PHARMACOLOGY BLOCK 2 : CNS & PAIN

caution... serotonin syndrome .; • Mild to life threatening – Cognitive‐ agitation, restlessness, hypomania, confusion – Autonomic‐ hyperthermia, hypertension, tachycardia – Neuromuscular‐ tremor, ataxia, hypertonia
neurotransmitters function and illness
1. Noradrenaline (NA)
  1. Dopamine (D)
    1. Serotonin 5-hydroxytryptamine (5-HT)
      1. Acetylcholine
        Gamma-amino butyric acid (GABA)
        Glutamate
        Memory, learning
        Alzheimers, stroke, huntingtons, epilepsy
        Motor control, memory, consciousness
        Anxiety, insomnia, aberrant behaviour, epilepsy
        Cognition, skeletal muscle movement, memory, consciousness
        Parkinson disease, dementia
      2. As for NA plus behaviour, pain transmission, emesis
        Depression, ADD, headaches, eating disorders, insomnia; vomiting
    2. Skeletal muscle movement, behaviour, emesis, hormone release
      1. Parkinson disease, schizophrenia, aberrant behaviour, psychoses; emesis
  2. Arousal, sleep, mood, appetite, hormone release, body temp
    1. Depression, insomnia, eating disorders, narcolepsy, ADD
2. illness occurs because imbalanced
  1. to much; over excite neuron or ^ in receptors or transmitters or activity
  2. to little; neurons not excited or - receptors transmitters or activity
  3. examples: depression...low serotonin and noradrenaline; anxiety insomnia... high glutamate low gaba low serotonin;
CNS CONTROLS input AND output in diffrent areas of brain
1. RETICULAR ACTIVATING SYSTEM: arousal;pain;consciousness;muscle tone
  1. LIMBIS SYSTEM: expressed emotions; behavoural; perseptions learning and memory
    1. EXTRAPYRAMIDAL SYSTEM; innervation of muscles limbs head and eyes
      1. BASAL GANGLIA; voluntary movements
antidepressants
1. antipsychotics
  1. anxiolytics
    1. mood stabillisers
      1. antiepileptics
        pain
        control or relive pain
        Narcotic-opium (morphine/codeine/ pethidine/fentanyl) bind to opioid receptors stop subtance p . liver high pass effect lwr dose result. kidney and bile out. Paracetamol, COX-2 inhibitors and NSAIDs are PG synthesis inhibitors • Paracetamol – unknown what enzyme/s are inhibited • COX-2 inhibitors – inhibits cyclooxgenase 2 enzyme (COX-2) • NSAIDs – inhibits cyclooxgenase enzymes (COX-1 BALANCING and COX-2 PROTECTIVE) GENRAL • nitrous oxide • isoflurane • desflurane • sevoflurane • propofol • thiopentone (Pentothal) LOCAL• lignocaine (Xylocaine) • amethocaine • bupivacaine • cocaine BLOCK PAIN
        Narcotic: mimic natural peptides in our bodies (endorphins) • The effects of narcotic from therapeutic to overdose includes analgesia, sedation, hypnosis, coma and finally death** benzos... • Morphine ‐ short half life (4 hrs) so dosing has to be frequent; tolerance develops • Pethidine – used in child birth and surgery for mild to severe pain ‐ causes less respiratory depression than morphine ‐ does not cause constipation. • Codeine • Fentanyl epidural (intrathecal) transdermal patch (Duragesic®) lollipop (Actiq®) • Tramadol • Methadone ‐ used as a substitute for morphine and heroin addiction as has lesser withdrawal symptoms ‐ 24 hrs half life ‐ strong analgesic NSAIDS AND COX2 -nausea, vomiting, ulcerations, and headache AND gi. PARACETAMOL- metabolised in the liver and can cause hepatotoxicity (alcoholics especially).
        • GENRAL Depress the CNS, ease pain and cause loss of consciousness (in most instances). • IV or inhalation • Used in major surgery. Examples: N2O, flurane gases, propofol LOCAL: • Block pain at site where drug administered • Allows consciousness to be maintained • Administration route: topical, intradermal, subcutaneous, epidural, intrathecal, intravenous. • Uses: dental surgery; suturing of skin lacerations; minor surgery at a localised area; epidural Examples: lignocaine; amethocaine; bupivicaine
        Adverse Effects of General Anaesthetics • CV – drop in blood pressure • CNS – respiratory depression • Liver – “Halothane Hepatitis” • Uterus – relaxes uterine muscles • Malignant Hyperthermia – rare • CTZ ‐ Nausea/vomiting. local 1. Local anaesthetics can also affect sodium channels in other parts of the body e.g. heart. This can lead to an abnormal heart beat. 2. Epidural anaesthetic could introduce foreign substances into the CSF. 3. Overdosage of local anaesthetic could lead to dosedependent CNS side effects; insomnia, visual and auditory disturbances, convulsions, shivering and CNS stimulation. 4. The ester containing local anaesthetics can cause allergic reactions.
        all addictive and abuseive
        Monitoring and Care Associated with General and Local Anaesthetics 1. Make sure vital signs and consciousness are monitored before, during and after general anaesthetic use. 2. Use narcotics sparingly while client is attempting to regain consciousness. 3. Monitor vital signs and conscious state regularly. Local anaesthetics can cause cardiac depression and CNS stimulation. 4. Evaluate local anaesthetised areas for sensation and movement.
        Pain • Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage (warning system!!!) • Pain threshold varies from individual to individual • Pain tolerance involves emotional aspects
        • Analgesia: controlling pain by blocking pain pathways without loss of sensation • Anaesthesia: prevention of pain by causing loss of sensation
        aim to reduce with minmum effects 1. Affecting the movement of sodium ions across the membrane Examples: Phenytoin (Dilantin); Carbamazepine (Tegretol) 2. Stabilising the nerve membranes directly Examples: Ethosuximide 3. Affecting the activity of Gamma‐amino butyric acid (GABA) Examples: benzodiazepines (enhances the inhibitory action of GABA); barbiturates (enhances the inhibitory action of GABA); vigabatrin (inhibits the enzyme that degrades GABA).CNS depressants Suppress abnormal electric impulses from the seizure focus to other cortical areas.
        Drugs that have combined action: 1. Valproic acid (Valproate): triggers release of GABA and inhibits sodium channels. 2. Lamotrigine: inhibits passage of sodium through voltage sensitive channels and reduces the release of glutamate (an excitatory amino acid).
        • GI upsets • headaches • mental confusion • nystagmus • allergic skin rash • Myelosuppression and sedation
        Drug‐Drug Interactions • The majority of the anticonvulsants are metabolised in the liver by the microsomal P450 liver enzymes. Some exceptions are gabapentin and vigabatrin. • Can affect their own metabolism • May affect the metabolism of other drugs as well.
      2. Used for people who cycle between mood swings
        Lithium carbonate (Lithicarb)::both manic and depressive state • Acts by enhancing the action of amine reuptake pump and inhibit noradrenaline release,Narrow therapeutic index drug‐....carbamazepine (BENZO) (Tegretol) and sodium valproate (Epilim) and lamotrigine
        LITHIUM treated like sodium,BLOODS ++ • Initially – slight nervousness, abdominal pain, anorexia, vomiting, diarrhoea • Giddiness, tremor, ataxia, slurred speech, depression • Oliguria, hypovolaemia, convulsive movements, coma • Potentially fatal outcome‐ cardiovascular, renal, failure • Hypothyroidism, nephrogenic diabetes insipidus (polyuria, polydipsia)...
    2. Benzodiazepines • Most have a suffix “–azepam” • Potentiates the inhibitory effect of gamma‐aminobutyric acid (GABA), a natural inhibitory neurotransmitter • GABA increases influx of chloride ions into the neuron which leads to hyperpolarisation and decreased excitability
      1. • Anxiety and panic disorders – anxiolytics • Sleeping disorders – hypnotics, sedative • Muscle spasms and seizure disorders – muscle relaxants; anticonvulsants • Preoperative medication
        • Majority lipid soluble and readily absorbed from GIT • Widely distributed in body and brain; highly protein bound • Liver metabolism; excretion via kidney • Half life ‐ helps to determine which one to use
        • Adverse effects – commonly cause excess CNS depression • Drug Interactions – e.g. other CNS depressants • Tolerance and dependence • Chronic administration – tolerance to sedation • Dependence – can lead to overuse and abuse • Withdrawal symptoms ‐ CNS stimulation e.g. Anxiety, sleep disorders, nervousness, seizures • Can cross placenta and into breast milk
        Other Anxiolytic/Sedative/Hypnotic Drugs • Barbiturates • Antihistamines • Buspirone • Zopiclone and zolpidiem • Chloral hydrate
  2. Dopamine receptor–blocking activity in the brain: All of the first generation and most of the second- generation antipsychotic drugs block dopamine receptors in the brain and the periphery (except clozapine-like atypical). – The clinical efficacy of the typical antipsychotic drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system of the brain
    1. OLD.TYPICAL • Phenothiazines – chlorpromazine Largactil (solution inj, tablet) – fluphenazine Modecate (depot injection) – methotrimeprazine (solution inj, tablet) • Thioxanthines – zuclopenthixol (solution inj; tablet) – flupenthixol Fluanxol (depot inj) • Butyrophenones – haloperidol Serenace (tablet, liquid; inj) – pimozide Orap (tablets) NEW-SECOND GEN-ATYPICAL Clozapine (oral suspension, tablet) Olanzapine (wafer, tablet, solution inj) Risperidone (oral solution, suspension, tablet; long acting inj) Quetiapine (tablet)
      1. OLD::• Extrapyramidal effects ADOPT (Akathisia (restless) Dystonia (spams) Oculogyric ( rolling eye) Parkinsonism (tremors) Tardive (unreversiable ticks) ) • Postural hypotension • Anticholinergic • Sedation • Weight gain • Endocrine effects ‐ e.g. hyperprolactinaemia • Neuroleptic Malignant Syndrome (NMS) ATYPICAL:: • Weight gain, dyslipidaemia‐ increased risk of CVD • Diabetes type 2 ‐ especially with Clozapine and Olanzapine‐ due to insulin antagonist effect – impair glucose entry into cells + impair lipolysis in adipose tissue • Therefore –assess risk factors for metabolic syndrome etc, family history, monitor‐ blood tests • Agranulocytosis – Clozapine; therapeutic monitoring BOTH;;;
        note: can effect people hours days years
2. overall mode of action is to… increase levels and activity of the excitatory neurotransmitters ‐ serotonin, noradrenaline...• First choice antidepressants ‐ SSRIs, RIMA, reboxetine, venlafaxine
  1. • Major groups: SSRIs; MOAIs; TCAs; RIMAs • Tetracyclic antidepressants ‐ maprotiline, mianserin Block the presynaptic (α2) receptors and noradrenaline re‐uptake and possibly serotonin action • Noradrenaline re‐uptake inhibitors (NRIs)‐ Reboxetine • Serotonin and noradrenaline reuptake inhibitor (SNRI) – venlafaxine • St John’s wort ‐ ‘Natural remedies’ OTCs
    1. ONSET: TAKE TIME ADVERSE +++++
    2. ADVERSE; AND DRUG INTERACTIONS
      1. TCAs anticholinergic; antiadrenergic (postural hypotension) antihistaminic (sedative); weight gain; cardiac arrhythmias MAOIs anticholinergic; adrenergic; risk of hypertensive crisis; sedation RIMAs lower risk of adrenergic; nausea; insomnia; headache SSRIs nausea; insomnia; sexual dysfunction
        TCAs other antidepressants; antimuscarinics; hypnotics; anxiolytics; anesthetics; antihypertensives; caution with antiepileptics MAOIs sympathomimetics(e.g. L‐DOPA, isoprenaline; pseudoephedrine etc); other antidepressants; antihistamines; hypnotics; anxiolytics SSRIs other antidepressants; antiepileptics; antipschotics; other drugs that increase serotonin (e.g St Johns Wort; tramadol etc)
  2. MODE OF ACTION
3. Definition • A sedative is a substance that diminishes the activity of an organ or tissue, in our context‐ CNS • Hypnotic (sleeping pills) is a substance that induces sleep • Anxiolytics (minor tranquilisers) are substances that alleviate anxiety

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