Applied Pharmacology - Analgesia

Question 1

Analgesic

Answer 1

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

Question 2

NSAIDs

Answer 2

Non-steroidal anti-inflammatory drugs

Question 3

Arachidonic acid cascade

Answer 3

AA produced by the enzyme phospholipase A2
Cyclooxygenase (COX) converts AA into intermediates then converted into prostanoids

Question 4

Arachidonic acid cascade: prostanoids

Answer 4

Chemicals
Prostaglandins - inflammation, activation of nociceptive nerve endings
Thromboxane - blood clotting, haemostasis

Question 5

Arachidonic acid cascade: NSAIDs

Answer 5

Block the Arachidonic acid binding site on COX
The action of prostanoids are inhibited
The rest of the cascade is stopped

Question 6

COX enzymes: COX 1

Answer 6

Humans
Most tissues and cells
Mainly endoplasmic reticulum
Gastric protection
Blood flow
Platelet aggregation
Prostroglandins and thromboxane

Question 7

COX enzymes: COX 2

Answer 7

Humans
Inflammatory cells - mast cells, fibroblasts, macrophages
Endothelial cells, more in nuclear membrane
Inflammation
Pain
Fever

Question 8

COX enzymes: COX 3

Answer 8

Mainly found in CNS (animal models)
Poorly understood
May not be active in humans

Question 9

NSAIDs example molecules

Answer 9

Aspirin
Ketoprofen
Fenoprofen
Celecoxib
Binding selectivity of NSAIDs - which NSAIDs will interfere with with enzyme
COX 1 and 2 selective

Question 10

NSAIDs example molecules: more COX 1 selective

Answer 10

E.g. ketoprofen
More prevalent effects - gastric protection, blood flow, platelet aggregation

Question 11

NSAIDs example molecules: more COX 2 selective

Answer 11

E.g. celecoxib
More prevalent effects - inflammation, pain, fever

Question 12

NSAIDs mechanism of action

Answer 12

Anti-inflammatory
Analgesic
Antipyretic
Platelet aggregation

Question 13

NSAIDs mechanism of action: anti-inflammatory

Answer 13

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

Question 14

NSAIDs mechanism of action: analgesic

Answer 14

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

Question 15

NSAIDs mechanism of action: analgesic - Dorsal horn

Answer 15

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

Question 16

NSAIDs mechanism of action: antipyretic

Answer 16

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

Question 17

NSAIDs mechanism of action: platelet aggregation

Answer 17

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

Question 18

NSAIDs side effects

Answer 18

Gastrointestinal
Respiratory
Renal
Liver

Question 19

NSAIDs side effects: gastrointestinal

Answer 19

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

Question 20

NSAIDs side effects: respiratory

Answer 20

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

Question 21

NSAIDs side effects: renal

Answer 21

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

Question 22

NSAIDs side effects: liver

Answer 22

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

Question 23

Paracetamol

Answer 23

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

Question 24

Paracetamol: usual dose

Answer 24

Up to 1g three to four times per day
Not exceeding 4g per day

Question 25

Paracetamol: pharmacokinetics

Answer 25

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

Question 26

Paracetamol overdose

Answer 26

Do not exceed 4g daily Glutathione - limited supply, only enough to detoxify metabolites of 4g of paracetamol Cause more toxics

Question 27

Opioids

Answer 27

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

Question 28

Opioid receptors

Answer 28

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

Question 29

Opioid receptors: Mu (u) and delta (d)

Answer 29

Found in the supraspinal (brain), spinal and peripheral areas Angesia, euphoria

Question 30

Opioid receptors: kappa (k)

Answer 30

Found in spinal areas Desphoria, discomfort

Question 31

Molecular mechanisms - spinal cord: 1st order neurone

Answer 31

Decreased activity of calcium channels Less glutamate release Causing reduced transfer of nociceptive information across the synapse

Question 32

Molecular mechanisms - spinal cord: 2nd order neurone

Answer 32

Increased potassium channels Leads to decreased neuronal excitability, sensitivity and level of nociceptive information to the brain

Question 33

Molecular mechanisms - spinal cord: overall effect

Answer 33

Decreasing neuronal excitability Decreased sensitivity of synapse Reduction of nociception, leading to analgesia

Question 34

General mechanism - peripheral

Answer 34

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

Question 35

Central analgesia mechanisms

Answer 35

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

Question 36

Mild opioids

Answer 36

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

Question 37

Strong opioids

Answer 37

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

Question 38

Opioid side effects

Answer 38

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

Question 39

Opioid long term issues

Answer 39

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

Question 40

Local anaesthetics

Answer 40

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