Pain week 1 Flashcards
describe nociception and its transmission to the spinal chord and brain
- the physical process of detection and transmission of damaging or potentially damaging stimuli.
- nociception by peripheral activation and release of pain mediators.
-pain gating at the dorsal horn of the spinal cord. - pain perception within the brain (thalamus, limbic and cortical systems)
describe the mechanisms of sensitisation of nociceptors
can be stimulated by high mechanical stim, thermal stim, low pH, chemicals (inflammatory response). Bradykinin + Histamine
Channels affected by bradykinin, prostaglandins and opioids. (opioids reduce sensitivity of channels)
stimuli –> channel opening–> change in membrane voltage–> depolarisation and action potential generation–> transmitter released –> second order ascending neurone response in spinal cord dorsal horn.
describe the modulation of pain pathways at the spinal cord and descending pain pathway
ascending pathway - goes upwards carrying sensory information from body via spinal cord to the brain.
Spinothalamic tract:
Sensory input from first order neurone –> spinal cord (dorsal horn) –> joins second order neurone through medulla –> synapse with neurone in Thalamus –> third order neuron extends to primary somatosensory cortex
descending pathway - neural pathways that go downwards from the brain to reflex organs via spinal cord. Neurones can affect neuronal signals in ascending pathway.
explain the role of opioids, NSAIDS and other agents in analgesia
-either inhibit ascending pain pathway or enhance descending pain pathway to relieve pain
which fibres are responsible for each type of pain
A delta fibber (myelinated) - first pain (sharp)
C fibber (non-myelinated) - second pain (dull burning)
what is allodynia and hyperalgesia in chronic pain development?
Allodynia - pain to non -noxious stimulus
Hyperalgesia - increased pain to mildly noxious stimulus.
where can sensitisation occur?
in the peripheral - increased sensitisation of nociceptors
centrally - transmission to second order neurone in the dorsal horn
how does peripheral sensitisation occur?
- stim by release of bradykinin and prostaglandins increase sensitivity of nociceptors
- allow more depolarisation and generation of action potentials
how does central transmission occur at the spinal cord?
- first order neurone synapsing second order neurone at dorsal horn.
- neurotransmitters e.g. glutamate, CGRP and substance P.
-Bind to NMDA and AMPA receptors. - substance P binds to NK-1 receptors.
-synaptic strengthening - actively repeating activation of fibers causes stronger signal to spine.
how is central wind - up prevented?
reduction of peripheral stimulation NMDA receptor antagonist
how does afferent pain gating at the spinal cord work?(Gate theory of Pain)
non-pain sensory fibres (second order neurones) can synapse with the first order neurone at the dorsal horn. Also connected via inhibitory interneuron, inhibits second order neurone –> reduces pain message travelling up afferent pathways/ascending.
How does the descending pain pathway modulate the ascending pain messages?
- PAG receives input from different brain areas (HUB)
- neurones descend through the medulla to spinal cord (inhibit pain pathway)
-neurones from Locus coeruleus (pons) to spinal cord also inhibit ascending pain pathway.
-when descending pathway is active it inhibits the ascending pathway.
how does peripheral analgesia work with NSAIDS and Aspirin?
non - opioid: Aspirin and NSAIDs inhibit COX/COX2 (catalyses generation of PGE2 from arachidonic acid). Paracetamol unclear.
NSAIDS: Acts on prostanoid receptor. Prostaglandins cause other channels to open. By inhibiting COX enzymes –> prostaglandins aren’t produced–> prostanoid receptor isn’t activated–> other channels don’t open–> no action potential generated in nociceptor.
what are the three main types of opioid receptors and say some key points about them?
mew, kappa, delta (natural ligands are endorphins).
GPCRs, inhibitory of Ca2+ or promote opening of K+ channels. (decreasing excitability leading to hyperpolarisation).
Act peripherally and centrally
centrally they activate pathways by acting on inhibitory interneurons causing disinhibition.
how do opioids act on the descending pain pathway?
- inhibits excitation in periphery (inhibits ascending pathway)
- inhibit transmission in dorsal horn(inhibits ascending pathway)
-activates descending pathway which inhibits the ascending pathway (receptors located in midbrain and medulla)
what are the classes of opioid drugs?
-opiates e.g. morphine and codeine
- synthetic e.g. heroin, oxycodone, methadone, fentanyl
-antagonists e.g. Naloxone/naltrexone
what receptor causes the analgesia effect mostly and where are they located in the CNS?
mu receptor
-forebrain (cerebral hemispheres)
-limbic system (amygdala)
-mid-brain
-spinal (dorsal horn)
which receptors when activated give the feeling of euphoria v dysphoria?
mu - euphoria
kappa - dysphoria
key side effects of opioids
respiratory centre - resp depression even at therapeutic dose
GI tract - reduced motility (constipation)
Cough - depression of cough reflex
chemoreceptive zone - N+V
pupillary constriction -pinpoint pupils
what are the pharmacokinetics of opioids?
most undergo first pass metabolism so less potent orally
codeine has good oral bioavailability
most morphine like drugs have a half life 3-6h
methadone has a half life of 15-30h so easy to use in drug addiction clinics
fentanyl = very potent in transdermal patch form pain relief of 12-24h. May leave a build up of drug even when patch is removed
morphine like drugs inactivated by hepatic metabolism and excreted via kidneys
interactions with benzodiazepines potential resp depression
how do non-opioid drugs work on noradrenaline within the pain pathways?
NA is transmitter of inhib pathway linking locus coeruleus to the dorsal horn. TCAs inhibit NA reuptake so more signalling. SNRIs and tramadol have the same effects
how do anti-seizure medications work e.g. gabapentin and pregabalin as a CCB
reduce primary afferent transmission used for neuropathic pain
how do cannabinoid drugs work for analgesic effects?
- central and peripheral effects
- act on CB1 and CB2 receptors
-help with neuropathic pain
what are the common paediatric dosage forms used for analgesics and examples?
suspensions - solid particles dispersed in aq vehicle e.g. paracetamol (calpol) and ibuprofen (Nurofen) (shake well)
Solutions - drug and excipients and completely dissolved in a liquid solvent e.g. paracetamol elixir BP for mild to mod pain (high ethanol content)
Suppositories - drug is incorporated in water soluble base which melts at body temp usually used for local effect, but can be systemic delivery of paracetamol, diclofenac and aspirin. Paracetamol usually available as 60mg,125mg,250mg,500mg of drug.
Tablets/capsules - older children
what is a orodispersible dosage form and give classifications and how they are manufactured?
formulated to dissolve rapidly in the mouth so that drugs + excipients can be swallowed.
orodispersible tablets - disintegrate within 3 min, using water as liquid medium. Formulated through direct compression and require incorporation of superdisintegrants e.g. croscarmellose Na, crospovidone. Can be formulated from sublimation using volatile substances e.g. methol, camphor. Phase transition method of manufacture - compression of high/low mpt sugar alcohols, heated to leave pores in the tablet.
oral lyophilisates - produced using lyophilisation/freeze-drying. Dosage forms are soft. A solid single dose preparation made by freeze-drying tended to be placed in the mouth before being dissolved. Need to understand phase diagrams.
orodispersible films - single/multi-layer sheets that dissolve in the mouth produced using solvent casting method e.g. Setofilm for nausea and vomiting
granules
four main stages of freeze-drying to create an oral lyophilisates
Freezing stage - carefully controlled to make ice crystals, blister packs exposed to -10 - -30 degrees cel in large drying units using liquid nitrogen.
Vacuum application stage - vacuum is applied to bring pressure down below the triple point.
Sublimation stage - heat of sublimation applied (increased temp/primary drying) Solid phase to gas phase. Vapour continually removed
secondary drying - temp raised to 50 - 60 degrees cel to remove final moisture present.
what dosage forms are used for chronic + moderate to severe pain in paediatrics?
- Parenteral dosage forms e.g. IV paracetamol or morphine
-Buccal route e.g. fentanyl lozenges
-Transdermal route e.g. fentanyl patches
-Intranasal route for specialised delivery of fentanyl using a MAD (mucosal atomization device)
-Medicinal gases e.g. Entonox (mixture of NO and O) short term analgesia administered using mask or mouthpiece
what is PEGylation?
Process of hiding peptide drugs “stealth” in order to avoid processes within the body
what classifies a protein drug from a peptide drug?
protein drugs have > than 50 AAs
most peptide drug classes are hormones e.g. insulin
what are issues with drug delivery of protein drugs?
stability on storage
in vivo delivery (hydrolysis of peptide bond + high MW absorption)
issue of clearance even with IV route
short half -lives for IV
how are protein drugs eliminated from the blood?
- renal excretion
-opsonisation
-neutralising antibodies
-proteolysis
approaches of hiding protein drugs?
1 - attach large MW polymer covalently
2- multiple lower MW polymers added covalently
“halo effect”
- Physiological benefits:
-reduce glomerulus filtration rate, shields from proteases, reduced opsonisation –> reduces clearance + increases half life.
what polymer can be used for hiding protein drugs and its properties?
- biocompatible
-lack immunogenicity
-water soluble
-mobile
-easily attached
-rapidly cleared from body
-Polyethylene glycol (PEG)
what is polyethylene glycol (PEG)
-synthetic linear homopolymer
-become the gold standard polymer of bioconjugation of protein drugs
-becomes heavily hydrated by water molecules due to hydrophilic properties.
issue with PEGylation?
could reduce efficacy if near the active site of the protein drug
how to we create a TNF-alpha inhibitor using Monoclonal antibodies for rheumatoid arthritis?
- Take the Fab portion (variable region) add 2 PEG chains –> increases half life to 13days
-MAB is expressed in E.coli
-Certolizumab pegol/ Cimzia
what is a PEGylated nanoparticle and what have they been used for?
used as carriers of drugs about 1nm-100nm. Critical in the development of Pfizer and Moderna mRNA COVID-19 vaccines. (use of lipid nanoparticles to protect genetic material - lipids are PEGylated)
Nanocarriers suffer from the same pharmacokinetic issues as protein drugs
what are some concerns for PEG antibodies?
may lead to rare side effects due to staying in the body
in response some researches have been trying to use other polymers rather than polyethylene glycol such as zwitterion polymers or other polysaccharides or hydrophilic polypeptides
what is the only non-PEGylated drug on the market which was approved for treatment of haemophilia A?
Sanofi’s efanesoctocog alfa which is compromised of two XTEN polypeptide chains
what is codeine used for, when was it listed as an essential medicine by the world health organisation and what other drugs can it be combined with?
used for pain relief, coughing and diarrhoea
listed as essential in 2021
combined with paracetamol or NSAIDs
if we have morphine, why isolate codeine?
- Morphine is analgesic, codeine is a pro-drug
-Morphine binds extremely well to mu receptors, codeine binds moderately
-Morphine binds to K receptors, codeine does not
-Morphine has a lot of side effects, codeine does not
what are some structural differences between morphine and codeine?
- Morphine has a hydroxyl group where codeine has a methoxy group
- Morphine has a logP = - 0.21 , Codeine has a logP = 1.19
what functional groups are important to the SAR of morphine
-OH group attached to benzyl ring
-benzyl ring
-N attached to methyl group
key points about Fentanyl
- synthetic opioid, lipophilic, opioid agonist
- has analgesic and anaesthetic properties
-selectively binds to mu receptors in CNS
-analgesic effect strong and rapid, 100 times more potent than morphine - commonly used for chronic cancer pain or anaesthesia
-over 100k drug overdose deaths per year in US
compare some drug properties of fentanyl v morphine
- Fentanyl is more potent
-Fentanyl passes through the skin more easily
-Fentanyl passes through membranes more easily
-Morphine remains at the site of administration for longer
-Morphine is more hydrophilic
-Both pass through the BBB
state some properties of paracetamol/acetaminophen
-analgesic and antipyretic (not anti-inflammatory)
-excellent tolerability at therapeutic doses
-Hepatotoxicity in overdose is an issue
-synthesised via acetylation of 4-aminophenol
state some properties of ibuprofen
- NSAID
-analgesic, antipyretic and anti-inflammatory
-commercial compound is racemic
-risks for those with hypertension, CVD or GI disorders
-synthesised from isobutylbenzene via Boots process
what is palliative medicine
reducing severity of symptoms without curing the underlying disease
what is the goal of palliative care
to make sure no patient dies in pain
what to identify to chose treatment of palliative care
-history of pain
-type of pain
-pain intensity
-aetiology
go through the steps of the analgesics ladder
1- non - opioid analgesics e.g. paracetamol and NSAIDs
2 - weak opioids e.g. codeine, dihydrocodeine and tramadol (dependence may occur)
3 - strong opioids e.g. morphine or oxycodone (should not cause euphoria)
how do we initiate morphine stating doses?
- based on symptoms, prev treatment and patient characteristics
-4 hourly dose (6 in a day) - initiate
-rescue doses = 1/10th-1/6th of 24h dose
-titrate against pain until relief satisfactory
Starting dose:
opioid naive = 20-30mg daily in divided doses
switched from weaker opioid: 40-60mg daily in divided doses
-regular review of doses required
what is the approx conversion from morphine to oxycodone?
oral dose about 2/3rds of morphine
what is the main side effect for someone taking 120mg bd of morphine and what can be co-prescribed along side it to help manage it?
Nausea and Vomiting - 30-60% of patients
may need anti-emetics
how do we chose anti-emetic
based on most likely mechanism:
direct or central (GI tract or vomiting centre) - cyclizine
chemical - via CTZ - haloperidol
mechanical - delayed gastric emptying - metoclopramide
what causes constipation with opioids and how is it managed?
- effects in GI tract and spinal cord
-prophylaxis required
-use of regular laxatives e.g. stimulant (biscodyl, senna and laxido). Osmotic (lactulose, macrogols (polyethylene glycols))
adverse effects of opioids
resp depression
urinary retention
mood alteration
drowsiness
cognition
when is fentanyl and buprenorphine used in pall care?
- available as transdermal patches
-used if adverse effects with morphine
-only if pain is stable
-not for breakthrough pain
-slow onset of action
what adjuvants can be used for pain poorly responsive to opioids?
radiotherapy
NSAIDs
bisphosphonates
tricyclic antidepressants
anticonvulsants
corticosteroids
what is kept for record keeping of controlled drugs and requirements
- date supplied
-name and address from whom received
-quantity received
-name and address of person who received
-prescriber or licence holders name
-person collecting schedule 2 controlled drug
-proof of identity provided
-quantity supplied - CD registers should be chronological order, entered promptly, in ink, unaltered
- electronic CD registers must be attributable, audited, capable of being printed, author must be identifiable, must be accessible to inspectors at all times.
what are requirements for the import and export of CD for travellers?
- get a covering letter signed by the prescriber
-may travel with less than three months supply
what form is needed to obtain Sch 2 and 3 controlled drugs
- WP10CDF form obtained from LHB
-hospices and prisons are exempt
requestion requirements for obtaining CD
- signature,name,address,profession,quantity,purpose of recipient
what drugs can a pharmacist not make a requisition for
Sch 1 CDs
how long must you hold onto a requisition and invoices of CDs for
min of 2 years
what licence is required for a sch 1 CD
Home office Licence
what is public health
the science and art of preventing disease, prolonging life, and promoting health through the organised efforts of society
what does the marmot review tell us?
health outcomes are poorer in societies in which inequalities exist
how can we deliver public health
-blood pressure taking
-advice on alcohol consumption
- diet and obesity
-smoking
-dementia
-physical activity
-improve mental health
-offering localised services from the pharmacy contract
define social prescribing
means of enabling primary care professionals to refer patients with social, emotional or practical needs to a range of local, non-clinical services
