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Stage 1 Seminar: Clinical Pharmacology of the Nervous System


Remember your pre-clinical pharmacology. Anaesthetic agents. Muscle relaxants ... Clinical Parkinsonism: hypokinesia, rigidity, tremor ... – PowerPoint PPT presentation

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Title: Stage 1 Seminar: Clinical Pharmacology of the Nervous System

Stage 1 SeminarClinical Pharmacology of the
Nervous System
  • Dr Fraz Mir
  • Clinical Pharmacology Unit
  • Department of Medicine
  • University of Cambridge

Topics to be Covered
  • Anti-epileptic medicines
  • Anti-parkinsonian drugs
  • Anti-depressants
  • And briefly
  • Anti-psychotics
  • Treatments for dementia

Remember your pre-clinical pharmacology..
  • Anaesthetic agents
  • Muscle relaxants
  • Anxiolytics / hypnotics
  • Anaesthetic / psychiatry attachments

Anti-Epileptic Drugs
  • Mechanism of Action
  • Epileptiform event - a sudden, excessive
    depolarisation of cerebral neurones which may
    remain localised (focal epilepsy) or spread
    (generalised epilepsy)
  • Anti-epileptic agents thus prevent depolarisation
    of neurones
  • inhibition of excitatory neurotransmitters
  • direct membrane stabilisation
  • stimulation of inhibitory neurotransmitters

Principles of Management
  • Education of the patient regarding
  • nature of the disease and drug therapy
  • importance of compliance
  • importance of never suddenly stopping
  • avoidance of precipitating factors
  • fit diary
  • Treatment of any underlying lesion
  • structural e.g. tumour
  • metabolic e.g. alcoholism

Principles of Drug Therapy
  • Initiation of therapy
  • Aim for monotherapy (efficacious and safe)
  • Start with low dose - escalate over about a month
  • Assist dose selection by therapeutic drug
  • Should control 80 of patients on one agent
  • If unable to achieve control
  • confirm compliance by trough level monitoring
  • change to new agent of different class OR add a
    second agent of a different class
  • About 3 months treatment required to determine

Therapeutic Drug Monitoring
  • Indications
  • 2-4 weeks after start of therapy (guide dose)
  • failure on standard dose of drug
  • failure of compliance
  • adverse effects
  • when other drugs added
  • pregnancy
  • hepatic or renal disease

Duration and Withdrawal of Therapy
  • Around 80 of patients are fit free at one year
  • Consider withdrawal of therapy after 3-4 years if
    fit-free (note side effects / effects on
    cognition/behaviour esp. children)
  • should reduce gradually over several months
  • expect 20 relapse in first year
  • 20 relapse over next five years
  • subsequent relapse rare

Driving and Epilepsy
  • Cannot drive a HGV or public service vehicle
  • Can drive a car if on/off medication and fit-free
    for 1 year OR if persisting nocturnal fits and no
    daytime fit for 3 years
  • Fear of losing licence for a year is often major
    consideration of patients when reduction of
    therapy considered

Special Cases Pregnancy
  • Seizures in pregnancy constitute major risk to
    mother and fetus
  • Must maintain therapy (carbamazepine drug of
  • Requires careful monitoring
  • change in plasma protein binding
  • change in hepatic drug metabolism
  • interaction with OCP
  • Drugs are secreted in small quantities into
    breast milk but not usually sufficient to prevent
    breast feeding (phenobarbitone significantly)
  • Teratogenicity
  • Antiepileptic drugs associated with increased
    (2-3 fold) incidence of birth defects (cleft
    lip/palate and cardiac defects)
  • Significant risk of neural tube defects (altered
    folate metabolism usual culprit)

Drugs of Choice in Treatment of Specific Seizure
  • Seizure disorder Drugs of choice (1st
    choice in bold)
  • Primary generalised tonic clonic valproate
  • (grand mal) carbamazepine
  • phenytoin
  • Partial, including secondary generalised carbamaz
  • phenytoin
  • valproate
  • Absence (petit mal) ethosuxamide
  • valproate
  • Atypical absence, myoclonic, atonic valproate

  • Considered a drug of choice for
  • tonic clonic seizures
  • partial seizures
  • trigeminal neuralgiaIs
  • prophylaxis of manic depressive illness
  • Potent inducer of hepatic drug metabolising
  • own half life reduces over 2-3 weeks
  • increases metabolism of theophylline, warfarin
    and various hormones
  • complex drug interactions with other
    anticonvulsant agents
  • Adverse effects
  • blurred vision, diplopia,dizziness,
    bradycardia, skin rashes, GI upsets,
    osteomalacia, folate deficiency, hyponatraemia
  • Cost about 25/yr

  • Considered drug of choice for
  • tonic clonic seizures
  • partial seizures
  • Also used for
  • cardiac arrhythmias
  • trigeminal neuralgic
  • Pharmacokinetics
  • 90 plasma protein bound
  • Saturable (zero order) kinetics in therapeutic
    dose range
  • potent hepatic enzyme inducer (interaction with
  • Adverse effects
  • Impaired cognition, sedation, cerebellar
    disorders, peripheral neuropathy, rashes, gum
    hyperplasia, coarsening of facial features,
    hirsutism, Dupuytrens, folate dependent
    megaloblastic anaemia, osteomalacia

  • Considered a drug of choice for
  • tonic clonic seizures
  • partial seizures
  • absences
  • atypical absence, myoclonic, atonic
  • Does not induce drug metabolism but can inhibit
    P450 system
  • Adverse effects
  • Nausea, elevated liver enzymes, rare hepatic and
    pancreatic disorders, coagulopathy (inhibition of
    platelet aggregation), increased appetite and
    weight gain, changes in hair growth
  • Cost 100/year

  • Drug of choice for
  • simple absence seizures
  • Is also used for
  • Myoclonic
  • atypical absences
  • atonic
  • Adverse effects
  • GI upset, drowsiness, dizziness, ataxia, allergic
    reactions, drug-induced SLE
  • Cost 150/yr

  • phenobarbitone
  • methylphenobarbitone
  • primidone (largely metabolised to phenobarbitone)
  • no longer drugs of choice need monitoring
  • can be used as 2nd-line in all forms of epilepsy
  • Adverse effects
  • sedation, folate-induced megaloblastic anaemia,
  • Cost 5/year (phenobarbitone)

  • Most too sedative for clinical use
  • Clonazepam and clobazam are used clinically
  • effectiveness wanes on long term therapy
  • Adverse effects
  • sedation, hypotonia, impaired co-ordination
  • Cost 150/year (clonazepam)

  • add on therapy in patients who are not adequately
    controlled with current medication
  • A licence for monotrherapy is usually obtained
    later when evidence of safety and efficacy
  • Agent mechanism comments
  • Vigabatrin structural analogue of GABA CNS
  • irreversible inhibition of causes weight
  • GABA-transaminase combination only
  • Lamotrigine membrane stabiliser by blocking
    voltage less CNS effects than older agents
  • dependent sodium channels maculopapular skin
    rash / SJ synd
  • secondary impaired release of excitatory mono
    or combination
  • aminoacids
  • Gabapentin GABA analogue but mechanism of
    action combination only
  • obscure
  • Topiramate blockade of voltage sensitive
    sodium adjunct in partial seizures

  • Definition - generalised tonic-clinic fit lasting
    more than 30 minutes or repeated fits without
    recovery of normal alertness in between.
  • Prompt treatment is required to prevent
  • hypoxic cerebral damage
  • metabolic complications
  • hypoglycaemia
  • lactic acidosis
  • Should be distinguished from pseudoseizures,
    typified by
  • atypical, asynchronous limb and trunk movements
  • gaze aversion
  • resistance to passive limb movements or eye
  • prevention of hand falling on face
  • absence of metabolic complications
  • no post ictal confusion

  • 1. Establish airway, oxygenate, recovery position
  • 2. Establish IV access and give IV lorazepam
    2-4mg (IV diazepam 5-10mg alternative Buccal
    midazolam 10mg preferred over rectal diazepam)
  • 4. Check blood for glucose, urea and
    electrolytes, Calcium, anticonvulsant levels, and
    arterial blood gas and pH.
  • 5. Give 100mg IV thiamine if high risk of
    alcoholism (prevents precipitation of Wernickes)
    and if known to have brain tumour or active
    vasculitis give dexamathasone 10mg IV.
  • 7. If continues to fit then load with phenytoin
    IV (increasingly replaced by its pro-drug,
    fosphenytoin, which is less cardiotoxic and
    causes fewer injection site reactions)
  • 8. If still fitting then contact ITU (needs
    intubation and paralysis)

  • Degeneration of neurones within nigro-striatal
    pathway resulting in loss of dopaminergic
  • Imbalance of dopaminergic and cholinergic
    activity within the extra-pyramidal system
  • Thus reduced dopaminergic activity
  • Increased cholinergic activity
  • Results in
  • Clinical Parkinsonism hypokinesia, rigidity,
  • Treatment thus aims to restore dopaminergic
    activity OR reduce cholinergic activity

  • High therapeutic index - drug of choice for
    symptom control especially in elderly (need
    DOPA-decarboxylase, DDC, inhibitor to block
    peripheral dopamine in periphery)
  • L-dopa honeymoon - early phase of treatment
    (lasts 5-6 years typically) dopaminergic neurons
    still present - L-dopa can be stored in nerve
    terminals - produces a physiological
    concentration without much fluctuation
  • Neurotoxicity of L-dopa - DOPA metabolism results
    in neurotoxic breakdown products - results in the
    progression of Parkinsons? Hence delay L-dopa
    use especially in younger patients.
  • Chronic use of L-DOPA results in motor
    fluctuations (on-off dyskinesias) as remaining NS
    nerve ending lost
  • Other side effects hallucinations, nausea and
    postural hypotension (last 2 usually prevented by
    DDC blockade)

Dopamine agonists
  • Ergot derivatives
  • bromocriptine (D2)
  • pergolide (D1 and D2)
  • lisuride
  • Nonergolines
  • apomorphine
  • pramipexol
  • Ropinirole
  • Long duration of action (especially cabergoline)
    so less fluctuation in symptom control.
  • L-DOPA sparing - useful to delay use of L-DOPA in
    younger patients
  • Not neurotoxic ? neuroprotective
  • Adverse effects
  • nausea (alleviated by peripherally acting
    dopamine antagonist domperidone), postural
    hypotension, hallucinations and daytime
    hypersomnolence. Rarely reported to produce
    pathological gambling behaviour!

Inhibition of Dopamine Metabolism
  • Entacapone inhibits COMT
  • Use in combination with L-DOPA and L-DOPA sparing
  • Result in less fluctuation of DOPA concentrations
  • Studies show reduction in off duration and
    increase in on times
  • Selegeline MAO-B inhibitor
  • Does not cause cheese reaction (at therapeutic
  • ? Excess mortality when combined with L-DOPA in
    single trial. Concern that metabolised partly to

Dopamine Release
  • Amantadine better known perhaps as
    anti-influenza agent (type A only).
  • Mechanisms of action
  • Increases dopamine synthesis and release
  • Diminishes neuronal re-uptake
  • Evidence of efficacy (very) limited
  • Adverse effects
  • oedema, postural hypotension, insomnia,

Anti-Muscarinic Drugs
  • Help redress imbalance
  • Benzhexol, orphenadrine, procyclidine
  • Especially useful for tremor
  • Useful in acute dystonic reactions too
  • Adverse effects
  • Antimuscarinic effects of dry mouth, blurred
    vision, constipation, urine retention, glaucoma.
  • Also hallucinations and psychoses (cf atropine
  • Elderly are often confused by them (remember
    agents used in Alzheimers are designed to
    augment cholinergic transmission!)

Management Guidelines
  • Early phase treatment in young (lt50 yrs old)
  • Delay L-DOPA (and motor fluctuations and
    further loss of neurons). Balance the need of
    treatment with functional capacity
  • 1st-line drugs dopamine agonists domperidone
  • others selegiline, amantidine, anticholinergics
  •   Eventually L-dopa can be started in standard
    or slow release formulations

  • Early phase treatment in elderly (gt70 yrs old)
  • need for symptom treatment more urgent because of
    physical independence
  • L-DOPA is good 1st- line because of high
    therapeutic index. Low incidence of psychotic,
    postural hypotension side effects
  • Anticholinergic best avoided because of
    intolerable side effects and confusion 

Late phase on-off fluctuations
  • Options (trialled in this order )
  • Increase dose frequency and give top up and/or
    kick start doses e.g. for early morning
    akinesis and wearing off
  • Switch change standard formulations to slow
  • Add COMT-inhibitors
  • Add apomorphine intermittent injections or even
    continuous infusions for kick start
  • Consider methods of improving gastric emptying eg
    diet change or meal times
  • Lithium
  • Botulinium toxin injection to dystonic muscles

  • chlorpromazine thioridazine
  • Sedation
  • Anti-cholinergic
  • EPS  
  • Dopamine theory blockade helps
  • Dopamine agonists worsen schizophrenia
  • ? Lots of other neurotransmitters involved
  • Rise in prolactin levels can cause gynaecomastia
    or galactorrhoea

Neuroleptic Malignant Syndrome
  • Rare not dose dependent
  • (c.f. serotoninergic syndrome)
  • Hyperthermia, fluctuating consciousness, muscle
    rigidity, autonomic dysfunction, raised CK,
    peripheral WBC
  • Supportive measures
  • cooling
  • withdrawal of drug
  • ?bromocriptine / dantrolene

  • theory (probably wrong) supposes central
    monoamine deficiency (5HT/NAd). Explains efficacy
    of drugs that
  • increase monoamine synthesis (tryptophan)
  • prevent reuptake of monoamines (TCAs/SSRIs)
  • prevent monoamine breakdown (MAOIs)
  • generally takes 3-4 weeks for effect to be
    evident (elderly longer).
  • No antidepressant is clearly more effective than
  • Most patients with major depression respond to
    initial medication regardless of the type of
  • In controlled trials about 30 responded to
    placebo overall clinical effect may be
    influenced by non-pharmacological factors.
  • Differences in toxicity and adverse reaction more
    important than small differences in clinical
    effect between drugs

Which drug to prescribe?
  • Mild to moderate depression avoid drugs with bad
    adverse effect profile (poor compliance likely)
  • Severe depression drugs acting on both NA and
  • TCA - start at a low dose and increase gradually
  • SSRI - start at recommended dose from day 1, or
    after 1 week
  • Review regularly to check
  • response, compliance, adverse reaction and
    suicide ideation
  • Other non-drug based support
  • Specific psychotherapy (eg cognitive therapy),
    supportive care, problem solving, therapeutic
    alliance between patient and doctor

When to refer to psychiatry
  • uncertain diagnosis
  • severe depression psychosis or high-suicide
  • bipolar depression
  • Combined with alcoholism drug abuse
  • no response
  • adverse reaction intolerance
  • Length of drug-treatment
  • 4 - 6 months after initial drug response wean
    off slowly
  • risk of relapse chronic life stresses, residual
  • risk of relapse high in first months of remission
  • recurrent depression consider prophylactic or
    life long treatment

Tricyclic Anti-Depressants
  • Eg amitriptyline, imipramine, lofepramine
  • Anti-muscarinic side-effects
  • Postural hypotension (from a1-blockade)
  • Lower seizure threshold
  • Cardiac death, especially in overdose or history
    of heart disease
  • Weight gain
  • Serious interaction with MAOIs
  • Indicated in children for nocturnal enuresis,
    chronic pain syndromes

Selective Serotonin Reuptake Inhibitors (SSRIs)
  • E.g. fluoxetine, paroxetine
  • Better tolerated
  • Safe in O/D, and for patients with IHD
  • Main side effect nausea (note 5HT3
    antagonists), GI bleeding?
  • More expensive (1 month amitriptyline costs 1
    c.f. 20 for fluoxetine)

  • NSRIs eg reboxitine like TCA
  • SNRIs eg venlafaxine
  • MAOIs eg moclobemide (non-competitive ones
    higher risk of cheese reaction)
  • Lithium
  • ?mechanism
  • for control of mania/bipolar disorder
  • needs careful monitoring
  • St Johns Wort
  • beware - potent enzyme inducer!

Drugs for Alzheimers
  • Cholinergic transmission decreased in Alzheimers
  • Drugs that enhance ACh activity by
    acetylcholinesterase inhibition theoretically
    should work
  • Eg. donepezil, rivastigmine, galantamine
  • ? Do they work
  • Adverse effects nausea, diarrhoea, abdo cramps,
    bradycardia, urine incontinence