LESSON 2: GLUCOCORTICOIDS & IMMUNOSUPPRESSANTS AGENTS Flashcards
are steroidal agent produced and released by the adrenal cortex
glucocorticoids
2 glucocorticoids predominantly affect carbohydrate metabolism; this 2 are also important naturally occuring glucocoticoids
- Cortisol
- corticosterone
Aldosterone, predominantly affect electrolyte and water metabolism
Mineralocorticoids
Predominates in human beings, pigs, and dogs
cortisol
Predominates in rabbit, mouse, and rat
corticosterones
to the non-esterified steroid component and determines its glucocorticoid, an anti-inflammatory potency, and extents its duration of action
glucocorticoid base
The ability of glucocorticoid formulation to suppress the hypothalamus-pituitary-adrenal axis (HPAA) is determined by:
● The dose
● Potency of the base, and
● Duration of the action of the formulation.
one of the major adverse effects of the glucocorticoids therapy
secondary hypoadrenocorticism
Therapeutic success with fewer side effects is possible with?
alternate-day therapy
hypothalamus secretes _________, which is brought to the anterior pituitary through the
hypothalamus-pituitary portal system
corticotropin –releasing hormone (CRH)
The ____ which are generally active during daytime (diurnal), have high blood
glucocorticoid concentration during the day, and low at night
DOG
_____ which are active at night (nocturnal), show the reverse pattern
cat
action, which may lead to increase glucose production from amino acid by way of gluconeogenesis, and to reduce the rate of incorporation of amino acid into proteins
hyperglycemic action
Glucocorticoids in large amounts (hyperadrenocorticism or Cushing’s disease)
inevitably lead to :
- polyuria- excretion of excessive volume of urine
- polydipsia- excessive thirst
Overdose of glucocorticoids may be leads to:
- hypernatremia- retention of high sodium concen. in blood
- hypokalemia- low cacium concen. in blood
Glucocorticoids in use of physiological replacement therapy:
This is used in the treatment of:
1. hypoadrenocorticism (Addison’s disease)
2. In iatrogenic HPA axis suppression, and
3. Adrenalectromized patients.
example of drugs with slow onset and intermediate duration are used for acute disease processes used for once-a-day therapy
● Triamcinolone acetonde
● Dexamethasone in propylene glycol
drugs with short duration are used for
acute and chronic condition and for
alternate –day therapy.
Prednisolone
Prednisone
Methylprednisolone
mimics diurnal cortisol production in most
animals; causes sodium retention
(not significant in dogs and cats)
Prednisolone
Those with slow onset and long
duration are for skin and joints.
● Triamcinolone acetonide
● Methylprednisolone acetate
Those with very rapid onset and short
duration are used in emergency
situation such as hemorrhagic-shock
and anaphylaxis. These are fast-acting
(within1 min) with short plasma
half-life (1-2 h), but are rather
expensive
● Hydrocortisone sodium succinate
● Hydrocortisone sodium
phosphate
● Prednisolone sodium succinate
glucocorticoids used in anti-inflammatory and anti – allergic therapy;
This is commonly employed in:
a. Symptomatic therapy of pruritic dermatoses
b. Allergic pulmonary disease, and
c. Allergic gastroenteritis
Immunosuppressive therapy (“immunosuppressive Agents “)
This use is designed for:
a. Immune mediated thrombocytopenia
b. Autoimmune hemolytic anemia
c. Systemic lupus erythematosus, and some forms of neoplasm
Prednisolone (for induction )
2.2-6.6 mg/kg divided bid until effects
Dexamethasone (for maintenance)
2-2.2 mg/kg every 2 days
Prednisolone (for maintenance)
0.33-1.1 mg/kg
This is employed in the condition such as chronic arthritis, hip dysplasia, etc. dosing
may be intermittent or on alternate-day basis. Do not withdraw erratically, this may
lead to pseudorheumatism
Chronic palliative therapy
Proper weaning from long-term glucocorticoids therapy should be tedious and drawn
out. Animals do not complain of minor aches and pains or of changes in mood.
However, the following signs might suggest that further prolongation of the weaning
process is necessary;
⮚ Dullness
⮚ Mental depression
⮚ Increase fatigability
⮚ Incoordination
⮚ Unthriftiness and weight loss
⮚ Diarrhea
⮚ Behavioural changes
This compound has been found to suppress adrenal cortical activity in the dog, but
it is less successful in other species. Rats and monkeys are unaffected. in goats caused atrophy of the cortex and transitory cytopathologic effects of adrenal cortical cells of calves
o,p’DDD
Is (3, 3- bis p-aminophenyl butane). It inhibits 17 - ketosteroid production in
human and dog
Amphenome B
is very lipophilic and hydrophobic and must be solubilized before administration. It specifically inhibits T cells early in their immune response to antigenic and regulatory stimuli without affecting suppressor T cells
Cylosporin A
Cylosporin binds with its cytoplasmic receptor protein
cyclophilin
The resulting cylosporin – cylosphilin complex then binds with
calcineurin (a phosphatase)
Unwanted effects of cylosporin is include:
⮚ Nephrotoxicity
⮚ Hepatotoxicity, and
⮚ Hypertension
Less severe side effects are:
⮚ Anorexia
⮚ Hirsutism (in human) tremor
⮚ Paraesthesia, gum hypertrophy, and
⮚ Gastrointestinal disturbance.
It is macrolide antibiotic with a very similar mechanism of action to cylosporin. The
main difference is that its cytoplasmic receptor is not cyclophilin but protein called
FK binding protein (FKBP)
Tacrolimus (a.k.a FK506)
another macrolides, also binds with FKBP. However, the rampamycin-FKBP complex does not bind with calcinuerin nor does it effects IL-2
transcription. It interferes with signal transduction pathway blocking the cell cycle of
activated T cells in G1 phase by inhibiting a novel kinase called mTOR
Rapamycin
It is an alkylating agent with particular action on lymphocytes. As a immunosuppressant it effects the clonal proliferative phase of the immune response and reduce both antibody-mediated and cell-mediated immune reactions.
Cyclophosphamide
It is another alkylating cytotoxic agent similar to cyclophosphamide
Chlorambucil
It is used particularly for tissue rejection in transplant surgery. It is metabolized to
mercaptopurine, a purine analogue that inhibits DNA synthesis. Both cell-mediated & antibody-mediated immune reactions, and are depressed by this drug since it inhibits clonal proliferation in the induction phase of the immune response by a cytotoxic reaction on dividing cells.
Azathioprine
A semi-synthetic derivative of a fungal antibiotic, it is converted to mycophenolic acid, which restrains the proliferation of both B and tT lymphocytes and reduces the production of cytotoxic. T cells by inhibiting inosine monophosphate dehydrogenase. This pathway is essential for de novo purine synthesis B and T lymphocytes are particularly dependent on this enzyme
Mycophenolate mofetil
in ring A, the double bond at _____ and keto group at ______ are essential for activity. Reduction of the double bond and the keto group result in loss of activity
c4 & c3
enhances the glucocorticoid activity and
decreases mineralocorticoid activity
double bond c1
this 2 are present in ring b
- a-fluorination at c9
- a- methylation at c6
this increases glucocorticoids & mineralacortiocids activity
a-fluorination at c9
this enhances glucocorticoids effects
a-methylation at c6
a glucocorticoid commonly use in clinical therapy, differs from cortisol only in having a keto- rather than B-hydroxyll group at c11
Cortisone
Cortisone is inactive, but can be transformed to _______ in the liver.
cortisol
It is not useful when administered topically or injected in ???
joint
in ring d The OH group at C21 must be free for ??
biologcal activity
______ markedly decreases mineralocorticoid effect
α - or β – methylation at C16
________ also markedly decrease mineralocorticoids effect
α – hydroxylation at C16
LONG ACTING DRUGS “
Paramethasone
Betamethasone
Dexamethasone
this 2 glucocorticoid ester is rapid onset of action; for IV and IM route
- Phosphates
- Hemmisuccinate
a glucocorticoid ester is poorly water soluble; used as depot
Acetonide
this glucocorticoid ester is very long duration of action (weeks to mo
Pivalate
this glucocorticod ester is slow absorption; available as depot; action last days duration
Acetate, diacetate, tebutate
secretion of _______ by the anterior pituitary is episodic rather than
continuous.
corticotropin
In the normal animal, the blood glucocorticoid concentration varies with
the ??
circadian rhythm
Pharmacological Effects of Glucocorticoids
The pharmacological effects of glucocorticoids are produced by rather than high doses. When a clinician administers a glucocorticoid to a patient, effect other than
those originally desired may also occur
glucocorticoids cause ________ and _______ an effect secondary to cell redistribution and/or lysis, and lead to increase de-margination of neutrophils
lymphocytopenia & eosinopenia
DNA-binding domain. The steroid-receptor
complexes move into the nucleus and bind to steroid-response elements in the DNA. The effects is either to ??
- repress- prevent transcription
or - induce- initiate expression
Effectively blocks cortisol production but not corticosterone production in young pig
Metyrapone
