To Study the Pharmacokinetic and Cardiovascular Effects of Propofol With Respect to Pharmacogenetics in Pakistani Population
Condition: Healthy Volunteer
Study type: Observational

Summary: 
      This study aimed to determine the effects of genetic variabilities among the Pakistani
      population on propofol serum concentration and its adverse effects mainly cardiovascular
      adverse effects. cardiovascular adverse effects are the main concern for the anesthetists, if
      a person is genetically more prone to these adverse effects it can be lethal for that.
    

Detailed description: 
      Propofol is a phenolic byproduct, available as an oil-in-water intravenous emulsion for
      calming and mesmerizing purposes. It is among the most widely used intravenous soporific
      drugs that are used for induction and maintenance of general anesthesia, procedural calmness,
      and to gain tranquility in ICU patients. Advantages of propofol include easy control of the
      depth of anesthesia, rapid recovery of consciousness, and less postoperative nausea and
      vomiting. Due to these characteristics, propofol has turned out to be the standard agent for
      induction of anesthesia. Although it is safe, it doesn't mean that it is devoid of any
      adverse effects. Important adverse effects of propofol include cardiovascular effects, mild
      respiratory depression, bronchospasm in patients with reactive airways, pain on the injection
      site, and rarely myoclonus. The most common cardiovascular effects are hypotension and
      bradycardia. These cardiovascular effects are produced by propofol-induced suppression of
      sympathetic activity, inhibitory effects on the baroreceptor reflex, stimulation of nitric
      oxide-mediated vasodilation, and blockage of voltage-gated sodium and potassium channel.

      However, in clinical practice, a large inter-individual variability is observed in response
      to this anesthetic. Concerning the effectiveness, standard dose, and harmful drug responses
      of propofol, genetic variations have been appraised to add about 20%-30% to this variability
      and it is due to variations in allele frequencies. These genotype frequencies have been
      studied in many racial populations and they were found to be correlated with variation in
      drug responses. Most of these studies have been practiced determining the pharmacogenetic
      information for better pharmaceutical care, by preventing therapeutic collapse or critical
      adverse reactions in a population linked to this genetic variability. These inter-individual
      differences in genotype frequencies affect the efficiency of enzymes that are required for
      the metabolism of propofol. This change in the metabolic rate of this drug necessitates the
      modifications in the optimum dose required for effective general anesthesia with minimum
      adverse effects.

      Propofol is primarily metabolized in the liver by cytochrome P450 2B6 (CYP2B6), cytochrome
      P450 2C9 (CYP2C9), and by UDP-glucuronosyltransferase 1A9 (UGT1A9). It is suggested that
      single nucleotide polymorphisms in the genes coding for these enzymes can be accountable for
      the inter-individual variations of propofol response. This can lead to unpredictable effects
      even with the recommended doses of propofol. The most common functionally deficient allele is
      CYP2B6*6 (c.516) G>T rs3745274 and (c.785) A>G rs2279343), which occurs at frequencies of 15
      to over 60% in different populations. These alleles are accountable for the low CYP2B6
      expression phenotype and are found to be associated with enhanced plasma levels of propofol.
      For the CYP2C9 gene, more than sixty-five haplotypes have been described, but in global
      studies, only two non-synonymous changes, (c.430C>T, rs1799853, CYP2C9*2) and (c.1075A>C,
      rs1057910, CYP2C9*3) are intensively analyzed. These two are found to be associated with low
      enzymatic activity and so raised serum levels of propofol.

      Concerning the Pakistani population, the prevalence of variant allele c.785A>G, rs2279343 is
      48% and 36% of c.516G>T, rs3745274 allele. These two alleles are linked with decreased
      activity of the CYP2B6 enzyme. The frequent alleles of CYP2C9 in Pakistani population are
      c.1075A>C, rs1057910 and rs1799853, c.430C > T, their frequencies are 10% & 7% respectively.
      Genetic testing suggested that around 30% Pakistani population has some level of compromised
      CYP2C9 function. So, the individuals with these genetic polymorphisms need modification in
      the induction and maintenance dose of the propofol because in normal doses the slow
      metabolism of propofol can lead to more intense cardiovascular effects and other adverse
      effects produced by the propofol. The effect of these variant alleles on propofol
      pharmacokinetics and adverse effect profile is not studied to date in the Pakistani
      population, so this study will verify this. Awareness of the consequences of important
      changes in the CYP2B6 and CYP2C9 genes in propofol metabolism would make it possible to
      increase the safety of patients undergoing general intravenous anesthesia.
    

Intervention name(s): Propofol Injection
Intervention type(s): Drug
Intervention description(s): propofol injections were used for the induction of anesthesia according to the body weight of the patients.
Intervention MeSH terms: Propofol
Observational model: Case-Only
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        study population contained patients of Pakistani origin.
      
Keywords: Pakistani population, Propofol serum concentration, adverse effects.