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Pharma 3 > Corticosteroids > Flashcards

Corticosteroids Flashcards

1
Q

Adrenal Cortex: Background Knowledge

A

Zona Glomerulosa: Mineralocorticoids–> reg. water and
salt balance
Zona Fasciculata: Glucocorticoids–> reg. carbohydrate
and protein metabolism; anti inflammatory and immune
suppression. Can act on both glucocorticoid and
mineralocorticoid receptors. Synthetic can differentiate.
Zona Reticulata: Androgen

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2
Q

Cushings Disease (Syndrome when iatrogenic)

Symptoms

A

Excessive Glucocorticoids (endogenous tumor, iatrogenic)
Decrease protein synth–> decrease muscle amount/tone
Euphoria / Depression, Buffalo hump, moon face,
abdominal fat (decreased hormone sensitive lipase due
to insulin)
Hypertension (action on mineralocorticoids), oedema
Osteoporosis: increased osteoclast and decreased
osteoblast activity.
Decreased Ca absorption in GIT; decreased collagen
and osteoid synthesis
Hyperglycemia: Increased gluconeogenesis

Various Symptoms due to high amount of receptors located all over the body

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3
Q

Excessive Mineralocorticoids

A

Disorders of salt-water balance–> hypertension
Primary hyperaldosteronism: Conn’s Syndrome
Secondary hyperaldost: increased RAAS activity

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4
Q

Adrenal Cortex Insufficiency

A

Addison’s Disease: Lack of all cortical hormones
ex: AI adrenalitis, infections (TB, AIDS), metastatic
disease

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5
Q

Regulation of Adrenocortical Hormones

A

Hypothalamus–> Corticotropin Releasing H (CRH)
that stimulates Ant. Pituitary
Ant. Pituitary–> ACTH stimulating Adrenal Cortex

Negative Feedback:
ACTH on Hypothalmus
Glucocorticoids on Ant. Pit. and Hypothalamus

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6
Q

Which enzyme makes all the difference between Mineralo- and Glucocorticoids? Significance.

A

17 alpha hydroxylase for mineralo–>glucocorticoid: single
OH group differs
Significance: Action on each others R

REM: Cholesterol is starting point for mineralo- and glucocorticoids, as well as androgens

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7
Q

Enzymatic Process

Cholesterol–>Mineralocorticoids

A

1) Cholesterol desmolase
Choelsterol into Pregnenolone

2) 3 beta hydroxysteroid dehydrogenase
Pregnenolone into Progesterone

3) 21 beta hydroxylase
Progesterone into 11 Deoxycorticosterone

4) 11 beta hydroxylase
11 DOC into Corticosterone

5) Aldosterone synthase (activated by angiotensin II)
Corticosterone into Aldosterone

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8
Q

Effects of Glucocorticoids
General and Metabolic
Effects of Mesenchymal Tissue
CNS Effects

A

Decrease glucose uptake and utilisation–>
Hyperglycaemia
Increase gluconeogenesis due to increase insulin secret.
Decrease protein synth, increase protein catabolism
–> Negative N balance
Increased fat depo on abdomen and back
Permission of catecholamine action
High dose (pharma): mineralocorticoid effect, negative Ca
balance–> osteoporosis

Immune suppression and antiinflammatory
decreased IL2 prod, decreased activity lymphatic
tissues, decreased wound healing, decreased PG
synth, increased osteoclast and decreased osteoblast
activities
Inhibit early and late phase of inflammation:
Early: Gq coupled R of glucocorticoid
Late: IC R mediated
Inhibit haematopoietic SC prolif and activation

CNS: seizures, sleeping disorders, insomnia

Negative Feedback on ant. pituitary and hypothalamus

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9
Q

Glucocorticoids

Genomic Mechanism of Action

A

Intracellular Receptor: dimerisation–> nucleus–> bind to SRE (steroid responsive element) of DNA

Effect:
Upregulation of:
Lipocortin 1 (anexin 1): endog. phospholip A2 inhibitor
Antiinflammatory cytokines: IL-10

   Downregulation of:
     COX 2
     Inflammatory Cytokines: IL2/3/4/5, TNFa
     Adhesion Factors: ICAM-1
     iNOS (resp for vasodilation)
     TF: NFkB, TGFb
      GF
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10
Q

Glucocorticoids

Non Genomic Mechanism of Action

A

Membrane Receptors: Gq: metabotropic glucocortic. R
Resp for fast effects
Location: vascular SM, endothelial cells, neurons

Effects: increase Ca–> vasoconstriction uA

Example: anti oedema effect

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11
Q

Categorisations of Glucocorticoids

A
  • Mineralo- vs Glucocorticoid Action
  • Systemic vs Local Effectiveness
  • Genomic vs Non Genomic Effect
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12
Q

Mineralocorticoid vs Glucocorticoid Action

A

M G
Cortisol 1 1
Aldosterone 800 1

Fludrocortisone 800 4-5
DOC 40 0
Prednisolone 0.7 5
Betamethasone 0 5-100
Dexamethasone 0 10-35

Some have huge range of efficacy due to pleiotropic effect of R

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13
Q

Systemic vs Local Effectiveness

A

S L
Prednisolone 4-5 1-2
Betamethasone 30 5-10
Dexamethasone 30-120 10

Mometasone 0 Next all have 40-100
Fluticasone
Budesonide
Ciclesonide

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14
Q

Genomic vs Non Genomic Effect

A

G NG
Prednisolone 0.8 0.4
Methyprednisolone 1 5—> best for acute
Betamethasone 5 0.23
Dexamethasone 5 1.2

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15
Q

Glucocorticoids
Clinical Use and Indications
Drug Formulations

A

Indications:
Substitution Th: Addisons
Inflammation, allergies, anaphylactic shock, AI,
haematological malignancies, transplantation

Short term systemic therapy indications:
Severe asthma, allergic contact dermatitis,
rhinoconjunctivitis (allergic)

Drug Formulations
Oral, rectal, IM/IV/, ointments, creams, eye drops, nasal,
inhalation

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16
Q

Glucocorticoids

Pharmacokinetics

A

Good oral absorption
Corticosteroid- binding globulin and albumin
endogenous: 90%–> possible displacement
synthetic: bind only to albumin, act more rapidly
Lipophylic
Inactivated in Liver, excreted into urine

17
Q

Glucocorticoids
Side Effects
Contraindications

A

Side Effects:
High risk of infection, peptic ulcers/erosions, Cushings,
osteoporosis, hypertension/oedema, atrophy of adrenal
cortex

Contraindications:
Absolute: active ulcers, severe psychosis, certain viral
infections
Relative: DM, pregnancy, Cushings, GI ulcers,
hypertension

18
Q

How to minimise occurrence of Adrenal Cortex Atrophy?

A

Coadminister ACTH to sustain tropic activity of ACTH on Adrenal Cortex

Gradual withdrawal of therapeutic drugs

19
Q

Glucocorticoids

Drug Names and Characteristics

A

Cortisol: endogenous. Substitution therapy

Cortisone: prodrug–>hydrocortisone, Substitution therapy

Fludrocortisone: Substitution therapy

DOC

Prednisolone, Methylpred, Betamethasone, Dexametha.
systemic for severe conditions ex severe asthma

Beclomethasone, Mometasone, Budesonide, Ciclesonide
Local admin

20
Q

Prerequisites: Asthmatic Inhalation Agents

A

High R affinity
Extensive hepatic 1st pass (min 80%)

Local side effects:
candidiasis
dysphonia

21
Q

Use of Glucocorticoids in Premies (<36 weeks)

A

Mg, b2 agonist, oxytocin R anta–> delay labour

GC injection–> boost surfactant

22
Q

Mineralocorticoids

Localisation of Receptors
Main Actions

A 
Receptor localisation:
   Tubular cells of kidney
   salivary and sweat glands
   pancreas
   intestinal epithelial cells

Main Actions:
Increase K and H secretion
Increase Na reabsorption

23
Q

Mineralocorticoids

Effects

A

Genomic:
Increased # Na channels in apical membrane
Increased # Na/K ATPase in basolateral membrane

Non Genomic
Rapid Na influx via Na/H exchange mechanism apical

Both IC and membrane bound receptors

24
Q

Mineralocorticoids used in Substitution Therapy

Names and Characteristics

A

Aldosterone: endogenous MC

Cortisol: endogenous GC with MC action

Fludrocortisones: synthetic, act on both Rs

25
Q

Mineralocorticoid Antagonists

Names and Characteristics

A

Spironolactone
Non specific aldosterone antagonist; acts on
MC R–> diuretic action, CV effects
Steroid R–> endocrine effects, progesterone R
agonist, androgen R antagonist
Uses: Diuretics; hyperaldosteronism; hirsutism and
seborrhea in females as androgen antagonist

Eplerenone
Specific aldosterone antagonist doesn’t act on steroid
Receptor due to epoxide group

Uses: Hypertension, Congestive HF, AMI

Pharma 3 (14 decks)

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