Flashcards
analgesics
Flashcards do conjunto (55)
- 1Analgesic CategoriesNSAIDs
Opioids
Paracetamol - 2what are the chemical mediators of painserotonin
substance P
bradykinin
leukotrines
histamine
thromboxjnes and prostaglandins (eicosanoids - synthesis blocked by NSAIDs) - 3Inflammatory mediatorsbradykinin
PGE
histamine
CCL2
CCL5
CxCL1
(GPCRs) - 4how are Eiconasoids formedunsaturated 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 - 5COX enzyme pathwayCOX enzymes are localised close to the cell membrane; inflammatory mediators activate COX-2
COX2 can increase by 50-100 fold during inflammation - 6Prostaglandins -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.
- 7what is the major prostaglandin mediating pain response?PGE2
- 8major 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) - 9NSAIDs - a bit of backgroundall 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 - 10NSAIDs- actionsanalgesic
antipyretic
anti-inflammatory - 11NSAIDs MOAanti-inflammatory = decrease in PGs and inflammation
analgesia = reduction of PGs in tissue, reduces nociception
antipyretic = blocks IL-1 to PGE2 in hypothalamus. - temperature reduction - 12NSAIDs COX Selectivitymost 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 - 13inhibition of COX-1this results in unwanted effects
impaired gastric cytoprotection
anti-platelet effects - 14inhibition of COX-2anti-inflammatory
analgesic - 15COX 2 specific NSAIDsRofecoxib (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 - 16NSAID adverse effects - brief listNSAID induced nephrotoxicity
airway resistance leading to asthma
NSAID induced gastropathy - 17NSAID GI AEsintolerance and ulceration:
nausea
dyspenia
heartburn
ulcers
this is because they block 'house keeping' prostaglandin production important in regulation of GIT mucosal protection - 18why give misoprostol with NSAIDsmisoprostol is a prostaglandin E1 analogue and is used to prevent NSAID induced ulcers
- 19NSAIDs AEs RENALkidney 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.
- 20NSAIDs AE prolongation of bleedingprevention 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.
- 21Avoiding GI problems with NSAIDsuse 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* - 22paracetamol / acetaminophencommonly 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 - 23glutathione (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
- 24opioids - how do they workopioids 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.
- 25Opioid Receptors Effects: muμ opioid receptor
- supra spinal analgesia
- sedation
- respiratory depression
-hypothermia
- euphoria
- pupil constriction
- reduced GI motility
- nausea, vomiting
-urinary retention - 26Opioid Receptors Effects: Kappaκ opioid receptor
- spinal analgesia
- sedation
-dysphoria
- diuresis - 27Opioid Receptor Effects: Deltaδ opioid receptor
- analgesia
- respiratory depression
-nausea and vomiting - 28μ opiod receptor endogenous ligandsβ-endorphin
endomorphins - 29κ opioid receptor endogenous ligandsdynorphins
- 30δ opioid receptor endogenous ligandsenkephalins
- 31μ opioid receptor - locationmost concentrated in the brain, responsible for most of the analgesic effects of opioids
- 32κ opioid receptor - locationsspinal level contribution to analgesia, few unwanted effects
- 33δ opioid receptor locationsmost potent in the periphery, may contribute to analgesia
- 34more about opioid receptorsthey 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. - 35role of endogenous opioidsmodulation of: (results in reduction)
pain
response to stress
respiration
motional response
increase in pleasure (like a runner's high) - 36Exogenous Opioid Agents - 4 categories1) original opiate (opium - form poppy seeds)
2) morphine, codeine (derivatives of opium)
3) chemical derivatives of morphine (heroin)
4) synthetic opiates (fentanyl, methadone) - 37direct effects of opioids due to inhibition of nerve transmissionanalgesia
reduced distress
sedation
euphoria
respiratory depression
pupil constriction
reduced body temp
dry mouth
GIT issues - 38HEROINDeveloped 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. - 39opioid activity is dependent on structure and addictive properties is related to their potential as pain releiverthey were trying to come up with a non addictive opioid but have long given up hope, as I have, with general life.
- 40antagonists of opioidsnaloxone
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 - 41strong opioidsmorphine
oxycodone
methadone
fentanyl
sufentanil
remifentanil
hydromoprhone - 42weak opioidscodeine
dextropropoxyphene
loperamide (anti-diarrhoeal) - 43partial opioid agonistbuprenorphine
- 44codeineprodrug
metabolised by CYP2D6 to convert to morphine
going to script in 2018 - 45fentanyl <3fentanyl has a high affinity for the mu receptor
- 46methadoneused to help people who have heroin addiction
can be just as deadly if misused - 47route of administration matersefficacy 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) - 48opioid Adverse effects - ACUTErespiratory depression
sedation (O/D - CNS effect)
Nausea/vomit (GI nerve blocking) - 49opioid adverse effects CHRONICconstipation (GI block)
endocrine effects
osteoporosis - 50mechanism of opioid toleranceit 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 - 51withdrawal from opioidsadaptations 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. - 52opioid DDIsother 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 - 53methylnatrexonedrug used to relieve opioid induced constipation *opioid antagonist*
- 54long term opioid use effect on endocrine systemreduction 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. - 55opioids and osteoporosiselevated risk of fractures with long term opioid use due to decreased bone mineral density due to endocrine disruption and effect on osteoblasts/