The Entry, Distribution, and Elimination of Drugs Duration of Drug Action after Single Doses First Order Elimination

For a 1st order elimination, the duration of a therapeutically effective drug concentration increases as the logarithm of the amount of drug in the body fluids

- Duration of action increases as the logarithm of the dose - Fig 4-6

Pharmacodynamics: Role of Drug Distribution and Tissue Responsiveness

- Many factors may modify the relation between plasma drug concentration and responses o Lack of rapid equilibration of drug in plasma with target tissue o A drugs action may be briefer than its presence in the blood or it may far outlast it. Bactericidal drugs, alkylating agents [after producing their irreversible chemical effects] quick destruction Organophosphate cholinesterase agents degraded rapidly buteffects last till new enzyme is synthesized

Drug concentration in plasma and tissue: Multicompartment Kinetics

- A drug entering the plasma is expected to distribute evenly in blood and well perfused tissues in a few minutes [CO = 5L/min, ~6L vol]

- The movement of a drug from blood to other tissues can significantly affect time course and extent of drug action o Eg, complete exclusion of certain drugs by the BBB o Slow diffusion in extracellular space o Low blood flow [poorly perfused tissues resting muscle, fat, and skin] - Fig 4-18

Two-compartment model
- In this model, the drug is considered to be in one of two pools or compartments
-

Drug is administered into the central compartment X1 considered to include blood and highly perfused tissues heart, brain, kidney X2 Tissue fluid or poorly perfused tissues

- Fig 4-19

Site of Drug Action: Effect Compartment

The time required for equilibrium of a drug between the central and peripheral compartments can vary greatly Atracurium [t1/2 for distribution = 2 mins] Digoxin [t1/2 for distribution = 35 mins] Amiodarone [t1/2 for distribution = many hours]

Site of Drug Action: Effect Compartment - If the receptors responsible for the drug effect are in equilibrium with
drug in the central compartment, the effect will peak rapidly and decline in a manner similar to the plasma drug concentration. - If the receptors are in equilibrium with drug in the peripheral compartment, there would be an expected delay in the onset of response - Eg: Digoxin plasma levels rise and fall rapidly, but the effect takes hours to develop - The response follows the time course calculated for the tissue compartment - Fig 4-20 - Eg: Lidocaine both the toxic effects on the CNS and the cardiac electrophysiological effects correlate best with the concentration of drug in the central compartment - For different drugs [digoxin and lidocaine], even though they are affecting the same tissue [the heart], the receptors may appear to be in equilibrium with either the peripheral or central compartment

- Effect compartment - Eg: Synthetic opiates fentanyl and alfentanil given to supplement nitrous oxide anesthesia - In contrast to digoxin, the delay in the onset of opiate response cannot be related to the time course of bulk tissue distribution - Distribution of fentanyl [t1/2 = 4.5 minutes] is slightly faster than the onset of response [t1/2 = 6.4 minutes]. For alfentanil [t1/2 = 6.2 minutes] is slower than the response [t1/2 = 1.1 minutes]

This can be explained by postulating that the entry of alfentanil into the target site [effect compartment] is faster than that of fentanyl even though both are distributed with similar kinetics into peripheral tissue

- Differences unlikely to be due to slow activation of receptors since both drugs have a rapid onset of action in vitro.

Nonlinear Concentration Effect Relations

- The magnitude of the response in relation to the concentration of the drug at the site of action. - Hyperbolic curve Eg; Fig 4-22 for theophylline Saturation of forced expiratory volume at higher concentrations

In the saturation range [x > EC80], very large changes in drug concentration result in only small changes in response. Eg: A 5 In the middle range of concentrations [EC80 > x > EC20] exponentially decreasing drug concentration results in a nearly linear decrease in response fold decrease in concentration [20xEC50 to 4xEC50] reduces the response only 15 % [from 95% to 80 %]

At lowest concentrations [EC20 > x] the response is a linear function of drug concentration

- For drugs with large therapeutic indices, effects of long duration can be achieved despite short elimination half-times, if doses in the saturation range are given. - Fig 4-23 A drug with a 2-hour elimination half-time may have an effective half-time of 10 hours if doses that produce 95 % response may be tolerated.

FINAL EXAM DATE: TUESDAY, MAY 14 PLACE: HCH [Hall behind the Bookstore] TIME: 6 PM

MATERIAL FROM TEXTBOOK: Pages 201 265, 277 288 Pages 297 308, 335 342