Session 15 opioids

Question 1

1. What are the three layers of the adrenal glands?

Answer 1

GFR/ the deeper you get the sweeter

Zona glomerulosa - Mineralocorticoids (e.g. aldosterone)

Zona fasiculata -Glucocorticoids (e.g. cortisol)

Zona reticularis - glucocorticoids + small amounts of androgens

Question 2

 Understand the importance and major signaling role of corticosteroids LO

want to replace aldosterone give fludrocortisone works on mineralocorticoid receptors

POMC (part of it is ACTH) synthesis is reduced & CRH production starts to repress the HPA axis

increased infevctions - e.g. chicken pox or measles, buccal cavity allow growth of candida albicans, can have steroid induced diabetes, imparied growth be cardeful in childeen , psychoactive effects seen with anabolic use of steroid e.g. those who use it at gym - roid rage??

need to have a steroid card e.g. if they are going to undergo surgergy need to increase steroid dose due to trauma/stress of surgery

hypoadrenal crisis -> need to gradually withdraw the steroid

Question 3

• Understand the requirement for pharmacovigilance LO
  1. What is pharmacovigilance?
  2. Aims
• Understand the limitations of Phase I-III clinical trials
• Be familiar with the ADR incidence scale
• Describe the general classification of Adverse Drug Reactions (ADRs)
• Understand the differences between surveillance methods and the challenge of causality assessment of ADRs

Answer 3

1. precess of IDENTIFYING & RESPONDING to SAFETY ISSUES about marketed drugs
2. things you would have never knoen about in previosu

FALSE POSITIVES - you think drug is unsafe but not to actually do with the drug

Question 4

 Be familiar with the feedback pathway of the HPA axis LO

Answer 4

Question 5

Appreciate how corticosteroids derive from cholesterol (no need to learn structures!!) LO

Answer 5

• Synthesised from cholesterol in adrenal glands and gonads
• Lipid soluble hormones
• Bind to receptors of the nuclear receptor family to modulate gene transcription (HRE)
• Glucocorticoids
• Mineralocorticoids
• Androgens
• Oestrogens
• Progestins

Question 6

What structures can be derived from cortisol ?

Answer 6

dexamethosone is a potent drug is mimicing cortisol but greater potency - so can give smaller dose to get same effect

hypotension - due to a mineralocorticoid effect

Question 7

 Understand the general pharmacology/physiological actions of Glucocorticoids LO

Answer 7

• Increased protein breakdown in muscle
• Increased lipolysis in fat (low conc) high conc redistribution
• Increased gluconeogenesis in liver
• Resistance to stress (increased supply of glucose, raise blood pressure by making vessels more sensitive to vasoconstrictors)

• Anti-inflammatory effects (inhibits macrophage activity + Mast cell degranulation)

• Depression of immune response (prescribed to organ transplant patients)

Question 8

State some corticoid drugs

Answer 8

Question 9

 Understand the general pharmacology/physiological actions of Glucocorticoids LO

Using the drug list state which receptors these corticoids act on

Answer 9

table shows the selectivity of the durg to different recpetors

hydrocortisone (cortisol/glucocorticoid) acts equally on both receptors

prednisolone much more selective for glucocorticoid receptors

dexamethasone and betamethasone both very selective for GC

Question 10

Explain what this table is showing

Answer 10

This table takes no account of mineralocorticoid effects, nor does it take account of variations in duration of action

betamethasone very potent so beter to give than prednisolone

shows relative POTENCOIES

Question 11

Pharmacokinetics

Answer 11

• Oral steroids have similar bioavailability
• Hepatic and renal clearance
• Clearance decreases with age

all steroids are metabolised in the liver can undergo phase 1 and phase 2 elimination if phase 2 - glucoronidation in the liver to make it more water soluble to be removed more easyer by the kidney, kidney can metabolise cortisol to cortisone which is inactive not only just clearance​

Question 12

State the routes of administration

Answer 12

steroids are very lipid soluble so can be administered by various/many routes

topical- get drug to were you want it to act ewithought the systemic side effects like the IV and oral route (long term)

inhaled e.g. betamethasone for asthma - reduce inflammation

eczema topical

intra-articular - pain relief

• Oral (by ingestion through the mouth) e.g., prednisone, prednisolone, methylprednisolone, betamethasone, hydrocortisone, dexamethasone
• Parenteral (intravenous or intramuscular) e.g., methylprednisolone, triamcinolone, dexamethasone
• Inhalation (e.g. aerosol in asthma) e.g., beclometasone, budesonide, flunisolide, fluticasone
• Topically (e.g. application to skin) e.g., beclometasone, betamethasone, clobetasol
• In addition, corticosteroids may also be administered by intra-articular, ocular, nasal, rectal (enema), in ear or spinal methods.

Question 13

Corticosteroids and the immune system

Answer 13

1 • Inhibition of B and T cell responses

2 • Inhibition of NF-κB

3 • Reduced transcription of cytokines

4 • Reduced expression of cell adhesion molecules

5 • Reduced phagocytic function

6 • Immunosuppression

7 • Reduced inflammation

Question 14

Mechanism of action of steroid hormones

Answer 14

NF-kB nucklear factor kappa b - key signalling molecule in flammation - if can inhibit this molecule eary on inhibit inflammtion early on

small element if immunosupression

EXAM QUES MOA asking for cellular molecular level- MOLECULAR- steroid binds to receptor (which can be associated with heat shocik protein) - heat shock protein dissociated and receptor is activated, binds to HRE on the DNA - effects can take time

Question 15

Answer 15

trans-repression: range of proteins synthesis is switched on by steroids e.g. Annexin-1 inhibits phospholipase A2 enzymes - reduce free arachidonic less prostagladins can be made

osteocalcium - inhibits osteoblast - thus a reduction means reduced bone formation

keratin in skin- thinning of the skin (not only the proteolysis)

interactions between proteins going on here GC recptor can bind to a binding proein CBP )cyclicAMP binding protein) inhibits NF-kB

growing evidence that some steroids can act on surface receptor e.g. progesterone - rapid response (as second messenger)

know the dexamethosone supression test - i think high dose steroid should inhibit HPA axis but due to cortisol will be high

Question 16

Non-genomic mechanism of action
Evidence that some steroids can act via membrane receptors

Answer 16

steroids have been given to women going into premature labour, can be gicen an acute course of steroids as will pass acrodd placenta lipid soluble and help with ling development, premature baby and respiratory distress syndrome -> beneficial for preterm infants -> not all pass placenta e.g. prednisolone

however dexamethosone in animal studies have seen to effect the brain e.g. hypocampus so question what it might do to the brain

but only used acutely and no evidence yet

Betamethosone might be a better drug as this has no CNS effects in animals

Question 17

Clinical uses of steroid drugs:

Answer 17

• Inflammatory disease
• Immuno-suppression
• Malignancy
• Adrenal insufficiency
• Cushing’s disease diagnosis

​

Question 18

It can be used as replacement therapy give examples of diseases it is used for and the drugs used

Question 19

Inflammatory disease where steroids are used LO

Answer 19

• Asthma (Beclomethasone, Budenoside, Fluticasone, dipropionate, Prednisolone)
• Gastro-intestinal disease
• Inflammatory skin conditions
• Nephrotic syndrome
• Haematological conditions
• Cerebral oedema
• Vasculitis
• Sarcoidosis
• Rheumatoid arthritis (IL - 1, IL - 6)

Question 20

Why do we use steroids in pre term birth

state the steroids given

Answer 20

Single course of antenatal corticosteroids offered to women, who are at risk of preterm birth, between 24 and 34 weeks of gestation.

Betamethasone 12 mg given IM in two doses or dexamethasone 6 mg given IM in four doses. Steroids of choice to enhance lung maturation.

steroids have been given to women going into premature labour, can be gicen an acute course of steroids as will pass acrodd placenta lipid soluble and help with ling development, premature baby and respiratory distress syndrome -> beneficial for preterm infants -> not all pass placenta e.g. prednisolone

however dexamethosone in animal studies have seen to effect the brain e.g. hypocampus so question what it might do to the brain

but only used acutely and no evidence yet

Betamethosone might be a better drug as this has no CNS effects in animals

Question 21

Glucocorticoid side-effects:

Answer 21

• Osteoporosis
• Avascular necrosis
• Peptic ulcers
• Increased infections
• Hypertension
• Diabetes
• Impaired growth
• Skin atrophy
• Cataracts
• Corneal damage
• Cushingoid features
• Psychoactive effects

Question 22

Corticosteroid effects on bone

Answer 22

• Inhibition of osteoblast formation
• Increased osteoclast proliferation
• Reduced calcium absorption in gut
• Reduced sex steroid production
• Osteoporosis

Question 23

Why cant we remove steroid straight away from a patient?

Answer 23

Adrenal suppression

• Suppression of HPA axis occurs after 3 weeks
• Prednisolone > 20mg will suppress HPA axis
• May persist for years if long term treatment
• Abrupt withdrawal may lead to hypo-adrenal crisis

Question 24

Hypoadrenal crisis

Answer 24

• Hypotension
• Hypoglycaemia
• Hyponatraemia
• Hyperkalaemia
• Severe dehydration
• Death if untreated

Question 25

 Appreciate clinical relevance of pharmacogenetics: How genetic variation affects drug efficacy and toxicity LO

1. Pharmacogenetics:
2. Pharmacogenomics:
3. Just because a drug is prescribed for a patient’s condition, it does not automatically follow that:

4. Potential risk factors for drug inefficacy or toxicity

5. Give an example of how genetics effects drugs given for hypertension

Answer 25

1. is the science of understanding how different individual genotypes relate to different drug. This enables physicians to know which drugs will therefore be safe and effective for an individual patient.
2. is pharmacogenetics applied to the entire genome
3. • The treatment will be effective
     - the treatment will not cause adverse drug reactions

This response is in part dictated by pharmacogenetics

4. • Drug-drug interactions

• Age

• Renal and liver function

• Concurrent illness

• Lifestyle variables such as smoking and alcohol consumption

• Genetic Variation – this is constant throughout life and is not always obvious!

5. ACEi / ARB:

• Young Caucasians have higher RAS activity – therefore ACEi / ARB treatment will lower the BP more effectively
• Older and afro-caribbean patients have lower RAS activity – first line therapy includes thiazide diuretics and CCBs

Question 26

 Apply simple two allele genetic model explaining variability in drug efficacy/toxicity (e.g. ACE inhibitors) LO

Question 27

 Give examples of Type ‘A’ and Type ‘B’ ADRs LO

Answer 27

Question 28

 Recognise importance of genetic polymorphism affecting PKs and PDs LO

Give examples

Answer 28

Question 29

 Appreciate how pharmacogenetics will influence future prescribing practice LO

Answer 29

Genetic polymorphism for receptor (PD) and metabolism (PK)

If you have both a metabolism and B receptor aB most likely get a type B ADR

Question 30

The CYP 2D6 isoform is responsible for the metabolism of ~25% of drugs, including certain antidepressants, antipsychotics, β- blockers and opioid analgesics LO

Answer 30

Question 31

Absent or reduced CYP 2D6 activity can lead to ADRs by the following mechanisms:

Answer 31

(1) decreased first pass metabolism and drug elimination (e.g. metoprolol and bradycardia)
(2) accumulation of the drug as a result of reduced metabolism (e.g. perhexilene and hepatotoxicity)
(3) re-routing of metabolism (e.g. paracetamol & methaemoglobinaemia)

​excessive methaemoglobin in the blood. methaemoglobin is an altered state of Hb where ferrous ions (Fe2+) of haem are oxidised to the ferric state (Fe3+) and rendered unable to bind O2. normal level is < 1.5%

Question 32

Answer 32

Question 33

Answer 33

Question 34

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Question 35

Answer 35

Question 36

 Appreciate how pharmacogenetics will influence future prescribing practice LO

Answer 36

Question 37

 Understand the requirement for pharmacovigilance LO