analgesics

Amelia Claire
Flashcards by Amelia Claire, updated more than 1 year ago
Amelia Claire
Created by Amelia Claire over 3 years ago
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existence is pain

Resource summary

Question Answer
Analgesic Categories NSAIDs Opioids Paracetamol
what are the chemical mediators of pain serotonin substance P bradykinin leukotrines histamine thromboxjnes and prostaglandins (eicosanoids - synthesis blocked by NSAIDs)
Inflammatory mediators bradykinin PGE histamine CCL2 CCL5 CxCL1 (GPCRs)
how are Eiconasoids formed unsaturated fatty acids (20 carbons) precursors of eiconsaoids are present in phospholipids of cell membranes. It is liberated by phospholipase A2 (PLA2) it is the limiting step - inflammatory mediators activate PLA2
COX enzyme pathway COX enzymes are localised close to the cell membrane; inflammatory mediators activate COX-2 COX2 can increase by 50-100 fold during inflammation
Prostaglandins - prostaglandin receptors are specified by the class sub-type, they are GPCRs, and therefore can be inhibitory pr stimulatory depending on the receptor type/sub-type. This obviously produces varying signal cascades.
what is the major prostaglandin mediating pain response? PGE2
major receptors mediation PGE2 action in nerves: EP2 - it is GPCR (Gs) stimulatory -> increases cAMP (any receptor that increases cAMP in the nerve will increase the pain signal)
NSAIDs - a bit of background all NSAIDs are COX-inhibitors little difference in the anti-inflammatory activity between NSAIDs co choice depends on patient response and tolerance - main difference is half life and side effects
NSAIDs- actions analgesic antipyretic anti-inflammatory
NSAIDs MOA anti-inflammatory = decrease in PGs and inflammation analgesia = reduction of PGs in tissue, reduces nociception antipyretic = blocks IL-1 to PGE2 in hypothalamus. - temperature reduction
NSAIDs COX Selectivity most NSAIDs inhibit both cox isoenzymes to varying degrees (are non-selective) the anti-inflammatory effects are due to inhibition of COX 2 unwanted effects on house keeping functions due to inhibition of COX -1
inhibition of COX-1 this results in unwanted effects impaired gastric cytoprotection anti-platelet effects
inhibition of COX-2 anti-inflammatory analgesic
COX 2 specific NSAIDs Rofecoxib (vioxx) and Celecoxib COX 2 specific cause a greater decrease in PGI2 and increase TXA2, resulting in greater risk of clots and MI. The TXA2:PGI2 ratio is important for coagulation regulation
NSAID adverse effects - brief list NSAID induced nephrotoxicity airway resistance leading to asthma NSAID induced gastropathy
NSAID GI AEs intolerance and ulceration: nausea dyspenia heartburn ulcers this is because they block 'house keeping' prostaglandin production important in regulation of GIT mucosal protection
why give misoprostol with NSAIDs misoprostol is a prostaglandin E1 analogue and is used to prevent NSAID induced ulcers
NSAIDs AEs RENAL kidney expresses COX-2 constitutively meaning renal ADRs occur with selective COX2 agents. Prostaglandins regulate renal blood flow and fluid balance. they constrict the afferent artery of the nephron, meaning that you reduce GFR.
NSAIDs AE prolongation of bleeding prevention of the formation of platelet aggregation agent, TXA2, accounts for NSAIDs increased bleeding time, the patient is more susceptible to haemorrhage and can mask infection through suppression of pain. Also, bleeding at ulcer sites.
Avoiding GI problems with NSAIDs use paracetamol as an alternative or to lower doses of NSAIDs Use lower risk NSAIDs (diclofenac) use lowest effective dose, for shortest time PPIs to suppress acid production H2 receptor antagonists to suppress histamine induced acid increase mucosal cytoprotective *misoprostol*
paracetamol / acetaminophen commonly used antipyretic, analgesic, with an unknown MOA Risk of hepatotoxicity at only 2-3 x normal max dose (10g) toxic metabolite produced resulting in around 100 deaths annually in the USA
glutathione (phase 2) glutathione detoxifies paracetamol and is the main metabolising paracetamol - it is a phase 2 agent. when it runs out, paracetamol forms toxic NAPQI via phase 1 metabolism
opioids - how do they work opioids block the ascending pathway to suppress the pain signal and they block the reuptake of NA at NET increasing the availability of NA to activate the descending inhibitory pathway, effectively reducing the pain signal this way also.
Opioid Receptors Effects: mu μ opioid receptor - supra spinal analgesia - sedation - respiratory depression -hypothermia - euphoria - pupil constriction - reduced GI motility - nausea, vomiting -urinary retention
Opioid Receptors Effects: Kappa κ opioid receptor - spinal analgesia - sedation -dysphoria - diuresis
μ opiod receptor endogenous ligands β-endorphin endomorphins
Opioid Receptor Effects: Delta δ opioid receptor - analgesia - respiratory depression -nausea and vomiting
κ opioid receptor endogenous ligands dynorphins
δ opioid receptor endogenous ligands enkephalins
μ opioid receptor - location most concentrated in the brain, responsible for most of the analgesic effects of opioids
κ opioid receptor - locations spinal level contribution to analgesia, few unwanted effects
δ opioid receptor locations most potent in the periphery, may contribute to analgesia
more about opioid receptors they are a group of GPCRs - opioids are their ligands. μ opioid receptor is Gi (inhibitory) and inhibits enzyme adenylate, leading to reduced levels of the secondary messenger, cAMP; this reduces cellular excitability and opens K+ channels -> K+ leaves the cell at presynaptic sites; this reduces neurotransmitter release.
role of endogenous opioids modulation of: (results in reduction) pain response to stress respiration motional response increase in pleasure (like a runner's high)
Exogenous Opioid Agents - 4 categories 1) original opiate (opium - form poppy seeds) 2) morphine, codeine (derivatives of opium) 3) chemical derivatives of morphine (heroin) 4) synthetic opiates (fentanyl, methadone)
direct effects of opioids due to inhibition of nerve transmission analgesia reduced distress sedation euphoria respiratory depression pupil constriction reduced body temp dry mouth GIT issues
HEROIN Developed by Bayer marketed for coughs heroin is a pro-drug, it becomes morphine, but it is better at crossing the BBB (more lipophilic) so is twice as potent as morphine.
opioid activity is dependent on structure and addictive properties is related to their potential as pain releiver they were trying to come up with a non addictive opioid but have long given up hope, as I have, with general life.
antagonists of opioids naloxone short acting pure antagonist of morphine works at mu receptor and is used to counter the effects of an opioid OD (morphine or heroin) and counteracts depression of CNS and respiratory system naltrexone long acting antagonist of opioids works at mu and kappa receptors, used to treat alcohol and opioid dependence, reduces cravings
strong opioids morphine oxycodone methadone fentanyl sufentanil remifentanil hydromoprhone
weak opioids codeine dextropropoxyphene loperamide (anti-diarrhoeal)
partial opioid agonist buprenorphine
codeine prodrug metabolised by CYP2D6 to convert to morphine going to script in 2018
fentanyl <3 fentanyl has a high affinity for the mu receptor
methadone used to help people who have heroin addiction can be just as deadly if misused
route of administration maters efficacy can be greatly effected by first pass. e.g. - oral dose = 30mg while injection into the spinal fluid (fun!) is 200 mcg (oral dose = 150x bigger)
opioid Adverse effects - ACUTE respiratory depression sedation (O/D - CNS effect) Nausea/vomit (GI nerve blocking)
opioid adverse effects CHRONIC constipation (GI block) endocrine effects osteoporosis
mechanism of opioid tolerance it occurs due to adaptations that reduce or oppose the opioid effect; it is a homeostatic response and not an indicator of addiction. changes include - decreased number of receptors -decreased production of endogenous ligands - compensatory changes i signalling cascades - e.g., incased expression of adenylate cyclase or calcium channels
withdrawal from opioids adaptations to opioid drugs can also result in withdrawal syndrome upon cessation of use adaptations do not immediately reverse when drugs is no longer present the adaptation produces effects opposite to that of the opioid drug, withdrawal occurs in many people. can manifest as the experience of pain at greater intensity than prior to opioid treatment.
opioid DDIs other sedatives- high risk of respiratory depression with alcohol or other CNS depressants due to additive effects. impairment of cognitive and psychomotor function with benzodiazepines. drugs to lower BP -- hypotensive effect additive constipation - mu opioid agonists inhibit gut motility
methylnatrexone drug used to relieve opioid induced constipation *opioid antagonist*
long term opioid use effect on endocrine system reduction in androgens erectile dysfunction menstrual irregularity sexual dysfunction opioids block nerves in hypothalamus and pituitary, causing artificial reduction in their function by stimulating negative feedback.
opioids and osteoporosis elevated risk of fractures with long term opioid use due to decreased bone mineral density due to endocrine disruption and effect on osteoblasts/
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