21. Drugs used in Neurological Disorders Flashcards
What are the clinical features of Parkinsonism?
Tremor, rigidity, bradykinesia, postural instability.
What are the non motor manifestations of Parkinson’s disease?
Mood changes, pain, cognitive changes, urinary symptoms, sleep disorder, sweating.
What is the prognosis in Parkinson’s disease after 15 years concerning dyskinesia, falls, cognitive decline, somnolence, swallowing difficulty, severe speech?
Dyskinesia in 94%, falls in 81%, cognitive decline in 84%, somnolence in 80%, swallowing difficulty in 50%, severe speech problems in 27%.
How is idiopathic Parkinson’s disease diagnosed?
Clinical features, exclude other causes, response to treatment, structural neuro imaging is normal, functional neuro imaging.
What are the pathological features of IPD?
Neurodegeneration of pigmented cells in substantia nigra, Lewy bodies, loss of pigment, reduced dopamine.
How does loss of dopaminergic neurons in the substantia nigra affect the basal ganglia circuit?
Reduces inhibition in neostriatum, loss of this inhibition allow increased production of ACh, this abnormal signalling leads to impaired mobility.
How is dopamine formed from L-tyrosine?
L-tyrosie -> L-DOPA (tyrosine hydroxylase) -> dopamine (DOPA decarboxylase).
How is epinephrine formed from L-tyrosine?
L-tyrosine -> L-DOPA (tyrosine hydroxylase) -> dopamine (DOPA decarboxylase) -> noradrenaline (dopamine B-hydroxylase) -> epinephrine (phenylethanolamine n-methyltransferase).
How is dopamine degradated?
To 3-methoxytyramine (catechol-O-methyl transferase) -> homovanillic acid (monoamine oxidase, aldehyde drydrogenase). Or to 3,4-dihydrophenyl-acetic acid (MAO or ADH) -> homovanillic acid (COMT).
What is a DAT scan?
Dopamine transporter - labelled tracer to measure presynaptic uptake of dopamine.
Why is L-DOPA used as treatment for IPD and not dopamine?
L-DOPA can cross the BBB, whereas dopamine can’t.
What is the mechanism of L-DOPA?
Taken up by dopaminergic cells in the substantia nigra to be converted to dopamine.
What are the pharmacokinetics of L-DOPA? (How much gets to cross BBB, half life).
<1% gets to CNS as 90% is inactivated in the intestinal wall and 9% is converted to dopamine in the peripheral tissues, half life is 2 hours.
What is the associated problem with the short half life of L-DOPA?
Fluctuations in blood levels and symptoms so control is variable.
What can be used alongside L-DOPA to reduce peripheral conversion to dopamine? What are the effects?
DOPA decarboxylast inhibitor - reduces the dose required, reduces side effects, increases L-DOPA reaching the brain.
What are the advantages of L-DOPA use in treatment of IPD?
Highly efficacious, low side effects.
What are the ADRs of L-DOPA?
Nausea/anorexia, hypotension, psychosis, tachycardia.
What are the disadvantages of using L-DOPA in IPD therapy?
Long term loss of efficacy as only effective in presence of dopaminergic neurones. Motor complications as it’s on/off in terms of frequently wearing off.
What are the DDIs of L-DOPA?
Pyridoxine increases peripheral breakdown of L-DOPA, MAOIs risk hypertensive crisis, antipsychotic drugs block dopamine receptors.
What are the types of dopamine receptor agonists? Give an example of each.
Ergot derived - bromocryptine, pergolide, cabergoline. Non ergot - ropinirole, pramipexole. Patch - rotigotine. Subcutaneous - apomorphine.
What are the advantages of dopamine receptor agonists in IPD therapy?
Direct acting, less dyskinesias/motor complications, possible neuroprotection.
What are the disadvantages of dopamine receptor agonists in IPD therapy?
Less efficacious than L-DOPA, impulse control disorders, more psychiatric side effect, expensive.
What are some examples of impulse control disorders?
Pathological gambling, hypersexuality, compulsive shopping, desire to increase dosage, punding (collecting).
What are the ADRs of dopamine receptor agonists?
Sedation, hallucinations, confusion, nausea, hypotension.
What is the mechanism of action of monoamine oxidase B inhibitors?
MAO metabolises dopamine so inhibitors of this enzyme enhance dopamine.
Name an example of an MAOBi.
Selegiline, rasagaline.
When can MAOBi be used?
Alone or to prolong action of L-DOPA, smooths out motor response and may be neuroprotective.
What is the mechanism of action of catechol-O-methyl transferase inhibitors?
The reduce peripheral breakdown of L-DOPA to 3-O-methyldopa, L-DOPA sparing effect to prolong motor response to L-DOPA.
Name an example of a COMT inhibitor?
Entacapone, tolcapone.
Why are COMT inhibitors not used as monotherapy for IPD treatment?
No therapeutic effect alone, their only action is to prolong L-DOPA life so must be used with L-DOPA.
What is the use of anticholinergic in IPD therapy?
They have antagonistic effects to dopamine so may help with reducing tremor.
Give an example of an anticholinergic used in IPD therapy.
Trihexyphenidydyl, orphenadrine, procyclidine.
What are the advantages to anticholinergic use in IPD therapy?
Treat tremor, don’t act via dopamine systems so have different ADRs.
What are the disadvantages of anticholinergic use in IPD therapy?
No effect on bradykinesia, ADRs - confusion, drowsiness, other ACh side effects.
What are the possible mechanisms of action of amantadine used in IPD therapy?
Enhanced dopamine release, ACH NMDA inhibition.
Which cases of IPD may be susceptible to successful surgery?
Dopamine responsive, significant side effects with L-DOPA, no psychiatric illness.
What are the distinguishing features of myasthenia gravis?
Fluctuating, fatiguable, weakness of skeletal muscle, seen most commonly in extraocular muscles.
What are the complications of mysasthenia gravis?
Acute exacerbation (Myasthenic crisis) or overtreatment (cholinergic crisis).
What is the mechanism of action of acetylcholinesterase inhibitors in myasthenia gravis therapy?
Enhance neuromuscular transmission so more control and power for skeletal and smooth muscle.
Give an example of an acetylcholinesterase inhibitor and its route of administration.
Pyridostigine - oral. Neostigmine - oral or IV.
What is the mechanism of action of pyridostigmine in the treatment of myasthenia gravis?
Prevents breakdown of ACh in NMJ so ACh is more likely to engage with the remaining receptors.
When should pyridostigmine be administered in Myasthenia gravis therapy?
30 mins before a meal as its onset is from 30 mins.
What are the ADRs of pyridostigmine?
Cholinergic side effects ‘SSLUDGE’ - salivation, sweating, lacrimation, urinary incontinence, diarrhoea, GI upset, emesis.
