Pain Flashcards by Nicholas Hewett

What is a pacinian corpuscle

Cutaneous rapidly adapting receptor in SC skin surrounding unmyelinated nerves
Unmyelinated nerve ending covered in lamellae
Touch or pressure deforms the lamellae and a generator potential is created
Present in skin and fascia
Large receptive field
Sensations - vibration and pressure

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What is a Meisner corpuscle

attached to A beta (highly myelinated large diamtre) when transmitting non painful perception of light touch through thick highly myelinated fibres –> rapid signals
* Rapidly adapting encapsulated receptor
* Small receptive field
* Low activation threshold
* Skin of fingertips and lips
* Velocity receptor

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What is a Merkel disc

n Abeta fibres (highly myelinated large diametre)
* Slowly adapting epithelial cell transducer
* Small receptive field
* Low activation threshold
* Signals continuous touch and location

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What is a Ruffini corpuscle

Touch and pressure
SKin deep tissues joint capsules
Slowly adaptign encapsulated

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Define pain

Pain is “an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.

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Nociception

◦ Nociception - somatosensory response of the nervous system to a potentially harmful stimulus and serves to avoid tissue damage

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What % of myelinated and unmyelinated fibres are nociceptors

10% of cutaneous myelinated fibres and 90% of unmyelinated fibres are nociceptive

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Hot receptors activate above

43 degrees

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Cold receptors activate below

26 degrees

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What is the diamtre of a C fibre

<2 mcirom

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What type fo receptors as C fibres - what do they sense

POlymodal receptors
heat
Mechanical
Chemical stimuli

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What is primary or peripheral hyperalgesia

‣ Stimulated C fibres release pro inflammatory peptides causing plasma extravasating reinforcing mediators suppply —> sensitising the high threshold nocicpetors so they can be activated by low intensity stimuli resulting in peripheral sensitisation at the site of injury (primary hyperalgesia)

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Where do C fibres terminate in the SC

Rexed lamina 2
Substantia gelatinosa

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What is the diamtre of A delta fibres

2-5micrm

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What are the two types of A delta fibres

Type 1 - mechanosensitive only. Well localised
Type 2 - mechanothermal - high threshold thermoreceptors

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How does the speed of conduction vary between A delta and C fibres

A delta 5 - 25m/sec

C fibres 2 m/s

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Where in the dorsal horn to A delta fibres synpase

‣ Go to laminae 1 and III, IV, V of dorsal horn to synpase with second order interneuon with substance P as the neurotransmitter (3rd order in thalamus)

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What are the mechanisms by which pain stimuli are detected and transduced to AP

Ion channels - TRP family non selective cation channels, sodium channels generally voltage gated, Potassium channels, acid sensing channels
Metabotropic - bradykinin, opioids, 5HT1B responding to CGRP, bradykinin, prostaglandins (activating), or seratonin or opioids inhibits

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What factors released from damaged cells cause activation of nociceptors

ATP
K
H

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What inflammatory mediators are released in the surrounding area activating nociceptors

Monoamines - seratonin from pltelets, histamine form amst cells
ACh
Bradykinin
Cytokines

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What factors sensitise rather than stimulate nociceptors

Eicosanoids - PG and LT
Neuropeptides - substance P, CGRP, Neurokinin

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What is a silent nociceptor

Requires inflammation to actually become active

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What are the 2 flaws in nociception

◦ For certain stimuli pain is detected in the absence of tissue damage e.g. small electric shocks
◦ For severe cases of tissue damage e.g. gamma radiation we have no detection of tissue damage

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How does a nerve cell increase the surrounding area of sensitivity

◦ Terminal branches release peptides including substance P causing vasodilation and neurogenic oedema with further bradykinin accumulation
‣ Substance P —> release of histamine from local mast cells and seratonin from platelets
* Both sensitise nearby nociceptors

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How is peripheral pain stimulus modulated in the SC 3

‣ Serotonergic neurons from the raphe nucleus
‣ Noradrenergic neurons from the locus coeruleus
‣ GABAergicneurons axons from the rostral ventromedial medulla - descending input from CNS, basis of central sensitisation or pain gating

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Where do fibres project from as pain signals other than the thalamus

◦ Nucleus of the solitary tract and caudal ventrolateral medulla - reflex tachycardia
◦ Caudal ventrolateral medulla which also regulates the cardiovascular response to pain
◦ Periaqueductal grey matter (descending regulation of pain signals) - central site of action of analgesics
◦ Lateral parabrachial area (emotional and affective response to pain) - connects hypothalamus and amygdala to integrate emotional and affective responses

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What is substance P

Peptide neurotransmitter
Primary afferent terminals of pain sensory neurons contain it
Also a neuromodulator
Primarily in Rexxed lamina 1 + 2
Metabotropic recepotrs increased cAMP (excitaotry)

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What is gate control theory

Afferent impulses arriving in dorsal horn initiate inhibitory mechanisms limiting subsequent impulses
◦ Local inhibitory interneurons (triggered by A-Beta non noxious stimuli) + descending inhibition
◦ Rubbing an injured area or the application of heat or ice reduces sensation of pain
Now largely disproved as internueons dedicated to carrying nociceptive impulses from Adeltafibres alone found

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Where are opioid receptors primarily

75% pre synaptic

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What type of receptor are opioid recepotrs

GPCR

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What are the 3 varieties of opioid recepotr

mu, kappa or delta

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What effect do opioid receptors have

‣ Reduces transmission to second order neurons by opening K channels in post synaptic membrane (post synpatic inhibition) and inhibition Ca influx into the presynaptic terminal reducing substance P release

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What are the endogenous opioids

encephalins, endorphins

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What modulates opioid receptors

‣ inflammation
‣ neuropathy
‣ morphine 3 glucoronide antagonsises the analgesic action of opioids
‣ NMDA receptor modulates sensitivity - reduces tolerance and prevents withdraw

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What are the 3 varieties of the psinothelamic tract

Neospinothalamic tract
◦ For fast pain contains Adeltaterminate in lamina 1 and second order neurons ascend in lateral anterolateral column to the ventral posterolateral nucelus of thalamus
◦ Important for localisation of painful stimuli
Paleospinothalamic tract
◦ C fibres lamina 2 and 3 - most then pass through short fibre neurons and enter lamina 5 and ascend medially within the anterolateral column
◦ Terminate in reticular formation (emotional and arousal) , superior colliculus, periaqueductal grey area

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What are 3 ascending nociceptive tracts other than the spinothalamic

Spinoreticular - near medulla to vasomotor centres
Spinomesencephalic - to VLF
Spinolimbic

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Where does central processing occur of pain

Somatosensory cortex responsible for localisation and sensation
Secondary somatosensory cortex for intensity, spatial appreciation
Insula for pain intensity and autonomic response
Anterior cingulate - response selection, attention, affect and appraisal
Pre-frontal cortex - affect, emotion, memory and modulation

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What are the key neurotransmitters of descending inhibitino

GABA
NA
5HT

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Where do you find opioid receptors in the CNS

Locus coreuleus
Periaqueductal grey area
Nucleus raphe magnus

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How is the periaqueductal grey area involved in pain management

◦ Surroudning cerebral aqueduct in midbrain
◦ Receives inputs from thalamus, hypothalamus, cortex, and spinothalamic tract
◦ PAG neurons project down the spinal cord to block pain transmission by dorsal horn cells - endorphins sythesised in the pituitary are released into CSF and blood

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How is the nucleus raphe magnus invovled in pain modulation? What is its primary neurotransmitter

◦ Second descending system of serotonin containing neurons from the raphe nuclei of the medulla
◦ Synapes in lamina 2 and 3 producing analgesia through activation of inhibitory internuerons
◦ Itself activated by PAG

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How is the locus coeruleus involved in pain modulation

◦ Pons and receives inputs from many structures, with descending fibres ipsilateral to ventrolateral funiculus
◦ Inhibits dorsal horn nociceptive activty post synaptically

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Pain pathways for facial sensation afferents

First order neurone (C or A-delta fibre) relays action potentials form the face to the trigeminal nucleus
◦ Trigeminal nerve relay to the brainstem (trigeminal nucleus)
◦ Small number of sensory afferent neurons from the oropharynx and the ear travel in the facial, glossopharyngeal and vagus nerves to the trigeminal nucleus in the brainstem

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Where is the 2nd order neuronal synapse for facial pain

Trigeminal nucleus - substance P involved in neurotransmission (medulla to the midbrain)

Pain generally more caudal, proprioception more cranial

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Second order neuronal pathway for facial pain

Decussate and ascend to thalamus

What is hyperalgesia? How is it different to allodynia?

Hyperalgesia - increased pain from a stimulus that normally probokes pain
Allodynia - pain from a stimulus that does not usually produce pain

Define central sensitisation

The process where following a normally innocuous mechanical stimuli in a zone of secondary hyperalgesia in uninjured tissue surrounding a primary site of injury

What is the mechanism of central sensitisation 3

What is Wind up?

How is Wind up and long term potentiation different?

◦ 1. A stimulus sufficient to activate C fibres causes progressive increase in neuronal activity throughout stimulus
‣ Repeated stimulus with no change in strength results in increased excitatory release - WIND UP - and NMDA receptor mediated
‣ Increase in the magnitude and duration of a response to stimuli above threshold
‣ Long term potentiation different to wind up is when there is strenghtening in the efficacy if synaptic transmission across a synapse (chronic pain)
◦ 2. Expansion of receptive field so spinal neurone responds to stimuli out of its usual range - * Morphological changes occur within the dorsal horn if there is peripheral nerve injury resulting in redistribution of central terminals of myelinated afferents resulting in connections which would not normally transmit noxious stimuli attaching to second order noxious afferents
◦ 3. Reduction in the threshold required for activation

What is peripheral sensitisation? What substances are implicated?

Nociceptive stimulation resulting in neurogenic inflammatory response - release from peripheral terminals of afferent fibres which sensitise surrounding neurons (secondary hyperalgesia)
◦ Substance P
◦ Neurokinin A
◦ CGRP - calcitonin gene related peptide
Changes excitability of sensory and sympathetic nerve fibres, vasodilation and extravasation of plasma proteins
With increased inflammatory cell activity there is increased inflammatory mediators sensitisating and stimulating nociceptive afferents
◦ K
◦ Seratonin
◦ Substance P
◦ Bradykinin
◦ Histamine
◦ Cytokines
◦ NO
◦ AA metabolism
Low intensity mechanical stimuli are then perceived as painful
The sympathetic nervous system also plays a role in abnormal activity of the primary afferent nerve fibre through its release of prostanoids and NA

Explain prostaglandin synthesis

How does the PNS change with age

◦ Nerve deterioration
◦ Decreased myelination
◦ Decreased conduction velocity
◦ Reduced range and speed of ANS responses
◦ Increased resting sympathetic tone

How does the CNS change with age affecting pain

◦ Decreased pain perception
◦ Increased sensitivity to anaesthetic and analgesics
◦ Reach ceiling effects more rapidly.
◦ Degeneration of myelin
◦ Subsequent cognitive dysfunction due to neuronal circuit dysfunction.
◦ Generalised atrophy
◦ Decreased neurotransmitter production

Opiodes are acids or bases

Basic amines

Natural opioids

codeine, morphine

Semi synthetic opioids

Buprenorphine, hydromorphone, oxycodone

Synthetic opiois

Fentanyl, alfentanyl, Methadone, Remi, tramadol

What is a partial agonist at the opioid receptor

Burprenorphine, tramadol

pKa of most opioids

What form are opioids in at physiological pH

Most lipid soluble

What is lipid solibility correlated with in opioids

analgesic efficacym, rapid onset of action

What is low lipid solubility associated with in opioids

Longer duration of action especially in the spinal space, morphine takes a LONG time to diffuse out of the CNS even though it has a short half life
Generally though reduced analgesic efficacy and slower onset of action

Which opioids have active metabolites

Codeine
Morphine
Buprenorphine
Herion

Mechanism of effect of opioids

Opioid receptors are G-protein coupled receptors, mainly situated on the presynaptic membrane, which increase potassium conductance and decrease calcium conductance. The net effect of their activation is to hyperpolarise the membrane and prevent neurotransmitter release.
Their mechanism of analgesic action is mainly related to the inhibition of glutamate release from primary pain afferent neurons in the spinal cord
A secondary effect is the potentiation of the descending inhibitory pathways which regulate pain (which originate in the midbrain)

When considering opioid infusions morphine vs fentanyl what administrative and pharmaceutical factors come into play

◦ The cost of morphine is approximately half the cost of fentanyl, and the longer duration of effect could make it even more cost-effective.
◦ The prolonged action of its effect, however, may increase the duration of ventilation of ICU stay, increasing the overall healthcare cost.
◦ Fentanyl is 100 times more potent than morphine, which means theoretically it should be more cost-effective to use it for analgesia

How does compartmental distribution and context sensitive half time differ between fentanyl and morphine

◦ Fentanyl is widely and rapidly distributed, accumulating in tissues with sustained infusion
◦ Because of tissue compartment distribution, context-sensitive half time for fentanyl is markedly prolonged following a long course of use as analgo-sedation (eg. after a 4-hour infusion, context sensitive half time is 200 minutes)
◦ Morphine is distributed less widely, and its context-sensitive half-time is independent of the duration of infusion
◦ However, the accumulation of morphine metabolites in critically ill patients may still produce a prolonged effect sustained long after the infusion has ceased.

What is the context sensitive half time of morphine infusion

Independent of duration of infusion

How does protein binding compare between fentanyl and morphine

◦ Fentanyl is 80-90% protein bound; with hypoalbuminaemia of critical illness, the free fraction will be increased, potentiating the clinical effects
◦ Morphine is only 30-35 % protein bound and therefore less affected by hypoproteinaemia

How does lipid solubility affect the behaviour of morphine and fentanyl as an infusion

◦ Morphine has relatively poor lipid solubility as compared to fentanyl.
◦ The clearance of morphine from the CNS is therefore delayed, producing a prolonged duration of effect
◦ Fentanyl has excellent lipid solubility, and is cleared rapidly from the CNS
◦ The rapid clearance of fentanyl is more likely to lead to opioid withdrawal following a long-term sustained infusion as part of ICU sedation (opioid withdrawal is an under-recognised contributor to ICU delirium)

What pharmacodynamic effects are different between morphine and fentanyl

◦ Morphine may act as a direct vasodilator through its histaminergic effects, which may be beneficial (eg. in CCF) or a disadvantage (eg. septic shock), whereas fentanyl does not have direct cardiovascular effects.

What opioids are not ideal for intrathecal use? Why?

Some opioid formulations cannot be administered intrathecally or via epidural because of specific excipients, eg. remifentanil comes as a lyophilized powder with a glycine buffer, and IV morphine comes with preservatives

How does absorption vary between intrathecal and epidural

Epidural
◦ Rate of diffusion into CSF is slower, and depends on Fick’s Law of Diffusion (volume, i.e. surface area of available meninges, concentration, protein binding and free fraction, as well as CSF flow rate/turbulence)
Intrathecal
◦ Rate of diffusion into target tissue is rapid:
‣ High CSF concentration
‣ Short diffusion distance (2-4mm)

How does local and systemic distribution differ between epidural and intrathecal opioids

Local distribution
* Epidural
◦ Epidural spaces are irregular, segmental, and the injected material encircles the dural sack.
* Intrathecal
◦ Depends on baricity (density of injectate relative to CSF)
Systemic distribution
* EPidural - Two-compartment model: Rapid early distribution (into epidural fat) and then slowly back out.
* Intrathecal slow absorption with increased half life

How does lipid solubulity affect behaviour of spinal/epidural effects

The effect of the lipid solubility of opioids on their spinal and epidural effect:
* High lipid solubility (eg. fentanyl)
◦ More rapid onset of effect
◦ More rapid offset of effect
◦ More rapid uptake into capillaries, and therefore faster clearance from the CNS spaces
* Lower lipid solubility (eg. morphine)
◦ Slower onset of effect
◦ Slower offset of effect
◦ Slow clearance from the CNS, and prolonged clinical effect
‣ (eg. hypotension).

How can spinal and epidurals affect their own clearance?

Because of the haemodynamic effects of spinal (anaesthetic) drugs, the perfusion of liver and kidneys may be decreased, which could delay clearance.

What is the receptor type for opioid receptors? What is the translation to effect from receptor binding?

When opiods bind –> inhibition of adenylcyclase –> reduced cAMP
◦ –> activation fo K+ channels –> K+ efflux and hyperpolarisation
◦ –> inactviates voltaged gated Ca channels reducing neurotransmitter release + smooth muscle excitability reduced
◦ Overall effect increased potassium conductance (hyperpolarises), reduced calcium conductance (decreases intracellular calcium necessary for neurotransmitter release)
◦ Decreases synpatic neurotransmission

What does a mu opioid receptor cause? Where do you find it?

◦ Mu - Morphine - responsible for analgesia, respiratory depression, constipation, CV effects
‣ Located all over the CNS but in particular
* dorsal horn of the spinal cord: μ-receptors are present presynaptically on primary afferent neurons (where they have an inhibitory influence on neurotransmission)
* Periaqueductal grey matter: This part of the brainstem sends descending efferents which act to inhibit nociceptive transmission in afferent fibres; μ-receptors remove some of the GABA-ergic inhibitory tone which regulates this descending inhibition
‣ Stimulation causes analgesia, miosis, euphoria, respiratory depression, bradycardia, inhibits gut mobility

Where is a delta opioid receptor?What does it cause?

◦ Delta - encephalins primarily active here and a small amount of Mu action - analgesia, miosis, respiratory depression, constipation and mood

Kappa opioid receptors act how?

◦ Kappa - dynorphin - sedation, analgesia, miosis and confusion
‣ Original agonist was ketocyclazocine (no respiratory depression)

How is respiraotry depression mediated by opioids (2)

Brainstem μ-receptor effect:
◦ The target is the pre-Bötzinger complex in the ventrolateral medulla
◦ This the respiratory pacemaker centre
◦ Here, opioids decrease the rate of firing, and at high doses produce a Mobitz-type effect, where some breaths are skipped
Medullary chemoreceptor (also a μ-receptor effect):
◦ Opioids decrease the sensitivity of the medullary chemoreceptors to hypoxia and hypercapnia
◦ This blunts the normal response to hypoventilation

How is opioid induced consitpation caused

δ- and κ-opioid receptors are expressed in the enteric nervous system
This produces direct activation of smooth muscle cells, leading to:
◦ Constant tonic contraction of smooth muscle
◦ Inhibition of normal intestinal secretions
◦ Inhibition of peristalsis
Little tolerance seems to develop to this effect

How is nausea ccaused by opioids

Nausea is a direct effect of opiates on the area postrema

Miosis is caused by oopioids how?

Miosis seems to be a direct opioid effect on the Edinger-Westphal nucleus of the midbrain, which is observed at even subanalgesic doses, and which is also not subject to tolerance

Are NSAIDs acids or bases?

weak acids

Describe absorption of NSAIDs

Excellent, most are lipid soluble in upper GI tract
Good bioavailability

Ibuprofen Vd

0.1L/kg

NSAID protein binding

Highly protein bound: most NSAIDs are 90-99% protein bound
◦ In overdose, saturation of all binding sites increases the free fraction of the drug
◦ This means the total drug levels (eg. salycilate levels) are not meaningful
◦ This also increases the free fraction available for harmful activity, as well as for clearance by urinary excretion and through dialysis

Metabolism of NSAIDs

Metabolism is mainly hepatic
◦ Diclofenac of which only about 70% is metabolised and 30% cleared via biliary excretion resulting in enterohepatic recirculation (liberated gluconide metabolites following gut bacteria processing leading to reabsorption)
◦ except for parecoxib which is a pro-drug rapidly hydrolysed into its active form (valdecoxib) - but then this is treated like a normal NSAID with renally excreted inactive metabolites
◦ The vast majority of metabolites are inactive and renally excreted

Half life of NSAIDs

Short 1-2 hours
Longer COX2 selective 8-12 hours
HJowever half life has no relatinship to duration of action

What is arachadonic acid

◦ Arachidonic acid is a 20-carbon fatty acid that is embedded in cell membranes
◦ Its metabolites (eicosanoids, after “eicoso”, i.e. twenty) are numerous, and can originate from numerous non-COX-related pathways (eg. when arachidonic acid is metabolised by lipoxygenase).

How is arachadonic acid used in platelets> What triggers this

◦ Thromboxane produced by platelets in response to adenosine, collagen or adrenaline and promiotes vasoconstriction and pltatlet aggregation (prostacyclin the inverse)

What is COX 1 responsible for

◦ COX-1 is constantly active and has a homeostatic role
‣ ubiquitous, pharmacologicaly relevant roles
* Synthessis of PGE2 and PGI2 promoting increased bicarbonate and mucous secretion in gastric mucosa
* Synthesis of thromboxane A2 in platelets contributing to aggregation
* Synthesis of PGI2 in vascular endothelium inhibiting platelet aggregation and vasodilating (renal blood flow)
‣ Active binding site is small - therefore COX2 selective drugs are larger

What is COX2 responsible for

◦ COX-2 is an enzyme induced by inflammatory cytokines (IL1, and TNFalpha)
‣ Involved in imune function - sy theiss of PGE2 and PGI2 in inlfamed and infected tissue increasing vascular permeability, oedema, sensitising peripheral nociceptors
‣ Synthesis of PGE2 in the hypothalamus setting the hypothalamic thermoregulatory set point to a higher temperature
‣ Mediates prostacyclin (protective) proudction in vascular endothelium

Side effects of COX1

◦ COX-1 inhibitor and nonselective NSAID side effects: bind to COX2 in irreversible fashio
‣ GI ulceration (decreased gastric mucosal pH and mucus synthesis)
‣ Acute kidney injury (microvascular renal dysfunction)
◦ COX-2 inhibitor side effects: bind COX2 in a reversible fashion
‣ Anti-inflammatory activity is mainly due to COX-2 inhibition
‣ Prothrombotic side effects are due to COX-2 inhibition
‣ CCF exacerbation and hypertension

Side effects of COX 2

How do NSAIDs affect pain

Prostanoids bind to nociceptor nerve endings (usually via G-protein coupled receptors)
This does not directly result in depolarisation of the membrane
Instead, they indirectly increase the sensitivity of the receptor to other inflammatory stimuli, eg. bradykinin and histamine
NSAIDs decrease the synthesis of these mediators and therefore decrease the sensitivity of the nociceptors.f

Main side effects of NSAIDs

MI and stroke
Nephrotoxin
Exacerbating CCF
Asthma
Drug interactions - plasma protein displacement
Gastric ulceration

How do NSAIDs affect the gut

Gastric ulceration - COX1 inhibitor effect causing increased acid proudction, rbicarvonate secretion (4-5x increased) - by being given PO givne their weak acid status they can become ion trapped producing increased gastric ulceration risk
◦ Aspirin acetylsalicylate adn salicylate ions trapped in alkaline environment of mucosal cells increasing side effects
◦ Effect on plt function increases the risk of haemorrhage
◦ Ibuprofen lowest risk, ketorloac highest

How is most paracetamol metabolised

Most paracetamol is metabolised by glucouronidation (50%) and sulfation (35%)
◦ Oxidation, reduction and hydrolysis can also occur

What is the aberrant pathway of PCM synthesis?

CYP2E1 –> NAPQI superoxide

Detoxified by conjugation with glutathione

How is NAPQI toxic

◦ In the presence of ample glutathione, NAPQI is rapidly detoxified by conjugation
◦ In the presence of massive overdose, glutathione is rapidly depleted
◦ As NAPQI levels increase, it binds covalently to numerous proteins (sulfahydryl groups), causing toxicity
◦ Of particular interest is the uncoupling of oxidative phosphorylation, which results in a failure of ATP synthesis, lactic acidosis, and the release of ionised calcium from mitochondrial stores
◦ The consequence of this is hepatocellular apoptosis and necrosis.

How does paracetamol act

COX 2 dependent peripheral mechanism - not clinically relevant suppression of COX activity to the point where effects of toxicity are absorbed some evidence it has some effect
◦ COX inhibition of PGE2 in the hypothalamus
COX3 central mechanism - descneding inhibition of pain
Endocannabinoid mechanism
TRP or transient receptor potential channels in peripheral nociceptors are mechanotransducers and chemotransducers responisble for some fo the sensation of pain, inflammation and heat
T type calcium channels involved in the modulation of cellular excitability
Nitric oxide synthesis

What factors predispose to PCM toxicity

Alcoholism
Phenytoin/carbamazapine
CF
HIV
Starvation

Benefits of NAC in PCM toxicity

Mechanism of NAC
* NAC is converted to glutathione, replenishing the reserves.
* Cysteine, the midproduct of metabolism, also supplies ample sulfate for the sulfation of paracetamol (so less of it goes down the toxic MEOS pathway).
* There are also theoretical antioxidant benefits.

NAC regime

‣ Modified for simplicity:
* 200 mg/kg over 4 h
* 100 mg/kg over 16 h

When do you need to transfer to a renal transplant unit for PCM toxciity

‣ INR more than 3.0 at 48 hours or greater than 4.5 at any time;
‣ Oliguria or creatinine greater than 200 μmol/L
‣ Persistent acidosis (pH < 7.3) or arterial lactate greater than 3 mmol/L
‣ Hypotension with blood pressure below 80 mmHg
‣ Hypoglycaemia, severe thrombocytopenia, or encephalopathy of any degree
‣ Any unexplained alteration of consciousness (Glasgow Coma Score < 15)

What do aspirin overdoses come in complaining of?

sweaty
Tinnitus
Blurred vision
Tachycardia
Pyrexia
Hyperventilation wtih respiratory alkalosis

What are prostanoids

A family of eicosanoids or 20 carbon molecules produced from arachadonic acid including thromboxane, prostacycline and prostaglandins

What is the fate of arachadonic acid

COX -cyclic endoperoxidases
- Thromboxane A2
- Prostacyclin
- PG
Leukotrienes by lipo-oxygenase

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