Neurological Drugs

Front 1

Action of Benzos

Back 1

Modulation of the γ-aminobutyric acid type A (GABA-A) receptor

opens the chloride channel, hyperpolarises the cell, leading to postsynaptic inhibition

readily crosses the BBB

Front 2

Benzo ADRs

Back 2

ataxia, confusion, memory loss, cog impairment, blurred vision
(especially of concern in the elderly)

behavioural changes (e.g. irritability, aggression, disinhibition)

(more common in children & elderly & patients with a history of aggression & alcohol abuse)

Front 3

Benzo parenteral admin risks

Back 3

Hypotension
Respiratory depression
(esp with repeated injections or continuous infusions of clonazepam, diazepam, midazolam)

Front 4

Minimise parenteral Benzo risks

Back 4

low dose
slow infusion/injection
large lumen vessel

Front 5

4 commonly used benzos in neurological medicine

Back 5

clobazam
clonazepam
diazepam
midazolam

Front 6

Clobazam
class?
indications?

Back 6

1,5-benzodiazepine
less sedating than other benzos
usually used as adjunctive Tx for refractory seizures
variable tolerance between individuals

Front 7

Clonazepam
class?
indications?
specific ADRs?

Back 7

benzodiazepine
mainly used in Tx of status epilepticus & refractory seizures
sedation is less common in children than adults
beh changes & excess salivary/bronchial secretions more common (in children)

Front 8

Diazepam
class?
ideal admin?
pharmacokinetics?

Back 8

Benzo
IV (undiluted) - rapid effects (minutes)
IM - variable & inefficient absorption
long elimination T1/2
redistributes outside CNS rapidly
seizure relapse may occur after 2 hours in 50% of cases

Front 9

Midazolam
class?
ideal admin?
pharmacokinetics?

Back 9

benzo
effective plasma concentrations with IM, buccal, intranasal admin
short elimination T1/2
useful for infusion Tx (e.g. refractory status epilepticus)
renally excreted active metabolites may accumulate in renal failure

Front 10

Carbamazepine
class & mechanism of effect?

Back 10

antiepileptic, blocks voltage-gated Na+ channels
(inhibit firing of action potentials)

Front 11

Tx for Trigeminal neuralgia

Back 11

carbamazepine
(antiepileptic Na+ channel blocker)

Front 12

Carbamazepine metabolism & active metabolite?

Back 12

metabolised by CYP3A4
(induces CYP3A4 to increase its own metabolism after 4-5 days of Tx - "autoinduction")
active metabolite = carbamazepine-10,11-epozide

Front 13

Carbamazepine adverse interactions

Back 13

bone marrow suppression with drugs causing agranulocytosis (e.g. clozapine)
inhibited metabolism with macrolide antibiotics ('mycins') = carbamazepine toxicity

Front 14

Carbamazepine ADRs

Back 14

dose related = sedation, ataxia, dizziness, diplopia, headache, nausea
(minimise with slow dose titration)

reversible mild leukopoenia is common (discontinue if infection or WCC < 2.0x10^9)

anti-diuretic action at high doses (usually mild asymptomatic hyponatraemia)

idiosyncratic ADRs = diarrhoea, hepatitis, rash

severe = Stevens-Johnson syndrome/toxic epidermal necrolysis
(10x higher risk in Asian population)

Front 15

Carbamazepine pharmacokinetics

Back 15

Controlled release preps = lower max plasma concentration than equivalent dose of immediate release preps (15% less bioavailability)
may induce seizures in patients switching from immediate release to equivalent dose controlled release

Front 16

Benzo dependence, tolerance & withdrawal

Back 16

Dependence develops rarely in patients taking normal therapeutic doses of these drugs for short periods (eg 1-2 weeks)
1/3 of patients on long-term treatment may have difficulty in reducing or stopping benzodiazepines
Tolerance occurs more with the sedative and hypnotic effects than with other benzodiazepine effects.
All benzodiazepines can produce withdrawal symptoms:
Abrupt discontinuation can result in symptoms of increasing anxiety, sleep disorder, aching limbs, nervousness and nausea (seizure in high dose withdrawal)

Front 17

Ethosuxamide
class?
mechanism of action?

Back 17

antiepileptic
T-type Ca2+ channel blocker

Front 18

Ethosuxamide
interactions?

Back 18

susceptible to inducers/inhibitors of CYP3A4
(e.g. carbamazepine induces CYP3A4 = less ethosuxamide concentration, sodium valproate inhibits CYP3A4 = higher ethosuxamide concentration)
increases phenytoin levels
reduces valproate levels

Front 19

Ethosuxamide
ADRs?

Back 19

N&V, abdo pain, lethargy, dizziness, ataxia (often not dose dependent)
severe: SJS, connective tissue syndromes resembling SLE, fatal blood dyscrasias

Front 20

Gabapentin
class?
mechanism of effect?

Back 20

Analogue of GABA.
(exact mechanism of action unknown)
theory: inhibit glutamate synthesis, elevate GABA levels, interact with subset of voltage gated Na+ channels & spinal Ca2+ channels

Front 21

Gabapentin
pharmacokinetics
metabolism
interactions
excretion

Back 21

absorbed by a saturable amino acid uptake system in the gut
bioavailability decreases as dosage increases
(e.g. 60% absorption fromm 300mg, 40% absorption from 900mg)
does not bind to plasma proteins
does not induce liver enzymes
minimal interaction profile
renally excreted unchanged (reduced dose requirement in renal impairment)

Front 22

Gabapentin ADRs

Back 22

somnolence, dizziness and ataxia (minimised by gradual dose titration)

Front 23

Lacosamide
class?
mechanism of action?
pharmacokinetics?
interactions?

Back 23

antoepileptic
selective enhancement of slow inactivation of voltage-gated Na+ channels
no significant interactions
IV & oral doses are bioequivalent

Front 24

Lacosamide ADRs

Back 24

transient = dizziness, headache, diplopia
cardiac = prolonged PR
renal = contraindicated in renal failure

Front 25

Lamotrigine
class?
mechanism of action?

Back 25

antiepileptic
blocks voltage-gated Na+ channels to prevent release of glutamate & aspartate and stabilise presynaptic neuronal membranes

Front 26

Lamotrigine
ADRs

Back 26

CNS = dizziness, diplopia, ataxia, blurred vision, somnolence, insomnia, tremor at high doses
derm = varying severity - mild rash to SJS
(higher risk = in children, concurrent valproate, rapid dose increase)

Front 27

Lamotrigine interactions

Back 27

higher risk of skin reactions with valproate
higher risk of carbamazepine ADRs

Front 28

Levetiracetam
class?
mechanism of action?

Back 28

broad spectrum anticonvulsant, useful as monotherapy & adjuct Tx

interaction with synaptic vescicle-associated protein

Front 29

Levetiracetam
pharmacokinetics?
interactions?

Back 29

95% renal excretion of drug & inactive metabolites
no dose modification required between IV or oral
no known induction/inhibition of liver enzymes
no known drug interactions

Front 30

Levetiracetam
ADRs?

Back 30

CNS = dizziness, somnolence, asthenia, emotional lability, nervousness, aggression, irritability, agitation

Front 31

Oxcarbazepine
class?
mechanism?

Back 31

antiepileptic
(chemically related to carbamazepine)
blockade of voltage-gated Na+ channels

Front 32

Oxcarbazepine
pharmacokinetics?
interactions?

Back 32

~100% oral bioavailability
rapid metabolism to active metabolite (10-monohydroxy-oxcarbazepine)
renally excreted active metabolite (reduced dose in renal failure)
no ‘autoinduction’ (unlike carbamazepine)
dose related toxicity if administered with carbamazepine

Front 33

Oxcarbazepine
ADRs?

Back 33

common CNS = somnolence, headache, dizziness, diplopia, N&V, fatigue
dose related = moderate (usually asymptomatic) hyponatraemia
(usually more pronounced than seen in carbamazepine)
(more common in elderly)
severe = SJS/toxic epidermal necrolysis, erythema multiforme, hepatitis

Front 34

Phenobarbitone
class?
mechanism of action?

Back 34

antiepileptic
enhances activity of GABA by facilitating Cl- entry into neurones at GABAA receptors

Front 35

Phenobarbitone
pharmacodynamics?
interactions?

Back 35

ARCHETYPAL ENZYME INDUCER
acelerates the metabolism of many drugs
induces CYP3A4, CYO1A2, CYP2C
greatly reduces the plasma concentration of warfarin (up to 10x anticoag requirement)
inhibited by enzyme inhibitors (e.g. antidepressants)
increasedplasma concentrations with concurrent valproate

Front 36

Phenobarbitone
ADRs?

Back 36

severe = local tissue necrosis at injection site if undiluted
altered cognition, mood, behaviour
fatigue & listlessness (adults)
insomnia, hyperactivity, aggression (children & elderly)

Front 37

Phenytoin
class?
mechanism of action?
pharmacokinetics?

Back 37

antiepileptic
blocks voltage-gated Na+ channels
nonlinear pharmacokinetics
highly bound to albumin

Front 38

Phenytoin
ADRs?

Back 38

dose related = drowsiness, dysarthria, tremor, ataxia, diplopia, cognitive impairment
severe = SJS (10x increase risk in Asian patients)
long-term use = sensory peripheral neuropathy, cerebellar degeneration
reversible = gum hypertrophy, acne, hirsutism (esp in children)

Front 39

Phenytoin
interactions?

Back 39

numerous & complex (induces hepatic enzymes)
increased concentration with acute alcohol intake
decreased concentration with chronic alcohol intake
valproate increases unbound phenytoin concentration & inhibits metabolism
impaired efficacy of warfarin, lamotrigine, cyclosporin
increased metabolism of methadone (opioid withdrawal!)

Front 40

Phenytoin
admin precautions?

Back 40

IM - irritation, erratic absorption, risk of sterile abscess (not recommended)
IV - hypotension, cardiac arrythmias, long QT, purple glove syndrome
(consider slower infusion)
oral - feeding reduced bioavailability

Front 41

Pregabalin
class?
mechanism of effect?

Back 41

anticonvulsant & analgesic
analogue of GABA (structurally similar to gabapentin)
(does not appear to interact with GABA receptors or interfere with GABA synthesis)
theory of effect: bind to CNS voltage-gated Na+ channels, reduce release of glutamate, noradrenaline, substance P

Front 42

Pregabalin
excretion?
ADRs?

Back 42

Renal excretion (reduce dose in renal failure)
somnolence, dizziness, blurred vision, weight gain, peripheral oedema
raised CK (creatinine kinase)

Front 43

Primidone?
class?
mechanism?
indications?
ADRs?

Back 43

antiepileptic
a pre-metabolite of phenobarbitone
similar efficacy of phenobarbitone
often less well tolerated
also used to Tx essential tremor
similar ADRs to phenobarbitone

Front 44

Sodium Valproate
mechanism of action?

Back 44

blocks voltage-gated Na+ channels
blocks T-type Ca2+ channels in the thalamus (anti-absence seizure effect)

Front 45

Sodium Valproate
indications?

Back 45

epilespy & seizures
migraine
persistent post-traumatic headache

Front 46

Sodium Valproate
pharmacokinetics?

Back 46

~100% oral bioavailability
immediate release formulation - peak plasma concentration 1-4 hours
enteric coated formulation - 3-7 hours
90% protein binding
extensive hepatic metabolism

Front 47

Sodium Valproate
ADRs?

Back 47

commonest = tremor, hair loss, sedation weight gain
GIT = anorexia, N&V (reduced with enteric coated preps)
prolonged use = ?PCOS
altered platelet function & thrombocytopoenia
severe = hepatotoxicity, pancreatitis (increased risk in young children & congenital metabolic or mitochondrial disorders, e.g. carnitine or ornithine carbamoyltransferanse deficiency)
highly teratogenic

Front 48

Sodium Valproate
interactions?

Back 48

enzyme inhibitor
variable & unpredictable interactions with other antiepileptics
increased risk of SJS with concurrent Lamotrigine

Front 49

Sulthiame
class?
mechanism of effect?

Back 49

antiepileptic
reduces voltage-gated Na+ channel currents
weak carbonic anhydrase inhibitor (decreased intracellular pH of neurons which reduces excitability)

Front 50

Sulthiame
ADRs?
interactions?

Back 50

commonest = hyperventilation (often dose related)
sulfonamide drug = rash, SJS
nausea, anorexia, headache, dizziness, ataxia, psychosis
dose related distal & peri-oral paraesthesia
increased concentrations of phenytoin, primidone, phenobarbitone

Front 51

Tetracosactrin
class?
mechanism of action?
indication?

Back 51

antiepileptic
analogue of corticotrophin (ACTH)
unknown mechanism of action
Tx of infantile spasms

Front 52

Tiagabine
class?
mechanism?
ADRs?
pharmacokinetics?

Back 52

inhibits GABA re-uptake from the synapse
(enhanced GABA mediated inhibition)
fatigue, dizziness, confusion, tremor, N&V (most transient & dose related)
does not induce/inhibit enzymes
increased clearance with enzyme inducing drugs
no issues with renal function

Front 53

Topirimate
class?
mechanism?
indications?

Back 53

antiepileptic
blocks voltage-gated Na+ channels
enhances GABA mediated inhibition
weak carbonic anhydrase inhibitor
useful for prophylaxis of migraine (low dose) as well as an antiepileptic

Front 54

Topirimate
ADRs?
pharmacokinetics?

Back 54

common = cog impairment, psychosis, child beh problems, dysarthria, tremor, dizziness, ataxia, headache, fatigue, N&V, weight loss
rare = paraesthesia, renal calculi, myopia, glaucoma, anhydrosis

mainly excreted unchanged in urine
increased clearance with phenytoin & carbamazepine

Front 55

Vigabatrin
class?
mechanism?
ADRs?

Back 55

antiepileptic
irreversibly inhibits GABA transaminase (an enzyme involved in the degradation of GABA)
common = IRREVERSIBLE peripheral visual field constriction (often asymptomatic)
formal testing recommended
sedation, fatigue, headache, dizziness, confusion, ataxia, diplopia, memory impairment, insomnia, psychosis

Front 56

Zonisamide
class?
mechanism?

Back 56

antiepileptic
blocks voltage-gated Na+ channels
blocks T-type Ca2+ channels
weak carbonic anhydrase inhibitor

Front 57

Zonisamide
ADRs?

Back 57

dose related = drowsiness, dizziness, ataxia, memory/cog impairment, anorexia, agitation, irritability
sulfonamide drug = rash, SJS
renal calculi & metabolic acidosis (carbonic anhydrase inhibition effects - higher risk with concurrent Topirimate or other carbonic anhydrase inhibitors)

Front 58

Zonisamide
interactions?

Back 58

increased effects with other concurrent carbonbic anhydrase inhibitors (renal calculi & metabolic acidosis)
reduced T1/2 with enzyme inducing drugs (e.g. carbamazepine, phenytoin, phenobarbitone)

Front 59

Anticonvulsant hypersensitivity syndrome
associated drugs?

Back 59

carbamazepine
oxcarbazepine
phenytoin
barbituates
(NOT sodium valproate)

Front 60

Anticonvulsant hypersensitivity syndrome
characteristics?

Back 60

1-4 weeks into Tx = fever, rash, systemic organ involvement (lymphanenopathy, hepatitis, myositis, myocarditis, pneumonitis), SJS, toxic epidermal necrolysis

Front 61

antiepileptics & BMD
cause?
management?

Back 61

inducers of the cytochrome P450 system (ie carbamazepine, oxcarbazepine, phenobarbitone, phenytoin, and primidone) increase the metabolism of vitamin D
the cause with Sodium Valproate is not known
assess vitamin D status
supplement vitamin D

Front 62

Amantadine
mechanism of effect?
clearance?

Back 62

enhances dopaminergic transmission
mild antimuscarinic properties
NMDA (N-methyl-D-aspartate) antagonist
Renal clearance

Front 63

Amantadine
indications?

Back 63

Used in tremor-dominant Parkinson’s disease and to reduce levodopa induced dyskinesias.
Used to treat fatigue in MS
Used occasionally for influenzae A prophylaxis (resistance is common)
(interferes with the uncoating of the virus inside the cell
M2 inhibitor - blocks the ion channel formed by the M2 protein that spans the viral membrane)

Front 64

Amantadine
ADRs?

Back 64

most are transient, mild and dose related:
antimuscarinic effects = dry mouth, constipation, blurred vision, urinary retention
rarely = hallucination, confusion, delirium
50% of patients develop livedo reticularis
5-10% of patients develop ankle oedema

Front 65

3 anticholinergics commonly used in movement disorders

name, admin, action?

Back 65

benztropine (oral, IM or IV for acute dystonic reactions)

(also has an antihistamine sedative effect)
benzhexol (oral)
biperiden (oral)

Front 66

benefits of anticholinergics in Parkinsonism?
limitations?

Back 66

decreases cholinergic influence in the basal ganglia
seldom used in idiopathic Parkinson’s disease due to poor efficacy & ADRs
Mostly used to reduce extrapyrimidal effects caused by antipsychotic drugs
Drug-induced parkinsonism, dystonias & akinesias respond reasonably well
Less effective for Tx of tremor or akathisia
May aggravate tardive dyskinesia

Front 67

anticholinergic ADRs?

Back 67

dose related and due to anticholinergic actions:
peripheral effects = dry mouth, urinary hesitancy & obstruction, constipation, paralytic ileus, nausea, pupillary dilation, blurred vision, worsening of glaucoma
central effects = dizziness, hallucnations, euphoria, hyperpyrexia, central excitation, delirium
taper dosage rather than withdraw suddenly to avoid cholinergic dyscontinuation syndrome

Front 68

anticholinergic interactions?

Back 68

peripheral anticholinergic effects are exacerbated by other concurrent medications with anticholinergic properties:
e.g. TCAs & antihistamines