PK by keeping the dose as low as possible.
1.5.1 Pharmacological Targets and Drug Action
A pharmacological effect often involves the modulation of an intrinsic physiological process by a drug that binds to a target protein. Pharmacological targets can be receptors and proteins involved in regulatory pathways, enzymes, structural proteins, nuclear receptors, transporter proteins, or ion channels (Table 1.5). Drugs may be classified depending on how they modulate their receptor and achieve drug effect. A drug is said to be an agonist (Figure 1.12) or partial agonist (Figure 1.13) if it binds to a receptor and functionally mimics or enhances the action of an endogenous ligand. by stimulating receptor activity fully or partially. Partial agonism may be explained by either an inefficient modulation of receptor conformation/transduction following receptor occupancy or by a higher drug affinity to the inactive form of a receptor, that isomerizes between an active and an inactive form. A drug that reduces receptor activity through competing with the endogenous agonist for the same active site is called a competitive antagonist. A drug is said to be a noncompetitive antagonist if it blocks or inhibits the pharmacological response of an endogenous agonist, by binding to a different site and triggering a conformational change in the receptor protein. A drug that binds to a target irreversibly (e.g., covalent binding) is called an irreversible inhibitor. Both noncompetitive and irreversible inhibitors decrease the receptor count that is available for the endogenous agonist, thereby reducing its efficacy. Inverse agonists appear to act in an opposite manner to agonists at a receptor site. Unlike an agonist which increases receptor activity, or an antagonist which blocks its activity, an inverse agonist reverses the activity of constitutively active receptors that are coupled to second messenger pathways even in the absence of an agonist. The binding of a drug to a target protein can initiate several direct or indirect responses depending on the type of target protein, its location, and target class (Figure 1.14). Most enzyme inhibitions lead to direct effect. Examples of indirect drug responses include the release of hormones and/or other endogenous ligands to stimulate a particular response or the activation of a second messenger which, in turn, initiates a series of biochemical reactions (e.g., drug binding to a G‐protein coupled receptor, GPCR) leading to the desired response.
TABLE 1.5. Classes of Pharmacological Targets
| Pharmacological Target Class | Examples of Targets | Location | Endogenous Ligands | Type of Drug |
|---|---|---|---|---|
| G‐protein‐coupled receptors (GPCRs) | Adrenoreceptor, metabotropic neurotransmitter receptors (metabotropic glutamate receptors or mGluRs, muscarinic acetylcholine receptors, GABA‐B receptor, 5HT1, 5HT2), CCR, opioid, NK | Transmembrane, cell surface or intracellular | Neurotransmittersa and hormonesb | Competitive, noncompetitive, and irreversible antagonist, agonists, partial agonist, or inverse agonist. |
| Receptor tyrosine kinase | EGF, VEGF, PDGF, FGF, HGF, TIE, Trk, MuSK, RYK, and insulin receptor families | Cell surface | Growth factors,c insulin | Competitive, noncompetitive, and irreversible antagonist, agonists, partial agonist, or inverse agonist. |
| Guanylyl cyclase receptors | GC‐A, GC‐B, GC‐C | Cell surface | Guanosine‐5′‐triphosphate (GTP) | Competitive, noncompetitive, and irreversible antagonist, agonists, partial agonist, or inverse agonist. |
| Nuclear receptors | Thyroid hormone‐like, estrogen‐like, glucocorticoid receptors, PPAR, FXR, LXR, and other orphan receptors | Cytosol or translocated to nucleus | Retinoic acid, vitamin D3, hormones | Competitive, noncompetitive, and irreversible antagonist, agonists, partial agonist, or inverse agonist. |
| Ligand‐gated ion channels or ionotropic receptors | Glutamate cationic receptor, nicotinicoid receptor (5‐HT3, nicotinic acetylcholine receptor, GABA‐A) | Synapses | Neurotransmitters | Competitive, noncompetitive, and irreversible antagonist, agonists, partial agonist, or inverse agonist. |
| Voltage‐gated ion channels | NaV, KV, and CaV | Transmembrane ion channels found along the axon and at the synapse in neurons and in other cells | Respond to changes in voltage | Blocker, inhibitor |
| Enzymes and factors | Transferases such as RNA directed DNA‐polymerase; oxidoreductases such as HMG‐CoA reductase and cyclooxygenases | Cell surface, intracellular, or membrane spanning | Large variety of endogenous and exogenous substrates | Inhibitor activator |
| Peptidases such as ACE, trypsin, thrombin, clotting factors, renin, HIV protease, cathepsin, and caspase | ||||
| Structural proteins | α,β,γ,δ, and ε tubulin | Extracellular or intracellular | GTP | Inhibitor |
a Neurotransmitters are amino acids such as glutamate, aspartate, serine, GABA, and glycine; monoamines such as dopamine, 5‐HT, adrenaline, noradrenaline, and melatonin; neuropeptides; acetylcholine, adenosine, histamine, anadamide, etc.
b Hormones could be derivatives of the amino acids tyrosine and tryptophan. Examples are catecholamines and thyroxine. Peptide hormones consist of chains of amino acids. Examples are TRH and vasopressin. Examples of protein hormones include insulin and growth hormone. More complex protein hormones bear carbohydrate side chains and are called glycoprotein hormones. Luteinizing hormone, follicle‐stimulating hormone, and thyroid‐stimulating hormone are examples of glycoprotein hormones. Lipid and phospholipid‐derived hormones are derivatives of lipids such as linoleic acid and arachidonic acid and phospholipids. Steroid hormones are derived from cholesterol and eicosanoids. Examples of steroid hormones are testosterone and cortisol. Sterol hormones such as calcitriol are a homologous system. The adrenal cortex and the gonads are primary sources of steroid hormones. Examples
