pharmacodynamics

Question 1

Physiologic receptor mechanisms vs non-physiologic receptor mechanisms.

Answer 1

Physiologic mechanisms have an endogenous signal that a drug can mimic (agonist) or block (antagonist). Non-physiologic mechanisms do not have endogenous signals. Drugs operate by otherwise disrupting a physiologic process.

Question 2

What is the difference between receptor and non-receptor mechanisms of drug action.

Answer 2

non-receptor mechanisms have direct physical or chemical effects on physiology (eg antacids that increase pH of stomach). Receptor mechanisms bind to endogenous receptors to induce or block effects.

Question 3

What is the quantitative dose-response relationship for receptor binding (basic binding equation)?

Answer 3

([DR]/Rt)=([D]/[D]+Kd) where Kd is the ratio k2/k1 (rate of dissociation/rate of association).

Question 4

Kd

Answer 4

the concentration of drug at which half of target receptors are bound. Analagous to Km in enzyme kinetics, a drug with a low Kd will have high affinity for receptor, and a drug with a high Kd will have a low affinity.

Question 5

Potency

Answer 5

Kd in a dose-response plot. Response can be biochemical/ionic (2nd messenger at cellular level), physiologic (effect at level of tissue/organ), or integrated body response AS LONG AS IT IS CONTINUOUS.

Question 6

Efficacy

Answer 6

The theoretical maximum effect that a drug can have (asymptote of continuous dose-response curve). Analagous to Vmax in enzyme kinetics.

Question 7

What type of drugs effect can be overcome by increasing the concentration of the endogenous substance.

Answer 7

A competitive antagonist. They decrease potency of the endogenous substance (or another drug) (increase Km).

Question 8

The effect of this type of drug cannot be overcome by increasing the amount of the endogenous substance.

Answer 8

Non-competitive antagonist. These decrease the efficacy (Vmax) without affecting the potency (Kd) of the endogenous substance or other drug.

Question 9

Graded vs quantal studies.

Answer 9

Graded studies are done in vitro usually. They measure the effect of a drug on a specific tissue or receptor with a continuous response variable. Quantal studies use a dichotomous outcome on a population of individuals (or animals). Give different groups of animals different doses and then plot the cumulative proportion protected (y) vs the log dose (x). Note that quantal studies only measure potency (not efficacy).

Question 10

Effective mean dose (ED50)

Answer 10

Dose at which the cumulative proportion of study participants with the outcome = 50%. It is analagous to Kd in graded response studies and is a measure of drug POTENCY.

Question 11

Therapeutic index (safety margin)

Answer 11

TD50/ED50 where TD50= toxic dose OR LD50, lethal dose.

Question 12

How can a difference in slopes of effective dose and lethal dose curves be interpreted?

Answer 12

It suggests that the mechanism by which a drug is lethal is different (different receptor target) than the principle drug effect.

Question 13

When does drug receptor supersensitivity occur?

Answer 13

After chronic use of a receptor antagonist, more receptor or more endogenous agonist (or both) are typically produced. Once antagonist is stopped, pt is supersensitive to the agonist.

Question 14

Tachyphylaxis

Answer 14

Stimulation of a receptor over time can produce a decreased response. If that response occurs in seconds to minutes, it is tachyphylaxis.

Question 15

Tolerance

Answer 15

desensitization to a drug that takes hours to days to develop.

Question 16

Clearance

Answer 16

the rate of elimination relative to it’s plasma concentration:
=rate of elimination (in ug/min)/conc. (in ug/mL)-

Gives units of mL/min

Question 17

t(1/2)=

Answer 17

The time it takes for the plasma concentration of a drug to be reduced by half. It is related to the elimination constant (Ke) by the equation: t(1/2)=0.7/Ke

It is also related to Vd and Cl by the equation:
t(1/2)=(0.7 x Vd)/Cl

Question 18

How do you find C(0)?

Answer 18

Concentration at time 0 if the drug were distributed instantly. Make a plot of log plasma concentration vs. time, then extrapolate the linear portion to the Y axis (where t=0). That is C0.

Question 19

Ke

Answer 19

Constant of elimination. If elimination is plotted on ln scale, then the slope of the straight line =-Ke.

If it is plotted on normal semilog (log10) paper, the conversion is -Ke/2.303

Question 20

How long does it take to completely eliminate a drug from the body?

Answer 20

About 5 x t(1/2) = 95% elimination.

Question 21

What happens when you deliver a drug by infusion? What does increasing the infusion rate do?

Answer 21

It will accumulate until it reaches a steady state (which takes about 5 half-lives). The actual plasma concentration that corresponds to the steady state depends on the infusion rate!

Increasing the infusion rate will increase the plasma concentration of the steady state (proportionally…double the dose, double the [SS], but will not change the time required to reach steady state.

By 1 half life in, half of steady state concentration will be reached.

Question 22

Vd=

Answer 22

dose (mg)/C(0)

Where C(0)= concentration at time 0 if all drug distributed instantly (extrapolated from plot of log concentration vs time).

Question 23

What are some drugs eliminated by zero order kinetics?

Answer 23

Ethanol, aspirin, phenyltoin

Question 24

What does zero order kinetics mean, and what are the implications for drug administration?

Answer 24

The drug’s half life varies with plasma concentration because a constant amount is eliminated from plasma by unit time (all receptors are saturated). If repeat dosing or infusing, a steady state will never be reached.