Stage 1 Seminar: Clinical 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 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

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 (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

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)

Drugs of Choice in Treatment of Specific Seizure Types

Seizure disorder Primary generalised tonic clonic (grand mal) Partial, including secondary generalised Drugs of choice (1st choice in bold) valproate carbamazepine phenytoin carbamazepine phenytoin valproate ethosuxamide valproate valproate

Absence (petit mal)

Atypical absence, myoclonic, atonic

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

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

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

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

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)

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)

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 mechanism structural analogue of GABA irreversible inhibition of GABA-transaminase ` comments CNS effects causes weight gain combination only Agent Vigabatrin

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 GABA analogue but mechanism of actioncombination only obscure blockade of voltage sensitive sodium channels, enhanced GABA, glutamate similar to carbamazepine adjunct treat for partial seizures adjunct in partial seizures inhibition

Gabapentin

Topiramate

Oxcarbazepine Levetiracetam

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

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)

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 reduced dopaminergic activity Increased cholinergic activity

Thus:

Results in: Clinical Parkinsonism: hypokinesia, rigidity, tremor Treatment thus aims to restore dopaminergic activity OR reduce cholinergic activity

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)

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

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

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!)

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

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

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

Anti-Psychotics
chlorpromazine Sedation +++ thioridazine ++ olanzepine/flupentixol/haloperidol +

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

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

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

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

Tricyclic Anti-Depressants
Eg amitriptyline, imipramine, lofepramine Anti-muscarinic side-effects Postural hypotension (from 1-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)

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!

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