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pharmacology > Treating Neurological Disorders > Flashcards

Treating Neurological Disorders Flashcards

1
Q

what is epilepsy?

A

Episodic discharge of abnormally high frequency electrical activity in the brain leading to seizure

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2
Q

What does diagnosis of epilepsy require?

A

It requires evidence of recurrent seizures which are unprovoked by other causes.

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3
Q

What are the two main types of epileptic seizure?

A

Partial

General

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4
Q

What are the two types of partial seizure?

A

Simple- motor, somatosensory or psychic symptoms, consciousness is not impaired.

Complex- temporal lobe, psychomotor, consciousness is imparied

Partial seizures can develop into secondary generalised seizures.

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5
Q

What are the different types of generalised seizure?

A

tonic clonic- initial rigid extensor spasm, respiration stops, defaecation, micturition and salivation occur (usually 1 min) then violent synchronous jerks (2-4 mins)

Myoclonic- seizures of a muscle or a group of muscles

Absence- abrupt loss of awareness or surroundings. Little motor disturbance (mainly occurs in children)

Atonic- loss of muscle tone/strength.

Status epilepticus- seizure lasts beyond 5 mins

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6
Q

What is the difference between primary and secondary causes of epilepsy?

A

Primary- no identifiable cause- idiopathic. Possibly caused by channelopathies.

Secondary- medical conditions affecting the brain eg vascular disease, tumours, much more common in elderly.

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7
Q

What are some of the major recognised precipitants of epilepsy?

A

Sensory stimuli eg flashing lights
Brain disease/trauma/stroke/drugs and alcohol/ structural abnormalities
Metabolic disturbances eg hypo/hyperglycaemia/natraemia.
Infections- eg febrile convulsion in infants
Therapeutics- some drugs can lower fit threshold.

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8
Q

How is epilepsy generated within the brain?

A

Imbalance of excitatory neurotransmitters and inhibitory neurotransmitters is altered meaning that neurones are closer to firing threshold.

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9
Q

How can untreated epilepsy become a life threatening condition?

A

It can become status epilepticus which can lead to brain damage or death (SUDEP)

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10
Q

What are the different classes of drugs than can be used to treat epilepsy?

A

Sodium channel blockers such as phenytoin, carbamezepine

Lamotrigine

GABA receptor agonists eg benzodiazepines and sodium valproate

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11
Q

What is the mechanism of action of carbamazepine?

A

Prolongs voltage gated sodium channel inactivation state

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12
Q

Which types of epilepsy can carbamazepine be used in?

A

Effective in most types except for absence seizures

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13
Q

What are the DDIs of carbamazepine?

A

Interacts with antidepressants eg SSRIs, MAOIs, TCAs

carbamazepine decreases the effectiveness of oral contraceptives, systemic corticosteroids, warfarin, phenytoin

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14
Q

What are the adverse drug reactions of carbamazepine?

A

CNS effects- dizziness, drowsy, ataxia
GI upset
Variation in BP
Contraindicated in AV conduction problems
Causes rashes, hyponatraemia
Rarely causes severe bone marrow depression.

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15
Q

What are the pharmacokinetics of carbamazepine?

A

Well absorbed, 75% protein bound. Linear PK. Half life of 30 hours.

Strong inducer of CYP450.

Induces its own phase I metabolism so on repeated use t1/2= 15 hours.

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16
Q

What is the mechanism of action of phenytoin?

A

Prolongs voltage gated sodium channel inactivation state

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17
Q

What types of seizures if phenytoin effective against?

A

Good for all seizures apart from absence.

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18
Q

What are the DDIs of phenytoin?

A

NSAIDs increase plasma levels of phenytoin due to protein binding so exacerbates non linear PK

Cimetidine increases effect of phenytoin

Phenytoin competitively binds with sodium valproate

Phenytoin decreases the effectiveness of oral contraceptives

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19
Q

What are the pharmacokinetics of phenytoin?

A

Well absorbed in gut, 90% is protein bound in plasma.
CYP450 inducer
Non linear PK at therapeutic concentrations so needs to be titrated up to dose.

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20
Q

What are the ADRs of phenytoin?

A

CNS- dizziness, ataxia, headache, nystagmus, nervousness.

Gingival hyperplasia

Rash- hypersensitivity

Stevens johnson syndrome

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21
Q

What is the mechanism of action of lamotrigine?

A

Targets dendrites of pyramidal neurons that synthesise glutamate and reduce its release-

Also prolongs VGSC inactivation state

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22
Q

Which seizure types can lamotrigine be used for?

A

All seizures including absence

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23
Q

What are the ADRs of lamotrigine?

A

Less marked CNS dizziness, ataxia, somnolence and nausea

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24
Q

Which drug can be substituted for sodium valproate in pregnancy?

A

Lamotrigine

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25
Q

What are the DDIs of lamotrigine?

A

No CYP450 induction so fewer DDIs
Oral contraceptives reduce its level
Valproate increases levels of Lamotrigine in plasma.

26
Q

What are the pharmacokinetics of lamotrigine?

A

Well absorbed, linear PK. Half life= 24 hours.

27
Q

What are the two major types of GABA receptor agonists?

A

Benzodiazepines and sodium valproate

28
Q

What anti epileptic drug can be used to treat status epilepticus?

A

A benzodiazepine such as diazepam

29
Q

What are the pharmacokinetics of benzodiazepines?

A

Well absorbed orally, highly protein bound. Linear PK. Half life varies 15-45 hours.

30
Q

What are the adverse drug reactions of benzodiazepines?

A 
Agression
Dependence- withdrawal symptoms
Sedation
Confusion, impaired coordination
Can develop tolerance with chronic use
31
Q

What is the mechanism of action of sodium valproate?

A

Potentiation of GABA, use dependent blockade of Na+ channels

32
Q

What are the pharmacokinetics of sodium valproate?

A

Well absorbed, highly protein bound

33
Q

What are the ADRs of sodium valproate?

A

Generally less severe than other AEDs but can cause:

CNS sedation
Ataxia
Tremor
Weight gain
Teratogenicity
34
Q

What are the DDIs of sodium valproate?

A

Aspirin- competitive binding in plasma so increases concentration of sodium valproate

Antipsychotics- antagonise valproate by lowering convulsive threshold

Antidepressants- SSRIs, MAOIs, TCAs inhibit action of valproate

35
Q

What is the drug of choice for partial seizures?

A

Lamotrigine

36
Q

What is the drug of choice for generalised seizures?

A

Sodium valproate

37
Q

Which AEDs can cause teratogenicity in pregnancy?

A

Sodium valproate- can cause congenital malformation and neural tube defects. Folate supplement is given to reduce the risk of this.

Valproate and carbamazepine can cause failure of contraception

The truth is many AEDs cause teratogenicity. Treatment is a balance between risk to the mother and risk to the baby.

38
Q

Why does phenytoin need to be monitored?

A

Metabolism can become saturated and then kinetics become non linear

39
Q

What is parkinsons disease?

A

It is a loss of dopaminergic neurons in the substantia nigra pars compacta and deposition of intracytoplasmic lewy bodies. This leads to neuronal death and degeneration of the nigrostriatal pathway

It is characterised by:

A resting tremor
Skeletal muscle rigidity
Bradykinesia

40
Q

Why does parkinsons disease worsen over time?

A

Number of dopaminergic neurons slowly decreases.

41
Q

How does L-DOPA work?

A

L-DOPA is a precursor to dopamine. Dopamine cannot pass through the blood brain barrier so L-DOPA is given which can.

It is then taken up by dopaminergic neurones which convert L-DOPA into dopamine.

This increases the amount of dopamine present in dopamine pathways which stimulates corpus striatum and basal ganglia and stimulates cortex so decreases bradykinesia.

42
Q

Why is L-DOPA commonly used in combination with a peripheral DOPA decarboxylase inhibitor (COMT inhibitor) such as co-careldopa or co-beneldopa?

A

90% of dopamine is inactivated in intestinal wall due to monoamine oxidase and DOPA decarboxylase

9% of this is converted to dopamine in peripheral tissues by DOPA decarboxylase

Therefore we give a dopamine decarboxylase inhibitor to prevent this from happening and maximise the amount of L-DOPA reaching the dopaminergic neurons. This allows a reduced dose of L-DOPA to be given so less side effects.

43
Q

How is L-DOPA absorbed? What limits absorption?

A

Oral administration and absorbed by gut by active transport in competition with amino acids.
Absorption is limited by vitamin B6 which increases peripheral breakdown.

44
Q

What is the half life of L-DOPA? What consequence does this have?

A

2 hours

This means that the drug has a short dose interval

45
Q

What are the side effects of taking L-DOPA?

A

Vomiting, hypotension, psychosis, tachycardia

46
Q

Why do we delay giving L-DOPA in parkinsons patients until it is absolutely necessary?

A

Long term use can lead to loss of efficacy due to loss of dopaminergic neurons. Patients also tend to develop extrapyramidal side effects.

47
Q

What are the DDIs of L-DOPA?

A

MAOIs risk hypertensive crisis.

48
Q

What are the advantages of using non ergot dopamine receptor agonists?

A

They are direct acting
Less dyskinesias
Offers possible neuroprotection

49
Q

What are the disadvantages of using non ergot dopamine receptor agonists?

A

Less efficacy than L-DOPA
Expensive
Causes impulse control disorders eg pathological gambling, hypersexuality

Side effects- sedation, hypotension, hallucinations, confusion, nausea

50
Q

What is an example of a dopamine receptor agonist? How is it given?

A

Apomorphine- for patients with severe motor fluctuations

Subcut injection

51
Q

What is the mechanism of action of Mono amine oxidase inhibitors such as selegiline or rasagiline?

A

Stops breakdown of dopamine

Smooths out motor response and may be neuroprotective

52
Q

What is the mechanism of action of amantidine?

A

Stimulates release of dopamine stored in nerve terminals, and is a glutamate NMDA receptor antagonist.

Has little effect on tremor, is poorly effective in treating parkinsons.

53
Q

What are the advantages and disadvantages of using anticholinergics such a procyclidine to treat parkinsons disease?

A

Treats tremor

But no effect on bradykinesia

Side effects- confusion, drowsiness

54
Q

What is the pathophysiology of myasthenia gravis?

A

It is caused by the body producing antibodies against the NAchRs on the post synaptic membrane so causing muscle weakness.

55
Q

How might myasthenia gravis present?

A

Fluctuating, fatiguable, weakness of skeletal muscle

Commonly presents with ptosis and diplopia due to weakness of extraocular muscle.

56
Q

What is a myasthenic crisis?

A

An acute exacerbation of myasthenia gravis

57
Q

What is a cholinergic crisis?

A

Caused by over treatment with acetyl cholinesterase inhibitors

Symptoms are 
SLUDGE
S-salivation
L-lacrimation
U-urinary incontinence
D-diarrhoea
G-GI upset
E-emesis
58
Q

What is the mechanism of action of acetyl cholinesterase inhibitors?

A

They stop the breakdown of acetylcholine in the neuromuscular junction so increases the amount of ACh that can bind.

59
Q

What drugs can exacerbate myasthenia gravis?

A 
Aminoglycosides
Beta blockers
CCBs
Quinidine
Procainamide
Chloroquine
ACEi
60
Q

What treatments exist for myasthenia gravis?

A

Acetylcholinesterase inhibitors eg pyridostigmine (oral), neostigmine (oral and IV- quicker action)

Corticosteroids- suppress immune system
Steroid sparing drugs- azothioprine
IV immunoglobulin
Plasmapheresis- removes AChR antibodies so causes short term improvement.

pharmacology (22 decks)

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