1. Pharmacogenetic; pharmacogenomic Dr. DATTEN BANGUN MSc,SpFK Dept. of Pharmacology and Therapeutic, School of Medicine, Universitas Sumatera Utara, Medan, Indonesia

2. Rx +  = Rx +  =  ???? 

3. Rx +  =  Differences in genetic constitution Rx +  = 

4. Pharmacogenetics and pharmacogenomics  Pharmacogenetics: the effect of genetic variation on drug response, including: –disposition –safety and tolerability, and –Efficacy  Pharmacogenomics : the application of genome science (genomics) to study of human variability in drug response.

5. Key Concepts and Terms Monogenic: due to allelic variation at a single gene Polygenic: due to variations at two or more genes Polymorphic: frequently occurring monogenic variants occurring at a frequency >1%

6. Monogenic vs. Gaussian Variations Monogenic All-or-none function in affected gene Mendelian inheritance Examples: Sickle cell, CYP2D6, Cystic fibrosis, Rb Gaussian or polygenic Function of affection gene shows a range that is defined by ED50 Multiple gene variation involved Accounts for majority of variations in drug responses Disease Susceptibility Alzheimer’s disease ApoE4, ApoE2 (19q13), 12q

7. Normal Distribution Frequency Activity Contoh: -Berat badan -Tinggi badan Banyak faktor mempengaruhi

8. Polymorphic Distribution From Pratt WB,Taylor P. Fig 7-5b

9. GENETIC POLYMORPHISMS PharmacokineticPharmacodynamic Transporters Plasma protein binding Metabolism Receptors Ion channels Enzymes Immune molecules

10. Genomic organization: chromosomes Every human cell with the exception of gametes contains 23 pairs of chromosomes,plus 1 pair sex-chromosome

11. Genomic organization: chromosomes structure  Chromosomes carry all of the genetic material coding for all the proteins in every cell  Chromosomes consist of DNA tightly wound around special protein structures called histones.

12. Structure of genes A segment of DNA containing all of the information needed to encode for one protein is called gene. The order and sequence of the base pairs in a gene determine which protein is made.

13. Transcription of genes  The transcription of DNA into messenger RNA is often assembled from discontinuous sequences in the genome called exons, which are separated by sequences called introns.  This process is referred to as splicing. A genomic sequence can yield more than one splicing product.  Transcription can be controlled through regulatory sequences known as the promoter sequences

14. Putting it all together: translation into protein Translation into protein sequences is accomplished at ribosome

15. Mutations in the genome One in every 1200 bases may be different in any two humans. This variation, which is called a polymorphism, is largley responsible for differences between how humans respond to drugs. Several types of mutations are associated with these variations:

16. Mutations in the genome Mutations can also affect gene expression when they occur in regulatory or promoter sequences or in the exon/intron boundary.

17. A Single Nucleotide Polymorphism, or SNP (pronounced "snip") is a small genetic change, or variation, that can occur within a person's DNA sequence. A single base change found in 1% of an ethnically diverse population is defined as a SNP.. Although many SNPs do not produce physical changes in people, scientists believe that other SNPs may predispose a person to disease and even influence their response to a drug regimen. What are SNPs

18. SNP Profiles and Response to Drug Therapy Does Not Respond to Standard Drug Treatment Breast Cancer Patients Individual SNP Profiles Are Sorted SNP profile ASNP profile B SNP profile D SNP profile ESNP profile C Responds to Standard Drug Treatment

19. Genetic variations that can modify responses to drugs. 1.Variation in target proteins/target pathways. 2.Variation in enzymes 3.Variation in genes unrelated to no. 1 & 2  result in indiosyncratic (typically unpredictable).

20. Ad.1. Variation in target proteins

21. Ad.2. Variation in enzymes in metabolism

22. Ad.2 Contoh : -INH -Succinylcholine -Acatalasia -Atropinesterase

23. Apa pengaruh genetik pada ensim acetylator? = 90 % Japanese Rapid acetylator = 50 % Western --------”--------- = Inuit (Arctic ) -----  rapid ---------  makin ke equator makin sedikit yang rapid (fast ) acetylator. Rapid acetylator===  hepatotoxic Slow acetylator ===  neuritis--  Indonesia INH=Isoniazid; 0bat tbc, dimetaboliser dg proses asetilasi,ensimnya acetylator

24. Polymorphic Distribution From Pratt WB,Taylor P. Fig 7-5b

25. Succinylcholine; = dimetaboliser dg bantuan ensim pseudo- choline-esterase Pada beberapa keluarga: - terdapat kekurangan ensim pseudocholine esterase ini,shg bisa terjadi paralisa pernafasan bila diberi succinylcholine-----  HATI-HATI !!! Family studies indicate variability in plasma cholinesterase activity consistent with 2 allelic, autosomal, codominant genes

26. peroxidase ( katalase) Acatalasia: = peroxid (H2O2)======== H2O + On (timbul buih/bubble) Bila tak ada katalase-----  akatalasia

27. Ad.2 Sex – linked 1.G 6 PD deficiency  affected older red cells. ~Primaquine ~Acetanilid ~Phenacetin ~Sulfonamide  haemolytic -Affected X – chromosome ~Male xy, female xx

28. Drugs and Chemicals Unequivocally Demonstrated to Precipitate Hemolytic Anemia in Subjects with G6PD Deficiency AcetanilideNitrofurantoinPrimaquine Methylene BlueSulfacetamideNalidixic Acid NaphthaleneSulfanilamideSulfapyridine Sulfamethoxazole

29. Ad.2 Ex. FemaleMale I.F 1 x x xy F 2 x x x y xx xy II. Warfarin resistance Receptor sensitivity berkurang

30. INCIDENCE OF G6PD DEFICIENCY IN DIFFERENT ETHNIC POPULATIONS Ethnic GroupIncidence(%) Ashkenazic Jews0.4 Sephardic Jews Kurds53 Iraq24 Persia15 Cochin10 Yemen 5 North Africa<4 Iranians8 Greeks0.7-3 Asiatics Chinese 2 Filipinos13 Indians-Parsees16 Javanese13 Micronesians<1

31. Some heritable conditions causing decreased drug responses: = Resistance to coumarin anticoagulant = Resistance to heparin = Resistance to vitamin D = Bacterial resistance to drugs: -genetically determined -of great clinical importance

32. Pharmacogenetics in Clinical Practice: Why, What and How?

33. Patient Response to Medicine Varies “One size does not fit all …” “I have hypertension which is not being controlled. My doctor prescribes a drug for hypertension, we wait 3-4 months to find it’s not working and then try another one. In 18 months, I’ve tried 6 new medications and I’m fast losing confidence in this hit or miss approach and in my physician ”.

34. Medicines are not Safe or Effective in all Patients Pharmacogenetics: To deliver: To deliver: ‘ the right medicine,in the right dose, to the right patient’ ‘ the right medicine,in the right dose, to the right patient’

35. Summary Pharmacogenetics has and will continue to provide novel insight into drug development and prescribing. Effective implementation in clinical practice may prove challenging. Each application should be explored on a case by case basis. Partnership with healthcare providers and recipients are vital. Pharmacogenetic Goal: Help healthcare providers select more accurately the medicines most likely to help, and least likely to cause serious side effects for patients.

36. Pharmacogenetics: Practice of medicine “If it were not for the great variability among individuals,Medicine might as well be a science and not an art.” Sir William Osler, 1892