Applied Pharmacology - Analgesia Flashcards
Analgesic
Objective of treatment in all types of pain, irrespective of origin, is to achieve symptom control and improve the patients quality of life
A drug that relieves or reduced pain
Interferes and reduces the pain experience
NSAIDs
Non-steroidal anti-inflammatory drugs
Arachidonic acid cascade
AA produced by the enzyme phospholipase A2
Cyclooxygenase (COX) converts AA into intermediates then converted into prostanoids
Arachidonic acid cascade: prostanoids
Chemicals
Prostaglandins - inflammation, activation of nociceptive nerve endings
Thromboxane - blood clotting, haemostasis
Arachidonic acid cascade: NSAIDs
Block the Arachidonic acid binding site on COX
The action of prostanoids are inhibited
The rest of the cascade is stopped
COX enzymes: COX 1
Humans
Most tissues and cells
Mainly endoplasmic reticulum
Gastric protection
Blood flow
Platelet aggregation
Prostroglandins and thromboxane
COX enzymes: COX 2
Humans
Inflammatory cells - mast cells, fibroblasts, macrophages
Endothelial cells, more in nuclear membrane
Inflammation
Pain
Fever
COX enzymes: COX 3
Mainly found in CNS (animal models)
Poorly understood
May not be active in humans
NSAIDs example molecules
Aspirin
Ketoprofen
Fenoprofen
Celecoxib
Binding selectivity of NSAIDs - which NSAIDs will interfere with with enzyme
COX 1 and 2 selective
NSAIDs example molecules: more COX 1 selective
E.g. ketoprofen
More prevalent effects - gastric protection, blood flow, platelet aggregation
NSAIDs example molecules: more COX 2 selective
E.g. celecoxib
More prevalent effects - inflammation, pain, fever
NSAIDs mechanism of action
Anti-inflammatory
Analgesic
Antipyretic
Platelet aggregation
NSAIDs mechanism of action: anti-inflammatory
Inhibition of COX 2 derived prostaglandins
Powerful vasodilators and promote substance P and histamine
COX 2 inhibition causes reduced vasodilation, oedema, swelling, redness and neurogenic inflammation
Control inflammatory response
Less prostaglandins means decreased inflammatory response
NSAIDs mechanism of action: analgesic
Inhibition of COX 2 derived prostaglandins
Reduced sensitisation of free nerve endings
COX not activating free nerve endings so less pain is felt
Guard against peripheral sensitisation
NSAIDs mechanism of action: analgesic - Dorsal horn
COX inhibition in dorsal horn
Reduced prostaglandin production, transmitter release and 2nd order neurone sensitivity
Fewer nociceptive signals travelling up spinal cord to the brain
Reduce peripheral and central sensitisation
NSAIDs mechanism of action: antipyretic
Pyrogens - stimulate prostaglandin E2 (PGE2) in hypothalamus, inhibited temperature sensitive neurones so the body temperature increases causing a fever
NSAIDs reduce PGE2 production by binding to COX 2
Controls fever and cause the body temperature to decrease
NSAIDs mechanism of action: platelet aggregation
COX 1 inhibition reduced thromboxane A2
Causes reduction in blood clotting and platelets
Aspirin - convalescence binding
Platelets never recover the ability to aggregate
New platelet production required
NSAIDs side effects
Gastrointestinal
Respiratory
Renal
Liver
NSAIDs side effects: gastrointestinal
Prostaglandins promote production of alkali mucus in the gastrointestinal tract
Blocking COX 1 means less prostaglandins
Causes decrease in production of alkali mucus
Leads to less protection causing damage and inflammation
Aspirin induced gastritis and ulceration
COX 2 - fewer gastric complications but increases thrombic/ cardiovascular risks
NSAIDs side effects: respiratory
Aspirin induced asthma
NSAIDs block prostaglandin and thromboxane pathway
More Arachidonic acid available for lipoxygenase
Too much leukotriene is produced
Causing to much bronchoconstriction
Leading to asthmatic symptoms
NSAIDs side effects: renal
Prostaglandins promote vasodilation and therefore glomerular filtration
NSAIDs block COX so less prostaglandin
Causes reduced vasodilation and filtration also causes sodium retention
Causes an accumulation of damaging metabolites which stay in the body
Lead to damage to the kidney
NSAIDs side effects: liver
Low incidence
Retention of bile - destroys hepatocytes
Mitochondrial damage - less ATP production
Inhibition of PGE2 - increased cell death
Reactive metabolites - breakdown of NSAIDs triggers autoimmune response, attack hepatocytes
Endoplasmic reticulum stress - not able to produce and process proteins, cause stress on the liver and rest of body
Paracetamol
Pain relief/ antipyretic effect
Non-opioid and not a NSAIDs
Action on COX 1 and 2 are poor
Targets COX 2 in CNS - may be a serotonin agonist
Not inhibit platelet aggregation
Not damage gut mucosa
Activation of descending inhibitory pathways
Reduce prostaglandin production or activate cannabinoid receptors
Paracetamol: usual dose
Up to 1g three to four times per day
Not exceeding 4g per day
Paracetamol: pharmacokinetics
Metabolised by cytochrome P450 in the liver into NAPQI
NAPQI - really toxic, damage proteins, DNA and RNA
NAPQI converted into glutathione then glutathione conjugate
NAPQI is detoxified so has become inactive and excretable
Paracetamol overdose
Do not exceed 4g daily
Glutathione - limited supply, only enough to detoxify metabolites of 4g of paracetamol
Cause more toxics
Opioids
Compound resembling opium in it physiological effects
Binds to specific opioid receptors
Mimic the action of endogenous peptide neurotransmitters e.g. endorphins, enkephalins and dynorphins
Opioid receptors
Mu (u) and delta (d)
Kappa (k)
G-protein coupled receptors - opioid receptors, facilitate the down regulation of nerve cell excitability, effect ion channels and activation of genes
Opioid receptors: Mu (u) and delta (d)
Found in the supraspinal (brain), spinal and peripheral areas
Angesia, euphoria
Opioid receptors: kappa (k)
Found in spinal areas
Desphoria, discomfort
Molecular mechanisms - spinal cord: 1st order neurone
Decreased activity of calcium channels
Less glutamate release
Causing reduced transfer of nociceptive information across the synapse
Molecular mechanisms - spinal cord: 2nd order neurone
Increased potassium channels
Leads to decreased neuronal excitability, sensitivity and level of nociceptive information to the brain
Molecular mechanisms - spinal cord: overall effect
Decreasing neuronal excitability
Decreased sensitivity of synapse
Reduction of nociception, leading to analgesia
General mechanism - peripheral
U-opioid receptors found on free nerve endings
When activated decrease the excitability of the free nerve endings/ 1st order neurone
Decreased nociceptive signal to the central nervous system
Central analgesia mechanisms
Limbic system - decrease salience of nociceptive signals and pain experience
Brain stem - nociceptive receptors, activates descending inhibitory pathways, decreasing nociceptive information to the brain
Spinal - inhibition of nociception
Supraspinal effects - limbic system and brainstem
Nociceptin receptors - descending control
Mild opioids
Morphine analogues e.g. codeine
Synthetic derivative e.g. tramadol
Weakly activating opioid receptors
Lower efficacy at the receptor
Codeine - converted in the liver by cytochrome P450 into morphine which is a stronger opioid
Strong opioids
Morphine analogues e.g. morphine
Synthetic derivative e.g. fentanyl
Strong agonist of opioid receptors
High potency/ good efficacy
Fentanyl - synthetic opioid
Jansenn - invented by humans
Opioid side effects
Constipation - down regulate nerves, less movement of faeces
Depression of cough reflex - infection, not clearing the throat, controlled by brainstem
Respiratory depression - respiratory areas of brainstem, down regulate inspiratory neurones
Nausea and vomiting - central/enteric, brainstem
Tolerance effect - adaptation of 2nd messenger cascade, dopaminergic reward pathway, when activated increase release of dopamine, overuse 2nd order neurone becomes less sensitive
Euphoria
Physical dependence
Opioid long term issues
Immune suppression - chronic use, infection risk
Decreased sex hormone production
Opiate induce hyperalgesia - change signalling, support cells have opioid receptors, long exposure causes down regulation of synapse, release pro-inflammatory chemicals, increases sensitivity, switched the synapses to increase its sensitivity
Local anaesthetics
Mode of action - block VGSC
Injected close to nerve and diffuse into it
Partition into the cytoplasm through cell membrane
Selectively blocks VGSC from the inside of the cell
Causes the channels to become inactive
Leads to decreased pain, sensitivity and excitability
