1442 SECTION XII I Pediatric Critical Care Pharmacology and Toxicology to mediate the downstream effects of analgesia These receptors can be found throughout the body, including the brain and gastroin[.]
1442 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology to mediate the downstream effects of analgesia These receptors can be found throughout the body, including the brain and gastrointestinal tract Most opioid analgesics have a higher affinity toward m-receptors and lead to dose-dependent analgesia, respiratory depression, euphoria, and decreased motility Opioids provide analgesia but can lead to life-threatening respiratory depression and opioid-induced constipation Each opioid has its own specific affinity and potency for the different m-receptor subtypes For instance, morphine is partly metabolized to M6G, which is more potent than morphine In order to produce or antagonize these receptors for analgesia, the drugs must cross the blood-brain barrier Tolerance to the analgesic effects of opioids can develop with long-term use, but tolerance to the constipation effects does not develop The choice of analgesia will depend on the intended duration of effect, potency, and its pharmacokinetics Potency increases from meperidine, codeine, tramadol, morphine, oxycodone, hydromorphone, methadone, and fentanyl Benzodiazepines act on g-aminobutyric acid type A (GABAA) receptors GABA receptors reduce the excitability of neurons; thus, they are effective for anxiety, muscle relaxation, insomnia, and epilepsy Benzodiazepine overdose includes symptoms of drowsiness, confusion, ataxia, and other central nervous system (CNS) effects, but lacks the respiratory and cardiovascular effects of opioids unless administered with other sedating medications Like opioids, potency and half-life differ between different compounds in this class Diazepam, oxazepam, and flurazepam are low potency, while alprazolam, lorazepam, midazolam, triazolam, and clonazepam exhibit higher potency Triazolam and midazolam have rapid onset and a relatively short duration of action, whereas diazepam and clonazepam have a long duration of action All benzodiazepines are metabolized in the liver, but only oxazepam and lorazepam are conjugated and eliminated in the bile Other benzodiazepines are metabolized and eliminated through the kidneys Barbiturates were commonly used before benzodiazepines came to the market but fell out of favor because of their toxicity profile and narrow therapeutic window owing to their interaction with many different brain receptors, including GABA and glutamate receptors Life-threatening respiratory and cardiovascular depression occurs at toxic levels Their potency and ability to inhibit CNS responses have led to their use in controlling seizures but could also be used as sedative agents for diagnostic imaging Propofol, ketamine, and dexmedetomidine are other drugs that are used for sedation and anxiolytic purposes Dexmedetomidine is an a2-agonist used for sedation owing to the ease of rousing patients with gentle stimulation Propofol is a sedative with a rapid onset and extremely short duration of action Ketamine is an analgesic that produces minimal respiratory depression, is a bronchodilator, and aids in sedation induction It does have the potential to cause myocardial depression; thus, blood pressure and heart rate should be monitored Cardiovascular Agents While cardiovascular dysfunction is common in critically ill children, there are limited studies focusing on the drugs administered to these patients Classes of cardiovascular agents used in critically ill children include antiarrhythmic agents, vasodilators, inotropes, vasopressors, and diuretics These substrates influence cardiac output by changing heart rate, contractility, or loading volume In children with cardiorespiratory failure, drugs may not be enough; ECMO may be needed to provide cardiopulmonary bypass and gas exchange to those who are the most critically ill Inotropes and vasopressors bind to adrenergic receptors to increase cardiomyocyte contractility and increase systemic vascular resistance (SVR), respectively The two main groups of adrenergic receptors are a- and b-receptors, each with their own receptor subtypes The subtypes of the adrenergic receptors have specific locations and effects (Table 122.7) Inotropes and vasopressors have individualized specificity for each adrenergic receptor The biosynthesis of endogenous catecholamines starts with tyrosine and produces dopamine, norepinephrine, and, finally, epinephrine These three are commonly administered exogenously to support cardiovascular function and have short duration of action Sympathomimetics are synthetic agents that mimic the effect of catecholamines with a longer duration of action and include phenylephrine, isoproterenol, and dobutamine All of them are metabolized by catechol-O-methyltransferase, conjugation, and monoamine oxidase for endogenous catecholamines The metabolites are eliminated through the urine Vasodilators reduce SVR Hydralazine relaxes the smooth muscles in the periphery Protein binding is about 85% to 90%; hydralazine undergoes extensive hepatic first-pass metabolism and is eliminated via the kidneys Elimination half-life is approximately hour but can produce an effect for up to 12 hours Nicardipine is a calcium channel blocker that is selective to peripheral smooth muscles It also undergoes extensive, saturable hepatic metabolism and has a low oral bioavailability It has a halflife of approximately hours There are three classes of antiarrhythmic agents characterized by their general mechanism of action Class I antiarrhythmics block sodium channels However, owing to the potential for inducing arrhythmias, increasing the QRS interval, and increasing the QT interval, class I agents are not commonly administered in pediatric subjects Class II antiarrhythmics block b-adrenergic receptors and vary in their b1 versus b2 selectivity Overall, these medications reduce heart rate but have the potential to block bronchodilation as well Drugs such as labetalol and propranolol are nonselective and lipophilic; thus, they undergo extensive hepatic metabolism Atenolol and metoprolol are selective b1-antagonists However, atenolol is hydrophilic and eliminated via the kidneys, and metoprolol is lipophilic and metabolized and eliminated via the liver Esmolol, another selective b1-antagonist, is metabolized by plasma esterases Thus, it has an extremely short half-life (5–10 minutes) and therefore is usually administered as a continuous infusion However, for patients with hepatic and/or renal dysfunction, esmolol is a good therapeutic alternative to other class II agents Class III antiarrhythmics block potassium channels Amiodarone is the most well-known agent in this class In addition to blocking potassium channels, it also blocks b-receptors, sodium channels, a-receptors, and calcium channels The half-life is extremely long (30–60 days); thus, loading doses are required to ready steady state It undergoes hepatic metabolism and can block hepatic transporters, leading to drug-drug interactions Longterm administration of amiodarone requires monitoring of hepatic, thyroid, and pulmonary functioning Fluid balance is an important consideration for cardiovascular function In cases of edema or fluid overload, diuretics are necessary to eliminate excess fluid and restore normal hemodynamics Loop diuretics are commonly prescribed and inhibit the Na1/ K 1/2Cl transporter and thus inhibit sodium and chloride CHAPTER 122 Principles of Drug Disposition 1443 TABLE 122.7 Adrenergic Receptors a1 a2 b1 b2 Locations Vascular smooth muscle Pupillary dilator muscle Genitourinary sphincters Presynaptic adrenoceptors Platelets Pancreas Cardiomyocytes Juxtaglomerular cells Bronchial smooth muscles Vascular smooth muscles Stimulation effects Cell contraction Inhibition of norepinephrine release h Heart rate Bronchodilation h Blood pressure Analgesia h Contractility Vasodilation h Systemic vascular resistance Sedation h In renin-angiotensin-aldosterone system and renin Pupil dilation Anxiolysis Urinary retention Platelet aggregation g insulin release Agonists Dopamine Phenylephrine Antagonists Dopamine Clonidine Dobutamine Albuterol Dexmedetomidine Isoproterenol Isoproterenol Norepinephrine Norepinephrine Norepinephrine Norepinephrine Epinephrine Epinephrine Epinephrine Epinephrine Labetalol Labetalol Propranolol Propranolol Labetalol Prazosin Doxazosin Mirtazapine Atenolol Metoprolol Esmolol reabsorption in the ascending Loop of Henle in the kidneys Blocking sodium reabsorption produces diuresis and natriuresis or an increase in urine production and excretion of sodium in the urine, respectively The two most common medications in this class are furosemide and bumetanide Both are highly protein bound (.95%) and eliminated via the kidneys Consequently, neonates and premature neonates who have lower plasma protein abundance and immature renal function have reduced clearance, longer half-life, and augmented volume of distribution of these medications Pulmonary Agents Many critically ill children experience pulmonary dysfunction either as a reason for or a result of admission Respiratory distress or asthma exacerbation are two frequently encountered problems in critically ill children The focus of therapy is to increase oxygenation and reduce airflow resistance For inflammation issues, glucocorticoids are administered and will be discussed in its own section The focus of airway resistance involves medications that induce bronchodilation The mainstay of therapy for this are agonists of the b2-receptor, which induce cyclic adenosine monophosphate (cAMP) and are located primarily in the bronchial and vascular smooth muscle cells Albuterol is a short-acting agonist that is first-line therapy for asthma and respiratory dysfunction It is commonly administered as a metered-dose inhaler or nebulized solution For either formulation, there is limited absorption into the systemic circulation Pulmonary arterial hypertension (PAH) is very common in premature neonates with underdeveloped lungs at the time of birth and those children born with congenital heart disease It is characterized by increased blood pressure in the pulmonary arteries, which leads to progressive shrinking of the pulmonary arteries This increased resistance forces the right ventricle to work harder to continue pumping blood to the lungs and eventually leads to heart failure if untreated Medications for PAH focus on vasodilation and antiproliferation in the vascular smooth muscle cells Inhaled nitric oxide is the first-line therapy for PAH and increases cyclic guanosine monophosphate (cGMP) by modulating its upstream mediator, soluble guanylate cyclase (sGC) Its use is associated with adverse events, including hypoxia or formation of nitric acid, and rebound PAH when therapy is discontinued Phosphodiesterase-5 inhibitors also increase cGMP by inhibiting its degradation Efficacy with sildenafil was demonstrated in adults and has been administered off-label in neonates It is metabolized by hepatic enzymes (predominantly CYP3A4), producing an active metabolite, and eliminated by the biliary system It is highly bound (,96%) in adults but has lower plasma protein binding in neonates (,94%), which is a 50% increase in the fraction unbound Volume of distribution is much higher in neonates and children as well as in subjects placed on ECMO Anticoagulants Anticoagulants are necessary when critically ill children experience thromboembolic events, such as pulmonary embolism or 1444 S E C T I O N X I I I Pediatric Critical Care: Pharmacology and Toxicology deep venous thrombosis There are a few different classes of anticoagulants, including low-molecular-weight heparin (LMWH), unfractionated heparin, vitamin K antagonists, factor Xa inhibitors, and direct thrombin inhibitors The main differences between these anticoagulants are where they bind and inactivate the clotting cascade Of these, only the heparin products, warfarin (vitamin K antagonist), and argatroban (a direct thrombin inhibitor) have been approved for use in pediatric patients Other direct thrombin inhibitors and the factor Xa inhibitors, including those from both classes that are orally administered (direct oral anticoagulants) have not been approved in children, and the data on their off-label use is limited Heparin products bind to antithrombin to inactivate factor Xa in the clotting cascade Unfractionated heparin is administered intravenously and has a short half-life (≈1–2 hours) It binds nonspecifically to plasma proteins and endothelial cell surfaces, which leads to variable and unpredictable pharmacokinetic properties Clearance is mainly through the reticuloendothelial system at low doses but also through the renal system at higher doses The LMWHs are derived from unfractionated heparin but are smaller and therefore have reduced binding This improvement in binding leads to a more predictable pharmacokinetic profile, with a half-life ranging from to hours (depending on the specific LMWH compound) as well as a better absorption profile, allowing for subcutaneous administration once or twice daily They are eliminated renally, and dosages must be adjusted in renal dysfunction, unlike unfractionated heparin Response is measured by monitoring factor Xa activity or activated partial thromboplastin time Protamine is used as an antidote for heparin overdoses A disadvantage of administering any heparin-based drug is the potential for heparin-induced thrombocytopenia (HIT) Heparin can bind to platelet factor (PF4) and antibodies can be formed against this complex This complex can stimulate additional release of platelets and PF4, leading to thrombocytopenia and thrombosis Owing to age-dependent changes in PF4 expression and platelet reactivity, HIT is less common, but not impossible in children Fondaparinux is another antithrombin-dependent inhibitor of factor Xa but does not interact with platelets or PF4; thus it does not produce HIT It is administered once daily, with a half-life of over 17 hours Warfarin is the only anticoagulant approved that is orally administered It inhibits the vitamin K epoxide reductase complex (VKORC1), which activates vitamin K in the body and therefore many vitamin K-dependent clotting factors Differences in response can be due to genetic polymorphisms in VKORC1 or nutritional intake changes in vitamin K–rich foods Genetic differences in VKORC1 haplotypes can contribute to the difference in warfarin requirements across individuals Warfarin is metabolized by hepatic enzymes, primarily by CYP2C9, which demonstrates pharmacogenetic differences that alter clearance Metabolites are then eliminated primarily through the kidneys It is 99% bound to plasma proteins; thus, the clearance is extremely susceptible to alterations in protein binding, including drug-drug interactions due to competition of binding sites on plasma proteins and age- and disease-dependent changes in protein abundance The narrow therapeutic index of warfarin exacerbates changes in binding, genetic polymorphisms, and nutritional changes Thus, any change in pharmacokinetics or pharmacodynamics can lead to minor or life-threatening bleeding A patient’s level of anticoagulation (measured by prothrombin time and the international normalized ratio) must be monitored carefully and doses adjusted only after days of therapy Steroids Corticosteroids are administered in critically ill children for a variety of reasons, including asthma exacerbations, acute respiratory distress syndrome, adrenal insufficiency, and septic shock This class of medications is differentiated into glucocorticoids and mineralocorticoids, both of which are endogenous (cortisol and aldosterone, respectively) and produced by the adrenal glands on top of the kidneys Mineralocorticoids cause sodium (and thus water) retention and affect cardiac output and blood pressure while glucocorticoids regulate glucose metabolism, immunomodulatory proteins, and vasoconstrictive mediators While each type of corticosteroid has its own receptor, there is overlap in specificity of each endogenous and exogenous substrate to these receptors The main exogenous mineralocorticoid is fludrocortisone The most commonly used exogenous glucocorticoids are prednisone, prednisolone, methylprednisolone, and dexamethasone Hydrocortisone possesses both mineralocorticoid and glucocorticoid activity; it is most commonly used for its mineralocorticoid effects Exogenous corticosteroids are metabolized and excreted in a similar fashion as endogenous corticosteroids Primarily, they are metabolized in the liver, and metabolites are then excreted through the kidney The pharmacokinetics of corticosteroids are subject to drug-drug interactions with other medications that inhibit or induce liver enzymes Disease effects, such as renal or hepatic insufficiency, can also impact pharmacokinetics, especially plasma binding, clearance, and half-life The choice of corticosteroid depends on the potency of the glucocorticoid versus mineralocorticoid receptors and the pharmacokinetics Since corticosteroids bind to receptors and effect a transcriptional change, the biological half-life—or duration of action—is longer than the plasma halflife In other words, the effect of corticosteroids can linger even after the body has cleared the corticosteroid from the plasma Hydrocortisone is structurally identical to cortisol, has a short half-life of approximately 90 minutes in plasma and 12 hours biologically, and has equal potency for mineralocorticoid and glucocorticoid receptors Prednisone is metabolized to prednisolone, the active form, both of which have a fivefold higher potency for glucocorticoid receptors compared with mineralocorticoid receptors Prednisone has a half-life in plasma of about hour, while prednisolone has a plasma half-life of about hours, but both demonstrate an intermediate duration of action with a biological half-life between 12 to 36 hours Methylprednisolone also has a plasma half-life of around hours and an intermediate duration of action with a biological half-life between 12 and 36 hours, but it has less potency for the mineralocorticoid receptors than prednisone/prednisolone, with a 10-fold higher potency for glucocorticoid receptors compared with mineralocorticoid receptors Dexamethasone has no effect on mineralocorticoid receptors, has a plasma half-life of hours and a very long duration of action with a biological half-life of over 48 hours, and the highest potency for glucocorticoid receptors Normal physiologic regulation of endogenous corticosteroids follows a classic negative-feedback loop mechanism The hypothalamus releases corticotropin-releasing hormone, which stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH), in turn, stimulating the adrenal cortex to release cortisol The adrenal cortex releases cortisol into the bloodstream, where it can act on the adrenal cortex itself to inhibit ACTH release Long-term administration of exogenous glucocorticoids dominates this system, with higher than physiologically normal blood levels of glucocorticoids and, consequently, CHAPTER 122 Principles of Drug Disposition constant suppression of ACTH, leading to adrenal atrophy and hypothalamus-pituitary-adrenal (HPA) suppression Abrupt discontinuation after long-term use of glucocorticoids can result in adrenal insufficiency, with symptoms such as fatigue, nausea, muscle weakness, hypoglycemia, and mental status changes Accordingly, the dose of glucocorticoid must be tapered after longterm use (10–14 days) or high doses (.5 mg prednisone or equivalent) The duration of action and potency can also affect the HPA suppression; thus, increased monitoring and a more conservative taper might be warranted for dexamethasone or when clearance of glucocorticoids is expected to be longer than normal owing to drug-drug interactions or disease-state clearance changes Neuromuscular Blockers Neuromuscular blockers are also known as paralytic agents that are often used in critically ill children to facilitate mechanical ventilation or sensitive procedures that need limited movement They block the postsynaptic nicotinic receptor at the neuromuscular junction to block polarization and muscle movement Biomarkers of comfort, such as heart rate and blood pressure, should be assessed often Duration of action, metabolism, elimination, and potency are all factors in which agent to choose Succinylcholine and mivacurium are metabolized by plasma esterases; consequently, they have quick onset and short duration of action Pancuronium and vecuronium have a quick onset and intermediate to long duration of action However, both are metabolized by the liver, with the vecuronium metabolite having 80% of parent activity Both can accumulate with liver dysfunction Vecuronium and its metabolite can accumulate with renal dysfunction, leading to longer than intended duration of action Atracurium naturally degrades at physiologic pH and temperature; thus, there is less concern about accumulation during organ dysfunction Conclusion Inappropriate medication choice or dosing could expose children to ineffective therapy or toxicity Rational therapeutic choices for the critically ill child must account for the impact of development 1445 and disease on drug action It is essential to target the correct concentration to produce the desired effect In other words, it is important to combine the pharmacokinetic and pharmacodynamic processes described earlier to identify the relationship between effect and time based on ADME processes and the clinically relevant pharmacokinetic parameters Therefore, targeting a pharmacokinetic or pharmacodynamic end point could involve administering loading doses for a drug with a long half-life, adjusting the dose owing to altered clearance, or altering the monitoring knowing that maturation of a pediatric patient’s system is incomplete and the response is different from that of an adult Overall, understanding the changes in drug disposition can improve drug therapy and patient care Key References Bouwmeester NJ, van den Anker JN, Hop WC, Anand KJ, Tibboel D Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants Br J Anaesth 2003;90(5):642-652 de Wildt SN, Kearns GL, Leeder JS, van den Anker JN Cytochrome P450 3A: ontogeny and drug disposition Clin Pharmacokinet 1999;37(6):485-505 Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE Developmental pharmacology—drug disposition, action, and therapy in infants and children N Engl J Med 2003; 349(12):1157-1167 Su F, Gastonguay MR, Nicolson SC, DiLiberto M, Ocampo-Pelland A, Zuppa AF Dexmedetomidine pharmacology in neonates and infants after open heart surgery Anesth Analg 2016;122(5):1556-1566 Zanger UM, Turpeinen M, Klein K, Schwab M Functional pharmacogenetics/genomics of human cytochromes P450 involved 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