Analgesia Flashcards
NSAIDs mechanism of action
Prevent breakdown of arachadonic acid and synthesis of prostaglandins by inhibiting COX enzymes.
COX-1 in found in all tissue and COX-2 is induced in inflammation. NSAIDs inhibit both. Produces analgesia, anti-inflammatory action and antipyretic action.
Can be irreversible: aspirin
Competitive: ibuprofen
Reversible: paracetamol
Describe the analgesic effect of NSAIDs
Analgesic effect produced by inhibition of prostaglandins at the site of pain and inflammation. Largely a peripheral effect.
Prostaglandins sensitise nocicepors to bradykinin, histamine and 5HT (inflammatory mediators) which amplify the pain signal.
Prostaglandins in the CNS act on prostanoid receptors to increase activity of VG-Na+ channels increasing sensitivity to pain signals.
Inhibting prostaglandin production reduces the effect.
Why can NSAIDs be used as an anti-inflammatory?
Prostaglandins produce increased vasodilation, vascualar permeability and oedema in an inflammatory reaction.
Inhibiton of prostaglandin synthesis therefore reduces this.
Name 3 classes of NSAIDS
Salicylic acid: aspirin
Propionic acid: ibuprofen
Acetic acid: indometacin
Fenemates: Mefenamic acid
para-aminophenols: paracetamol
Adverse effects of NSAIDs
GI: nausea, dyspepsia, vomiting, ulcer formation. PGs normally inhibit acid secretion and promote gastric mucus production.
CV incidents: causes thrombosis
Tinnitus
Renal: damage and nephrotoxicity. PGs cause vasodilation in the renal medulla and glomeruli to control renal blood flow and excretion of salt and water. Reduced renal blood flow may result in renal failure.
Hypersensitivity: Bronchospasm, rash,
Name 3 endogenous opiods
enkephalin
endorphin
endomorphin
dynorphin
Downstream effects of opiod receptor activation
Activation of receptors by opiods results in:
inhibiton of adenylate cyclase, therefore reduced CAMP
Inhibiton of VG-Ca2+ channel opening
K+ channel activation, causing hyperpolarisation
Clinical effects of NSAIDs
Anit-inflammation
Anti-pyretic
Analgesic (Ibuprofen)
Anti-coagulant (Aspirin)
Drug interactions of NSAIDs
Increased risk of bleeding with SSRIs
Increased risk of nephrotoxicity with ACEi and diuretics
Enhances effects of other anti-coagulant drugs
Describe the effects of PLA2
Activation of PLA2 converts phospholipids in the cell membrane to Arachadonic acid.
Arachadonic acid is converted to endoperoxides (PGH2) by COX enzymes.
PGH2 is the precursor for prostaglandins which result in hyperalgesia, thromoxane A2 which causes platelet activation and vasoconstriction and prostacyclins which cause vasodilation
Analgesic action of NSAIDs
When tissue is damaged, chemical mediators e.g. bradykinin, 5-HT and H+ depolarise C fibres. Prostaglandins sensitise nociceptors to these mediators which lower the threshold for firing.
Inhibiting PG synthesis produces analgesia
Give 3 examples of clinical uses of NSAIDs
Analgesia:
Short term - ibuprofen, naproxen (stronger)
Non-inflammatory - paracetamol
Chronic - piroxicam
Anti-inflammatory:
ibuprofen/naproxen to start, then piroxicam
COX-2 inhibitors used in patients with risk of GI effects (etoricoxib, celecoxib)
Fever: paracetamol
Anti-pyretic action of NSAIDs
During fever, endogenous pyrogens (IL-1) are is produced in the hypothalamus to increase temperature. This is associated with an incrase in prostaglandins in the brain.
NSAIDS prevent the effects of IL-1 by preventing an increase in prostaglandins.
Side effects of opiods
Respiratory Depression
Conscious Depression/Mood Alterations
Miosis
Reduced Gastric Motility
Nausea and Vomiting
Smooth muscle spasm
Anaphylaxis
Psychiatric changes
Clinical uses of opiods
Analgesia
Anaesthesia (fentanil, alfentanil)
Antitussive (relieves or suppresses cough)
Antidiarrhoeal (codeine, loperamide)
Coronary care
Cancer care (diamorphine, morphine)
Mechanism of action of opiods
Opiods inhibit transmission of pain in the dorsal horn mainly by presynaptic inhibition of afferent impulses.
Opiods receptors are GPCRs that inhibit adenylate cyclase, decreasing cAMP.
Activation causes K+ channels to open, hyperpolarising the cell and closes Ca2+ channels which inhibits transmitter release. This reduces post-synaptic activity, action potentials in nociceptive fibres are inhibited.
Opiods also activate descending inhibition of pain by inhibiting GABA-ergic interneurones in the PAG (disinhibition)
What are endorphins
Endogenous compounds released in the CNS in response to pain.
µ-receprots cause analgeia at a supraspinal level and are responsible for drug-induced euphoria, respiratory depression and drug dependence
K-receptors cause analgesia at the spinal level. Produce miosis and sedation.
Treatment of neurogenic pain
Neurogenic pain normally results from damage to the CNS, and is felt in the periphery e.g. neuralgia
Does not respond to analgesics.
Treated with Tri-cyclic antidepressants and anti-epileptic drugs
How does morphine produce analgesia?
Morphine relieves both sensory and emotional components of pain.
It produces analgesia by:
- inhibiting the transmission of pain in the dorsal horn
- activating the descending pathways in the PAG that inhibit pain transmission in the dorsal horn
- inhibiting activation of nociceptive afferents in the tissues
Feeling of euphoria mediated by µ-receptors.
Side effects of opiods
Respiratory depression: activation of µ-receptors reduces teh sensitivity of the respiratory centre to CO2.
Nausea and vomiting: stimulation of the chemoreceptor zone in the medulla
Miosis: stimulates the oculomotor nucleus which mediates parasympathetic constriction of the pupil
Constipation: Opiods inhibit enteric nerves, reducing gut motility. Useful in treatment of diarrhoea
Biliary spasm: causes spincter of Oddi to contract
Opiate antagonists
Naloxone.
Used in opiate overdose and to reverse the effects of opiates e.g. respiratory depression and coma.
Symptoms of aspirin overdose
Tinnitus
Hypoventilation
Dyskinesia
Hallucinations
Tachycardia/bradycardia
