Applied pharmacology Flashcards
What are the two classes of opioid receptors
µ / ð and k
Define opioids
‘A compound resembling opium in its physiological effects’
1 .Bind to specific opioid receptors
- ‘Mimic the action of endogenous peptide neurotransmitters
(for example, endorphins, enkephalins, and dynorphins)’
How do opioids work centrally?
- Opiates reduced inhibition of the descending pain pathway by increasing its activity.
- This increases the release of seretonin.
- This increases release of endogenous opiates
•Nociceptin receptors – descending control
Describe the steps in the arachidonic acid cascade
- Phospholipase A2 produces Arachidonic acid (AA) from fatty acids
- COX enzymes convert AA into intermediates
- Other enzymes convert intermediates into prostanoids- prostaglandin or thromboxanes
State 3 side effects of strong opioids such as morphine
- Constipation
- Depression of cough reflex
- Respiratory depression
- Nausea & vomiting (central / enteric)
- Tolerance effects (adaptation of 2nd messenger cascade)
Why is paracetamol a sort of NSAID
Non-opioid – not strictly an NSAID
Targets COX2 (maybe cox-3) in CNS
Poor peripheral COX1/2 inhibition
How do NSAIDs effects platlet aggregation
COX-1 inhibition reduces thromboxane A2 production, which prevents the haemolytic cascade
Describe effects of tramadol
- Racemic mixture
- Multiple therapeutic targets
- Acts at µ opioid receptors
- Serotonin / norepinephrine reuptake inhibitor
Less potential for-
respiratory depression
GI effects
(low dependency risk also)
How do gabapentin/pregablin (anticonvulsants) work for pain relief?
They antagonise thrombospondin
(secreted by astrocytes and agonist at VG ca2+ channels)
Thrombospondin promotes synaptogenesis- which can be linked to maintenance of central chronic pain
What are 2 effects of long term use of strong opioids
- Possible immune suppression (downregulation of t-killer and macrophages)
- Decreased sex hormone production
- Opiate induced hyperalgesia - have effects on astrocytes/microglia to drive release pro-inflam cytokines which driver peripheral/central sensitisation
How do NSAIDs negatively impact the kidneys
- prostaglandins cause vasodilation in the kidney
- NSAIDs reduce renal filtration, and reduce sodium retention
- Leads to physical damage to the nephron
How can antidepressants i.e. fluoxetine reduce pain?
•Selective serotonin reuptake inhibitors e.g. fluoxetine
- Reduces reuptake of seretonin
- greater activation of enkephalin containing interneurons in dorsal horn
Also involved in:
- Sodium channel blockade i.e. neuronal excitability
- NMDA receptor antagonism i.e. reduced central sensitisation
How do NSAIDs have antipyretic effects
NSAIDS reduce PGE2 production by binding to COX-2
Pyrogens – stimulate PGE2 in hypothalamus
PGE2 – inhibits temperature sensitive neurons making us think we’re cold = shiver = increased temperature
Finish this table:
Receptor: µ / ð
- Analgesia
- Respiratory depression
- Pupils
- GI motility
- Smooth muscle spasm
- Behaviour
- Dependence
- Analgesia- supraspinal / spinal / peripheral
- Respiratory depression ++
- Pupils- constriction
- GI motility- reduced
- Smooth muscle spasm- ++
- Behaviour- euphoria ++ and sedation ++
- Dependence- ++
How do opioid receptors cause a reduction in pain signals
- opioid receptors are a type of g-protien coupled receptor
- they are involved in the downregulation of cell excitability by blocking:
- dorsal horn pre-synpase (reduced Ca2+)
- dorsal horn post-synpase (K+ channel leak)
What is the site of action, and function of COX 2 enzymes?
- Mast cells, fibroblasts, macrophages
- Endothelial cells,
- More in nuclear membrane
- Inflammation
- Pain
- Fever
Describe what happens to codiene in the liver, and its side effects
codiene is converted to morphine by cytochrome p450
side effects include: respiratory depression and GI motility
How does capsaicin work?
- Massive activation of TRPV1 receptors (temp sensitive, nociceptor)
- Release of Substance P
- Leads to depletion of substance P
Describe the pharmacokinetics of NSAIDs
- Absorption from stomach & small intestine
- Significant plasma binding (albumin)
- Hepatic metabolism
- Some NSAIDs enter enterohepatic circulation
Different NSAIDs have different binding selectivities. What does this mean in relation to COX enzymes
Some NSAIDS will act more on COX 1 or 2- affect different tissues, having different therapeutic effects
Benefits of COX-2 selective NSAIDS?
- Fewer gastric complications
- Reduced effect of platelet aggregation
What is the site of action, and function of COX 1 Enzymes?
- Most tissues / cells
- Mainly endoplasmic reticulum
- Gastric protection
- Blood flow
- Platelet aggregation
What are the 4 main therapeutic effects of NSAIDs
- Anti-inflammatory
- Analgesic
- Antipyretic
- Platelet aggregation
How do NSAIDs have analgesic effects
- Inhibition of COX-2 derived prostaglandins
- Reduced sensitisation of free nerve endings
How do NSAIDs negatively affects the GI tract
- prostaglandins promote bicarbonate containing muscus in the stomach (protective)
- NSAIDs reduce prostaglandin production
- over time could lead to stomach ulceration
How do NSAIDs have antiinflammatory properties
- Inhibition of COX-2 derived prostaglandins
- Which are powerful vasodilators
- Promote release of other vasodilators
- e.g. substance P and histamine
=
- Reduced oedema
- Reduced swelling
- Reduced redness
What are the 3 main mechanisms of anticonvulsants as a painkiller
- Enhancement of GABA action
- Inhibition of voltage-dependent sodium channels
- Inhibition of T-type calcium channels
What are NSAIDS
non-steroidal anti-inflammatory drugs i.e. ibuprofen
How can an overdose of paracetamol cause liver damage
- drug detoxified by liver
- processed by cytochrome p450
- converted into NAPQI (v harmful to liver tissue)
- NAPQI immediately conjugated with glutathione
- but there is a limited supply of glutathione
- So if NAPQI builds up, causing irreversible liver damage
How do NSAIDs negatively impact the respiratory system
- They can cause ‘aspirin induced asthma’
- Where the blocking of COX enzymes mean more lipoxygenase production (from Arachinodonic acid)
- Lipoxygenase increases production of leukotrienes (prominant bronchoconstrictors)
- This can exacerbate asthma symptoms
How do NSAIDS disrupt the arachidonic acid cascade?
NSAIDS block the action of the COX enzymes, thus reducing prostaglandin/thromboxane production
What does activation of µ-opioid receptors do
- located on free nerve endings
- reduces 1st order nociceptor sensitivity
Purpose of analgesics?
To control symptoms and improve QoL by reducing pain/perception of pain
State 2 ways in which NSAIDs may cause liver damage
- Retention of bile (cholestasis)
- Mitochondrial damage
- Inhibition of prostaglandin E2 production
- Reactive metabolites
What is the WHO ladder of opioids
3 steps meant to promote a better use of stronger analgesics
Step 1- non opioids i.e. paracetamol
Step 2- mild opioids i.e. codiene
Step 3- strong opioids i.e. morphine
Finish this table:
Opioid receptor: K
- Analgesia
- Respiratory depression
- Pupils
- GI motility
- Smooth muscle spasm
- Behaviour
- Dependence
- Analgesia- spinal
- Respiratory depression- +
- Pupils- no effect
- GI motility- no effect
- Smooth muscle spasm- no effect
- Behaviour- dysphoria + sedation +
- Dependence +
What systems have common side effects of NSAIDs
•Gastrointestinal/renal/respiratory
State 3 pharmacological approaches to pain management
- analgesics
- nerve block/transmission
- complementary therapies i.e. accupuncture
How do NSAIDs affect pain central sensitisation
- COX inhibition in dorsal horn-
- Reduced prostaglandin production
- Reduced transmitter release
- Reduced 2nd order neuron sensitivity
What are the three classes of opioids
- natural
- semi-synthetic
- synthetic
