What is epilepsy?
Epilepsy actively affects about 1 in 200 people and is a tendency towards recurrent “seizures’.
A seizure is a convulsion or transient abnormal event from episodic discharge of high frequency impulses in the brain, or a part of it. Various types of seizures occur, their symptoms characterised by the location and extent of the discharges.
It is important to understand that having a single seizure is not sufficient to make a diagnosis of epilepsy. It is the tendency towards recurrent seizures that defines the condition. Many acute medical emergencies may present as tonic clonic seizures in response to traumatic, metabolic or infective processes. In these cases, there may be no underlying susceptibility to seizures.
Therefore the diagnosis of epilepsy can only be made if more than one attack occurs.
Diagnosis requires evidence of recurrent seizures unprovoked by other identifiable causes
Reckless labelling of patients as “epileptic” has huge social, financial and medical implications and should not be made lightly.
What are possible treatment options for epilepsy?
For 75% of those with epilepsy, drug treatment can completely control symptoms but side effects and interactions are common especially with older drugs. However, 10% of patients still have frequent fits during treatment.
Anti-epileptic drugs have common ADRs, some serious.
DDIs: some positive combined with other AEDs, often significant negative pharmacokinetic interactions
Epilepsies should be viewed as a symptom of underlying neurological disorder and not a single disease entity.
Common condition. Prevalence estimates about 0.5-1.0% (`450,000 in UK) with some form of epilepsy.
Chronic epilepsy – 500 sudden deaths / year in UK
Therapeutics currently effective for about 75%
Vagal Nerve Stimulation: in some cases, where patients are refractory to AEDs, is effective.
What could epilepsy be caused by?
Epilepsy can be caused due to
Increased excitatory activity, decreased inhibitory activity and/or loss of homeostatic control => spread of neuronal hyperactivity
What are the two main types of seizures?
During a seizure, large groups of neurones are activated repetitively, unrestrictedly and hyper-synchronously, with inhibitory neurones failing. A partial (focal) seizure is confined to one area of the cortex, yet can spread to cause a secondary generalisation. Generalised seizures can also occur as a focal seizure, thus can also be a primary generalised major convulsion. The two main types are described but there is a whole spectrum.
Describe partial seizures
Partial seizures: here the discharges begin in a localised area of the brain. Thus the symptoms reflect the area affected, but might include abnormal sensations or thoughts, a change in behaviour or an involuntary motor action.
Loss of local excitatory/inhibitory homeostasis
Increased discharges in focal cortical area
- Simple (conscious)
- Complex partial seizures (impaired consciousness) (neuronal hyperactivity spreads)
- Secondary generalised seizures (neuronal hyperactivity has spread through the corpus callosum to the other hemisphere).
Symptoms reflect area affected e.g. involuntary motor disturbance, behavioural change, impending focal spread accompanied by ‘Aura’ (strange inner feeling) e.g. unusual smell or taste (smell of burning rubber), déjà vu/jamais vu (don’t recognise something you’ve seen many times).
Partial seizures may become secondarily generalised.
Other partial seizure types include Jacksonian (focal motor seizures) or Temporal Lobe (develops as feelings of déjà vu/ jamais vu)
Describe generalised seizures
Generalised seizures: the whole brain is affected, including the reticular system, and there is immediate loss of consciousness (generated centrally spread through both hemispheres with loss of consciousness). Neuronal hyperactivity spreads very quickly. These are further divided into the tonic-clonic (Grand mal) seizure (60%) and the absence (petit mal) seizure (5%). Many other types/subtypes recognised.
Tonic-clonic: following vague, warning signs, the tonic phase commences, as the body becomes rigid and the patient commonly falls to the floor (as all the muscles contract), tongue is bitten and incontinence of both urine and faeces occur, The clonic phase will then begin with a generalised convulsion, frothing at the mouth and rhythmic jerking of muscles. Normally self-limiting and followed by drowsiness, confusion or a coma for several hours.
Typical absences – generalised epilepsy that occurs in childhood, where the patient will stare, eyelids may twitch and a few muscle jerks occur. After an attack, normal activity is resumed yet children with typical absence attacks are more likely to develop generalised grand mal seizures as adults.
Other types include tonic, clonic, myoclonic, atonic.
What is meant by Status Epilepticus?
Status Epilepticus: prolonged seizure of any type
The most common and dramatic is convulsive status epilepticus, although non-convulsive status epilepticus also occurs. It is defined as either a single convulsion lasting >30 minutes or convulsions occurring back to back with no recovery between them (no recovery interval).
However, any convulsion lasting longer than 5 minutes or two convulsions without full recovery of consciousness in between should receive emergency treatment.
Uncontrolled convulsions – untreated status epilepticus - can lead to hypoxia and irreversible brain damage or death (Sudden Unexpected Death in Epilepsy)
Diagnosis should be self-apparent but a careful consideration of underlying cause must be made. Additionally, if the seizures seem odd or atypical, one must consider the possibility of pseudoseizures, which are non-epileptic in nature.
Describe how Status Epilepticus is a medical emergency
Status Epilepticus is a Medical Emergency
Adult mortality ~20%
Risk increases with length of SE
50% of cases occur without a previous history of epilepsy
Serial epilepsy may lead to SE
Priorities are ABC (airway, breathing and circulation)
Hypoventilation may result with high AED doses
ITU for paralysis and ventilation if failing
How would you treat Status Epilepticus?
Priorities include airway protection, the delivery of supplemental oxygen, identification of the cause and its reversal, and the termination of the seizure as quickly as possible.
Investigations should include a bedside glucose, lab U&Es and calcium, blood gases and further tests (perhaps later) to ascertain underlying cause (e.g. CT/MRI head – especially in trauma or focal fits).
Treatment of the seizures is vital. First line treatment includes benzodiazepines (e.g. IV lorazepam) and then IV phenytoin. Phenytoin is not widely used for long term control but because of its zero order kinetics, a therapeutic level can be reached quickly. It is however, toxic, and has a narrow therapeutic index. If these measures are failing, or if the patient’s airway is compromised, ITU referral, sedation and paralysis and intubation will be required.
Lorazepam (0.1 mg/kg) preferred – longer pharmacodynamic half life than diazepam (0.2 mg/kg). IV route (rectal if difficult IV access)
- Zero order kinetics (15-20 mg/kg)
- Rapidly reaches therapeutic levels IV
- Cardiac monitoring – arrhythmias + hypotension
Other drugs: midazolam, pentobarbital, propofol (targets GABA, used in anaesthesia)
What are the dangers of severe (uncontrolled) epilepsy?
Physical injury relating to fall/crash
Varying degrees of brain dysfunction/damage
Serious psychiatric disease
Significant adverse reactions to medication
Stigma / Loss of livelihood (person cannot function fully in livelihood)
Epilepsy and driving
- All patients should be advised appropriately and to inform the DVLA.
- Check DVLA for specific guidance
What's important in an epilepsy history?
A detailed history of the attacks is essential. This should include witness statements from family and ambulance crew etc. This is of the utmost importance in determining the nature of the attack, differentiating it from non-epileptic attacks and to decide on the likelihood of underlying structural brain disease.
The history should include assessment of precipitants, a description of the warning phase (if any), the unconscious phase and the period of recovery.
What is meant by the primary and secondary causes of epilepsy?
Seizures may result as a consequence of a medical condition affecting the brain (secondary – about 1/3 – 30-35%) or as an inherent tendency of an individual towards seizures (primary – about 2/3 – 65-70%). It is always important to consider secondary causes of convulsions when assessing patients presenting with fits.
Aetiology of epilepsy
Primary: idiopathic (no identifiable cause), most likely channelopathies (mutations where there is leakage of currents => drifting towards depolarisation)?
Secondary: medical conditions affecting brain, vascular disease, tumours
Describe some of the major recognized precipitants in epilepsy
A seizure may have no antecedent (especially in primary epilepsy) but many conditions are associated with either a fit in a person who does not have epilepsy, or the lowering of the fit threshold in those that do.
Relevant conditions to consider when appropriate include
Sensory stimuli e.g. flashing lights/strobes or other periodic sensory stimuli (provoked seizures)
- Head injury (traumatic or “chemical”) – perinatal trauma, decreased skull fracture, intracranial haematoma or cerebral contusion can cause sufficient damage to result in epilepsy
- Pyrexia causing seizures is common in children yet reoccurrence is rare
- Drugs and alcohol including drug withdrawal
- Structural abnormality/lesion – brain tumours will cause a partial focal or secondary generalised seizure
- CVA/subarachnoid haemorrhage etc
Metabolic disturbances: Hypoglycaemia (including diabetics), hypocalcaemia (calcium is important in regulating excitability of neurons), hyponatraemia
Infections (especially CNS but elsewhere too), particularly in children – febrile convulsions in infants, cerebral abscesses or neurosyphilis
Therapeutics: Poor compliance with anti-epileptic drug therapy; some drugs can lower fit threshold, AEDs + polypharmacy can lead to reduced plasma levels of the AED (PKs lower levels)
What are the therapeutic targets in management of epilepsy?
Therapeutic Targets: the mechanisms of action of the AEDs are described by the known pharmacology associated with the following targets
Enhancement of GABA(A) Action (benzodiazepines, phenobarbitones but ironically not gabapentin) – enhancing GABA mediated inhibition
Inhibition of voltage gated sodium channel function (phenytoin, valproate, carbamazepine, lamotrigine)
Inhibition of calcium channel function (ethosuximide, gabapentin)
Inhibition of glutamate release or function
What are the common drugs used?
The majority of patients seen in everyday clinical experience are generally on those commonly prescribed drugs. However, increasing use of the newer drugs (lamotrigine, gabapentin etc) is occurring. Additionally, few patients are started on barbiturates or even phenytoin these days but some people who have been on them for a long time may still be on them.
Major Drug Classes:
- Valproate Sodium
- Lamotrigine (increasingly first line nowadays)
The following drugs are used more rarely and generally only by neurology specialists
7. Barbiturates (few started on this now, but some on it for decades)
Carbamazepine is a Voltage Gated Sodium Channel Blocker. How do they work?
Mechanism of action: VGSC blockers reduce probability of high abnormal spiking activity
- Local loss of membrane potential homeostasis starts at focal point
- Relatively small number of neurones form generator site
- Neurones heavily depolarise (vicious positive feedback loop)
- Hyperactivity spreads via synaptic transmission to other neurones => loss of homeostasis – bursting high discharge (spontaneous).
The VGSC blocker gets access to binding site on the internal face of the sodium channel only during depolarisation – hence VOLTAGE-DEPENDENT. The VGSC prolongs inactivation state – firing rate returns back to normal. Once neurone membrane potential returns back to normal, VGSC blocker detaches from binding site.
They work by acting preferentially on the neurones causing the high frequency discharge that occurs in an epileptic fit, whilst not interfering with the low-frequency firing neurones in their normal state.
Depolarisation of a neurone increases the proportion of the sodium channels in the inactivated state, and VGSC blockers bind preferentially to channels in this state, preventing them from returning to a resting state where they would continue to depolarise the neurone – keep the sodium channels in the inactivated state for a longer amount of time. They thus reduce the number of functional channels available to generate action potentials
NB: remember sodium channels have 3 states: open, closed and inactivated
Describe the pharmacology of Carbamazepine including ADRs and DDIs
Carbamazepine prolongs VGSC inactivation state
Pharmacokinetics: well absorbed, 75% protein bound – shows linear pharmacokinetics, initial half life = 30 hours but STRONG INDUCER OF CYP 450 (specifically CYP A4). This affects its own Phase I metabolism. Repeated use half life gradually decreases to 15 hours thus close monitoring is required.
ADRs: wide ranging Type As:
- CNS – dizziness, drowsy, ataxia, motor disturbance, numbness, tingling
- GI: upset, vomiting
- CVS: can cause variation in BP
- Contraindicated with AV conduction problems
- Others: rashes, hyponatraemia
- Rarely – severe bone marrow depression => neutropenia
DDIs: because CYP450 inducer can affect many other drugs
- Decreased phenytoin concentration + PK binding => leading to increased Carbamazepine plasma concentration thus increasing risk of side effects.
- Decreased warfarin concentration
- Decreased systemic corticosteroids levels
- Decreased oral contraceptives levels (reduced effectiveness of OCP)
- Antidepressants – SSRIs, MAOIs, TCAs and TCA interfere with action of carbamazepine.
Describe drug monitoring and what seizures you would treat with Carbamazepine
Drug Monitoring: dosing to effect and adjust dosing as half life decreases. CHECK BNF with any other drugs given
Epilepsy types treated with Carbamezepine
- Generalised Tonic Clonic
- Partial – all
- Not absence seizures
Phenytoin is another VGSC. Describe its pharmacology including ADRs and DDIs
Phenytoin prolongs VGSC inactivation state
Pharmacokinetics: well-absorbed but 90% bound in plasma so competitive binding can increase levels of other drugs. It is also a CYP 450 inducer (CYP 3A4 – not CYP2C9 & CYP2C19 which metabolise phenytoin – so doesn’t self-induce its own metabolism). But as it is a CYP 3A4 inducer, it induces the rate of metabolism of other drugs including Carbamazepine.
Sub-therapeutic concentrations shows linear PK but shows NON-LINEAR PK at therapeutic concentrations – very variable half life = 6-24 hours. Depends and varies from individual to individual so very close titration of the drug is required to gain effective control – limits its use.
NB: Graph shows variation in the daily dose to get to the therapeutic range. Paracetamol is also a drug that shows non-linear PKs.
ADRs : very wide ranging Type As
- CNS: dizziness, ataxia, headache, nystagmus, nervousness
- Gingival hyperplasia (20%)
- Rashes – hypersensitivity
- + Stevens Johnson (2-5%) – life threatening toxic epidermal necrolysis in which cell death causes the epidermis to separate from the dermis.
- Competitive binding e.g. with Valproate (AED)/NSAIDs/salicylate, increases plasma levels of phenytoin – exacerbates Non-Linear PKs
- Very wide range of interactions including decreases oral contraceptives. Cimetidine increases the concentration of phenytoin. Need to check BNF for any other drugs given in combination.
Describe drug monitoring and what seizures you would use to treat Phenytoin with
- Close monitoring of free concentration plasma
- Can use salivary levels as indicator of concentrations in free plasma (so blood test not required)
Epilepsy types treated with Phenytoin
- Generalised Tonic-Clonic
- Partial – all
- Not Absence seizures
Lamotrigine is a VGSC. Describe its pharmacology including ADRs, DDIs and uses
Pharmacology: Lamotrigine (LTG) prolongs VGSC inactivation state
- - Possibly also a Calcium channel blocker? May also decrease glutamate release?
Pharmacokinetics: not metabolised by CYP
- Well absorbed – linear PK (once daily dosage drug)
- Half life = 24 hours (phase II)
- No CYP450 induction => fewer DDIs
ADRs: less marked
- CNS: dizziness, ataxia, somnolence (drowsiness, sleepiness)
- Some mild (10%) and serious (0.5%) skin rashes
- Adjunct therapy with other AEDs
- Oral contraceptives reduce Lamotrigine plasma level
- Valproate increases lamotrigine in plasma (competitive binding)
Epilepsy types treated with Lamotrigine
- Partial seizures
- Generalised - tonic-clonic and Absence (where specific pathways and neurotransmitters are involved – theory that LTG acts on these whereas the other VGSC blockers have no effect) seizures and other subtypes
- LTG increasingly first line AED for epilepsy
- Not first line paediatric use as ADRs increase
- Appears safer in pregnancy?
Apart from blocking sodium channels, what's the other main therapeutic target?
Enhancing GABA Mediated Inhibition
Major role in post-synaptic inhibition – 40% synapses in brain are GABA-ergic
Increased GABA is natural anticonvulsant or excitatory ‘brake’ – thought to help dampen down activity
Describe Direct GABA agonists
Distinct Pharmacological Targets I: binding with GABA(A) receptor (direct GABA agonists)
- Benzodiazepine Site: enhance GABA action
- Barbiturate Site: enhance GABA action
- Binding on their own – nothing happens. But when GABA happens, both enhance GABA effect. Can work synergistically together.
- Increased chloride current into neurone – increases threshold for action potential generation (facilitates the GABA-mediated opening of chloride ion channels).
- Reduces likelihood of epileptic neuronal hyper-activity
- Makes membrane potential more negative
- Valporate acts as a GABA-agonist.
Describe the 2nd therapeutic target - GABA metabolism
- Inhibition of GABA inactivation => increased GABA concentration
- Inhibition of GABA re-uptake => increased GABA
- Increased rate of GABA synthesis => increased GABA
- Targeting these sites enhance action of GABA
Describe the pharmacology, pk and ADRs of Valporate
- Evidence in vitro for mixed sites of action – pleiotropic
- Weak inhibition of GABA inactivation enzymes => increased GABA
- Weak stimulus of GABA synthesising enzymes => increased GABA
- VGSC blocker + weak Ca2+ channel blocker => decreased Discharge
- Absorbed 100% - then 90% plasma bound
- Linear pharmacokinetics
- Half life = 15 hours
- Generally less severe than with other AEDs
- CNS sedation, ataxia, tremor
- Weight gain
- Hepatic function – increased transaminases in 40% patients
- Rarely – hepatic failure (but monitoring is required)
Describe the DDIs, drug monitoring and types of seizures you would treat with Valporate
- Not mainline - Adjunct therapy with other AEDs
- Care needed with adjunct therapy. Both Valproate and adjunct PKs affected. Always check BNF.
- Antidepressants: SSRIs, MAOIs, TCAs and TCA inhibit action of Valproate
- Antipsychotics: antagonise Valproate by lowering convulsive threshold
- Aspirin: competitive binding in plasma Valproate (increased Valporate)
- Close monitoring of free concentration plasma
- Can use salivary levels as indicators of free plasma
- Plasma valproate not closely associated with efficacy
- Monitor for blood, metabolic and hepatic disorder
Epilepsy types treated with Valproate
- Partial seizures
- Generalised: tonic-clonic + absence seizures (probably because of its pleiotropic effects)
Describe the pharmacology and PK of benzodiazepines
- Benzodiazepines (BZDs) act at distinct receptor site on GABA Chloride channel
- Binding of GABA or BZD enhance each other’s binding – act as positive allosteric effectors
- Increases Chloride current into neurone – increases threshold for action potential generation
- Well absorbed 90-100% - highly plasma bound 85-100%
- Linear pharmacokinetics
- Half-life varies between 15-45 hours (highly variable – so close monitoring is required)
Describe the ADRs and DDIs of Benzodiazepines. What seizures would you treat them?
- Toleration with chronic use
- Confusion impaired co-ordination
- Dependence/withdrawal with chronic use
- Abrupt withdrawal can act as a seizure trigger
- Respiratory and CNS depression
- Some adjunctive use – perhaps for fine control
- Overdose reversed by IV flumazenil but use may precipitate seizure/arrhythmia
Epilepsy types treated with BZDs
- Side effects limit first line use
- IV Lorazepam/rectal Diazepam & buccal Midazolam – Status Epilepticus
- Clonazepam – Absence seizure short term use
Describe the basic rules of prescibing AEDs
Basic Prescribing Rules: Epilepsy is a highly specialised field, and expert advice should generally be sought for all but the most basic of management issues. However, certain principles should be borne in mind when managing drug therapy in a person with epilepsy
The choice of drug should be based on the individual patient and their syndrome, and the side-effect profile of the drug.
Treatment should be started at a low dose and increased only gradually to maximize effect and limit side effects. This will aid the patient’s adherence to therapy.
With the exception of phenytoin, drug levels are generally not useful except to prove that the drug is being taken.
IF a first line drug is ineffective despite adequate compliance, it should be replaced by a second drug. Monotherapy should always be the aim unless this has obviously failed
Patients started on anti-epileptic drugs must remain under review (e.g. monthly follow-up).
Significant variation in AED plasma levels – monitor and titrate to therapeutic effect
ITU sedation is a treatment
Side effects with AEDs are very common. Adjunctive drug use and polypharmacy with epilepsy is common. Always consult BNF in detail when managing patients on AEDs.
Describe the very basic rule of thumb for prescribing AEDs
Valproate sodium as first line therapy for primary generalised seizures
Carbamazepine for partial seizures (or generalised seizures)
Lamotrigine can be used in either circumstances and is probably the drug of choice for women of childbearing age.
Benzodiazepines and phenytoin are first line therapies for acute life threatening status epilepticus. Phenytoin has non-linear kinetics and so can reach therapeutic (and toxic) levels rapidly.
What do you need to consider with re to AEDs and pregnancy?
AEDs and Pregnancy: there is considerable difficulty in the management of women of child-bearing age and potential who also have epilepsy requiring pharmacological therapy. There are several points to consider regarding treatment:
Balance of risk (epilepsy vs AED teratogenicity): The risk of seizures to mother and foetus if treatment is stopped. Careful history taking is required to ascertain the frequency and severity of seizures in the individual patent. Those with extremely rare and mild seizures might tolerate being off treatment during gestation quite well. Those with frequent fits run the risk of status epilepticus and harm to both themselves and the baby if treatment is stopped.
Certain anti-epileptics drugs have been associated with congenital malformations (AED teratogenicity). The risk of foetal abnormalities in a normal pregnancy is about 2%. Valproate has been associated with about a 9% risk of foetal abnormalities, including neural tube defects, and possible learning difficulties later in life. Other monotherapy is associated with a doubling of the baseline risk of malformation.
Failure of Contraception with AEDs
- Failure rate x 4 with Carbamazepine/Phenytoin
- Failure rate between 5 and 10% (normal baseline failure rate between 1 and 2%)
Consider the possible dangers to the foetus during pregnancy? Why would you consider dietary supplements as well?
Dangers to foetus during pregnancy
- Congenital malformations (all AEDs? Maybe not with Lamotrigine)
- Valproate – neural tube defects
- Facial and digit hypoplasia
- Learning difficulties/mild neurological dysfunction?
- AED risk of birth defects ~8% vs ~2% normally.
- With multiple AEDs, teratogenic risk increases so use single AED agent if possible at lowest dose.
- Valproate is best avoided – because neural tube defect increases
- Lamotrigine may be safest – birth defect rate approximately 2% (about baseline rate)
AEDs and Dietary Supplements
- Folate supplement – reduce risk of neural tube defects
- AEDs associated with Vitamin K deficiency in newborn – coagulopathy and cerebral haemorrhage
- Vitamin K supplement 10mg/day in last trimester to offset that
The two main neurological conditions associated with movement disorders are Idiopathic Parkinson’s Disease (IPD) and Myasthenia Gravis (MG). What is IPD?
Idiopathic Parkinson’s Disease is a neurodegenerative disorder that has a progressive clinical course whereby there is a loss of dopaminergic neurones in the Substantia nigra. The result is a classic triad of Tremor, Rigidity and Bradykinesia, yet can also cause non-motor symptoms such as mood changes (e.g. depression), pain, cognitive change (dementia may develop), urinary symptoms, sleep disorders (e.g. REM-sleep behaviour disorder may be an early onset sign), constipation, sweating or somnolence.
It is diagnosed by its clinical features, response to treatment (L-DOPA; other Parkinsonisms do not respond as well) and any functional neurological imaging (structural neuro imaging is normal so not useful, function neo imaging can include SPECT and PET).
Motor symptoms improve with leveodopa. Non-motor manifestations do not respond to treatment.
What is MG?
Myasthenia Gravis is an autoimmune condition that causes blockage (by IgG blockage of the binding site – ACh rarely binds and acetyl cholinesterase begins to break it down) and/or degradation of the nAChRs at the NMJ. The result is a fluctuating fatigable, weakness in skeletal muscles; commonly the extraocular muscles (causing diplopia or ptosis) are the first to be affected yet it can result in bulbar involvement (causing dysphagia, dysphonia, dysarthria), limb weakness (proximal symmetrical) and respiratory involvement (can cause death).
Dysphonia: patients can sound breathy as palate doesn’t occlude pharynx appropriately.
You examine Myasthenia Gravis by assessing fatigability e.g. ask patient to look at a spot superiorly, then notice how eyebrows are raised (attempt to keep eye open) and drooping as seconds go on.
How do you treat MG? What drugs can exacerbate the symptoms of MG?
It is mainly treated with acetylcholinesterase inhibitors. While an acute exacerbation can cause a Myasthenic crisis, over treatment of the condition can lead to a cholinergic crisis (a flaccid paralysis and respiratory failure).
- Myasthenic crisis: eyes drooping, slack face, SOB, can’t swallow => drooling, requires acute treatment – myasthenic crisis is a life threatening condition, which is defined as weakness from acquired myasthenia gravis that is severe enough to necessitate intubation or to delay extubation following surgery – respiratory failure).
- Overtreatment of Pyridostigmine (max 350mg/day) => overdepolarisation => fatigability.
Drugs affecting neuromuscular transmission exacerbate Myasthenia Gravis such as aminoglycosides, Beta-blockers, CCBs, quinidine, procainamide, Chloroquine, pencillamine, Succinylcholine, Magnesium (used for seizures in pre-eclampsia) and ACE inhibitors.
How do Acetylcholinesterase inhibitors work? Side effects? Describe the pharmacology of Neostigmine and Pyridostigmine
- Enhance neuromuscular transmission – potentiate effect of ACh by stopping breakdown
- Skeletal and smooth muscle
- Excess dose can cause depolarisin g block (cholinergic crisis)
- Cholinergic side effects – miosis and SSLUDGE (Salivation, Sweating, Lacrimation, Urinary incontinence, Diarrhoea, GI hypermobility and Emesis)
Pyridostigmine – oral
- Prevents breakdown of ACh in NMJ; simply treats symptoms – does not treat underlying condition. To treat the underlying condition – treat like an autoimmune condition (steroids etc).
- ACh more likely to enage with remaining receptors
- Onset 30min; peak 60-120 mins; duration 3-6 hours (short half life)
- Dose interval and timing crucial (give meds ½ hour before meal so they’re able to eat otherwise they may not be able to swallow)
Neostigmine – oral and IV preparations (ITU)
- Quicker action, duration up to 4 hours
- Significant cholinergic side effects
Apart from Acetylcholinesterase inhibitors, what are other possible treatments for MG?
Other possible treatments for Myasthenia gravis include corticosteroids (decrease immune response), steroid sparing (Azathioprine), IV immunoglobulin (but acute decline or crisis – 60% will respond after 7-10 days) and plasmaphresis (removes nAChR antibodies and short term improvement).
What are possible causes of Parkinsonism apart from IPD? In particular focus on Multi System Atrophy, Wilson's Disease and Corticobasal Degeneration
If Parkinson’s disease can be excluded, there are a few other conditions that present with Parkinsonism symptoms which include
- Multi System Atrophy: commonly occurs in men in 50-60 years. MSA is associated with the degeneration of nerve cells in specific areas of the brain. This cell degeneration causes problems with movement, balance and other autonomic functions of the body such as bladder control or blood-pressure regulation. The cause of MSA is unknown and no specific risk factors have been identified.
- Wilson’s Disease: accumulation of copper in the tissues, resulting in neurological and hepatic disease. Copper-dopamine complexes form, producing the Parkinsonism symptoms
- Corticobasal Degeneration: a rare, progressive neurodegenerative disease involving the cerebral cortex and the basal ganglia. It is characterised by marked disorders in movement and cognitive dysfunction.
If a patient has Parkinsonism symptoms yet are not diagnosed with the condition, these alternatives should be considered and treated appropriately. Other causes of Parkinsonism include Drug Induced Parkinsonism, Vascular Parkinsonism (e.g. due to strokes) and Progressive Supranuclear Palsy.
What are the clinical features of Parkinsonism? (extrapyrimidal)
- Tremor: low-frequency, pin-rolling resting tremor – doesn’t occur during movement
- Lead pipe rigidity – velocity independent (evidence during whole-range movements) – compared to spasticity (clasp-knife; velocity-dependent)
- Bradykinesia: slowness of movement, small amplitude motor movements
Tremor and rigidity are due to low dopamine and disturbance in other neurotransmitter levels, bradykinesia is due to low dopamine levels.
Describe the prognosis in PD
Prognosis in PD (slowly progressive): 15-year follow up
94% Dyskinesia – often related to treatment (high doses of Levodopa)
81% Falls – uncommon at diagnosis (so red flag symptom at presentation)
84%: Cognitive decline (50% hallucinations), could also be due to side effects f medication
50% Swallowing difficulty
27% Severe speech problems
Describe the pathology of IPD
Lewy bodies – Synucleinopathy (alpha-synuclein deposited in neurons)
Loss of pigment
- 50% loss of dopaminergic cells > symptoms
- Increased turnover
- Upregulate receptors (body tries to compensate – so symptoms will appear after >50% loss)
- Reduced dopamine
Describe a simplified version of basal ganglia
Loss of dopaminergic neurones in substantia nigra results in reduced inhibition in neostriatum – particularly the putamen
Loss of inhibition in neostriatum allows increased production of acetylcholine (excitatory) => exciting inhibitory cells => vicious cycle => greater inhibitory effect
Chain of abnormal signalling leads to impaired mobility
What are the stages in Catecholamine synthesis?
Describe Dopamine Degradation
Describe Neurotransmitter Synthesis and Release
- Synthesis of neurotransmitter (in this case dopamine) and formation of vesicles in the cell body
- Transport of neurotransmitter down axon
- Action potential travels down the axon – guided by microtubules
- Action potential causes calcium to enter, evoking release of neurotransmitter
- Neurotransmitter attaches to receptor, exciting or inhibiting post-synaptic neuron
- Separation of neurotransmitter molecules from receptors
- Reuptake of neuro-transmitter to be recycled (“spare dopamine recycled”
- Vesicles without neurotransmitter transported back to the cell body.
Why may a DAT scan be useful?
Presynaptic uptake (Step 7) – can help determine how much dopamine is available
Not diagnostic but can be used to help rule out other diseases that may have similar symptoms like essential tremor, neuroleptic and vascular causes.
What are the possible treatment options in Parkinson's Disease?
Dopamine is synthesis within the cytosol of neurones (mainly in their cell body) n the metabolic pathway of: L-Tyrosine => L-DOPA => Dopamine (=> Noradrenaline => Adrenaline)
Its degradation involves either a Monamine Oxidase (MAO) enzyme or a Catechol-O-Methyl Transferase (COMT) enzyme, and both these enzymes can be targeted to treat IPD.
There are many drug classes that are used to treat IPD, mainly acting on the synthesis and degradation pathways, but also can be used in its diagnosis because if patients respond well to the initial treatment (commonly L-DOPA) then IPD can be confirmed.
What is L-DOPA?
Dopamine cannot cross the BBB directly yet L-DOPA can so as a consequence L-DOPA can be administered to be taken up by dopaminergic cells in the Substantia Nigra and converted to dopamine (i.e. it will only work if dopaminergic neurones are left, so has little effect in advance IPD). If there are fewer remaining dopaminergic cells, the effect of levodopa is less reliable – at risk of motor fluctuations.
Absorbed by active transport across BBB so competition with amino acids (so advise patients not to take their medication with high protein meals e.g. steak decreases absorption of tablets)
90% of leveodopa is inactivated in intestinal wall (by monoamine oxidase and DOPA decarboxylase) – so very little is actually available to cross into the CNS (poorly absorbed)
Half life is 2 hours so short dose interval (patients can take up to 6x a day), leads to fluctuations in blood levels and symptoms. NB: physiologically dopamine is produced tonically.
<1% enters CNS – competes with amino acids for active transport across blood brain barrier.
Why is L-DOPA commonly administered alongside a peripehral decarboxylase inhibitor?
It is commonly administered along with a peripheral DOPA decarboxylase inhibitor, as DOPA decarboxylase acts in peripheral tissues to breakdown DOPA, so more L-DOPA crosses the BBB and does not have its action peripherally. L-DOPA is given as co-careldopa (Sinemet) or co-benedolpa (Madopar), both of which are combined drugs. This leads to reduced dose required, reduced side effects (as preventing peripheral breakdown, makes it more tolerable) and increased L-DOPA reaches the brain.
Tablet formulations only are available (not allowed to crush, problem for patients with difficulty swallowing)
- Standard dosage – variable strengths
- Controlled release preparations (CR) – helps them turn over in bed, makes their symptoms more tolerable when they wake up in the morning etc
- Dispersible Madopar (not soluble) but useful for patients with swallowing defects
What are the advantages and side effects of L-DOPA?
L-DOPA main advantage is that it is highly efficacious and has minimal side effects (such as nausea and vomiting, hypotension (central and peripheral), psychosis (Schizophrenia-like effects: hallucination/delusion/paranoia) or tachycardia (+/-arrhythmias)). NB all PD drugs have cardiac effects – L-dopa is the gentlest.
Main disadvantages are that it is a precursor so needs enzyme conversion and in long term use, may show a loss of efficacy (from loss of dopaminergic neurones as it is only effective in presence of dopaminergic neurones), causes involuntary movements and can cause motor complications (such as “on/off”, wearing off, dyskinesia, dystonia and freezing).
- On/off: episodes of mobility and episodes of stiffness and rigidity – flip between 2 states really fast
- Wearing off: effect of tablet drops off so symptoms appear before next tablet is due
- Dyskinesias: difficulty or distortion in performing voluntary movements, look like smooth tics so sometime an uncoordinated dance
- Dystonia: antagonist and agonist contracting at same time – twisting and rotatory postures
- Freezing: feature of PD, sometimes feature of under-treatment or over-treatment
- Think of L-Dopa as a pendulum – sometimes overshoots => too much movement
What are important drug-drug interactions to consider with L-Dopa?
Pyridoxine (vitamin B6) increases peripheral breakdown of L-DOPA
MAOIs risk hypertensive crisis with L-DOPA (but not MAOBIs at normal dose – lose specificity at high dose)
Many antipsychotic drugs block dopamine receptors and Parkinsonism is a side effect e.g. Valporate (newer, ‘atypical antipsychotics less so)
Describe Dopamine Receptor Agonists
These drugs act by binding to dopamine receptor agonists directly to produce the required response in the neurones. Old dopamine receptor agonists such Bromocryptine, Pergolide and Cabergoline (ergot-derived – no longer used) produces a large amount of ADRS (such as retroperitoneal, cardiac and pulmonary fibrosis) yet newer agent such as Ropinirole and Pramipexole (non-ergot-derived) have significantly reduced ADRs.
Patch drugs include Rotigotine (useful for patients who can’t swallow) and Subcutaneous such as Apomrphine (injection or infusion, only used in end-stage or very severe PD – with severe motor fluctuations).
They can be de novo therapy (don’t have to start with L-DOPA) or add-on therapy.
Describe the main advantages and disadvantages of dopamine agonists?
Their main advantages are that they are direct acting, show less motor complications (less wearing off, less freezing, less dyskinesias) and have a possible neuroprotective role, however their disadvantages are less efficiacy than L-DOPA, tendency to produce impulse control disorders, expensive and psychiatric side effects (such as sedation, hallucination, confusion, nausea and vomiting) which is dose-limiting.
Impulse control disorders (also called Dopamine Dysregulation Syndrome) can include pathological gambling (including their whole fortune, house etc), hypersexuality, compulsive shopping, desire to increase dosage and punding (pathological collecting e.g. dolls, stamps etc). This can be destructive to their families as well as themselves. Very important to take a full personal social history e.g. previous gambling and need to be warned to come back.
NB: the side effect hypotension can be a problem – postural hypotension is a problem with the existing unsteadiness (postural instability) and tendency to fall.
Describe MOAB inhibitors
Monoamine Oxidase B metabolises dopamine so any MAO-inhibitor will enhance dopamine levels in the brain – predominates in dopamine containing regions in brain. As a result MAO-inhibitors will prolong the life of dopamine and also can be used alongside L-DOPA to enhance its effects.
MOAB inhibitors include Selegiline and Rasagaline (more commonly used, used once daily).
Can be used alone or to prolong the action of L-DOPA
Smooths out motor response
May be neuroprotective
Not as effective as dopamine agonists or L-DOPA but less side effects
Descrieb COMT inhibitors
(Catechol-O-methyl Transferase Inhibitors):
COMT inhibitors reduce the peripheral breakdown of L-DOPA to 3-O-methyoldopa (3-O-methyldopa competes with L-DOPA active transport into CNS) so more L-DOPA is available to cross BBB + removes competition.
Yet has no therapeutic effect alone. However, they can be used to produce a L-DOPA sparing effect and act to prolong the response to L-DOPA – can use combination tablets COMT inhibitor and L-DOPA and peripheral dopa decarboxylase – Stalevo. They don’t work alone because they only work by potentiating the action of L-DOPA. But they prolong motor response to L-DOPA (reduces symptoms of ‘wearing off’ and motor fluctuations)
Entacapone: doesn’t cross BBB
Tolacpone – crosses BBB but main effect is peripheral. Need to monitor liver function as can cause fulminant liver failure so tends not to be used very much – only used in specialised centres.
Acetylcholine may have an antagonistic effect to dopamine meaning that anticholinergics can have a minor role in the treatment of IPD, especially treating a tremor (which is not solely due to dopamine levels).
Anticholinergics include Trihexyphenidyl, Orphenadrine and Procyclidine
Advantages: treat tremor + not acting via dopamine systems
Disadvantages: no effect on bradykinesia and side effects include confusion, drowsiness and usual anticholinergic side effects (dry mouth, blurred vision, constipation, urinary retention etc)
Describe Amantidine (not common)
Mechanism action uncertain – possibly
- Enhanced dopamine release
- Anticholinergic NMDA inhibition
- Poorly effective
Few side effects
Little effect on tremor
(Used for other things e.g. tiredness in multiple sclerosis)
Describe surgery in treatment of IPD
Carried out stereotactically (minimally invasive, makes use of a three-dimensional coordinate system to locate small targets)
Of value in highly selected cases – patients have to show
- Dopamine responsive
- Significant side effects with L-DOPA
- No psychiatric illness (side effect of surgery can be depression)
Ongoing controlled trials
Lesion – targets
- Thalamus for tremor
- Globus Pallidus Interna for dyskinesias
Deep brain stimulation – very effective, not as dangerous as lesion surgery though
- Subthalamic nucleus
- Placement of electrodes in specific parts of the brain – very accurate