Question 11

Compare and contrast hydrocortisone, methylprednisolone and dexamethasone.

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College Answer

Hydrocortisone represents the main endogenous glucorticoid. Methylprednisolone anddexamethasone are synthetic glucocorticoids that all have metabolic, anti – inflammatory and immunosuppressive effects. These are commonly encountered drugs in intensive care practice, yet overall this question was poorly answered. For a good answer candidates were expected to mention the differences in their pharmacokinetics, relative glucocorticoid and mineralcorticoid effects and adverse effects. These drugs share some common features (eg all have a steroid nucleus, hepatic metabolism and renal excretion and adverse effects), features that were poorly
covered by the candidates, but also expected to be mentioned for a good answer.
Syllabus: N2,2c 
References: Stoelting, Pharmacology and Physiology in Anaesthetic Practice, pge 416, Peck Hill
and Williams Pharmacology for Anaesthesia and Intensive Care, pg 355-8

Discussion

Name Hydrocortisone Dexamethasone Methylprednisolone
Routes of administration IV, oral, s/c, IM, intranasal, topical, intra-articular, etc Oral or IV IV or topical
Absorption 97% oral bioavailability 70-100% oral bioavailability 80% oral bioavailability
Solubility pKa=12.59; lipid soluble; available as water-soluble salts for IV injection pKa=12.42; lipid soluble; available as water-soluble salts for IV injection pKa=12.61; lipid soluble; available as water-soluble salts for IV injection
Distribution VOD = 0.5L/kg ; 90% protein-bound VOD=0.65L/kg; 65% protein-bound (mainly to albumin) VOD= 1.38L/kg; 77% protein-bound (mainly to albumin)
Target receptor Glucocorticoid receptor, which is a cytoplasmic and nuclear receptor, that regulates gene transcription and protein synthesis (but some actions are also attributed to membrane-bound receptors and nongenomic pathways) Glucocorticoid receptor, which is a cytoplasmic and nuclear receptor, that regulates gene transcription and protein synthesis (but some actions are also attributed to membrane-bound receptors and nongenomic pathways) Glucocorticoid receptor, which is a cytoplasmic and nuclear receptor, that regulates gene transcription and protein synthesis (but some actions are also attributed to membrane-bound receptors and nongenomic pathways)
Metabolism Metabolised mainly in the liver. Several metabolic steps produce daughter molecules with progressively lower steroid effect and progressively higher water solubility
Elimination Free drug is reabsorbed in the distal tubule; there is minimal renal excretion of active molecules. Inactive metabolites are eliminated in the urine Inactive metabolites are eliminated in the urine; there is minimal excretion of unchanged drug (~1%)
Time course of action Half-life 60 minutes, maximum 2 hours (with high doses) Half-life 4-5 hours (though biological activity persist for 36-72 hours) Half-life 2-3 hours
Mechanism of action A combination of genomic effects and nongenomic effects, where some (medium and long term) activity is mediated by the regulation of protein synthesis, and some more immediate effects are mediated by the interference in cell membrane function, intracellular second messenger systems and membrane-bound glucocorticoid receptors
Clinical effects - Immunosuppression (decreased granulocyte and lymphocyte activity)
- Reduced airway oedema, bronchodilation
- Sensitisation to catecholamines, increased cardiac output
- Neuropsychiatric effects (euphoria, mania, insomnia, psychosis)
- Metabolic effects (hyperglycaemia, hyperlipidemia, decreased insulin sensitivity)
- Fatty tissue redistribution, osteoporosis, proximal myopathy
- Hypernaremia, hypokalemia, water retention
- Adrenal suppression
- Increased risk of opportunistic infections (Aspergillus, Pneumocystis, Strongyloides)
Single best reference for further information Minigh (2008) Czock et al (2019) Czock et al (2019)

References

Czock, David, et al. "Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids." Clinical pharmacokinetics 44.1 (2005): 61-98.

Williams, Dennis M. "Clinical pharmacology of corticosteroids." Respiratory care 63.6 (2018): 655-670.

Timmermans, Steven, Jolien Souffriau, and Claude Libert. "A general introduction to glucocorticoid biology." Frontiers in immunology 10 (2019): 1545.