PARKINSONS, SEIZURES, STROKES, MIGRAINES Flashcards
What are the 3 pharmacological targets for treating parkinsons?
Increase dopamine levels
Reduce dopamine breakdown - MAO-B inhibitors or COMT inhibitors
Directly act on dopamine receptors
An example of a drug that directly increases dopamine levels in the pharmacological management of Parkinson’s disease?
Levodopa
Examples of drugs that reduces dopamine breakdown in the pharmacological management of Parkinson’s disease?
MAO-B inhibitors - selegiline and rosagiline
COMT inhibitors - entacapone and tolcapone
An example of a drug that directly acts on dopamine receptors in the pharmacological management of Parkinson’s disease?
Pramipexone
Ropinirole
Rotigotine
Give examples of MAO-B inhibitors?
Selegiline
Rasagiline
Give examples of COMT inhibitors?
Entacapone
Tolcapone
What drugs are typically offered for Tx of parkinsons disease when its the early stages and the motor symptoms are not impacting on QOL?
Dopamine agonists or MAO-B inhibitors - this can delay the need for levodopa
How are COMT inhibitors used in the Tx of parkinsons disease?
They are often given as adjuvant therapy alongside levodopa as they prevent it from breaking down, potentiating the effects
What is levodopa?
Why can’t we just give dopamine directly to treat parkinsons disease?
An amino acid precursor of dopamine
As dopamine cannot cross the blood brain barrier but levodopa can and then levodopa is converted to dopamine within the brain
What is carbidopa and benserazide? Why do we give it alongside levodopa?
They are dopadecarboxylase inhibitors
Dopadecarboxylase can convert levodopa peripherally into dopamine
So we give a dopa decarboxylase inhibitor alongside levodopa to prevent it being converted to dopamine before it reaches the brain.
This means more of the drug can act within the central NS but also we dont get excessive dopamine peripherally
Central physiological effects of dopamine?
Psychosis and mania
Impaired cognition e.g. memory, attention, executive function
Restlessness and agitation
Suppress lactation
Peripheral effects of too much dopamine?
Nausea and GI effects
Anti-kinetic effects on the GI system
Vasoconstriction
Peripheral efefcts of too much dopamine?
GI e.g. nausea
Anti-kinetic effects on GIT
Vasoconstriction
Which groups of pt should never be prescribed medications containing levodopa?
Severe psychiatric illness
Severe pulmonary or cardiovascular disease
Severe nausea or GI motility problems
Breast feeding
Common and important side effects of co-careldopa and co-beneldopa?
N&v
Abnormal dreams and sleep disturbances
Dizziness and syncope
Dyskinesia
Rapid fluctuations in clinical state
Postural hypotension
Psychological effects
Impulse control disorders - pathological gambling, binge eating and hypersexuality
Interactions of co-careldopa and co-beneldopa?
Monoamine oxidase inhibitors
General anaesthetic
Anti-hypertensives
What must you communicate to the patient when they start co-careldopa or co-beneldopa?
The side effects
Not to stop abruptly as can cause maligannt neuroleptic syndrome
They can cause postural hypotension so esp in elderly warn them of this
Warn them of sleepiness if they drive or work
What is co-careldopa?
A mixture of carbidopa and levodopa
What is co-beneldopa?
A combination of benserazide and levodopa
What should you do if the pt on levodopa treatment is experiencing the wearing off phenomenon?
Adjust the dose to smaller, more frequent doses
Use prolonged-release levodopa preperations and take at bedtime
Advise about taking levodopa 30 mins before food to enhance the absorption
What does it mean to Call levodopa a time critical drug?
It must be taken at the same time exactly each day to avoid the wearing off phenomenon
This is why in A&E if you get a pt you cannot trust the electronic records you MUST ask the pt how they take their levodopa at home and continue this routine exactly
What are the “on-off” fluctuations seen in levodopa treatment?
When the drug is working and symptoms are well controlled and then suddenly/gradually the drug isnt working and motor symptoms appear e..g during the wearing off phase
Can also mean when patients switch from severe dyskinesia to immobility in a few minutes
How can we help a pt struggling with on-off fluctuations when on levodopa treatment?
Combine levodopa with a dopamine agonist
Give fewer doses of levodopa
Use liquid forms of levodopa
What should you do as an F1 if you think the pt does not require their parkinsons meds?
NEVER ABRUPTLY DISCONTINUE PARKINSONS MEDICATIONS WITHOUT A SPECIALIST ADVICE
Options for levodopa if pt are unable to swallow?
Crush tablet (not if modified release!!)
Consider liquid
Patch
NG/NJ/PEG tube
What is the transdermal drug that can be given for parkinsons called? Whats its MOA?
Rotigotine - a dopamine agonist
Why should you not stop parkinsons drugs abruptly?
Neuroleptic malignant syndrome - a rare but life threatening condition!!
Pathophysiology of neuroleptic malignant syndrome?
Blockage of D2 receptors in the hypothalamus results in elevated temperature set point and impairment of heat-dissipating mechanisms
Blockages of D2 receptors in the nigrostriatal pathway results in muscle rigidity
Symptoms of neuroleptic maligannt syndrome?
Pyrexia
Muscle rigidity
Autonomic lability e.g. hypertension, tachycardia, tachonoea
Agitated delirium with confusion
Management of neuroleptic maligannt syndrome?
Stop offending drug if that’s the cause
IV fluids
Dantrolene may be used in selective cases (a muscle relaxant)
Bromocroptine may also be used
When considering an AED, what factors influence the choice of treatment?
The type of seizure
Age
Tolerance, compliance, SE
Gender - for pregnancy
Lifestyle - occupation and driving
Coexisting medical condition or medications
First line Tx for tonic-clinic seizures?
Sodium valproate first line in males and females unable to conceive
Lamotrigine or levetiracetam second line or for fertile females
First line Tx for absence seizures?
Ethosuximide
First line Tx for myoclonic seizures?
Sodium valproate in males and infertile females
Levetiracetam in fertile females
First line Tx for atonic or tonic seizures?
Sodium valproate for males and infertile females
Lamotrigine for fertile females
First line Tx for dravet syndrome?
Sodium valproate males and females due to severity
First line Tx for lennox-gustaut syndrome?
Sodium valproate for males and females due to severity
Why does drug history influence the choice of AEDs?
Must be aware of other inhibitors or promotes of CYP450 enzyme
Sodium valproate MOA/
Inhbits GABA transminase which inhibits GABA breakdown and enhances the inhibitory effect
Contraindications for sodium valproate?
Acute porphyria’s
Mitrochondrial disorders (higher rates of acute liver failure and liver-related deaths)
Personal or FHx of severe hepatic dysfunction
Urea cycle disorders
Pregnancy
Side efefcts of sodium valproate?
GI disturbances
Weight gain
Transient hair loss with re growth of curly hair
Neurological features
Blood dyscrasias
Interactions with sodium valproate?
CYP450 inhibitor
Other AEDs
Risk of hepatotoxicity with - statins, alcohol, antibiotics, anti-fungal, chemotherapy
Drug monitoring for sodium valproate?
Monitor LFTs before therapy and during first 6 months
Measure FBC before starting and before any surgery to assess bleeding risk
Only measure drug concentration levels if you suspect non-adherence, toxicity or there is status epilepticus or organ failure
What are the teratogenic effects of sodium valproate?
Neural tube defects
Significant risk of neurodevelopmental delay
What AED is best for pregnancy?
Lamotrigine
Moa of lamotrigine?
Sodium channel blocker stabilising presynaptic neuronal membranes and modulating presynaptic release of excitatory neurotransmitters
Cautions for lamotrigine?
Can exacerbate myoclonic seizures, dravet syndrome and Lennox-gastat sundrome and parkinsons disease
Side efefcts of lamotrigine?
Rashes
Steven Johnson syndrome
Hypersensitivity syndrome
GI disturbance
CNS effects
Bone marrow supression
Interactions with lamotrigine?
Increases CNS effects - Alcohol, anti-psychotics, local anaesthetics, opioids, anti-histamines, benzodiazepines
COCP and desogestrel
Other AEDs
Immediate management of a confirmed non-haemorrhagic stroke?
Aspiring 300mg orally or rectally (immediately if TIA, after 24 hours if thrombolysed)
Thrombolysis with alteplase within 4.5 hours of onset of stroke symptoms
Thrombectomy can be done in some cases
MOA of alteplase?
A recombinant tissue plasminogen activator - converts plasminogen to plasmin
Contraindications to thrombolysis?
active internal bleeding
recent haemorrhage, trauma or surgery (including dental extraction)
coagulation and bleeding disorders
intracranial neoplasm
stroke < 3 months
aortic dissection
recent head injury
severe hypertension
Side effects of thrombolysis?
haemorrhage
N&V
Cerebral oedema
hypotension - more common with streptokinase
allergic reactions may occur with streptokinase
What should you do about the aspirin given after a stroke?
Continue for 2 weeks before converting to a long-term anti-thrombotic treatment
What is the standard anti-thrombotic treatment given as secondary prevention after a stroke?
Clopidogrel 75mg
How does clopidogrel work?
Antagonist of P2Y12 adenosine diphosphate receptor, inhibiting the activation of platelets
How does Ticagrelor work differently to clopidogrel?
Ticagrelor does reversible inhibition due to a different binding site whereas clopidogrel does not
Contraindications for clopidogrel?
Active bleeding
Discontinue 7 days before elective surgery
Pregnancy
Caution in hepatic and renal impairment
Side effects of clopidogrel?
Bleeding
GI disturbances
Rashes
Headaches
Dizziness
Paraesthesia
Interactions with clopidogrel?
Anticoagulants and anti-platelets - increase bleeding risk
NSAIDs - increase bleeding risk
SSRIs - may make clopidogrel less effective
PPIs - omeprazole and esomeprazole may make clopidogrel less effective (lansoprazole should be ok)
Erythromycin
Secondary prevention after stroke?
Clopidogrel 75mg
Check lipids, BP - start statin and hypertensive
Physical activity
Smoking cessation
Diet and exercise
Reduce alcohol consumption
Optimise control of other co-morbidities
Systolic bp target post-stroke in the acute phase?
<130
(In the acute phase you don’t control bp unless its between 150-220 and presenting within 6 hours OR if its >220mmHg)
Post-stroke statin?
High intensity statin such as atorvastatin 20-80mg
Cautions for statins?
Elderly
High alcohol intake or liver disease
Hypothyroidism (must be managed adequately before starting statin)
Pt at risk of muscle toxicity e.g. muscle disorders
Known genetic polymorphism
Haemorrhagic stroke
Interactions for statins?
Macrolide antibiotics - increase statin levels
Penicillin antibiotics - increased risk of hepatotoxiity
Colchicine - increased risk of rhabdomyolysis
SE of statins?
GI disturbances - diarrhoea, constipation, flatulance, nausea
CNS effects - dizziness, headache, blurred vision
Hepatic effects
Myopathy
Sleep disorders
Skin reactions
Hyperglycaemia
Weight gain
Epistaxis/thrombocytopemia
Example of antimuscarinic used in parkinsons?
Orphenadrine
Procyclidine
When might you use antimuscarinic drugs in parkinsons disease?
For disabling tremor or excessive salivation
Na+ channel blocking AEDs?
Carbamazepine
Phenytoin
Lamotrigine
GABA receptor agonist AEDs?
Clonazepam
Diazepam
Lorazepam
Phenobarbital
MOA of vigabatrin?
GABA transaminase inhibitor - prevents breakdown of GABA
Moa of gabapentin and pregabalin?
GABA analogues
MOA of topiramate?
Glutamate receptor antagonist
MOA of ethosuximide?
Neuronal calcium channel blocker
Whats the MOA of Triptans?
Selective 5-HT receptor agonists with a high affinity for 5HT1B and 5HT1D receptors - this causes cranialvasoconstriction
Examples of 5HT 1B and 1d agonists?
Sumatriptan
Zolmitriptan
Drugs used for prophylaxis of migraines?
Beta adrenoreceptor antagonists - propranolol
AED and TCAs - topiramate, sodium valproate, gabapentin, amitryptiline
Acute migraine Tx?
Monotherapy with aspirin, ibuprofen or a triptan as soon as they know they are developing a migraine (if aura they should take sumatriptan)
Prophylaxis Tx for migraines?
Propranolol hydrochloride is first line
Other beta blockers can be considered
Topiramate can be used if BB is unsuitable
Amitryptiline can be considered
Contraindications for topiramate?
Pregnancy
Hypersensitivity
Renal or liver issues
Acute porphyria
Glaucoma
What drug is best for menstrual migraine prophylaxis?
Frovatriptan
Contraindications for sumatriptan?
Coronary vasospas, IHD, moderate hypertension, PVD, previous cerebrovascular accident, previous MI/TIA, prinzmetals angina
Side effects of Triptans?
Nausea and vomiting
Dizzy or drowsy
Flushing
Angina pectoris, palpitations, MI
What drugs do Triptans interact with?
SSRIs
MAOIs
- risk of serotonin syndrome
Why is it beneficial to delay the need for levodopa treatment by starting parkinsons patients on dopamine agonists or MAOIs in the early stages of disease?
As overtime levodopa efficacy can reduce
Levodopa comes with motor side effects
