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imed3004 COPY > Pharm: Glucocorticoids > Flashcards

Pharm: Glucocorticoids Flashcards

1
Q

Which hormones exhibit changes diurnally?

A

ACTH

GH

PRL (prolactin)

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2
Q

What is the job of the HPA axis?

A

Regulates synthesis and secretion of adrenal corticosteroids.

CRF -> ACTH (ALP) -> GC

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3
Q

Why do the adrenal glands shrink with prolonged use of steroid drugs?

A

Steroid drugs act on the HPA axis to provide negative feedback to reduce ACTH production (GCs).

ACTH has a trophic effect on the adrenal cortex so lack of ACTH will result in reduced adrenal gland size.

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4
Q

What does ACTH do?

A

Stimulates GC release from adrenal cortex

Trophic effect on adrenal cortex

Negative feedback effect on hypothalamus

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5
Q

Which hormones provide negative feedback effect on the hypothalamus?

A

Glucocorticoids

ACTH

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6
Q

What are the main glucocorticoids and mineralocorticoids?

A

GCs follow circadian/diurnal rhythm:

Hydrocortisone/cortisol

Corticosterone

Mineralocorticoids: Aldosterone

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7
Q

How are steroids produced in adrenal glands?

A

Cholesterold to pregnenolone via Side Chain Cleavage.

Different zones of the adrenal cortex express specific enzymes to produce MCs, GCs, and sex hormones.

ACTH and AtII postitively regulate cholesterol -> pregnenolone

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8
Q

What does aminoglutethimide do and what is it?

A

Drug which inhibits Side Chain Cleavage preventing production of all steroids.

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9
Q

What does cortisol/hydrocortisone and other GCs do?

A

CHO metabolism

Protein catabolism

Adipose tissue redistribution

Anti-inflammatory/immunosuppressive effects

Resistance to stress

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10
Q

What do mineralocorticoids like aldosterone do?

A

Water and electrolyte homeostasis via:

Na+ retention

H2O retention

K+ excretion

H+ excretion

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11
Q

What is the overall result of GC and MC action?

A

Both are important for the stress response and for maintaining BP.

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12
Q

How do corticosteroids work?

A

Through binding nuclear receptors.

Plasma cortisol - bound to CBG then enters cell by crossing plasma membrane and binding to cytoplasmic receptor (GR)

GR dimerises then translocates to the nucleus to alter transcription of target genes.

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13
Q

What kind of effects does GR have in the nucleus?

A

Most metabolic effects arise from transcriptional activation.

Most anti-inflammatory effects arise from transcriptional repression of pro-inflammatory genes.

Sometimes they tether partner TFs to DNA (eg NFkappaB)

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14
Q

What is aldosterone and cortisol specific to? Which has higher affinity to which receptor?

A

Aldosterone is specific for the MR

Endogenous GC bind both GR and the MR

Cortisol and aldosterone bind the MR with equal affinity

Cortisol circulates at much higher levels than aldosterone

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15
Q

Cortisol and aldosterone bind the MR with equal affinity and cortisol circulates at much higher levels in the blood than aldosterone. So how do MR-expressing tissues respond to aldosterone but not cortisol?

A

In the cells expressing MR they express 11beta hydroxy-steroid dehydrogenase which converts cortisol to cortisone making it inactive in that receptor.

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16
Q

What causes primary adrenal insufficiency/addison’s disease?

A

Autoimmune destruction (80%)

Infection (20%)

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17
Q

How is primary adrenal insufficiency diagnosed? (clinical symptoms)

A

Affects all 3 layers and causes:

Fatigue, weakness, hypoglycaemia

Nausea, vomiting, diarrhoea, salt craving, drop in BP

Hyper-pigmentation (increase in ACTH)

Impaired stress tolerance (Addisonian crisis)

MC deficiency (low BP, low Na+, high K+)

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18
Q

What is the most common cause of secondary adrenal insufficiency?

A

Exogenous steroid use -> HPA axis suppression.

Hypopituitarism

Postpartum pituitary necrosis (Sheehan’s syndrome)

19
Q

What are the clinical symptoms of secondary deficiency of corticosteroids?

A

MC secretion preserved -> Intact RAAS -> Na+/K+ balance normal

All the other symptoms od adrenal insufficiency are present

20
Q

How can secondary deficiency of CS be differentiated from primary CS?

A

Normal Na+/K+ balance

ACTH levels low-normal with no hyperpigmentation

Rapid ACTH test can differentiate

21
Q

What can precipitate an addisonian crisis?

A

Any stress that increases adrenal demands

22
Q

How is addisonian crisis treated?

A

IV/IM hydrocortisone/cortisol ASAP

23
Q

What causes cushing’s syndrome?

A

Increase in ACTH from ALP (70%) = cushing’s disease

Increase in ACTH from ectopic source (eg lung cancer)

Increase in GCs from adrenal adenoma/carcinoma

Increase in GCs from prescribed GCs (iatrogenic causes)

24
Q

What happens in cushing’s syndrome?

A

CHO - hyperglycaemia, Type 2 DM

Protein catabolism -> thin skin, fragile blood vessels (bruising), osteoporosis, muscle wasting

Fat redistribution to face, back and abdomen.

Anti-inflammatory effects and immunosuppression

CNS - mood changes, cognitive impairment, psychosis

Other symptoms (hirsutism (excessive body hair), HY (aldosterone), glaucoma)

25
Q

How are GC doses manipulated during replacement therapy?

A

Twice as much GCs are used in the morning as in the evening.

In times of stress dose is doubled (eg Surgery, Infection, or major trauma)

26
Q

What drugs are used for replacement therapy?

A

Hydrocortisone to replicate diurnal rhythm

Fludrocortisone once daily.

27
Q

How are GCs used?

A

Inhibit inflammation (early - heat, pain, and swelling. Late - wound healing and repair)

Target all types of inflammation (infections, chemical and physical stimuli, as well as inappropriate immune responses such as hypersensitivity and AI)

Prophylactically (allograft rejection)

Neoplasia (Chemotherapy)

28
Q

What is the objective of GC drug development?

A

To keep anti-inflammatory effects while minimising metabolic effects

29
Q

Comparison of common corticosteroids:

A

Hydrocortisone is a short acting GC with high MC activity making it unsuitable for long term anti-inflammatory use and causes fluid retention. (acts for 8 - 12 hrs)

Prednisolone is 4 times as potent and has longer activity with lower MC potency. (acts for 12 - 36 hours)

Methyl-prednisolone is 5 times more potent than hydrocortisone and has low MC potency making it better than normal prednisolone

Triamcinolone is the same as methyl-prednisolone but has no MC activity and is not an oral steroid. It must be applied topically.

Dexamethasone is the most potent of the drugs and has no MC activity. It is long acting (36 - 54 hours)

Fludrocortisone is used for its extremely high MC potency and it acts for 24 - 36 hours.

30
Q

Why isn’t dexamethasone used very often?

A

It is very potent and makes the HPA axis not work as well.

31
Q

When is dexamethasone used?

A

In emergency situations like cerebral oedema.

32
Q

How are corticosteroids administered?

A

All routes (oral, IM, IV, rectal, topical, inhaled, intra-articular)

Local adminstration is ideal

33
Q

How are corticosteroids absorped?

A

Good bioavailability

Injectable - Succinate/PO4 esters are rapidly absorbed (eg methylpred) whereas valerate and acetate esters are slowly absorbed)

Topical/local - huge variety but all have systemic effects.

34
Q

How are corticosteroids Distributed, Metabolised, and Eliminated?

A

Lipid soluble so carried on corticosteroid binding globulins + albumin and rapidly distributed to cells.

Plasma half life is short but biological half life is long.(Nuclear Receptor activity).

Sulphonated/glucoronated in the liver and excreted in bile and urine.

35
Q

What are the adverse effects of corticosteroids?

A

patients look cushingoid

children growth suppression if P>6 months

Suppression of HPA axis:

Adrenal atrophy

Abrupt GC Px withdrawal -> Addisonian crisis

Slowly withdraw GCs (not always predictable but if course is >20mg/day or >5mg at night for >3 weeks)

36
Q

How are adverse effects minimised?

A

Minimise dose (GC sparing agents, lowest effective dose)

Timing dose (Once daily, morning dose, alternate days with double dose)

Steroid card/bracelet

Topical therapy whenever possible

37
Q

How are topical/local GCs administered?

A

Topical: Preparations (creams, gels, lotions, drops, etc) and applications (psoriasis, eczema, dermatitis, etc)

Inhaled (metered dose inhalers eg fluticasone)

Intralesional (long acting depot injections)

Rectal (Hydrocortisone ointment/suppositories)

38
Q

What important DDIs exist with GCs?

A

Vaccines and attenuated live virus immunisations

Insulin and oral hypoglycaemic agents

Antacids

Carbamazepine phenytoin, barbiturates

Digoxin

39
Q

What are the DDIs with GCs and vaccines/live attenuated viruses?

A

Systemic infection and failure to develop immunity

40
Q

What are the DDIs with GCs and insulin and oral hypoglycaemic agents?

A

hyperglycaemia

41
Q

What are the DDIs with GCs and insulin and Carbamazepine phenytoin, barbiturates?

A

Induction of GC metabolism which means higher doses may be required

42
Q

What are the DDIs with GCs and insulin and digoxin?

A

MC effects of GCs may decrease K+ which can lead to arrhythmias

43
Q

What are the DDIs with GCs and insulin and antacids?

A

Impaired GC absorption

imed3004 COPY (50 decks)

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