Week 1 09/11-13/11 Flashcards
What are the 4 main symptoms that are often presented in skin disease?
Itch
Pain
Dysfunction
Cosmesis
How would you examine different skin disease?
2 main things to looks at
Lesion - type, colour, shape, associated signs
Distribution - body sites, extent, pattern
What are the different types of lesions in skin disease?
6
Macule, patch Plaque, weal Papule, nodule Vesicle, bulla Pustule, abscess Erosion, ulcer
What are the ways skin disease can be distributed?
Generalised Localised Palmo-plantar Flexor/extensor Dermatomal Scalp, nails
What are some examples of drugs with analgesic activity?
Opiods (morphine-like) NSAIDs (aspirin-like) Paracetamol Local anaesthetics Gabapentinoids
What receptors depolarise sensory nerve endings in response to:
a) Damaging heat?
b) ATP released from damaged cells?
c) Acid?
a) TRPV1 receptors
b) P2X receptors
c) Acid Sensing Ion Channels (ASICs)
What food product can activate TRPV1 receptors?
Capsaicin in chili peppers
What inflammatory mediators can sensitise sensory nerve endings in nocioception?
Bradykinin
Prostaglandins
How do local anaesthetics work to reduce pain?
Why are they inherently toxic?
Block voltage dependant Na channels (Nav)
Not selective for Nav in sensory nerve endings (affect any nerve type) so local administration produces localised effects
What subtype of Nav are found in sensory nerves for nocioception?
Nav 1.7
What NTs are released in dorsal horn of spinal cord during synaptic transmission? (nocioception)
Glutamate
neuropeptide substance P
calcitonin gene related peptide (CGRP)
What happens in ‘central sensitisation’?
What does it cause?
Enhanced transmission at synapse for nociception, strengthens synaptic connection
Leads to hyperalgesia and allodynia
What are gabapentanoids?
Gabapentin and pregabalin
Analogues of GABA (inhib NT, gamma aminobutyric acid)
How do gabapentinoids work to reduce pain?
Decrease expression of functional voltage-dependent Ca channels on sensory nerve endings in dorsal horn
Decrease NT release
How does the marine cone snail toxin conotoxin help reduce pain?
Synthetic analogue (ziconotide) blocks voltage-dependant Ca channels Administer intrathecally (into spinal canal/subarachnoid space) to treat intractable pain
What happens to ascending axons in nociceptive pathway? (After synapse on dorsal horn?)
Travel in contralateral spinothalamic tract
Synapse in medial thalamus
Further projections travel to somatosensory cortex.
How do antidepressant drugs enhance descending inhibition to decrease pain?
Examples?
Inhibit Noradren uptake - so increase Norad conc in CNS
Enhances descending inhibition produced by noradrenergic neurons in dorsal horn
Noradren hangs around longer so synapse keeps uptaking it
Amitriptyline, duloxetine, venlafaxine
Do SSRIs have the same analgesic effect as antidepressant drugs?
No
Where is arachidonic acid stored and released?
Phospholipids in most cell membranes
Released by phospholipase a2
What can arachidonic acid be metabolised into?
Via what enzymes?
Cyclooxygenase ==> prostaglandins, thromboxanes
Lipoxygenase ==> leukotrienes
What molecule production increases during acute and chronic inflammation?
Prostaglandins
Where are PGE2 and PGI2 released from?
What do they do?
Endothelial cells + WBC
Mediate increased blood flow + hyperalgesia
Where is PGD2 released from?
What are it’s functions?
Mast cells
Mast cell maturation
Vasodilation
Eosinophil recruitment + allergic reactions
What is function of LTC4 and LTD4?
Increase microvascular permeability
Broncho-constrictors
What is function of LTB4?
Chemotaxin
Recruits neutrophils to inflammatory sites
What are functions of PGE2?
Vasodilation + vascular leakage Pyrogenic (fever) Hyperalgesia Decrease gastric acid production Increase gastric acid mucus secretion Increase uterine contraction
What are functions of PGFalpah2?
Vasoconstriction
Uterine contraction
Bronchoconstriction
What is role of prostaglandins at inflammatory sites?
Vasodilation
Potentiate oedema formation
Sensitise nerves (hyperalgesic)
How do NSAIDs affect arachidonic acid?
Inhibit its metabolism via COX
What are some non-specific NSAIDs?
Side effects?
Aspirin
Ibuprofen
Indomethacin
Gut and kidney
What are some COX-2 selective inhibitors?
Side effects?
Celecoxib
Rofecoxib (Vioxx)
Meloxicam
Fewer gut side effects but adverse cardiac effects
What are functions of thromboxane?
Enhance platelet aggregation
Vasoconstriction
What are functions of prostacyclin? (PGI2)
Vasodilation
Decrease platelet aggregation
What enzyme does glucocorticoids inhibit in inflammatory pathway?
Phospholipase A2
What enzyme do NSAIDs inhibit in inflammatory pathway?
Non-selective, COX 1 and 2
What enzyme does the drug zileuton inhibit in inflammatory pathway?
5-lipoxygenase
How do the drugs zafirlukast and montelukast inhibit in inflammatory pathway?
Competitive inhibitors for receptors of LTC4, D4, E4
How do leukotrienes aggravate bronchial asthma?
Induce bronchoconstriction, mucous secretion + accumulation
What is difference between NSAIDs and paracetemol?
NSAIDs - analgesic, antipyretic, anti-inflammatory
Paracetamol - analgesic, antipyretic
What are side effects of NSAIDs and why?
Stomach upset/ulcers - PG increase blood flow, increase mucous secretion to protect gut
Kidney problems - PG increase blood flow so lack of this affects kidney
Bleeding risk - from ulcers
Hypertension/stroke
Where is COX-1 found and what is it’s functions?
Found most cells
Constitutive (always there)
Involved normal physiology to maintain homeostasis
e.g. in GI tract, PGs wichtig maintaining good blood flow
e.g. in vasculature TxA2 stimulates platelets to aggregate (thrombus), PGI2 inhibits this
Where is COX-2 found and what is it’s functions?
Induced in inflammatory cells by inflammatory stimuli
Releases high levels of PGs at inflammatory sites
What is another name for paracetamol?
Acetaminophen (APAP)
What systems is the mechanism of paracetamol mediated by?
Serotonergic system
Eicosanoid system
Cannabinoid system
Opioid system
How does the serotonergic pathway work aid in the descending pain system?
How does paracetamol affect this?
Activation of pathways results in suppression of pain transmission in CNS, esp spinal cord
Enhances inhibitory effects
How does paracetamol affect the eicosanoid pathway?
Non-selectively inhibits COX-1 and 2
Why does paracetamol not reduce inflammation?
Found to mostly inhibit peroxidase enzyme which is normally low conc in CNS so paracet can effectively inhibit
During inflammation in peripheral tissues, destroyed cells produce large amounts peroxidase that paracet x inhibit
How does paracetamol affect the cannabinoid pathway?
Helps produce metabolite AM404 which:
Activates cannabinoid receptors
Mediates release of endogenous cannabinoids
Mediates anti-pyretics though inhibition of central PG production
How does paracetamol partially affect opioid pathway?
Activation of mu + kappa (greek letters) opioid receptors
Synergism of opioid and serotonergic pathway
AM404 (paracet metabolite) activates both opioid and cannabinoid receptors
What is the efficacy of paracetamol?
Same as: equivalent dose of NSAID/ 10mg iv morphine
What are the clinical uses of paracetamol?
Acute + chronic mild-moderate pain Musculoskeletal pain Headaches - tension + migraine Various surgical procedure Pyrexia
What can paracetamol be combined with?
NSAIDs, Codeine, Caffeine, Tramadol
What is the benefit of combining paracetamol with other analgesics?
Increases analgesic efficacy
Decreases dose of analgesics
Decreases side effects
What is the main side effect of paracetamol?q
Hepatotoxicity
Why can paracetamol induce hepatotoxicity even at therapeutic doses in v small % of pop?
(CYP450)
Many CYP450 isozymes involved in oxidation of paracet + production of NAPQI
CYP-2D6 isozyme has genetic polymorphism
Few peeps have ultra-rapid + extensive CYP-2D6 activity
Why can paracetamol induce hepatotoxicity even at therapeutic doses in v small % of pop?
(Glutathione)
Glutathione storage may be low in:
Infants, malnourished, alcoholic, malabsorption, elderly
Low NAPQI detoxification ability, accumulates in liver
What medicine is used in paracetamol overdose?
How does it work?
N-acetylcysteine
Precursor to glutathione so can conjugate NAPQI
Enhances sulphate conjugation so more paracet is conjugated
How can paracetamol be administered?
Orally, rectally, IV
What is the oral dose of paracetamol of adults >50kg?
0.5-1.0g every 4-6 hours
Max dose is 4g
How are opioids pharmacologically defined?
Any substance whose actions are reversed by naloxone
What opiates are derived from the opium ?- dried sap from seed capsule of Papaver Somniferum plant
Morphine, codeine, diamorphine (heroine)
What are the 3 subtypes of opioid receptors?
What is the close relative receptor?
mu - MOP
delta - DOP
kappa - KOP
Nociceptin opioid receptor - NOP, distinct pharmacology (x blocked by naloxone), activated by nociceptin peptide
How many endogenous opioid peptides have been found?
What families are they in?
What do they have in common?
13
Beta endorphins - from proopiomelanocortin
Enkephalins - from pro-enkephalin
Dynorphins - from pro-dynorphin
Same N-terminal sequence Tyr-Gly-Gly-Phe-Met/Leu
What is structure and origin of nocioceptin?
From pro-nociceptin pro hormone
17 AA long, diff N-terminal sequence
- Phe-Gly-Gly-Phe-Thr
What type of receptors are all 4 opioid receptors?
G protein coupled - Gi/Go
What cellular responses arise from activation of opioid receptors?
Inhibition of adenylyl cyclase
Activation of MAP kinase
Inhibition of Ca entry into nerve terminals through voltage gated Ca channels
Activation of K channels, so hyperpolarization of neurons
What NT do opioids inhibit the release of?
Substance P/glutamate from dorsal horn
AcH release from nerves in GI tract - constipation
How do opioids affect the cortex to help reduce pain?
Euphoric effects of opioids acting in cortex contribute to analgesia, make pain less troublesome
How do opioids affect PAG to help reduce pain?
Produce disinhibition
Inhibit inhibitory GABAergic neurones within PAG
Overall increase in excitatory output to RVM
Enhanced descending inhibition
How do opioids affect the synapse in the dorsal horn to help reduce pain?
Pre + post synaptic opioid receptors present
Pre - inhibit Ca entry by voltage gated Ca channels, less NT released
Post - open K channels to hyperpolarize, decrease excitability of projection neurone in spinothalamic tract
How are opioid receptors in synapse of dorsal horn activated?
Enkephalins, produced by enkephalinergic interneurons
What is neuropathic pain?
Pain to sensory nerves themselves
What are clinically important actions of morphine?
Analgesia - moderate-severe pain, x neuropathic pain
Euphoria
Respiratory depression - resp centre in medulla less sensitive to pCO2
Nausea + vomiting
Inhibit GI motility - constipation
Contraction of gall bladder + biliary sphincter
Inhibit cough reflex
Centrally mediated pupil constriction
Tolerance + dependance
What can prolonged use of morphine cause?
How can this be reduced?
Hyperalgesia
Change to another opioid
What effect of morphine causes death in overdose?
Respiratory depression
What is administered alongside morphine to reduce nausea and vomiting?
Anti-emetic e.g. prochlorperazine
What substance is used in cough remedies to reduce cough reflex?
Pholcodeine
What medicine is used in lung cancer to reduce cough reflex?
Diamorphine linctus
What is a important diagnostic sign in opioid overdose?
Pin-point pupil
Definition of tolerance in drugs?
Reduced effect upon repeated administration of a drug at a constant dose
Definition of dependance in drugs?
Repeated, compulsive use of a drug to receive chemical rewarding effect/ avoid punishing effects of drug withdrawal
What are the 2 types of dependance?
Psychological - user takes drug to experience pleasurable, rewarding effects, oft characterized by powerful “craving” for drug
Physical - user takes drug to avoid unpleasant withdrawal symptoms; abstinence syndrome
What is the relationship between tolerance and physical dependance?
Adaptive changes occur to counteract effects of prolonged exposure to opioids
E.g. desensitisation of receptors, changes in intracellular signalling pathways
On removal of opioid, adaptive changes now lead to excessive activity - withdrawal symptoms
How can withdrawal symptoms and addicts be helped?
Severe withdrawal precipitated in addicts by administration of naloxone - only severe cases as withdrawal symptoms bad af
Methadone wean addicts off heroin as withdrawal response less severe - leaves body slowly
How can morphine be administered?
Orally or injection
How is morphine processed in liver?
1st pass metabolism - conc of drug greatly reduced b4 reaches systemic circulation
Glucuronidation occurs at 3- + 6-OH positions
Morphine-6-glucuronide is potent analgesic
Glucuronides excreted in urine
What is the plasma half-life of morphine in adults?
Neonates?
3-6 hrs
Longer in neonates cos low conjugating capacity of liver - risk of neonatal resp depression if morphine given during childbirth
What is codeine and diamorphine metabolised into?
Morphine
How is buprenorphine administered?
Sublingually
How is fentanyl and sufentanil administered?
Intrathecally during surgery
What opioid is used in obstetrics?
Why?
Pethidine - shorter half life than morphine
May still need to reduce effects of neonate resp syndrome using naloxone
N-demethylation of pethidine by liver produces norpethidine, hallucogenic + convulsant effects
