1. Stage 1 Seminar:
Clinical Pharmacology of the
Nervous System
INDIAN DENTAL ACADEMY
Leader in continuing dental education
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2. Topics to be Covered
• Anti-epileptic medicines
• Anti-parkinsonian drugs
• Anti-depressants
• And briefly –
• Anti-psychotics
• Treatments for dementia
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4. 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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5. 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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6. Principles of Drug Therapy
Initiation of therapy
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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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7. Therapeutic Drug Monitoring
Indications
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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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8. 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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9. 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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10. Special Cases: Pregnancy
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Seizures in pregnancy constitute major risk to mother and fetus
Must maintain therapy (carbamazepine drug of choice)
Requires careful monitoring
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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
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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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11. Drugs of Choice in Treatment of
Specific Seizure Types
Seizure disorder
Drugs of choice (1st
choice in bold)
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Primary generalised tonic clonic
(grand mal)
valproate
carbamazepine
phenytoin
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Partial, including secondary generalised
carbamazepine
phenytoin
valproate
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Absence (petit mal)
ethosuxamide
valproate
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Atypical absence, myoclonic, atonic
valproate
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12. CARBAMAZEPINE
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Considered a drug of choice for
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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
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Adverse effects
blurred vision, diplopia,dizziness, bradycardia, skin rashes, GI upsets,
osteomalacia, folate deficiency, hyponatraemia
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Cost about £25/yr
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13. PHENYTOIN
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Considered drug of choice for
– tonic clonic seizures
– partial seizures
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Also used for
– cardiac arrhythmias
– trigeminal neuralgic
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Pharmacokinetics
– 90% plasma protein bound
– Saturable (zero order) kinetics in therapeutic dose range
– potent hepatic enzyme inducer (interaction with inhibitors)
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Adverse effects
– Impaired cognition, sedation, cerebellar disorders, peripheral neuropathy, rashes,
gum hyperplasia, coarsening of facial features, hirsutism, Dupuytren’s, folate
dependent megaloblastic anaemia, osteomalacia
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14. SODIUM VALPROATE
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Considered a drug of choice for
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tonic clonic seizures
partial seizures
absences
atypical absence, myoclonic, atonic
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Does not induce drug metabolism but can inhibit P450 system
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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
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Cost £100/year
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15. ETHOSUXAMIDE
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Drug of choice for
– simple absence seizures
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Is also used for
– Myoclonic
– atypical absences
– atonic
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Adverse effects
– GI upset, drowsiness, dizziness, ataxia, allergic reactions, drug-induced SLE
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Cost
£150/yr
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16. BARBITURATES
phenobarbitone
methylphenobarbitone
primidone (largely metabolised to phenobarbitone)
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no longer drugs of choice – need monitoring
can be used as 2nd-line in all forms of epilepsy
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Adverse effects
sedation, folate-induced megaloblastic anaemia, ataxia
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Cost £5/year (phenobarbitone)
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17. BENZODIAZEPINES
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Most too sedative for clinical use
Clonazepam and clobazam are used clinically
effectiveness wanes on long term therapy
• Adverse effects
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sedation, hypotonia, impaired co-ordination
Cost £150/year (clonazepam)
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18. NEWER ANTIEPILEPTIC AGENTS
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add on therapy in patients who are not adequately controlled with current medication
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A licence for monotrherapy is usually obtained later when evidence of safety and efficacy obtained
Agent
mechanism
comments
Vigabatrin
structural analogue of GABA
irreversible inhibition of
GABA-transaminase
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CNS effects
causes weight gain
combination only
Lamotrigine
membrane stabiliser by blocking voltage
dependent sodium channels
secondary impaired release of excitatory
aminoacids
less CNS effects than older agents
maculopapular skin rash / SJ synd
mono or combination
Gabapentin
GABA analogue but mechanism of action
obscure
combination only
Topiramate
blockade of voltage sensitive sodium
channels, enhanced GABA, glutamate
adjunct in partial seizures
inhibition
Oxcarbazepine
similar to carbamazepine
Levetiracetam
adjunct treat for partial seizures
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19. STATUS EPILEPTICUS
Definition - generalised tonic-clinic fit lasting more than 30 minutes or
repeated fits without recovery of normal alertness in between.
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Prompt treatment is required to prevent
– hypoxic cerebral damage
– metabolic complications
• hypoglycaemia
• lactic acidosis
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Should be distinguished from pseudoseizures, typified by
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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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20. 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 Wernicke’s) 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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21. PARKINSON’S DISEASE
PATHOPHYSIOLOGY
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Degeneration of neurones within nigro-striatal pathway resulting in loss of
dopaminergic activity
THERAPEUTIC RATIONALE
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Imbalance of dopaminergic and cholinergic activity within the extra-pyramidal system
Thus:
reduced dopaminergic activity
Increased cholinergic activity
Results in:
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Clinical Parkinsonism: hypokinesia, rigidity, tremor
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Treatment thus aims to restore dopaminergic activity OR reduce cholinergic activity
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22. L-DOPA
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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 Parkinson’s?
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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23. Dopamine agonists
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Ergot derivatives
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bromocriptine (D2)
pergolide (D1 and D2)
lisuride
Nonergolines
– apomorphine
– pramipexol
– Ropinirole
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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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24. 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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25. Dopamine Release
Amantadine – better known perhaps as anti-influenza agent (type A
only).
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Mechanisms of action
– Increases dopamine synthesis and release
– Diminishes neuronal re-uptake
– Evidence of efficacy (very) limited
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Adverse effects
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oedema, postural hypotension, insomnia, hallucinations
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26. Anti-Muscarinic Drugs
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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 Alzheimer’s are
designed to augment cholinergic transmission!)
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27. Management Guidelines
• Early phase treatment in young (<50 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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28. • Early phase treatment in elderly (>70 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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29. Late phase “on-off” fluctuations
Options (trialled in this order …)
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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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32. 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)
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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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33. 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
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TCA - start at a low dose and increase gradually
SSRI - start at recommended dose from day 1, or after 1 week
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Review regularly to check
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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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34. When to refer to psychiatry:
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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
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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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35. Tricyclic Anti-Depressants
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Eg amitriptyline, imipramine, lofepramine
Anti-muscarinic side-effects
Postural hypotension (from α1-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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36. Selective Serotonin Reuptake
Inhibitors (SSRIs)
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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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37. 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 John’s Wort
beware - potent enzyme inducer!
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38. Drugs for Alzheimer’s
• Cholinergic transmission decreased in Alzheimer’s
• 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
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39. Thank you
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