Week 2 Flashcards
What are anaesthetics?
Drugs that cause loss of consciousness, usually with loss of reflexes and some alagesia
What are analgesics?
Drugs that relieve pain
What are psychotropics?
Drugs that affect mood and/or behaviour
What are anxiolytics/ hypnotics/ sedatives/ minor tranquilisers?
Drugs that relieve anxiety and reduce excitability. In higher doses may induce sleep.
What are major tranquilisers/ antipsychotics/ neuroleptics?
Drugs used in humans for the treatment of schizophrenia, in animals used to produce profound sedation
What are antidepressants?
Drugs that alleviate the symptoms of depressive illness in humans and are used in veterinary medicine to treat compulsive behavioural disorders
Where do virtually all drugs act in the CNS?
Virtually all drugs that act in the CNS produce their effects by modifying some step in chemical synaptic transmission
- action potential in presynaptic fibre
- Synthesis of transmitter
- Storage of transmitter
- Metabolism (breakdown) of transmitter
- Release of transmitter
- Reuptake of transmitter
- Degradation of transmitter
- Binding of transmitter to receptor
- Receptor induced increase or decrease in ionic conductance
What are the chemical mediators in the CNS? What kind of effects can they produce?
- Neurotransmitters- released by presynaptic terminals and produce rapid excitatory response in post synaptic neurons
- Neuromodulators- released by neurons, and produce slower pre- or post- synaptic responses, mediated mainly by G-protein coupled receptors
- Neurotrophic factors- released mainly by non-neuronal cells, act on tyrosine-kinase-linked receptors that regulate gene expression
** chemical mediators in the brain have long slow lasting effects, can act diffusely at considerable distances from the site of release and can have diverse effect on transmitter synthesis, on expression of neurotransmitter receptors and on ionic conductance
What are some fast neurotransmitters? What do they operate through?
Glutamate, glycine, GABA, ACh– that operate through ligand gated ion channels
* Speed depends on the receptor that it binds to. E.g. the same agent may act through both ligand gated and GPCR like glutamate or ACh
What are the slow neurotransmitters and neuromodulators? What do they operate through? What ultimately causes a transmitter to be fast or slow?
Dopamine, 5HT, ACh, neuropeptides– operate through G-protein-coupled receptors.
* Speed depends on the receptor that it binds to. E.g. the same agent may act through both ligand gated and GPCR like glutamate or ACh
What is an example of an amino acid neurotransmitters that are excitatory?
Glutamate, the principal fast “classical” excitatory transmitter and is widespread through the CNS. Several different glutamate receptors have been characterized according to particular agonists that bind to them e.g. NMDA, AMPA, kainate
What are three examples of an amino acid neurotransmitters that are inhibitory?
Gamma-amino butyric acid (GABA) is a major inhibitory neurotrasmitter in the CNS. GABA receptors are of two main types GABA (A) receptor is ligand gated to Cl- ion channels and is the site of action of many neuroactive drugs e.g. barbituates, benzodiazepines, steroid anaesthetics GABA (B) receptor is G-protein-coupled receptor, coupled to biochemical processes and regulation of ion channels
* Glycine is an inhibitory transmitter acting mainly in the spinal cord. Strychnine is a competitive glycine antagonist.
* Acetyl choline- ACh is widely distributed in the brain. Both nicotinic and muscarinic receptors occur in the CNS. Muscarinic receptors mediate the main behavioural effects associated with ACh- arousal level, learning and short term memory
What are three examples of monoamines?
* Dopamine- neurotransmitter as well as being a precursor of NA. But distribution of dopamine in the brain is very different from NA. There are two main families of dopamine receptors- D1 and D2. D2 receptors are implicated in the pathophysiology of Parkinson’s disease and schizophrenia.
* Noradrenaline- Pathways for NA neurotransmission in the CNS are essentially the same as in the PNS. Adrenergic receptors in the CNS are alpha1, alpha2, beta. NA is important in the “arousal” system, controlling wakefulness, blood pressure regulation, control of mood. Drugs acting on noradrenergic transmission in the CNS include alpha 2 agonists, antidepressants, cocaine, and amphetamine.
* 5-hydroxytryptamine (serotonin)- an important CNS transmitter with complex and varied effects. 5-HT can exert excitatory or inhibitory effects, acting presynaptically or post synaptically. 5-HT pathways are involved in physiological and behavioural functions, namely hallucinations and behaviour changes, sleep, wakefulness, and mood, control of sensory transmission. A variety of new drugs influence 5-HT pathways in selective ways: for example selective serotonin reuptake inhibitors (SSRIs), ondansetron (an anti-emetic) 5-HT3 receptor antagonist, buspirone (anxiolytic) 5-HT1a receptor agonist.
What are four examples of non adrenergic non cholinergic (NANC) transmitters?
* Histamine- fulfills the criteria of CNS neurotransmitter. H1, H2, H3 receptors are widespread in the brain. Many of the functions are unclear, but H1 receptor antagonists are strongly sedative and anti-emetic.
* Purines- (ATP and adenosine)
*nitric oxide
*arachidonic acid metabolites
^all have established roles as CNS transmitters and modulators.
What are neuropeptides? Three examples?
* Many neuropeptides that act on specific CNS receptors.
EX: Opioid peptides that modulate pain pathways, substance P, neuropeptide Y
Why is it difficult to predict the therapeutic effect of a particular pharmacological agent?
Because of the complexity of neuronal interconnections in the CNS and because of secondary adaptive responses. For example, an increase in transmitter release may lead to a decrease in transmitter synthesis, an increase in transporter expression, or in decreased receptor expression.
What are the classes of analgesics used in veterinary medicine?
* local anaesthetics
* NSAIDs
* Opioid analgesics
* Centrally acting non-opioid analgesics
* alpha 2 adrenergic agonists
In nociceptive afferent neurons in a peripheral sensory nerve, what are the two possible fibre types?
* C-fibres that are non-myelinated, have a low conduction velocity (< 1 m/sec) and sense dull pain.
* A fibres that are fine myelinated and have faster conduction velocities (6-30 m/sec). Sense sharp, localized pain. Terminate in the dorsal horn of the spinal cord.
What is the gate control mechanism in the dorsal horn?
This centre modulates pain transmission. Inhibitory interneurons in teh substantia gleatinosa of the dorsal horn act to inhibit the transmission pathway.
* Inhibitory interneurons are activated by descending pathways from the mid-brain and brainstem, as well as non-nociceptive afferent input.
* Inhibitory interneurons are inhibited by persistent C-fibre activity, hence “wind up” phenomenon- increasing duration of stimulation leads to increased transmission of pain signals.
What is the “wind up” phenomenon in regards to pain signals?
* Inhibitory interneurons are inhibited by persistent C-fibre activity, hence “wind up” phenomenon- increasing duration of stimulation leads to increased transmission of pain signals.
What are the two parts of the brain involved in pain modulation?
*Mid-brain/ pons “peri aqueductal grey area”
* Lower pons/ medulla “nucleus raphe magnus”
* initiate descending pathways that exert a strong inhibitory effect on the dorsal horn. This descending inhibition is mediated by enkephalins, 5-HT, noradrenaline, and adenosine.
What are the major inhibitory neurotransmitters in nociceptive pathways?
* Endogenous opioids
There are more than 20 endogenous opioids, the most important of which are beta- endorphin, enkerphalins, and dynorphin
What are the three types of opioid receptors?
1) mu- receptors: two types mu-1 mediate most analgesic effects, euphoria supraspinal; enkephalins are enodgenous mu 1 ligands. mu-2 mediate most of the undesirable side effects such as respiratory depression and constipation
2) delta receptors: are important in the periphery where they contribute to analgesia
3) kappa receptors: mediated analgesia primarily at the spinal cord level and have fewer side effects- less respiratory depression, miosis, etc. They tend to cause sedation and dysphoria rather than euphoria.
What is an opioid? What is an endogenous opioid? What is the first synthetic opioid?
* An opioid is any substance whether endogenous or synthetic that produces morphine like effects that are blocked by antagonists such as naloxone. They vary in their receptor specificity and their efficacy at different types of receptors.
* endogenous (aka opioid peptides): endorphins (bind to opioid receptors)
* first exogenous opioid derived from the resin of the opium poppy- Opiates
What do pure agonists have affinity for?
Mu receptors
This group includes most of the morphine like drugs e.g. morphine, pethidine, fentanyl.
Pure agonists may be strong (morphine, heroin, fentanyl, etorphine) or mild/ moderate (codeine, pethidine)
What receptor affinity do mixed agonist- antagonists and partial agonists have?
Combine agonist effect on one receptor subtype with antagonist activity on another receptor type.
For example, butorphanol- is an antagonist at the mu-receptor, and an agonist at the kappa-receptor. Pentazocine is a weak mu antagonist and kappa agonist buprenorphine a partial mu receptor agonist (it has high affinity for the receptor, but only partial activity)
What effect do opioid antagonists produce?
Produce very little effect when given on their own but block the effects of opioids. They are used to treat overdoses to opioids.
What are the cellular actions of opioids?
Opioid receptors are linked to G-proteins. On neurons opioids have two different actions:
* Close voltage gated Ca++ channels on presynaptic terminals, and thereby reduce transmitter release
* Open K+ channels on post synaptic neurons, thereby causing hyperpolarization and inhibition of action potentials in post synaptic neuron.
What are the sites of action of opioid drugs?
* Dorsal horn of spinal cord, so powerful analgesic effect direct on spinal cord
* supraspinal sites- pain modulating descending pathways opioids directly inhibit neurons
* opioids activate neurons that inhibit pain transmission
* Exogenous opioids stimulate release of endogenous opioid peptides that have actions at and receptors
* Peripheral opioid action- at sites outside the CNS, particular in pain associated with inflammation
What are the pharmacological actions of opioids on the CNS?
* analgesia (mu mediated) reduces nociception at periaqueductal grey level at spinal level; reduces stress at limbic system
* euphoria (mu mediated) contentment and well being; balanced by kappa mediated dysphoria
* excitement, constant motor response, and convulsions. Seen more often in domestic animals particularly horses and cats, than in humans. Presumed mu mediated as seen with morphine and pethidine but not agonist-antagonists such as butorphanol.
* respiratory depression (mu-mediated) decreased sensitivity of respiratory centre to pCO2 that occurs at therapeutic doses
* depression of coughing reflex, mechanism uncertain. Codeine gives cough suppression in subanalgesic doses
* Nausea and vomiting (mu mediated) through activation at chemoreceptor trigger zone
* Pupillary constriction- centrally mediated via oculomotor nucleus. Important emergency diagnostic in humans
* Marked species variability
What are the pharmacological action of opioids on the GI tract? And any other actions aside from CNS?
* Increased tone and reduced motility (mu, kappa, and delta mediated) leading to constipation, delay in gastric emptying, mediated mainly intramurally and partly centrally
* morphine stimulates release of histamine from mast cells, which can cause urticaria, bronchoconstriction (risk for asthmatics), hypotension
* Bradycardia and hypotension with high doses through a direct effect on medulla
What is Methadone? Why is it necessary at times? What are opioid analgesics classified as?
* Methadone is a weak, long acting mu receptor agonist used to relieve withdrawal symptoms
* Tolerance develops rapidly along with physical withdrawal syndrome. Some opioid analgesics are much less likely to cause dependence- codeine, buprenorphine, butorphanol.
* Because of their dependence characteristics all opioid analgesics are Schedule 8 poisons
What are the pharmacokinetics of opioids?
* Generally administered by injection in domestic animals
* They are metabolized by the liver, by conjugation with glucuronide- these glucuronides may be pharmacologically active
* The low conjugating capacity of neonates means opioids have much longer duration of action in neonates
What are eyes protected by?
Adipose tissue, lacrimal glands, and eyelid
What is binocular vision?
* Occurs where visual field of both eyes overlap
* allows for focus on near objects and for depth perception
* greater in carnivores than in their prey (i.e. herbivores)
monocular vision does occur in some species- this is the field of view does not overlap between the two eyes (most herbivores)
What are the three tunics that comprise the eyeball? What else is part of the eyeball?
- outer fibrous tunic
- middle vascular tunic
- internval nervous tunic
* lens for focussing light on receptors, partly liquid, parly gelatinous centre
What is the fibrous tunic?
* Dense collagenous tissue
* Resists internal pressure
* Consists of sclera (posteriorly) and cornea (anteriorly) which meet at limbus
What is sclera?
* Opaque, penetrated by fibres of optic nerve, continuous with dura mater of optic nerve, provides attachment for tendons of extrinsic muscles of eye
What is the cornea?
* Specialized transparent, dense connective tissue
* covered by anterior and posterior epithelial layers
* transparency depedent on: highly organized layers of collagen fibres, continuous pumping out of interstitial fluid by posterior epithelium
* avascular- nutrition by diffusion from lacrimal fluid (tears) and aqueous fluid of anterior chamber
* Very sensitive due to nerve endings (branches of ophthalmic division of CN V)
What is the limbus?
The point at where the sclera and cornea meet
What is the vascular tunic?
* Also known as uvea- consists of choroid, ciliary body, and iris (from posterior to anterior)
What is the choroid?
* Lines sclera from optic nerve almost to limbus
* contains blood vessels in pigmented connective tissue
* provides nutrients for outer layers of retina
* contains avascular tapetum lucidum: area of dorsal choroid, reflective, iridescent, not present in pigs (or humans), probably assists in nocturnal vision
What is the ciliary body?
* Thickening of choroid anteriorly in radial ridges (ciliary processes)
* Provides anchoring point for zonular fibres, which suspend lens
* Produces aqueous humour
What is the iris?
* ring of tissue suspended between cornea and lens
* Opening in centre is pupil
* consists of pigmented connective tissue covered with epithelium (pigmented posteriorly) - connective tissue layer contains smooth muscle sphincter (circular- PS) and dilator (radial-symp.), which regulate pupillary size
* Separates anterior from posterior chamber
What is the internal tunic?
Retina
* contains light sensitive receptor cells (posterior two thirds of retina)
* lines vascular tunic from pupillary margin posteriorly to optic nerve
* thin outer layer (pigmented except over tapetum) and thick inner layer (neuroepithelial)
* neuroepithelial layer (from outer to inner):
- photoreceptor layer
- horizontal cells
- bipolar cells
- amacrine cells
- ganglion cells
What are photoreceptor cells?
* Contain light sensitive receptors in extended membrane of outer segment
* Two types: rods (highly sensitive for night vision) and cones (colour perception); dogs and horses have fewer rods and limited colour perception compared to humans
* synapse with bipolar cells, which synapse with ganglion cells
What are ganglion cells?
* nonmyelinated axons extend across inner surface of retina to optic disc where they meet to form the optic nerve i.e. ganglion cells are cell bodies of CN II
What are horizontal cells?
Modify transmission between photoreceptors and bipolar cells
What are amacrine cells?
Modify transmission between bipolar cells and ganglion cells
Where do blood vessels enter the eyeball?
At the optic disc with optic nerve
What is the anterior chamber of the eye? What is the posterior chamber?
anterior chamber: fluid filled space inside the eye between the iris and the cornea
posterior chamber: narrow space behind the peripheral part of the iris and in front of the suspensory ligament of the lens and the ciliary processes
What is the lens?
* Soft, transparent, biconvex structure
* Composed of “lens fibres” - epithelial cells running in layers from anterior to posterior pole of lens
* Avascular- nourished by aqueous and vitreous humour
* focuses images on retina
* surrounded by an elastic capsule (basement membrane)
How do you know an animal is in pain?
In terms of sensitizers, what do you need for hyperalgesia?
Pain is the sum of a range of different stimuli
Speak through the ascending nociceptive pathway
Speak through the total potential nociceptive pathways (ascending and descending)
How is pain the sum of different signals?
Where are the descending inhibitory pathways of nociception initiated?
* midbrain/pons
* lower pons/ medullay
Where are opioid receptors?
(have no managed to create a selective mu-1 antagonist)
What is a major side effect of opioids?
* respiratory depression
* reduced GI motility
* dysphoria - state of unease (altered reality)
* dependence (physiological, not just psychological- can demonstrate at the tissue level)
(recall from table- mu is all over the CNS)
* species differences- humans on morphine- pinpoint non-responsive pupils (= overdose). Cats- dilated pupils.
What are actions of opioids?
* excitement- species dependent (cats and horses)
What is the receptor subtype for morphine, buprenorphine, and butorphanol, fentanyl?
What are alpha2 adrenergic agonists?
Produce a dose dependent sedation, analgesia, and muscle relaxation. Alpha adrenergic agonists bind to and stimulate alpha2 adrenoceptors. These receptors are found in CNS and periphery. They may be presynaptic, where their activation inhibits release of NA, or postsynaptic, for example on vascular smooth muscle, where binding of the drug and activation of alpha2 receptors cause contraction.
** Sedation is dose dependent and varies from anxiety relief to profound sedation. Analgesia is of much shorter duration than sedation (approx 15-20 mins of 60-120 mins and Muscle relaxation due to inhibition of inter neuronal transmission at the CNS level– more pronounced in ruminants and horses)…
Where are alpha 2 receptors?
In CNS: brainstem locus coeruleus (modulator of wakefulness) sedation, in brainstem (cardiovascular regulating centre), in dorsal horn of spinal cord (analgesia), thalamus (analgesia), sympathetic neurones (analgesia)
In periphery: in autonomic ganglia, in blood vessels *(pre and post synaptic alpha 2)*
What does activation of alpha 2 receptors lead to?
* Presynaptically- inhibition of NA release
* Postsynaptically- contraction of vascular smooth muscle
Why is it so important to consider pre-medicating agents with alpha 2 adrenergic agonists?
Additive effect- could kill patient
Good news is there are reversing agents
Where do emobli/ infarctions often occur if in the brain?
At the junction of the grey and white matter due to the loop of vessels
* Venous infarction is uncommon
Anisocoria
Variation in pupil size. Can indicate increased cranial pressure.
Glial scar, astroglial scar-filled with reactive astrocytes are the main cellular components. After injury, they extend their processes and increase sythesis of GFAP– they form a dense web of their plasma membrane extensions. SO they fill the space of the dead or dying neuronal cells (astrogliosis)
Basisphenoid fracture- some skull fractures can be difficult to find
* visual deficits are common - an area with the pituitary, optic nerves
Cerebral oedema
* acute or chronic
* in grey matter impossible to pick with the naked eye- grey matter is more dense than white matter with the cell processes
* White matter will show it better
* chronic oedema- smaller, yellow, flattened gyri, narrow sulci
Coning of the cerebellum due to cerebral oedema– due to contact with the occipital bones
When the vermis is actually herniating- it is known as lipping of the vermis
