Steroids- Everything u need to know about !!!!

History: 

In 1935 -1936, a limited amount of cortisone was extracted from animal adrenals.

In 1948; Philip S Hench was used for the first time in a 29-year-old female with rheumatoid arthritis; which worked miraculously and been awarded Nobel prize in medicine along with Kendel & Reichstein for their work in "Investigations of the hormones of adrenal cortex"  in 1950.

To date, these drugs are the anchor drugs for various rheumatological diseases and are also being used in various other conditions in Medicine. 

Structure :

Precursors of all steroids are cholesterol. They are also precursors for Vitamin D. 

All of them have Sterol Skeleton i.e 3 x Hexane ring + 1 x Pentane ring.

Potency, Efficacy, and other biologic characteristics of the molecule depend on configuration.

Synthetic/Exogenous steroids act similarly when compared to endogenous steroids.

Classification : 

General term steroid includes mineralocorticoid, glucocorticoids (GCs) & sex steroids secreted from the adrenal cortex.

Since sex steroids are also synthesized in gonads, mineralocorticoids & glucocorticoids are termed as corticosteroids i.e exclusively secreted from the adrenal cortex.

Basic Pharmacokinetics:

Glucocorticoids such as cortisone & prednisone possess 11- keto group & are prohormones that must be reduced by 11 beta-hydroxysteroid dehydrogenases (b - HSD) to 11 - hydroxy configurations—cortisone and prednisolone, respectively—to become biologically active form i/e cortisol (hydrocortisone)  & prednisolone. The process of activation takes place in the Liver; hence patients with cirrhosis should be given the active form like prednisolone.

11 b- HSD exists in two types -  type 1 & 2; type 1 is the major type which has both oxidation & reduction activity while type has only oxidation property (dehydrogenation) which leads to inactivation of the hormone. The balance between both forms maintains homeostasis.

Clinical implication : 

Deficiency or mutation of type 2 b HSD leads to condition Syndrome of apparent mineralocorticoid excess (SAME).

Mechanism of action :

Genomic & Non- genomic pathways. Genomic pathways are mainly exhibited when the dosage is therapeutically relevant; these are slow as compared to nongenomic pathways which have a rapid onset of action & seen mainly with high doses.

Source - Kelley's textbook of rheumatology - 11th edition; page 995.

Genomic pathway: 

GCs are lipophilic & low molecular weight substances and can pass cell membranes easily.

After binding with GCs membrane receptor it gets dimerized & translocated to the nucleus and bind to DNA response element modulating transcription; the process is called transactivation & if the monomer

binds results in the downregulation of the transcription process called transrepression.

It was hypothesized that the process of transrepression was responsible for anti-inflammatory effects and transactivation is responsible for the metabolic adverse events related to GCs.

Nongenomic pathway : 

It is seen with high doses of GCs; action onset is rapid i.e within a few minutes. The mechanism is not completely clear but one of the mechanisms responsible are direct inhibition of membrane-based GC receptor in certain T cell inactivating their signaling & related immune response.

Pharmacodynamics: 

With the current knowledge that efficacy, potency & other biological characteristics of steroids depend on their configuration. Various modifications in the basic structure helped to make more potent and efficacious siblings.

Biological characteristics apart from configuration also depend on other characteristics like whether they're in free form or bound form (chemical structure - esters like acetonide or hexacetonide or salts like sodium phosphate or sodium succinate). Esters form are lipid-soluble hence are longer acting and compatible for Intramuscular/Intralesional (e.g Triamcinolone acetonide). Salts are water-soluble forms and preferred for Intravenous (e.g dexamethasone sodium phosphate, methylprednisolone sodium succinate).

Free forms are alcohol-based, insoluble in water, and can be used as oral tablets.

Biological Characteristics also depend on plasma protein binding( Transcortin & albumin). Unbound GCs are biologically active. (Hypoproteinemic patients should be prescribed in a relatively low dose as unbound forms will be more.)

The biological half-life of GCs is 2 to 36 times more than the plasma half-life because of plasma protein binding.

Glucocorticoid & HPA Axis : 

Proinflammatory cytokines ( IL- 1, IL -6), Prostaglandins, endotoxins, physical stress all can stimulate CRH secretion at the hypothalamus level, ACTH release at the Pituitary level (pulsatile secretion), and in turn increase GCs secretion directly & indirectly from the adrenal cortex. HPA axis works on negative feed mechanisms. 

Primary & Tertiary Adrenal Insufficiency : 

Adrenal insufficiency: 

Described by Thomas Addison in 1855

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Primary adrenal insufficiency is due to disorders affecting the adrenal cortex(e.g Addison's). (Increased CRH, ACTH)(Low GCs)

Secondary adrenal insufficiency is due to disorders affecting the pituitary. ( Increased CRH, Low ACTH & GCs)

Tertiary adrenal insufficiency: term tertiary denotes suppression at the level of the hypothalamus. (Low CRH, ACTH & GCs) 

Chronic usage of exogenous corticosteroids leads to suppression of the HPA axis as a result of negative feedback on CRH & ACTH leading to partial or complete atrophy of adrenals.

Since the HPA axis regulates the secretion of GCs only mineralocorticoid activity remains intact in secondary & tertiary adrenal insufficiency.

Primary adrenal insufficiency present with features of decreased GCs & mineralocorticoids i.e anorexia, abdominal pain, nausea, vomiting, excessive fatiguability, salt craving, hyperpigmentation, hypotension, hyponatremia, hyperkalemia, etc.

Secondary & tertiary adrenal insufficiency have unusual fatiguability, hypoglycemia, and less severe clinical presentation. Features like hyperpigmentation, hyperkalemia, hypotension, hyponatremia are not seen.

One of the most common causes of tertiary adrenal insufficiency of the sudden stoppage of GCs or stopping without inappropriate tapering. 

Tapering of GCs is not uniform for various forms of GCs and mainly depends on biological half-life.

There is no proper guideline to taper doses of GCS.  Most of the rheumatologists follow a slow tapering for eg. Prednisolone (whose biological half-life is 18 - 36 hours) decrement of 5 -10 mg /week if doses are > 40mg /day and 5mg per week for 20- 40 mg per day and below 15 - 20, mg/day doses tapering should be more gradual with reduction of 2.5 mg per 1 - 2 weeks. 

Stress regimen & Perioperative care:- 

Patients on long term low dose GCs have suppressed adrenal activity and should be advised to double their dose or increase to prednisolone or 15mg per day or equivalent in case of infections or other stress.

For peri and post-operative care, many physicians prefer a shot of hydrocortisone 100mg stat just before surgery followed by  50 -100mg TDS to 6 hourly for 3 days and later switched to oral medications.

For minor surgeries just doubling the dose of GCs for 1 -3 days may suffice.

Administration : 

GCs come in all forms Oral as well as Parenteral.

The choice of GCs depends on the physician and their experience. But all forms of GCs are interconvertible as per convenience and equivalence dosing as mentioned above ( Table 63.1).

Glucocorticoid effect on the immune system : 

GCs reduces activation, proliferation, differentiation, survival and promote apoptosis of the various inflammatory cell thereby producing profound anti-inflammatory effect and still is considered one of the anchor drug to treat various inflammatory, autoimmune and rheumatological disorders.

The spectrum of Glucocorticoids effects :  

 

Adverse Events : 

Numerous Adverse effects have been attributed to glucocorticoids. It is related to both the average dose and cumulative duration of use.

Low-dose glucocorticoid therapy is safer than is commonly thought, and medium- to long-term glucocorticoid therapy in people with Rheumatoid Arthritis is associated with limited toxicity compared with placebo but sensitivity for adverse effects varies among individual.
Osteoporosis, Diabetes & Cardiovascular diseases are ranked among the most worrisome adverse effects.

Patients with severe disease (in terms of disease activity) require more frequent GCs. Both disease activity and GCs can cause unfavorable signs & symptoms. GCs decrease disease activity and related complications but in terms of the above mentioned adverse events. 

Hence minimizing the cumulative dose of drug exposure can minimize GCs related adverse events.

Drug Interactions : 

Cytochrome P 450 family of isoenzymes is responsible for the biotransformation of several drugs.

Drug Inducers like phenytoin, rifampicin increases metabolism and decrease the biological effect of GCs.

Inhibitors like ketoconazole, erythromycin, grapefruit juice can decrease metabolism and increase the biological effect of GCs.

Pregnancy & Lactation : 

Most of the glucocorticoids are safe in Pregnancy as it does not get transported through the placenta and the placenta has 11 b HSD type 2 activity which inactivates it. The exception to this is fluorinated GCs i.e Dexa and Betamethasone which can cross the placenta and can lead to adverse events. 

Hence Prednisone, Prednisolone, Methylprednisolone are the preferred drug to be used.

Low to medium dosage of GCs are safe in pregnancy. High doses should be avoided.

Breastfeeding is considered safe. 

Thank you for patient reading.