Stage 1 Seminar: Clinical Pharmacology of the Nervous System : 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 : Topics to be Covered Anti-epileptic medicines
Anti-parkinsonian drugs
Anti-depressants
And briefly –
Anti-psychotics
Treatments for dementia
Remember your pre-clinical pharmacology….. : Remember your pre-clinical pharmacology…..
Anaesthetic agents
Muscle relaxants
Anxiolytics / hypnotics
Anaesthetic / psychiatry attachments
Anti-Epileptic Drugs : 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 : 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 : 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 : 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 : 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 : 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 : 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 : 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
CARBAMAZEPINE : 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 : 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
SODIUM VALPROATE : 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 : 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 : 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 : 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 : 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
STATUS EPILEPTICUS : 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 : 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)
PARKINSON’S DISEASE : 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
L-DOPA : 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)
Dopamine agonists : 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 : 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 : 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 : 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!)
Management Guidelines : 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
Slide28 : 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 : 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 : 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
Neuroleptic Malignant Syndrome : 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 : 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? : 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: : 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 : 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
Selective Serotonin Reuptake Inhibitors (SSRIs) : 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 : 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!
Drugs for Alzheimer’s : 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