Genetic Disease


11
Genetic Disease


Tania Perez Jimenez


Veterinary Clinical Sciences, College of Veterinary Medicine, Program in Individualized Medicine (PrIMe), Washington State University, Pullman, WA, 99164, USA


Introduction


Genetic factors have been described to affect an individual’s response to anesthetic drugs in humans for more than 50 years [1]. Some of these responses have been attributed to either gender, comorbidities, size, previous drug use, drug interactions, or the characteristics of the procedure being performed [2]. Findings associated with the recent advancements in genome sequencing and genetic mapping have revealed that genetic differences and interindividual variability play an important part in drug response. This has brought us to the era of individualized medicine, which has opened the door to a rapid and vast knowledge base regarding congenital malformations, inherited diseases, and the genetic implication of treatment, either drug‐ or nondrug‐related. Genetic inheritance is a very important component of anesthesia practice. Providing this primer on pharmacogenetics and clinical genetics will provide us with the tools and basic knowledge necessary to understand the implications of genetics on anesthesia practice.


Pharmacogenetics


The basic definition of pharmacogenetics encompasses the individual’s response to a medication based on their genetic makeup. The main principle of pharmacogenetics is based on the identification of these genetic variants (polymorphisms) that affect the individual’s response to medications and drugs, a significant number of which are used in anesthesia practice. Some of the drugs that have been described are codeine, tramadol, inhalant anesthetics, local anesthetics, and muscle relaxants, among others [3]. The altered response to these drugs can be due in part to issues with the drug interacting with its target (effect) and drug disposition (metabolizing enzymes, transporters, and receptors) [4]. Pharmacogenetics has the possibility to make drug therapy individualized, to decrease or completely avoid the occurrence of adverse drug reactions (ADRs) and toxicity, and to improve drug efficacy by tailoring the treatment to the patient’s genotype [5]. In veterinary medicine, significant discoveries have been made due to observations by practicing clinicians worldwide, and some others will be made in part with the development of the canine genome [6].


We have determined the existence of breed‐related differences in drug response in companion and production animals. Some examples in small animals are propofol and thiopental use in Greyhounds, acepromazine in boxers, and drug effects in herding breeds [7]. These few examples bring another relationship, which is not just drug metabolism and disposition, but, more specifically, the difference in breeds and the incidence of specific diseases that also become a challenge for the anesthetist.


Genetically Related Diseases


Breed‐Related Differences


The wide variety of breeds and the genetic variation within them can affect drug pharmacokinetics and pharmacodynamics. There can be an inconsistency in dosages and response across multiple breeds. The impact of this in pharmacokinetic and pharmacodynamic studies can be significant, since the results obtained in one breed can be inapplicable in another and have inconsistent effects. The consequences can be important in new drug development when trying to identify a dosage of a medication in veterinary practice. It is important to remember that some of these differences can be metabolic and physiologic [8].


Drug Metabolism and Disposition


Enzymes responsible for the metabolism and disposition of many drugs, xenobiotics, and other compounds are the cytochrome P450 enzymes. In humans, some members of this group are polymorphic, with some significant differences found according to race/ethnic population [9]. One of these enzymes, which is responsible for metabolizing many medications, is the CYP2D6 in humans, with its canine ortholog (equivalent) CYP2D15. CYP2D15 has been investigated in the dog, and five polymorphisms have been described [10]; the impact of these on drug metabolism has not been fully elucidated. There are only a few studies that look into drugs metabolized by CYP2D15 in small animals. One describes the pharmacokinetics of celecoxib in a population of laboratory Beagles [11], where two phenotypes could be differentiated by their elimination capacity (the extensive metabolizer [EM] and the poor metabolizer [PM] phenotypes). This showed a predominant role of CYP2D15 and variants in celecoxib metabolism, with slightly over 50% of the 242 dogs in the study being in the PM group, which will ultimately impact drug effect and help guide additional or alternative therapy for nonsteroidal anti‐inflammatory drugs (NSAID)‐related analgesia. Related to the possibility of this variability causing alterations on other drugs, work with tramadol has shown that the active metabolite, O‐desmethyltramadol (M1), is formed exclusively by CYP2D15 in the dog [12]. It is possible then that CYP2D15 polymorphisms could potentially affect the analgesic properties of tramadol, with less analgesia in the population with the PM phenotype. The effect of these variants on other drugs metabolized by the same enzyme is unknown at the moment in veterinary medicine.


One clear example where a polymorphism that affects metabolism has been described in detail is that found in CYP2B11, the enzyme responsible for hydroxylating propofol in dogs, among other drugs. Remarkably, there is a decrease in the clearance and a lower liver metabolism of propofol overall in Greyhounds [13], and when Greyhounds are compared to mixed‐breed dogs [14, 15] and Beagles [15]. The metabolism of other anesthetic drugs is also affected in Greyhounds, such as the thiobarbiturates (thiopental) [16]. This decrease in clearance and lower liver metabolism ultimately cause delayed and prolonged recoveries. This enzyme polymorphism might not only affect Greyhounds, but has been extrapolated to other members of the Sighthound family (Irish Wolfhound, Afghan Hound, borzoi, saluki, etc.). Another anesthetic drug that has also shown prolonged recoveries in Greyhounds is alfaxalone [17]. Following premedication with morphine and acepromazine, Greyhounds induced with alfaxalone had a duration of anesthesia up to five times longer than dogs not premedicated, with a prolonged elimination half‐life, even though the clearance is still small. However, this difference may be due in part to the transient decrease in blood pressure and hepatic blood flow caused by the acepromazine/morphine combination and not solely genetic differences in this breed.


Anesthetic Recommendations


In addition to abnormalities in drug disposition as described, Sighthounds tend to present with high hematocrits (>50%) and low serum proteins (mostly low albumin), which can affect drug binding and free fractions of drugs, increasing the active portion [18]. Furthermore, their lean bodies (low amount of fat) can affect drug redistribution (lipophilic drugs will have a lower volume of distribution) [8] and thermoregulation [18]. When anesthetizing a Greyhound or any member of the Sighthound family, attention should be paid not just to the drug administered, but also to the dosage used. For anesthetic induction, anesthetic agents should be administered to effect to titrate the minimum amount of drug necessary. To this end, premedications should be encouraged to avoid stress and decrease the required amount of induction agent. When deciding which premedication agents to use, preference should be given to drugs that can be reversed in the event of a prolonged recovery, such as alpha‐2‐adrenergic receptor agonists, opioids, and benzodiazepines.


Transporters


One of the most clinically important drug (efflux) transporters (pumps) is the P‐glycoprotein (P‐gp). They belong to the family of adenosine triphosphate (ATP)‐binding cassette (ABC) transporters. Polymorphisms on this transporter, specifically ABCB1, are well‐studied in veterinary medicine. They are expressed on cell membranes in many tissues (brain, intestine, kidney, and liver), and the main function is to limit systemic and organ uptake of drug and contribute to their excretion [19]. There is a genetic mutation that encodes for this protein, the MDR1 gene in dogs [20] and cats [21]; the mutation is referred as ABCB1‐1Δ. There are three phenotypes described in dogs: homozygous (mutant), intermediate (heterozygous), and the wild type. Dogs affected by this mutation include a variety of breeds classified under the herding breed category (Collies, Border Collies, Australian, English, and German Shepherds, Old English and Shetland Sheepdogs, etc.), with more than 75% of Collies and 50% of Australian and English Shepherds carrying at least one mutant allele [22]. The ABCB1‐1Δ has been identified in some Sighthounds (Longhaired Whippet) with a somewhat high frequency (30–50%) and in some mixed‐breed dogs with a lower frequency (≤1%). In cats, approximately 4% carry the polymorphism. Particularly important is the loss of function of the P‐gp on the brain since this protein is a component of the blood–brain barrier. It is then expected that drug penetration is increased, and these animals would be sensitive to the neurological toxicity caused by some of the substrates. Anesthetic drugs that are substrates of this transporter are acepromazine, butorphanol, loperamide, vecuronium [23, 24], verapamil, diltiazem, morphine, and fentanyl [25]. Additionally, some drugs may act as inhibitors of the P‐gp efflux activity, such as the antimicrobial agents erythromycin and ketoconazole, the antidepressants fluoxetine and paroxetine, the opioids methadone and pentazocine, and the cardiac drugs verapamil, amiodarone, carvedilol, quinidine, and nicardipine [25].


Anesthetic Recommendations


Caution is warranted when administering some of the drugs mentioned previously to patients that have been diagnosed or are suspected of having the mutant allele (Collies). Doses should be carefully chosen (likely decreased) and close monitoring should be performed for any untoward signs. For example, with acepromazine, sedation is increased and prolonged when administered at dose of 0.04 mg kg−1 IV [26]. Other drugs commonly administered with acepromazine, such as the opioids morphine, butorphanol, fentanyl, and methadone (known P‐gp substrates), may also affect the degree of sedation. Particular attention should be paid to the coadministration of substrates of P‐gp and inhibitors (Table 11.1). Careful consideration when selecting antimicrobials, opioids, and cardiac drugs is warranted.


Malignant Hyperthermia


Malignant hyperthermia (MH) is a rare pharmacogenetic disorder in dogs. Onset is due to exposure to a triggering agent such as depolarizing neuromuscular blockers (NMBs; succinylcholine) or inhalant anesthetics (halothane, isoflurane, sevoflurane). Clinical signs associated with this syndrome include hypercapnia, which is the most prominent clinical sign in dogs, muscle rigidity, increased body temperature (which lags behind the hypercapnia), hyperkalemia, metabolic acidosis, tachycardia, rhabdomyolysis, and disseminated intravascular coagulation [27, 28]. Death will rapidly ensue if signs are not detected early, and treatment is started. No specific breed has been associated with this disorder; reports in the literature include Pointer, Greyhound, Labrador Retriever, Saint Bernard, and Springer Spaniel breeds [29].


This syndrome can be explained by a mutation in the gene that encodes for the ryanodine receptor (RyR1), which is a skeletal muscle calcium release channel (Figure 11.1). It is transmitted in dogs as an autosomal‐dominant trait [30]; therefore, only one copy of the mutation is needed to produce offspring with MH. There could also be other genes involved and associated with the RyR1 receptor, such as CACNA1S, the α‐subunit of the L‐type voltage‐gated dihydropyridine (DHP) receptor [31]. The result is an increase in sensitivity of the channel to open, triggered by anesthetic medications. About 10 cases have been reported through the years in the literature, 4 of which were Greyhounds; this suggests a possible breed predisposition.


The diagnosis of MH is usually based on clinical signs without a specific diagnostic test (contracture testing muscle biopsies or gene sequencing). Often it occurs in healthy animals that present for anesthesia and have no history of anesthesia‐related complications. One of the first indications seen by the anesthetist is the marked increase in end‐tidal (ETCO2) or arterial carbon dioxide levels without an alternative explanation [29]. Genetic sequencing is available for dogs that looks for and verifies the presence of the dominant MH mutation through a buccal swab, blood, or dewclaw sample. It can be tested on any breed [32].


This syndrome as such has not been diagnosed in cats. There are three reports in the literature that describe very similar clinical findings to the dog: changes in heart rate, arrhythmias, and increases in body temperature and limb rigidity. All three cats died during cardiopulmonary resuscitation (CPR) attempts. MH was presumed but not confirmed [33].


Anesthetic Recommendations


If there is no familial or any other history of an anesthetic adverse event, it is difficult to say with any degree of certainty which animals can develop MH. Early recognition of symptoms and avoidance of the possible causative agent should prevent most episodes of MH. An anesthetic protocol free of triggering agents (succinylcholine and volatile anesthetics) should be chosen.


A safe protocol could include benzodiazepines (diazepam, midazolam), phenothiazines (acepromazine), alpha‐2‐adrenergic receptor agonists (dexmedetomidine), etomidate, propofol, alfaxalone, opioids, dissociative agents (ketamine, Telazol), nitrous oxide, nondepolarizing NMBs (atracurium, cis‐atracurium, vecuronium, rocuronium, etc.) and local anesthetics. Protocols with total intravenous anesthesia (TIVA) and or local/regional anesthesia techniques can be used successfully. The doses do not change from any other patient for any of the drugs mentioned in the preceding text.


Table 11.1 Selected P‐glycoprotein substrates and inhibitors [25].






























































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Oct 18, 2022 | Posted by in SUGERY, ORTHOPEDICS & ANESTHESIA | Comments Off on Genetic Disease
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Substrates Inhibitors
Anticancer drugs Antidepressants
Doxorubicin Fluoxetine
Docetaxel St. John’s wort
Vincristine Paroxetine
Vinblastine
Etoposide Antimicrobial agents
Mitoxantrone Erythromycin
Actinomycin D Itraconazole

Ketoconazole
Steroid hormones
Aldosterone Opioids
Cortisol Methadone
Dexamethasone Pentazocine
Methylprednisolone

Cardiac drugs
Antimicrobial agents Verapamil
Erythromycin Amiodarone
Ketoconazole Carvedilol
Itraconazole Quinidine