Question 12

List the effects of stimulation of adrenoreceptors on target organs and tissues (60% marks). Describe the mechanism of action and pharmacokinetics of metoprolol (40% marks).

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College Answer

This question required a list of effects of the stimulation of adrenoreceptors, thus detailed description of downstream effects and exact mechanisms was not required. Using a systems based structure with a subdivision into each receptor (or vice versa) meant that important GIT, GUT, endocrine and metabolic effects were not omitted. Given the need for little depth, this part of the question required breadth particularly within cardiovascular effects. Venoconstriction, dromotropy and lusitropic effects should also be covered. The second part of the question required a detailed description of the mechanism of action and pharmacokinetics only, thus dose, pharmaceutics and pharmacodynamic information was not required. Here it would be important to elaborate on the downstream effects of blocking the beta adrenergic receptors as compared with the information required in the first part of the question.

Discussion

Adrenoceptor activation:

  • α receptors: G-protein coupled receptors
    • α-1 : Gq protein coupled – second messenger is IP3, causing an increase of intracellular calcium
      • Arteriolar vasoconstriction
      • Contraction of the radial muscle of the iris (dilates pupil)
      • Contraction of the gut sphincters
      • Decreased secretion of intestinal glands
      • Contraction of the urethral sphincter
      • Increased sodium reabsorption in the renal tubule, and increases renin release
      • Contraction of piloerector muscles
    • α-2– Gi protein coupled – inhibit adenylyl cyclase, decrease cAMP
      • Peripheral effects:
        • Relaxation the walls of the gut wall smooth muscles
        • Inhibition of noradrenaline release from nerve terminal
        • Inhibition of adrenaline release from the adrenal cortex
        • Inhibition of insulin release (α-2A)
      • Central effects:
        • Sedating, antinociceptive effects
        • Presynaptic inhibition of norepinephrine, dopamine and serotonin release - thus, systemic sympatholytic effects
  • β receptors: Gs protein coupled – activate adenylyl cyclase, increase cAMP levels
    • β-1: equal affinity for adrenaline and noradrenaline
      • accelerates sinoatrial node
      • accelerates ectopic pacemakers
      • increases contractility of the heart
      • increases rennin release by the kidney
    • β-2: minimal affinity for noradrenaline; found on tissues which do not receive direct sympathetic innervation; mostly a receptor to catch circulating adrenaline
      • accelerates sinoatrial node
      • accelerates ectopic pacemakers
      • increases contractility of the heart
      • relaxes the smooth muscle of skeletal muscle arterioles
      • relaxes bronchiolar smooth muscle
      • relaxes gut wall smooth muscle
      • relaxes the bladder wall
      • relaxes the pregnant uterus
      • increases gluconeogenesis and glycogenolysis in the liver
    • β-3: minimal affinity for noradrenaline
      • all these do is increase the rate of lipolysis in fat cells

Metoprolol:

Name Metoprolol
Class Beta blocker
Chemistry aryloxypropanolamine
Routes of administration Oral or IV
Absorption 50% oral bioavailability
Solubility pKa 9.7, poor lipid solubility
Distribution VOD 2.8-4.8 L/kg; only 12% protein bound
Target receptor Selective β1 receptor blocker
Metabolism Mainly hepatic clearance
Elimination minimal renal excretion; half-life 3-4 hrs
Time course of action Clinical effects persist for longer than the half life would suggest, because they are mainly determined by drug-receptor affinity
Mechanism of action By binding to Gs-protein coupled β1 receptors, blocks cAMP synthesis
Clinical effects β1 effects: decreased heart rate, cdecreased contractility, decreased blood pressure, lower myocardial oxygen demand and increased diastolci coronary fillng, and decreased arrhythmogenicity.
Single best reference for further information Oliver et al (2019)

References

William Tank, A., and Dona Lee Wong. "Peripheral and central effects of circulating catecholamines." Comprehensive Physiology 5.1 (2011): 1-15.

Motiejunaite, Justina, Laurence Amar, and Emmanuelle Vidal-Petiot. "Adrenergic receptors and cardiovascular effects of catecholamines." Annales D'endocrinologie. Vol. 82. No. 3-4. Elsevier Masson, 2021.

Levitzki, Alexander. "Catecholamine receptors." Reviews of Physiology, Biochemistry and Pharmacology, Volume 82 (1978): 1-26.

Ciccarelli, M., et al. "Adrenergic receptors." Endocrinology of the Heart in Health and Disease (2017): 285-315.

Sannerstedt, R., and H. Wasir. "Acute haemodynamic effects of metoprolol in hypertensive patients." British Journal of Clinical Pharmacology 4.1 (1977): 23-26.

Frishman, William H., and Elijah Saunders. "β‐adrenergic blockers." The Journal of Clinical Hypertension 13.9 (2011): 649.

Frishman, William H. "β-Adrenergic blockers." Medical Clinics of North America 72.1 (1988): 37-81.