PD Principles: Drug-Receptor Interactions and Dose Response Curves; Drug Accumulation and Effects

Question 1

Onset of action (effect):

Answer 1

• When MEC is reached
– MEC=Minimum effective conc.
– For desired response

Occurs after lag period, and before duration of action

Question 2

Duration of action:

Answer 2

Time MEC is maintained

Question 3

Safe dosing:

Answer 3

• Cp remains below toxic MEC

Question 4

Peak time/concentration:

Answer 4

Time to maximal response

Question 5

Therapeutic window:

Answer 5

Above therapeutic MEC & below MEC for adverse effects

– Does not mean no side effects

Question 6

Steady state (Css):

Answer 6

• Drug elimination = drug availability (F and/or dosing)
– Dosing interval = CL * Css

 Reached after 4 half-lives (t1/2) of drug

Question 7

Half-life affects drug accumulation (concept):

Answer 7

relationship between the dosing

interval and the rate of elimination for the drug

Question 8

Half-life affects drug accumulation (application):

Answer 8

• Accumulation Factor (AF) = (1/Fraction lost in 1 dosing interval) = (1/(1 – Fraction remaining))

• Dosing interval = t1/2 of drug
 steady state (AF = 2)

• Dosing interval 2)
• Dosing interval > t1/2 of drug

Question 9

True or False: Dosing frequency affects accumulation.

Answer 9

True

Question 10

Dosing every half-life causes:

Answer 10

• Significant accumulation
• Reaches steady-state after the fourth dose
• Peak and troughs are in therapeutic range

Question 11

Dosing every fourth half-life causes:

Answer 11

• Negligible accumulation

* Significant peaks and troughs

Question 12

Drug effect with respect to Cp changes; Immediate:

Answer 12

• Directly related to changes in plasma concentration
–  CP will result in decreased physiological response to drug

• Overcome by high initial concentration relative to EC50
– Example: enalapril (ACEI)

Question 13

Drug effect with respect to Cp changes; Delayed:

Answer 13

• May be a result of distribution (mins) or drug action (hrs)
– (re-) Distribution in/out of plasmasite of action ( /  CP)
– Drug targets may have slower turn-over, require resynthesis (CP)

Question 14

Drug effect with respect to Cp changes; Cumulative:

Answer 14

• Aggregated transport or accumulated insult (Chronic use)

• Long dilute infusion versus periodic drug administration
– Bolus doses may saturate a given transporter or mechanism

Question 15

Changes in Cp: Immediate effects:

Answer 15

• Cp drops significantly over time
– Effect does not decrease as fast
– CP will remain above the EC50

Result:
 Drugs with short half-lives can still be dosed once per day
• Drugs with broad therapeutic window
• Help with compliance

Question 16

Changes in Cp: Delayed effects:

Answer 16

• Effects may be delayed with respect to the change in Cp

• Short delays:
o Time required for distribution from plasma to the site of action

• Long delays or extended effects:
o Direct enzyme inhibition may be rapid, but effect is slow
o Termination of effect may be slower than CP decrease
• Reversible inhibitors may bind tightly
• Irreversible inhibitors will require enzyme resynthesis

• Onset of effect may be slower than CP increase
o Pre-dosage enzyme product must be depleted before an effect

Question 17

Changes in Cp: Cumulative effects:

Answer 17

Bolus vs. Continuous infusion (drug and patient specific)

• Beneficial: Bolus injection to quickly stabilize a patient (acute event – cardiac arrest, anaphylactic shock, breakthrough pain, etc)

• Harmful: Bolus injection of digoxin, phenytoin, or potassium → cardiovascular collapse (cardiac arrest)
o Continuous infusion is preferred

• Continuous infusion can also be harmful in some cases:
     o Gentamicin (aminoglycoside antibiotic) – continuous infusion→ renal accumulation→ renal toxicity
     o Intermittent bolus injections is preferred

Bolus injections may saturate transport mechanisms
o May reduce side effects observed with continuous infusion