Lecture 23 - Neuropharmacology Flashcards
What is idiopathic Parkinson’s disease?
Neurodegenerative disorder where we lose dopaminergic neurones in the substantia Nigra so the basal ganglia (putamen) receive less dopamine
What structures can form in Idiotpathic Parkinson’s disease?
Lewy bodies
What occurs in the basal ganglia due to lack of dopamine in IPD?
Loss of dopaminergic neurones in substantia nigra pars compacts means neostriatum isn’t inhibited as much
More ACh is made which impairs mobility
What are the 4 main clinical features of Parkinsonism?
Rest tremor
Lead pipe rigidity
Bradykinesia
Postural instability
What is the rest tremor that is seen in Parkinson’s?
Its a low frequency pilll rolling tremor which disappears when you ask a patient to do a movement
What is lead pipe rigidity that is seen with Parkinsonism?
Where you try and move the patients limb and there’s resisitance all the way
What is bradykinesia?
Slow in intiating movements
Shuffling steps
Lack. Of arm swinging
How do you diagnose Idiopathic Parkinson’s disease?
Clinical features of Parkinson’s (BRADYKINESIA is main one)
Must also respond to treatment of Levodopa
Structure neuro imaging is normal and other causes of parkinsonism has been ruled out
What are some non motor manifestations of Parkinson’s?
Mood changes
Hallucinations
Cognitive change
REM sleep disorder
Restless leg
Fatigue
Pain
Urinary symptoms
Sweating
Low blood pressure
What is the prognosis in Parkinson’s disease after 15years?
Most people get:
-dyskinesia (involuntary movements)
-falls
-cognitive decline (some hallucinations)
-somnolence (drowsiness and sleepiness)
-Swallowing difficulty
-hypophonia (quiet)
Describe the process of dopamine release at a synaptic cleft:
Depolarisation of dopaminergic neurone leads to Ca2+ influx
Ca2+ binds to vesicles contacting dopamine
Vesicles bind to presynaptic membrane and release contents (dopamine) into synaptic cleft via exocytosis
What is the gold standard drug for treating idiopathic Parkinson’s disease?
Levodopa
Why dont we just use dopamine to treat Parkinson’s?
Dopamine cant cross BBB whereas levodopa does
Also dopamine would cause peripheral adverse effects
Why does levodopa have a very limited effect in late stage Parkinson’s?
Levodopa works by the functioning dopaminergic neurones converting levodopa to dopamine
So in late stage Parkinson’s there are very few functioning dopaminergic neurones so little L-dopa is converted to dopamine
How is levodopa administered?
Oral administration
How is levodopa absorbed?
Active transport
What enzymes inactivate levodopa in the gut wall?
Monoamine oxidase
Dopa decarboxylase
Why does levodopa need regular dosing?
Short half life (2hrs)
This leads to fluctuations in blood levels and symptoms
What is levodopa always prescribed with?
Why?
Peripheral dopa decarboxylase inhibitor
To prevent the conversion of levodopa into dopamine in the peripheries
What is the drug given with levodopa which is a peripheral dopamine decarboxylase inhibitor?
Carbidopa
What is the formulation called which contains levodopa and carbidopa?
Sinemet
Why is the sinemet formulation better than just levodopa?
Reduces dose required and reduced side effects since more levodopa reaches brain
What are the advantages of levodopa?
Highly efficious
Low side effects:
Nausea/anorexia (vomiting)
Hypotension
Psychosis (schizophrenia, hallucinations)
Tachycardia
What drug do you not give as an antiemetic caused by giving levodopa and why?
Metoclopramide
Can cause extrapyradimal effects causing Parkinsonian symptoms
What drug can be used as an anti-emetic caused by levodopa?
Domperidone
What are the disadvantages of levodopa?
Its a precursor so needs conversion
Long term:
-loss of efficacy
-involuntary choreform movements
-motor complications:
May get rigid
Wearing off
Dyskinesias
Dystopia (limb held in abnormal position)
Freezing (will suddenly stop and become rigid)
What vitamin increases the peripheral breakdown of levodopa?
Vitamin B6 (pyridoxine)
What is the interaction of monoamine oxidase inhibitors with levodopa?
Can cause hypertensive crisis
What is the interaction of monoamine oxidase inhibitors with levodopa?
Can cause hypertensive crisis
What is the interaction of monoamine oxidase inhibitors with levodopa?
Can cause hypertensive crisis
What drugs can block dopamine receptors and cause Parkinsonism as a side effect?
Antipsychotic drugs
What is the point of giving levodopa with a Catechol-O-methyl Transferase (COMT) inhibitor?
Decreases breakdown of levodopa so prolongs the motor repsonse to levodopa
What are some COMT inhibitors given with levodopa?
Can they cross the BBB?
Entacapone
Opicapone
Can’t cross BBB
What is the effect of giving COMT inhibitors by themselves?
Why?
No therapeutic effect since doesn’t cross the blood brain barrier so is never given alone
What are some dopamine receptor agonists?
Ropinirole (tablet)
Pramipexole (tablet)
Rotigotine (patch)
Apomorphine (subcutaneous)
When is apomorphine given?
How is it given?
What type of drug is this?
For patients with severe motor fluctuations
Subcutaneously
Dopamine receptor agonists
What are the advantages of dopamine receptor agonists?
Direct acting on receptors
Less dyskinesias and motor complications
Possible neuroprotection
What are the disadvantages of dopamine receptor agonists?
Less efficacy than levodopa
Impulse control disorders
More psychiatric s/e like hallucinations
Expensive
What are some impulse count troll disorders that are caused by dopamine receptor agonists?
Can lose ability to control impulsiveness
-pathological gambling
-hypersexuality
-compulsive shopping
-desire to increase dose
-punding
What is punding?
Compulsive sorting of things
What are the side effects of dopamine receptor agonists?
Sedation
Hallucinations
Confusion
Nausea
Hypotension
What drug do you give to a patient having severe motor fluctuations with Parkinson’s?
How do you administer it?
Apomorphine
Subcutaneously (dopamine receptor agonist)
What is the function of monoamine oxidase B?
What effect do monoamine oxidase B inhbitors have?
Metabolises dopamine
So inhibitors MAOB so dopamine is enchanced/stays around longer
What are some examples of monoamine oxidase B inhbitors?
Rasagaline
Safinamide
What are some examples of anticholinergics to help treat Parkinson’s disease?
Trihexyphenidydyl
Orphenadrine
Procyclidine
What are the advantages of anticholinergics?
Treat tremor
Not acting via dopamine systems
What are disadvantages of anticholinergics?
Doesnt help the bradykinesia
Confusion
Drowsiness
When is Amantadine rarely used for Parkinson’s?
When levodopa is inducing dyskinesia (choreiform movements)
What are the side effects of amantadine?
Hallucinations
Confusion
When are Parkinson’s patients eligible for surgery?
Need good response to levodopa
No psychiatric illness
Significant side. Effects with levodopa so that’s not an eligible treatment
What are some consequences of not reveinving enough l-dopa?
L dopa withdrawal
Severe akinnetic mutism
Life threatening neuroleptic malignant syndrome (confusion, rigidity, fever, autonomic dysregulation)
What are some consequences of withdrawal from dopamine agonists?
Dopamine agonist withdrawal syndrome (DAWS)
Neurophsyciatric symptoms (agitation, antic, anxiety, depression) autonomic symptoms
What is the pathophysiology of myasthenia Gravis?
Auto immune antibodies attatching to post synaptic ACh receptors blocking signals reaching muscle
What are some symptoms of myasthenia Gravis?
Flucatuating
Fatiguable
Weakness of skeletal muscle
Extraocularmusucels
Bulbar involvement (Dysphagia, dysphonia)
Limb weakness
Resp. Muscle involvement
What is meant by fatiguable in myasthenia gravis?
Muscles that are being used get weaker as you use it for seconds to minutes
They will be back to full strength after rest for a couple mins
What are some drugs that can worsen myasthenia gravis?
Aminoglycosides
B blockers
Chloroquine
Magnesium
ACE inhibitors
Syuccinylcholine
What are some complications of myasthenia gravis?
Acute exacerbation (myasthenic crisis)
Overtreatment (cholinergic crisis)
What is the most commonly used drug to treat myasthenia?
Pyridostigmine
What is the mechanism of action of pyridostigmine?
Acetylcholinesterase inhibitors
What drugs except pyridostigmine can be used for myasthenia gravis?
Corticosteroids decrease immune response
Steroid sparing drugs like azathioprine
What effects does pyridostigmine have?
Enhances neuromuscular transmission
Skeletal and smooth muscle
Excess does can cause depolarising block (paralysis) cholinergic crisis
Muscarinic side effects (gut churning, diarrhoea, bradycardia)
When is neostigmine given?
How is it given?
Why is it only given here?
In the ITU
Oral and IV
Acts much quicker than neostigmine but causes SIGNIFICANT anti Muscarinic side effects
Why is the dosing interval for pyridostigmine crucial?
If not given on time can get Dysphagia, dysarthria and respiratory depression
What are the muscarinic side effects of pyridostigmine?
Miosis
SLUDGE
Salivation
Sweating
Lacrimation
Urinary incontinence
Diarrhoea
GI upset and hypermotility
Emesis
When do you dose patients withi pyridostigmine in relation to their meals and why?
40 to 60mins before meals to optimise swallowing
Since it has peak actioon after 60 mins
