INTRODUCTION
Pharmacogenomics is the study of how chromosomal variations influences their response and is considered a highly important area for improving drug therapy and prescribing. The days are not very far when  patients in Pre-anaesthetic assessment room will carry his Genomics  E-Card and will be prescribed safe sedation, analgesia and anesthetics accordingly. Depending on the patient`s genetic makeup, some drugs may work more or less effectively than they do in other people. Likewise, some drugs may produce more or fewer side effects than in someone else. Pharmacogenomics deals with the genetics of drug-response phenotypes that have a complex genetic basis. It is an understanding of this pharmacogenomic variability that is the  genesis of personalized medicine.
GENOMES AND GENETICS : Approximately 3 billion base pairs encoding around 30,000 genes makes a set of complete human genome. The majority of drug metabolism occurs via the cytochrome P450 (CYP) enzyme system, which is made up of 57 genetic subtypes. Variations in genes that code these enzymes may influence their ability to metabolize certain drugs.  Pharmacogenetics has been defined as the study of variability in drug response due to heredity, largely used in relation to genes determining drug metabolism, and the term ‘pharmacogenomics’ has been used as a broader based term that encompasses all genes in the genome that may determine drug response [1]. In recent years many clinical trials and reviews have surfaced describing genetic associations with clinical outcomes in the field of of peri-operative medicine [2][3]. Different polymorphisms seem to influence pain perception also in numerous ways, and the response to analgesics differs depending on the pain modality and the opioids that is prescribed.  The pharmacogenomic impact of polymorphisms, which are genetic alterations (and occur in more than 1% of the population), is most noted among 3 categories: enzymes, transporter proteins, and receptors.[4] . Although various genetic disorders like malignant hyperthermia, porphyrias, α-thalassemia, down's syndrome and other congenital disorders have been recognized and their guidelines have been evolved but many more genetic disorders are surfacing in genomics studies and their implications on anesthetic susceptibilities are yet to be delineated and thus it  makes an interesting subject for the future anesthesiologists.
Malignant Hyperthermia -There are almost 50 mutations that have been found associated with MH but the RYR1 gene mutation on chromosome 19 is the most predominant. Ryanodine receptors mediate calcium release from the sarcoplasmic reticulum, which is an essential step in muscle contraction. In MH the release of calcium from the sarcoplasmic reticulum outweighs the uptake resulting in the inability to terminate muscle contraction. Once MH is recognized it is imperative to act quickly to discontinue the inhalational agent, hyperventilate with 100% oxygen and administer dantrolene, cool patient and treat symptoms. Dantrolene decreases the release of calcium from the sarcoplamic reticulum and restoring the balance between the release and re- uptake. The contracture halothane caffeine test is the most common diagnostic test for the MH diagnosis.
Butyrylcholinesterase (BChE) deficiency- All inherited causes of psudo-cholinesterase deficiency are located at Chromosome-3 and all variants occur as a point mutation of Chromosome-3. So far there are 50 genetic variant of BChE which have been proposed. Psudo-Cholinesterase deficiency is usually due to homozygosity for the abnormal allele. The enzyme produced by the homozygous state is usually altered both quantitatively and qualitatively. Patients who are homozygous for the A variant are very sensitive to mivacurium and suxamethoium and long duration of action has been reported after 0.12 – 0.2 mg/kg .The time for full spontaneous recovery of neuromuscular function is 6-8 hr, compared to 30minutes in patients with normal BChE. If plasma from the patient with normal BChE is added to a water bath containing benzylcholine, a chemical reaction occurs which emits light and can be measured spectrophotometrically but if dibucaine is added the reaction is inhibited and no light is produced. The percentage of inhibition of BChE by dibucaine is termed the dibucaine number which is a diagnostic test in 80 percent cases.
Prophyria- The deficiency in the haem bio-synthetic pathway results in the accumulation of haem precursors and porphyrins. The genetic defect which causes this deficiency has been attributed to chromosome-1 (African type) and chromosome 11 (acute intermittent porphyria)  in Sweden and other European population.[6] The anaesthesiologist should have concern regarding porphyria to avoid agents that may precipitate an acute porphyric attack. And he must treat an acute life threatening  attack by withdrawing precipitating drug, correct dehydration and electrolytes.
Safe Drugs to be  used in porphyric patients:-
Premedication- Triazolam is the only safe agent available  Minimise the fasting period
Induction – Propofol & Muscle relaxants- Suxamethonium is safe,  Atracurium has been used safely.
Maintenance- Total intravenous anaesthesia using propofol and remifentanil ,isoflurane and desflurane . Halothane is not advocated as safe by all sources and sevoflurane should not be used
Analgesia- Morphine, pethidine, fentanyl, alfentanil, sufentanil and naloxone
Reversal- Neostigmine and glycopyrrolate
Postoperative - Morphine, pethidine, codeine, paracetamol and ibuprofen
Antiemetics- Prochlorperazine  and droperidol
Regionals blocks - Bupivacaine or lignocaine can be used safely.
Genetic polymorphism  and  Anaesthetic Drugs-
VOLATILE AGENTS- Among the various anesthetic agents, halothane is metabolized by cytochrome P450 (CYP) 2E1 mainly and, to a lesser extent, by CYP3A4 and CYP2A6. The various volatile anesthetic agents like isoflurane, sevoflurane, enflurane and desflurane are primarily metabolized by CYP2E1. Mutations of the genes which code for the subunit of GABA receptors in brain can account for increased anaesthetic requirement as the resistance to volatile anaesthetics increases, possibly affects to individual variously in response to these drugs. Genes like Syntoxin, Stomatin, Gas-1, White/brown Drosophila genes, Para genes, etc , which undergo mutation when subjected to volatile anaesthetics have been identified in experimental animals such as mice, flies and worms and they can influence  cell function and the response to analgesics and anaesthetic drugss.[5]
INDUCTION AGENTS- The induction agent like ketamine is metabolized by CYP2B6, CYP3A4 and CYP2C9 while enzymes involved in the metabolism of thiopental and etomidate are not known. Propofol is metabolized mainly by glucuronidation by uridine diphosphate- glucuronosyl-transferases (UGTs) and by hydroxylation by CYP2B6 and CYP2C enzymes and finally by enzymes SULT1A1 and NQO1. CYP2D6 is responsible for the breakdown of a number of commonly used substances including the β-blocker like metoprolol, the antidepressants like nortriptyline and opiates including codeine and dextromethorphan. Dysfunctional melanocortin-1 receptors found in  red haired person  requires higher concentration of volatile agents like Desflurane, sevoflurane and even higher dosage of  local anesthetics.
Nitrous Oxide Toxicity- Megaloblastic anaemia, agranulocytosis, and neuropathy secondary to acute demyelination were attributed to prolonged exposure to nitrous oxide earlier but few rare cases have drawn attention to catastrophic acute demyelination after relatively short durations of exposure to nitrous oxide in children with variants in the gene encoding 5,10-methylene tetrahydrofolate reductase (MTHFR). Nitrous oxide should not be administered to patients known to have MTHFR deficiency or those with a family history of this condition. [8]
Opioids & other analgesics affected by genes- . Knowledge about genes governing pharmacodynamic and pharmacokinetic processes involving analgesic agents like intra-thecal fentanyl, tramadol, pentazocine etc. are gaining more importance. While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype–phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored except the μ-opioid receptor. Analgesic effect of opioid therapy can be influenced by alterations in the metabolism of analgesic drugs (CYP), mutations of the μOR, alterations in the metabolism of dopaminergic and adrenergic neurotransmitters catechol-O-methyl transferase, ( COMT). COMT regulates the metabolism of catecholamines such as norepinephrine, epinephrine, and dopamine; thus, mutations in the COMT gene can affect the perception of pain. Reduced COMT activity leads to larger levels of catecholamine neurotransmitters and increased pain sensitivity in animal models of pain. The females with variant MC1R alleles have been reported to have altered sensitivity to the kappa-opioid agonist pentazocine.
 Pain genes – Pain perception altering genes have been identified where a number of genes responsible for heritable conditions causing alterations in pain perception. The hereditary sensory and autonomic neuropathies I–IV (HSANs I–V) are examples of a family of syndromes in which pain perception and responses are reduced or absent as the result of single point mutations. More recent scientific discoveries have confirmed a pivotal role for the sodium channel Nav1.7 in a growing range of human familial and de novo gain-of-function and loss-of-function pain syndromes.
Problem with Codeine- Codeine must be converted into morphine to elicit its analgesic effect as individuals who have poor metabolism do not achieve analgesia with codeine, while they still encounter side effects such as nausea and vomiting. On the  other hand codeine overdose and toxicity can be anticipated with ultra-rapid CYP2D6 metabolism. Decreased CYP2D6 activity results in less morphine production and little or no pain relief from codeine. Medication like antihistamines, calcium channel blockers, erythromycin and grapefruit juice will also decrease CYP2D6 activity.
Tramadol & Fentanyl- The effect of tramadol analgesia is also influenced by the CYP2D6 genotype as these patients may be overdosed. O-Desmethyltramadol is a metabolite endproduct of tramadol and is more potent at mu-opioid receptors. Genetic variations in the mu-receptors caused by G variant of OPRM1304 receptor can lead to exaggerated effects of intrathecally administered fentanyl also.[7] Prolonged exposure to agonist drugs like morphine, pethidine or fentanyl results in desensitization of opioid receptors due to beta-arrestin protein.
Paracetamol hepatotoxicity is the most common cause of acute liver failure in the west. Under normal conditions, paracetamol is extensively conjugated with glucuronic acid and sulphate as part of phase 2 metabolism in order to make it water soluble, preceding its excretion via the kidneys. A total of 5% of the remaining drug undergoes phase 1 oxidation in the liver via the CYP system. Cytochrome P450 2E1 and 3A4 convert paracetamol to a toxic intermediary metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which is instantly cleared by conjugation with glutathione to form cysteine and other conjugates. This glucuronidation process was noted to be impaired in sufferers from Gilbert’s syndrome, increasing the risk of paracetamol toxicity in affected individuals. Furthermore, new evidence has shown that up to 33% of Oriental subjects displayed relatively extensive glucuronidation with clinically relevant lower incidence of acute liver failure in patients belonging to this ethnic group who ingested large amounts of paracetamol.[9] Activity of CYP2E1 can be decreased by variety of environmental factors such as liver cirrhosis, chronic alcohol abuse and so on.
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POSTOPERATIVE NAUSEA AND VOMITING – It has been noticed that about 10 percent of patients experience nausea and vomiting post-operatively having no risk factors like  use of postoperative narcotics, history of motion sickness and female sex etc. and they constitute a group having genetic polymorphisms in CYP2D6 enzymatic action. Ondansetron, palonosetron, ,  dolasetron and granisetron are used as antiemetics and they are classed as  serotonin receptor antagonists which works by binding to the serotonin receptor located centrally in the chemoreceptor trigger zone and peripherally at the vagus nerve terminals. All are metabolised through the CYP2D6 iso-enzyme. Genetic polymorphisms in CYP2D6 may lead to therapeutic failure in the case of ultrarapid metabolism if it is known that a person has quicker metabolism and would allow for dose adjustments or choosing another agent not metabolized by the isoenzyme CYP2D6. CYP3A4 is subject to inhibitors such as cimetidine, ketoconazole, and grapefruit juice, which leads to decreased action of CYP3A4 and subsequent increased drug efficacy.[10]
Other drugs relevant to Anesthesiologists to be affected by genetic polymorphism:

1. Beta- Blockers- The Arg389 receptor of the beta-1-adrenergic receptor confers an increases sensitivity to pharmacological beta-blockade and  the Gly389 receptor results in a hypofunctional response as if it were already beta-blocked. Therefore, this apparent increased beta-1-adrenergic tone in individuals with Arg389 may represent an opportunity to use beta-blockers with a greater impact in diseases responsive to anti-adrenergic therapy. Individual genetic association studies have examined the association between the two common SNPs of ADRB1 and resting haemodynamics and hypertension as potential causal genes. However so far no conclusive evidence is forthcoming and how it is going to change our use of this important peri-operative drug has to be seen.[11]
2. Warfarin- Iso-enzyme CYP2C9 is almost exclusively responsible for the metabolism  of the pharmacologically more active form of warfarin . The CYP2C9 genotype explains approximately 10% of the observed variability in the therapeutic warfarin dose and VKORC1 polymorphisms account for approximately 30% of the variance in stabilized warfarin dose. Both the enzymes responsible for its metabolism, CYP2C9,and  Vitamin K epoxide reductase complex 1 (VKORC1) involves pharmacogenomics and various genetic polymorphism can disturb the normal pathway. In addition, VKORC1 contributes to a greater variability in dose response in Caucasians compared with Black individuals and Asians . The CYP4F2 gene has also been associated with warfarin dosing as  combination of CYP2C9, VKORC1 and CYP4F2 genotyping should allow to predict warfarin dosing. [12]
3. Clopidogrel :- Clopidogrel is metabolised in parts by the enzyme CYP2C19 to achieve its antiplatelet activity. CYP2C19*1 is the wild-type genotype and results in a normal metabolic function. CYP2C19*2 and CYP2C19*3 are two common ‘loss-of-function’ alleles that result in poor metabolism. Known ethnic differences in allele distribution account for differences in clinical outcomes with clopidogrel therapy. [13]

Future of Personalized Drug therapy in Anesthesiology:
So far what we have seen in the field of pharmaco-genomics in relation to anesthesiology and pain therapy is a tip of iceberg as millions of projects are underway to determine the genetic- profiling, polymorphism and their implications on the personal genetic architecture of individuals. This will certainly entails our future anesthesiologist to keep themselves updated in this field and help in the targeted population with individual dose variations and avoiding over dosage or toxic complications accordingly. Legal and ethical issues will erupt and financial aspect will override these considerations but future remains not that elusive as it was 50 years back when it all started. Personalized medication with the help of advanced genetic engineering technologies might look like fantasy at present  but not impossible in future. It is anticipated that, over the next decade, the Human Genome Project, coupled with DNA array technology, high-throughput screening systems and advanced bioinformatics, will permit rapid elucidation of complex genetic components of human health and disease.[14]
References
1. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 1999;286:487–491. 10.1126/science.286.5439.487. [PubMed]
2.Allen PD. Anesthesia and the human genome project: the quest for accurate prediction of drug responses. Anesthesiology 2005; 102: 494–5.
3.Ama T, Bounmythavong S, Blaze J, et al. Implications of pharmacogenomics for anesthesia providers. American Association of Nurse Anesthetists Journal 2010; 78: 393–9.
4. Iohom G, Fitzgerald D, Cunningham AJ. Principles of pharmacogenetics: implications for the anaesthetist. Br J Anaesth.      2004;93(3):440-450.
5. Yamakura T, Bertaccini E, Trudell JR, Harris RA. Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23–51
6. James MFM, Hilt RJ. Porphyrias. Br. J. Anaesth, 2000, 85:143-153
7.  Landau R, Kern C, Columb MO, Smiley RM, Blouin JL. Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women. Pain. 2008;139:5–14
8. K Hogan. Pharmacogenetics of nitrous oxide: standing at the crossroads. Anesthesiology; Volume 109: 5–6 (2008).
9-. Marzilawati AR, Ngau YY and Mahadeva S. Low rates of hepatotoxicity among Asian patients with paracetamol overdose: a review of 1024 cases. BMC Pharmacol Toxicol 2012; 13(1): 8.
10-. Ho KY, Gan TJ. Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol. 2006;19(6):606-611.
11- Metra M, Covolo L, Pezzali N, et al. Role of b-adrenergic receptor gene polymorphisms in the long-term effects of b-blockade with carvedilol in patients with chronic heart failure. Cardiovascular . Drugs Therapeutics 2010; 24: 49–60.
12- Limdi NA, Wadelius M, Cavallari L, et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood 2010; 115: 3827–34.
13. Sofi F, Giusti B, Marcucci R, et al. Cytochrome P450 2C19(*)2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics Journal 2011; 11: 199–206.
14- Puri A (2012) Pharmacogenetics Variations in Anesthesia. J Anesth Clin Res 3:233.