Stage 1 Seminar: Clinical Pharmacology of the Nervous System

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Stage 1 SeminarClinical Pharmacology of the
Nervous System

• Dr Fraz Mir
• Clinical Pharmacology Unit
• Department of Medicine
• University of Cambridge

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Topics to be Covered

• Anti-epileptic medicines
• Anti-parkinsonian drugs
• Anti-depressants
• And briefly
• Anti-psychotics
• Treatments for dementia

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Remember your pre-clinical pharmacology..

• Anaesthetic agents
• Muscle relaxants
• Anxiolytics / hypnotics
• Anaesthetic / psychiatry attachments

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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

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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

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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
  monitoring
• 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
  efficacy

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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

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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

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Driving and Epilepsy

• Cannot drive a HGV or public service vehicle
  (PSV)
• 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

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Special Cases Pregnancy

• Seizures in pregnancy constitute major risk to
  mother and fetus
• Must maintain therapy (carbamazepine drug of
  choice)
• 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)

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Drugs of Choice in Treatment of Specific Seizure
Types

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

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CARBAMAZEPINE

• Considered a drug of choice for
• tonic clonic seizures
• partial seizures
• trigeminal neuralgiaIs
• prophylaxis of manic depressive illness
• Potent inducer of hepatic drug metabolising
  enzymes
• 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

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PHENYTOIN

• 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
  inhibitors)
• Adverse effects
• Impaired cognition, sedation, cerebellar
  disorders, peripheral neuropathy, rashes, gum
  hyperplasia, coarsening of facial features,
  hirsutism, Dupuytrens, folate dependent
  megaloblastic anaemia, osteomalacia

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SODIUM VALPROATE

• 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

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ETHOSUXAMIDE

• 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

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BARBITURATES

• 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,
  ataxia
• Cost 5/year (phenobarbitone)

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BENZODIAZEPINES

• 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)

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NEWER ANTIEPILEPTIC AGENTS

• 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
  obtained
• Agent mechanism comments
• Vigabatrin structural analogue of GABA CNS
  effects
• irreversible inhibition of causes weight
  gain
• 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

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STATUS EPILEPTICUS

• 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
  opening
• prevention of hand falling on face
• absence of metabolic complications
• no post ictal confusion

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Management

• 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)

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PARKINSONS DISEASE

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

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L-DOPA

• 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)

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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!

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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
  doing)
• ? Excess mortality when combined with L-DOPA in
  single trial. Concern that metabolised partly to
  methylamphetamine.

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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,
  hallucinations

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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
  poisoning).
• Elderly are often confused by them (remember
  agents used in Alzheimers are designed to
  augment cholinergic transmission!)

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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

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• 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 

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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
  release
• 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

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Anti-Psychotics

• chlorpromazine thioridazine
  olanzepine/flupentixol/haloperidol
• 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

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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

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Anti-Depressants

• PRINCIPLES
• 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
  another
• Most patients with major depression respond to
  initial medication regardless of the type of
  antidepressant
• 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

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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
  serotonin  
• 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

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When to refer to psychiatry

• uncertain diagnosis
• severe depression psychosis or high-suicide
  risk
• 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
  symptoms
• risk of relapse high in first months of remission
• recurrent depression consider prophylactic or
  life long treatment

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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

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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)

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Miscellaneous

• 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!

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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