Sober Action potential GABA Cl K and Cl

Sober Action potential GABA +++++-----+++++++ -----+++++-------Cl- K+ and Cl. Na+or K+ Neuron Glutamate (Glu) GABA A receptor (Ligand-gated Ion Channel) Glutamate receptor (Ligand-gated Ion Channel) KCC 2 (K+/Cl- symporter) (a. k. a. SLC 12 A 5) Na+ and K+ Voltage-Gated Ion Transporter 1

Drunk Action potential GABA ethanol ++++++++++++ ------------Cl- K+ and Cl. Na+or K+ Neuron Glutamate (Glu) GABA A receptor (Ligand-gated Ion Channel) Glutamate receptor (Ligand-gated Ion Channel) KCC 2 (K+/Cl- symporter) (a. k. a. SLC 12 A 5) Na+ and K+ Voltage-Gated Ion Transporter 2

Ro 15 -4513 Action potential GABA +++++-----+++++++ -----+++++-------Cl- K+ and Cl. Na+or K+ Ro 15 -4513 Glutamate (Glu) Neuron GABA A receptor (Ligand-gated Ion Channel) Glutamate receptor (Ligand-gated Ion Channel) KCC 2 (K+/Cl- symporter) (a. k. a. SLC 12 A 5) Na+ and K+ Voltage-Gated Ion Transporter 3

Lecture #18 ONSET AND DURATION OF RESPONSE 4

Rate Limitation of a Response • Pharmacokinetics Rate-limiting – Response sensitive to [drug]plasma • Pharmacodynamics Rate-limiting – Response not sensitive to [drug]plasma 5

Equation of a Line m y x y m x 6

Pharmacokinetics is Rate-Limiting • Region 1 -0 -20% • Region 2 -20 -80% • Region 3 -80%-100% 7

Pharmacokinetics Rate-Limiting slope = m 8

Pharmacokinetics Rate-Limiting ln([Drug]) 10 -slope = -k 1 0. 1 9

Pharmacokinetics is Rate-Limiting slope = m 10

Pharmacokinetics Rate-Limiting Pharmacokinetics Pharmacodynamics m Effect increases linearly between 80% and 20% 11

Example: Pharmacokinetics Rate. Limiting 1. 2. 3. 4. 5. 6. Injection Twitch Suppression Complete twitch suppression 20% recovery 50% recovery 80% recovery Paralysis succinylcholine 12

Pharmacodynamics Rate-Limiting cyclooxygenase thromboxane synthetase prostacyclin synthetase 13

Pharmacodynamics Rate Limiting 14

Pharmacokinetics or Pharmacodynamics Rate-Limiting? Pharmacodynamics (PD) Pharmacokinetics (PK) t 1/2=2 weeks t 1/2=6 days t 1/2=15 hours t 1/2=8 hours 15

time 16 [drug]plasma

MED and MEC • Minimum Effective Dose (MED) and Concentration (MEC) [Drug] ADR 17

[drug]plasma X Cmin 0 td • 20% of the maximum response • MEC time 18

Duration of Effect 19

Duration of Effect Increases by One Half Life for Each Doubling of Dose 32 16 Amin 8 4 2 20

Duration of Effect Increases by One Half Life for Each Doubling of Dose 4. 0 2. 0 1. 0 0. 5 Assuming pharmacokinetic rate limitation 21

LD 50 Drug LD 50 Ro 15 -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 22

Duration of Effect • • • Dose = 50 mg IV V (normalized)=1. 1 L/kg Ro 15 -4513 Clh(normalized)=0. 8 L/(hr*kg) ED 50(normalized)=0. 35 mg/kg LD 50(normalized, mouse IV)=100 mg/kg 23