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Drug- or hormone-induced adaptation: Model of adrenergic hypersensitivity

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Abstract

A pharmacokinetic/pharmacodynamic model of hypersensitivity to adrenergic stimulation following abrupt withdrawal of chronic β blockade was developed. The model employs the Hill equation, a term which describes the competition between isoproterenol and l- propranolol for β receptors, and a kinetic term which characterizes the appearance and disappearance rates of up-regulated β receptors. The model predicted peak chronotropic hyperresponsiveness to isoproterenol 48 hr following abrupt withdrawal of chronic treatment with daily propranolol doses of 160 mg, and a drug half-life of 3.5 hr. The model also predicted that increasing the dose rate and prolonging the half-life of propranolol delayed and decreased the extent of adrenergic hypersensitivity. The time-course of adrenergic hypersensitivity simulated by our model was in excellent agreement with that observed in studies which were published earlier by our laboratory. The model underestimated the extent of adrenergic hypersensitivity. The results of our simulation are consistent with a β agonist-receptor-effector system, which involves spare receptors, amplification of response by second and third messengers, and β agonist-antagonist-induced receptor regulation.

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Abbreviations

R :

Unoccupied receptor concentration

A :

Unbound agonist concentration surroundingR

RA :

Receptor-agonist complex concentration

k 1:

Association rate constant

k 2:

Dissociation rate constant

B :

β receptor density

B max :

Maximumβ receptor density

A 50 :

A at which B/Bmax is 0.5

E :

Intensity of response

E max :

Maximum intensity of response

Ce :

Unbound blood concentration of the agonist eutomer

Ce 50 :

Ce at whichE/E max is 0.5

γ :

Slope of the response-concentration curve

e :

Dimensionless proportionality factor denoting power of agonist to produce a response

I :

Unbound antagonist concentration surroundingR

RI :

Receptor-antagonist complex concentration

KI :

Equilibrium dissociation constant ofRI

Ei :

Intensity of response to the agonist in presence of antagonist prior to up-regulation

Ci :

Unbound blood concentration of the antagonist

Ki :

Ci at whichEi/E max is 0.5

Cij :

Coefficient of theCi, time curve

λij :

Slope of theCi, time curve

t :

Time following administration of the antagonist

N :

Number of doses of the antagonist administered

τ :

Dosing interval

Cb :

Blood concentration of the antagonist

fu :

Unbound fraction of antagonist in blood

B: P :

Blood to plasma ratio

B∼ max :

Sum of Bmax and density of antagonist-induced up-regulatedβ receptors

fr :

Fractional increase inβ receptor density, Bmax Bmax)/Bmax

kd :

Disappearance rate constant of antagonist-induced up-regulatedβ receptors

T :

Duration of antagonist treatment

t′ :

Time following withdrawal of antagonist treatment

E′ :

Intensity of response to agonist in presence of antagonist and up-regulated receptors

E hr :

Heart rate in presence of isoproterenol

Diso :

Dose of isoproterenol

Do25:

Dose of isoproterenol which produces a 25-BPM increase in heart rate in absence of propranolol

ΔHR:

Isoproterenol-induced change in heart rate in absence of propranolol

ΔHR′:

Isoproterenol-induced change in heart rate in presence of propranolol

S :

Slope of the Diso -@#@ ΔHR curve

INT :

Intercept of the Diso-ΔHR curve

HR rest :

Resting heart rate

HR para :

HR rest under parasympathetic control

HR sym :

HR rest under sympathetic control

Pin :

Percentage inhibition ofHR sym induced by propranolol

Pin max :

maximal fractional inhibition ofHR sym induced by propranolol

Ehr :

Heart rate response to isoproterenol, when receptors are upregulated

Rhr :

Percentage change in isoproterenol-induced tachycardia above control

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Authors and Affiliations

  1. Division of Pharmacy Practice, College of Pharmacy, The Ohio State University, 500 W. 12th Avenue, 43210, Columbus, Ohio

    John J. Lima, Julie J. Krukemyer & Harisios Boudoulas

  2. Division of Cardiology, College of Medicine, The Ohio State University, 43210, Columbus, Ohio

    John J. Lima & Harisios Boudoulas

Authors
  1. John J. Lima
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  2. Julie J. Krukemyer
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  3. Harisios Boudoulas
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Supported in part by a grant from the American Heart Association, Central Ohio Chapter.

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Lima, J.J., Krukemyer, J.J. & Boudoulas, H. Drug- or hormone-induced adaptation: Model of adrenergic hypersensitivity. Journal of Pharmacokinetics and Biopharmaceutics 17, 347–364 (1989). https://doi.org/10.1007/BF01061901

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  • DOI: https://doi.org/10.1007/BF01061901

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