Role of Genetics in Anesthesia - Genetic Impact, Considerations, Management

Introduction:

In the last decade, significant progress has been made in understanding how the body's liver enzymes, responsible for breaking down substances, can be influenced by environmental factors. These factors can be natural, like air pollutants, or man-made, such as chemicals in solvents and petrochemicals. Even compounds in fruits like citrus can have an impact. Notably, common substances like alcohol and tobacco are part of this equation. They can alter how our bodies process medications, even those used in anesthesia. In essence, what we consume and encounter in our environment can directly affect how our bodies respond to drugs, which, in turn, affects the effectiveness of anesthesia.

How Genetic Disorder Is Identified in Anesthesia Practice?

• Genetic disorders are gaining attention in anesthesia due to improved testing, greater awareness, and advanced genetic knowledge.

• Some disorders are discovered coincidentally before surgeries, while others are known beforehand.

• Managing genetic disorders during emergency surgeries is challenging due to limited preparation time.

What is the Influence of Genetics on Anesthesia?

• Specific genes influenced by anesthesia have been identified in animals.

• Genetic variations impact drug responses, studied within the field of pharmacogenomics.

• Pharmacogenomics has led to improved anesthesia outcomes and reduced complications.

How Do Genetic Disorders Have Their Impact on Anesthesia?

Problems within genes or chromosomes cause genetic disorders. Mutations, deletions of genes, or gene combinations can lead to these disorders. They can be present since birth or appear later in life. There are currently over 4,000 known genetic disorders, with more being discovered.

Different Types of Genetic Disorders:

1. Single Gene Disorders: These are caused by mutations in a single gene's DNA. Examples include:

   • Autosomal Disorders: Like achondroplasia causing bone development issues.
   • Autosomal recessive Disorders: Such as sickle cell anemia, come from abnormal genes from both parents.
   • X-linked Disorders: Like hemophilia from a single abnormal gene on the X chromosome.

2. Y-linked Disorders: Affecting the Y chromosome, passed from father to son.

3. Polygenic Disorders: These arise from multiple gene interactions. Diseases like heart disease and diabetes fall into this category.

4. Multifactorial Problems: Result from both gene mutations and environmental factors. Conditions like heart disease, diabetes, and autism belong here.

5. Chromosomal Abnormalities: These occur due to issues with the number or structure of chromosomes. Examples are Down's syndrome and Turner's syndrome.

6. Mitochondrial Mutations: These mutations are inherited only from the mother due to mitochondria being inside egg cells. Conditions include Leber's hereditary optic neuropathy (an uncommon mitochondrial illness that usually manifests as progressive optic neuropathy-related visual loss in young males) and Leigh's syndrome (a serious neurological condition that typically manifests during the first year of birth).

Genetics and Anesthesia Management:

1. Impact of Genetic Expression on Anesthesia:

• Genetic changes causing developmental anomalies can complicate anesthesia management.

• Abnormalities can affect anatomy, physiology, and function due to gene mutations.

• Airway problems may arise due to craniofacial abnormalities, like cleft lip/palate.

• Heart defects, often linked to other anomalies, need special anesthesia attention.

• Kidney/liver issues are rare but can complicate anesthesia and other problems.

• Central nervous system (CNS) problems and mental retardation can be related to chromosomal or systemic issues.

2. Anesthesia Influence on Genetic Makeup:

• Investigating how anesthesia affects genetic makeup is essential, especially for intra-uterine exposure.

• Understanding the interaction between anesthesia drugs and genetics can shed light on potential genetic disorders.

How Is Anesthesia Considered in Genetic Disorders?

When dealing with anesthesia for patients with genetic disorders, specific challenges arise based on their unique conditions. Some examples of these challenges include:

1. Micrognathia (small jaw), Coarctation of aorta (narrowing of a major blood vessel), Horseshoe kidney (kidney fusion), and Thoracic and vertebral anomalies are common issues in Turner's syndrome. Patients often face airway difficulties. A thorough evaluation of the airway and systemic functions is essential. Minimizing the use of certain drugs and paying attention to post-operative care is important.

2. Goldenhar's syndrome requires a detailed assessment of the upper and lower airway. Pulmonary, hepatic, and renal functions need to be monitored. The use of certain drugs should be limited. Intravenous induction is preferred over inhalation. Critical care after surgery is crucial.

3. Klippel-Feil syndrome, characterized by a short neck and fused cervical vertebrae, poses airway and neuraxial block challenges. Anesthetic planning should account for these factors.

4. In Noonan syndrome, general anesthesia could trigger Malignant Hyperpyrexia, making regional techniques more suitable.

5. For patients with Sickle cell disease, preventing complications by maintaining oxygen levels, hydration, and temperature control is important. General anesthesia is usually preferred.

6. In Neurofibromatosis (NF), sevoflurane inhalational induction is recommended, although these patients may be more sensitive to muscle relaxants.

These disorders present various complexities for anesthesiologists due to the associated anatomical, physiological, and systemic challenges.

Impact of Anesthesia on Genetic Makeup:

• There is an ongoing debate about whether anesthesia exposure affects genetic makeup, especially in developing fetuses. While some studies in rats suggest a connection between nitrous oxide exposure and birth defects, there's no clear evidence of similar effects in humans.

• Some recent research suggests that infants born to mothers exposed to general anesthesia in the first trimester might have a higher incidence of certain congenital disabilities, but other studies refute this.

• The fear of anesthesia-induced birth defects among pregnant women and OR personnel might be exaggerated. Using balanced judgment when considering anesthesia exposure during early pregnancy is important, especially nitrous oxide.

How Is Pharmacogenetics Relevant to Anesthesia?

Clinical Pharmacogenetics Implementation Consortium (CPIC):

• Established in 2009 to create evidence-based guidelines for incorporating pharmacogenetics into clinical practice.

• Aims to provide clear recommendations for using genetic test results to guide drug prescriptions.

• Evaluate the strength of evidence linking gene variations to drug responses and provide dosing recommendations based on genotypes.

Codeine:

• Genetic variations in CYP2D6 gene affect codeine metabolism into morphine.

• Ultra-rapid and poor metabolizers may have different drug effects.

• Breastfeeding mothers with ultra-rapid metabolism are advised to avoid codeine due to the risk of elevated morphine in breast milk.

Oxycodone:

• Metabolized by enzymes CYP3A4 and CYP2D6.

• Genetic variations impact oxycodone processing and effects.

• Studies show genetic factors influence pain relief and side effects of oxycodone.

Morphine:

• Wide variability in response to morphine among individuals.

• Genetic and pharmacogenetic factors studied for pain and analgesia response.

• Associations with μ-opioid receptor gene (OPRM1), catechol-O-methyltransferase gene (COMT), and others explored.

Warfarin:

• Warfarin's narrow therapeutic window and variability in dose-response.

• Genetic variants of CYP2C9 and VKORC1 influence warfarin dosing.

• FDA-approved label change to include pharmacogenetic information for warfarin dosing.

Clopidogrel:

• Clopidogrel's role as an antiplatelet drug.

• CYP2C19 gene variants impact clopidogrel metabolism and effectiveness.

• FDA label warns about reduced effectiveness in patients with specific genotypes.

β-Blockers:

• Use of β-blockers in anesthesia and heart conditions.

• Genetic variations in ADRB1 and ADRB2 genes influence β-blocker response.

• Studies examine associations between gene variants and clinical outcomes.

How Do Genes Influence Outcomes From Anesthesia?

Liver Enzymes and Environmental Factors:

1. Liver enzymes that break down foreign substances (xenobiotics) in the body can be influenced by environmental factors like pollutants and enzyme inhibitors in solvents, petrochemicals, and citrus fruits.

2. Alcohol and tobacco also impact these liver enzymes, affecting how quickly medications, including volatile anesthetic agents used during surgery, are metabolized.

Genetic Differences and Drug Responses:

1. Advances in biotechnology and decoding the human genome have revealed that genetic differences underlie varied responses to illnesses and drugs.

2. Genetic polymorphisms refer to variations in genes that lead to different traits.

3. Ancient observations of people reacting differently to foods and medicines were later linked to genetic variations.

Genetic Variations in Drug Metabolism:

1. Enzymes like CYP2D6 metabolize various drugs, including anesthetics. Genetic variations in CYP2D6 can cause individuals to respond poorly to certain drugs or experience unexpected side effects.

2. Similar genetic variations impact enzymes like CYP2C19 and CYP2C9, which metabolize medications like antiarrhythmics, painkillers, and antipsychotics.

3. Genetic differences in these enzymes can lead to varying drug responses among individuals and ethnic groups.

Impact of Smoking and Alcohol:

1. Smoking and alcohol consumption influence how these enzymes function.

2. Alcohol and smoking can affect drug responses during and after anesthesia by impacting enzyme activity.

Advancements in Genetic Analysis:

1. Modern technology allows for quick and accurate analysis of a person's genetic makeup.

2. Future screenings could identify genetic factors affecting anesthesia and medication responses.

3. Tailoring treatments based on genetic profiles could enhance drug effectiveness and safety.

Ethical and Social Considerations:

Implementing personalized medicine based on genetic information raises ethical and social questions that need careful consideration.

What Are the Management and Guidelines for Genetic Disorder Associated With Anesthesia?

• Established guidelines exist for managing recognized genetic disorders like malignant hyperthermia and Down's syndrome.

• Many genetic disorders are addressed case-by-case, considering their unique characteristics.

• These disorders can be inherited in different ways, contributing to their complexity.

Conclusion:

Gene screening is crucial for categorizing COVID-19 patients into groups and helping doctors choose the right anesthesia for severe cases, especially those with ARDS in the ICU. This genetic screening should be done for everyone, whether healthy or sick, to check for genetic differences that might affect anesthesia. For ICU care, drugs like Sevoflurane, Fentanyl, and Propofol are safe choices. Researchers are still studying dexmedetomidine for COVID-19. We must investigate other anesthetics to weigh their risks and benefits for personalized use based on a person's genes. Personalized medicine and dose adjustments based on genetics are recommended in all surgery stages, including before, during, and after.