Neuro Flashcards
role of the thalamus
Processes and relays sensory information to the varying parts of the brain. Plays a major role in motor systems and signals, as well as regulation of consciousness and alertness.
how pain is transmitted
-When tissue damage occurs, algogenic substances are released due to the damage.
-sensory afferents sense these substances and sends signal to brain so will feel pain.
-brain sends a response out on the motor fibres to react to the pain (e.g. the patient jumps away)
What is an algogenic substance and name examples. which ones have key roles in analgesia
-released in pain which are associated with tissue damage. work on nociceptors to send the message of pain to the brain
-K+, H+, histamine, serotonin, bradykinin, substance P, prostaglandins, leukorienes
-Substance P inhibited by opioids
-Prostoglandins inhibited by NSAIDs
difference between, A beta, A delta and C fibres
A beta = thick myelinated. mechanoreceptors - touch and pressure. Fastest
A delta = short sharp pain. Fast myelinated. Larger. Respond to high intensity mechanical stimuli
C = slow dull ache. Unmyelinated. Respond to pressure, mechanical, thermal and chemical stimuli. Exist in vessels so feel pressure
Explain the pain pathway of the trigeminal nerve. where is the trigeminal ganglion located
- Tissue damage
- Release of algogenic substances
- Signal sent to trigeminal ganglion via A delta and C fibres. Ganglion in Meckel’s cave, a cavity in the dura mater of the brain, near the petrous part of the temporal bone
- A sensory root exits ganglion and into brainstem at the level of the pons
- Thalamus
- The brain interprets signals and sense pain.
a descending motor response is sent out
What is nociception convergence and divergence. which causes referred and radiated pain
-Convergence= causes referred pain. when brain struggles to well where an impulse originally came from.
-Divergence = radiation of pain, afferents synapse several different second order neurones so brain interprets the pain to be from a larger area than the original site of stimulation.
Explain sensitisation, hyperalgesia and allodynia
-Sensitisation is caused by progressive increase in response following continual repeated experience of a stimulus/ tissue damage. Releasing continual algogenic substances causes either:
Hyperalgesia – signal that would normally be painful is interpreted as being much more painful. Peripheral sensitisation
Allodynia – something that would normally not be painful is very painful. Central sensitisation
-It is a protective function but can become chronic pain
what pain can depend on and be affected by
-pain: the nocicetive pathway is fixed but it can be interpreted differently by different people due to psychological and social variables (hormone production, physical conditioning, behavioural responses, avoidance of activity, psychology, environment, culture, emotions)
Multidisciplinary management required for dealing with chronic pain
what do most peripheral acting analgesics target in order to inhibit the nociceptive pathway. Are opioids peripheral or central analgesics
-Algogenic substances, released in response to tissue damage that cause trigger the inflammatory and nociceptive pathway
-central
what do COX 1 and 2 do
-COX1 = stimulate prostoglandins that secrete mucous in the stomach. So inhibition of COX1 causes unwanted stomach ulcers.
-COX2 = stimulate prostaglandins that activate inflammatory cells, so inhibition reduces inflammation, pain, fever, platelets.
-Prostoglandins: lipid compounds made at damaged sites to induce inflammation to deal with injury, raise temperature.
-Arachidonic acid is converted to prostaglandins by COX. Thromboxane (platelet aggregation) and prostacyclin (platelet inhibition) are produced in the pathway too
-made form fatty acid metabolism
NSAIDs action and functions
-analgesics, anti-inflammation, anti platelet, antipyretic.
-irreversibly inhibit COX 2 which inhibits prostaglandin production. nociceptors are less sensitive to the effects of chemical mediators (5-HT, kinins)
-Aspirin: all 4 functions. For mild analgesia.
-Ibuprofen: all 4 except anti-platelet.
First choice in inflammatory joint disease. Less gastric irritation, more effective and better tolerated than other NSAIDs.
-Paracetamol: only analgesic and antipyretic.
Effective in mild analgesia, less so in inflammatory conditions.Overdose causes heptatoxicity
Paracetamol maxmimum daily dose, fatal dose, dose causing acute liver damage. what patients to avoid in
500mg to 1g 4 times daily
max is 4g
10-15g = acute liver damage
25g is fatal
Reduce in patients with pre-existent liver disease (2-3g)
Explain phase 1 and 2 metabolism
-Phase 1= decreases lipid solubility, increases the drug’s activity so may become toxic. [reduction, oxidation, hydrolysis]
-Phase 2= Conjugation. Adds hydrophilic component (eg. glucuronyl group via glucuronidation) to further decrease lipid solubility, more water soluble, and also to make it inactive and not toxic. This conjugate can then be excreted in urine or bile.
Paracetamol: metabolism in overdose, overdose symptoms and treatment
-phase 2 metabolism becomes saturated
-more phase 1 metabolism. Build-up of hepatotoxic NAPBQI
-no immediate symptoms. yellowing of skin,
-Early treatment: (4h) activated charcoal; (12h) with N-acetylcysteine (precursor of glutathione)
* N-acetylcysteine upregulates glutathione, to ‘mop up’ NAPBQ
Aspirin absorption. how it is antiplatlet. and unwanted effects if <16 years old
-Rapid absorption via GI
-blocks thromboxane A2, which is involved in promoting platelet aggregation.=anti-platelet
Reyes syndrome if given in children -affects all organs, mainly increasing intracranial pressure, fat accumulation in liver
Ibuprofen total daily dose
- 1.2g – 2.4g total daily dose
- Adults: 400mg (2x200mg), 3 times a day
NSAID unwanted effects
-Gastric ulceration (Avoid pts with pre-existent gastric ulcers)
-Non-selective prostaglandin block leads to renal toxicity (avoid in pre-existent renal dysfunction)
-Platelet effects (avoid in other coagulopathies) =increased bleeding during procedures
-Can induce asthmatic attack (avoid in asthmatics)
-Avoid in 3rd trimester of pregnancy
-Reyes syndrome (Rare childhood disorder, caused by aspirin and infection so do not prescribe aspirin to <16 year olds)
-Extensive protein binding -increased drugs interaction
Opioids mechanism, indications and main uses.
-Agonists on mainly u opioid receptors which are G-protein couples receptors on neurons that regulate pain perception.
-Binding inhibits adenylate cyclase, increasing potassium influx so decreases Ca and causes hyperpolarization which turns off neuronal excitability.
* Causes euphoria and analgesia
* Oral or rectal but usually IV or IM due to unreliable gut absorption and extensive first pass metabolism
-for moderate to severe pain that has major impact on life, terminal illness, severe post-op pain, chronic pain unresponsive to NSAIDs, heart failure pain
Opioid unwanted effects. What is tolerance and dependence
-Drowsiness and sedation
-Respiratory depression, cough suppressive, nausea
-Decrease urinary flow, pinhole pupils
-Constipation (inhibition of smooth muscle in gut) so usually IV than oral
* Tolerance: patient no longer responds to it in the same way so needs a higher concentration to get the same analgesic effect.
* Dependance: sudden withdrawal after chronic treatment causes sweating or tremors for example
effect of alcohol on paracetamol
-Alcohol enhances CYP450 enzyme (more phase 1 into inactive metabolite)
* so decreases drug effectiveness
Interaction of aspirin and warfarin
-It increases risk of bleeding as it is an anti-platelet agent.
-It inhibits COX involved in prostaglandin production so blocks synthesis of prostaglandin and so inhibits platelet-derived thromboxane A2 (used for aggregation) and endothelium-derived prostacyclin (inhibits aggregation)
-Endothelium can make new COX but platelets cannot so net effect of prostacyclin increase which inhibits aggregation.
which antibiotics affect warfarin and to avoid
- penicillins, erythromycin, metranidazole inhibits P450 so inhibits metabolism so enhance anticoagulant activity so increase risk of bleeding.
- Rifampicin induces P450 so decreases its activity
=AVOID
how to manage opioid addiction, and overdose
-Addiction managed by methaodone - High affinity for µ receptor, Long half life, Reduces withdrawal symptoms
-overdose managed by oxygen and naloxone
Opioid overdose diagnosis and management
-Diagnosis – mioisis (pupil contraction) and bradypnoea (slow breathing)
-Management
ABC 100% high flow oxygen
Naloxone 0.2-0.4 mg IV
Repeat every 2-3 mins (Max 10 mg)
Guided by state of respiration NOT consciousness
Strong and weak opioid drugs
1-Strong:
* Morphine-for severe pain relief, terminal care.
* Pethidine
2-Weak: used for mild to moderate pain.
* Dextroproxyphene
* Dihydrocodeine- cause nausea and constipation
* Codeine
* Tramadol -causes less constipation, dependence, resp depression
* Remifentanyl, alidentanyl
Morphine metabolism, excretion, why decrease dose in kidney disease
-Extensive 1st pass metabolism when taken orally, only 20% reaches systemic circulation
-Hepatic and renal metabolism
-Excreted via kidneys: Pharmacologically active metabolite produced so Decreased dose required for those with renal disease
Difference between LA , GA and analgesics
-LA: loss of sensation to a defined area. still feel pressure
-Analgesics: drugs used to control pain. No total loss of feeling (eg. morphine)
-General anaesthesia: loss of feeling and also loss of consciousness (eg. propofol)
Criteria for LA
reversible action
non-irritant, non-allergic, non-addictive
no permanent damage
no systemic toxicity
high therapeutic window
topical or injectable
rapid onset
suitable duration
sterilisable
can be stored, chemically stable
specific: this would be in an ideal world, however LA is not specific as can affect CNS, motor neurones etc.
Explain the membrane expansion theory and specific receptor theory for LA
- LA enter nerve cell membrane, expands it, blocking the sodium channels so sodium cannot enter cells so it stops depolarisation so no message can be conveyed
- LA binds to receptors on the h gate, holding it closed. This holds it in refractory period where no more impulse can be fired and no message conveyed
Structure of sodium channels - subunits. domains, segments, gates
made of alpha, beta 1 and beta 2
Na passes at alpha subunit
Na channel surrounded by protein domains I-IV, each domain with segments S1-S6
At rest, m gate is closed (S4) and h gate is open (linker between domain III and IV)
Explain the structure of an LA molecule (3 components)
- Aromatic group (lipophilic)
- Intermediate chain (ester or amide link)
- amino terminal (hydrophilic)
Name examples of amide and ester LA. describe amide and ester links. which have increased allergy risk and why
|
1. Amides: NH - C = O
-lidocaine, articane, mepivicaine, prilocaine, bupivicaine |
2. Esters: O=C-O -
-benzocaine, amethocaine, procaine
-increased allergic risk so less used. metabolised to PABA which can cause allergy
is LA ionised or unionised outside or inside the cell. why LA won’t work in infected tissues
-LA is a weak base. Outside cell the pH is 7.4 so is unionised and lipid soluble so can enter the membrane. [higher proportion of uncharged molecules means enters cell quicker so more effective]
-inside is slightly acidic so becomes ionised so can bind to Na channel
-But in infected tissue, the tissue is more acidic so it is in an ionised state and less lipid soluble so it is difficult for it to penetrate the membrane and into the cell
What chemical-physical properties of LA influences its onset and duration of action
- Ionisation (pH of tissue and pKa of drug) - onset [small difference=quick]
- Oil:gas Partition coefficient (lipid solubility) - onset
- Protein binding – duration of action
- Vasodilator ability – duration of action
Explain pH and pKa. how to work out level of ionisation. do you rather want low or high pKa and why
pKa = dissociation constant. the strength of the acid or base drug
pH minus pKa = level of ionisation. how much drug is unionised and neutral. 50% ionized and 50% unionized when the surrounding pH equals the drug’s pKa
To cross membrane you want:
HIGH pH
LOW pKa - more uncharged and lipid soluble
HIGH PARTITION COEFFICIENT (lipid soluble, crosses membrane)
these are the pKa values of LA. Lidocaine (7.9), Articaine (7.8), Bupivicaine (8.1), Procaine (9.1). explain the significance of this
ideally want lower pKa as more uncharged molecules exist so more lipid soluble to cross membrane. articaine is most effective at crossing membrane so most effective and quicker onset
(lidocaine has high lipid solubility value)
how protein binding affects duration of action. Does lidocaine or articaine have more protein binding
-drug bound to protein acts as a reservoir which can replace drug that has been metabolised. more protein binding= longer half life = longer lasting = released slowly
-Articaine = 94% bound, half life 108 minutes so longer lasting
-Lidocaine = 64%, 90 minutes half life
Why vasoconstrictors added to LA. name the 2 vasoconstictors used
-LA is vasodilatory so vasoconstrictor needed to overcome this
-longer duration of action (prevents dilated vessels washing it away), better haemostasis, prevents systemic effects (as constricts vessels and contains the drug)
-adrenaline (a catecholamine), felypressin (a synthetic peptide)
Purpose of reducing agent and ringer’s solution in LA
-Reducing agent (only present if vasoconstrictor is – prevents it breaking down)
-Ringer’s solution – solvent the drug is dissolved in, forms bulk of cartridge
which 3 adrenoreceptors does adrenaline act on and their action. other effects of adrenaline on the body
a1: vasoconstriction (prolongs anaesthesia, blanching). Inhibits insulin release so increases blood glucose
b1: increases HR. CO
b2: bronchodilator
-hypokalaemia, decreases oxygen tension in tissues, increases fibrinolysis (less stable clot)
amount of adrenaline in articaine and lidocaine
Lidocaine = 1:80,000. 12.5ug/mL in a cartridge so 27.5ug in 2.2ml cartridge
Articaine= 1:100,000.
felypressin. potential toxic effect, amount in lidocaine
-given if can’t tolerate adrenaline
-Causes:
- Coronary artery vasoconstriction
- Oxytocic action on uterus - can induce labour (although would need >100 cartridges for this)
- Poorer control of haemorrhage than adrenaline
-Amount in cartridge:
- 0.54ug/mL
- 2.2ml contains 1.2ug (compared to 27.5ug adrenaline)
what factors affect the ability of LA to enter the bloodstream (be absorbed)
- More vasodilation= quicker
Presence of vasoconstrictor =slower - More protein binding = slower
- Higher concentration= quicker
- IV (PDL and intraosseous) =quicker
- More vascular tissue = quicker
How are esters and amides metabolised. which have longer half life
- Amides: longer and more complex than amides so longer half life. Most is in the liver (prilocaine partly in lungs, articaine partly in blood)
- Esters: more rapid metabolism. In the blood and some in the liver
-excreted in kidneys (<3% unchanged in urine)
what enzyme metabolises esters in the blood. what is the major metabolites. how sux apnoea can occur
pseudocholinesterase.
Metabolites are non-active, so once broken down has no effect
* Major metabolite is para-aminobenzoic acid (PABA) – most ester allergies
-1 in 2800 lack pseudocholinesterase so risk of overdose and sux apnoea (permanent paralysis)
how is adrenaline metabolised
mostly in liver
-appears in systemic circulation rapidly (peak level within minutes)
-methylation by COMT enzyme
-transported to liver for deamination
-conjugation with sulphate
-alcohol dehydrogenase and monamine oxidase involved
-excreted in urine, 1% excreted unchanged in urine
how many mg/L of lidocaine in plasma is toxic to CNS. 44mg lidocaine is given to an adult with 3.5l of plasma. How much is in the CNS (remember 64% protein bound)
5mg/l = CNS toxicity
44 / 3.5 = 12.6mg/l. 64% of this is 4.5mg/l
how many mg of lidocaine is in a cartridge. how many ml in a cartridge. what is the maximum dose per kg. Max amount of cartridges can be given to a 70kg adult. and how many for 20kg child.
what is the ceiling dose, regardless of their weight
-44mg
-2.2ml
-4.4mg/kg
Ignore the 2.2ml for these questions.
A tenth of a 44mg cartridge gives you the max dose per kg. (44 / 4.4) so 1 cartridge per 10kg. and 7 cartridges for 70kg. and 2 cartridges for child.
max is 11 cartridges (500mg)
Why LA taken with care in liver disease
o Major site of metabolism of LA. Produces plasma cholinesterase for metabolism
* Impaired liver function → relative LA overdose
-Mild disease = dose reduction.
-Or severe disease – consult with physician
-Elderly=Liver function decreases with age. So over 65 years – care with dose
Symptoms of initial then progressive LA CNS toxicity
-Initial = excitatory effects. Involuntary muscle activity, dizziness, anxiety, increased HR and BP, irritation, tremor
-Then, inhibitory. confusion, slowed speech, drowsiness , shivering, cardiac instability, nausea
-Finally, seizure, coma, cardiac arrest, death
ways to reduce LA toxicity
-reduce dose in liver disease patients as drug metabolism will be decreased
-give correct dose, based on MH and body weight
-do not inject Intravascular (aspirate)
-inject slowly - allows time to monitor patient for signs of toxicity
How to treat LA overdose
- Stop procedure
- Get help, remember ABCDE: Airways, breathing, circulation, disability, exposure
- Lie patient flat
- Maintain airway – head tilt chin lift
- Administer oxygen (high flow, 15L/min)
- IV anticonvulsants/ iv lipid emulsion/ iv fluids = dentist doesn’t do this
- Basic life support
Treatment of adrenaline overdose
-highly unlikely in dentistry as so little in a cartridge
-Stop procedure. Get help, remember ABCDE. Place in semi-supine or erect position – minimise increase in cerebral BP.
- Reassure so they don’t start producing more adrenaline.
-Administer oxygen if not hyperventilating
what is an idiosyncratic reaction
not true toxicity. patient thinks they are allergic due to having palpitations, feeling shaky
what drugs interact with adrenaline so when to reduce dose to 2-3 cartridges
-Tricyclic antidepressants (eg. Amytripiline):
Decrease re-uptake of adrenaline into nerve cells so effects of adrenaline doubled
-Beta-blockers (propranolol, atenolol)
Adrenaline opposes their action - Increase systolic BP. Increased stroke risk.
[however reducing adrenaline means less effective LA so risk of more pain which could initiate heart problems]
-Diuretics
Adrenaline increases hypokalaemia so increases effects.
-recreational drugs increase adrenaline toxicity so avoid for 24 hours if possible, otherwise limit dose
which amide LA are better for hepatitis patients and why
amides are mostly metabolised in liver but
-Articaine is also metabolised in plasma
-Prilocaine is also metabolised in lungs and kidneys
so better options
How benzodiazepines work. name drugs
-midazolam, diazepam, temazepam, flumazenil
-bind to alpha and gamma subunits of GABA, increasing its frequency of channel opening, increasing Cl influx, hyperpolarising the cell and decreasing excitability (as GABA inhibits neurotransmission)
-BDZ can also mimic glycine, another inhibitory neurotransmitter
-can also BDZ receptors in peripheral organs
-not analgesics, for sedation
How is midazolam and diazepam administered. metabolism. differences - short/ long acting, water soluble/ insoluble, half life, recovery time, which is painful on injection, which is more potent, uses
IV. Liver
1. Diazepam = long lasting, insoluble in water, long half life (43 hrs), rebound sedation, pain on injection, less potent. For seizures, muscle spasms, fits, anxiety.
2. Midazolam = short acting (20s from IV to brain), water soluble, lipophilic, painless, rapid recovery, short half life, more potent. sedative, anxiety, seizures
How temazepam is administered. short or long acting. metabolism. when it is used. Why it is ideal for elderly, instead of using diazepam
oral, gastric absorption, slow onset, used as a pre-sedative morning of procedure
short lasting as metabolised by glucuronidation (phase 2) to inactive compounds. Ideal for elderly as oxidation is lacking, needed in phase 1 of long lasting.
what is diazepam dissolved in. what harmful effects it can have. what is added to prevent pain on injection
-dissolved in organic solvent - propylene glycol (valium)
-glycol is very irritant - in an artery will cause severe long lasting or irreversible vasoconstriction. and may induce gangrene. Can give pain on injection or thrombophlebitis
-emulsified in soya bean oil (Diazemulsl) to prevent pain
what makes midazolam short acting. why are elderly sensitive to it.
lipophilic in blood so rapid penetration of blood-brain barrier
-Elderly markedly sensitive to midazolam – less protein binding in older people so more of the drug available to cross the blood brain barrier. So more careful when administering (reduce increments given from 1 a minute, to 1 every 2 minutes)
Why diazepam is long lasting
metabolised in phase 1 to active forms
Side effects of midazolam and diazepam. which drugs inhibit metabolism of midazolam
-repiratory depression, muscle relaxation, worse in chronic bronchitis,
-reduced BP, increased HR to compensate BP drop. CO unaffected
-sexual fantasy
-increases effects of other CNS depressants - opiates, alcohol, anti-histamines
-erythromycin and cimetidine (for gastric ulcers) inhibits midazolam metabolism, increasing sedation duration
why Nitrous oxide has rapid induction and recovery. why cannot achieve anaesthesia with it. how long takes for 95% of the gas to be eliminated. How many ppm is recommended over 8 hours
-very insoluble in blood, so rapid induction and recovery
-the mean alveolar concentration that will cause sedation is 105% so very safe
-95% of the inspired gas is eliminated within 10 minutes of a typical dental administration (Even after longer administrations 90% is gone within 15 minutes)
-1000ppm over 8 hours
clinical signs of nitrous oxide. and side effects
-analgesia, relaxation, feel warm, tingling in fingers, butterflies in tummy, become dissociated, euphoria,
-only hazardous if prolonged exposure.
-chronic exposure risks= impairs DNA synthesis, bone marrow depression, inhibits haematopoiesis, pernicious-like anaemia. Pins and needles. Liver disease. Increased miscarriage. Decreased fertility. Cervical cancer
Side effects of inhalation anaesthetics
-Malignant hyperthermia: hypermetabolism, increased sympathetic activity
-Hypotension, vasodilation, decreased cardiac output
-Respiratory depression (low oxygen saturation)
-Hepatic toxicity
-Decreased glomerular filtration and urine output (although not usually a problem due to the decreased cardiac output)
4 factors that affect the efficiency of inhalation anaesthetics
1-Blood/ gas partition coefficient = Low blood solubility means rapid induction & recovery as less drug needed to produce equilibrium. Less retention of the drug following distribution.
2-Oil: gas partition coefficient= High lipid solubility means high potency
3-Vascularisation - Good blood flow in brain means high levels of drug. Poor blood flow in body fat means drug doesn’t accumulate.
4-Ventilation rate: high rate means high rate of removal.
where is inhaled anaesthetics metabolised and eliminated
-Most drug is eliminated in the lungs
-little is metabolised via hepatic metabolism as it is toxic (halothane is metabolised a lot by liver so toxic)
Causes of facial paralysis (intra cranial and extracranial)
-Intra= stroke, tumour, multiple sclerosis, HIV, Lyme disease, Ramsay hunt syndrome, trauma to base of skull
-extra= Bell’s palsy, parotid neoplasm, post-parotidectomy, sarcoidosis, incorrect LA administration
