PHARMACOLOGY Flashcards
During his last few months of life the patient was prescribed morphine. Describe how morphine works
- Morphine attaches to opioid receptors (Mu receptors)
- Morphine reduces membrane excitability and hence action potential firing frequency
- Opioids act on the dorsal horn as well as the peripheral terminals of nociceptive afferents neurons
- Thus preventing pain signals travelling up the spinal column
- Morphine also increases release of enkephalins and 5-HT (serotonin) onto dorsal horn neurons via stimulation of the periaqueductal grey matter (PAG) and the raphe nucleus
Describe how paracetamol helps to reduce fever
- Paracetamol is a COX enzyme inhibitor
- It is thought to be selective for COX-3
- COX enzymes stimulate the production of prostaglandins
- In fever, the temperature set point is elevated by the production of PGE2
- Bacteria/viruses act on the immune system and stimulate production of cytokines (IL-1. TNF-alpha) which stimulates PGE2 synthesis
- Paracetamol helps to prevent PGE2 synthesis which is the main compound that alters the homeostatic temperature set point in the hypothalamic neurons that regulate body temperature
- By blocking PGE2 synthesis, paracetamol brings down the temperature set point to normal
where are glucocorticoids secreted from?
- from the cortex within adrenal glands
what are the 3 main types of opioid receptors and their functions?
- Mu (for morphine): analgesia, euphoria (but also constipation, respiratory depression)
- Kappa (for ketcyclazocine): analgesic at periphery (but also dysphoria, hallucinations)
- Delta for vas Deferens: analgesic effects at spinal cord
what are the effects and side effects of morphine?
EFFECTS:
- analgesia, euphoria, sedation, pupil constriction
SIDE EFFECTS:
- nausea and vomiting (chemoreceptor trigger zone in medulla)
- constipation (from reduced motility and muscle tightening)
- respiratory depression (inhibits respiratory centres in brainstem)
- suppressed cough reflex
- tolerance with recurrent use: desensitisation of Mu receptors, dose has to be increased
- dependence: physical (restless, aggression, runny nose, shivering) and psychological (cravings may persist for months and years)
where are opioids metabolised and excreted?
- metabolised in liver
- excreted in urine
what are some considerations to take into account when prescribing morphine?
- most morphine derivatives have a short half-life so have to be given several times a day
- IV/IM morphine: choose lower dose as compared to oral
- synthetic opioid patches go on releasing the drug for days and days so check and remove if toxicity is suspected, or if change in drug/dose is needed
what should you do if patient has toxicity to opioids?
- Naloxone is most important drug (opioid receptor antagonist)
- reverses opioid actions on mu receptor
- given IV/sc in acute opioid toxicity (eg. drowsy patient with small pupils and poor respiration)
- however, can trigger acute physical withdrawal (patient can become aggressive)
what pathways do NSAIDs and aspirin block?
- cyclooxygenase (COX enzymes)
- COX 1, COX 2, COX 3
what pathways do corticosteroids block?
- they block the conversion of phospholipids to arachidonic acid
why can NSAIDs cause GI problems?
- NSAIDs block COX enzymes
- one of the multiple things produced from COX enzymes are prostaglandins
- prostaglandins provide GI mucosal protection which prevents acid from dissolving your stomach
- NSAIDs also directly erode the gastric lining
why do NSAIDs have anti-inflammatory, analgesic, and antipyretic effects?
- Anti-inflammatory: decreases lvls of prostaglandin E2 and prostacyclin
- Analgesic: decreases lvls of prostaglandins which makes nerves less sensitive to inflammatory mediators (eg. bradykinin)
- Anti-pyretic: decreases lvls of IL-1
what drugs can be given to reduce the risk of GI problems?
- Proton pump inhibitor (PPI) or H2 antagonist: to reduce gastric acid
- Misoprostol: prostaglandin analogue that increases gastric mucus to protect stomach
what pathway does methotrexate target?
- folate pathway
what drug should be taken with methotrexate, when should you not give methotrexate, and what drug should you not give methotrexate with?
- folic acid should be given (on another day) to reduce toxicity
- avoid if patient has liver problems
- do not give methotrexate and trimethoprim together
how much and when should methotrexate be prescribed, and folic acid?
- methotrexate 7.5mg once a week (oral or subcutaneous injection)
- folic acid 5mg once a week (on a different day to methotrexate)
- do FBC, renal, and liver function tests regularly
what are the main anti-TNF biologics?
- Infliximab
- Entanercept
- Adalimumab
when should anti-TNF biologics be prescribed according to NICE guidance?
- patient has active RA disease activity
- tried at least 2 DMARDs (including methotrexate) for >6 months
- anti-TNFs should usually be used together with methotrexate
- problem with anti-TNFs: expensive, have to be given by injection or infusion
what should be prescribed if anti-TNF biologics do not work?
- Rituximab: targets CD20
- Tocilizumab: targets IL-6
which corticosteroids are given in what forms?
- local injection: triamcinolone, methylprednisolone
- oral tablets: prednisolone (eg. 30mg daily for 2 weeks in acute flares)
- IV: hydrocortisone, methylprednisolone (eg. 1g a day for 3 days)
what are the side effects of too much steroids/overdose (Cushing’s disease)
- osteoporosis
- obesity
- hypertension
- hyperglycaemia
- myopathy
what are the side effects of too little steroids/withdrawal (Addison’s disease)?
- nausea
- headache
- joint pain
- fever
- hypogylcaemia
- hypotension
what drugs are prescribed for acute gout flare-ups?
- NSAIDs (ibuprofen, naproxen)
- colchicine
- corticosteroid (local injection or oral)
what drugs are prescribed for chronic gout (prevention)?
- allopurinol
- (or febuxostat)
what drugs are prescribed for osteoporosis?
- bisphosphonates
- denosumab
what is the mechanism by which colchicine works?
- inhibtis granulocyte migration
- this causes depolarisation of microtubules
- this causes inhibtion of lymphocyte migration and division
- results in decrease in inflammation
what are the side effects of colchicine?
- nausea and diarrhoea very common
- bone marrow suppression and renal failuer over longer term
when should corticosteroids be given in gout?
- local injection should be given if only single joint affected
- (this is better than patient taking naproxen for eg. for 2 weeks)
when should corticosteroids be given in gout?
- local injection should be given if only single joint affected
- (this is better than patient taking naproxen for eg. for 2 weeks)
what is the mechanism of action for allupurinol?
- Xanthine oxidase inhibitor
- reduces uric acid production
- less likely for urate crystals to form in joints
what is the mechanism by which bisphosphonates work?
- pyrophopshate analogue
- attach to bone crystals and inhibit osteoclast breakdown of bone
what is the main side effect of bisphosphonates?
- GI problems
how does Denosumab work?
- monoclonal antibody: RANK ligand inhibitor
- reduces osteoclast activation, differentiation, and survival
- used if patients cannot have bisphosphonates, 1 injection every 6 months
What enzyme is required to generate arachidonic acid from membrane phospholipids and what drug class can stop this reaction?
Phospholipase A2 and steroids
What enzymes are required to generate Prostaglandins from Arachidonic acid and name 2 drugs which can block these enzymes?
- Cyclooxygenase 1+2 (COX 1+2)
- Aspirin/Non-steroidal anti-inflammatory drugs
