Lecture 24- Neuropharmacology Flashcards
1
Q
Idiopathic Parkinson’s disease (IPD)
A
- Neurodegenerative disorder
- Progressive clinical course
- Motor symptoms improve with levodopa (symptomatic medication)
- Non motor symptoms
2
Q
Pathophysiology of IPD
A
- Degeneration of dopaminergic neurones present in substantia nigra
- If we remove dopamine provided by the SN, then we lose net excitation on the cortex (dopamine stimulates direct pathway (which increases movement)and inhibits indirect pathway (which decreases movement))
- Therefore cortical activity decreases- corticospinal pathways aren’t stimulating LMN adequately
- Tremor
- Rigidity- reduction in proper coordination in flexors and extensors
- Bradykinesia- most easily explained by this pathway
- Psychiatric features- cognition circuit interlinked with the basal ganglia circuit
3
Q
Histological hallmarks
A
4
Q
basal ganglia rev
A
5
Q
Clinical features of parkinsonism
A
- Tremor*
- Rigidity*
- Bradykinesia**
- Postural instability
6
Q
Non motor manifestations
A
- Mood changes
- Pain
- Cognitive change
- Urinary symptoms
- Sleep disorder
- Sweating
- Low Blood Pressure
- Restless legs
- Fatigue
- Hallucinations
7
Q
Diagnosis of IPD (based on clinical opinion and not on tests)
A
- Clinical Features
- Exclude other causes of Parkinsonism
- Response to Treatment e.g. Levadopa
- Structural neuro imaging is normal
8
Q
prognosis
A
9
Q
Catecholamine synthesis
A
10
Q
one way to target low dopamine is
A
to prevent its degradation
e.g. COMT or MAO inhibitors
11
Q
outline neurotransmission starting at synthesis of NT e.g. dopamine
A
AP causes releases into synaptic cleft via action of calcium which causes vesicle docking
12
Q
treatment of parkinsons disease
A
- symptomatic e.g. movement disorders and non motor feautres
- levodopa (LDOPA)
- dopamine receptor agonists
- MAOI type B inhibitors
- COMT inhibitors
- anticholinergics
- amatidine
- Neuroprotection
- surgery
13
Q
Why use precursor Levodopa (L-dopa)and not dopamine?
A
- Dopamine cannot cross the BBB
- Also causes many peripheral side effects
- Irregular beart beat
- Anxiety
- Headache
- SoB
- Nausea
14
Q
Levodopa
A
is a drug used in combination with a peirpheral DOPA decarboxylase inhibitor e.g. carbidopa or benserazide
- reduces dose required
- reduces side effects
- increase L-DOPA reaching the brain
15
Q
co-careldopa
A
sinemet (levodopa/carbidopa)
16
Q
co-beneldopa
A
madopar (levodopa/ benserazide)
17
Q
how are LDOPA formations taken
A
tablet formualtions only
18
Q
pharmacokinetics of LDOPA
A
19
Q
mode of action of levodopa
A
- Once Levodopa has crossed the BBB it must be taken up by dopaminergic cells in the substantia nigra to be converted to dopamine
- As disease progresses and cell degenerated- fewer remaining cells mean levodopa is less reliable- motor fluctuations
20
Q
advantages of LDOPA
A
21
Q
disadvantages of LDOPA
A
*freezing when drug wearing off*
*requires some cells to be left to produce enzyme for conversion in the SN
22
Q
Drug-drug interactions LDOPA
A
- Pyridoxine (vitamin B6) increases peripheral breakdown of L-DOPA
- MAOIs risk hypertensive crisis
- (not MOABIs at normal dose-lose specificity at high dose)
- Many antipsychotic drugs block dopamine receptors and parkinsonism is a side effect (newer, ‘atypical’ antipsychotics less so)
23
Q
name 2 alternatives to LDOPA
A
dopamine receptor agonists
Monoamine oxidase B inhibitors
24
Q
name some Dopamine receptor agonists
A
25
uses of dopamine receptor agonists
* Alternative to L-dopa
* Can be first line or add on therapy
26
**Mode of action of dopamine receptor agonists**
Mimic dopamine at their receptors
27
**Adverse drug response of dopamine receptor agonists**
* Impulse control disorder
* Pathological gambling
* Hypersexuality
* Compulsive shopping
* Desire to increase dose
* Punding- a compulsive need to carry out repetitive behaviour such as sorting materials that you are no longer using
* Sedation
* Hallucinations
* Confusion
* Nausea
* Hypotension
28
advantages of dopamine receptor agonists
* direct acting
* less dyskinesias/ motor complications
* possible neuroprotection
29
disadvantages of dopamine receptor agonists
* less efficacy than LDOPA
* impulse control disorders
* more psychiatric symptoms
* expensive
30
name someMonoamine oxidase B inhibitors
31
**Uses of monoamine oxidase B inhibitors**
* Can be used alone to treat IPD
* Prolong action of L-DOPA
* Smooths out motor response
* Maybe neuroprotective
32
**Mode of action** of Monoamine oxidase B inhibitors
Inhibits monoamine oxidase B to decrease metabolism of dopamine and therefore increase amount found in synaptic cleft
33
name 3 COMT inhibitors
34
**Uses of COMT inhibitors**
No therapeutic effect alone (can use combination tablets COMT inhibitors and L-DOPA and peripheral dopa decarboxylase inhibitor- Stalevo)
35
**Mode of action of COMT inhibitors**
‘L-DOPA sparing effect’- prolonging motor response to L-DOPA to reduce symptoms of wearing off
* Reduces peripheral breakdown of L-DOPA to 3-O-methyldopa
* 3-O-methyldopa competes with L-DOPA active transport into CNS
36
name some anticholinergics used in parkinsons
minor role in parkinsons- used to treat symptoms e.g. tremor and rigidity
37
MOA of anticholinergics in parkinsons
* may have an Antagonistic effect to dopamine
38
advantages of anticholonergics
treat tremor
not acting via dopamine system
39
disadvantages of anticholinergics
40
uses of amatadine
parkinsons
* poorly effective
* few side effects
* little effect on tremor
41
MOA of amantadine
NMDAr inhibition
It is thought to work to control movement problems by increasing the amount of dopamine in certain parts of the body.
42
ADR amatadine
hallucinations
43
44
**Surgery for IPD**
45
**Myasthenia gravis**
* **Autoimmune**
* **Antibodies for AchR on post synaptic membrane**
* **‘Fluctuating, fatigable, weakness skeletal muscle’**
46
signs and symptoms of MG
* Extraocular muscles – commonest presentation
* Bulbar involvement – dysphagia, dysphonia, dysarthria
* Limb weakness – proximal symmetric
* Respiratory muscle involvement (myasthenic crisis)
47
**Drugs affecting neuromuscular transmission – exacerbate myasthenia gravis**
* Aminoglycosides
* Beta-blockers, CCBs, quinidine, procainamide
* Chloroquine, penicillamine
* Succinylcholine
* Magnesium
* ACE inhibitors
48
**Complications of MG**
**• Acute exacerbation – Myasthenic crisis**
**• Overtreatment
– Cholinergic crisis**
49
**Therapeutic management of MG**
* Acetylcholinesterase inhibitors
* Corticosteroids (treat underlying disease)
* Decrease immune response
* Steroid sparing (treat underlying disease)
* Azathioprine
* IV immunoglobulin
* Acute decline or crisis – 60% will respond after 7-10 days
* Plasmapheresis
* Removes AChR antibodies and short-term improvement
50
name 2 Acetylcholinesterase inhibitors used to treat MG
pyridostigmine (oral)
neostigmine
51
pyridostigmine pharmacokinetics
* Onset 30min; peak 60-120min; duration 3-6hr
* Dose interval and timing crucial
* antiacetylcholinesterase side effect – miosis and the SLUDGE syndrome:
* » Salivation,
* » Sweating,
* » Lacrimation
* » Urinary incontinence
* » Diarrhea,
* » GI upset and hypermotility
* » Emesis)
52
* **Neostigmine**
* **oral and IV preparations (ITU)**
* **Quicker action, duration up to 4 hours**
* **Signidic antimuscarinic side effects**
53
MOA of acetylcholinesterase inhibitors
**Mode of action**
* Prevents breakdown of ACh in NMJ
* ACh more likely to engage with remaining receptors
* Enhance neuromuscular transmission
* Skeletal and smooth muscle
54
**Adverse drug response** of Acetylcholinesterase inhibitors
* Excess dose can cause depolarising block- cholinergic crisis
* Muscarinic side effects
