Stage 1 Seminar: Clinical Pharmacology of the Nervous System

1. Stage 1 Seminar:Clinical Pharmacology of the Nervous System Dr Fraz Mir Clinical Pharmacology Unit Department of Medicine University of Cambridge

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

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

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

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

6. 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

7. 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

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

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

10. 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)

11. 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 carbamazepine phenytoin valproate • Absence (petit mal) ethosuxamide valproate • Atypical absence, myoclonic, atonic valproate

12. 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

13. 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, Dupuytren’s, folate dependent megaloblastic anaemia, osteomalacia

14. 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

15. 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

16. 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)

17. 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)

18. 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 channels, enhanced GABA, glutamate inhibition Oxcarbazepine similar to carbamazepine Levetiracetam adjunct treat for partial seizures

19. 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

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)

21. PARKINSON’S 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

22. 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 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)

23. 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!

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.

25. 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

26. 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 Alzheimer’s are designed to augment cholinergic transmission!)

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

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 

29. 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

30. 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

31. 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

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) • 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

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   • 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

34. 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

35. Tricyclic Anti-Depressants • 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

36. 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)

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!

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