BASIC OF PHARMACOLOGY
The goal of drug therapy is to prevent, cure, or control various disease states. To achieve this goal, adequate drug doses must be delivered to the target tissues so that therapeutic yet nontoxic levels are obtained. Pharmacokinetics examines the movement of a drug over time through the body. Pharmacological as well as toxicological actions of drugs are primarily related to the plasma concentrations of drugs. Thus, the clinician must recognize that the speed of onset of drug action, the intensity of the drug's effect, and the duration of drug action are controlled by four fundamental pathways of drug movement and modification in the body
First, drug absorption from the site of administration (Absorption) permits entry of the therapeutic agent (either directly or indirectly) into plasma.
Second, the drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids (Distribution).
Third, the drug may be metabolized by the liver, kidney, or other tissues (Metabolism). Finally, the drug and its metabolites are removed from the body in urine, bile, or feces (Elimination). This chapter describes how knowledge of these four processes (Absorption, Distribution, Metabolism, and Elimination) influences the clinician's decision of the route of administration for a specific drug, the amount and frequency of each dose, and the dosing intervals.
Most drugs exert their effects, both beneficial and harmful, by interacting with receptors—that is, specialized target macromolecules—present on the cell surface or intracellularly. Receptors bind drugs and initiate events leading to alterations in biochemical and/or biophysical activity of a cell, and consequently, the function of an organ
Drugs may interact with receptors in many different ways. Drugs may bind to enzymes (for example, inhibition of dihydrofolate reductase by trimethoprim), nucleic acids (for example, blockade of transcription by dactinomycin), or membrane receptors (for example, alteration of membrane permeability by pilocarpine).
In each case, the formation of the drug–receptor complex leads to a biologic response. Most receptors are named to indicate the type of drug/chemical that interacts best with it; for example, the receptor for histamine is called a histamine receptor. Cells may have tens of thousands of receptors for certain ligands (drugs). Cells may also have different types of receptors, each of which is specific for a particular ligand. On the heart, for example, there are β receptors for norepinephrine, and muscarinic receptors for acetylcholine. These receptors dynamically interact to control vital functions of the heart. The magnitude of the response is proportional to the number of drug–receptor complexes.
This concept is closely related to the formation of complexes between enzyme and substrate,1 or antigen and antibody; these interactions have many common features, perhaps the most noteworthy being specificity of the receptor for a given ligand. However, the receptor not only has the ability to recognize a ligand, but can also couple or transduce this binding into a response by causing a conformational change or a biochemical effect.
Although much of this chapter will be centered on the interaction of drugs with specific receptors, it is important to be aware that not all drugs exert their effects by interacting with a receptor; for example, antacids chemically neutralize excess gastric acid, reducing the symptoms of “heartburn.” This chapter introduces the study of pharmacodynamics—the influence of drug concentrations on the magnitude of the response. It deals with the interaction of drugs with receptors, the molecular consequences of these interactions, and their effects in the patient. A fundamental principle of pharmacodynamics is that drugs only modify underlying biochemical and physiological processes; they do not create effects de novo.
Drugs affecting the ANS
- The AutonomicNervous System
The autonomic nervous system, along with the endocrine system, coordinates the regulation and integration of bodily functions. The endocrine system sends signals to target tissues by varying the levels of blood-borne hormones. In contrast, the nervous system exerts its influence by the rapid transmission of electrical impulses over nerve fibers that terminate at effector cells, which specifically respond to the release of neuromediator substances. Drugs that produce their primary therapeutic effect by mimicking or altering the functions of the autonomic nervous system are called autonomic drugs and are discussed in the following four chapters. These autonomic agents act either by stimulating portions of the autonomic nervous system or by blocking the action of the autonomic nerves. This chapter outlines the fundamental physiology of the autonomic nervous system, and it describes the role of neurotransmitters in the communication between extracellular events and chemical changes within the cell.
Drugs affecting the autonomic nervous system are divided into two groups according to the type of neuron involved in their mechanism of action. The cholinergic drugs, which are described in this and the following chapter, act on receptors that are activated by acetylcholine. The second group act on receptors that are stimulated by norepinephrine or epinephrine. Cholinergic and adrenergic drugs both act by either stimulating or blocking receptors of the autonomic nervous system.
Figure 2.2 Transmembrane signaling mechanisms. A. Ligand binds to the extracellular domain of a ligand-gated channel. B. Ligand binds to a domain of a serpentine receptor, which is coupled to a G protein. C. Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor.
Binding of a ligand to an extracellular domain activates or inhibits this cytosolic enzyme activity. Duration of responses to stimulation of these receptors is on the order of minutes to hours. The most common enzyme-linked receptors (epidermal growth factor, platelet-derived growth factor, atrial natriuretic peptide, insulin, and others) are those that have a tyrosine kinase activity as part of their structure. Typically, upon binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting from its inactive form to an active kinase form. The activated receptor autophosphorylates, and phosphorylates tyrosine residues on specific proteins. The addition of a phosphate group can substantially modify the three-dimensional structure of the target protein, thereby acting as a molecular switch. For example, when the peptide hormone insulin binds to two of its receptor subunits, their intrinsic tyrosine kinase activity causes autophosphorylation of the receptor itself. In turn, the phosphorylated receptor phosphorylates target molecules—insulin-receptor substrate peptides—that subsequently activate other important cellular signals such as IP3 and the mitogen-activated protein kinase system. This cascade of activations results in a multiplication of the initial signal, much like that which occurs with G protein–coupled receptors
Figure Mechanism of intracellular receptors.
Drugs affecting the autonomic nervous system are divided into two groups according to the type of neuron involved in their mechanism of action. The cholinergic drugs, which are described in this and the following chapter, act on receptors that are activated by acetylcholine. The second group act on receptors that are stimulated by norepinephrine or epinephrine. Cholinergic and adrenergic drugs both act by either stimulating or blocking receptors of the autonomic nervous system.
The cholinergic antagonists (also called cholinergic blockers, parasympatholytics or anticholinergic drugs) bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects. The most useful of these agents selectively block muscarinic synapses of the parasympathetic nerves. The effects of parasympathetic innervation are thus interrupted, and the actions of sympathetic stimulation are left unopposed. A second group of drugs, the ganglionic blockers, show a preference for the nicotinic receptors of the sympathetic and parasympathetic ganglia. Clinically, they are the least important of the anticholinergic drugs. A third family of compounds, the neuromuscular blocking agents, interfere with transmission of efferent impulses to skeletal muscles. These agent are used as adjuvants in anesthesia during surgery.
The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. Some adrenergic drugs act directly on the adrenergic receptor (adrenoceptor) by activating it and are said to be sympathomimetic. block the action of the neurotransmitters at the receptors (sympatholytics), whereas still other drugs affect adrenergic function by interrupting the release of norepinephrine from adrenergic neurons. This chapter describes agents that either directly or indirectly stimulate adrenoceptors .
The adrenergic antagonists (also called blockers or sympatholytic agents) bind to adrenoceptors but do not trigger the usual receptor-mediated intracellular effects. These drugs act by either reversibly or irreversibly attaching to the receptor, thus preventing its activation by endogenous catecholamines. Like the agonists, the adrenergic antagonists are classified according to their relative affinities for α or β receptors in the peripheral nervous system. [Note: Antagonists that block dopamine receptors are most important in the central nervous system (CNS) and are therefore considered in that section
major receptor family
Pharmacology defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes and structural proteins can be considered to be pharmacologic receptors. However, the richest sources of therapeutically exploitable pharmacologic receptors are proteins that are responsible for transducing extracellular signals into intracellular responses. These receptors may be divided into four families:
1) ligand-gated ion channels,
2) G proteincoupled receptors,
3) enzyme-linked receptors, and
4) intracellular receptors
4) intracellular receptors
Figure 2.2 Transmembrane signaling mechanisms. A. Ligand binds to the extracellular domain of a ligand-gated channel. B. Ligand binds to a domain of a serpentine receptor, which is coupled to a G protein. C. Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor.
The type of receptor a ligand will interact with depends on the nature of the ligand. Hydrophobic ligands interact with receptors that are found on the cell surface (families 1, 2, and 3). In contrast, hydrophobic ligands can enter cells through the lipid bilayers of the cell membrane to interact with receptors found inside cells (family 4)
A. Ligand-gated ion channels
The first receptor family comprises ligand-gated ion channels that are responsible for regulation of the flow of ions across cell membranes (see Figure above A).
The first receptor family comprises ligand-gated ion channels that are responsible for regulation of the flow of ions across cell membranes (see Figure above A).
The activity of these channels is regulated by the binding of a ligand to the channel. Response to these receptors is very rapid, having durations of a few milliseconds. The nicotinic receptor and the γaminobutyric acid (GABA) receptor are important examples of ligand-gated receptors, the functions of which are modified by numerous drugs. Stimulation of the nicotinic receptor by acetylcholine results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle. Benzodiazepines, on the other hand, enhance the stimulation of the GABA receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell. Although not ligand-gated, ion channels, such as the voltage-gated sodium channel, are important drug receptors for several drug classes, including local anesthetics.
B. G protein–coupled receptors
A second family of receptors consists of G protein–coupled receptors. These receptors are comprised of a single peptide that has seven membrane-spanning regions, and these receptors are linked to a G protein (Gs and others) having three subunits, an α subunit that binds guanosine triphosphate (GTP) and a βγ subunit.
A second family of receptors consists of G protein–coupled receptors. These receptors are comprised of a single peptide that has seven membrane-spanning regions, and these receptors are linked to a G protein (Gs and others) having three subunits, an α subunit that binds guanosine triphosphate (GTP) and a βγ subunit.
Figure : The recognition of chemical signals by G protein-coupled membrane receptors triggers an increase (or, less often, a decrease) in the activity of adenylyl cyclase.
Binding of the appropriate ligand to the extracellular region of the receptor activates the G protein so that GTP replaces guanosine diphosphate (GDP) on the α subunit. Dissociation of the G protein occurs, and both the α-GTP subunit and the βγ subunit subsequently interact with other cellular effectors, usually an enzyme or ion channel. These effectors then change the concentrations of second messengers that are responsible for further actions within the cell. Stimulation of these receptors results in responses that last several seconds to minutes.
-Second messengers: These are essential in conducting and amplifying signals coming from G protein–coupled receptors. A common pathway turned on by Gs, and other types of G proteins, is the activation of adenylyl cyclase by α-GTP subunits, which results in the production of cyclic adenosine monophosphate (cAMP)—a second messenger that regulates protein phosphorylation. G proteins also activate phospholipase C, which is responsible for the generation of two other second messengers, namely inositol-1,4,5-trisphosphate and diacylglycerol. These effectors are responsible for the regulation of intracellular free calcium concentrations, and of other proteins as well. This family of receptors transduces signals derived from odors, light, and numerous neurotransmitters, including norepinephrine, dopa-mine, serotonin, and acetylcholine. G protein–coupled receptors also activate guanylyl cyclase, which converts (GTP) to cyclic guanosine monophosphate (cGMP), a fourth second messenger that stimulates cGMP-dependent protein kinase. cGMP signaling is important in only a few cells, for example, intestinal mucosa and vascular smooth muscle, where it causes relaxation of vascular smooth muscle cells. Some drugs such as sildenafil produce vasodilation by interfering with specific phosphodiesterases, the enzymes that metabolically break down cGMP.
C. Enzyme-linked receptors
A third major family of receptors consists of those having cytosolic enzyme activity as an integral component of their structure or function (see Figure above C).
A third major family of receptors consists of those having cytosolic enzyme activity as an integral component of their structure or function (see Figure above C).
Binding of a ligand to an extracellular domain activates or inhibits this cytosolic enzyme activity. Duration of responses to stimulation of these receptors is on the order of minutes to hours. The most common enzyme-linked receptors (epidermal growth factor, platelet-derived growth factor, atrial natriuretic peptide, insulin, and others) are those that have a tyrosine kinase activity as part of their structure. Typically, upon binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting from its inactive form to an active kinase form. The activated receptor autophosphorylates, and phosphorylates tyrosine residues on specific proteins. The addition of a phosphate group can substantially modify the three-dimensional structure of the target protein, thereby acting as a molecular switch. For example, when the peptide hormone insulin binds to two of its receptor subunits, their intrinsic tyrosine kinase activity causes autophosphorylation of the receptor itself. In turn, the phosphorylated receptor phosphorylates target molecules—insulin-receptor substrate peptides—that subsequently activate other important cellular signals such as IP3 and the mitogen-activated protein kinase system. This cascade of activations results in a multiplication of the initial signal, much like that which occurs with G protein–coupled receptors
D. Intracellular receptors
The fourth family of receptors differs considerably from the other three in that the receptor is entirely intracellular and, therefore, the ligand must diffuse into the cell to interact with the receptor
The fourth family of receptors differs considerably from the other three in that the receptor is entirely intracellular and, therefore, the ligand must diffuse into the cell to interact with the receptor
Figure Mechanism of intracellular receptors.
This places constraints on the physical and chemical properties of the ligand in that it must have sufficient lipid solubility to be able to move across the target cell membrane. Because these receptor ligands are lipid soluble, they are transported in the body attached to plasma proteins, such as albumin. For example, steroid hormones exert their action on target cells via this receptor mechanism. Binding of the ligand with its receptor follows a general pattern in which the receptor becomes activated because of the dissociation of a small repressor peptide. The activated ligand–receptor complex migrates to the nucleus, where it binds to specific DNA sequences, resulting in the regulation of gene expression.
The time course of activation and response of these receptors is much longer than that of the other mechanisms described above. Because gene expression and, therefore, protein synthesis is modified, cellular responses are not observed until considerable time has elapsed (thirty minutes or more), and the duration of the response (hours to days) is much greater than that of other receptor families.
The time course of activation and response of these receptors is much longer than that of the other mechanisms described above. Because gene expression and, therefore, protein synthesis is modified, cellular responses are not observed until considerable time has elapsed (thirty minutes or more), and the duration of the response (hours to days) is much greater than that of other receptor families.
Drug Distribution
Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on blood flow, capillary permeability, the degree of binding of the drug to plasma and tissue proteins, and the relative hydrophobicity
A. Blood flow
The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs. Blood flow to the brain, liver, and kidney is greater than that to the skeletal muscles; adipose tissue has a still lower rate of blood flow. This differential blood flow partly explains the short duration of hypnosis produced by a bolus IV injection of thiopental .
The high blood flow, together with the superior lipid solubility of thiopental, permit it to rapidly move into the central nervous system (CNS) and produce anesthesia. Slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration sufficiently so that the higher concentrations within the CNS decrease, and consciousness is regained. Although this phenomenon occurs with all drugs to some extent, redistribution accounts for the extremely short duration of action of thiopental and compounds of similar chemical and pharmacologic properties.
B. Capillary permeability
Capillary permeability is determined by capillary structure and by the chemical nature of the drug.
1. Capillary structure: Capillary structure varies widely in terms of the fraction of the basement membrane that is exposed by slit junctions between endothelial cells. In the brain, the capillary structure is continuous, and there are no slit junctions.
(Figure Cross-section of liver and brain capillaries.)
This contrasts with the liver and spleen, where a large part of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass. a. Blood-brain barrier: To enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported. For example, a specific transporter for the large neutral amino acid transporter carries levodopa into the brain. By contrast, lipid-soluble drugs readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells. Ionized or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS, which have no slit junctions. These tightly juxtaposed cells form tight junctions that constitute the so-called blood-brain barrier.
2. Drug structure: The chemical nature of a drug strongly influences its ability to cross cell membranes. Hydrophobic drugs, which have a uniform distribution of electrons and no net charge, readily move across most biologic membranes. These drugs can dissolve in the lipid membranes and, therefore, permeate the entire cell's surface. The major factor influencing the hydrophobic drug's distribution is the blood flow to the area. By contrast, hydrophilic drugs, which have either a nonuniform distribution of electrons or a positive or negative charge, do not readily penetrate cell membranes, and therefore, must go through the slit junctions.
C. Binding of drugs to plasma proteins
Reversible binding to plasma proteins sequesters drugs in a nondiffusible form and slows their transfer out of the vascular compartment. Binding is relatively nonselective as to chemical structure and takes place at sites on the protein to which endogenous compounds, such as bilirubin, normally attach. Plasma albumin is the major drug-binding protein and may act as a drug reservoir; that is, as the concentration of the free drug decreases due to elimination by metabolism or excretion, the bound drug dissociates from the protein. This maintains the free-drug concentration as a constant fraction of the total drug in the plasma.
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