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Principles of Pharmacodynamics and Toxicodynamics
1
Introduction: Definition of Pharmacodynamics and Toxicodynamics
In simple terms, pharmacodynamics (PD) and toxicodynamics (TD) describe the relationship between exposure (concentration at the site-of-action) of the drug, toxicant, or toxin (xenobiotic) and the extent of resulting effect on the body over a time course ( ). PD and TD can be evaluated through in vitro, ex vivo, or in vivo studies and endpoints can range from the molecular to the whole organism level.
The adverse effect of a therapeutic drug or toxic agent is determined by its mechanism and duration of action. Together with PK considerations and tissue concentrations, the mechanism of action will determine the tissue sites at which most severe consequences will occur. The combination of either the drug's presence (determined by pharmacokinetic (PK) analyses) and/or its mechanism and duration of action (PD) will determine the nature and degree of altered cellular physiology.
For in vivo studies, PK and PD phases are not always synchronized, such that there may be a delay between the peak of drug concentration (usually measured in plasma) and the observed response. A widely known illustration on this time-dependent PK/PD or TD alteration in vivo is the “hysteresis loop” ( Figure 5.1 ), where the xenobiotic concentration and effect are not in phase. This may be caused by the delay of drug moving from plasma and interstitial fluid to the site-of-action (usually on cell surface or cell interior). Another common mechanism is a delay resulting from the time from target interaction, mRNA synthesis, and finally translation to protein.
2
Mechanism of Drug Action and Adverse Drug Reaction
2.1
Physiochemical Property Based
Examples of drugs that interact through physical or chemical reactions with body fluids or tissues include the osmotic diuretic mannitol and orally administered antacids. Osmotic diuretics, which are not cell permeable, can be filtered into the renal tubules but not reabsorbed. Therefore, they limit the osmosis in the tubular lumen and inhibit the reabsorption of water and electrolytes including sodium and chloride. Antacids like aluminum salts neutralize gastric acid and bind with phosphate in the intestine. These compounds are designed to alter, respectively, osmolarity and pH , but do not interact directly with cellular processes. Drugs that exert these types of actions are typically older since the mechanism of action of newly discovered drugs is usually based on biochemical reactions, which are discussed at below.
2.2
Biochemical Based
Most xenobiotics cause their effects through biochemical interactions with macromolecules that involve normal physiological or pathological process in animals, ectoparasites, or microbial organisms. Those include nonreceptors (e.g., enzymes, ion channel proteins, transporters, nucleic acids, and cell skeleton molecules) and signal transduction receptors.
Action on Nonreceptors
Examples of enzyme inhibitors include nonsteroidal antiinflammatory drugs, which inhibit cyclooxygenases during prostanoid synthesis; the anticancer drug methotrexate, which inhibits tetrahydrofolate reductase catalyzing methionine formation; acetylcholinesterase inhibitors like the drug physostigmine or the toxin sarin which prevents the hydrolysis of the neurotransmitter acetylcholine; and digoxin, an inhibitor of sodium (Na + ), potassium (K + ) ATPase in cardiac muscle cells.
Examples of drugs which interact with DNA include the anticancer drugs like lomustine (CCNU), which alkylates DNA, and the fluoroquinolones that interact with DNA gyrase resulting in alteration of the three-dimensional structure of DNA leading to reduced bacterial replication and death.
Drugs interacting with microtubules include taxanes and vinca alkaloids and anticancer agents that stabilize or destabilize the polymerization of microtubules during cell mitosis. Through this mechanism, the mitotic spindle of the cell is disrupted leading to cell cycle arrest and apoptosis.
Action on Signal Transduction Receptors
Through interaction with a receptor, a drug often alters the receptor protein's three-dimensional structure triggering signal transduction processes within the cell resulting in a biological effect ( ). Understanding the details of signal transduction leads to understanding of the timeframe and persistence of the biological effect, sometimes long after removal of the agent. Signal transduction mechanisms also underlie the phenomena of the cell's adaptation to chronic exposure of the xenobiotic.
Although a complete review of cellular signal transduction is beyond the scope of this chapter, the reader is directed to a web database maintained by the International Union of Basic and Clinical Pharmacology which maintains updated information on signal transduction systems linked with receptors ( https://www.guidetopharmacology.org/ ). This resource is particularly useful because it tracks information about orphan receptors , which are receptors proteins identified by genome sequencing and molecular biology with homology to known receptors, but which, to date, have not been unequivocally linked to a known effect.
Signal transduction is usually accomplished with one or more of the following key cellular processes, each of which results in allowing a signal (drug) to move its effect from outside the cell to the intracellular compartment. Transmembrane receptors are classified as either ionotropic (linked to ion channels) or metabotropic (linked to biochemical processes). Intracellular receptors include cytosolic and nuclear receptors.
Ionotropic receptors or ligand-gated transmembrane ion channels include γ-aminobutyric acid (GABA) and ionotropic glycine receptors linked to Cl − channels, nicotinic acetylcholine and glutamate receptors (AMPA [2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl)propanoic acid], kainate, and NMDA [ N -Methyl- d -aspartate]) linked to Na + channels, and serotonin (5HT) 3 receptors are linked to cation currents. There are also subtypes of GABA (GABA A and GABA B ), glutamate, and 5HT receptors that are metabotropic. The human ether-a-go-go related gene codes for a protein subunit, functioning as a voltage-dependent K + ion channel that mediates ventricular action potential repolarization. Inhibition of this channel by drugs such as terfenadine and dofetilide may lead to QT prolongation and arrythmias such as torsades de pointes. Metabotropic receptors either act directly or indirectly as signal transduction enzymes, or are linked to enzymes that have an extracellular domain recognizing a drug and an intracellular domain that catalyzes a biochemical response. Transmembrane metabotropic receptors include the following:
G-Coupled Receptors
- a.
Gs-stimulatory , e.g., coupled to adenylate cyclase—increases intracellular cyclic AMP resulting in activation of protein kinase A, which phosphorylates proteins associated with cellular action. Examples include glucagon, thyrotropin, adrenocorticotropic hormone, β-adrenergic, and dopamine 1(D 1 and D 5 subtypes).
- b.
Gi/ o-inhibitory —inhibits adenylate cyclase or closes Ca ++ and opens K + channels. Examples: α 2- adrenergic, muscarinic acetylcholine (M 2 and M 4 subtypes), dopamine (D 2 , D 3 and D 4 subtypes), serotonin (5HT 1 ), and GABA B.
- c.
Gq-coupled to phospholipase C-β —increases formation of inositol triphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 increases intracellular Ca ++ and DAG activates protein kinase C that phosphorylates proteins associated with cellular action.
Receptors With Associated Enzymatic Activity
- a.
Plasma membrane kinase–linked receptors: Enzyme activity is part of the receptor's intracellular domain. Tyrosine kinase (TK) or serine kinases (SKs) phosphorylate a cellular substrate including other kinases that phosphorylate proteins associated with cellular action often through altered gene transcription. Examples include insulin (via TK), IGF-1 (via TK), TGF-β (via SK), and other growth factors.
- b.
Cytosolic kinase–linked receptors: Janus kinase (JAK; a TK) is phosphorylated by the activated plasma membrane receptor. JAK then phosphorylates transcription (STAT) proteins, which form dimers when phosphorylated and move into the nucleus acting as nuclear transcription factors.
- c.
Guanylyl cyclase (GC) linked: Plasma membrane receptors have GC activity and the cyclic GMP formed activates protein kinase G that phosphorylates proteins associated with cellular action. Nitric oxide (NO) can also directly activate cytosolic GC. Examples include atrial natriuretic factor and NO (including that stimulated by M 3 muscarinic agonists in vascular endothelium).
Intracellular Receptors (Nuclear or Cytosolic)
Compounds that permeate plasma membranes can bind to cytosolic and/or nuclear receptors, which in turn bind to a DNA response element , which then results in inhibition or activation of mRNA and protein transcription. Some hormone receptors act as homodimers (e.g., glucocorticoid receptor) and some as heterodimers (e.g., thyroid hormone with retinoic acid receptors) as they interact with the DNA response element. Agents with effects through nuclear receptors generally have a lag time up to several hours associated with new protein synthesis, and their effect can persist for as long as days after removal of the agent because of slow turnover of proteins associated with the effect. Examples include lipid-soluble xenobiotics (e.g., rifampin, polychlorinated biphenyls) or hormones (e.g., thyroid hormone, glucocorticoids, mineralocorticoids, vitamin D, vitamin A) or analogues.
3
Types of Adverse Drug Reaction: Intrinsic (Type A) Versus Idiosyncratic (Type B)
There are two types of adverse drug reactions: intrinsic (type A) and idiosyncratic (type B). Type B reactions, which by definition rarely happen, are nondose dependent and cannot be described by a mass–action relationship. The cause of idiosyncratic toxicities is often attributed to immune-mediated mechanisms ( ). Due to their low incident frequency, idiosyncratic toxicities cannot be properly characterized in preclinical studies or clinical trials and are discovered only after many thousands of patients have taken these medications.
Type A reactions are dose (concentration) dependent and predictable. This type of adverse effect is usually an extension of the therapeutic effect (see Figure 5.2 ). The rest of this chapter will focus on the type A reactions. In most cases, xenobiotics act on biological macromolecules. For the sake of the following discussion, drug interaction with these macromolecules will be collectively characterized according to receptor theory to explain the dose nonlinear interactions leading to xenobiotic exposure response.
The structural specificity of drug–target(s) interaction predicts the clinical selectivity of drug action. More precisely, the ability of receptors to recognize and respond to a given xenobiotic is based upon the three-dimensional structure of the binding pocket. Absolute specificity is uncommon. In fact, for those involved in nonclinical phases of drug development, it is important to screen for binding ( affinity and capacity , see more detailed discussion in Section 5.1 ) and activity to a variety of receptor types that may be expressed in a variety of tissues to help predict therapeutic and potentially adverse effects. Drug companies often externalize off-target safety pharmacology profiling screens to commercial suppliers.
Most drugs interact with a variety of receptors with varying affinities. However, eventually, it is important to evaluate the drug's effect in vivo, as relative tissue effects, integrated tissue responses, and counterresponses to a drug are difficult to predict accurately. When a drug's dosage and concentration is increased, off-target effects may occur on lower affinity receptors in the same or other tissues and may contribute to adverse effects. For example, when used as a therapeutic, dopamine stimulates renal dopaminergic D 1 receptors to induce renovascular dilation at low dosage infusion rates, then stimulates cardiac β 1 -adrenergic receptors at intermediate rates causing tachycardia as a side effect, and at even higher dosage infusion rates stimulates arterial α 1 -receptors causing vasoconstriction and counteracting the renovascular dilatory effect.
By definition, drugs or toxins will generate biological effects when dosed to an organism. Among them, efficacy is defined as a “desired” therapeutic effect, and toxicities are “undesired.” For an effect mediated by a single receptor, the log dose–effect relationship parallels that of the log dose receptor binding relationship ( Figure 5.2 ). Efficacy should be distinguished from the term potency, a term used to compare the affinity among ligands that bind to the same receptor. The greater the maximal effect (E max ) of a drug, determined by the signal transduction systems in a cell per unit receptor occupied, the greater is the efficacy of that drug. The more potent compound has a lower Kd (dissociation constant, a term describing the concentration of free drug when 50% of the total molecules of receptors forms the drug–receptor complex) or lower EC 50 , defined as the concentration causing 50% of E max . EC 50 represents the middle of the linear part of the log dose (concentration)–response curve, with the slope steepness representing its sensitivity, often termed n, or the Hill coefficient. More details about the quantitative dose-dependent relationship will be discussed later in this chapter ( Section 5 ).
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