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Pharmacogenomics

Pharmacogenomics =. + IPO. Pharmacogenomics. Pharmacogenetics. SNPs (single nucleotide polymorphisms) occur once every 100- 300 nucleotides SNPS can have profound effects on drug responses. Single nucleotide polymorphisms in the ß2-adrenergic receptor.

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Pharmacogenomics

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  1. Pharmacogenomics = + IPO Pharmacogenomics Pharmacogenetics SNPs (single nucleotide polymorphisms) occur once every 100- 300 nucleotides SNPS can have profound effects on drug responses

  2. Single nucleotide polymorphisms in the ß2-adrenergic receptor At least 13 SNPs identified in the human ß2-adrenergic receptor gene Amino acid # 16: Arg homozygotes: 15% Gly homozygotes: 45% ß2-AdR with Gly16 shows greatly increased agonist-induced down-regulation Amino acid #164: Thr homozygotes: 97% Thr/Ile heterozygotes: 3% ß2-AdR with Ile164 shows greatly reduced functional activity

  3. Gly16 SNP causes decreased sensitivity to albuterol 16 12 Arg16 homozygotes 8 % Increase in FEV1 4 Gly16 homozygotes 0 0 4 8 12 Time (Hours)

  4. Gly16 SNP causes increased desensitization to ß2 agonist Asthma patients given placebo or ß2 agonist bid for 4 weeks (and then crossed-over) Compare ß2-mediated bronchodilation after placebo treatment and after long-term agonist treatment: -Arg 16 homozygotes: no decrease in agonist-induced bronchodilation after 4 weeks agonist treatment -Gly16 homozygotes: big (46%) decrease in agonist- induced bronchodilation after 4 weeks agonist treatment

  5. Single nucleotide polymorphisms in the ß2-adrenergic receptor At least 13 SNPs identified in the human ß2-adrenergic receptor gene Amino acid # 16: Arg homozygotes: 15% Gly homozygotes: 45% ß2-AdR with Gly16 shows greatly increased agonist-induced down-regulation Amino acid #164: Thr homozygotes: 97% Thr/Ile heterozygotes: 3% ß2-AdR with Ile164 shows greatly reduced functional activity

  6. One crummy amino acid in the ß2 adrenergic receptor makes a big difference in CHF patients 1.0 Thr 164 0.8 (n= 247) 0.6 Proportion Surviving Ile164 0.4 (n= 10) 0.2 (p < 0.001) 0.0 200 0 100 300 400 Days in study

  7. Polymorphism in 2C-AdR affects function Deletion of AA#322- 325Del322-325 has decreased coupling to Gi and decreased inhibition of NE release Deletion associated associated with five-fold increase in incidence of heart failure

  8. Polymorphism in ß1-AdR affects function Arg389: 55-75%; Gly389: 25-45% Arg389 has increased coupling to Gs and functional responsiveness Arg389 exhibited 2.3-fold greater decrease in IOP in response to ß-blocker treatment after 6 weeks

  9. Polymorphisms can interact synergistically ß1 (Arg389)-AdR: no increase in incidence of heart failure a2c(Del322-325):five-fold higher incidence of heart failure Both polymorphisms: 10- fold higher incidence of heart failure

  10. Orthostatic Intolerance/Postural Tachycardia Syndrome -Volatile heart rate and blood pressure -Tachycardia, especially when standing -Increased levels of plasma NE, especially when standing -Due to an inactivating point mutation in NE transporter WT HET WT HET WT HET WT HET

  11. Now- Some Oldies But Goodies

  12. DA NE EPI ISO (0.5 µg/min) (10 µg/min) (10 µg/min) (10 µg/min) 100 Pulse rate 50 180 BP (mm. Hg) 120 60 Peripheral Resistance 15 min 15 min 15 min 15 min Slow IV administration in humans

  13. Beta- Adrenergic Receptors Mediate Positive Chronotropic Effect 80 Isoproterenol Norepinephrine 60 40 Change in HR. BPM 20 0 Dose, µg/kg 0.1 100 0. 01 0.001 1 10

  14. BP HR + DMPP + McN-A-343 +Hexamethonium: BP HR + DMPP + McN-A-343 Effect of Ganglionic Stimulants

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