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1447CHAPTER 123 Molecular Mechanisms of Drug Actions bind to their target receptor in a nontarget organ Affinity refers to the strength of the drug receptor interaction Efficacy is the ability of a dr[.]

CHAPTER 123  Molecular Mechanisms of Drug Actions 1447 DRUG DISPOSITION DEVELOPMENT GENETIC FACTORS ENVIRONMENT DISEASES Co-medications DRUG EFFICACY and TOXICITY Nutrition Others DRUG TARGETS and SIGNALING MECHANISMS • Fig 123.1  ​Relationships among genetic factors, development, diseases, and the environment and drug efficacy and toxicity bind to their target receptor in a nontarget organ Affinity refers to the strength of the drug-receptor interaction Efficacy is the ability of a drug to elicit the desired response and is generally represented by a sigmoid concentration-effect curve The shape of this curve is a function of selectivity, affinity, and efficacy and reflects a drug’s potency The concentration at which half of the maximal effect is attained is the EC50 A smaller EC50 means that less drug is needed to achieve the same effect Drugs can be further classified based on their concentrationeffect relationship Drugs that bind with receptors are termed agonists if their binding results in the expected effect and are termed antagonists if binding stops or decreases an agonistinduced activity (Fig 123.3C).8 Administration of a receptor antagonist in the absence of an agonist results in no effect because antagonists bind to receptors but not activate them Competitive antagonism (surmountable or reversible) is when a drug with affinity for a receptor but lacking intrinsic efficacy competes with the agonist for the primary binding site on the receptor In such an antagonism, there is a concentration-dependent production of a parallel shift to the right of the agonist dose-response curve with no change in the maximal response (Fig 123.3C).9 In the case of noncompetitive antagonism (insurmountable or irreversible) with a slowly dissociating or nondissociating antagonist, there is a shift of the dose-response curve to the right and a further depression of the maximal response; no change in the antagonist occupancy takes place when the agonist is applied (Fig 123.3C) The duration of action of an insurmountable antagonist depends mostly on synthesis of new receptors, which can take several days This may have clinically important consequences For example, phenoxybenzamine, an insurmountable a-adrenergic receptor antagonist sometimes used in stage I Norwood procedures to balance the pulmonary and systemic circulations, can produce symptomatic hypotension in some patients The attenuation or reversal of the decrease in systemic vascular resistance that it produces may not be achieved with an a-adrenergic receptor agonist such as dopamine or norepinephrine, depending on the dose of phenoxybenzamine given In such circumstances, the use of a pressor agent that does not act through the a-adrenergic receptor—such as vasopressin, which binds on V1 receptors of smooth muscle cells—must be considered.10 Partial agonists are ligands that bind to the same receptor as full agonists but have less intrinsic capacity to produce a response as strong as full agonists despite full receptor occupancy (Fig 123.3C) The exact mechanism that accounts for the blunted maximal response seen with partial agonists is unknown Simultaneous administration of a partial agonist and a full agonist prevents the maximal response usually observed with the full agonist alone because partial agonists have the ability to occupy the receptor population Consider what would happen to the maximum effect (Emax) of an agonist in the presence of increasing concentrations of a partial agonist As the number of receptors occupied by the partial agonist increases, the Emax would decrease until it reached the Emax of the partial agonist This potential of partial agonists to act both agonistically and antagonistically may be therapeutically exploited For example, aripiprazole, an atypical neuroleptic agent, is a partial agonist at selected dopamine receptors Dopaminergic pathways that were overactive would tend to be inhibited by the partial agonist, whereas pathways that were underactive may be stimulated This might explain the ability of aripiprazole to improve many of the symptoms of schizophrenia, with a small risk of causing extrapyramidal adverse effects Finally, inverse agonists are ligands that reduce the level of constitutive activation encountered in some receptor systems.11 In addition to the primary binding site to which agonists and antagonists bind, receptor proteins possess many other (allosteric) binding sites through which drugs can influence receptor function by increasing (allosteric facilitators) or decreasing (allosteric antagonists) the affinity of agonists for their binding site, or by modifying efficacy The resulting effect may be to alter the slope and maximum of the agonist concentration-effect curve.12 An example of allosteric facilitation includes the activation of benzodiazepines on g-aminobutyric acid A (GABAA) receptors In summary, receptors play a central role in determining the nature of the pharmacologic effects that a drug produces First, receptors bind with only one or a limited number of structurally related ligands, thus ensuring that the final effect seen in a normal 1448 S E C T I O N X I I I   Pediatric Critical Care: Pharmacology and Toxicology RECEPTORS Direct Agonist Ion channel opening/closing Enzyme activation/inhibition Transduction mechanisms Ion channel modulation DNA transcription No effect Endogenous or exogenous agonist blocked Antagonist ION CHANNELS Blockers Permeation blocked Modulators Increased or decreased opening probability ENZYMES Inhibitor Normal reaction inhibited False substrate Abnormal metabolite produced Prodrug Active drug produced CARRIER PROTEINS Normal transport Inhibitor Transport blocked or Agonist/normal substrate False substrate Antagonist/inhibitor Abnormal product Prodrug Active drug • Fig 123.2  ​Targets for drug action (Modified from Rang HP, Dale MM, Ritter JM, et al Rang and Dale’s Pharmacology 7th ed Philadelphia: Elsevier; 2012.) setting occurs only in response to defined stimuli Second, for a given dose or concentration of a drug, both that drug’s affinity to bind to the receptor and the total number of available receptors directly influence the maximal effect a drug can produce Third, drugs differ in their intrinsic activity in regard to their receptors (e.g., partial agonist versus full agonist) Thus, the magnitude of the response to any drug is proportional to both the extent of receptor occupancy and the intrinsic activity of the receptor itself, resulting in different dose or concentration relationships for different agonists CHAPTER 123  Molecular Mechanisms of Drug Actions 1449 TABLE 123.1 Targets of Drugs Commonly Used in Critically Ill Children Drug Target Agonist Antagonist Adenosine Adenosine  Atropine Muscarinic  Bosentan ETA, ETB  Clonidine a2-Adrenergic  Receptors G Protein–Coupled Receptors Dopamine D1  Dopamine a- and b-Adrenergic  Dobutamine b-adrenergic  Epinephrine a- and b-Adrenergic  Haloperidol D2 Isoproterenol b-Adrenergic Neuromuscular blockers (depolarizing and nondepolarizing) Nicotinic Norepinephrine a- and b-Adrenergic  Opioids m, d, k opioid  Phenoxybenzamine a-Adrenergic Phenylephrine a1-Adrenergic       Propranolol b-Adrenergic  Ranitidine H2  Vasopressin V1, V2, V3  Salbutamol b2-Adrenergic  Channel-Linked Receptors Barbiturates GABAA-gated Cl2  Benzodiazepines GABAA-gated Cl  Flumazenil GABAA-gated Cl2  Ketamine Glutamate-gated (NMDA) cation  Enzyme-Linked Receptors Nitric oxide Soluble guanylate cyclase  Insulin Insulin  Glucocorticoids Glucocorticoid  Spironolactone Mineralocorticoid  Adenosine Ca21  Amiodarone Na , K , Ca  Lidocaine Na  Nuclear Receptors Ion Channels 1 21 Enzymes Acetazolamide Carbonic anhydrase  Captopril Angiotensin-converting enzyme (peptidyl dipeptidase)  Milrinone Phosphodiesterase III  Nonsteroidal antiinflammatory drugs Cyclooxygenase-1 and -2  Sildenafil Phosphodiesterase V  1450 S E C T I O N X I I I   Pediatric Critical Care: Pharmacology and Toxicology TABLE 123.1 Targets of Drugs Commonly Used in Critically Ill Children—cont’d Drug Target Agonist Antagonist Ion Pumps and Transporters Digoxin Na1/K1-ATPase pump  Loops diuretics Na /K /Cl cotransporter  Omeprazole H /K -ATPase pump  Thiazides Na1/Cl2 cotransporter  1 Ca21, Calcium; Cl2, chloride; D, dopaminergic; ET, endothelin; GABA, g-aminobutyric acid; H, histamine; H1, hydrogen; Na1, sodium; NMDA, N-methyl-d-aspartate; V, vasopressin A 100 % Maximum response Fraction of maximal effect 1.00 Low potency High potency 0.50 EC50 0.00 0.01 0.1 Drug concentration 50 Drug action at β2-adrenoceptor EC50 10 100 B A1 Response (%) D2 D3 D1 Increasing dose of β-adrenoceptor agonist (logarithmic scale) • Fig.123.3  ​(A) Concentration-effect curve EC50 is the concentration that 100 A2 A2 + RA A3 50 A2 + IA C Drug action at β1-adrenoceptor Concentration of agonist (logarithmic scale) Ion Channels Ion channels are molecular machines that serve as principal integrating and regulatory devices for the control of cellular excitability Different types of ion channels have been described: channels responding to electrical (voltage-dependent ion channels), mechanical, or chemical (ligand-gated ion channels) stimuli; ion channels controlled by phosphorylation/dephosphorylation mechanisms; and G protein–gated ion channels Most ion channels are of the voltage-dependent type and consist mainly of sodium (Na1), potassium (K1), and calcium (Ca21) channels Drugs can affect ion channel function directly by binding to the elicits 50% of the maximal effect (B) Concentration-effect curves and selectivity A hypothetical b-agonist is more selective for the b1-receptor At the lower dose (D1), b1-activity is elicited As dose increases, more b2-activity is elicited (C) A1 and A2 show concentration-effect curves for two different agonists (A1 is more potent, as it requires lower concentration to achieve the same effect) A3 shows a partial agonist that is not able to produce a maximal response even at high concentrations The concentration-effect curve for A2 in the presence of a competitive (reversible) antagonist (RA) requires a higher concentration to overcome the competitive antagonist and elicit the same effect The same agonist (A2) in the presence of a noncompetitive (irreversible) antagonist requires a higher concentration to achieve an effect but also decreases the maximal effect (A, Modified from Hemmings HC Jr, Egan TD Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application 2nd ed Philadelphia: Elsevier; 2019 B–C, Modified from Waller DG, Sampson AP Medical Pharmacology and Therapeutics 5th ed Edinburgh: Elsevier; 2017.) channel protein and altering its function or indirectly through G proteins and other intermediates Lidocaine is a good example of a drug that directly affects voltage-gated Na1 channels by blocking the channel and thus Na1 entry into the cell Channel-linked receptors (ligand-gated ion channels) are discussed later Enzymes Enzymes are a specialized class of proteins responsible for catalyzing chemical reactions within the cell and thus are ideal drug targets Most drugs that alter enzyme activity are substrate analogs of enzymes that inhibit their activity either reversibly CHAPTER 123  Molecular Mechanisms of Drug Actions (e.g., angiotensin-converting enzyme inhibitors acting on peptidyl dipeptidase) or irreversibly (e.g., acetylsalicylic acid acting on cyclooxygenase) Drugs may also prevent the normal functioning of enzymes Fluorouracil, an anticancer drug, is a good example; it is converted into an abnormal nucleotide that inhibits thymidylate synthetase thus blocking DNA synthesis Carrier Proteins Several biological elements, such as ions and small organic molecules, are not lipid soluble enough to cross membranes and require a carrier protein (an ion pump or a membrane transporter) to so.13 Some carrier proteins use the energy of adenosine triphosphate (ATP) hydrolysis to move ions or small molecules across a membrane against a chemical concentration gradient or an electrical potential (primary active transport; Fig 123.4) These include ion pumps (or ATPases), which transport ions only, and the ATP-binding cassette (ABC) transporters, which catalyze transmembrane movements of various organic compounds, including amphipathic lipids and drugs Other carrier proteins, such as transporters from the solute carrier (SLC) superfamily, use energy derived secondarily from the electrochemical potential generated by the concentration gradient of sodium or potassium under the control of the Na1/K1-ATPase pump itself coupled with ATP hydrolysis (secondary active transport; see Fig 123.4) In such instances, the transport of organic molecules is usually coupled to the transport of hydrogen (H1) or Na1, either in the same direction (symport) or opposite direction (antiport) The SLC membrane transporters include more than 380 members organized into 52 families Solute carrier transporters facilitate the transport of a wide array of substrates across biological membranes and have important roles in physiologic processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics The Na1/H1 exchanger (NHE), Na1/Ca21 exchanger (NCX), and Na1/K1/Cl– cotransporters belong to this superfamily The carrier proteins embody a recognition site that makes them specific for a particular permeating species; these recognition sites can also be targets for drugs whose effect is to block the transport system (see Fig 123.2).12 Indeed, some drugs bind to these carrier proteins and interfere with the transport system Digoxin is a typical example of drugs that produce their effect by blockade of an ion pump (the Na1/K1-ATPase pump), while furosemide is a typical example of drugs that block a membrane transporter (the Na1/K1/Cl– cotransporter) Transporters are not just potential drug targets—they play an important role in allowing drugs to reach their site of action in specific organs and tissues To reach its target, a drug may have to cross several membranes For example, an oral drug that is active in the brain needs first to cross intestinal epithelial cells and then the blood-brain barrier The majority of drugs cross cell membranes using an active transport mechanism, either primary or secondary (as discussed previously), that is under the control of membrane transporters Membrane transporters are widely expressed throughout the body, most notably in the epithelia of major organs, such as the liver, intestine, kidney, and organs with barrier functions, such as the brain, testes, and placenta Several membrane transporters have been discovered The ABC and the SLC superfamilies are the two main types of membrane transporters involved in drug transport The ABC superfamily has CH3 CHn CH3 CHn N+ Na+/K+ - ATPase Na+ K+ apical membrane CH3 CHn NBD1 basal membrane NBD2 Na+ CH3 CHn N+ CH3 CHn ADP + 2Pi ATP MDR1(ABCB1) 1451 OTC (SLC22A) • Fig 123.4  ​Structure and underlying transport mechanism of the MDR1 transporter (or P-glycoprotein) and of the ornithine transcarbamylase (OTC) transporter The MDR1 transporter uses the energy of adenosine triphosphate (ATP) hydrolysis to facilitate the efflux of drugs out of the cells (primary active transport) The OTC transporter uses energy derived secondarily from the electrochemical potential generated by the concentration gradient of sodium under the control of the sodium-potassium adenosine triphosphatase pump itself coupled with ATP hydrolysis (secondary active transport) (Modified from Du Souich P Transporteurs membranaires In: Beaulieur P, Pichette V, Desroches J, Du Souich P, eds Précis de Pharmacologie Montreal PUM; 2015.) K+ ... the total number of available receptors directly influence the maximal effect a drug can produce Third, drugs differ in their intrinsic activity in regard to their receptors (e.g., partial agonist... Digoxin Na1/K1-ATPase pump  Loops diuretics Na /K /Cl cotransporter  Omeprazole H /K -ATPase pump  Thiazides Na1/Cl2 cotransporter  1 Ca21, Calcium; Cl2, chloride; D, dopaminergic; ET, endothelin;... Enzymes Enzymes are a specialized class of proteins responsible for catalyzing chemical reactions within the cell and thus are ideal drug targets Most drugs that alter enzyme activity are substrate

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