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146 Cards in this Set
- Front
- Back
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What is the mechanism of action of glucocorticoids?
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Modulates cytokine levels, inhibits NF-kB transcription factor, and inhibits phospholipase A2
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What is phopholipase a2?
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Enzyme that releases arachadonic acid from phospholipids
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What molecules is arachidonic acid a precursor for?
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Prostaglandins (incl thromboxane) & leukotrienes
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What are anti-proliferative immunosupressants?
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Drugs that prevent immune cell proliferation by inhibition of DNA synthesis
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What are methotrexate and azathioprine?
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Anti-proliferative immunosupressants
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What is OKT-3?
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Murine monoclonal anti-human-CD3 antibody, used for immunosupression (mediated through T-cell CD3 modulation)
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What is cyclosporine?
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Immunosupressant, works by inhibiting activation of T-cells (expression of IL-2) by inhibiting calcineurin
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What is calcineurin?
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Enzyme that activates T-cells by inducing IL-2 production
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What is Tacrolimus?
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Calcineurin inhibitor, stops T-cell (IL-2) activation (also known as FK-506
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What is the least expensive form of immunosupressants?
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Corticosteroids
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What is FK-506?
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Tacrolimus, immunosupressant (via calcineurin)
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What are the calcineurin mediated immunosupressants?
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Tacrolimus (FK-506) & cyclosporine
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What are the two sources of glutamate synthesis?
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The metabolic pool and the NTM pool
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How does glutamate cross the BBB?
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It can't
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How is glutamate metabolised?
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Altered to glutamine by glutamine synthase, after being taken up by excitatory aa transporters
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What are the glutamate receptors?
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Three ionotropic (AMPA, NMDA, kainate) & metabotropic GCPR receptors
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What ions do the AMPA & kainate receptors allow through?
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Na+
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What ion does the NMDA receptor allow through?
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Ca2+
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What is required for the NMDA receptor to activate?
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Glutamate, glycine, & depol
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What role does Mg2+ play in the NMDA receptor?
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Blocks channel until pushed away by depol
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How does the AMPA receptor differ from the kainate receptor?
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AMPA has resting Na+ permeability
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In the CNS, what role are ionotropic glutamate receptors involved in?
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Long term potentiation - learning & memory
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CNS glutamate ionotropic receptors: difference in result between moderate & robust (tetanic) presynaptic glutamate release?
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Robust release opens NMDA channel and removes Mg block for strong postsyn depol
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How do synapses become more sensitive to glutamate?
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Robust tetanic presyn glu release causes NMDA activation and Ca++ influx, which ppi's kinases, and ppi's AMPA, giving a potentiated response
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What is glutamate exitotoxicity?
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Cell death due to toxic levels of glutamate
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What three pathologies is glutamate excitotoxicity suspected to be linked to?
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Ischaemic stroke, Alzheimer's, Parkinson's
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How does excitotoxicity occur in ischaemic stroke?
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No bf, no ATP, transporters reverse, high glutamate levels in synapse, gives high Ca2+ levels in cell, proteins damaged
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What is ketamine?
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An NMDA antagonist
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What is memantine?
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An uncompetitive NMDA antagonist, requires NMDA activation, stops excitotoxicity
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What drugs react with metabotropic glutamate receptors?
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None
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What is allodynia?
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Increased sensitivity, things that don't normally cause pain now do
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What is hyperalgesia?
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Increased response to painful stimuli
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How does a local anaesthetic stop pain?
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Blocks voltage channels that propogate pain signal
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What are the four stages of nociceptive pain?
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Production of pain, propogation, processing, perception
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What stages do opiods act in pain signals?
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At production, processing, and perception
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What stages do NSAIDs act in pain signals?
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At production, and processing
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How do NSAIDs act?
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Block inflammatory pathway by inhibiting COX2, stopping production of prostaglandins from arachidonic acid
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Three effects of NSAIDs?
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Anti-inflammatory, analgesia, antipyretic
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What is COX1?
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Receptor expressed in all cells, has constituitive activity in stomach to produce prostaglandins and protect against ulcers
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What is COX2?
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Receptor induced in response to inflammation, major source of inflammation prostaglandins
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What are COX1&2 inhibitors?
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Aspirin, ibuprofen, diclofenac
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What are COX2 inhibitors?
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Celecoxib (Celebrex), rofecoxib (Vioxx)
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What are the main side effects of NSAIDs?
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Gastric irritation, nephrotoxicity, allergy
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How do NSAIDs cause gastric damage?
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Inhibition of prostaglandin production through COX1
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How can aspirin have an anti-platelet effect?
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Irreversibly binds to COX1 in platelets, which cannot synth new receptors, thromboxane a2 not produced
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What are the forms of the opioid receptor?
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Mu, delta, kappa
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What are the roles of the delta and kappa opioid receptors?
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Delta minor role, likely in periphery, kappa part of dysphoria and sedation
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What are the two main therapeutic effects of opioid analgesics?
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The analgesic effect, and supression of the cough reflex
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What is naloxone?
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Opioid antagonist, higher affinity for mu and kappa receptors
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What are the adverse effects of opioid analgesics?
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Respiratory depression, constipation, tolerance, dependance
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How do opioid analgesics cause respiratory depression?
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Decreases sensitivity to CO2 levels in resp centre
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What responses to opioid analgesics are modulated by tolerance?
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Euphoria, respiratory depression, analgesia
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What responses to opioid analgesics are not modulated by tolerance?
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Pupil constriction, constipation
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What three cell types release histamine?
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Mast cells & basophils, enterochromaffin-like cells in stomach, histamine neurons
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Four main effects of the histamine H1 receptor?
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Endothelial vasodilation & permeability, GIT sm musc contraction, CNS arousal, ileum & bronchial sm musc contraction
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Main effects of the histamine H2 receptor?
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Gastric acid release in the stomach, smooth muscle relaxation
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What are the 2nd gen antihistamines?
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Cetirizine, desloratadine, loratadine, fexofenadine
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What are the 1st gen antihistamines?
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Promethazine, chlorpheniramine
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Main differences between the 1st & 2nd gen antihistamines?
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2nd gen don't cross BBB, more selective for H1
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How do 1st gen antihistamines give fatigue, dizziness, and sedation?
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Peripheral anticholinergic effect and interferance with CNS NTMs (since cross BBB)
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What is GORD?
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Gastrointestinal oesophageal reflux disorder
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What are H2 antagonists?
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Ranitidine, cimetidine, famotidine
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How do antihistamines help with motion sickness?
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1st gen H1 antagonist helps stop emesis through anticholinergic action
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Key active ingredient in cannabis?
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delta-9-tetrahydrocannabinol (delta-9-THC)
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What areas of the brain have the highest concs of cannabinoid receptors?
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The cortex & cerebellum
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What part of the neuron are CB1 receptors found, and what role are they thought to play?
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Presynaptically, gate/control release of classical NTMs
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What is anandamide?
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Cannabinoid antagonist isolated from porcine brain
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What are endocannabinoids thought to be derived from?
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Arachadonic acid
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What are the cannabinoid receptor subtypes?
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CB1 and CB2
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Where are CB1 receptors found?
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Mostly in the brain
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Where are CB2 receptors found?
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Peripheral NS, immune system, testes, retina
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Which cannabinoid receptor is delta-9-THC selective for?
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Not selective
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How potent is delta-9-THC?
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Only a weak partial agonist - synthetic cannabinoids are much more potent
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Therapeutic effects of cannabinoids?
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Reduce nausea & vomiting, stimulate appetite, analgesia, reduce intraocular pressure, reduce spasticity
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What is Sativex?
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Delta-9-THC compound extract product used therapeutically
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What is Rimonabant?
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Cannabinoid receptor antagonist, blocks CB1 more than CB2, now withdrawn
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Potential long term side effects of cannabis extracts like Sativex?
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Psychiatric disorders, cognitive dysfunction, effects on fetus, tolerance, dependance
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How does CB1 tolerance occur?
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GCPRs are internalised and phosphorylated
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Effects of cannabis withdrawal after chronic use?
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GI pain, sleeping problems, reduced food intake
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How does cannabis dependance occur?
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Associated with dopamine release in the nucleus accumbens (pleasure pathway)
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Effects of cocaine in ascending dose order?
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Increased alertness, SNS stimulation, euphoria, anxiety, seizures, arrhythmia, resp failure, death
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What is the mechanism of action of cocaine?
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Blocks the dopamine transporters, increasing dopamine levels in the cleft
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What are the desired effects of amphetamines?
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Euphoria, depressed appetite, increased energy & concentration
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Adverse/undesired effects of amphetamines?
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SNS stimulation (hypertension, tachycardia), agitation, violent episodes, paranoid psychosis, brain damage
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Mechanism of action of amphetamines?
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Enters neuron (passive & by dopa transporter), causes release of dopamine vesicles, increases dopamine synth, decreases expr of dopa transporters, inhibits MAO
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What is ritalin?
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Methylphenidate, amphetamine used in low doses to treat ADHD
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Desired effects of MDMA?
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Energy, empathy, and euphoria
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Adverse/undesired effects of MDMA?
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Hallucination, panic attacks, confusion, irritability, midweek blues, SNS disorders, hyperthemia
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Mechanism of action of MDMA?
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Enters neuron through 5HT transporter, causes release of 5HT from vesicles into neuron (which them move into synapse), inhibits trytophan hydroxylase & MAO
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What are piperazines?
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Synthetic drugs trying to mimic MDMA (BZP = benzylpiperazine)
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Mechanism of action of piperazines?
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Interact with dopamine, 5HT, NA to enhance NTM release, and inhibit updake
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What is chronic pain?
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Pain that outlasts the original trauma, duration of at least 3-6 months, can be nociceptive or neuropathic
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Disadvantage of using COX1 inhibitors for treating chronic pain?
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GI adverse effects due to prostaglandin supression
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Disadvantage of using COX2 inhibitors for treating chronic pain?
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Increased risk of CV events due to prostacyclin supression
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Main concept of central pain sensitisation?
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Continual stim activates NMDA receptors (removes Mg block), increased Ca++ levels stimulate increased receptor density (the wind up)
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Main concept of peripheral pain sensitisation?
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First afferent neuron becomes sensitised due to inflammation, and discharge without stimulation, including demyelination and spontaneous APs
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How do corticosteroids help with chronic pain?
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Reduce COX activity, inhibiting phospholipase a2 breakdown of arachidonic acid into mediators, as COX2 has a key role in sensitisation
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What is opioid hyperalgesia?
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Paradoxical sensitisation to pain due to use of opioids, mechanism only theorised
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How is neuropathic pain similar to epileptic pain?
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Both involve hyperexcitable nerve cells
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Drugs that can be used for neuropathic pain?
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Carbemazepine, gabapentin (since similar to epileptic hyperexcitable nerve cells)
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What drugs can be used as adjuncts for neuropathic pain?
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Alpha-1 agonists (clonidine, tizanidine), NMDA antags (ketamine, methadone)
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What multimodal approaches can be used for neuropathic pain?
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Cognitive-behavioural or behaviour-modification therapy, non-drug treatment (surgey, acupuncture, TENS), multi-drug treatment (impr efficacy at lower doses, less adverse effects)
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Effects of caffeine?
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CNS arousal, incr psychomotor performance, diuresis, incr HR, incr BP, incr resp, bronchodilation
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Adverse affects of caffeine?
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Nervousness, anxiety, irritability, twitching, headache, confusion, insomnia, heart palpitations
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What receptors does caffeine affect in normal doses?
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Antagonist of A1 & A2a adenosine receptors
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What pharmacological effects does caffeine have at high doses?
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Inhibits phosphodiesterase, blocks GABAa receptors, mobilises intracellular Ca2+
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Which adenosine receptor mediates the psychomotor effect of caffeine?
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A2a
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What effect does the adenosine A2 receptor have on the dopamine D2 receptor?
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A2 and D2 receptors dimerise in the post syn cleft, adenosine binding to A2 reduces the affinity of the D2 receptor for dopamine
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How does caffeine affect the A2/D2 receptor interaction?
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Caffeine prevents adenosine from binding, enhances dopamine effect
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Which receptor mediates caffeine CNS arousal?
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Adenosine A2a
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How is caffeine metabolised?
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CYP1A2
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How is nicotine metabolised?
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CYP2A6 & 2B6, then aldehyde oxidase, then CYP2A6
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Half life of caffeine?
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Around 5 hours
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Half life of nicotine?
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Around 1-2 hours
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What is 3-hydroxycontinine?
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Final metabolite of nicotine that can be measured in urine
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What is the mechanism of action of nicotine?
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ACh agonist
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What reactions to nicotine have tolerance?
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Peripheral ACh effects
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How does nicotine induce reward?
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Three mechanisms (postsyn nicot receptors on dopa neurons, presyn nicot receptors on gluta neurons, desensitises nicot receptors on GABA neurons) that increase dopamine neuron excitation, increase dopamine in nucleus accumbens
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What is buproprion?
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NA & dopamine uptake inhibitor, offsets loss of dopamine from nicotine cessation
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What is varenicline?
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Partial nicotinic receptor agonist, used in nicotine cessation
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What area is linked to all dependance drugs?
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Nucleus accumbens
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Nicotine and caffeine are theorised to play what role in Parkinson's disease?
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Neuroprotective - no effect once damage done
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Two highest occurring toxic agents the poisons centre gets called about?
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Therapeutics and household agents
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What are the top therapeutic groups that the poisons centre gets called about?
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Analgesics, anti-inflammatories, topicals, antidepressants
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What is the highest frequency circumstance for acute exposure in calls to the poisons centre?
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Child exploratory
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When is dilution appropriate in poisonings?
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If there is risk of local damage (corrosive effect)
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How is whole bowel irrigation performed?
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Administer 2L/h of a isotonic non-absorbed solution (eg PEG) until effluent is clear
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What is activated charcoal not used for in poisonings?
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Acids, alkalis, some pesticides, some metals (Fe, Li), alcohols
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How is NAPQI formed?
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2E1/3A4 metabolism of paracetamol
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What factors increase the risk of paracetamol toxicity?
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Chronic alcoholism, prolonged fasting, 3A4 inducers
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How does prolonged fasting increase the risk of paracetamol toxicity?
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Depletes glutathione, less is conjugated, more NAPQI is created
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What is stageII of paracetamol toxicity?
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Apparent recovery, right upper quadrant abdominal pain, elevated LFTs/bilirubin, prolonged prothrombin clotting time
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What is stageI of paracetamol toxicity?
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Off colour - pale, sweaty, no appetite, nausea
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What is stageIII of paracetamol toxicity?
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Hepatic necrosis - coagulation defects, jaundice, hypoglycemia, cardiac failure, renal failure
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When does stageII of paracetamol toxicity occur?
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24-48 hours
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When does stageIII of paracetamol toxicity occur?
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72-96 hours
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When does stageI of paracetamol toxicity occur?
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First 24 hours
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What is stageIV of paracetamol toxicity?
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Recovery, normalisations of LFTs, liver returns to normal within 3mo
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When does stageIV of paracetamol toxicity occur?
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4 days - 2 weeks
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What is N-acetyl-cysteine used for?
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Facilitates glutathione synthesis, used for paracetamol overdose
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How is N-acetyl-cysteine given?
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By IV, and monitored for anaphylactoid reaction, esp in 1st hour
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Adult levels of paracetamol toxicity?
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>200mg/kg or 10g in under 8 hours
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Child levels of paracetamol toxicity?
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>200mg/kg in under 8 hours
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Fatal dose of methadone in children?
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10-20mg
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Fatal dose of methadone in non-tolerant adult?
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50mg
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Management of methadone overdose?
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Establish airway, prevent aspiration, AC, naloxone
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