loops (IL) are formed by this configuration. The protein in the cell membrane forms a circle with TM1 and TM7 in close proximity but is shown here in a two-dimensional view for clarity.

A number of ligands inhibit the function of specific enzymes by competitive or noncompetitive inhibition. A ligand that binds to the same active, catalytic site as the endogenous substrate is called a competitive inhibitor. Ligands that bind at a different site on the enzyme and alter the shape of the molecule, thereby reducing its catalytic activity, are called noncompetitive inhibitors.


Drugs also target membrane transport proteins, including ligand- and voltage-gated ion channels and neurotransmitter transporters. At ligand-gated ion channels, drugs can bind at the same site (called an orthosteric site) as the endogenous ligand and directly compete for the receptor site. Drugs can also bind at a different site, called an allosteric site, that alters the response of the endogenous ligand binding to the ligand-gated ion channel and increase or decrease the flow of ions. Some drugs directly bind and inactivate voltage-gated ion channels; these are ion channel proteins that do not have an endogenous ligand (as ligand-gated ion channels do) but open or close as a function of the membrane voltage potential. Neurotransmitter transporter proteins are large, 12-transmembrane domain proteins that transfer neurotransmitter molecules out of the synapse and back into the neuron. A large group of agents, known generally as reuptake inhibitors, target these transport proteins.


Steroid hormone receptors are intracellular proteins that translocate to the nucleus on ligand (steroid) binding. In the nucleus, the steroid-receptor complex alters the transcription rate of specific genes (Fig. 3-2). DNA is also a receptor site for ligands that bind directly to nucleic acids, most notably the antineoplastic agents. Other macromolecules that serve as receptors include the various lipids and phospholipids that make up the membrane. Some of the effects of general anesthetics and alcohol are caused by interaction with membrane lipids.


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FIGURE 3-2 Signal transduction with a steroid hormone receptor. Steroid hormones diffuse through the cell membrane and bind to steroid receptors in the cytoplasm. Binding of the steroid ligand displaces accessory heat-shock proteins (hsp) and allows steroid receptor dimerization. The dimerized steroid hormone–receptor complex is translocated to the nucleus and binds to specific sequences on the DNA upstream of a gene, leading to increased transcription of a gene, messenger RNA (mRNA), and translation of proteins.


Receptor Classification


Drug receptors are classified according to drug specificity, tissue location, and, more recently, their primary amino acid sequence. For example, adrenoceptors were initially divided into two types (α and β), based on their affinity for norepinephrine, epinephrine, and other agents in different tissues. Subsequently, the distinction between the types was confirmed by the development of selective antagonists that blocked either α-adrenoceptors or β-adrenoceptors. Later, the two types of receptors were divided into subtypes, based on more subtle differences in agonist potency, tissue distribution, and varying effects.


At present, most receptors for drug targets and endogenous ligands are cloned and their amino acid sequences determined. There are also numerous other receptor-like proteins predicted from the human genome for which an endogenous ligand is not identified, called orphan receptors. The orphan receptors are of great interest to pharmaceutical companies, as they represent targets for the development of new drugs. Families of receptor types are grouped by their sequence similarity using bioinformatics, and this classification supports results from earlier in vivo and in vitro functional studies. In many cases, each type of receptor corresponds to a single, unique gene with subtypes of receptors arising from different transcripts of the same gene by the process of alternative splicing.



Drug-Receptor Interactions


Receptor Binding and Affinity


To initiate a cellular response, a drug must first bind to a receptor. In most cases, drugs bind to their receptor by forming hydrogen, ionic, or hydrophobic (van der Waals) bonds with a receptor site (Fig. 3-3). These weak bonds are reversible and enable the drug to dissociate from the receptor as the tissue concentration of the drug declines. The binding of drugs to receptors often exhibits stereospecificity, so that only one of the stereoisomers (enantiomers) will form a three-point attachment with the receptor. In a few cases, drugs form relatively permanent covalent bonds with a specific receptor. This occurs, for example, with antineoplastic drugs that bind to DNA and with drugs that irreversibly inhibit the enzyme cholinesterase.


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FIGURE 3-3 Drug binding to receptors. A, L-Isoproterenol, a β-adrenoceptor agonist, forms hydrogen, ionic, and hydrophobic (van der Waals) bonds with three sites on the β-adrenoceptor. B, D-Isoproterenol binds to two sites on the β-adrenoceptor but is unable to bind with the third site. C, L-Propranolol, a β-adrenoceptor antagonist, binds to two sites on the receptor in the same way that L-isoproterenol does. The naphthyloxy group (N) forms weak bonds with the third receptor site, but these are not sufficiently strong for the drug to have intrinsic (agonist) activity. iC3H7, Isopropyl.

The tendency of a drug to combine with its receptor is called affinity, which is a measure of the strength of the drug-receptor complex. According to the law of mass action, the number of receptors (R) occupied by a drug depends on the drug concentration (D) and the drug-receptor association and dissociation rate constants (k1 and k2):


[D]+[R]⇌k2k1[D-R]→Effect


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The ratio of k2 to k1 is known as the KD and represents the drug concentration required to saturate 50% of the receptors. The lower the KD is, the greater is the drug’s affinity for the receptor. Most drugs have a KD in the micromolar to nanomolar (10-6 to 10-9 M) range of drug concentrations. As discussed later, receptor affinity is the primary determinant of drug potency.



Signal Transduction


Signal transduction describes the pathway from ligand binding to conformational changes in the receptor, receptor interaction with an effector molecule (if present), and other downstream molecules called second messengers. This cascade of receptor-mediated biochemical events ultimately leads to a physiologic effect (Table 3-2).

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Pharmacodynamics

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