PHCY 1202 – RECITATION #13

PHARMACODYNAMICS
April 27, 2018

1.) Mark whether the following statements on concentration-effect relationships

characterized by a sigmoid Emax-model are true (T) or false (F):

T F In an Emax-model, the EC50 is the plasma drug concentration at steady-

state that produces 50% of the maximum effect.
T F A hysteresis loop in an effect vs. plasma drug concentration curve is not
expected to be observed after i.v. administration of a single bolus dose.
T F Increasing the plasma steady-state concentration of a drug by 100%
usually results in doubling the effect intensity of the drug.
T F For responses less than 20% of the maximum, the effect is directly
proportional to drug concentration only when the slope factor n equals
one.
T F A drug that achieves only 10% of its maximal pharmacologic effect at
peak plasma concentration following administration of a single dose
(i.e., E/Emax = 0.1 at Cmax) is always ineffective for routine clinical use.

2.) Considering the sigmoid Emax-model, an increase in the value of the slope factor n
from 1 to 3 would
a) Increase the Emax and increase the range of concentrations associated with 20
to 80% maximal effect.
b) Have no effect on Emax and decrease the range of concentrations associated
with 20 to 80% maximal effect.
c) Increase the Emax and decrease the range of concentrations associated with 20
to 80% maximal effect.
d) Have no effect on Emax and increase the range of concentrations associated
with 20 to 80% maximal effect.
e) None of the above.

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3.) Predict the general tendencies (clockwise (a), counterclockwise (b), or no
hysteresis(c)) for the observed relationship between effect and plasma drug
concentration after a single oral dose of a drug as a consequence of each of the
following situations:

3.1) Slow distribution of drug to the site of action.

a) b) c)
3.2) Drug given in controlled release dosage form. The effect intensity is solely
determined by the drug, which equilibrates rapidly between plasma and site of
action.
a) b) c)
3.3) Rapid development of metabolic tolerance to the drug.
a) b) c)
3.4) Rapid development of functional tolerance to the drug.
a) b) c)

4.) A drug may be characterized by functional tolerance if it demonstrates

a) receptor downregulation with chronic therapy resulting in lowered response.

b) clockwise hysteresis in the concentration-response relationship.
c) identical plasma concentrations at 0.5 hr and 4 hr, but lesser response at 4 hr
as compared to 0.5 hr.
d) all of the above.

5.) In a case report on a hypokalemic nine-month infant, a directly linked sigmoid

Emax-model was used to relate potassium concentration to muscle strength quantified
as grip strength (measured as pressure in mm Hg). Weakness is an early
manifestation of hypokalemia, and prompt improvement in muscle strength with
potassium therapy is typical. The reported pharmacodynamic parameters for the
infant were EC50 = 1.8 mmol/L, Emax = 114 mm Hg, and n = 3.79 (from Anaesthesia
and Intensive Care 1997, 25, 525-7).
What potassium level is necessary to maintain at least 80% of maximum muscle
strength ?
a) 1.4 mmol/L
b) 2.6 mmol/L
c) 3.0 mmol/L
d) 3.5 mmol/L
e) 4.5 mmol/L

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6.) Julia S. (53 yrs, female, 5’4”, 66 kg) shall be started on an oral theophylline dosing
regimen with an immediate release dosage form to control her asthma. The effect
of theophylline on respiratory function was reported as an improvement in peak
expiratory flow rate from baseline (PEFR) using a simple E max-model. The reported
population average parameters are Emax= 344 L/min and EC50=11 mg/L. For the
pharmacokinetic parameters of theophylline, assume a CL of 0.04 L/hr/kg, a V ss of
0.5 L/kg, an oral bioavailability of F = 1, and a fast absorption rate constant.

6.1) Determine the D50 and DR50 for theophylline in this patient.

D50 a) 160 mg b) 230 mg c) 270 mg d) 360 mg e) 440 mg

DR50 a) 19 mg/hr b) 23 mg/hr c) 29 mg/hr d) 35 mg/hr e) 41 mg/hr

6.2) It was decided to target a PEFR improvement of 200 L/min from baseline. Determine
the appropriate loading dose and maintenance doses necessary for the respective
theophylline therapy.

LD a) 250 mg b) 350 mg c) 450 mg d) 500 mg e) 600 mg

MD a) 20 mg/hr b) 30 mg/hr c) 40 mg/hr d) 50 mg/hr e) 60 mg/hr

6.3) What is the expected fluctuation in concentration F C and effect FE at steady-state if

the maintenance dose is given every 8 hours?

FC a) 1.0 b) 1.3 c) 1.6 d) 1.9 e) 2.1

FE a) 1.0 b) 1.3 c) 1.6 d) 1.9 e) 2.1

7.) A potential side effect of treating asthmatic patients with inhaled corticosteroids is the
suppression of the hypothalamic-pituitary-adrenal (HPA) axis. HPA-suppression is
caused by that fraction of the administered corticosteroid that is absorbed into the
systemic circulation. This effect is frequently quantified by the suppression of
endogenous cortisol levels.
Rohatagi et al. (J Clin Pharmacol 1996 (36), 938-41) described for the suppression of
endogenous cortisol by the inhaled corticosteroid fluticasone propionate (FP) an Emax
of 100% (complete cortisol suppression) and an EC 50 for unbound concentrations of
0.013 ng/mL. The pharmacokinetic parameters for FP are: CL 69 L/h, V 318 L, plasma
protein binding 90%, F(after inhalation) 31%.
What maximum total daily dose of FP (dose rate in µg/day) can be used clinically
without exceeding an average cortisol suppression of 70% (use a simple E max-model)?
a) 88 µg/day b) 220 µg/day c) 440 µg/day d) 880 µg/day e) 1760 µg/day

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