Session 15 opioids Flashcards
- What are the three layers of the adrenal glands?
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
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
- 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
- precess of IDENTIFYING & RESPONDING to SAFETY ISSUES about marketed drugs
- things you would have never knoen about in previosu
FALSE POSITIVES - you think drug is unsafe but not to actually do with the drug
Be familiar with the feedback pathway of the HPA axis LO
Appreciate how corticosteroids derive from cholesterol (no need to learn structures!!) LO
- 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
What structures can be derived from cortisol ?
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
Understand the general pharmacology/physiological actions of Glucocorticoids LO
- 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)
State some corticoid drugs
Understand the general pharmacology/physiological actions of Glucocorticoids LO
Using the drug list state which receptors these corticoids act on
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
Explain what this table is showing
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
Pharmacokinetics
- 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
State the routes of administration
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.
Corticosteroids and the immune system
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
Mechanism of action of steroid hormones
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
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
Non-genomic mechanism of action
Evidence that some steroids can act via membrane receptors
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
Clinical uses of steroid drugs:
- Inflammatory disease
- Immuno-suppression
- Malignancy
- Adrenal insufficiency
- Cushing’s disease diagnosis
It can be used as replacement therapy give examples of diseases it is used for and the drugs used
Inflammatory disease where steroids are used LO
- 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)
Why do we use steroids in pre term birth
state the steroids given
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
Glucocorticoid side-effects:
- Osteoporosis
- Avascular necrosis
- Peptic ulcers
- Increased infections
- Hypertension
- Diabetes
- Impaired growth
- Skin atrophy
- Cataracts
- Corneal damage
- Cushingoid features
- Psychoactive effects
Corticosteroid effects on bone
- Inhibition of osteoblast formation
- Increased osteoclast proliferation
- Reduced calcium absorption in gut
- Reduced sex steroid production
- Osteoporosis
Why cant we remove steroid straight away from a patient?
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
Hypoadrenal crisis
- Hypotension
- Hypoglycaemia
- Hyponatraemia
- Hyperkalaemia
- Severe dehydration
- Death if untreated
Appreciate clinical relevance of pharmacogenetics: How genetic variation affects drug efficacy and toxicity LO
- Pharmacogenetics:
- Pharmacogenomics:
- 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
- Give an example of how genetics effects drugs given for hypertension
- 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.
- is pharmacogenetics applied to the entire genome
- The treatment will be effective
- the treatment will not cause adverse drug reactions
- The treatment will be effective
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!
- 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
Apply simple two allele genetic model explaining variability in drug efficacy/toxicity (e.g. ACE inhibitors) LO
Give examples of Type ‘A’ and Type ‘B’ ADRs LO
Recognise importance of genetic polymorphism affecting PKs and PDs LO
Give examples
Appreciate how pharmacogenetics will influence future prescribing practice LO
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
The CYP 2D6 isoform is responsible for the metabolism of ~25% of drugs, including certain antidepressants, antipsychotics, β- blockers and opioid analgesics LO
Absent or reduced CYP 2D6 activity can lead to ADRs by the following mechanisms:
(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%
Appreciate how pharmacogenetics will influence future prescribing practice LO
Understand the requirement for pharmacovigilance LO
