sober +++++-----++++++++++++++ -----+++++-------------- neuron cl - na + or k + gaba a receptor...
TRANSCRIPT
1
Sober
+++++-----++++++++++++++-----+++++--------------
Neuron
Cl-
Na+or K+
GABA A receptor (Ligand-gated Ion Channel)
GABA
Glutamate (Glu)
Action potential
Glutamate receptor (Ligand-gated Ion Channel)
KCC2 (K+/Cl- symporter) (a.k.a. SLC12A5)
Na+ and K+ Voltage-Gated Ion Transporter
Na+or K+
GABA
K+ and Cl-
2
Drunk
++++++++++++++++++++++++------------------------
Neuron
Cl-
Na+or K+
GABA A receptor (Ligand-gated Ion Channel)
GABA
Glutamate (Glu)
Action potential
Glutamate receptor (Ligand-gated Ion Channel)
KCC2 (K+/Cl- symporter) (a.k.a. SLC12A5)
Na+ and K+ Voltage-Gated Ion Transporter
Na+or K+
GABA
K+ and Cl-ethanol
3
Ro15-4513
+++++-----++++++++++++++-----+++++--------------
Neuron
Cl-
Na+or K+
GABA A receptor (Ligand-gated Ion Channel)
GABA
Glutamate (Glu)
Action potential
Glutamate receptor (Ligand-gated Ion Channel)
KCC2 (K+/Cl- symporter) (a.k.a. SLC12A5)
Na+ and K+ Voltage-Gated Ion Transporter
Na+or K+
GABA
K+ and Cl-
Ro15-4513
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ONSET AND DURATION OF RESPONSE
Lecture #18
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Rate Limitation of a Response
• Pharmacokinetics Rate-limiting– Response sensitive to [drug]plasma
• Pharmacodynamics Rate-limiting– Response not sensitive to [drug]plasma
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Equation of a Line
x
y
x
ym m
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Pharmacokinetics is Rate-Limiting
• Region 1-0-20% • Region 2-20-80%• Region 3-80%-100%
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Pharmacokinetics Rate-Limiting
slope = m
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Pharmacokinetics Rate-Limiting
-slope = -k
ln([D
rug]
)
0.1
1
10
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Pharmacokinetics is Rate-Limiting
slope = m
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Pharmacokinetics Rate-Limiting
m Effect decreases linearly between 80% and 20%
Pharmacokinetics Pharmacodynamics
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Example: Pharmacokinetics Rate-Limiting
1. Injection2. Twitch Suppression3. Complete twitch suppression4. 20% recovery5. 50% recovery6. 80% recovery
succinylcholine
Paralysis
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Pharmacodynamics Rate-Limiting
cyclooxygenase
thromboxanesynthetase
prostacyclinsynthetase
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Pharmacodynamics Rate Limiting
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Pharmacokinetics or Pharmacodynamics Rate-Limiting?
t1/2=15 hours
t1/2=2 weeks
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time
[dru
g]pl
asm
a
MED and MEC• Minimum Effective Dose (MED) and Concentration (MEC)
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ADR[Drug]
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time
[dru
g]pl
asm
a
Cmin
td
0
• 20% of the maximum response• MEC
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Duration of Effect
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Duration of Effect Increases by One Half Life for Each Doubling of Dose
A min
2
4
8
16
32
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Duration of Effect Increases by One Half Life for Each Doubling of Dose
0.5
1.0
2.0
4.0
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LD50
Drug LD50
Ro15-4513 (Sobriety) 100 mg/kg
Caffeine 127 mg/kg
Sugar (Glucose) 30 g/kg
Water 90 g/kg
Acetaminophen 2 g/kg
Polonium-210 10 ng/kg
Capsaicin (Hot sauce) 47 mg/kg
Ethanol 7 g/kg
Nicotine 0.75 mg/kg
Midazolam (GABAA Agonist) 50 mg/kg
Flumazenil (GABAA Antagonist) 4.2 g/kg
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Duration of Effect
• Dose = 50 mg IV• V (normalized)=1.1 L/kg
• Clh(normalized)=0.8 L/(hr*kg)
• ED50(normalized)=0.35 mg/kg
• LD50(normalized, mouse IV)=100 mg/kg
Ro15-4513