Week 3 - PD & E Flashcards
What are the cardinal signs of PD?
BRADYKINESIA
+ 1 of:
Rigidity, Tremor or Postural Instability
What is the pathophysiology of PD?
Loss of dopaminergic cells in substantia nigra»_space;> degeneration of projections to other areas of basal ganglia
What is the protein found in lewy bodies?
Alpha-synuclein
What is the site of action of Levodopa?
Increases L-Dopa levels in the presynaptic cleft
What is the site of action of Dopamine Agonists?
Act directly on postsynaptic dopamine receptors in striatum (D1 and/or D2)
What is the site of action of Amantadine (antiviral)?
Stimulates release of DA and inhibits re-uptake at the pre-synaptic cleft
What is the site of action of COMT inhibitors (catechol-O-methyltransferase) such as Entacapone or Tolcapone?
Block degradation of DA and L-Dopa in the synapse (prolong effect)
What is the site of action of MAOIs (Monoamine-oxidase-B inhibitors) such as Selegiline & Rasagiline?
Irreversible inhibitors of MAOB which decreases break down of DA»_space;> which leaves more in the synapse.
Where is levodopa absorbed?
Small bowel via AA transport system
What is the half life of levodopa?
~60 mins
What are the short term side effects of levodopa?
N&V, reduced appetite, confusion, delusions, visual hallucinations, postural hypotension, insomnia, vivid dreams/nightmares
What are the long term side effects of levodopa?
Dyskinesias (abnormal involuntary movemnets), Confusion,
Hallucinations
Response fluctuations (end of dose deterioration and unpredictable on-off switching)
Name 3 dopamine agonists…
Ropinirole, Pramipexole, Rotigotine, Apomorphine
How can dopamine agonists be administered?
Oral, transdermal (Rotigotine) or subcutaneous (Apo) administration
What are the common side effects of dopamine agonists?
N&V, loss of appetite, postural hypotension, confusion, hallucinations, somnolence and
Impulse control disorder (gambling, hypersexuality, over spending etc. prewarn patient and family)
What are the side effects of MAOIs?
Nausea, vomiting, confusion
There is a potential interaction with anti-depressants (SSRIs) → serotonin syndrome
Name 2 MAOIs…
Selegiline, Rasagiline
Why do you use COMT inhibitors?
Inhibit COMT → more LD available to cross the BBB to produce prolonged effect
What are the side effects of COMT inhibitors?
N&V, Confusion etc. +
Increased dyskinesias, diarrhoea and discolouration of body fluids
When do you use amantadine?
Largely used in later disease to treat dyskinesia
What are the s/e of amantadine?
Confusion (do not use in elderly), Hallucinations, psychosis, Livedo reticularis, ankle oedema
When do you use anticholinergics?
How do they work?
Used more in younger patients with tremor
Reduce effects of relative central ACh excess that occurs due to dopaminergic deficiency
What are the side effects of anticholinergics?
Cognitive impairment (in elderly)
Dry mouth, constipation, dizziness, blurred vision, urinary retention, glaucoma
What non-dopamine related treatments may be used?
Always remember PD patients have non neuro symptoms such as nocturia, urgency, constipation, depression, anxiety etc. All of which will need addressing.
What are the 2 mechanisms of underlying seizures?
Excess excitation – of inward Na+, Ca++ currents or too many neurotransmitters such as: glutamate, aspartate
Inadequate inhibition – Of inward Cl- and outward K+ currents or not enough of the neurotransmitter GABA
What are the possible prophylactic measures taken with epileptic patients?
Prophylactic measures include ways of minimising epileptogenic stimuli such as:
Fever, flicking lights, loss of sleep, alcohol abuse (induced and withdrawal), abrupt withdrawal of medication and certain epileptogenic drugs such as antibiotics.
What is the 1st line treatment in generalised tonic clonic seizures?
Sodium valproate
When can you not use sodium valproate?
Pregnancy - teatrogenic
What are the alternatives to sodium valproate in the management of generalised tonic clonic seizures?
lamotrigine if sodium valproate unsuitable (women)– but may exacerbate myoclonus).
Also consider carbamazepine or oxcarbazepine (may exacerbate myoclonus)
When can you not use carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine or vigabatrin?
In presence of myoclonus or absences
What is the 1st line treatment in absence seizures?
Ethosuximide (absences only) or valproate
Lamotrigine if above unsuitable or not tolerated
What is the second line treatment in absence seizures?
2nd line - Clobazam, clonazepam, levetiracetam, topiramate or zonisamide
What drugs should you avoid in absense seizures?
Avoid - carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabaline, tiagabine and vigabatrin.
What drugs should you avoid in myoclonic seizures?
Avoid - carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabaline, tiagabine and vigabatrin.
What is the 1st line treatment in absence seizures?
Sodium valproate
Consider levetiracetam or topiramate if sodium valproate unsuitable or not tolerated
What is the 1st line treatment in focal/partial seizures?
Carbamazepine
lamotrigine
What are the adverse effects of antiepileptics?
Acute allergic reaction - eg skin rash, Toxic effect - eg unsteadiness, blurred vision, tremor, confusion.
Teratogenicity – eg spina bifida (sodium valproate)
Chronic adverse reactions: Weight gain, weight loss, hair loss, overgrown gums, memory loss, behavioural disturbances, mood changes, anaemia, osteomalacia
What are the specific adverse effects of Sodium valproate?
Teratogenicity (spina bifida - folate involvement)
Weight gain, tremor, Parkinsonism,
What are the specific adverse effects of Carbamazepine, phenytoin, lacosamide and lamotrigine?
Tiredness, double vision, unsteadiness
What are the specific adverse effects of Topiramate and zonisamide?
Weight loss, behavioural changes, paraesthesiae, kidney stones
What are the specific adverse effects of Levetiracetam?
Tiredness, dizziness, aggression
What are the specific adverse effects of Clobazam & clonazepam?
Sedation
What is the contraception advise given to woman on antiepileptics?
If using enzyme-inducing antiepileptic – need COCP containing at least 50µg oestrogen. Using tri-cycle (3 pill packs then 4 days off)
Avoid Implanon implants, POP, patches.
Coil and Depo can be used
Which are the anti epileptics that are primarily metabolised by p450 system?
Carbamazepine, ethosuximide, oxcarbazepine, phenytoin, phenobarbital, primidone, tiagabine, zonisamide
Which drugs are primarily renally excreted?
Gabapentin, levetiracetam, vigabatrin, pregabalin
When does a seizure become status epilepticus?
After 5 mins of a continuous seizure
What is the initial treatment of status epilepticus?
Community - PR diazepam or buccal midazolam
Hospital - IV lorazepam
What do you use to treat serial seizures in status epilepticus?
Clobazam
When do you give phenytoin in patients with status epilepticus?
New patient who has been seizing for 20 - 30 mins
Whats the definition of a seizure?
A seizure is defined by release of excessive and uncontrolled electrical activity in the brain
What are the symptoms of delerium tremens (DT) when will you get it?
Acute alcohol withdrawal
Severe agitated confusion:
o Hallucinations, confusion, delusions, sever agitation, GENERALISED TONIC-CLONIC SEIZURES
What is the pharmacological treatment of DT?
Chlordiazepoxide PO
How do you treat wernicke’s encephalopathy?
thiamine IV
What is the metabolism of phenytoin?
And its subsequent relevance to dosing?
Metabolism is dose dependent
• 1st order kinetics initially – as dose increases, metabolism increases at a proportional rate. (Fixed PERCENTAGE of drug metabolized during a per unit time)
At a certain point it undergoes 0 order kinetics (fixed AMOUNT of drug metabolized per unit time – rate is independent of the concentration of the reactants). This is due to saturation kinetics.
• Enzymes are used up, so extra dose wont be metabolised as quickly as its administered.
• Enzyme activity can be enhanced or competitively inhibited by drugs that share the same hepatic enzyme
What is phenytoin’s effect on the p450 system?
Phenytoin is an inducer of cytochrome P450 enzymes
What is the most appropriate drug in generalised seizures?
Sodium valproate
What is sodium valproate’s effect on the P450 system?
Sodium valproate is an inhibitor of cytochrome P450 enzymes
What is the key counselling you need to give patients with newly diagnosed epilepsy?
Driving, Dangerous situations, Pregnancy and teratogenicity, Interactions of AEDs esp with OCP
What is the acute management of generalised seizures?
ABCDE - extra attention to patients airway, try to gain IV access
• Oxygen – to prevent hypoxia
• Safe environment – clear surroundings
• Keep patient supported during seizure protecting from injury. As soon as movements cease put into recovery position and ensure she is watched until she has recovered consciousness
• Drug treatment considered after 5 mins (status epilepticus
Drugs in status epilepticus
What is the drug class of lorazepam?
o Lorazepam
• Benzodiazepine: enhances effect of GABA
• Low lipid solubility
Drugs in status epilepticus
What is the route of administration of diazepam and when shouldnt it be used?
Diazepam • Can be given rectally • Not suitable for IV use >>> thrombophlebitis • High lipid solubility • CAUTION – Respiratory depression
Drugs in status epilepticus
What is the route of administration of Midazolam
and when shouldnt it be used?
Midazolam • If facilities for resuscitation not available • Given intranasally/buccally • Unlicensed use • CAUTION – Respiratory depression
Drugs in status epilepticus
What is the route of administration of Phenytoin Sodium
and how should you keep an eye on potential ADRs?
Phenytoin Sodium
• Slow IV injection
• ECG monitoring
• CAUTION – Bradykinesia, Hypotension
What is the main drug in partial seizures?
Carbamazepine
What is Carbamazepine’s effect on the P450 system & therefore how will it effect warfarin?
Enzyme inducer
• Drug interaction with warfarin
• If carbamazepine used, need more frequent INR monitoring for 4-6 weeks
(INR will fall, therefore increased stroke risk)
What are the side effects of carbamazepine?
Drowsiness, Rash (4-6 weeks), Hyponatraemia (SIADH) & Neutropenia
What are the effects of carbamazepine in OD?
Carbamazepine causes cerebellar toxicity in OD.
Nystagmus, Ataxia (falls risk), Increased seizure frequency
What are the clues that a patients parkinsonism is drug induced?
- Subacute bilateral onset
- Progression of symptoms concurrent with medication intake
- Early presence of postural tremor
What are some of the high risk drugs that can cause parkinsonism?
Dopamine antagonists – Neuroleptics e.g…
HALOPERIDOL & RISPERIDONE
Anti-emetics e.g metoclopramide.
others = Valproate, Lithium, CCBs, SSRIs (fluoxetine)
What is the surgical treatment of PD?
What are the advantages & disadvantages?
Deep brain stimulation of subthalamic nucleus
• Improves motor fluctuations
• Improves PD features and may permit drug dose reduction
• Does not improve axial problems
• May worsen speech
