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 - 1

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 2

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 3

4. ONSET AND DURATION OF RESPONSE Lecture #18 4

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

6. Equation of a Line 6 x y x y m m

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

8. Pharmacokinetics Rate-Limiting 8 slope = m

9. Pharmacokinetics Rate-Limiting 9 -slope = -k ln([Drug]) 0.1 1 10

10. Pharmacokinetics is Rate-Limiting 10 slope = m

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

12. Example: Pharmacokinetics Rate- Limiting 1.Injection 2.Twitch Suppression 3.Complete twitch suppression 4.20% recovery 5.50% recovery 6.80% recovery succinylcholine Paralysis 12

13. Pharmacodynamics Rate-Limiting cyclooxygenase thromboxane synthetase prostacyclin synthetase 13

14. Pharmacodynamics Rate Limiting 14

15. Pharmacokinetics or Pharmacodynamics Rate-Limiting? 15 t 1/2 =15 hours t 1/2 =2 weeks

16. 16 time [drug] plasma

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

18. 18 time [drug] plasma C min tdtd 0 20% of the maximum response MEC

19. Duration of Effect 19

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

21. Duration of Effect Increases by One Half Life for Each Doubling of Dose 21 0.5 1.0 2.0 4.0

22. LD 50 22 DrugLD 50 Ro15-4513 (Sobriety)100 mg/kg Caffeine127 mg/kg Sugar (Glucose)30 g/kg Water90 g/kg Acetaminophen2 g/kg Polonium-21010 ng/kg Capsaicin (Hot sauce)47 mg/kg Ethanol7 g/kg Nicotine0.75 mg/kg Midazolam (GABA A Agonist)50 mg/kg Flumazenil (GABA A Antagonist)4.2 g/kg

23. Duration of Effect Dose = 50 mg IV V (normalized)=1.1 L/kg Cl h (normalized)=0.8 L/(hr*kg) ED 50 (normalized)=0.35 mg/kg LD 50 (normalized, mouse IV)=100 mg/kg Ro15-4513 23