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Pharmacogenomics
Pharmacogenomics = Pharmacogenetics + IPO
SNPs (single nucleotide polymorphisms) occur once every 100300 nucleotides
SNPS can have profound effects on drug responses
Single nucleotide polymorphisms in the ß2adrenergic 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
Gly16 SNP causes decreased sensitivity to albuterol
% Increase in FEV1
16
12
Arg16 homozygotes
8
4
Gly16 homozygotes
0
0
4
8
Time (Hours)
12
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 agonistinduced bronchodilation after 4 weeks agonist
treatment
Single nucleotide polymorphisms in the ß2adrenergic 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
One crummy amino acid in the ß2 adrenergic
receptor makes a big difference in CHF patients
Proportion Surviving
1.0
Thr 164
0.8
(n= 247)
0.6
Ile164
0.4
(n= 10)
0.2
(p < 0.001)
0.0
0
100
200 300
400
Days in study
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
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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
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Polymorphisms can interact synergistically
ß1 (Arg389)-AdR: no increase in incidence of heart failure
2c(Del322-325):five-fold higher incidence of heart failure
Both polymorphisms: 10- fold higher incidence of heart failure
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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
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WT HET
WT HET
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WT HET
NowSome Oldies But Goodies
Slow IV administration in humans
(10 µg/min)
EPI
(10 µg/min)
ISO
(10 µg/min)
DA
(0.5 µg/min)
100
50
180
120
60
Peripheral
Resistance
BP (mm. Hg) Pulse rate
NE
15 min
15 min
15 min
15 min
Beta- Adrenergic Receptors Mediate Positive Chronotropic Effect
80
Isoproterenol
Norepinephrine
60
40
20
0
0.001 0. 01 0.1
1
10
100 Dose, µg/kg
Effect of Ganglionic Stimulants
BP
HR
+ DMPP
+ Hexamethonium:
+ McN-A-343
BP
HR
+ DMPP
+ McN-A-343